Derivatives of acylphenylurea, pharmaceutical composition and method for its preparing

FIELD: organic chemistry, medicine, endocrinology, pharmacy.

SUBSTANCE: invention relates to new derivatives of acylphenylurea of the formula (I) and to their physiologically acceptable salts possessing property of glycogen phosphorylase inhibitors. In compound of the formula (I) A means phenyl and phenyl residue can be substituted three times with fluorine (F), chlorine (Cl), bromine (Br) atoms, -CF3, -NO2, -O-(C1-C6)-alkyl, -SO2-(C1-C6)-alkyl, (C1-C6)-alkyl, -COOH; R1 means hydrogen atom (H), (C1-C6)-alkyl; R2 means H, (C1-C6(-alkyl, -CO-(C1-C6)-alkyl; 3, R4, R5 and R6 mean independently of one another H, F, Cl, Br, -O(C1-C6)-alkyl, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, -COOH, -COO-(C1-C6)-alkyl; X means oxygen (O), sulfur (S) atom; R7 means (C1-C10)-alkylene-COOH, (C1-C10)-alkylene-COO-(C1-C6)-alkyl, (C1-C10)-alkylene-NH2, (C1-C10)-alkylene-NH-(C1-C6)-alkyl, (C1-C10)-alkylene-N-[(C1-C6)-alkyl]2, (C1-C10)-alkylene-B wherein B means piperidinyl or furyl. Also, invention relates to a pharmaceutical composition and a method for preparing the pharmaceutical composition. Proposed compounds can be used for preparing pharmaceutical composition useful for declining level of blood glucose and for treatment of diabetes mellitus type II.

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

7 cl, 2 sch, 2 tbl, 1 ex

 

The invention relates to a derivative of Allgemeine, as well as their physiologically compatible salts and physiologically functional derivatives.

The use of derivatives Allgemeine as insecticides already described in the prior art (European patent EP 0136745, EP 0167197, German Patent DE 2926480, J. Agric. Food Chem. 1999, 47, 3116-3424).

The objective of the invention is the obtaining of compounds exhibiting the effect of lowering therapeutically acceptable blood sugar level.

Therefore, the invention relates to compounds of formula I,

which means

A phenyl, naphthyl, and phenyl or naftalina group can contain up to three substituents, such as F, Cl, Br, OH, CF3, NO2CN, OCF3, O-(C1-C6)-alkyl, O-(C1-C6)-alkenyl, O-(C1-C6)-quinil, S-(C1-C6)-alkyl, S-(C1-C6)-alkenyl, S-(C1-C6)-quinil, SO-(C1-C6)-alkyl, SO2-(C1-C6)-alkyl, SO2-NH2, (C1-C6)-alkyl, (C1-C6)-alkenyl, (C1-C6)-quinil, (C3-C7-cycloalkyl, (C3-C7-cycloalkyl-(C1-C4-alkylene, (C0-C6-alkylene-COOH, (C0-C6-alkylene-COO(C1-C7)-alkyl, CONH2, CONH(C1-C6)-alkyl, CON[(C1-C6)-alkyl]sub> 2, CONH(C3-C6-cycloalkyl, (C0-C6-alkylene-NH2, (C0-C6-alkylene-NH(C2-C6)-alkyl, (C0-C6-alkylene-N[(C1-C6)-alkyl]2, NH-CO-(C1-C6)-alkyl, NH-CO-phenyl, NH-SO2-phenyl, with phenyl ring may contain up to two substituents, such as F, Cl, CN, OH, (C1-C6)-alkyl, O-(C1-C6)-alkyl, CF3, OCF3, COOH, COO(C1-C6)-alkyl or CONH2;

R1, R2 independently from each other signify H, (C1-C6)-alkyl, O-(C1-C6)-alkyl, CO-(C1-C6)-alkyl, COO-(C1-C6)-alkyl, (C1-C6-alkylene-COOH, (C1-C6-alkylene-COO-(C1-C6)-alkyl;

R3, R4, R5, R6 independently of one another denote H, F, Cl, Br, OH, CF3, NO2CN, OCF3, O-(C1-C6)-alkyl, O-(C1-C6)-alkenyl, O-(C1-C6)-quinil, S-(C1-C6)-alkyl, S-(C1-C6)-alkenyl, S-(C1-C6)-quinil, SO-(C1-C6)-alkyl, SO2-(C1-C6)-alkyl, SO2-NH2, (C1-C6)-alkyl, (C1-C6)-alkenyl, (C1-C6)-quinil, (C3-C7-cycloalkyl, (C3-C7-cycloalkyl-(C1-C4-alkylen, COOH, COO(C1-C6)-alkyl, CONH2, CONH(C1-C6)-alkyl, CON[(C1-C6)-alkyl]2, CONH(C3-C7)-cyclea the keel, NH2, NH(C1-C6)-alkyl, N[(C1-C6)-alkyl]2, NH-CO-(C1-C6)-alkyl, NH-CO-phenyl, NH-SO2-phenyl, and the phenyl ring may bear up to two substituents, such as F, Cl, CN, OH, (C1-C6)-alkyl, O-(C1-C6)-alkyl, CF3, OCF3, COOH, COO(C1-C6)-alkyl or CONH2;

X is O, S;

R7 (C1-C10-alkylene-COOH, (C6-C10-alkylene-COO-(C1-C6)-alkyl, (C1-C10-alkylene-CONH2, (C1-C10-alkylene-CONH-(C1-C6)-alkyl, (C1-C10-alkylen-CON-[(C1-C6)-alkyl]2, (C1-C10-alkylene-NH2, (C1-C10-alkylene-NH(C1-C6)-alkyl, (C1-C10-alkylene-N[(C1-C6)-alkyl]2, (C1-C10-alkylen-B;

B (C3-C7-cycloalkyl, pyrrolyl, imidazolyl, thiazolyl, azetidine, thienyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridyl-methyl or furyl, and cycloalkyl, phenyl, pyrrolyl, imidazolyl, thiazolyl, azetidine, thienylmethyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridyl or furyl may contain up to two substituents, such as Cl, F, CN, CF3, OCF3, COOH, COO-(C1-C6)-alkyl, CONH2, CONH-(C1-C6)-alkyl, CON-[(C1-C6)-alkyl]2, (C1-C6)-alkyl, OH, O-(C1-C6)-alkyl;

and their fiziologicheskimi salt,

this excludes the compounds of formula

as well as the compounds of formula I, where the remains of simultaneously mean

Aphenyl;
XO;
R1H;
R7-(C1-C4)-alkyl-B;
B(C3-C7-cycloalkyl, heteroaryl.

Preferred compounds of formula I, where mean

A phenyl, naphthyl, and phenyl or naftalina group can contain up to three substituents, such as F, Cl, Br, OH, CF3, NO2CN, OCF3, O-(C1-C6)-alkyl, O-(C1-C6)-alkenyl, O-(C1-C6)-quinil, S-(C1-C6)-alkyl, S-(C1-C6)-alkenyl, S-(C1-C6)-quinil, SO-(C1-C6)-alkyl, SO2-(C1-C6)-alkyl, SO2-NH2, (C1-C6)-alkyl, (C1-C6)-alkenyl, (C1-C6)-quinil, (C3-C7-cycloalkyl, (C3-C7-cycloalkyl-(C1-C4-alkylene, (C0-C6-alkylene-COOH, (C0-C6-alkylene-COO(C1-C6)-alkyl, CONH2, CONH(C1-C6)-alkyl, CON[(C1-C6)-alkyl]2, CONH(C3-C7-cycloalkyl,(C0-C6-alkylene-NH2, (C0-C6)-Alki the eh-NH(C 2-C6)-alkyl, (C0-C6-alkylene-N[(C1-C6)-alkyl]2, NH-CO-(C1-C6)-alkyl, NH-CO-phenyl, NH-SO2-phenyl, with phenyl ring may contain up to two substituents, such as F, Cl, CN, OH, (C1-C6)-alkyl, O-(C1-C6)-alkyl, CF3, OCF3, COOH, COO(C1-C6)-alkyl or CONH2;

R1, R2 independently from each other signify H, (C1-C6)-alkyl, O-(C1-C6)-alkyl, CO-(C1-C6)-alkyl, COO-(C1-C6)-alkyl, (C1-C6-alkylene-COOH, (C1-C6-alkylene-COO-(C1-C6)-alkyl;

R3, R4, R5, R6 independently of one another denote H, F, Cl, Br, OH, CF3, NO2CN, OCF3, O-(C1-C6)-alkyl, O-(C1-C6)-alkenyl, O-(C1-C6)-quinil, S-(C1-C6)-alkyl, S-(C1-C6)-alkenyl, S-(C1-C6)-quinil, SO-(C1-C6)-alkyl, SO2-(C1-C6)-alkyl, SO2-NH2, (C1-C6)-alkyl, (C1-C6)-alkenyl, (C1-C6)-quinil, (C3-C7-cycloalkyl, (C3-C7-cycloalkyl-(C1-C4-alkylen, COOH, COO(C1-C6)-alkyl, CONH2, CONH(C1-C6)-alkyl, CON[(C1-C6)-alkyl]2, CONH(C3-C7-cycloalkyl, NH2, NH(C1-C6)-alkyl, N[(C1-C6)-alkyl]2, NH-CO-(C1-C6)-alkyl, NH-C-phenyl, NH-SO2-phenyl, and the phenyl ring may contain up to two substituents, such as F, Cl, CN, OH, (C1-C6)-alkyl, O-(C1-C6)-alkyl, CF3, OCF3, COOH, COO(C1-C6)-alkyl or CONH2;

X is O, S;

R7 (C1-C10-alkylene-COOH, (C6-C10-alkylene-COO-(C1-C6)-alkyl, (C1-C10-alkylene-CONH2, (C1-C10-alkylene-CONH-(C1-C6)-alkyl, (C1-C10-alkylen-CON-[(C1-C6)-alkyl]2, (C1-C10-alkylene-NH2, (C1-C10-alkylene-NH(C1-C6)-alkyl, (C1-C10-alkylene-N[(C1-C6)-alkyl]2, (C1-C10-alkylen-B;

B (C3-C7-cycloalkyl, pyrrolyl, imidazolyl, thiazolyl, azetidine, thienylmethyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridyl-methyl or furyl, and cycloalkyl, phenyl, pyrrolyl, imidazolyl, thiazolyl, azetidine, thienyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridyl or furyl may contain up to two substituents, such as Cl, F, CN, CF3, OCF3, COOH, COO-(C1-C6)-alkyl, CONH2, CONH-(C1-C6)-alkyl, CON-[(C1-C6)-alkyl]2, (C1-C6)-alkyl, OH, O-(C1-C6)-alkyl;

as well as their physiologically compatible salt,

this excludes the compounds of formula

the compounds of formula I, where the remains of simultaneously mean

Aphenyl;
XO;
R1H;
R7-(C1-C4)-alkyl-B;
B(C3-C7-cycloalkyl, heteroaryl.

