Derivatives of 3-hydroxy-2-pyridone and pharmaceutical composition based on thereof

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compound of the formula (I): wherein (a) each R1 is chosen independently from hydrogen atom and alkoxy-group; (b) R2 represents hydrogen atom; (c) each R3 and R4 is chosen independently of one another from hydrogen atom, alkyl, alkynyl, heteroalkyl group, aryl; or R3 and R4 in common with nitrogen atom bound with them form heteroaryl or heterocycloaryl substitute optionally substituted with one or more hydroxo-group, carboxyl group, keto-, thioketo-, phenyl group, alkyl, heteroalkyl group, heteroaryl, heterocycloalkyl, spirocycloalkyl and their combinations; (d) each R5 and R6 represents hydrogen atom; or optical isomers, diastereomers and enantiomers represented by above given formula, and their pharmaceutically acceptable salts also. Also, invention describes using compound of the formula (I) for preparing a pharmaceutical composition possessing antibacterial activity and antibacterial pharmaceutical composition containing the safety and effective amount of compound of the formula (I) and a pharmaceutically acceptable carrier. Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable properties of compounds and pharmaceutical composition.

7 cl, 37 ex

 

The present invention is directed to some N-alkyl-4-methylamino-3-hydroxy-2-pyridone, suitable as antimicrobial agents.

The level of technology

In the chemical and medical literature describes compounds with antimicrobial activity that is capable of destroying or suppressing the growth or reproduction of microorganisms, such as bacteria, for Example, antibiotic and other antimicrobial drugs are described in Antibiotics, Chemotherapeutics and Antibacterial Agents for Disease Control (M.Grayson, editor, 1982), as well as in E.Gale et al., The Molecular Basis of Antibiotic Action, 2nd edition (1981).

The mechanism of action of these antimicrobial drugs is different. One known mechanism is bacterial inhibitors amino peptidases (bMAP). Inhibition of bMAP is an important therapeutic task with anti-infective point of view, as it is included in the transfer destination proteins and remains in the environment known pathogenic bacteria. Therefore, inhibition of this enzyme will lead to the broadening of the spectrum antimicrobial agents.

Numerous attempts of synthesis of antimicrobial drugs with improved properties has led to questionable results. Indeed, resulted in some antimicrobials that have been clinically suitable from the point of view of their antimicrobial is aktivnosti, the suppression of the resistance of bacteria and pharmacology. Thus, there remains a need for antimicrobials wide range of actions that would be effective against resistant microbes.

Disclosure of inventions

The present invention discloses compounds which are potential inhibitors bMAP and has efficacy in the treatment of microbial infections. In particular, the invention relates to compounds having the structure represented by formula (I)

Another aspect of the present invention is directed to methods of using compounds of formula (I) for the treatment of microbial infections in need of this entity.

Another aspect of the invention is the methods of synthesis of compounds of formula (I).

All cited documents, in relevant part, included in the application by reference; the citation of any of them should not be interpreted as preceding the present invention, the level of technology.

Detailed description of the invention

I. Terms and definitions.

Below is a list of definitions for terms used in the application.

"Acyl" or "carbonyl" refers to a radical formed by removal of hydrogeography of the carboxylic acid (i.e., R-C(=O)-). Preferred acyl groups include, for example, acetyl, FD is nice and propionyl.

"Alkyl" is a saturated hydrocarbon chain consisting of 1-15 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-4 carbon atoms. "Alkene" refers to a hydrocarbon chain containing at least one (preferably only one) carbon-carbon double bond and from 2 to 15, preferably from 2 to 10, more preferably from 2 to 4 carbon atoms. "Alkyne" refers to a hydrocarbon chain containing at least one (preferably only one) carbon-carbon triple bond and from 2 to 15, preferably from 2 to 10, more preferably from 2 to 4 carbon atoms. Alkenone, alkyl and askinosie chain (called in General the hydrocarbon chain may be branched or unbranched and substituted or unsubstituted. Preferably branched alkyl, alkenone and askinosie chains have one or two branches, preferably one branch. Preference is given to alkyl chains. Alkyl, alkenone and askinosie hydrocarbon chains, each by itself, can be unsubstituted or can have 1-4 substituent, in the presence of preferred substituents are mono-, di - or tizamidine chain. Each of the alkyl, alkenovich and alkenovich hydrocarbon chains may be substituted with halogen, hydroxyl, aryloxy (e.g., fenoxaprop), gets the realloca-, acyloxy (e.g., acetoxypropionyl), carboxypropyl, aryl (e.g. phenyl), heteroaryl, cycloalkyl, heterocyclization, spirocycles, amino-, amido-, acylamino-, keto-, tyketto-, cyano, or any combination thereof. Preferred hydrocarbon groups include methyl, ethyl, propyl, isopropyl, butyl, vinyl, allyl, butenyl and eksootilisel.

"Lower" alkyl, Allenova or alkyne group, as here indicated, for example, "lower alkyl", is a chain of 1-6, preferably 1-4, carbon atoms in the case of alkyl and 2-6, preferably 2-4 carbon atoms in the case of alkene or alkyne.

"Alkoxy" represents an oxygen radical having a hydrocarbon Deputy, in which the hydrocarbon chain is an alkyl or alkenyl (for example, -O-alkyl or-O-alkenyl). Preferably, alkoxygroup include, for example, methoxy, ethoxy-, propoxy - or alliancegroup.

"Aryl" is an aromatic hydrocarbon ring. Aryl rings are monocyclic or condensed bicyclic systems. Monocyclic aryl ring containing 6 carbon atoms in the ring. Monocyclic aryl rings are also called phenyl rings. Bicyclic aryl rings contain from 8 to 17 carbon atoms, preferably from 9 to 12 carbon atoms,in the ring. Bicyclic aryl ring include a system of rings in which one ring is aryl and the other ring - aryl, cycloalkyl or heteroseksualci. Preferably bicyclic aryl ring include 5-, 6 - or 7-membered cycles, condensed with 5-, 6 - or 7-membered rings. Aryl ring may be unsubstituted or substituted, with 1-4 substituent in the loop. The aryl may be substituted with halogen, a cyano, a nitro-group, a hydroxy-group, carboxypropyl, amino group, allmineral, alkyl, heteroalkyl, halogenation, phenyl, arroceros, alkoxygroup, getrealcursorpos, karbonilnoj group, halogenation, methylendioxyphenyl, heteroepitaxial or any combination thereof. Preferred aryl rings include naphthyl, tolyl, xylyl and phenyl. The most preferred cyclic aryl radical is phenyl.

"Aryloxy-" is an oxygen radical having an aryl Deputy, i.e. "- O-aryl". Preferred alloctype include, for example, fenoxaprop, naphthyloxy, methoxyphenoxy and methylenedioxyphenoxy.

"Cycloalkyl" is a saturated or unsaturated hydrocarbon cycle. Cycloalkyl rings are not aromatic, and may be monocyclic and condensed, the pyro - or bridged bicyclic ring systems. Monocyclic cycloalkyl contain from 3 to 9, preferably from 3 to 7 carbon atoms in the ring. Bicyclic cycloalkyl rings contain from 7 to 17, preferably from 7 to 12 carbon atoms in the ring. Preferred bicyclic cycloalkyl ring containing 4-, 5-, 6 - or 7-membered ring condensed with a 5-, 6 - or 7-membered rings. Cycloalkyl rings can be unsubstituted or substituted by 1-4 substituents in the ring. Cycloalkyl may be substituted with halogen, cyano, alkyl, heteroalkyl, halogenation, phenyl, geography, hydroxy-group, amino group, allmineral, arroceros, heteroepitaxial, or their combination. Preferred cycloalkyl - cyclopropyl, cyclopentyl and cyclohexyl.

"Halo" or "halogen" is fluorine, chlorine, bromine or iodine. The preferred halogen is fluorine, chlorine or bromine, more preferred is chlorine and fluorine, especially fluorine.

"Halogenated" is unbranched, branched or cyclic hydrocarbon, substituted by one or more Halogens. Preferably this is1-C12-halogenated, more preferably C1-C6-halogenated, even more preferably C1-C3-halogenoalkane. The preferred halogen is fluorine and chlorine. The most preferred halogenation is trifluoromethyl.

"Heteroatom"is nitrogen, sulfur or oxygen. Groups containing more than one heteroatom may include different heteroatoms.

"Heteroalkyl" is a saturated or unsaturated carbon chain containing at least one heteroatom, the heteroatoms are not adjacent. Heteroalkyl chains contain from 2 to 15 atoms (carbon and heteroatoms), preferably from 2 to 10, more preferably from 2 to 5. For example, in heteroalkyl includes alkoxygroup (i.e.- O-alkyl or-O-heteroalkyl). Heteroalkyl chain can be unbranched or branched. Preferably branched heteroalkyl has one or two branching, preferably one branch. Preferably heteroalkyl saturated. Unsaturated heteroalkyl has one or more double carbon-carbon bonds and / or one or more triple carbon-carbon bonds. Preferred unsaturated heteroalkyl having one or two double bond or one triple bond, preferably one double bond. Heteroalkyl chain can be unsubstituted and substituted by 1-4 substituents. Preferred mono-, di - or tizamidine heteroalkyl. Heteroalkyl may be substituted by lower alkyl, halogenation, halogen, hydroxy-group, arroceros, heteroepitaxial, alloctype, carboxypropyl, monocyclic the Kim-aryl, heteroaryl, cycloalkyl, heterocyclization, spirocycles, amino group, allmineral, aminogroups, geography, tokyograph, cyano or their combination.

