Substituted phenyl derivatives, method of production thereof, containing pharmaceutical composition and method of treatment (options)

 

(57) Abstract:

Describes the new substituted phenyl derivatives of the General formula I, where one of R1, R2and R3represents a 4-hydroxy-1,2,4-triazolyl, 3-oxo-1,2-dihydro-1,2,4-triazolyl, 2-oxo-3H-1,3,4-oxadiazolyl or tetrazolyl; R4and R5represent hydrogen; the other two Deputy R1, R2and R3each independently selected from hydrogen, halogen, nitro, amino, acylamino, benzoylamine, phenyl, naphthyl, diphenyl or 5 - or 6-membered monocyclic heterocyclic group containing 1 heteroatom selected from N, S and O, where the phenyl group can be substituted once or more than once, by substituents selected from trifloromethyl, nitro, phenyl, carboxy, alkoxycarbonyl, aminocarbonyl, dialkylaminoalkyl and onlinebarbara; Y represents-CO - or-CS-; X represents-NH-; Z represents NH; one of R11, R12, R13, R14and R15selected from hydrogen, halogen, trifloromethyl, -R7, phenyl or 5 - or 6-membered monocyclic heterocyclic group containing from 1 to 3 heteroatoms selected from N, S and O, and four other of R11, R12, R13, R14and R1UP>14and R15together form a cyclic structure, and the other substituents R11, R12, R13, R14and R15represent hydrogen; R7represents alkyl, the method of production thereof, pharmaceutical composition and methods of treatment, in particular sickle cell anemia. 5 C. and 4 h.p. f-crystals, 3 PL.

The invention relates to new substituted phenyl derivatives, which are strong blockers chlorine ion channels and as such are useful in the treatment of sickle cell anemia, cerebral edema that accompanies ischemia or tumor, diarrhea, hypertension (diuretic), osteoporosis and to reduce the intraocular pressure for the treatment of disorders such as glaucoma.

Background of the invention

Chlorine ion channels perform a huge variety of specific cellular functions. So, chlorine ion channels contribute to the normal functioning of cells, skeletal and smooth muscle. It is known that the blockers chlorine ion channels used in the treatment of brain edema that accompanies ischemia or tumor, diarrhea, hypertension (diuretic), osteoporosis and to reduce intraocular pressure in these races the extreme conditions and to promote healing.

The use of blockers chlorine ion channels for the treatment of sickle cell anemia is a new therapeutic approach.

Sickle cell anemia and the presence of hemoglobin sickle cell was the first genetic disease, which was able to explain at the molecular level. The genetic defect underlying sickle cell anemia, causes the substitution of one amino acid, resulting in mutant hemoglobin, hemoglobin sickle erythrocytes.

Physical manifestations of sickle cell disease are anemia and painful ischemic stroke due to occlusion of the microcirculation deformed red blood cells (sickle erythrocytes). The main reason for sickle deformation of erythrocytes and curvature (or develop sickle-shaped red blood cells) is a reversible polymerization and gel hemoglobin sickle erythrocytes induced at low pressures of oxygen prevailing in metabolically active tissues. Sickle erythrocytes have increased cation permeability, leading to cation depletion and cellular dehydration. Since the delay time of polymerization of their cell volume should significantly increase the likelihood of developing sickle cell erythrocytes and, thus, occlusion of blood vessels. Compounds that block deoksigenirovanii, causing the loss of salt and volume (water), can delay the process of developing sickle cell erythrocytes sufficiently to avoid occlusion when transferring sickle erythrocyte through metabolically active tissue. It is estimated that sufficient can be a time delay, accounting for only 10 seconds.

It was suggested that some membrane ion channels and carriers present in normal cells, are involved in altered membrane permeability sickle erythrocytes. Received recognition hypothesis on stimulation of CA2+-activated K+channel, and several blockers of this channel have been proposed as therapeutic agents for the treatment of sickle cell anemia [Effects of Cetiedil on Monovalent Cation Permeability in the Erythrocyte: An explanation for the Efficacy of Cetiedil in the treatment of Sickle Cell Anaemia, Berkowitz, L. R. Orringer, E. P, Blood cells, 283-288 (1982) and U.S. patent 5273992].

Because after emanation TO+through To the channel to maintain electroneutrality must follow equal to the emanation of Cl-need to blockade chlorine ion channels in erythrocytes was as effective as a block of salt, which may occur due to the activation of unknown types To channels, and indirectly also will be blocked.

Compounds of the present invention are potent blockers chlorine ion channels that are defined concomitant measurements of total conductive threads chlorine ions and membrane potentials in suspensions of red blood cells, and for this reason it is stated that these compounds are suitable for the treatment of sickle cell anemia.

Some blockers chlorine ion channels and their use have already been described.

Described [ (1986), 407 (suppl. 2), pages 128-141] several compounds with blocking chlorine ion channel activity. Very strong connection described in this publication represents 5-nitro-2-(3-phenylpropylamine)benzoic acid. The use of blockers chlorine ion channels for the treatment of sickle cell anemia in this publication are not disclosed.

In U.S. patent 4889612 described derivatives of Calixarenes and their use as blockers chlorine ion channels.

In U.S. patent 4994493 described some derivatives of 5-nitrobenzoic acids and their use in the treatment of brain edema.

In WO 96/16647 described p is tori chlorine ion channels for the treatment of glaucoma.

The present invention relates to a series of substituted phenyl derivatives, which are potent blockers of chlorine-ion channels and their use in the treatment of, for example, sickle-cell anemia.

Objectives of the invention

The present invention is to provide new substituted phenyl derivatives and their pharmaceutically acceptable salts, which are useful in the treatment of disorders or diseases that are sensitive to the blockade of chlorine ion channels.

Another objective of the present invention is to develop a method of treatment of disorders or diseases that are sensitive to the blockade of chlorine ion channels, such as, for example, brain edema that accompanies ischemia or tumor, diarrhea, hypertension.