Especially preferred compounds of formula I, where

A phenyl, and the phenyl group may contain up to two substituents, such as F, Cl, Br, O-(C1-C6)-alkyl;

R1, R2 independently from each other signify H, (C1-C6)-alkyl, CO-(C1-C6)-alkyl, -O(C1-C6)-alkyl;

R3, R4, R5, R6 independently of one another denote H, Cl, F, (C1-C6)-alkyl, COO-(C1-C6)-alkyl;

X O;

R7 (C1-C10-alkylene-COOH, (C6-C10-alkylene-COO-(C1-C6)-alkyl, (C1-C10-alkylene-CONH2;

as well as their physiologically compatible salt,

this prevents the connection of the formula

In addition, the invention also concerns the use of compounds of formula I

where mean

A phenyl, naphthyl, and phenyl or naftalina group can contain up to three substituents, such as F, Cl, Br, OH, CF3, NO2CN, OCF3, O-(C1-C6)-alkyl, O-(C1-C 6)-alkenyl, O-(C1-C6)-quinil, S-(C1-C6)-alkyl, S-(C1-C6)-alkenyl, S-(C1-C6)-quinil, SO-(C1-C6)-alkyl, SO2-(C1-C6)-alkyl, SO2-NH2, (C1-C6)-alkyl, (C1-C6)-alkenyl, (C1-C6)-quinil, (C3-C7-cycloalkyl, (C3-C7-cycloalkyl-(C1-C4-alkylene, (C0-C6-alkylene-COOH, (C0-C6-alkylene-COO(C1-C6)-alkyl, CONH2, CONH(C1-C6)-alkyl, CON[(C1-C6)-alkyl]2, CONH(C3-C7-cycloalkyl, (C0-C6-alkylene-NH2, (C0-C6-alkylene-NH(C1-C6)-alkyl, (C0-C6-alkylene-N[(C1-C6)-alkyl]2, NH-CO-(C1-C6)-alkyl, NH-CO-phenyl, NH-SO2-phenyl, with phenyl ring may bear up to two substituents, such as F, Cl, CN, OH, (C1-C6)-alkyl, O-(C1-C6)-alkyl, CF3, OCF3, COOH, COO(C1-C6)-alkyl or CONH2;

R1, R2 independently from each other signify H, (C1-C6)-alkyl, O-(C1-C6)-alkyl, CO-(C1-C6)-alkyl, COO-(C1-C6)-alkyl, (C1-C6-alkylene-COOH, (C1-C6-alkylene-COO-(C1-C6)-alkyl;

R3, R4, R5, R6 independently of one another denote H, F, Cl, Br, OH, CF3, NO2CN, OCF3, O-(C1-C6)-Alki is, O-(C1-C6)-alkenyl, O-(C1-C6)-quinil, S-(C1-C6)-alkyl, S-(C1-C6)-alkenyl, S-(C1-C6)-quinil, SO-(C1-C6)-alkyl, SO2-(C1-C6)-alkyl, SO2-NH2, (C1-C6)-alkyl, (C1-C6)-alkenyl, (C1-C6)-quinil, (C3-C7-cycloalkyl, (C3-C7-cycloalkyl-(C1-C4-alkylen, COOH, COO(C1-C6)-alkyl, CONH2, CONH(C1-C6)-alkyl, CON[(C1-C6)-alkyl]2, CONH(C3-C7-cycloalkyl, NH2, NH(C1-C6)-alkyl, N[(C1-C6)-alkyl]2, NH-CO-(C1-C6)-alkyl, NH-CO-phenyl, NH-SO2-phenyl, and the phenyl ring may contain up to two substituents, such as F, Cl, CN, OH, (C1-C6)-alkyl, O-(C1-C6)-alkyl, CF3, OCF3, COOH, COO(C1-C6)-alkyl or CONH2;

X is O, S;

R7 (C1-C10-alkylene-COOH, (C1-C10-alkylene-COO-(C1-C6)-alkyl, (C1-C10-alkylene-CONH2, (C1-C10-alkylene-CONH-(C1-C6)-alkyl, (C1-C10-alkylen-CON-[(C1-C6)-alkyl]2, (C1-C10-alkylene-NH2, (C1-C10-alkylene-NH(C1-C6)-alkyl, (C1-C10-alkylene-N[(C1-C6)-alkyl]2, (C1-C10-alkylen-B;

B (C3-C7)-C is cloaker, phenyl, pyrrolyl, imidazolyl, thiazolyl, azetidine, thienyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridyl or furyl, and cycloalkyl, phenyl, pyrrolyl, imidazolyl, thiazolyl, azetidine, thienyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridyl or furyl may contain up to two substituents, such as Cl, F, CN, CF3, OCF3, COOH, COO-(C1-C6)-alkyl, CONH2, CONH-(C1-C6)-alkyl, CON-[(C1-C6)-alkyl]2, (C1-C6)-alkyl, OH, O-(C1-C6)-alkyl;

as well as their physiologically compatible salts to obtain drugs to reduce blood sugar levels and diabetes type II.

The invention includes compounds of formula I in the form of their racemates, racemic mixtures and pure enantiomers, and their diastereoisomers and mixtures thereof.

Alkyl groups in the substituents R1, R2, R3, R4, R5, R6, R7, A and B can be both linear and branched.

For applications in medicine especially suitable pharmaceutically acceptable salts due to their high water solubility compared to the parent compounds. These salts must be pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable salts of accession acid compounds according to the invention are salts of inorganic acids such as hydrochloric acid, bromatologia the acid, phosphoric, metaphosphoric, nitric acid, sulfonic and sulfuric acids, and organic acids such as acetic acid, benzosulfimide, benzoic acid, citric acid, econsultancy, fumaric, piknova and glycolic acid, sotynova, lactic, lactobionic, maleic, malic, methansulfonate, succinic, p-toluensulfonate and tartaric acid. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (e.g. sodium and potassium salts) and alkaline earth metals (e.g. magnesium and calcium).

Salts with a pharmaceutically unacceptable anion, such as trifurcation, are also covered by the framework of the invention as a necessary intermediate products to obtain or purification of pharmaceutically acceptable salts and/or for use in non-therapeutic purposes, for example for use in vitro.

Used herein, the term "physiologically active derivative" means any physiologically compatible derivative compounds of formula I according to the invention, for example an ester, which when administered to a mammal, such as man, in the state (directly or indirectly) to form a compound of formula I or an active metabolite.

To physiologically active derivatives also include prodrugs of the compounds according to the invention, for example, described H. Okada and others, Chem. Pharm. Bull. 1994, 42, 57-61. Such prodrugs can be metabolized in vivo to compounds according to the invention. These prodrugs can be both effective and ineffective.

Compounds according to the invention can exist in different polymorphic forms, for example as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds according to the invention are covered by the invention are the object of the present invention.

Hereinafter all references to "compound(I) of formula I" are treated as compound(s) of formula I, as described above, and their salts, solvate and physiologically functional derivatives.

The amount of the compounds of formula I required to achieve the desired biological effect depends on a number of factors, for example the specific compound, intended use, type of administration and the clinical condition of the patient. In General, the daily dose is in the range from 0.3 to 100 mg (typically from 3 to 50 mg) per day per kilogram of body weight, for example 3-10 mg/kg/day. An intravenous dose may be, for example, from 0.3 to 1.0 mg/kg, with the infusion of a suitable dose is from 10 to 100 ng per kilogram per minute. Suitable for this purpose solutions for injection may contain, for example, from 0.1 ng to 10 mg, (usually from 1 ng to 10 mg) on Miller the Tr solution. Single doses may contain, for example, from 1 mg to 10 g of the active substance. Thus, ampoules for injection may contain, for example, from 1 mg to 100 mg, and the value of a single oral input dose, for example tablets or capsules, may contain, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg For the treatment of the above diseases can be applied to the compounds of formula I directly as connection, however, it is preferable to apply them with appropriate filler in the form of pharmaceutical compositions. The filler should be, of course, compatible in the sense that it is compatible with other components of the composition and not injurious to health of the patient. The filler may be either solid or liquid or both and is preferably used together with the compound in a single dose, for example in the form of tablets which may contain from 0.05% to 95% by weight. the active substance. There may be also other pharmaceutically active agents, including other compounds of formula I. the Pharmaceutical compositions according to the invention can be obtained by any of the known pharmaceutical methods, which basically is to mix a composite part with a pharmaceutically compatible excipient and/or auxiliary substances.

Pharmaceutical to the position according to the invention suitable for oral, rectal, local, oral (e.g., under the tongue) and parenteral (e.g. subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable methods of application in each case depend on the type and severity of the condition of the patient and on the type of the applied compounds of formula I. Index finished dosage forms and index prolonged dosage forms also apply to the present invention. The preferred finished dosage forms, resistant to acids and gastric juice. Suitable membranes that are resistant to gastric juice, cover acetated cellulose, polyvinylacetate, phthalate of hydroxypropylmethylcellulose and anionic polymers of methacrylic acid and methyl methacrylate.