"Heteroaryl" - aromatic ring containing carbon atoms and from 1 to 6 heteroatoms in the ring. Heteroaryl ring is monocyclic or bicyclic saturated system. Monocyclic heteroaryl rings contain 5 to 9 atoms (carbon and heteroatoms), preferably 5-6 atoms. Bicyclic heteroaryl rings contain from 8 to 17 atoms, preferably from 8 to 12 atoms. Bicyclic heteroaryl rings include a system of rings, in which one ring - heteroaryl, and the other is aryl, heteroaryl, cycloalkyl or heteroseksualci. Preferably the system bicyclic heteroaryl rings include 5-, 6 - or 7-membered condensed ring or 5-, 6 - or 7-membered ring. Heteroaryl rings may be unsubstituted and substituted by 1-4 substituents in the ring. Heteroaryl may be substituted with halogen, a cyano, a nitro-group, a hydroxy-group, carboxypropyl, amino group, allmineral, alkyl, heteroalkyl, halogenation, phenyl, alkoxygroup, arroceros, heteroepitaxial or any combinations thereof. Preferred heteroaryl rings include, but are not limited to - the following cycles:

"Heteroanalogues" is an oxygen radical having a heteroaryl Deputy, i.e. the "-O-heteroaryl". Preferred heterokaryosis include, for example, pyridyloxy, furanose - (thiophene)oxy, (oxisol)hydroxy - (thiazole)hydroxy - (isoxazol)hydroxy, pyrimidinone, pyrazinone and benzothiazolylthio.

"Heteroseksualci" represents an unsubstituted or substituted cycle which consists of carbon atoms and having from 1 to 4, preferably from 1 to 3, heteroatoms in the ring. Heterocytolysine rings are not aromatic. Heterocytolysine ring may be monocyclic or condensed, bridged or spirobicyclic ring systems. Monocyclic heterocytolysine ring formed of 3 to 9 carbon atoms and heteroatoms, preferably 5-7 atoms. Bicyclic heterocytolysine rings contain from 7 to 17, preferably from 7 to 12 the volumes in the ring. Bicyclic heterocytolysine ring may be condensed, bridged or spirocyclohexane systems. Preferred bicyclic heterocytolysine ring containing 4-, 5-, 6 - or 7-membered ring condensed with a 5-, 6 - or 7-membered rings. Bicyclic heterocicluri can be unsubstituted or have from 1 to 4 substituents in the ring; they can be substituted with halogen, cyano, hydroxy-group, carboxypropyl, keto-, tokyograph, amino group, allmineral, alkyl, heteroalkyl, halogenation, phenyl, alkoxyl, alloxylon or any combination of these substituents. Preferred substituents of heterocyclization include halogen and halogenated. Preferred heterocytolysine rings include, but are not limited to - the following cycles:

Under the "spiricom" refers to alkyl or heteroalkyl biradially Deputy alkyl or heteroalkyl, which are pairwise connected to the specified biradical the first Deputy, and the specified biradially Deputy form a ring comprising 4 to 8 carbon atoms or heteroatoms, preferably from 5-6 atoms.

When alkyl, heteroalkyl, cycloalkyl and heterocytolysine groups can be substituted, hydroxo-, amino - and aminopropane, as mentioned above, the following examples are not relevant to the present invention:

1) Enol (HE is the group connected to the carbon atom at the double bond).

2) an Amino group connected to the carbon with the double bond (except vinyl amides).

3) More than one hydroxyl, amino or aminogroups connected to a single carbon atom (excluding the case when two atoms of nitrogen combine with one atom of carbon and three atoms are members of a heterocyclic ring).

4) Hydroxyl, amino or aminogroups connected to a carbon atom that is already bound to the heteroatom.

5) Hydroxyl, amino or aminogroups connected to a carbon atom that is already bound to a halogen atom.

"Pharmaceutically acceptable salt" is a cationic salt formed any acidic group, for example, hydroximino or carboxylic acid, or an anionic salt of any of the basic group such as amino group. Many such salts are known from the literature, for example from WO 87/05297, Johnston et al., publ. on September 11. predpochtitelnye cationic salt - alkali metal salts (such as sodium and potassium), salts of alkaline-earth salts (such as magnesium and calcium) and organic salts. Preferred anionic salts are the halides (such as chlorides), sulfonates, carboxylates, phosphates, and the like.

Such salts are well known to the specialist, and it can synthesize any of these salts on the basis of literature data. In addition, it is clear that the specialist is able to give preference to one of salt compared to others on the basis of its solubility, stability, ease of preparation and the like. Selection and optimization of such salts is within the competence of a specialist.

"Biohydrology amide" is an amide compound of the present invention, which does not affect the activity or easily recycled in vivo in animals, preferably mammals, more preferably humans, with the receipt of pharmacologically active compounds. Examples of such amide derivatives - alkoxyamine, in which the hydrogen atom of the hydroxyl group of hydroxyamino acid compounds of formula (I) substituted by alkyl, and allocine, in which the hydrogen atom of the hydroxyl group substituted by acyl (i.e., R-C(=O)-).

"Biohydrology hydroxyamide" represents an imide compounds containing hydroxyamino acid, in accordance with the present invention that do not affect Akti is the ability of this compound, any connection that is easy to process in vivo in animals, preferably mammals, more preferably humans, with the receipt of pharmacologically active compounds. Examples of such imenik derivatives are compounds in which the hydrogen of the amino group hydroxyamino acid compounds of formula (I) substituted acyl group (i.e. R-C(=O)-).

"Biohydrology ester" is an ester compound containing the group of carboxylic acids that do not affect the activity of this compound, or compounds, which can be easily processed animals, forming a pharmacologically active compound. Such esters include lower alkyl esters, lower aryloxyalkyl esters (for example, acetoxymethyl, ecotoxicology, aminocarbonylmethyl, pivaloyloxymethyl and pivaloyloxymethyl esters), lactonase esters (for example, Caligraphy or tittilicious esters), lower alkoxyalkanols esters (for example, methoxy-carbonyloxy, ethoxycarbonylmethylene and isopropoxycarbonyloxymethyl esters), alkoxyalkyl esters, chlorinated ethers and alkyl - acylaminoalkyl esters (such as complex acetamidomethyl esters).

"MES" is a complex formed by the combination of the solute (for example the EP, the compounds of formula (I)and a solvent such as water; see J. Honig et al., The Van Nostrand Chemist''s Dictionary, p.650 (1953). Pharmaceutically acceptable solvents used in this invention include those that do not affect biological activity of the invented compounds (for example, water, ethanol, acetic acid, N,N-dimethylformamide and other well-known expert in this field).

The term "optical isomer", "stereoisomer" and "diastereoisomer are generally accepted (see, for example, Hawlev's Condensed Chemical Dictionary, 11th edition). Bringing a separate protected forms and other derivative compounds of the present invention should not be construed as limiting the invention. The use of other suitable blocking groups, forms, salts, etc. is obvious to the expert.

II. Connection.

The present invention includes compounds of formula (I)

Below is a description private preferred embodiments of the deputies, not limiting the scope of the present invention.

Each R1independently selected from hydrogen atom, halogen, cyano, hydrogeography, carboxyl group, keto-, tyketto-, amino-, alluminare, acyl, amide, phenyl groups, aryloxides, alkyl, alkenylphenol, alkenylphenol, heteroalkyl groups, Gal is gene halogenoalkane, alkoxygroup, aryl, heteroaryl, cycloalkyl and geterotsiklicheskie. In one embodiment, R1represents hydrogen.

Each R2independently selected from hydrogen atom, halogen, cyano, hydrogeography, carboxyl group, keto-, tyketto-, amino-, acylamino group, acyl, amide, phenyl groups, aryloxides, alkyl, alkenylphenol, alkenylphenol, heteroalkyl groups, halogen, halogenoalkane, alkoxygroup, aryl, heteroaryl, cycloalkyl and geterotsiklicheskie. In one embodiment, R2represents hydrogen.

R3and R4each independently from another selected from hydrogen, alkyl, alkenylphenol, alkenylphenol, heteroalkyl groups, aryl, heteroaryl, cycloalkyl and alkylchlorosilanes or R3and R4together with the associated nitrogen atom form a heteroaryl or geteroseksualy Deputy, optionally substituted by at least one atom of hydrogen, halogen, cyano, hydrogeography, carboxyl group, keto-, tyketto-, amino-, allmineral, acyl, amide, phenyl group, aryloxides, alkyl, alkenylphenol, alkenylphenol, heteroalkyl group, halogen, halogenation, alkoxygroup, aryl, heteroaryl, cycloalkyl, heterocyclization, spirocyclohexane and comb the nation.

R5and R6independently selected from hydrogen, halogen, cyano, hydrogeography, carboxyl group, keto-, tyketto-, amino-, alluminare, acyl, amide, phenyl groups, aryloxides, alkyl, alkenylphenol, alkenylphenol, heteroalkyl groups, halogen, halogenoalkane, alkoxygroup, aryl, heteroaryl, cycloalkyl and geterotsiklicheskie. In one embodiment of the invention, each of R5and R6represents hydrogen.

III. Getting connections.

Compounds of the present invention can be obtained in different ways. In particular, the preferred methods of synthesis describes the General synthesis scheme below. (Group, R, is used to illustrate the synthesis schemes, not necessarily coincide with the R groups used to describe various embodiments of compounds of formula I. for example, R1of formula I does not coincide with the group R1shown here). Some examples of ways to produce compounds of the present invention are provided later, in section VII.