The invention

Further, this invention comprise, inter alia, one or combination of

the compound having the formula

< / BR>
or its pharmaceutically acceptable salt,

where one of R1, R2and R3represents a 4-hydroxy-1,2,4-triazolyl, 3-oxo-1,2-dihydro-1,2,4-triazolyl, 2-oxo-3H-1,3,4-oxadiazolyl or tetrazolyl;

R4isimo selected from hydrogen, halogen, nitro, amino, acylamino, benzoylamine, phenyl, naphthyl, diphenyl or 5 - or 6-membered monocyclic heterocyclic group containing one heteroatom selected from N, S and O, where the phenyl group can be substituted once or more than once, by substituents selected from trifloromethyl, nitro, phenyl, carboxy, alkoxycarbonyl, aminocarbonyl, dialkylaminoalkyl and onlinebarbara;

Y represents-CO - or-CS-;

X represents-NH-;

Z represents NH;

one of R11, R12, R13, R14and R15selected from hydrogen, halogen, trifloromethyl, -COOR7, phenyl or 5 - or 6-membered monocyclic heterocyclic group containing one heteroatom selected from N, S and O, and four other of R11, R12, R13, R14and R15represent hydrogen or one of R11and R12, R12and R13, R13and R14, R14and R15together form a cyclic structure, and the other substituents R11, R12, R13, R14and R15represent hydrogen; R7represents alkyl;

the connection as it appears above, where one of R1, R2and R3represents by NH and Y represents CO;

the connection as it appears above, and the specified connection is:

3-triptoreline-4-nitro-2-(5-tetrazolyl)phenylacetone,

3-triptoreline-4-(2-naphthyl)-2-(5-tetrazolyl)phenylacetone,

3-triptoreline-4-(3-pyridyl)-2-(5-tetrazolyl)phenylacetone,

3-triptoreline-4-(1-naphthyl)-2-(5-tetrazolyl)phenylacetone,

3-triptoreline-4-(4-triptoreline)-2-(5-tetrazolyl)phenylacetone,

3-triptoreline-4-(3-furyl)-2-(5-tetrazolyl)phenylacetone,

3-triptoreline-4-(3-thienyl)-2-(5-tetrazolyl)phenylacetone,

3-triptoreline-4-(3-nitrophenyl)-2-(5-tetrazolyl)phenylacetone,

3-triptoreline-4-(4-ethoxycarbonylphenyl)-2-(5-tetrazolyl)phenylacetone,

3-triptoreline-4-(4-diethylaminocarbonylmethyl)-2-(5-tetrazolyl)phenylacetone,

3-triptoreline-4-(4-aminocarbonylmethyl)-2-(5-tetrazolyl) phenylacetone,

3-triptoreline-2-(4-hydroxy-1,2,4-triazole-3-yl)phenylacetone,

3-triptoreline-2-(3-oxo-1,2-dihydro-1,2,4-triazole-1-yl)phenylacetone,

3-triptoreline-2-(2-oxo-3H-1,3,4-oxadiazol-5-yl) phenylacetone,

3-triptoreline-4-diphenylol-2-(3-oxo-1,2-dihydro-1,2,4-triazole-1-yl)phenylacetone,

3-triptoreline-4->3-triptoreline-4-benzoylamino-2-(5-tetrazolyl)phenylacetone,

3-triptoreline-4-(4-carboxyphenyl)-2-(5-tetrazolyl)animaciya,

3-triptoreline-4-(4-unlinkability)-2-(5-tetrazolyl)phenylacetone,

4-diphenylol-2-(5-tetrazolyl)phenylacetone,

3-diphenylol-2-(5-tetrazolyl)phenylacetone,

5-indanyl-2-(5-tetrazolyl)phenylacetone,

3-bromophenyl-4-bromo-2-(5-tetrazolyl)phenylacetone,

3-acetylphenyl-2-(5-tetrazolyl)phenylacetone,

3-diphenylol-4-bromo-2-(5-tetrazolyl)phenylacetone,

3-(3-pyridyl)phenyl-4-bromo-2-(5-tetrazolyl)phenylacetone,

3-triptoreline-4-bromo-2-(5-tetrazolyl)phenylacetone,

3-triptoreline-2-(5-tetrazolyl)phenylacetone,

3-triptoreline-4-phenyl-2-(5-tetrazolyl)phenylacetone,

4-triptoreline-2-(5-tetrazolyl)phenylacetone,

3-chlorophenyl-2-(5-tetrazolyl)phenylacetone,

phenyl-2-(5-tetrazolyl)phenylacetone or

3-triptoreline-4-amino-2-(5-tetrazolyl)phenylacetone;

pharmaceutical composition having activity blocker chlorine ion channels in normal and sickle erythrocytes containing a therapeutically effective amount of a compound, such as any of the above, or in pharmaceutical preparations is m;

connection, such as described above, for use as an active ingredient for the preparation of drugs for treatment of disorders or diseases of the animal or human, the treatment of which the useful blockade chlorine ion channels;

connection, such as described above, for use as an active ingredient for the preparation of drugs for the treatment of sickle cell anemia;

the method of treatment of a disorder or disease of an animal or human, the treatment of which the useful blockade chlorine ion channels, in which such animal or a person in need, administered a therapeutically effective amount of a compound, such as described above;

the method of treatment of a disorder or disease of an animal or human, which is sickle-cell anemia, in which such animal or a person in need, administered a therapeutically effective amount of a compound, such as any of the above;

the method of obtaining compounds, such as described above, in which

the compound having the formula

< / BR>
where W represents O or S, a R11, R12, R13, R14and R15are as defined is UP>3, R4R5are as defined above,

after which the compound obtained may turn into another compound of the invention and/or form of its pharmaceutically acceptable salt, using conventional methods.

Examples of pharmaceutically acceptable salts of the accession of the compounds according to the invention include inorganic and organic salts of joining acids, such as hydrochloride, hydrobromide, phosphate, nitrate, perchlorate, sulfate, citrate, lactate, tartrate, maleate, fumarate, mandelate, benzoate, ascorbate, cinnamate, bansilalpet, methanesulfonate, stearate, succinate, glutamate, glycolate, toluene-p-sulfonate, formate, malonate, naphthalene-2-sulfonate, salicylate and acetate. Such salts are obtained by methods well known in the prior art.

Other acids, such as oxalic acid, although are not pharmaceutically acceptable may be used to obtain salts useful as intermediates in obtaining the compounds according to the invention and their pharmaceutically acceptable salts accession acid.

Halogen represents fluorine, chlorine, bromine or iodine.

Alkyl means a straight chain or branched shall sapropel, butyl, isobutyl, tert-butyl, pentyl and hexyl. Methyl, ethyl, propyl and isopropyl are preferred groups.

Alkoxy represents O-alkyl where alkyl is as defined above.

Amino represents NH2or NH-alkyl or N-(alkyl)2where alkyl is as defined above.

Heteroaryl represents a 5 - or 6-membered monocyclic heterocyclic group. Such monocyclic heteroaryl group includes, for example, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazole-3-yl, 1,2,4-thiadiazole-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl, 1,2,5-thiadiazole-3-yl, 1,2,5-thiadiazole-4-yl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl and 4-pyrazolyl, 2-furyl, 3-furyl, 4-furyl, 5-furyl.