Pharmaceutically suitable compounds for oral administration can be produced in the form of individual doses, for example in the form of capsules, capsule shell, sucking tablets or tablets that contain a certain amount of the compounds of formula I; and also in the form of powder or granules; as solution or suspension in aqueous or non-aqueous medium; or in the form of an emulsion oil-in-water" or "water in oil". These composition can be prepared, as already indicated, any suitable pharmaceutical method, providing the stage at the cat the rum active substance and the filler (which may consist of one or more additional components) are brought into contact. In General, the composition passes through a uniform and homogeneous mixing of the active substance with a liquid and/or pulverized solid filler, and then, if necessary, the molded product. So can be obtained, for example, tablets, when the powder or granules of the compound is extruded or molded, if necessary, with one or more additional components. Molded tablets can be obtained by tableting the compound being in free flowing form such as powder or granules, optionally mixed with a binder, a softening agent, an inert diluent and/or one (several) of surface-active/dispersing agent in a suitable apparatus. Molded tablets can be obtained by molding the powdered compound moistened with an inert liquid diluent in a suitable apparatus.

For pharmaceutical compositions which are suitable for oral administration (under the tongue)are sucking tablets which contain a compound of formula I with a flavoring agent, is commonly sucrose and gum Arabic or tragant, and lozenges, which include compounds in an inert basis such as gelatin and glycerin, or sucrose and gum Arabic.

To pharmaceutical compositions suitable for parenteral administration include predpochtitelno sterile aqueous compositions of the compounds of formula I, which preferably is isotonic with the blood of the intended recipient. These songs are mainly used intravenously, but may also be made subcutaneously, intramuscularly or intradermally in the form of injections. These compositions can be preferably obtained by mixing with water, sterilizing the resulting solution and give it isotonic with the blood of properties. Composition for injection according to the invention contain, as a rule, from 0.1 to 5% by weight of the active compounds.

Pharmaceutical compositions suitable for rectal, offered preferably in the form of a unit dose suppositories. They can be obtained by mixing the compounds of formula I with one or more conventional solid fillers, for example cocoa butter, and shaping the resulting mixture.

Pharmaceutical compositions suitable for topical application to the skin, preferably offered in the form of ointment, cream, lotion, paste, spray, aerosol or oil. The filler may be lanolin, polyethylene glycol, alcohol, or a combination of two or more of these substances. The concentration of the active substance is usually from 0.1 to 15% by weight of the composition, for example from 0.5 to 2%.

It is also possible transdermal application. Pharmaceutical compositions suitable for transdermal applications, can be the ideal patches, suitable for prolonged close contact with the epidermis of the patient. These patches contain a suitable active substance, optionally buffered aqueous solution, dissolved and/or dispersed in an adhesive or dispersed in the polymer. A suitable concentration of the active substance is from about 1% to 35%, preferably from about 3% to 15%. According to the special form of the introduction of the active substance may be released by electrophoresis or iontophoresis, as described, for example, in Pharmaceutical Research, 2(6): 318 (1986).

A further object of the invention is a method of obtaining compounds of General formula I, characterized in that compounds of the formula I get according to the following reaction scheme:

For this purpose, compounds of General formula II

in which

R8 means (C1-C10-alkylene-COO(PG-1), (C6-C10-alkylene-COO-(C1-C6)-alkyl, (C1-C10-alkylen-CON-(PG-2)2, (C1-C10-alkylene-CONH-(C1-C6)alkyl, (C1-C10-alkylen-CON-[(C1-C6)-alkyl]2, (C1-C10-alkylen-N-(PG-2)2, (C1-C10-alkylene-NH(C1-C6)-alkyl, (C1-C10-alkylene-N[(C1-C6)-alkyl]2, (C1-C10-alkylen-B'

where PG-1 means known is th for protective ester group, for example (C1-C6)-alkyl, benzyl or p-methoxybenzyl, and

PG-2 is a known protective group for the amino group, for example (C1-C6-alkylsulphonyl, (C1-C6-allyloxycarbonyl or (C6-C12)-aryl-(C1-C4-allyloxycarbonyl, which only replaces one or both of the hydrogen atoms of an amino group,

B' (C3-C7-cycloalkyl, (C3-C7-cycloalkyl-(C1-C4-alkylene, phenyl, pyrrolyl, imidazolyl, thiazolyl, azetidine, thienyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridyl and furyl, and cycloalkyl, phenyl, pyrrolyl, imidazolyl, thiazolyl, azetidine, thienyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridyl and furyl may bear up to two substituents, such as Cl, F, CN, CF3, OCF3, COO-(PG-1), COO-(C1-C6)-alkyl, CON-(PG-2)2, CONH-(C1-C6)-alkyl, CON-[(C1-C6)-alkyl]2, (C1-C6)-alkyl, O-(PG-3), O-(C1-C6)-alkyl,

where PG-3 denotes a known protective group for an alcohol, such as benzyl, carbonyl, tetrahydropyranyl or tetrahydrofuranyl,

and

LG - known removable group, for example halogen, arylsulfonate or alkylsulfonate-,

alkylate with aniline General formula III

where X and PG-2 have the meanings described above, and

R9, R10, R11, R12 independently of one another OSN is given: H, F, Cl, Br, O-(PG-3), CF3, NO2CN, OCF3, O-(C1-C6)-alkyl, O-(C1-C6)-alkenyl, O-(C1-C6)-quinil, S-(C1-C6)-alkyl, S-(C1-C6)-alkenyl, S-(C1-C6)-quinil, SO-(C1-C6)-alkyl, SO2-(C1-C6)-alkyl, SO2-N-(PG-2)2, (C1-C6)-alkyl, (C1-C6)-alkenyl, (C1-C6)-quinil, (C3-C7-cycloalkyl, (C3-C7-cycloalkyl-(C1-C4-alkylene, COO-(PG-I), COO(C1-C6)-alkyl, CON-(PG-2)2, CONH(C1-C6)-alkyl, CON[(C1-C6)-alkyl]2, CONH(C3-C7-cycloalkyl, N-(PG-2)2, NH(C1-C6)-alkyl, N[(C1-C6)-alkyl]2, NH-CO-(C1-C6)-alkyl, NH-CO-phenyl, NH-SO2-phenyl, and the phenyl ring may bear up to two substituents, such as F, Cl, CN, O-(PG-3), (C1-C6)-alkyl, O-(C1-C6)-alkyl, CF3, OCF3, COO-(PG-1), COO(C1-C6)-alkyl, or CON-(PG-2)2;

R13 is H, (C1-C6)-alkyl, O-(C1-C6)-alkyl, CO-(C1-C6)-alkyl, COO-(C1-C6)-alkyl, (C1-C6-alkylene-COO-(PG-1), (C1-C6-alkylene-COO-(C1-C6)-alkyl,

and PG-1, PG-2 and PG-3 have the meanings described above in the presence of a base, for example potassium carbonate or cesium, in an organic solvent, for example acetone or dimethylformamid the de, obtaining compounds of General formula IV

where X, R8, R9, R10, R11, R12, R13 and PG-2 have the above values, the reaction time ranges from 2 to 24 hours and the reaction temperature is from 10°C to the boiling point of the used solvent, followed by selective removal of the protective group PG-2 receives the connection of General formula V

where X, R8, R9, R10, R11, R12 and R13 have the abovementioned meanings, compounds of General formula V is subjected to interaction with isocyanates of General formula VI

where

A' is phenyl, naphthyl, and phenyl or naftalina group can have up to three substituents, such as F, Cl, Br, O-(PG-3), CF3, NO2CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkenyl, O-(C1-C6)-quinil, S-(C1-C6)-alkyl, S-(C1-C6)-alkenyl, S-(C1-C6)-quinil, SO-(C1-C6)-alkyl, SO2-(C1-C6)-alkyl, SO2-N-(PG-2)2, (C1-C6)-alkyl, (C1-C6)-alkenyl, (C1-C6)-quinil, (C3-C7-cycloalkyl, (C3-C7-cycloalkyl-(C1-C4-alkylene, (C0-C6-alkylene-COO-(PG-1), (C0-C6-alkylene-COO(C1-C6)-alkyl, CON-(PG-2)2, CONH(C1-C6)-alkyl, CON[(C1-C6)-alkyl]2, CONH(Csub> 3-C7-cycloalkyl, (C0-C6-alkylen-N-(PG-2)2, (C0-C6-alkylene-NH(C1-C6)-alkyl, (C0-C6-alkylene-N[(C1-C6)-alkyl]2, NH-CO-(C1-C6)-alkyl, NH-CO-phenyl, NH-SO2-phenyl, with phenyl ring may bear up to two substituents, such as F, Cl, CN, O-(PG-3), (C1-C6)-alkyl, O-(C1-C6)-alkyl, CF3, OCF3, COO-(PG-1), COO(C1-C6)-alkyl, or CON-(PG-2)2,

while PG-1, PG-2 and PG-3 have the above values

in an anhydrous organic solvent, for example benzene, toluene or acetonitrile, in the atmosphere of inert gas at the reaction temperature between 10°C and the boiling point of the used solvent to obtain compounds of General formula VII

in which X, R8, R9, R10, R11, R12, R13 and A' have the above meanings, compounds of General formula VII, if R1 in the compounds of General formula I is not a hydrogen atom, alkylate by reacting with compounds of General formula VIII

where LG has the above value, and

R14 is H, (C1-C6)-alkyl, O-(C1-C6)-alkyl, CO-(C1-C6)-alkyl, COO-(C1-C6)-alkyl, (C1-C6-alkylene-COO-(PG-1), (C1-C6-alkylene-COO-(C1-C6)-alkyl,

and PG-1 has the meaning described is use,

using a base, for example,

1,8-diazabicyclo[5.4.0]-undec-7-ene, in an organic solvent, for example dichloromethane or acetonitrile, to obtain the compounds of General formula IX

where X, R8, R9, R10, R11, R12, R13, R14 and A' have the meanings described above, and after the well-known from the literature for the removal of all possible protective groups in the residues R8, R9, R10, R11, R12, R13, R14, A' and B' obtain compounds of General formula I. the Transfer of compounds of General formula I in its salt is adding the equivalent of the appropriate acid or base in an organic solvent, such as acetonitrile or dioxane, or in the water and by subsequent removal of solvent.