On the General scheme I the source material S1 is known, prepared by known methods, or is commercially available. S1 is blocked by reaction with an alkylating reagent in the presence of a base in an alcohol solvent, while arr is by S2, in which Ar represents an aryl group. Hereinafter, the term "alkylating agent" refers to a reagent that interacts with nitrogen and hydroxyl S1 with the formation of new carbon-nitrogen and carbon-oxygen connection, respectively. Not limiting the invention, examples of the alkylating agent include halogenosilanes or halogennitromethanes. As an example, an alcoholic solvent may be methanol. Suitable examples of bases include potassium hydroxide, potassium carbonate, tert-piperonyl potassium, sodium methoxide and Triton-B.

In turn, S2 selectively enabled under the influence of the hydrogenating agent with the formation of the S3. Here and hereinafter the term "moisturizing agent" means the agent, adding a hydrogen atom to the other remaining atom such as a carbon atom. Suitable examples of moisturizing agents include palladium or rhodium deposited on charcoal, in a solution of methanol and in the atmosphere of hydrogen gas.

Finally, S3 is subjected to formirovanie or aminating the corresponding familyroom or aminimum agent. Here and hereinafter the term "formulirui agent" means a reagent carrying methylene group CH2or group. Not limiting the invention examples formuliruiutsia agent include a pair of Formaldehyd, formaldehyde, a mixture of formamide and formic acid, formylindole, p-nitrophenylphosphate. Alternative aldehyde (R-SON) can be used as formuliruiutsia agent in this application. The result is further branching of methylene groups on the basis of the aldehyde. These formuliruya agents are commercially available or can be synthesized by known methods. Here and hereinafter the term "miniraise agent" refers to a primary amine having the formula other3or secondary amine of the formula NR3R4. These amines are commercially available products or can be synthesized by known methods. For example, many of such amines can be identified using databases ChemOffice Webserver and ChemACX. These amines can be further modified by known literature methods.

These stages can be modified to increase the yield of the target product. The specialist will be able to make sensible choices in relation to the reagents, solvents, and temperatures as important components of a successful synthesis. Determination of optimal conditions, etc. is standard procedure. Thus, following the above schemes, the specialist is able to synthesize various compounds.

Discovered that the Bank is in the field of organic chemistry will be able to perform standard operations with organic compounds without any additional guidelines; thus, the implementation of these operations corresponds to the scope and practice inherent in the specialist. These operations include, but are not limited to the reduction of carbonyl compounds to the corresponding alcohols, oxidation of hydrogeography and the like, acylation reaction, aromatic nucleophilic and electrophilic substitution reactions of formation of simple and complex esters, reaction of saponification and the like. Examples of such operations are described in well-known sources, such as March, Advanced Organic Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemictry (vol.2), as well as other sources available to the specialist.

The specialist is also clear that certain reactions are best carried out under conditions, when potentially active molecules blocked or protected, thus avoiding undesirable side reactions and / or to increase the yield of the reaction product. Often specialists use a blocking group to secure such high outputs or to avoid adverse reactions. Such reactions are described in the literature and well known to specialists in this field. Examples of most of these operations can be found, for example, in the book T.Greene, Protecting Groups in Organic Synthesis.

Compounds of the present invention can have one or more chiral centers. As a consequence, can be obtained Odie the optical isomer, including diastereoisomer or enantiomer or the other, for example, when using materials with a chiral center, catalysts or solvents, or may be obtained both stereoisomer or both optical isomers, including diastereomers and enantiomers (racemic mixture). Because the connections in accordance with the present invention can exist as racemic mixtures, mixtures of optical isomers, including diastereomers and enantiomers, or stereometry can be separated using known methods, such as the formation of chiral salts, chiral chromatography and the like.

In addition, we discovered that one optical isomer, comprising the diastereoisomer-and enantiomer, or stereoisomer may have preferable properties in front of the other isomer. Accordingly, when in the description and the formula of the present invention discloses one racemic mixture, it is assumed that both optical isomers, including diastereomers and enantiomers, or stereoisomers, almost separated from each other, are also disclosed and claimed.

IV. Applications.

Compounds of the present invention, can be used as antimicrobials. Not wishing to be bound to theory, we note that these compounds can act is as chelat forming agents in relation to ion cobalt active centre of the bMap. As chelat forming agents, these compounds can act as inhibitors of metalloenzymes.

V. Composition.

The compositions of the present invention include

a) a safe and effective amount of the claimed compounds and

b) a pharmaceutically acceptable carrier.

Compounds of the present invention can be introduced into pharmaceutical compositions used for the treatment of microbial infections. Commonly used standard forms of education such pharmaceutical compositions, such as described in the latest edition Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa.

"Safe and effective amount" of the compounds of formula (I) is the quantity that effectively kills or inhibits the growth and multiplication of microorganisms in the bodies of animals, preferably mammals, more preferably humans, not having an undue adverse side effects such as toxicity, ability to irritation or allergic response, commensurate with a reasonable ratio of benefit/risk, when used in accordance with the present invention. Obviously, the specific "safe and effective amount" will vary depending on factors such as, in particular, the conditions of admission, the physical condition of the patient, dlitelnost the treatment, the competitive nature of therapy (if any)used dosage form, the type of media and the solubility of the compounds of formula (I) therein, and the dosage of the composition.

In addition to this connection, the compositions of the present invention contain a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier", as used in this application means one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for appointment to animals, preferably mammals, more preferably humans. The term "compatible", as used here, indicates that these components of the specified composition is able to connect with this substance, as well as with each other so that between them no interaction occurs, which could significantly reduce the pharmaceutical efficacy of the inventive compositions when used in normal conditions. Of course, pharmaceutically acceptable carriers must be of sufficiently high purity and very low toxicity to be assigned for ingestion by animals, preferably the person being treated.

Some examples of substances which can serve as pharmaceutically acceptable carriers or their components, are presented in sugars, this is as lactose, glucose and sucrose; starches, such as wheat and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethylcellulose and methylcellulose; crushed tragakant; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; poliorama, such as propylene glycol, glycerin, sorbitol, lures, and polyethylene glycol; alginic acid; emulsifiers, such as twins®; wetting substances, such as lauryl sulfate; coloring agents; flavoring agents; substances obladaushimi tableting; stabilizers; antioxidants; preservatives; free from pyrogens water; isotonic saline and phosphate buffer solutions.

The choice of pharmaceutically acceptable carrier, which will be used together with the active substance, mainly depends on the method of treatment is assigned.

If the active substance is injected through an injection, the preferred pharmaceutically acceptable carrier is sterile, physiological saline solution containing miscible with blood suspendisse agent, the pH value is otorongo is 7.4.

In particular, pharmaceutically acceptable carriers when the system include sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, paioli, alginic acid, phosphate buffer solutions, emulsifiers, isotonic saline solution and free from pyrogens water. Preferred carriers when parenteral reception are propylene glycol, etiloleat, pyrrolidone, ethanol and sesame oil. Preferably pharmaceutically acceptable carrier for the compositions appointed by parenteral, is at least 90 wt.% of the total weight of the composition.

In accordance with this invention the composition is preferably supplied in a dosed portions. Hereinafter, "a La carte dosed view" refers to the composition of the present invention, containing a number of substances represented by formula (I)suitable for the purpose mammal, particularly a human, in the form of a single dose, in accordance with the medical practice. Such compositions preferably contain from about 5 mg to about 1000 mg, more preferably from about 10 to about 500 mg, more preferably from about 10 to about 300 mg of the compounds of formula (I).

Comp the positions in this invention can be in one of the many forms suitable for oral, rectal, local, nasal, ocular or parenteral administration. Depending on the form of the appointment may be used several well-known pharmaceutically acceptable carriers. It is a solid or liquid fillers, diluents, hydrotropes, surface-active agents and encapsulating substances. You can enter an optional pharmaceutically active substances that do not have a noticeable effect on the inhibitory activity of the compounds of formula (I). The number of media used together with the compound of the formula (I)is sufficient to provide the necessary amount of the compounds of formula (I) in one metered portions. Compositions and methods for producing a metered portions used in accordance with the present invention are described in the following sources, listed here by reference: Modern Pharmaceutics, Chapter 9 and 10 (Banker &Rhodes, editors, 1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976).

Can be used in various dosage forms for oral administration, including such solid forms as tablets, capsules, granules and powders. These forms contain a safe and effective amount, usually at least 5%, more preferably from 25% to 50% of compounds of formula (I). Tabla the key can be pressed, pelletized powders, coated enteric-soluble shell, covered with sugar, covered with a film or maharatna-compressed, containing suitable linking, lubricants, diluents, agents of decay, colorants, flavoring agents, agents that facilitate fluidity, and melters. Liquid dosage forms for oral administration include aqueous solutions, emulsions, suspensions, solutions and / or suspensions recovered from not emit gas pellets, and emit gas compositions recovered from the emitting gas granules, containing suitable solvents, preservatives, emulsifying agents, suspendresume agents, diluents, sweeteners, emulsifying, coloring and flavoring agents.

Pharmaceutically acceptable carriers suitable for receiving dosage forms for oral administration are well known. Tablets usually contain conventional pharmaceutically acceptable auxiliary means as diluents, for example calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; the agents of decay - starch, alginic acid and crosscarmellose; lubricants such as magnesium stearate, stereonova acid and talc. Easy slip additives, such as silicon dioxide, can be used to improve the characteristics of the IR fluidity of the powder mixture. The appearance can add colorants, such as FD&C Sweeteners and aromatic additives, such as aspartame, saccharin, menthol, peppermint and fruit aromatic additives, are suitable additional components chewable tablets. Capsules typically contain one or more solid diluents mentioned above. Media components selected from considerations such as taste, price, and stability during storage, which are not critical to the objectives of the present invention and can be readily selected by the person skilled in the field.