The compounds of this invention can exist as in resolutional, team, solvated forms are considered equivalent nonsolvated forms for purposes of the present invention.

To a person skilled in the art it is obvious that the compounds of the present invention contain several chiral centers and that such compounds exist in the form of isomers (i.e. enantiomers). The invention includes all such isomers and any mixtures thereof, including racemic mixtures.

Some compounds of the present invention exist in (+) and (-) forms as well as in racemic forms. The racemic forms can be separated into the optical antipodes known methods, for example by separating them diastereoisomeric salts using an optically active acid and liberation of the optically active amino compounds by treatment with a base. Another method of separation of racemates on the optical antipodes based on chromatography on optically active matrix. Racemic compounds of the present invention, thus, can be separated into their optical antipodes, for example, by fractional crystallization of d - or l - salts (tartratami, mandelate or camphorsulfonate). Compounds of the present invention can be also section of the Cesky active activated carboxylic acid, such as acid, derived from (+) or (-) phenylalanine, (+) or (-) phenylglycine, (+) or (-) Campanula acid, or by education diastereoisomeric carbamates by the interaction of the compounds according to the present invention with an optically active chloroformiate or similar.

For the separation of optical isomers can be used additional methods known to experts in the art, and these methods are obvious to a person skilled. Such methods include the methods described in J. Jaques, A. Collet and S. Wilen "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, New York (1981).

Compounds according to the invention can be obtained in various ways. Compounds according to the invention and their pharmaceutically acceptable derivatives, thus, can be obtained from any known prior art method of obtaining compounds of similar structures and methods, which are shown in the typical examples that follow.

Biology

Compounds of the present invention are potent blockers chlorine ion channels in normal and sickle erythrocytes. The ability of compounds to block chlorine ion channels erythrocyte not moskalik conductivity units of the channel is below the limit of detection of these methods.

Therefore, all experiments on the estimation of the dose-response was performed by concomitant measurements of total conductive threads CL-(JCl) and membrane potential (Vmin suspensions of erythrocytes [Bennekou, P. and Christophersen, P. (1986), the Flux ratio of Valinomycin-Mediated K+Fluxes across the Human Red Cell Membrane in the presence of the Protonophore the USSR. J. Membrane Biol. 93, 221-227.].

Membrane CL-conductivity (GCl) was calculated according to the following equation [Hodgkin, A. L. and Huxley, A. F. (1952) The components of membrane conductance in the giant axon of Loligo. J. Physiol. Lond. 116, 449-472]:

< / BR>
where F is the Faraday constant,

ECl- Nernst potential for Cl-ion.

Introduction 3-triptoreline-2-carboxyprimaquine in the suspension of normal erythrocytes resulted in blocking of GClmore than 95% when KD-value of 1.3 μm. This connection with equal force blocked the GClfrom oxygenated as well as from deoxygenating homozygous sickle cell erythrocytes.

The value of KD3-trifluoromethyl-4-bromo-2-(5-tetrazolyl)prilocaine in this test was 1.9 μm.

Experimentally induced loss of cell volume was measured as a change in the relative volume of erythrocyte mass. Indutsirovalo cell volume by 26%. 3-Triptoreline-2-carboxyprimaquine dose-dependent (value IC501.2 µm) reduced the loss of up to 7%.

The increase in conductivity of sickle cells, induced deoksigenirovanii, was evaluated by measuring the extracellular concentration of K+depending on time. Normal erythrocytes showed very small K+-threads that did not respond to deoksigenirovanii and did not respond to 10 μm 3-triptoreline-2-carboxyprimaquine. TO+-the flow of oxygenated sickle erythrocytes was found to be 2-3 times higher than normal cells, and these flows were increased by 4-8 times after desoxyribose. In the presence of 3-triptoreline-2-carboxyprimaquine (10 μm) for the main thread TO+from sickle cell normalized and flow component induced by deoksigenirovanii, was virtually eliminated.

3-Triptoreline-2-carboxyprimaquine non-toxic to mice and rats at concentrations up to 250 mg/kg intraperitoneally and intravenously.

Pharmaceutical compositions

Although it is possible to apply therapy to enter the compound according to the invention in the form of a chemical substance, preferably present a the time the proposed pharmaceutical preparations containing the compound of the invention or its pharmaceutically acceptable salt or a derivative thereof together with one or more pharmaceutically acceptable carrier for him and, perhaps, other therapeutic and/or prophylactic ingredients. The carrier(s) must be "acceptable" in the sense that it must be compatible with other ingredients of the drug and should not be harmful to its recipient.

Pharmaceutical products include medicines that are suitable for oral, rectal, nasal, local (including buccal and sublingual), vaginal or parenteral (including intramuscular, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflate.

Compounds according to the invention together with a conventional adjuvant, carrier or diluent, thus, can be represented in the form of pharmaceutical compositions and their standard doses, and in this form they can be used as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or in the form of capcha injection or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and their standard dosage forms may include traditional ingredients in suitable proportions together with additional active compounds or active basis or without them, and such a standard dosage forms may contain any suitable effective amount of the active ingredient commensurate with assigned for use to the range of the daily dose. Drugs, containing ten (10) milligrams of active ingredient or, more generally, from 0.1 to 100 milligrams per tablet, are accordingly suitable typical standard dosage forms.

Compounds of the present invention can be introduced in the composition of a wide variety of oral and parenteral dosage forms. Specialists in the art it is clear that the dosage forms may comprise as the active component, either a compound according to the invention, or pharmaceutically acceptable salt of the compounds according to the invention.

For preparing pharmaceutical compositions from the compounds according to the present invention, pharmaceutically acceptable carriers can be solid or liquid. Drugs in the uly. A solid carrier can be one or more than one substance, which may also act as a diluent, corrigenda, solvent, lubricant, suspending agent, binder, preservative, baking powder tablets or as the substance of the shell.

In powders, the carrier is a finely powdered solid substance that is mixed with finely ground active ingredient.

In tablets, the active ingredient is mixed with carrier having the necessary binding capacity in suitable proportions and compacted into tablets of the desired shape and size.

The powders and tablets preferably contain from five or ten to about seventy percent of the active compounds. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, gelatin, tragakant, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter, etc., it is Assumed that the term "drug" includes the preparation of the active compound with encapsulating substance as a carrier providing a capsule in which the active ingredient together with carriers or without the words of such drugs included wafers and cakes. Tablets, powders, capsules, pills, wafers and cakes can be used as solid forms suitable for oral administration.