Another possibility of obtaining compounds of General formula I, where R2 is a hydrogen atom, shown in the following diagram:

thus compounds of General formula V in which R2 means a hydrogen atom,

and X, R8, R9, R19, R11 and R12 have the above values into the isocyanates of General formula X

by known methods, for example, the interaction with oxalylamino in organic solvents, such as 1,2-dichloroethane or dichloromethane, at a reaction temperature between room temperature and the boiling point of the solvent,

p> the isocyanates of General formula X is introduced into reaction with inorganic salts of General formula XI

where A' has the above meaning,

and obtain compounds of General formula VII where R2 means a hydrogen atom,

and X, R8, R9, R10, R11 and R12 have the above values.

If R1 is not a hydrogen atom, compounds of General formula VII may be converted, as already described above, by alkylation with compounds of General formula VIII with obtaining compounds of General formula IX, and, if necessary, followed by removal of protective groups in compounds of General formula I. the transfer of the compounds of General formula I and their salts is adding the equivalent of the appropriate acid or base in an organic solvent, such as acetonitrile or dioxane, or in the water and by subsequent removal of solvent.

The following examples serve to illustrate the invention, but without limiting it. The measured melting point (MP) or decomposition has not been adjusted in the General case depend on the heating rate. (see table 1).

td align="center"> 6-H
Table 1

Examples

< / br>
The formula I
Ave. No.AR1R2R3 R4R5R6R7XSolMP (°C)MS*
1phenyl-2-ClHH2-H3-Cl6-H5-Cl(CH2)5-COOH4-O-164Yes
2phenyl-2-ClHH2-H3-Cl6-H5-Cl(CH2)5-COONa4-O-177-179Yes
3phenyl-2-ClHH2-H3-Cl6-H5-Cl(CH2)5-COOH4-Obis-2-hydroxyethylaminoYes
4phenyl-2-ClHH2-H3-Cl6-H5-Cl(CH2)5-COOH4-O3-hydroxy-1-(2-hydroxyethyl)-1-hydroxymethyl-Propylamine163-165Yes
5phenyl-2-ClHH2-H3-Cl6-H5-Cl(CH2)5/sub> -COOH4-Olysine170-172Yes
6phenyl-2-ClHH2-H3-Cl6-H5-HCH2COOCH34-S-168-169Yes
7phenyl-2,6-F2HHHHHHCH2COOCH34-S-152Yes
8phenylHHHHHH4-Ofumaric acid182Yes
9phenylCH3HHHHH4-OHCI82Yes
10phenyl-2-ClHCOCH32-H3-Cl6-H5-Cl(CH2)5-COOH4-O-137-139Yes
11 phenylHH2-H3-Cl6-H5-Cl(CH2)5-COOH4-O-189-191Yes
12phenyl-2,4-Cl2HH2-H3-Cl6-H5-Cl(CH2)S-COOH4-O-202-204Yes
13phenyl-2-ClHH2-H3-Cl6-H5-Cl(CH2)5-COOC2H54-O-119-121Yes
14phenyl-4-OCH3HH2-H3-Cl6-H5-Cl(CH2)5-COOH4-O-188-190Yes
15phenyl-3-FHH2-H3-Cl6-H5-Cl(CH2)5-COOH4-O-210-214Yes
16phenyl-2-FHH2-H3-Cl6-H/td> 5-Cl(CH2)5-COOH4-O_147-151Yes
17phenyl-2-OCH3HH2-H3-Cl6-H5-Cl(CH2)5-COOH4-O-149-153Yes
18phenyl-2,3-Cl2HH2-H3-Cl6-H5-Cl(CH2)5-COOH4-O-170-172Yes
19phenyl-2-FHHHHHH4-S-139-143
20phenyl-2,6-F2HHHHHH4-S-162-163
21phenyl-2,6-F2HH2-H3-Cl6-H5-Cl4-S -152
22phenyl-2-ClHHHHHHCH2-COOCH34-S-125-126
23phenyl-3-OCH3HH2-H3-Cl6-H5-Cl(CH2)5-COOH4-O-136Yes
24phenyl-2,4-Cl2HH2-H3-Cl6-H5-Cl4-O-189Yes
25phenyl-3-FHH2-H3-Cl6-H5-Cl4-O-204Yes
26phenyl-2,3-Cl2HH2-H3-Cl6-H5-Cl4-O-182Yes
27phenyl-3-OCH3/sub> HH2-H3-Cl6-H5-Cl4-O-176Yes
28phenyl-2-FHH2-H3-Cl6-H5-Cl4-O-144Yes
29phenylHH2-H3-Cl6-H5-Cl4-O-204Yes
30phenyl-4-OCH3HH2-H3-Cl6-H5-Cl4-OTFAYes
31phenyl-2-OCH3HH2-H3-Cl6-H5-Cl4-OTFAYes
32phenyl-2-ClHH2-H3-Cl5-Cl(CH2)3-COOH4-O-Yes
33phenyl-2-ClHH2-H3-Cl6-H5-Cl(CH2)4-COOH4-O-Yes
34phenyl-2-ClHH2-H3-Cl6-H5-Cl(CH2)6-COOH4-O-Yes
35phenyl-2-ClHH2-H3-Cl6-H5-Cl(CH2)7-COOH4-O-Yes
36phenyl-2-ClCH3H2-H3-Cl6-H5-Cl(CH2)5-COOH4-O-Yes
37phenyl-2-ClHH2-H3-Cl6-H5-Cl(CH2)3-COOH4-O3-hydroxy-1-(2-hydroxyethyl)-1-hydroc imethyl-Propylamine Yes