Compositions for oral administration include liquid solutions, emulsions, suspensions and so on. Pharmaceutically acceptable carriers for such compositions are well known from the literature. Typical media components for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. Typical suspendresume agents for suspensions are methyl cellulose, sodium carboxymethyl cellulose, Avicel™ RC-591, tragakant and sodium alginate; typical wetting agents include lecithin and Polysorbate 80; typical preservatives include methyl paraben and sodium benzoate. Oral liquid compositions may also contain one who does more components, such as sweeteners, taste - aromatic additives and dyes of the above.

Such compositions may also be coated, using conventional methods, shells, whose properties depend on pH or time to the active substance is released in the gastrointestinal tract in the immediate vicinity of the destination, or at different duration of the desired effect. Such dosage forms typically include, but are not limited to, one or more of the phthalate of acetylcellulose, polyvinyl acetate phthalate, polyhydroxyvalerate methylcellulose, ethylcellulose, coatings Eudragit', waxes and shellac.

Compositions of the present invention may also, optionally, include other active medicinal components.

Other compositions suitable for systematic delivery of drugs include sublingual, buccal and nasal dosage forms. Typically, such compositions contain one or more soluble substances, fillers, such as sucrose, sorbitol and mannitol, as well as such a binder, as gum Arabic, microcrystalline cellulose, carboxymethyl cellulose and hypromellose. Can also be added above the lubricant that facilitates the sliding of substances, sweeteners, colouring agents, antioxidant is Lanta and aromatic additives.

The compositions of the present invention can also be administered to a patient locally, for example, by overlaying or rubbing the composition on the skin or skin tissue of the patient, or transdermal, using a flap. Such compositions are, for example, lotions, creams, solutions, gels and solid substances. These local compositions preferably contain a safe and effective amount, usually at least 0.1 percent, more preferably from 1% to 5% of compounds of formula (I). Suitable for the local introduction of the carriers preferably remain on the skin surface in the form of a solid film, stable, but removed when exposed to perspiration or immersion in water. In General, the carrier is a substance of organic nature and connection of the formula (I)capable of dissolving or dispergirujutsja. This media may include pharmaceutically acceptable emollients, emulsifiers, thickeners, solvents and the like.

VI. Methods of introduction.

The present invention discloses methods of treating microbial infections in humans or other objects of the living world, which are administered in a safe and effective amount of a substance of formula (I).

Compositions of the present invention can be taken topically or systematically. Systematic the reception includes any method of introducing the compounds of formula (I) in the fabric body, for example, percutaneous (transdermal) administration, intravenous, intra-abdominal, subcutaneous, sublingual, rectal, and oral administration. The compounds of formula (I) according to the present invention preferably introduced orally.

The specific dosage taken inhibitor, as well as the duration of treatment depends on the treatment topically or systematically. The dosage and treatment regimen will also depend upon factors such as the use of specific compounds of formula (I), indications for use, the ability of the compounds of formula (I) to establish the minimum concentration to suppress the source of infection, the individual characteristics of the patient (such as weight), compliance with the treatment regimen, the presence and severity of side effects during treatment.

Typically, an adult (weighing approximately 70 kg) is assigned, when systematic reception from 5 to 3000 mg, preferably from 5 to 1000 mg, more preferably from 10 to 100 mg of the compounds of formula (I) daily. It should be understood that the dosage limits are determined experimentally, and the specified daily intake can be changed depending on the above factors.

Preferably, a systematic procedure is performed orally. Preferred individual dosage is from 10 to 1000 mg, preferably from 10 to 300 mg.

Local administration can be used for the systematic introduction of the compounds of formula (I), or for local treatment of the patient. The amount of compounds of formula (I) for local injection depend on such factors as skin sensitivity, type and location of tissue to be treated, take the composition and carrier (if any). A specific compound of formula (I)shown to the reception, as well as a specific disease to be treated, and the degree of manifestation of the desired systematic (as opposed to local) effects.

For local conditions, it is preferable thematic introduction. For example, for the treatment of microbial infection of the eye can be directly applied on the affected eye may be in the form of spray or eye drops. For the treatment of the cornea can also be used compounds of the present invention in the form of gels, drops or ointments, or they can be incorporated into collagen or hydrophilic polymer cover. Such materials also may be injected in the form of contact lenses or reservoir, or in the form of subconjunctival compositions. In the treatment of microbial infection of the skin, this compound is applied topically and thematically in the form of a gel, paste, ointment or ointment. For the treatment of oral infections the specified connection can be used in the form of a gel, paste,elixir for oral or implant. Thus, the method of treatment shows that suitable conditions and formulations for each selected path is available from the technical level.

All of the above, of course, the compounds of the present invention can be taken individually or as mixtures, and these compositions can additionally contain other drugs or excipients which are suitable according to the testimony.

VII. Examples of the connection.

The following substructure and table show the structure of the compounds of examples 1-38 synthesized in accordance with methods described below. Group R or X, is used to illustrate examples of compounds does not necessarily correlate with the appropriate groups R and X, used to describe the various substituents in the formula (I) in the claims.

A preferred Synthesis of intermediate N-benzyl-3-hydroxypyridine-2-it

1-Benzyl-3-benzyloxy-1H-pyridin-2-he (Ghosh et al., J. Org. Chem. 1989, 54, 5073) dissolved in 10 ml of anhydrous methanol and to fully obezvojennom solution was added catalytic amount of Pd-C (0.1 per cent). The mixture hydronaut hydrogen from a cylinder until then, until you used up all the source material. After the solution is filtered through Celite™. The solvent is distilled off in vacuum, the residue is washed with ether, and ucaut target product. 1H NMR (300 MHz, CDCl3), δ further 5.15 (s, 2H), 6,14 (t, J=7.2 MHz, 1H); of 6.71 (m, 1H), 7,31 (m, 6H), 9,07 (s, 1H).

B. General method for the three-component combination of Spiridonov, formaldehyde and amines.

In 10 ml of aqueous ethanol mix 1 EQ. intermediate of the pyridone obtained at stage A, 2.2 EQ. NSNO or aldehyde, and stirred for 30 minutes. Add 2.2 EQ. Amin, stirred for 12 hours and evaporated. The residue is dissolved in 10 ml of ethyl alcohol and purified using HPLC (high performance liquid chromatography; water/acetonitrile/0.1% of triperoxonane acid). Separate the product as a salt triperoxonane acid, unless otherwise indicated. The output is 75-95%.

Century Examples 1-37. Examples prepared for various amines, in accordance with the above method.

Example 1. 1-Benzyl-3-hydroxy-4-piperidine-1-ylmethyl-1H-pyridine-2-he

1H NMR (300 MHz, CD3OD) δ is 1.81 (m, 6N), of 3.07 (m, 2H), 3,51 (m, 2H), 4,23 (s, 2H), 5,24 (s, 2H), of 6.31 (d, J=6,9 Hz, 1H), 7,35 (m, 6N);19F (252 MHz, CD3OD) δ 85,5;13With NMR (75 MHz, DMSO) δ 21,3, 22,7, 51,8, 52,5, 53,1, 106,4, 117,4, 127,7, 128,0, 128,2, 128,9, 137,3, 147,4, 158,0; ES MS (M+1) 299,12; HRMS calculated for C18H22N2O2: 298,38, found (M+1) 299,17.

Example 2. 1-Benzyl-3-hydroxy-4-morpholine-1-ylmethyl-1H-pyridine-2-he

1H NMR (300 MHz, DMSO) δ of 3.25 (m, 4H), 3,81 (m, 4H), 4,18 (s, 2H), 5,17 34 (s, 2H), of 6.31 (d, J=6,9 Hz, 1H), 7,35 (m, 6H);19F NMR (300 MHz, DMSO) δ 88,5;13With NMR (300 MHz, DMSO) δ 51,6, 51,8, 53,4, 63,5, 107,9, 119,1, 127,8, 128,0, 128,2, 128,9, 137,3, 147,5, 158,3; ES MS (M+1) 301,12; HRMS calculated for C17H20N2About3: 300,35.

Example 3. 1-Benzyl-3-hydroxy-4-thiomorpholine-1-ylmethyl-1H-pyridine-2-he

1H NMR (300 MHz, DMSO) δ 2,92 (m, 4H), to 3.38 (m, 4H), 4,17 (s, 2H), 5,16 (s, 2H), 6,29 (d, J=7.5 MHz, 1H), 7,34 (m, 6H), becomes 9.97 (s, 1H);19F NMR (300 MHz, DMSO) δ 88,4;13With NMR (75 MHz, DMSO) δ 24,3, 51,9, 53,4, 53,7, 107,9, 110,9, 127,8, 128,0, 128,2, 128,8,137,2, 147,6, 157,6; ES MS (M+1) 317,14; HRMS calculated for C17H20N2O2S, found: (M+1) 317,13.

Example 4. 1-Benzyl-3-hydroxy-4-thiazolidin-1-ylmethyl-1H-pyridine-2-he

1H NMR (300 MHz, DMSO) δ to 3.09 (t, J=6.3 Hz, 2H), 3,42 (t, J=6.3 Hz, 2H), a 4.03 (s, 2H), 4,29 (s, 2H), 5,16 (s, 2H), 6,34 (d, J=7.2 Hz, 1H), 7,34 (m, 6H), 10,48 (broad s, 1H);19F NMR (300 MHz, DMSO) δ 87,9;13With NMR (75 MHz, DMSO) δ 28,3, 48,3, 50,1, 56,3, 57,0, 107,4, 122,1, 127,8, 128,2, 128,8, 137,4, 146,3, 157,6; ES MS (M+1) 303,08; analytical calculated for C18H19N2O4SF: 51,92; N 4,60; N Of 6.73; S 7,70 found: 51,67; N 4,48; N 6,69; S 7,65.