For preparing suppositories low-melting wax such as a mixture of glycerides of fatty acids or cocoa butter, is first melted and the active component is homogeneous dispersed therein by stirring. The molten homogeneous mixture is then poured into molds of the desired size, allow to cool and harden.

Drugs suitable for vaginal introduction can be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers which are known in the art as suitable.

The liquid forms include solutions, suspensions and emulsions, such as water or water-propylene glycol solutions. For example, liquid preparations for parenteral injection can be prepared as solutions in aqueous polyethylene glycol.

Compounds of the present invention, thus, can be prepared for parenteral administration (e.g. by injection, for example bolus injection or continuous syringes, in containers for infusion of a small volume or mnogochasovykh containers with added preservatives. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous carriers, and may contain auxiliary agents, such as suspendida, stabilizing and/or dispersing agents. Alternative active ingredient may be in powder form, obtained by aseptic allocation of sterile solid or by lyophilization from solution, for reconstitution before use with an appropriate carrier, such as sterile, pyrogen-free water.

Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and, if desired, by the addition of suitable pigments, corrigentov, stabilizers and thickeners.

Aqueous suspensions suitable for oral use can be prepared by dispersing finely ground active component in water with viscous substance, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose or other well-known suspendresume agents.

In the number of drugs over the use of to turn into a liquid form for oral administration. Such liquid forms include solutions, suspensions and emulsions. In addition to the active component of these preparations may contain colouring agents, corrigentov, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickening agent, solubilizing agents, etc.

For the local introduction of the epidermis, the compounds according to the invention can be prepared in the form of ointments, creams or lotions, or as transdermal patches. Ointments and creams can be prepared, for example, using aqueous or oily base with the addition of suitable thickeners or gelling agents. Lotions can be prepared using water or oil base, and, as a rule, they will also contain one or more than one emulsifying, stabilizing, dispersing, suspendisse agents, thickening agent or dye.

Drugs suitable for local administration in the mouth include pellet containing the active agent in Corrientes basis, usually sucrose and Arabian gum or tragakant; tablets containing the active ingredient in an inert basis such as gelatin and glycerin or sucrose and Arabian gum; rinse containing active is th nose using traditional means, for example, a dropper, pipette or spray. Drugs can be presented in the form of a single dose or in divided doses. In the latter case, when using 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 aerosol this can be achieved, for example, by metering atomizing spray pump.

Introduction to the respiratory tract may also be achieved by means of aerosol preparations in which the active ingredient is in the package under pressure together with a suitable propellant such as a chlorofluorocarbon (CFC), for example DICHLORODIFLUOROMETHANE, Trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide or other suitable gas. The aerosol may also contain a surfactant such as lecithin. The dose of the drug can be controlled using a metering valve.

Alternative active ingredients can be represented in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, derivatives of starch, such as hypromellose and polycomposite can be presented in a standard dosage form, for example, capsules or cartridges, for example, from gelatin or blister packs from which the powder can be introduced through the inhaler.

In products intended for introduction into the respiratory tract, including the preparations for intranasal, connection, typically, will be in the form of particles of small size, for example of the order of 5 microns or less. This particle size can be obtained by methods known from the prior art, for example by micronization. Optionally, you can use products that are adapted for sustained release of active ingredient.

The pharmaceutical preparations are preferably in a standard dosage form. In this form, the drugs are divided into standard doses containing appropriate quantities of the active component. Standard dosage form can be a drug in the package, and the package contains a separate share of the drug, such as packaged tablets, capsules, and powders in vials or ampoules. Standard dosage form can also be itself capsule, tablet, wafer or cake or it can be the appropriate number of any of the above in the packaging which represent preferred compositions.

Treatment

Compounds of the present invention is very useful in the treatment of sickle cell anemia, cerebral edema that accompanies ischemia or tumor, diarrhea, hypertension (diuretic), osteoporosis and glaucoma due to their strong blocking chlorine ion channel activity. These properties make the compounds of this invention are extremely useful in the treatment of sickle cell anemia, cerebral edema that accompanies ischemia or tumor, diarrhea, hypertension (diuretic), osteoporosis and glaucoma and other disorders, the treatment of which is useful for blocking peripheral chlorine ion channel activity of the compounds of the present invention. Accordingly, the compounds of this invention can enter the animal or human in need of treatment, alleviation, or elimination of indications associated with a blocking chlorine ion channel activity or sensitive to it. This reading includes, in particular, sickle cell anemia, brain edema that accompanies ischemia or tumor, diarrhea, hypertension (diuretic), osteoporosis and glaucoma.

A suitable dosage range costal per day depending as usual, the specific method of administration, form in which administered, the indication, in respect of which the scheduled introduction, the intended subject and the body weight of the intended subject, and, in addition, from the choice and experience of the attending physician or veterinarian.

The following examples illustrate the invention, but they should not be construed as limiting the invention.

Example 1

3-Triptoreline-4-bromo-2-(5-tetrazolyl)prilocaine

3-Triftormetilfullerenov (of 0.41 ml, 3.0 mmol) and 5-(2-amino-5-bromophenyl)tetrazol (0.6 g, 2.5 mmol) was added to toluene (10 ml). The reaction mixture was stirred at room temperature overnight. The precipitate was filtered and washed with toluene and then with petroleum ether with the receipt of 0.53 g of the desired connection, so pl. 269-270oC.

The following compounds were obtained by analogy:

3-triptoreline-2-(5-tetrazolyl)phenylacetone, so pl. 257oC;

3-triptoreline-2-(5-tetrazolyl)phenyltoloxamine, so pl. >200oC (decomp);

3-triptoreline-4-phenyl-2-(5-tetrazolyl)phenylacetone, so pl. 260oC;

4-triptoreline-2-(5-tetrazolyl)phenylacetone, so pl. 240oC (decomp.);

3-chlorophenyl-2-(5-tetrachlorodiphenyl-4-nitro-2-(5-tetrazolyl)phenylacetone, so pl. 204-205oC;

3-triptoreline-4-(2-naphthyl)-2-(5-tetrazolyl)phenylacetone, so pl. 257-258oC;

3-triptoreline-4-(3-pyridyl)-2-(5-tetrazolyl)phenylacetone, so pl. 148-152oC;

3-triptoreline-4-(1-naphthyl)-2-(5-tetrazolyl)phenylacetone, so pl. 207-208oC;

3-triptoreline-4-(4-triptoreline)-2-(5-tetrazolyl)-phenylacetone, so pl. 135-140oC;