H (CH2)5-COOH
38phenyl-2-ClHH2-H3-Cl6-H5-Cl(CH2)4-COOH4-O3-hydroxy-1-(2-hydroxyethyl)-1-hydroxymethyl-PropylamineYes
39phenyl-2-ClHH2-H3-Cl6-H5-Cl(CH2)6-COOH4-O3-hydroxy-1-(2-hydroxyethyl)-1-hydroxymethyl-PropylamineYes
40phenyl-2-ClHH2-H3-Cl6-H5-Cl(CH2)7-COOH4-O3-hydroxy-1-(2-hydroxyethyl)-1-hydroxymethyl-PropylamineYes
41phenyl-2,4-Cl2HH2-H3-Cl6-H5-Cl(CH2)3-COOH4-O3-hydroxy-1-(2-hydroxyethyl)-1-hydroxymethyl-PropylamineYes
42phenyl-2,4-Cl2H2-H3-Cl6-H5-Cl(CH2)4-COOH4-O3-hydroxy-1-(2-hydroxyethyl)-1-hydroxymethyl-PropylamineYes
43phenyl-2,4-Cl2HH2-H3-Cl6-H5-Cl(CH2)6-COOH4-O3-hydroxy-1-(2-hydroxyethyl)-1-hydroxymethyl-PropylamineYes
44phenyl-2,4-Cl2HH2-H3-Cl6-H5-Cl(CH2)7-COOH4-O3-hydroxy-1-(2-hydroxyethyl)-1-hydroxymethyl-PropylamineYes
45phenyl-2-ClHH2-H3-Cl6-H5-Cl4-OHCIYes
46phenyl-2,4-Cl2HH2-H3-Cl6-H5-Cl4-OHCI 182Yes
47phenyl-2-CH3HH2-H3-Cl6-H5-Cl(CH2)5-COOH4-O3-hydroxy-1-(2-hydroxyethyl)-1-hydroxymethyl-PropylamineYes
48phenyl-4-CH3HH2-H3-Cl6-H5-Cl(CH2)5-COOH4-O3-hydroxy-1-(2-hydroxyethyl)-1-hydroxymethyl-PropylamineYes
49phenyl-3-CH3HH2-H3-Cl6-H5-Cl(CH2)5-COOH4-O3-hydroxy-1-(2-hydroxyethyl)-1-hydroxymethyl-PropylamineYes
50phenyl-4-FHH2-H3-Cl6-H5-Cl(CH2)5-COOH4-O3-hydroxy-1-(2-hydroxyethyl)-1-hydroxymethyl-PropylamineYes
51phenyl-3-ClHH2-H3-Cl 6-H5-Cl(CH2)5-COOH4-O3-hydroxy-1-(2-hydroxyethyl)-1-hydroxymethyl-PropylamineYes
52phenyl-2-ClHH2-H3-Cl6-H5-Cl(CH2)5-COOK4-O-Yes
53phenyl-4-BrHH2-H3-Cl6-H5-Cl(CH2)S-COOH4-O3-hydroxy-1-(2-hydroxyethyl)-1-hydroxymethyl-PropylamineYes
54phenylHH2-H3-Cl6-H5-Cl(CH2)5-COOH4-O3-hydroxy-1-(2-hydroxyethyl)-1-hydroxymethyl-Propylamine172Yes
55phenyl-3-FHH2-H3-Cl6-H5-Cl(CH2)5-COOH4-O3-hydroxy-1-(2-hydroxyethyl)-1-hydroxymethyl-Propylamine170Yes
56the dryer is l-2-OCH 3HH2-H3-Cl6-H5-Cl(CH2)5-COOH4-O3-hydroxy-1-(2-hydroxyethyl)-1-hydroxymethyl-Propylamine119Yes
57phenyl-2,3-Cl2HH2-H3-Cl6-H5-Cl(CH2)5-COOH4-O3-hydroxy-1-(2-hydroxyethyl)-1-hydroxymethyl-Propylamine160Yes
58phenyl-4-ClHH2-H3-Cl6-H5-Cl(CH2)5-COOH4-O3-hydroxy-1-(2-hydroxyethyl)-1-hydroxymethyl-PropylamineYes
59phenyl-2,4-Cl2HH2-H3-Cl6-H5-Cl(CH2)5-COOH4-O3-hydroxy-1-(2-hydroxyethyl)-1-hydroxymethyl-PropylamineYes
60phenyl-2-CH3HH2-H3-Cl6-H5-Cl(CH2)3 -COOH4-O-207Yes
61phenyl-2-CH3HH2-H3-Cl6-H5-Cl(CH2)4-COOH4-O-167Yes
62phenyl-2-CH3HH2-H3-Cl6-H5-Cl(CH2)6-COOH4-O-185Yes
63phenyl-2-CH3HH2-H3-Cl6-H5-Cl(CH2)7-COOH4-O-153Yes
64phenyl-2,4-Cl2HH2-H3-F6-H5-H(CH2)3-COOH4-O.Yes
65phenyl-2,4-Cl2HH2-H3-F6-H5-H(CH2)4-COOH4-O.Yes
66 phenyl-2,4-Cl2HH2-H3-F6-H5-H(CH2)5-COOH4-O-Yes
67phenyl-2,4-Cl2HH2-H3-F6-H5-H(CH2)6-COOH4-O-Yes
68phenyl-2,4-ClzHH2-H3-F6-H5-H(CH2)7-COOH4-O-Yes
69phenyl-2,4-Cl2HH2-CH34-H6-H5-H(CH2)3-COOH3-O-Yes
70phenyl-2,4-Cl2HH2-CH34-H6-H5-H(CH2)4-COOH3-O-Yes
71phenyl-2,4-Cl2HH2-CH3 4-H6-H5-H(CH2)5-COOH3-O-Yes
72phenyl-2,4-Cl2HH2-CH34-H6-H5-H(CH2)6-COOH3-O-Yes
73phenyl-2,4-Cl2HH2-CH34-H6-H5-H(CH2)7-COOH3-O-Yes
74phenyl-2,4-Cl2HH2-CH33-H6-H5-H(CH2)3-COOH4-O-Yes
75phenyl-2,4-Cl2HH2-CH33-H6-H5-H(CH2)4-COOH4-O-Yes
76phenyl-2,4-Cl2HH2-CH33-H6-H5-H4-O-Yes
77phenyl-2,4-Cl2HH2-CH33-H6-H5-H(CH2)6-COOH4-O-Yes
78phenyl-2,4-Cl2HH2-CH33-H6-H5-H(CH2)7-COOH4-O-Yes
79phenyl-2,4-Cl2HH2-H3-CH36-H5-CH3(CH2)3-COOH4-O-Yes
80phenyl-2,4-Cl2HH2-H3-CH36-H5-CH3(CH2)4-COOH4-O-Yes
81phenyl-2,4-Cl2HH2-H3-CH36-H5-CH3(CH2)5-COOH 4-O-Yes
82phenyl-2,4-Cl2HH2-H3-CH36-H5-CH3(CH2)6-COOH4-O-Yes
83phenyl-2,4-Cl2HH2-H3-CH36-H5-CH3(CH2)7-COOH4-O-Yes
84phenyl-2,4-Cl2HHHHHH(CH2)3-COOH3-O-Yes
85phenyl-2,4-Cl2HHHHHH(CH2)4-COOH3-O-Yes
86phenyl-2,4-Cl2HHHHHH(CH2)5-COOH3-O-Yes
87phenyl-2,4-Cl2HHHHHH(CH2)7-COOH3-O-Yes
88phenyl-2,4-Cl2HHHHHH(CH2)3-COOH4-O-Yes
89phenyl-2,4-Cl2HHHHHH(CH2)4-COOH4-O-Yes
90phenyl-2,4-Cl2HHHHHH(CH2)S-COOH4-O-Yes
91phenyl-2,4-Cl2HHHHHH(CH2)6-COOH4-O-Yes
92phenyl-2,4-Cl2HHHH HH(CH2)7-COOH4-O-Yes
93phenyl-3,4-Cl2HH2-H3-Cl6-H5-Cl(CH2)5-COOH4-O-Yes
94phenyl-2,4-Cl2HH2-H.3-Cl6-H5-Cl4-OHClYes
95phenyl-3-FHH2-H3-Cl6-H5-Cl4-OHClYes
96phenyl-2,3-Cl2HH2-H3-Cl6-H5-Cl4-OHClYes
97phenyl-3-OCH3HH2-H3-Cl6-H5-Cl 4-OHClYes
98phenyl-2-FHH2-H3-Cl6-H5-Cl4-OHClYes
99phenylHH2-H3-Cl6-H5-Cl4-OHClYes
100phenyl-3-S02CH3HH2-H3-Cl6-H5-Cl(CH2)5-COOH4-O-Yes
101phenyl-2-SO2CH3HH2-H3-Cl6-H5-Cl(CH2)5-COOH4-O-Yes
102phenyl-2-Cl-4-SO2CH3HH2-H3-Cl6-H5-Cl(CH2)5-COOH4-O- Yes
103phenyl-2,4-(CHS)2HH2-H3-Cl6-H5-Cl(CH2)5-COOH4-O-Yes
104phenyl-4-Cl-2-FHH2-H3-Cl6-H5-Cl(CH2)5-COOH4-O-Yes
105phenyl-2-Cl-4-FHH2-H3-Cl6-H5-Cl(CH2)5-COOH4-O-Yes
106phenyl-4-COOCH3HH2-H3-Cl6-H5-Cl(CH2)5-COOH4-O-Yes
107phenyl-4-SO2CH3HH2-H3-Cl6-H5-Cl(CH2)5-COOH4-O-Yes
108phenyl-2-ClH 2-H3-Cl6-H5-Cl4-O-Yes
109phenyl-4-Cl-2-CH3HH2-H3-Cl6-H5-Cl(CH2)5-COOH4-O-Yes
110phenyl-3-F-4-N02HH2-H3-Cl6-H5-Cl(CH2)5-COOH4-O-Yes
111phenyl-2-COOCH3HH2-H3-Cl6-H5-Cl(CH2)5-COOH4-O-Yes
112phenyl-3-SOON3-5-NO2NN2-N3-Cl6-H5-Cl(CH2)5-COOH4-O-Yes
113phenyl-3-CF3NN2-N3-Cl6 Mr./td> 5-Cl(CH2)5The PINES4-O-Yes
114phenyl-2,4-Cl2NNNNNN(CH2)6-COOH3-O-Yes
115phenyl-2,4-Cl2NN2-N3-Cl6-H5-N(CH2)4-COOH4-O-Yes
116FINEP-2,4-Cl2NN2-F3-H6-H5-N(CH2)S-COOH4-O-Yes
117phenyl-4-CF3NN2-N3-Cl6-H5-Cl(CH2)5-COOH4-O-Yes
118phenyl-2-ClNN2-N3-Cl6-H5-Cl(CH2)5-CONH2 4-O-Yes
119FINEP-2,4-Cl2NN2-CH33-H6-CH35-N(CH2)4-COOH4-O-Yes
120phenyl-2,4-Cl2NN2-N4-CH36-H5-N(CH2)4-COOH3-O-Yes
121phenyl-2,4-Cl2NN2-N4-och36-H5-N(CH2)4-COOH3-O-Yes
122phenyl-2,4-Cl2NN2-N3 SOON36-H5-N(CH2)4-COOH4-O-Yes
123phenyl-2,4-Cl2NN2-Cl3-N6-H5-N(CH2)4-COOH4-O -Yes
124phenyl-2,4-Cl2NN2-N3-ZyXEL6-H5-N(CH2)4-COOH4-O-Yes
125phenyl-2,4-Cl2NN2-CH33-CH36-H5-N(CH2)4-COOH4-O-Yes
126phenyl-2,4-Cl2NN2-CH33-N6-CH35-N(CH2)5-COOH4-O-Yes
127phenyl-2,4-Cl2NN2-N4-CH36-H5-N(CH2)5-COOH3-O-Yes
128phenyl-2,4-Cl2NN2-N4-och36-H5-N(CH2)5-COOH3-O -Yes
129FINEP-2,4-Cl2NN2-N3 SOON36-H5-N(CH2)5-COOH4-O-Yes
130phenyl-2,4-Cl2NN2-Cl3-N6-H5-N(CH2)5-COOH4-O-Yes
131phenyl-2,4-Cl2NN2-N3-ZyXEL6-H5-N(CH2)5-COOH4-O-Yes
132phenyl-2,4-Cl2NN2-CH33-N6-H5-CH3(CH2)5-COOH4-O-Yes
133phenyl-2,4-Cl2NN2-CH33-CH36-H5-N(CH2)5-COOH4-O Yes
134phenyl-2,4-Cl2NN2-CH33-N6-CH35-N(CH2)7-COOH4-O-Yes
135FINEP-2,4-Cl2NN2-N4-CH36-H5-N(CH2)7-COOH3-O-Yes
136phenyl-2,4-Cl2NN2-N4-och36-H5-N(CH2)7-COOH3-O-Yes
137phenyl-2C4-Cl2NNC-N3 SOON36-H5-N(CH2)7-COOH4-O-Yes
1C8phenyl-2,4-Cl2HCN2-Cl3-C6-H5-N(CH2)7-COOH4-O-Yes
139phenyl-2,4-Cl2NN2-CH33-N6-H5-CH3(CH2)7-COOH4-O-Yes
140phenyl-2,4-CC2NN2-CH33-CH36-H5-N(CH2)7-COOH4-O-Yes
141phenyl-2,4-Cl2NN2-CH33-N6-CH35-N(CH2)3-COOH4-O-Yes
142phenyl-2,4-Cl2NN2-N4-CH36-H5-N(CH2)3-CCOH3-O-Yes
143phenyl-2,4-Cl2NN2-N4-och36-H5-N(CH2)3-COOH3-O CYes
144Cphenyl-2,4-Cl2NN2-N3 SOON36-H5-N(CH2)3-CCOH4-O-Yes
145phenyl-2,4-Cl2NN2-Cl3-N6-H5-N(CH2)3-COOH4-O-Yes
C46phenyl-2,4-Cl2NN2-N3-ZyXEL6-H5-N(CH2)3-COOH4-O-Yes
147phenyl-2,4-Cl2NN2-CH33-N6-H5-CH3(CH2)3-COOH4-O-Yes
148phenyl-2,4-Cl2NC2-CH33-CH36-H5-N(CH2)3-COOH4-O Yes
149phenyl-2,6-Cl2NN2-N3-Cl6-H5-Cl(CH2)5CCOOH4-O-Yes
150phenyl-6-Cl-3-COOHNN2-N3-Cl6-H5-Cl(CH2)3-COOH4-O-Yes
151phenyl-2,4-Cl2NN2-CH34-H6-H5-N(CH2)4-COOH3-Obis-2-hydroxyethylaminoYes
152phenyl-2,4-Cl2HH2-Cl3-H6-H5-H(CH2)3-COOH4-Obis-2-hydroxyethylaminoYes
153phenyl-2,4-Cl2HH2-CH33-CH36-H5-H(CH2)3-COOH4-Obis-2-hydroxyethylamino Yes
154phenyl-2,4-Cl2HH2-H4-OCH36CH5-H(CH2)2-N-(C2H5)23-O-Yes
155phenyl-2,4-Cl2HHHHHH(CH2)2-N-(C2H5)24-O-Yes
* In the column "MC" under "Yes" means that the mass spectrum of the measured and detected molar peak (mol. weight + H+).