Example 5. 1-Benzyl-4-(benzylamino)-3-hydroxy-1H-pyridine-2-he

1H NMR (300 MHz, DMSO) δ 4,01 (s, 2H), 4,20 (s, 2H), 5,16 (s, 2H), 6,34 (d, J=7.2 Hz, 1H), was 7.36 (m, 11H), 9,16 (broad s, 1H);19F NMR (252 MHz, DMSO) δ 88,6;13With NMR (75 MHz, DMSO) δ; ES MS (M+1) 321,16; analytically calculated the C 22H21F3N2O4: 60,83; N To 4.87; N 6,45 found: 60,75; N 4,56; N 6,34.

Example 6. 1-Benzyl-3-hydroxy-4-[(2-pyridin-2-ylethylamine)methyl]-1H-pyridine-2-he

1H NMR (300 MHz, DMSO) δ 3,26 (m, 2H), 3,37 (m, 2H), 4,08 (s, 2H), 5,17 (s, 2H), 6,34 (d, J=7.2 Hz, 1H), 7,38 (m, 6H), 7,86 (d, J=5.7 Hz, 2H), 8,84 (m, 2H), to 9.32 (broad s, 1H);19F NMR (252 MHz, DMSO) δ 88,6;13With NMR (75 MHz, DMSO) δ 31,5, 44,1, 46,3, 51,8, 106,9, 114,8, 127,1, 128,8, 137,4, 143,8, 146,1, 155,3, 157,5, 158,4; ES MS (M+1) 336,18; HRMS calculated for C20H21N3O2335,40 found: 336,16.

Example 7. 1-Benzyl-3-hydroxy-4-pyrrolidin-1-ylmethyl-1H-pyridine-2-he

1H NMR (300 MHz, DMSO) δ a 1.96 (s, 4H), and 3.16 (s, 2H), 3.43 points (s, 2H), 4,23 (s, 4H), to 5.17 (s, 2H), 6,34 (d, J=7.2 Hz, 1H), 7,34 (m, 6H);19F NMR (252 MHz, DMSO) δ 88,7;13With NMR (75 MHz, DMSO) δ 22,8, 50,9, 51,8, 53,7, 107,3, 118,0, 128,0, 128,2, 128,9, 137,3, 146,7, 157,6; ES MS (M+1) 285,13; calculated for C19H21F3N2O4: 57,28; N 5,31; N, 7.03 is found: 57,10; N 5,11; N 7,02.

Example 8. 1-Benzyl-4-(4-benzylpiperidine-1-ylmethyl)-3-hydroxy-1H-pyridine-2-he

1H NMR (DMSO) δ of 1.43 (m, 2H), 1,72 (m, 4H), 2,96 (m, 2H), 3,41 (m, 3H), 4.09 to (s, 2H), 5,16 (s, 2H), 6,34 (d, J=7.2 Hz, 1H), 7,35 (m, 11H);19F NMR (252 MHz, DMSO) δ 88,8;13With NMR (75 MHz, DMSO) δ; ES MS (M+1) 389,21; HRMS calculated for C25H28N2O2: 388,50 found: (M+1) 389,22.

Example 9. 1-Benzyl-4-(4-benzylpiperazine-1-ylmethyl)3-hydroxy-1H-pyridine-2-he

1H NMR (300 MHz, DMSO) δ 3,11 (broad s, 4H), 3,81 (s, 2H) 4,18 (s, 2H), further 5.15 (s, 2H), 6,24 (d, J=7.2 Hz, 1H), 7,34 (m, 6N), 7,46 (m, 5H);19F NMR (252 MHz, DMSO) δ 88,2;13With NMR (75 MHz, DMSO) δ; ES MS (M+1) 390,21; HRMS calculated for C24H27N3O2: 389,49 found: (M+1) 390,21.

Example 10. 1-Benzyl-3-hydroxy-4-(3-hydroxypyrrolidine-1-ylmethyl)-1H-pyridine-2-he

1H NMR (300 MHz, DMSO) δ 1,90 (m, 1H), 3,18 (m, 2H), 3,47 (m, 3H), 4,24 (s, 2H), 4,43 (s, 1H), 5,17 (s, 2H), 6,34 (d=7.2 Hz, 1H), 7,34 (m, 6N);19F NMR (252 MHz, DMSO) δ 89,0;13With NMR (75 MHz, DMSO) δ 51,8, 52,6, 61,3, 68,6, 107,4, 117,9, 128,0, 128,9, 137,3, 146,7, 157,6; ES MS (M+1) 301,13; HRMS calculated for C17H20N2O3: 300,35 found: (M+1) 301,15.

Example 11. 1-Benzyl-4-[([1,3]dioxolane-2-iletilmedigini)methyl]-3-hydroxy-1 H-pyridin-2-he

1H NMR (300 MHz, DMSO) δ of 2.81 (s, 3H), 3,35 (d, J=3,9 Hz, 2H), with 3.89 (m, 2H), 4,01 (m, 2H), 4,21 (m, 2H), 5,17 (s, 2H), 5,27 (t, J=3,9 Hz, 1H), 7,35 (m, 6N);19F NMR (252 MHz, DMSO) δ 88,5;13With NMR (75 MHz, DMSO) δ; ES MS (M+1) 331,18; HRMS calculated for C18H22N2O4: 330,38 found: (M+1) 331,16.

Example 12. 1-Benzyl-3-hydroxy-4-{[(tetrahydrofuran-2-ylmethyl)amino]methyl}-1H-pyridine-2-he

1H NMR (300 MHz, DMSO) δ and 1.56 (m, 1H), to 1.86 (m, 2H), 1,99 (m, 1H), 37 of 2.92 (m, 1H), 3,05 (m, 1H), 3,80 (m, 2H), 4.09 to (m, 3H), 5,16 (s, 2H), 6,34 (d, J=7.2 Hz, 1H), 7,34 (m, 6H), 8,91 (broad s, 1H);19F NMR (252 MHz, DMSO) δ 88,5;13With NMR (75 MHz, DMSO) δ; ES MS (M+1) 315,16; HRMS calculated for C18H22N2O3: 314,38 found: (M+1) 315,16.

Example 13. 1-Benzyl-hydroxy-4-[(2-methoxyethylamine)methyl]-1H-pyridine-2-he

1H NMR (300 MHz, DMSO) δ 3,13 (broad s, 2H), 3,30 (s, 3H)and 3.59 (t, J=5.4 Hz, 2H), was 4.02 (s, 2H), 5,16 (s, 2H), 6,34 (d, J=7.2 Hz, 1H), 7,34 (m, 6H), 8,91 (broad s, 1H);19F NMR (252 MHz, DMSO) δ 88,4;13With NMR (75 MHz, DMSO) δ; ES MS (M+1) 289,13; HRMS calculated for C16H20N2O3: 288,34 found: (M+1) 289,15.

Example 14. 1-Benzyl-4-(1,4-dioxa-8 azaspiro[4,5]Dec-8-ylmethyl)-3-hydroxy-1H-pyridine-2-he

1H NMR (300 MHz, DMSO) δ 1,90 (m, 4H), 3,11 (m, 2H), 3.43 points (m, 2H), 3,93 (s, 4H), 4,19 (s, 2H), 5,16 (s, 2H), 6,34 (d, J=7.2 Hz, 1H), 7,34 (m, 6H), 10,01 (broad s, 1H);19F NMR (252 MHz, DMSO) δ 88,3;13With NMR (75 MHz, DMSO) δ 31,7, 50,7, 51,9, 52,5, 64,5, 101,1, 108,0, 116,5, 127,8, 128,0, 128,3, 128,9, 137,3, 147,5, 157,6; ES MS (M+1) 357,19; HRMS calculated for C20H24N4O2: 356,42 found: (M+1) 357,18.

Example 15. 4-Azepin-1-ylmethyl-1-benzyl-3-hydroxy-1H-pyridine-2-he

1H NMR (300 MHz, DMSO) δ to 1.61 (m, 4H), of 1.80 (m, 4H), 3,20 (m, 4H), 4,17 (s, 2H), 5,16 (s, 2H), 6,34 (d, J=7.2 Hz, 1H), 7,34 (m, 6H);19F NMR (252 MHz, DMSO) δ 88,9;13With NMR (75 MHz, DMSO) δ 22,8, 26,4, 51,8, 53,4, 54,4, 107,6, 117,2, 127,9, 128,0, 18,2, 128,9, 137,3, 147,2, 157,6; ES MS (M+1) 313,18; HRMS calculated for C19H27N4About3: 312,41 found: (M+1) 313,19.

Example 16. 4-Asokan-1-ylmethyl-1-benzyl-3-hydroxy-1H-pyridine-2-he

1H NMR (300 MHz, DMSO) δ to 1.59 (m, 10H), 3,18 (m, 2H), 3,38 (m, 2H), 4,17 (s, 2H), 5,16 (s, 2H), 6,34 (d, J=7.2 Hz, 1H), 7.34 (m, 6H);19F NMR (252 MHz, DMSO) δ 88,9;13With NMR (75 MHz, DMSO) δ; ES MS (M+1) 327,2; HRMS calculated for C20H26 N2O2: 326,43, found (M+1) 327,20.