3-triptoreline-4-(3-furyl)-2-(5-tetrazolyl)phenylacetone, so pl. 260-261oC;

3-triptoreline-4-(3-thienyl)-2-(5-tetrazolyl)phenylacetone, so pl. 259-260oC;

3-triptoreline-4-(3-nitrophenyl)-2-(5-tetrazolyl)phenylacetone, so pl. 135-140oC;

3-triptoreline-4-(4-ethoxycarbonylphenyl)-2-(5-tetrazolyl)phenylacetone, so pl. 262-263oC;

3-triptoreline-4-(4-diethylaminocarbonylmethyl)-2-(5-tetrazolyl)phenylacetone, so pl. 264oC;

3-triptoreline-4-(4-aminocarbonylmethyl)-2-(5-tetrazolyl)phenylacetone, so pl. 252-253oC;

3-triptoreline-2-(4-hydroxy-1,2,4-triazole-3-yl)phenylacetone, so pl. 220-221oC;

3-triptoreline-2-(3-oxo-1,2-dihydro-1,2,4-triazole-1-yl)phenylacetone, so pl.>300oC;

3-triptoreline-2-(2-oxo-3H-1,3,4-oxadiazol-5-yl)phenylacetone, so pl.>300oC;

enyl-4-bromo-2-(5-tetrazolyl)phenylacetone, so pl. 142oC.

Example 2

5-(2-AMINOPHENYL)tetrazole

2-Aminobenzonitrile (9,44 g, 80 mmol), sodium azide (6,24 g, 0.1 mol), ammonium chloride (5,12 g, 0.1 mol) and dimethylformamide (50 ml) were mixed and heated at 120oWith during the night. The solvent is evaporated and the residue is transferred into the water. The crude product was isolated by filtration and recrystallized from water. The yield of pure amounted to 8.4,

Similarly were obtained:

5-(2-amino-5-bromophenyl)tetrazol,

5-(4-amino-3-diphenyl)tetrazol,

5-(2-amino-5-nitrophenyl)tetrazole,

5-(2-amino-4-(2-naphthyl)phenyl)tetrazol,

5-(2-amino-4-(3-pyridyl)phenyl)tetrazol,

5-(2-amino-4-(1-naphthyl)phenyl)tetrazol,

5-(2-amino-4-(4-triptoreline)phenyl)tetrazol,

5-(2-amino-4-(3-furyl)phenyl)tetrazol,

5-(2-amino-4-(3-thienyl)phenyl)tetrazol,

5-(2-amino-4-(4-triptoreline)phenyl)tetrazol,

5-(2-amino-4-(3-nitrophenyl)phenyl)tetrazol,

5-(2-amino-4-(4-ethoxycarbonylphenyl)phenyl)tetrazol,

5-(2-amino-4-(4-diethylaminocarbonylmethyl)phenyl)tetrazol,

5-(2-amino-4-(4-aminocarbonylmethyl)phenyl)tetrazol.

Example 3

2-Amino-4-phenylbenzoate

A mixture of 2-amino-5-bromobenzonitrile (1.0 g, 5 mmol), phenylboronic acid (0,92 g, 7.5 mmol), Tetra at reflux distilled for 4 hours. After cooling to room temperature the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried and the solvent evaporated. Kneading the powder with petroleum ether resulted in the receipt of 0.89 g of the desired compound.

In this way were obtained:

2-amino-4-(2-naphthyl)benzonitrile,

2-amino-4-(3-pyridyl)benzonitrile,

2-amino-4-(1-naphthyl)benzonitrile,

2-amino-4-(4-triptoreline)benzonitrile,

2-amino-4-(3-furyl)benzonitrile,

2-amino-4-(3-thienyl)benzonitrile,

2-amino-4-(3-nitrophenyl)benzonitrile,

2-amino-4-(4-ethoxycarbonylphenyl)benzonitrile,

2-amino-4-(4-diethylaminocarbonylmethyl)benzonitrile,

2-amino-4-(4-aminosulphonylphenyl)benzonitrile,

1-(3-nitro-4-diphenylol)-1,2-dihydro-1,2,4-triazole-3-one.

Example 4

3-Triptoreline-4-amino-2-(5-tetrazolyl)prilocaine

A solution of 3-triptoreline-4-nitro-2-(5-tetrazolyl)phenylacetone (0.8 g, 2.0 mmol) in 96% ethanol was first made over 5% palladium on coal for 3 hours at room temperature. The reaction mixture was filtered through a layer of celite and the solvent evaporated to obtain 0.75 g of the desired product, so pl. 175-180oC.

Example 5

3-Trif who was solil)phenylacetone (0,22 g, 0.6 mmol) in 17% aqueous sodium acetate (5 ml), cooled in an ice bath, was added acetic anhydride (1 ml). The reaction mixture was stirred at 0oC for one hour. The precipitate was filtered and recrystallized from 96% ethanol to obtain 0.12 g of the desired substance, so pl. 280-282oC.

Example 6

3-Triptoreline-4-benzoylamino-2-(5-tetrazolyl)prilocaine

To a solution of 3-triptoreline-4-amino-2-(5-tetrazolyl)phenylacetone (0.36 g, 1.0 mmol) in tetrahydrofuran (40 ml) was added triethylamine (0.17 ml, 1.2 mmol). The solution was cooled in an ice bath was added benzoyl chloride (about 0.14 ml, 1.2 mmol). The reaction mixture was stirred at 0oWith in the next 30 minutes, the Reaction mixture was poured into water. The precipitate was filtered and recrystallized from 96% ethanol to obtain 0.28 g of the desired substance, so pl. 271-272oC.

Example 7

4-Metilenhloridov acid

To a solution of 4-iodotoluene (35 g, 160,5 mmol) in diethyl ether (400 ml) was added n-utility (2M in pentane, 88,3 ml, 176,6 mmol) at 0oC. After stirring at 0oWith in the next 15 minutes the solution was cooled to -60oWith and added tributyrate (60,6 ml, 224,7 mmol). The cooling bath was removed and react., 280 ml) and the organic phase was separated. The aqueous phase was extracted with diethyl ether (CH ml). The combined organic phases were extracted with sodium hydroxide (1 N., h ml). The combined aqueous extracts were acidified to obtain 18.6 g of the desired substance.

Example 8

4-Carboxyhemoglobinemia acid

To a solution of 4-methylphenylacetic acid (34 g, 0.25 mol) in aqueous sodium hydroxide (0,5 N. , 1000 ml) was added potassium permanganate (83 g of 0.53 mol), maintaining the temperature of 35-40oC. After the addition, the reaction mixture was filtered and the filtrate was acidified with concentrated hydrochloric acid (65 ml). The product was filtered. Got out of 29.6 g, so pl. 228oC.