The compounds of formula I are different beneficial effects on sugar metabolism, in particular they lower the blood sugar and is suitable for the treatment of type II diabetes. Connections can be used both independently and in combination with other lower sugar level active substances. Such lower blood sugar active substances are, for example, sulfonylurea (e.g., glimepiride, glyburide), Gleason (for example, troglitazone, rosiglitazone), an inhibitor of alpha-glucosidase (e.g., acarbose, miglitol) or insulin.

<> The effectiveness of the compounds was tested as follows:

Test for the activity of glycogen phosphorylase a

The influence of compounds on the activity of the active form of glycogen phosphorylase (GFA) was measured in the reverse direction, by monitoring the synthesis of glycogen from glucose-1-phosphate by determining the release of inorganic phosphate. All reactions were carried out with double determination in 96-well tablets for micrometrology (Half Area Plates, Costar Nr. 3696), with the help of the device Multiskan Ascent Elisa Reader (Lab Systems, Finland) were measured by the change in absorption at a certain wavelength as a result of formation of the reaction product. To change the enzyme activity GFA in the opposite direction, the conversion of glucose-1-phosphate C glycogen and inorganic phosphate was measured by the General method of Angers and others (Engers H.D., Shechosky S., Madsen N.B., Can. J. Biochem. 1970 Jul; 48(7):746-754) with the following modifications: human glycogenolysis a (for example, 0,76 mg protein/ml, (Aventis Pharma Deutschland GmbH)dissolved in a buffer solution E (25 mm β-glycerol, pH 7.0, 1 mm EDTA and 1 mm dithiothreitol) was diluted with buffer T (50 mm Hepes, pH 7.0, 100 mm KCl, 2.5 mm EDTA, 2.5 mm MgCl2·6H2O) and by adding 5 mg/ml glycogen concentrations up to 10 µg protein/ml Samples for testing were prepared as 10 mm solution in DMSO and diluted to 50 mm solution of buffer T. To 10 ml of this is about solution was added 10 ml of 37.5 mm glucose, dissolved in a buffer solution T, and 5 mg/ml glycogen, and 10 ml of a solution of human glycogen phosphorylase a (10 µg protein/ml) and 20 μl of glucose-1-phosphate, 2.5 mm. The basal level of activity of glycogen phosphorylase a in the absence of the test substance was determined by adding 10 μl of buffer solution T (0,1% DMSO). The mixture is incubated for 40 minutes at room temperature, and the released inorganic phosphate was measured using the General method of Druces and others (Drueckes P., Schinzel R, Palm D., Anal. Biochem 1995 Sep 1; 230(1): 173-177) with the following modifications: 50 ál stoppering solution of 7.3 mm ammonium molybdate, 10,9 mm zinc acetate, 3.6% of ascorbic acid, 0.9% of LTOs were added to 50 μl of a mixture of enzymes. After 60 minutes of incubation at 45°C was measured by the absorbance at 820 nm. To determine background absorbance in a separate sample immediately after injection of a solution of glucose-1-phosphate was added to a solution of the stopper. This test was conducted at concentrations of test substances 10 mm in order to determine the appropriate glycogen phosphorylase a in vitro inhibition due to the test substance. (see tab. 2).

147
Table 2

Biological activity
Etc.% inhibition at 10 µm
187
73
375
479
577
1292
2035
2978
3076
3186
4150
4411
4636
4746
4913
5136
5322
6036
7086
7541
8050
8444
8990
9034
10078
10193
10214
10635
11188
112100
116100
117A9
11870
11997
12040
12212
12895
88
14976

From table 2 it is seen that the compounds of formula I inhibit the activity of glycogen phosphorylase a and therefore are well suited for lowering blood sugar.

Here's an example, similar to that received from other compounds of formula I.

Experimental part

Example 1:

6-{(2,6-dichloro-4-[(2-chlorobenzoyl)aminocarbonyl]-phenoxy}hexanoic acid

a) ethyl ester of 6-(4-acetylamino-2,6-dichlorophenoxy) hexanoic acid

To a solution containing 15.0 g (68,1 mmol) N-(3,5-dichloro-4-hydroxyphenyl)ndimethylacetamide in 300 ml of acetone, add a 13.3 ml (74.9 mmol) of ethyl ester of 6-Bromhexine acid and 52.1 g (160 mmol) of cesium carbonate. The suspension is boiled for 8 hours under reflux. Then add 600 ml of water, extracted twice with adding each time with 400 ml of dichloromethane and 400 ml of MTB ether. The combined organic phases are washed with water and concentrated on a rotary evaporator. Product without any treatment served to the next stage. Crude yield: 30,

b) 6-(4-acetylamino-2,6-dichlorophenoxy)hexanoic acid

30 g of crude product obtained in stage a), combined with 800 ml of 1 M solution of potassium chloride and stirred for 3 days at room temperature. Then add 600 ml of water and add about 80 ml of glacial acetic sour the s brought to a pH of 5.5. The precipitated product is sucked off and washed twice using each time with 40 ml of water. The residue is dried under high vacuum and obtain 14.6 g of the desired compound.

c) 6-(4-amino-2,6-dichlorophenoxy)hexanoic acid

7.5 g (of 22.4 mmol) 6-(4-acetylamino-2,6-dichlorophenoxy)hexanoic acid added to 140 ml of a 1 M solution of potassium hydrochloride in a mixed solvent of methanol-water (3:1) and heated overnight under reflux. The methanol is removed on a rotary evaporator and the residue is diluted with water in an amount of about 30 ml and acidified with glacial acetic acid to pH 5. The mixture is stirred for 30 minutes in an ice bath and then sucked off. The crude product is separated on a chromatographic column using a mixture of n-heptane/ethyl acetate = 1/1 and obtain 4.3 g (14.7 mmol, 66%) of the desired product.

d) 6-{2,6-dichloro-4-[(2-chlorobenzoyl)aminocarbonyl]phenoxy}hexanoic acid

To a suspension of 10.0 g (a 34.2 mmol) 6-(4-amino-2,6-dichlorophenoxy)hexanoic acid in 700 ml of dry acetonitrile in the atmosphere of inert gas at room temperature, add a solution of 7.5 g (41,1 mmol) 2-chlorobenzenesulfonate in 300 ml of acetonitrile. Boiled for 2 hours under reflux and cooled to room temperature. The formed precipitate is sucked off and washed with 50 ml of acetonitrile. The residue is stirred with 100 ml of methanol, sucked off, washed with a small the quantity of methanol and dried overnight at 40° C under vacuum. Gain of 13.7 g (of 28.9 mmol, 85%) of the desired product. Melting point: 171-173°C.

1. The compounds of formula I

where A denotes phenyl, and the phenyl residue may be up to three-fold substituted by F, Cl, Br, CF3, NO2, O-(C1-C6)-alkyl, SO2-(C1-C6)-alkyl, (C1-C6)-alkyl, COOH;

R1 denotes H, (C1-C6)-alkyl;

R2 denotes H, (C1-C6)-alkyl,CO-(C1-C6)-alkyl;

R3, R4, R5, R6 independently of one another denote H, F, Cl, Br, O-(C1-C6)-alkyl, (C1-C6)-alkyl, (C3-C7-cycloalkyl, COOH, COO(C1-C6)-alkyl;

X represents O, S;

R7 means (C1-C10-alkylene-COOH, (C1-C10-alkylene-COO-(C1-C6)-alkyl, (C1-C10-alkylene-NH2, (C1-C10-alkylene-NH(C1-C6)-alkyl, (C1-C10-alkylene-N[(C1-C6)-alkyl]2, (C1-C10-alkylen-B;

B means piperidinyl or furyl;

and their physiologically acceptable salt,

this excludes the compounds of formula

as well as the compounds of formula I, where the remains of simultaneously mean

A-phenyl;

X-O;

R1 is H;

R7-(C1 -C4)-alkyl-B;

B-(C3-C7-cycloalkyl, heteroaryl.