Example 17. 1-Benzyl-4-[1,4']-bipiperidine-1'-ylmethyl-3-hydroxy-1H-pyridine-2-he

1H NMR (300 MHz, DMSO) δ 1,43-to 1.98 (m, 10H), of 2.21 (m, 2H), 3,01 (m, 4H), 3.43 points (m, 3H), of 4.12 (s, 2H), 5,16 (s, 2H), 6,34 (d, J=7.2 Hz, 1H), 7,34 (m, 6H), 9,85 (broad s, 1H);19F NMR (252 MHz, DMSO) δ 88,7;13With NMR (75 MHz, DMSO) δ 21,6, 22,9, 23,8, 49,6, 50,5, 51,8, 53,0, 59,5, 108,0, 127,8, 128,0, 128,2, 128,9, 137,3, 147,5, 157,6; ES MS (M+1) 382,4; HRMS calculated for C23H31N3O2: 383,51, found (M+1) 382,25.

Example 18. 1-Benzyl-4-(3,4-dihydro-2H-quinoline-1-ylmethyl)-3-hydroxy-1H-pyridine-2-he

1H NMR (300 MHz, DMSO) δ of 3.13 (t, J=6.3 Hz, 2H), 3,52 (m, 2H), 4,28 (s, 2H), to 4.41 (s, 2H), by 5.18 (s, 2H), 6,34 (d, J=7.2 Hz, 1H), 7.23 percent-7,41 (m, 10H), 10,15 (broad s, 1H);19F NMR (252 MHz, DMSO) δ 88,9;13With NMR (75 MHz, DMSO) δ 25,4; 49,3, 51,8, 52,7, 52,9, 107,6, 11,6, 116,8, 126,9, 127,0, 127,9, 128,0, 128,1, 128,2, 128,8, 128,9, 131,7, 137,3, 147,3, 157,6; ES MS (M+1) 347,40; HRMS calculated for C22H22N2O2: 346,42, found (M+1) 347,17.

Example 19. Methyl ester 1-(1-benzyl-3-hydroxy-2-oxo-1,2-dihydropyridines-4-ylmethyl)pyrrolidin-2-carboxylic acid

1H NMR (300 MHz, DMSO) δ a 2.01 (m, 3H), of 2.45 (m, 1H), 3,26 (m, 1H), 3,53 (m, 1H), 3,69 (s, 3H), 4,30 (m, 3H), of 5.17 (s, 2H), 6,27 (d, 6.9 Hz, 1H), 7,35 (m, 6H),19F NMR (252 MHz, DMSO) δ 88,3;13With NMR (75 MHz, DMSO) δ; ES MS (M+1) 343,20; HRMS calculated for C19H22N2O4: 342,39, found (M+1).

Example 20. 1-Benzyl-3-hydroxy-4-[(2-hydroxy-1,1-dimethylethylamine)methyl]-nereden-2-he

1H NMR(300 MHz, DMSO) δ 1.27mm (s, 6N), 3,49 (s, 2H), 3,95 (s, 2H), 5,17 (s, 2H), 6,34 (d, J=7.2 Hz, 1H), 7,34 (m, 6H), of 8.47 (broad s, 2H), 9,94 (broad s, 1H);19F NMR (252 MHz, DMSO) δ 88,7;13With NMR (75 MHz, DMSO) δ; ES MS (M+1) 303,19; HRMS calculated for C17H22N2About3: 302,37, found (M+1) 303,17.

Example 21. 1-Benzyl-3-hydroxy-4-{[(pyridine-4-ylmethyl)amino]methyl}-N-pyridin-2-he

1H NMR (300 MHz, DMSO) δ 4,07 (s, 2H), 4,32 (s, 2H), 5,16 (s, 2H), 6,34 (d, J=7.2 Hz, 1H), 7,34 (m, 6H), a 7.62 (d, J=5.7 Hz, 2H), 8,71 (d, J=4.5 Hz, 2H);19F NMR (252 MHz, DMSO) δ 88.0;13With NMR (75 MHz, DMSO) δ; ES MS (M+1) 322,17; HRMS calculated for C19H19N3About2: 321,37, found (M+1) 322,15.

Example 22. 1-Benzyl-3-hydroxy-4-(2-methoxypiperidine-1-ylmethyl)-1H-pyridine-2-he

1H NMR (300 MHz, DMSO) δ 1,71 (m, 1H), of 1.84 (m, 1H), 1,99 (m, 1H), 2,15 (m, 1H), 3,19 (m, 1H), 3,30 (s, 3H), 3,41 (m, 1H), 3,62 (m, 2H), of 3.77 (m, 1H), 4,15 (m, 1H), 4,39 (m, 1H), 5,17 (s, 2H), 6,34 (d, J=7.2 Hz, 1H), 7,34 (m, 6H), 9,60 (broad s, 1H);19F NMR (252 MHz, DMSO) δ 88,3;13With NMR (75 MHz, DMSO) δ; ES MS (M+1) 329,2; HRMS calculated for C19H24N2O3: 328,41, found (M+1).

Example 23. 1-Benzyl-4-{[(furan-2-ylmethyl)amino]methyl}-3-hydroxy-1H-pyridine-2-he

1H NMR (300 MHz, DMSO) δ 4,00 (s, 2H), 4,28 (s, 2H), 5,16 (s, 2H), 6,27 (d, J=6,9 Hz, 1H), 6,54 (m, 1H), 6,65 (m, 1H), 7,34 (m, 6H), 7,80 (m, 1H), 9,27 (broad s, 1H);19F NMR (252 MHz, DMSO) δ 88,3;13With NMR (75 MHz, DMSO) δ; ES MS (M+1) 323,15; HRMS calculated for C18H18 2About3: 310,35, found (M+1).

Example 24. 1-Benzyl-3-hydroxy-4-[(2-methylsulfonylamino)methyl]-1H-pyridine-2-he

1H NMR (300 MHz, DMSO) δ 2,10 (s, 3H), 2,74 (t, J=6.9 Hz, 2H), and 3.16 (t, J=8,1 Hz, 2H), of 4.05 (s, 2H), 5,17 (s, 2H), 6,34 (d, J=7.2 Hz, 1H), 7,34 (m, 6H);19F NMR (252 MHz, DMSO) δ 89,0; ES MS (M+1) 305,14; HRMS calculated for C16H20N2O2S: 304,41, found(M+1).

Example 25. 1-Benzyl-3-hydroxy-4-(2-pyridin-2-iparralde-1-ylmethyl)-1H-pyridine-2-he

1H NMR (300 MHz, DMSO) δ 2,12 (m, 4H), 3,39 (m, 1H), 3,63 (m, 1H), 4,07 (m, 2H), 4,60 (m, 1H), 5,10 (m, 2H), x 6.15 (d, J=6,9 Hz, 1H), 7,33 (m, 6H), 7,44 (m, 1H), with 8.05 (d, J=8,1 Hz, 1H), 8,59 (d, J=4,8 Hz, 1H), total of 8.74 (s, 1H);19F NMR (252 MHz, DMSO) δ 88,0; ES MS (M+1) 362,22; HRMS calculated for C22H23N3O2: 361,44, found (M+1).

Example 26. 1-Benzyl-3-hydroxy-4-[(4-methoxybenzylamine)methyl]-1H-pyridine-2-he

1H NMR (300 MHz, DMSO) δ 3,70 (s, 3H), 3,98 (s, 2H), 4,13 (s, 2H), 5,16 (s, 2H), 6,28 (d, J=7.5 Hz, 1H), 7,00 (d, J=9.0 Hz, 4H), 7,34 (m, 6H); 9,07 (broad s, 1H);19F NMR (252 MHz, DMSO) δ 89,0; ES MS (M+1) 351,10; HRMS calculated for C21H22N2O3: 350,41, found (M+1) 351,17.

Example 27. 1-Benzyl-3-hydroxy-4-[(1-phenylethylamine)methyl]-1H-pyridine-2-he

1H NMR (300 MHz, DMSO) δ to 1.59 (d, J=7.2 Hz, 3H), 3,71-3,93 (m, 2H), of 4.45 (m, 1H), further 5.15 (s, 2H), 6,28 (d, J=7.5 Hz, 1H), 7,34 (m. 11H);19F NMR (252 MHz, DMSO) δ 88,9;13With NMR (75 MHz, DMSO) δ 19,6, 42,5, 51,7, 58,0, 106,8, 119,3, 128,0, 128,1, 128,2, 128,9, 129,3, 129,4, 137,3, 145,9, 158,3; ES MS (M+1) 335,13; HRMS calculated the La C 21H22N2O2: 334,41, found (M+1) 335,17.

Example 28. 1-Benzyl-4-[4-(6-chloropyridin-3-yl)piperazine-1-ylmethyl]-3-hydroxy-1H-pyridine-2-he

1H NMR (300 MHz, DMSO) δ 3,18 (m, 2H), 3,48 (m, 4H). 4,19 (s, 2H), 4,46 (m, 2H), 5,16 (s, 2H), 6,62 (d, J=7.2 Hz, 1H), 7,35 (m, 6H), of 7.48 (m, 1H), 7,68 (m, 1H), and 11.5 (broad s, 1H);13With NMR (75 MHz, DMSO) δ 42,1, 50,3, 51,9, 52,5, 108,2, 116,2, 118,0, 128,0, 128,2, 128,9, 129,8, 137,3, 147,4, 157,6, 158,8; ES MS (M+1) 476,09. HRMS calculated for C21H22ClN5O2: 411,88, found (M+1) 412,76.