Example 9

4-Ethoxycarbonylphenyl acid

A solution of 4-carboxybenzeneboronic acid (15 g, 0.09 mol), 99% ethanol (150 ml) and concentrated sulfuric acid (0.5 ml) was heated to education phlegmy within two days. The volume was reduced to approximately 20 ml, the Residue was ground into powder with petroleum ether to obtain a 13.4 g of the desired substance.

Example 10

4-Aminocarbonylmethyl acid

A solution of 4-carboxybenzeneboronic acid (10 g, 0.06 mol) and thionyl chloride (875 ml) was heated to 50-60 is). The reaction mixture was heated up to the formation of phlegmy. Hot filtration and subsequent acidification of the filtrate allowed to obtain the crude material. This crude substance was purified by suspension in dilute sodium bicarbonate with the receipt of 1.09 g of the desired substance.

In this way there was obtained 4-dimethylaminocarbonylmethyl acid.

Example 11

3-Triptoreline-4-(4-carboxyphenyl)-2-(5-tetrazolyl)prilocaine

To a suspension of 3-triptoreline-4-(4-ethoxycarbonylphenyl)-2-(5-tetrazolyl)phenylacetone (4.5 g, 9 mmol) in 96% ethanol was added sodium hydroxide (4 N., 25 ml). The reaction mixture was heated up to the formation of phlegmy for 30 min, then cooled to room temperature and acidified with hydrochloric acid. The precipitate was filtered to obtain 3.8 g of the desired substance, so pl. 300oC (decomp.).

Example 12

3-Triptoreline-4-(4-unlinkability)-2-(5-tetrazolyl)prilocaine

A mixture of 3-triptoreline-4-(4-carboxyphenyl)-2-(5-tetrazolyl)phenylacetone (1.9 g, 4 mmol) and thionyl chloride (10 ml) was heated to 50oC for 6 hours. The excess thionyl chloride are evaporated. To the residue was added diethyl ether to obtain 2.2 g of solid fuel shall triethylamine (0.5 ml, 3.6 mmol). After stirring for 30 min the solvent evaporated. The residue is suspended in water and added a small amount of diluted hydrochloric acid. The solid was filtered and recrystallized from 96% ethanol to obtain 0.2 g of the desired substance, so pl.>300oC.

Example 13

4-Diphenylol-2-(5-tetrazolyl)prilocaine

To a solution of N,N-carbonyldiimidazole (0.96 g, 5.0 mmol) and imidazole (0.68 g, 10 mmol) in tetrahydrofuran (10 ml) atoWith added 4-aminodiphenyl (1.0 g, 5.9 mmol) in tetrahydrofuran (10 ml). After stirring at 0oC for 10 min was added 5-(2-AMINOPHENYL)tetrazole (1,14 g, 7.1 mmol). The reaction mixture was stirred over the next 4 hours and filtered. The filtrate is evaporated until dry and the crude product was purified column chromatography. The obtained yield 0.28 g, so pl. 224-226oC.

In this way were obtained:

3-diphenylol-2-(5-tetrazolyl)phenylacetone, so pl. 189-191oWITH,

5-indanyl-2-(5-tetrazolyl)phenylacetone, so pl. 154-157oWITH,

3-acetylphenyl-2-(5-tetrazolyl)phenylacetone, so pl. 115oWITH,

3-diphenylol-4-bromo-2-(5-tetrazolyl)phenylacetone,

3-(3-pyridyl)phenyl-4-bromo-2-(5-tetrazolyl)phenylacetic is risola (0,38 g, 1.8 mmol), obtained by H. G. O. Becker (J. Prakt. Chem., 1970, 312, 610), in 96% ethanol was first made over 5% palladium on coal at room temperature for 1 hour. The reaction mixture was filtered through a layer of celite to obtain, after evaporation of the solvent, the desired substance.

Example 15

1-(4-Bromophenyl)-1,2-dihydro-[1,2,4]triazole-3-one

A mixture of the hydrochloride of 4-brompheniramine (5.0 g, of 22.4 mmol) and urea (8,1 g, 134 mmol) was heated to 80oWith over night in 1-methyl-2-pyrrolidinone (25 ml). The reaction mixture was poured into water (250 ml) was added concentrated ammonia until basic pH. The solution was cooled in an ice bath and semicarbazone was filtered. Semicarbazone (1.0 g, 4.4 mmol) was stirred in triethylorthoformate (8 ml) at 90oWith in three days. The reaction mixture was cooled to room temperature and the crude substance was filtered. Recrystallization from methanol allowed to obtain the desired product.

Example 16

1-(4-Bromo-2-AMINOPHENYL)-1,2-dihydro-1,2,4-triazole-3-one

To a solution of 1-(4-bromophenyl)-1,2-dihydro-[1,2,4]triazole-3-one (0.25 g, 1.0 mmol) in concentrated sulfuric acid (10 ml) at 0oWith added potassium nitrate (0,13 g, 1.2 mmol). The reaction mixture was stirred for sleduyuschaya to obtain 0.28 g of the desired nitro compounds. Nitrosoaniline (0.28 g, 1.0 mmol), suspended in 96% ethanol, was first made over 5% palladium on coal to obtain the desired substance.

Example 17

5-(2-AMINOPHENYL)-3H-1,3,4-oxadiazol-2-he

A solution of 2-nitrobenzonitrile (9,05 g, 0.05 mol) in dioxane (30 ml) was slowly added to a solution of trichloromethylcarbonate (4.6 ml, 0.04 mol) in dioxane (30 ml) at room temperature. Upon completion of addition the reaction mixture was heated up to the formation of phlegmy for 4 hours. The solvent is evaporated and the residue was recrystallized from 96% ethanol (50 ml) to give to 7.15 g of 5-(2-nitrophenyl)-3H-[1,3,4]oxadiazol-2-it, so pl. 157-158oC. a Solution of nitro compounds (2 g, 9.7 mmol) in 96% ethanol (25 ml) was first made over 5% palladium on coal to obtain 1.6 g of the desired amine.

Example 18

1-(2-Amino-4-diphenylol)-1,2-dihydro-1,2,4-triazole-3-one

A solution of 1-(2-nitro-4-diphenylol)-1,2-dihydro-1,2,4-triazole-3-one in 96% ethanol (25 ml) was first made over 5% palladium on coal with obtaining the desired amine.