2. The compounds of formula I according to claim 1, where

A denotes a phenyl, and the phenyl residue may be up to three-fold substituted by F, Cl, Br, O-(C1-C6)-alkyl,

R1 denotes H, (C1-C6)-alkyl;

R2 denotes H, (C1-C6)-alkyl,CO-(C1-C6)-alkyl;

R3, R4, R5, R6 independently of one another denote H, F, Cl, O-(C1-C6)-alkyl, (C1-C6)-alkyl, COO(C1-C6)-alkyl;

X represents O;

R7 means (C1-C10-alkylene-COOH, (C6-C10-alkylene-COO-(C1-C6)-alkyl;

and their physiologically acceptable salts, thus the compound of the formula

3. The pharmaceutical composition inhibiting the activity of glycogen phosphorylase containing one or more compounds according to claim 1 or 2.

4. Compounds according to claim 1 or 2 to obtain a pharmaceutical composition inhibiting the activity of glycogen phosphorylase.

5. Compounds according to claim 1 or 2 to obtain a pharmaceutical composition inhibiting the activity of glycogen phosphorylase, suitable for reducing blood sugar level.

6. Compounds according to claim 1 or 2 to obtain a pharmaceutical composition inhibiting the activity of glycogen phosphorylase, suitable for treatment is of type II diabetes.

7. A method of obtaining a pharmaceutical composition inhibiting the activity of glycogen phosphorylase in a form suitable for use, contains one or more compounds according to claim 1 or 2, characterized in that the active substance is mixed with pharmaceutically suitable excipient and the mixture result in a usable form.



 

Same patents:

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to compounds of formula I ,

where R(1), R(2), R(3), R(4), R(5), R(6), R(7), R(8), R(30), and R(31) are disclosed in claims. Compound of present invention are particularly useful as new antiarrythmia bioactive substances, in particular for treatment and prophylaxis of atrial arrhythmia (e.g., atrial fibrillation or auricular flutter).

EFFECT: higher efficiency.

13 cl, 18 ex, 1 tbl

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new biphenylsulfonylcyanamides of the formula (I): wherein R1 means: 1. (C1-C8)-alkyl; 4. -CnH2n-nn-Y wherein nn = 0 or 2 and n = 0-4, and n is not 0 or 1 if nn = 2; 5. CnH2n-nn-Y wherein nn = 0 or 2 and n = 1-4, and n is not 1 if nn = 2, and 1 hydrogen atom in bivalent residue CnH2n-nn is substituted with amino-group or NR(22)R(23); R2 means: 2. (C1-C)-alkyl; 4. (C2-C12)-alkenyl; 5. (C2-C8)-alkynyl; 6. -CnH2n-nn-Z wherein nn = 0 or 2; n = 0-4, and n is not or 1 if nn = 2; 7. -CnH2n-nn-Z wherein nn = 0 or 2; n = 1-4, and n is not 1 if nn = 2, and 1 hydrogen atom in bivalent residue CnH2n-nn is substituted with a residue taken among a series: 1. phenyl; 3. NR(22)R(23); 5. COOR(16); R3 and R4 mean hydrogen atom; R5, R6 and R7 mean independently of one another hydrogen atom (H), (C1-C8)-alkyl; SO2-(C1-C4)-alkyl, F, Cl, Br, J, OR(10) wherein R(10) means hydrogen atom, (C1-C4)-alkyl that is substituted if necessary with methoxy- or ethoxy-group; R(9) means OR(13) wherein R(13) means hydrogen atom, H,(C1-C8)-alkyl;X means carbonyl group, -CO-CO- or sulfonyl group; Y and Z mean independently of one another: 1. phenyl, 1-naphthyl, 2-naphthyl; 2. one of residues determined in cl. 1 substituted with 1-5 similar or different residues taken among a series: phenyl, F, Cl, Br, J, CF3, SOqR(18), OR(16), NR(19)R(20), -CN, NO2, COR(9), or two residues form methylenedioxy-group; 3. furyl, thienyl, pyridyl, benzimidazolyl, indolyl, benzothiophenyl, dihydroquinazolinyl; 5. (C3-C10)-cycloalkyl wherein cyclopropyl, cyclopentyl, cyclohexyl and indalyl are preferable; 6. one of residues determined in cl. 5 substituted with phenyl; R(16) means: 1. hydrogen atom; 2. (C1-C4)-alkyl; 3. (C1-C4)-alkyl substituted with (C1-C4)-alkoxy-group; R(19) and R(20) mean independently: hydrogen atom (H), (C1-C4)-alkyl; R(22) and R(23) mean independently of one another hydrogen atom (H) or CO-OR(24) wherein R924) means -CnH2n-phenyl wherein n = 1-4; q = 2; and their physiologically acceptable salts. Compound of the formula (I) inhibit sodium-dependent chloride-bicarbonate exchange "NCBE".

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

4 cl, 2 tbl, 568 ex

The invention relates to new derivatives of N, S-substituted N'-1-[(hetero)aryl] -N'-[(hetero)aryl] methylisothiazoline General formula I or their salts with pharmacologically acceptable acids HX in the form of a racemic mixture or in the form of a mixture of stereoisomers, which can be used for the treatment and prevention of diseases associated with dysfunction glutamatergic nanoperiodic

The invention relates to derivatives of 5-areolation formula I, where a represents-CH2-, -C(O)- or-S(O)2-; Z denotes a group of formula b or D:

< / BR>
where X is O or S; R6and R7independently from each other selected from the group including hydrogen, C1-C6alkyl, CF3WITH1-C6alkylthio,1-C6alkoxy, halogen, nitro, hydroxy, and-NR9R10where R9and R10independently of one another denote hydrogen or C1-C6alkyl; R1means hydrogen, C1-C6alkyl, C1-C6alkoxy, hydroxy2-C6alkyloxy, hydroxy, halogen, cyano, carboxy, co2SOP(CH3)2, -СОNR9R10, -ОСОNR9R10or ОSO2R11where R9and R10have the meanings indicated above, and R11means1-C6alkyl or CF3; R3means-SO2R12or-SO2NR13R14where R12means1-C6alkyl; R13means hydrogen or C1-C6alkyl, and R14means hydrogen, C1-C6alkyl, C3-C6cycloalkyl,2-C6alkenyl, hydroxy SS1-C6alkyl, benzyl, phenethyl, naphtalate, acyl, morpholino-C1-C6alkyl, pyrrolidino-C1-C6alkyl, pyridyl-C1-C6alkyl, furanyl-C1-C6alkyl, or R13and R14together with the nitrogen atom to which they are attached, optionally form heterocyclization selected from piperidino, morpholino, di-(C1-C6alkyl)morpholino, pyrrolidino, methylpiperazine, phenylpiperazine, forfilipino; and their pharmaceutically acceptable salts or their esters or carbamates, individual isomers and mixtures of isomers and method thereof

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of nitrogen-containing heterocyclic compounds of the general formula (I'):

wherein R represents the group:

m = 0-3; R1 represents halogen atom, cyano-group and others; X represents oxygen or sulfur atom, or the group -CH2 and others; Z1 and Z2 represents the group -CH2 and others; Q represents oxygen or sulfur atom, or the group -CH2 or -NH; R2 represents substituted phenyl; n = 0-2; R3 represents (C1-C6)-alkyl, (C1-C6)-alkoxycarbonyl group and others; R4, R5, R6 and R7 represent hydrogen atom or (C1-C6)-alkyl and others; R8 represents hydrogen atom, (C1-C6)-alkyl. Compounds of the formula (I') possess of activity modulating activity of chemokine MIP-1α receptors and can be used in medicine in treatment of inflammatory diseases and respiratory ways diseases.

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

20 cl, 283 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds. Invention describes compounds or their salts of the general formula (I): A-B-N(O)s (I) wherein s = 2; A means R-T1- wherein R represents radical of a medicinal substance under condition that a medicinal substance by the formula R-T1-Z or R-T1-OZ wherein Z represents hydrogen atom (H) or (C1-C5)-alkyl is taken among paracetamol, salbutamol, ambroxol, alendronic acid,, cetirizine, ampicillin, aciclovir, doxorubicin, simvastatin, diphylline, tacrine, clopidogrel, dimethylomeprazol, diclofenac, ferulic acid, enalapril, propranolol, benfurodil hemisuccinate, tolrestate or sulindac; T1 means (CO), oxygen atom (O) or NH; B means TB-X2-O- wherein TB means bivalent radical R1B-X-R2B wherein R1B and R2B are similar or different and represent linear or branched (C1-C6)-alkylenes and X represents a bond, oxygen (O), sulfur (S) atom or NR1C wherein NR1C represents hydrogen atom (H) or linear or branched (C1-C6)-alkyl; corresponding precursor B is represented by the formula -TB-X2-OH wherein TB means (CO) and free valence in TB represents -OZ wherein Z is determined above, or TB means oxygen atom (O), and free valence in TB represents hydrogen atom (H) under condition that in the formula (I) when X2 in precursor B represents linear or branched (C2-C20)-alkylene then a medicinal substance by the formula R-T1-Z or R-T1-OZ used in the formula (I) doesn't belong to the following substances: enalapril (ACE inhibitors) and diclofenac (NSAID). Also, invention describes pharmaceutical compositions for using in cases of oxidative stress and 4-nitroxybutanoic acid 4'-acetylaminophenyl ester. Invention provides preparing novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of medicinal substances and compositions.