Example 29. 1-Benzyl-3-hydroxy-4-[(3-imidazol-1-ylpropionic)methyl]-1H-pyridine-2-he

1H NMR (300 MHz, DMSO) δ 2,19 (m, 2H), 2,97 (m, 2H), was 4.02 (s, 2H), 4,30 (t, J=6.6 Hz, 2H), 5,17 (s, 2H), 6,30 (d, J=6,9 Hz, 1H), was 7.36 (m, 6H), 7,26 (s, 1H), 7,76 (s, 1H), 9,03 (s, 1H), 9,11 (s, 1H);19F NMR (252 MHz, DMSO) δ 88,5;13With NMR (75 MHz, DMSO) δ 26,5, 44,0, 46,0, 51,8, 106,8, 118,7, 120,5, 122,2, 127,9, 128,2, 128,9, 135,8, 137,4, 146,0, 158,2; ES MS (M+1) 339,05; HRMS calculated for C19H22N4O2: 338,44, found (M+1) 339,18.

Example 30. 1-Benzyl-4-cycloheptylmethyl-3-hydroxy-1H-pyridine-2-he

1H NMR (300 MHz, DMSO) δ of 1.55 (m, 10H), 2,03 (m, 2H), 3,18 (s, 1H), 3,99 (m, 2H), 5,17 (s, 2H), 6,32 (d, J=6,9 Hz, 1H), 7,35 (m, 6H), 8,65 (broad s, 2H), 9,98 (broad s, 1H);19F NMR (252 MHz, DMSO) δ 88,6;13With NMR (75 MHz, DMSO) δ 23,0, 27,2, 30,4, 41,6, 51,7, 58,9, 107,0, 111,7, 127,9, 128,0, 128,2, 128,8, 137,4, 146,0, 157,5; ES MS (M+1) 327,13; HRMS calculated for C20H26N2O2: 326,43, found (M+1) 327,20.

Example 31. 1-Benzyl-3-hydroxy-4-[(4-methylcyclo is ciclamino)methyl]-1H-pyridine-2-he

1H NMR (300 MHz, DMSO) δ of 0.93 (d, J=6.9 Hz, 3H), of 1.38 (m, 4H), of 1.74 (m, 4H), of 2.05 (m, 1H), 3,10 (m, 1H), 4,01 (s, 2H), 5,17 (s, 2H), of 6.31 (m, 1H), 7,34 (m, 6H), with 8.05 (broad s, 2H), 9,98 (broad s, 1H);19F NMR (252 MHz, DMSO) δ 88,9;13With NMR (75 MHz, DMSO) δ; ES MS (M+1) 327,14; HRMS calculated for C20H26N2O2: 326,43, found (M+1) 372,20.

Example 32. 1-Benzyl-4-[(1-benzylpiperidine-4-ylamino)methyl]-3-hydroxy-1H-pyridine-2-he

1H NMR (300 MHz, DMSO) δ or 1.77 (m, 2H), 2,31 (m, 2H), 2,98 (m, 2H), 3,30 (m, 3H), 3.46 in (m, 2H), a 4.03 (s, 2H), 29 (s, 2H), 5,16 (s, 2H), 6,30 (d, J=7.5 Hz, 1H), 7,34 (m, 6H), 7,49 (s, 5H), 9,12 (broad s, 1H), of 10.05 (broad s, 1H);19F NMR (252 MHz, DMSO) δ 88,8;13With NMR (75 MHz, DMSO) δ 27,1, 43,4, 51,8, 52,1, 54,2, 54,7, 57,6, 106,9, 118,5, 128,0, 128,1, 128,8, 129,3, 129,8, 130,7, 131,3, 137,3, 146,2, 157,4; ES MS (M+1) 404,56; HRMS calculated for C25H28N3O2: 403,52, found (M+1) 404,23.

Example 33. 3-[(1-Benzyl-3-hydroxy-2-oxo-1,2-dihydropyridines-4-ylmethylamino]azepin-2-he

1H NMR (300 MHz, DMSO) δ 1,25 (m, 1H), 1,59 (m, 2H), 1,74 (m, 1H), 1,92 (m, 1H), 2,10 (m, 1H), 3,18 (m, 3H), a 4.03 (s, 2H), 4,2 (m, 1H), 5,17 (s, 2H), 6,33 (d, J=7.5 Hz, 1H), 7,34 (m, 6H), 8,31 (t, J=a 5.4 Hz, 1H), 9,07 (broad s, 2H), 9,90 (broad s, 1H);19F NMR (252 MHz, DMSO) δ 88,4;13With NMR (75 MHz, DMSO) δ 27,0, 27,2, 28,4, 43,4, 51,7, 59,3, 107,1, 118,9, 127,8, 127,9, 128,1, 128,9, 137,4, 146,0, 157,5, 166,3; ES MS (M+1) 342,01; HRMS calculated for C19H23N3About3: 341,40, found (M+1) 342,18.

Example 34. 1-Benzyl-4-[(1-benzylpyrrolidine-3-ylamino)methyl]-3-hydroxy-1 H-pyridin-2-he

1H NMR (300 MHz, DMSO) δ 2,22 (m, 2H), 2,42 (m, 1H), 3,39 (m, 3H), 3,68 (m, 1H), 4,06 (s, 2H), 4,39 (s, 2H), 5,17 (s, 2H), 6,33 (d, J=7.5 Hz, 1H), 7,30-7,52 (m, 11H);19F NMR (252 MHz, DMSO) δ 88,5;13With NMR (75 MHz, DMSO) δ 27,1, 43,4, 51,8, 52,1, 54,2, 54,7, 57,5, 106,9, 118,5, 128,0, 128,8, 129,3, 129,8, 130,7, 131,3, 137,3, 146,2, 157,5; ES MS (M+1) 390,14; HRMS calculated for C34H27N3O2: 389,49, found (M+1) 390,21.

Example 35. 3-Hydroxy-1-(3-methoxybenzyl)-4-pyrrolidin-1-ylmethyl-1H-pyridine-2-he

1H NMR (300 MHz, DMSO) δ 1,89 (m, 2H), 1,99 (m, 2H), of 3.07 (m, 2H), 3,41 (m, 2H), 3,74 (s, 3H), 4,17 (m, 2H), 5,17 (s, 2H), 6,51 (d, J=7.2 Hz, 1H), 6.90 to (m, 3H), 7,27 (t, J=7.5 Hz, 1H), 7,37 (d, J=7,2 Hz, 1H), 9,98 (broad s, 1H), of 10.72 (broad s, 1H);13With NMR (75 MHz, DMSO) δ 23,0; 50,3, 51,7, 53,2, 55,4, 107,6,113,2,114,2, 118,2, 120,3, 127,8, 130,0, 18,8, 146,4, 157,6, 159,6; ES MS (M+1) 315,82; HRMS calculated for C18H22N2O3: 314,38, found (M+1) 315,17.

Example 36. 1-Benzyl-3-hydroxy-4-[4-(2-methoxyphenyl)piperazine-1-ylmethyl]-1H-pyridine-2-he

1H NMR (300 MHz, DMSO) δ 2,95 (m, 2H), 3,30 (m, 2H), 3,48 (m, 4H), of 3.80 (s, 3H), 4,25 (s, 2H), by 5.18 (s, 2H), 6,34 (d, J=7.2 Hz, 1H), 6,93(m, 2H), 7,01(m, 2H), 7,34 (m, 6H);19F NMR (252 MHz, DMSO) δ 88,5;13With NMR (75 MHz, DMSO) δ 47,2, 51,8, 53,0. 55,3, 108,1, 112,2, 114,8, 116,2, 118,6, 121,2, 123,8, 127,8. 128,0, 128,9, 137,3, 139,6, 147,5, 152,2, 157,6; ES MS (M+1) 405,82; HRMS calculated for C24H27N3About3: 405,49, found (M+1) 406,21.

Example 37. 1-Benzyl-3-hydroxy-4-[(1-phenylethyl-R-amino)methyl]-1H-pyridine-2-he

1H NMR (300 MHz, DMSO) δ was 1.58 (d, J=6.9 Hz, 3H), 3,74 (m, 2H), of 4.44 (m, 1), 5,14 (s, 2H), 6,23 (d, J=7.2 Hz, 1H), 7,35 (m, 6H);19F NMR (252 MHz, DMSO) δ 89,4;13With NMR (75 MHz, DMSO) δ 19,6, 42,6, 51,7, 58,0, 106,9, 18,7, 128,0, 128,1, 128,8, 129,3, 129,4, 137,2, 137,4, 145,9, 157,5; ES MS (M+1) 335,13; analytical calculated for C21H22N2O2: 334,41, found (M+1) 335,31.

All quantities, including quantities, percentages, fractions and ratios, presents "approximately" and the number may not correspond exactly to the given value, if not specified otherwise.

Unless otherwise specified, the indefinite and definite articles mean "one or more".

All documents cited in the description of the invention, includes, in its relevant part, by reference; the citation of any document is not to be construed as recognition of its prior art against the present invention.

Although described and illustrated private embodiment of the invention, those skilled in the art should be apparent that numerous variations and modifications can be made without going beyond the scope of this invention. Thus, in these claims reflect all such variations and modifications that fall within the scope of this invention.

Below are data on the biological activity of compounds in accordance with the above examples.