Example 19

The pharmaceutical composition

Chemical compound according to this invention can be incorporated into pharmaceutical compositions of any desired shape and may be entered in any desired kalijogo solution, respectively. As the active ingredient used in the compound of example 1 - [3-triptoreline-4-bromo-2-(5-tetrazolyl)phenylacetone].

The standard drug in the form of a capsule

Capsules containing 1 mg of active pharmaceutical ingredient per capsule, can be obtained using the composition shown in table.1.

Weigh the calculated amount of drug and filler corresponding to 1 mg of active drug, and 117 mg of filler on one capsule and mixed in a dry state. Then the mixture is filled calculated the number of capsules (size 4).

The standard drug in tablet form

Tablets containing 1,585 mg of active ingredient per tablet were obtained using the composition shown in table.2.

The active ingredient is dissolved in the granulating solution, which consists of microcrystalline cellulose and water which is then used for the granulation of microcrystalline cellulose. The granulate is left to dry on the pallet.

Above the granulate containing the active pharmaceutical ingredient, microcrystalline cellulose, lactose and sodium kroska the Ute in the mixer together with the above mixture, and then mix. The resulting mixture was then pressed into tablets.

Standard preparation in the form of injection solution

Injectable solution containing 1 mg/ml of the active ingredient was obtained using the composition shown in table.3.

The calculated amount of active ingredient is weighed, dissolved in sterile purified water, add the prescribed amount of sodium chloride and sodium citrate, and then the pH of the solution was adjusted to the desired value, typically in the range of from about pH 6.5.

1. Substituted phenyl derivative having the formula

< / BR>
or their pharmaceutically acceptable salt,

where one of R1, R2and R3represents a 4-hydroxy-1,2,4-triazolyl, 3-oxo-1,2-dihydro-1,2,4-triazolyl, 2-oxo-3H-1,3,4-oxadiazolyl or tetrazolyl;

R4and R5represent hydrogen;

two other substituent R1, R2and R3each independently selected from hydrogen, halogen, nitro, amino, acylamino, benzoylamine, phenyl, naphthyl, diphenyl or 5 - or 6-membered monocyclic heterocyclic group containing one heteroatom selected from N, S and O, where the phenyl group can be the replacement of the carbonyl, aminocarbonyl, dialkylaminoalkyl and onlinebarbara;

Y represents-CO - or-CS-;

X represents-NH-;

Z represents NH;

one of R11, R12, R13, R14and R15selected from hydrogen, halogen, trifloromethyl, -COOR7, phenyl or 5 - or 6-membered monocyclic heterocyclic group containing one heteroatom selected from N, S and O, and four other of R11, R12, R13, R14and R15represent hydrogen; or one of R11and R12, R12and R13, R13and R14, R14and R15together form a cyclic structure, and the other substituents R11, R12, R13, R14and R15represent hydrogen;

R7represents alkyl.

2. Connection on p. 1, where one of R1, R2and R3represents a 4-hydroxy-1,2,4-triazolyl, tetrazolyl, 3-oxo-1,2-dihydro-1,2,4-triazolyl, 2-oxo-3H-1,3,4-oxadiazolyl, Z represents NH and Y is FROM.

3. Connection on p. 1 representing:

3-triptoreline-4-nitro-2-(5-tetrazolyl)phenylacetone,

3-triptoreline-4-(2-naphthyl)-2-(5-tetrazolyl)phenylacetone,

3-cryptomate the inu,

3-triptoreline-4-(4-triptoreline)-2-(5-tetrazolyl)phenylacetone,

3-triptoreline-4-(3-furyl)-2-(5-tetrazolyl)phenylacetone,

3-triptoreline-4-(3-thienyl)-2-(5-tetrazolyl)phenylacetone,

3-triptoreline-4-(3-nitrophenyl)-2-(5-tetrazolyl)phenylacetone,

3-triptoreline-4-(4-ethoxycarbonylphenyl)-2-(5-tetrazolyl)phenylacetone,

3-triptoreline-4-(4-diethylaminocarbonylmethyl)-2-(5-tetrazolyl)phenylacetone,

3-triptoreline-4-(4-aminocarbonylmethyl)-2-(5-tetrazolyl)phenylacetone,

3-triptoreline-2-(4-hydroxy-1,2,4-triazole-3-yl)phenylacetone,

3-triptoreline-2-(3-oxo-1,2-dihydro-1,2,4-triazole-1-yl)-phenylacetone,

3-triptoreline-2-(2-oxo-3H-1,3,4-oxadiazol-5-yl)phenylacetone,

3-triptoreline-4-diphenylol-2-(3-oxo-1,2-dihydro-1,2,4-triazole-1-yl)phenylacetone;

3-triptoreline-4-amino-2-(5-tetrazolyl)phenylacetone,

3-triptoreline-4-acetylamino-2-(5-tetrazolyl)phenylacetone,

3-triptoreline-4-benzoylamino-2-(5-tetrazolyl)phenylacetone,

3-triptoreline-4-(4-carboxyphenyl)-2-(5-tetrazolyl)-phenylacetone,

3-triptoreline-4-(4-unlinkability)-2-(5-tetrazolyl)-phenylacetone,

4-diphenylol-2-(moonvine,

3-bromophenyl-4-bromo-2-(5-tetrazolyl)phenylacetone,

3-acetylphenyl-2-(5-tetrazolyl)phenylacetone,

3-diphenylol-4-bromo-2-(5-tetrazolyl)phenylacetone,

3-(3-pyridyl)phenyl-4-bromo-2-(5-tetrazolyl)phenylacetone,

3-triptoreline-4-bromo-2-(5-tetrazolyl)phenylacetone,

3-triptoreline-2-(5-tetrazolyl)phenylacetone,

3-triptoreline-4-phenyl-2-(5-tetrazolyl)phenylacetone,

4-triptoreline-2-(5-tetrazolyl)phenylacetone,

3-chlorophenyl-2-(5-tetrazolyl)phenylacetone,

phenyl-2-(5-tetrazolyl)phenylacetone or

3-triptoreline-4-amino-2-(5-tetrazolyl)phenylacetone.

4. Pharmaceutical composition having activity blocker chlorine ion channels in normal and sickle erythrocytes containing a therapeutically effective amount of a compound according to any one of paragraphs. 1-3 or its pharmaceutically acceptable salt together with at least one pharmaceutically acceptable carrier or diluent.

5. Connection PP. 1-3 for use as an active ingredient for the preparation of drugs for treatment of disorders or diseases of the animal or human, the treatment of which the useful blockade chlorine ion channels.