7 cl, 8 tbl, 32 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new N-(2-arylpropionyl)-sulfonamides of the formula (1): wherein R2 means phenyl, thiophenyl optionally substituted with 1-3 substitutes taken independently among halogen atom, (C1-C4)-alkyl, phenyl, phenoxy-group, benzyl, benzoyl, (C1-C7)-acyloxy-group, 2-thienoyl or 1-oxo-2-isoindolyl; R means linear or branched (C1-C16)-alkyl, trifluoromethyl, cyclohexyl, o-tolyl, 3-pyridyl, p-cyanophenylmethyl, p-aminomethylphenylmethyl, 2-cyano-1-propyl, alkoxyethylene group CH3-(CH2)ni-(OCH2CH2)mi- wherein ni and mi mean a whole number from 1 to 3, or the group P1P2N-CH2-CH2- wherein P1 and P2 represent independently hydrogen atom (H), (C1-C3)-alkyl, benzyloxycarbonyl, α-, β- or γ-pyridocarbonyl, carboxycarbonyl or carbalkoxycarbonyl; or R1 and P2 in common with nitrogen atom to which they are bound form morpholino-group; R' means hydrogen atom (H) or linear or branched (C1-C3)-alkyl, or their salts with strong or mean bases. Compounds of the formula (1) show inhibitory activity with respect to chemotaxis and degranulation of neutrophiles induced with interleukin-8 and can be used in pharmaceutical composition used for prophylaxis and treatment of tissue injures.

EFFECT: valuable medicinal properties of compounds.

13 cl, 2 dwg, 2 tbl, 18 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to new acid-additive nitrate salts of compounds taken among salbutamol, cetirizine, loratidine, terfenadine, emedastine, ketotifen, nedocromil, ambroxol, dextrometorphan, dextrorphan, isoniazide, erythromycin and pyrazinamide. Indicated salts can be used for treatment of pathology of respiratory system and elicit an anti-allergic, anti-asthmatic effect and can be used in ophthalmology also. Indicated salts have less adverse effect on cardiovascular and/or gastroenteric systems as compared with their non-salt analogues. Also, invention proposes pharmaceutical compositions for preparing medicinal agents for treatment of pathology of respiratory system and comprising above indicated salts or nitrate salts of metronidazol or aciclovir.

EFFECT: improved and valuable properties of compounds.

6 cl, 5 tbl, 19 ex

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

SUBSTANCE: invention relates to a method for preparing {2-[4-(α-phenyl-p-chlorobenzyl)piperazine-1-yl]ethoxy}acetic acid (cetirizine) of the formula (I): (I).

Method involves hydrolysis of compound of the formula (II): (II)

wherein R1 and R2 represent independently (C1-C4)-alkyl that can be substituted with phenyl, (C2-C4)-alkenyl or cyclohexyl; or R1 and R2 in common with adjacent nitrogen atom form morpholine group. Hydrolysis is carried if necessary in the presence of interphase catalyst. Cetirizine is used as a component in anti-allergic pharmaceutical compositions. Also, invention describes a method for preparing intermediate compounds of the formula (II).

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

5 cl, 25 ex

FIELD: organic chemistry, medicine, pharmacology.

SUBSTANCE: invention relates to new derivatives of carbamic acid esters of the general formula (I):

and their pharmaceutically acceptable salts eliciting activity with respect to metabotropic glutamate receptors mGlu of group I that can be used for treatment of acute and/or chronic neurological disorders. In the general formula (I) R1 means hydrogen atom or (C1-C7)-alkyl; R2 and R2' mean independently of one another hydrogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom or trifluoromethyl; X means oxygen (O), sulfur (S) atom or two hydrogen atoms not forming a bridge; A1/A2 mean independently of one another phenyl or 6-membered heterocycle comprising 1 or 2 nitrogen atom; B represents group of the formula:

wherein R3 means (C1-C7)-alkyl and others; Y means -O-, -S- or a bond; Z means -O- or -S-; or B means 5-membered heterocyclic group of formulae: (a) , (b) , (c) or (d) . Also, invention relates to methods for preparing compounds and to a medicinal agent based on thereof.

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

22 cl, 1 tbl, 2 sch, 78 ex

The invention relates to the use of compounds of formula I to obtain medical drug suitable for the treatment of asthma, seasonal or chronic allergic rhinitis, sinusitis, conjunctivitis, food Allergy, scombroid poisoning, psoriasis, urticaria, pruritus, eczema, rheumatoid arthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, thrombosis and otitis and preferably asthma, seasonal and chronic allergic rhinitis

The invention relates to the derivatives of benzosulfimide formula (I):

< / BR>
where X represents a nitro-group, a cyano or halogen; Y1represents a secondary or tertiary amino group; Y2represents nitrogen or NH group; Z represents oxygen, sulfur, -N-CN or CH-NO2; and R1and R2that may be the same or different, are each independently saturated or unsaturated linear or branched alkyl group containing from 2 to 12 carbon atoms, saturated or unsaturated alicyclic group containing from 3 to 12 carbon atoms, phenyl, unsubstituted or substituted by one or more substituents, which represents a1-C4alkyl group, nitro, cyano, trifluoromethyl, carboxy and halogen, benzyl group or phenylethylene group, or Y1means tertiary amino group and R1form a morpholine or homopiperazin and Y2represents nitrogen and R2forms homopiperazin, except for derivatives, for which X is a nitro-group, Y1represents a secondary amino group (-NH-), Y2represent the group, includes m-toluyl, phenyl and cyclooctyl, and with the exception of N-[(2-cyclooctylamino-5-cyanobenzoyl)sulfonyl] N'-Isopropylamine, or its pharmacologically acceptable salt

FIELD: medicine, endocrinology.

SUBSTANCE: treatment involves prescription to patient light water as drinking water with the total mineralization 200-500 mg/l, the deuterium content 100 ppm, not above, and the oxygen-18 content 1800 ppm, not above, on the background of dietetic therapy and insulin therapy or intake of hypoglycemic preparations in the daily dose 1000-1500 ml. The first intake is carried out before eating in the morning in the dose 200-250 ml and the remaining amount for a day, 30-40 min before eating or in breaks of eating every day. The curative course is from 28 to 45 days. Method provides declining the blood glucose content and to improve metabolic processes.

EFFECT: improved treatment method.

2 ex

FIELD: organic chemistry, biochemistry, medicine, endocrinology.

SUBSTANCE: invention relates to O-arylglucoside inhibitors of SGLT2 of the formula (I): wherein Y means compounds of formulae: A means -O(CH2)m, sulfur atom (S), -NH(CH2)m or -(CH2)n wherein n = 0-3; m = 0-2; R1-R6 are determined above, and to a pharmaceutical composition based on thereof, and to methods for treatment of diabetes mellitus type 2, and micro- and macrovascular diabetic complications.

EFFECT: valuable medicinal properties of inhibitors.

15 cl, 1 tbl, 99 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative of triazaspiro[5.5]undecane of the formula (I): wherein R1 means compound of the formula (1): or (2): wherein G represents a bond, (C1-C4)-alkylene, (C2-C4)-alkenylene or -CO-; ring A represents: (1) C5-10-membered mono- or bicarbocyclic ring or (2) 5-10-membered mono- or bicyclic heterocycle comprising 1-2 nitrogen atoms and/or 1-2 oxygen atoms; substitute R6 means the following values: (1) (C1-C4)-alkyl, (2) halogen atom, (3) nitrile group, (4) trifluoromethyl group and others; R2 represents: (1) (C1-C4)-alkyl, (2) (C2-C4)alkynyl or (3) (C1-C4)-alkyl substituted with a substitute represented in claim 1 of the invention claim; each R3 and R4 represents independently: (1) hydrogen atom, (2) (C1-C4)-alkyl or (3) (C1-C4)-alkyl substituted with 1-2 substituted taken among: (a) Cyc 2 and (b) hydroxy-group (wherein Cyc 2 represents (1) C5-6-membered monocarbocyclic ring or (2) 5-6-membered monocyclic heterocycle comprising 1-2 nitrogen atoms and/or one oxygen atom), or R3 and R4 form in common group of the formula: wherein R26 represents (C1-C4)-alkyl or Cyc 2; R5 represents hydrogen atom or (C1-C4)-alkyl, its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to pharmaceutical composition inhibiting HIV, regulator of chemokine/chemokine receptor and agent used in treatment and prophylaxis of some diseases, such as inflammatory diseases, asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis and other diseases that comprise as an active component above described compound of the formula (I) or its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane or its pharmaceutically acceptable salt and pharmaceutical composition based on thereof, and to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane hydrochloride and pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of derivative and composition.

16 cl, 32 ex

FIELD: medicine and veterinary.

SUBSTANCE: invention relates to method for prophylaxis of oncological diseases, or infections mordibidized by bacteria or fungi and protozoa, or arteriosclerosis, or diabetes mellitus, or diseases mediated by delayed hyperresponsiveness reaction, or diseases mediated by somatic cell gene mutations. In the first embodiment of invention blood extracellular DNA destroying agent, such as DNAase, is administered into blood. In the second embodiment agent, binding to blood extracellular DNA, such as anti-DNA antibody is administered into blood. According to the third embodiment enzyme altering of blood extracellular DNA chemical structure is administered into blood. According to the forth embodiment agent, stimulating synthesis and/or activity of endogenic deoxyribonuclease or agent stimulating synthesis of antibody binding to blood extracellular DNA are administered into blood.

EFFECT: effective method for treatment of abovementioned diseases without side effects when prolonged using of preparation affected on blood extracellular DNA.

7 cl, 11 tbl, 18 ex, 5 dwg

FIELD: medicine and veterinary.

SUBSTANCE: invention relates to method for treatment of diseases, associated with alterations of blood extracellular DNA, such as generalized infections mordibidized by bacteria or fungi and protozoa, or arteriosclerosis, or diabetes mellitus, or diseases mediated by delayed hyperresponsiveness reaction, or diseases mediated by somatic cell gene mutations. Method includes administering of blood extracellular DNA destroying agent into blood. As such agent DNAase is used, in particular in doses providing alteration of electrophoretic profile of blood extracellular DNA, detectable by pulse gel electrophoresis. DNAase may be administrated in doses and regimes providing exceeded levels of blood plasma DNA-hydrolytic activity, namely 150 Kuntz/l of plasma, during 12 h/day in total.

EFFECT: effective method for treatment of abovementioned diseases without side effects.

4 cl, 14 tbl, 15 ex, 5 dwg

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