6. Soedinenieto anemia.

7. The method of treatment of a disorder or disease of an animal or human, the treatment of which the useful blockade chlorine ion channels, in which such animal or a person in need, administered a therapeutically effective amount of the compounds according to paragraphs. 1-3.

8. The method of treatment of a disorder or disease of an animal or human, which is sickle-cell anemia, in which such animal or a person in need, administered a therapeutically effective amount of the compounds according to paragraphs. 1-3.

9. The method of obtaining connection PP. 1-3, wherein the compound having the formula

< / BR>
where W represents O or S;

R11, R12, R13, R14and R15are as defined above,

subjected to interaction with the compound having the formula

< / BR>
where R1, R2, R3, R4and R5are as defined above,

after which the compound obtained may turn into another compound of the invention and/or form of its pharmaceutically acceptable salt, using conventional methods.

 

Same patents:

The invention relates to piperazine derivatives of General formula I, in which R1denotes pyridyl or phenyl, unsubstituted or once substituted Ph or 2 - or 3-Tiepolo, R2indicates Ph1or Het

The invention relates to new derivatives of arylsulfonamides having, in particular, valuable pharmacological properties, more particularly to a derivative of arylsulfonamides General formula (I)

< / BR>
where R1benzyl, thienyl, chloranil, tetramethylene pentamethylbenzyl, phenyl, unsubstituted or monosubstituted by a halogen atom, a nitro-group, stands, metaxylem or trifluoromethyl, phenyl, disubstituted by chlorine atoms or methoxypropane,

R2a hydrogen atom, methyl,

R3pyridyl,

R4and R5hydrogen atoms or together denote a carbon-uglerodnoi communication,

R6hydroxyl, methoxyl,

A group of the formula

< / BR>
where R7and R8a hydrogen atom or together denote a methylene or ethylene group

X N-methyl-aminogroup or sulfur atom, and the group-CHR7associated with the group-NR2-,

B a carbon-carbon bond or unbranched Allenova group with 2-4 carbon atoms,

their mixtures, isomers or individual isomers and physiologically tolerated additive salts with bases, if R6means hydroxyl, which

The invention relates to new triazinyl compounds of formulas Ia and Ib:

< / BR>
or their salts, where in the formula Ia W represents N or C-CO-R, where R denotes HE OC1-C6alkyl or NR3R4where R3and R4- N or C1-C6alkyl, or formula Ib Az denotes imidazopyridine and in both formulas Ia and Ib R1represents C1-C4alkyl, R2denotes phenyl fragment or 2,5-cyclohexadiene-3,4-ridin-1 silt fragment

The invention relates to new 1-(biphenyl-4-yl)methyl-1H-1, 2,4-triazole compounds and 1-(biphenyl-4-yl)methyl-4H-1,2,4-triazole compounds, and each of them has as a substituent in the 2'-position (2,4-dioxopyrimidine-5-ilidene)methyl or (2,4-dioxotetrahydrofuran-5-ilidene)methyl, and their salts

The invention relates to a derivative of a simple ester, application and intermediate compounds used for their production

The invention relates to new benzododecinium the compounds containing pharmaceutical compositions, method of production thereof, and to a method for producing an intermediate product

The invention relates to new derivatives of 3-phenylpyrazole, to methods for their preparation, to compositions containing them and to a method of protecting plants from fungal diseases

The invention relates to novel benzimidazole compounds represented by the General formula I

< / BR>
where denotes the number 0, 1, 2 or 3; R1represents an alkyl group, phenyl group or a monocyclic heterocyclic group containing as the heteroatom N or O, and these groups may be substituted once or more than once, by substituents selected from alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy, cyano, amino and nitro; or R1represents cyano or a group of formula-alkyl-CO2R2alkenyl-CO2R2, -CO-R2, -CO2(CH2)mR2or-C(R3)=N-OR2where m denotes the number 0, 1, 2 or 3; R2represents hydrogen, alkyl, phenyl, benzyl, 5 - or 6-membered heterocyclic group, which 5 - or 6-membered heterocyclic group may be substituted once or more than once by alkyl or alkoxy; or R2may represent a group of the formula -(CH2)q-NR4R5, -(CH2)q-CON(R4R5), -(CH2)q-CO2R4or-alkyl-CO2R4where R4and R5independently представляюUP> represents a group of General formula-CO2-R9where R9represents an alkyl or R9can represent a 6-membered heterocyclic group, and this 6-membered heterocyclic group may be substituted once or more than once by alkyl or alkoxy; or R9represents a group of General formula-alkyl-N(R10R12), where R10and R12independently represent hydrogen or alkyl; or R11represents a group of General formula II

< / BR>
where n denotes the number 0, 1, 2 or 3; R' and R" together with the N atom to which they are attached, form a heterocyclic ring with the number of members from 5 to 7, and this heterocyclic ring can contain as a ring member, one oxygen atom and/or one additional nitrogen atom; and in this formula, a heterocyclic ring with the number of members from 5 to 7, formed by R' and R", may be substituted once or more than once by a group of the formula -(CH2)px, where p denotes the number 0, 1, 2 or 3; X represents hydrogen, hydroxyl, alkyl or alkenyl, and these alkyl and alkenyl can be possibly substituted by one or more the>R6or-CON-R6R7where R6and R7independently represent hydrogen or alkyl; or R11may represent a group of General formula III

< / BR>
where n denotes the number 1; R' represents hydrogen or alkyl; R'" and R" 'together with the atoms to which they are attached, form a heterocyclic ring with the number of members from 5 to 7, and this heterocyclic ring can contain as a ring member one chain-CH=CH-; and in this formula, a heterocyclic ring with the number of members from 5 to 7, formed R'" and R"", may be substituted once or more than once by a group of the formula -(CH2)pX, where p denotes the number 0, 1, 2 or 3; X represents hydrogen, alkyl; or its pharmaceutically acceptable salt; provided that if R11is morpholinyl, R1may not represent tert-butyl; pharmaceutical compositions having the properties of the modulator of the GABAANDreceptors and the treatment of disorders and diseases of the living organism, and it is a disorder or disease responsive to modulation of GABAAND-receptor complex of the Central nervous

The invention relates to a derivative of a simple ester, application and intermediate compounds used for their production

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The invention relates to new compounds of formula I, where b and E are independently selected from CH or N; R4is hydrogen, halogen, hydroxy; G represents the compounds of formula II (a, b, c) and their optical and geometric isomers; and nontoxic pharmaceutically acceptable acid salt additive
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