The activity of N-periods in relation to AMI is peptidase (bMAP)

1. The compound of formula (I)

where (a) each R1independently selected from hydrogen, and alkoxygroup;

b) R2represents a hydrogen atom;

in R3and R4each independently from another selected from hydrogen, alkyl, alkenylphenol, heteroalkyl groups, aryl; or R3and R4together with the associated nitrogen atom form a heteroaryl or geteroseksualy Deputy, optionally substituted by one or more hydrogeography, carboxyl group, keto-, tyketto-, phenyl group, alkyl, heteroalkyl group, heteroaryl, heterocyclization, spirocyclohexane, and combinations thereof;

g) R5and R6each represents a hydrogen atom;

or optical isomers, diastereomers and enantiomers represented by the above formula and their pharmaceutically acceptable salts.

2. The compound according to claim 1, where R1represents a hydrogen atom.

3. The compound according to claim 1 or 2, where R3and R4and connected with them the nitrogen atom, represent pyrrolidino ring.

4. Compounds according to claim 1, selected from

1-benzyl-hydroxy-4-piperidine-1-ylmethyl-1H-pyridine-2-it;

1-benzyl-3-hydroxy-4-morpholine-1-ylmethyl-1H-pyridine-2-it;

1-benzyl-3-hydroxy-4-thiomorpholine-1-ylmethyl-1H-pyridine-2-it;

1-benzyl-3-hydroxy-4-thiazolidin-1-ylmethyl-1H-pyridine-2-it;

1-benzyl-3-hydroxy-4-pyrrolidin-1-ylmethyl-1H-pyridine-2-it;

1-benzyl-3-hydroxy-4-(3-hydroxypyrrolidine-1-ylmethyl)-1H-pyridine-2-it;

1-benzyl-4-[([1,3]dioxolane-2-iletilmedigini)methyl]-3-hydroxy-1H-pyridine-2-it;

1-benzyl-4-(1,4-dioxa-8 azaspiro[4,5]Dec-8-ylmethyl)-3-hydroxy-1H-pyridine-2-it;

4-azepin-1-ylmethyl-1-benzyl-3-hydroxy-1H-pyridine-2-it;

4-asokan-1-ylmethyl-1-benzyl-3-hydroxy-1H-pyridine-2-it;

1-benzyl-4-[1,4']-bipiperidine-1'-ylmethyl-3-hydroxy-1H-pyridine-2-it;

1-benzyl-4-(3,4-dihydro-2H-quinoline-1-ylmethyl)-3-hydroxy-1H-pyridine-2-it;

1-(1-benzyl-3-hydroxy-2-oxo-1,2-dihydropyridines-4-ylmethyl)pyrrolidin-2-carboxylic acid methyl ester;

1-benzyl-3-hydroxy-4-(2-methoxypiperidine-1-ylmethyl)-1H-pyridine-2-it;

1-benzyl-3-hydroxy-4-[(4-methoxybenzylamine)methyl]-1H-pyridine-2-it;

1-benzyl-3-hydroxy-4-[(3-imidazol-1-ylpropionic)methyl]-1H-pyridine-2-it;

3-hydroxy-1-(3-methoxybenzyl)-4-pyrrolidin-1-ylmethyl-1H-pyridine-2-it.

5. The compound according to claim 4 represents 1-benzyl-3-hydroxy-4-(2-methoxypiperidine-1-ylmethyl)-1H-feast of the DIN-2-it.

6. The use of compounds according to claim 1 for obtaining a pharmaceutical composition having antimicrobial activity.

7. Antimicrobial pharmaceutical composition containing

a) a safe and effective amount of a compound according to claim 1; and

b) a pharmaceutically acceptable carrier.



 

Same patents:

FIELD: organic chemistry, insecticides.

SUBSTANCE: invention relates to compounds of formula I , wherein W is halogen, C1-C6-alkyl, C1-C6-alkoxy, C1-C4-haloalkyl or C1-C4-haloalkoxy; X is hydrogen, halogen, C1-C6-alkyl; Y is hydrogen, halogen, C1-C6-alkyl, C1-C4-haloalkyl, C1-C4-haloalcoxy or cyano; Z is hydrogen, halogen, etc.; G is halogen or nitro; meanings of the other substituents are as defined in specification. Also disclosed are methods for production of said compounds by interaction compounds of formula II with halogenation agents in presence of solvent and optionally of radical initiator of with fumed nitric acid in presence of solvent.

EFFECT: new compounds with insecticide activity.

17 cl, 20 tbl, 114 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of derivatives of indolinospiropyrane of the formula (1): wherein R1 means (C1-C18)-alkyl; each among R2 and R3 mean independently (C1-C4)-alkyl; R4 means hydrogen atom, hydroxy-group, trichloromethyl, trifluoromethyl formyl, (C1-C)-alkyl, halogen atom, (C1-C4)-alkoxy-, nitro-group; x = 1 or 2. Method comprises the following steps: (i) synthesis of indoline on polymeric carrier of the formula (III): wherein R1 means (C1-C18)-alkyl; each among R2 and R means independently (C1-C4)-alkyl; (ii) treatment of indoline-carrying polymeric carrier wherein this carrier represents hydroxy-resin at temperature from 50°C to 120°C in inert atmosphere for time from 14 h to 11 days with a derivative of salicylic aldehyde of the formula (VI): wherein R4 means hydrogen atom, hydroxy-group, trichloromethyl, trifluoromethyl, formyl, (C1-C4)-alkyl, halogen atom, (C1-C4)-alkoxy-, nitro-group; x = 1 or 2 to yield indolinospiropyrane compound of the formula (I), and (iii) release of indolinospiropyrane compound of the formula (I). Invention proves synthesis of novel derivatives of indolinospiropyrane possessing photochromic properties.

EFFECT: improved method of synthesis.

8 cl, 28 ex

FIELD: organic chemistry.

SUBSTANCE: invention describes C2-phenyl-substituted cyclic ketoenols of the general formula: wherein W means hydrogen atom, alkyl with 1-6 carbon atoms; X means alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms; Y means hydrogen atom, methyl, ethyl, isopropyl, alkenyl with 2-6 carbon atoms, ethynyl; Z means hydrogen atom, alkyl with 1-6 carbon atoms under condition that at least one of residues W, X, Y or Z means a chain with at least 2 carbon atoms but only one of residues X and Y can mean alkenyl with 2-6 carbon atoms; CKE means one of the following groups: , , and wherein A means hydrogen atom, alkyl with 1-6 carbon atoms; B means hydrogen atom, alkyl with 1-6 carbon atoms; A and B in common with carbon atom to which they are bound mean cycloalkyl with 5-6 carbon atoms wherein the ring carbon atom can be substituted with oxygen atom and can be substituted with alkyl with 1-6 carbon atoms or alkoxyl with 1-6 carbon atoms; A and B in common mean group of the formula: D means hydrogen atom or phenyl substituted with fluorine atom if CKE means group of the formula (4); G means hydrogen atom (a) or one of groups of the formula: or wherein R1 means alkyl with 1-6 carbon atoms, alkoxymethyl with 1-2 carbon atoms; R2 means alkyl with 1-4 carbon atoms; A and Q1 in common mean alkanediyl with 3-4 carbon atoms; Q2 means hydrogen atom. Invention provides preparing compound of the formula (I) possessing with insecticide, acaricide and herbicide activity.

EFFECT: valuable properties of compounds.

2 cl, 8 tbl, 32 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes derivative of 3,4-dihydroisoquinoline of the formula (I) or its nontoxic salt and a pharmaceutical agent comprising its as an active component (wherein all symbols have the same values as given in description). Compound of the formula (I) possesses agonistic effect on CB2-receptors and, therefore, it can be used for prophylaxis and/or treatment of different diseases, for example, asthma, nasal allergy, atopic dermatitis, autoimmune diseases, rheumatic arthritis, immune dysfunction, postoperative pain and carcinomatous pain.

EFFECT: valuable medicinal properties of derivatives.

14 cl, 33 tbl, 561 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to substituted 3-oxo-1,2,3,4-tetrahydroxinoxalines of general formula 1 , wherein R1 represents substituted sulfanyl or substituted sulfonyl group, containing as substituent optionally substituted C1-C4-alkyl, optionally substituted C3-C8-cycloalkyl, aryl-(C1-C4)alkyl optionally substituted in aril or alkyl group, heterocyclyl-(C1-C4)alkyl optionally substituted in heterocycle or alkyl group; R2 and R3 independently represent hydrogen, halogen, CN, NO2, optionally substituted hydroxyl, optionally substituted amino group, optionally substituted carboxylic group, optionally substituted carbamoyl group, optionally substituted arylcarbonyl group or optionally substituted heterocyclylcarbonyl group; R4 and R5 independently represent hydrogen or inert substituent. Claimed compounds are high effective kaspase-3 inhibitors and are useful in production of pharmaceutical compositions for treatment of diseases associated with excess apoptosis activation, as well as for experimental investigations of apoptosis in vivo and in vitro. Also disclosed are pharmaceutical composition in form of tablets, capsules or injections in pharmaceutically acceptable package, as well as method for production thereof and therapy method.

EFFECT: pharmaceutical composition for apoptosis treatment and investigation.

6 cl, 3 dwg, 8 ex, 1 tbl

FIELD: pharmaceutical chemistry, in particular pharmaceutical compositions.

SUBSTANCE: new spyro(2H-1-benzopyrane-2,4'-piperidine) derivatives of general formula I

and pharmaceutically acceptable salts thereof are disclosed. In formula dotted line is optional bond; Y is 1-4 substituents independently selected from hydrogen, halogen, C1-C4-alkyl, optionally substituted with one or more halogen, C1-C6-alkyloxy, optionally substituted with halogen or C3-C6-cycloalkyl, C2-C6-alkenyloxy, C2-C6-alkinyloxy, C3-C6-cycloalkyloxy, C6-C12-aryloxy, arylalkyloxy, pyridilmethoxy, SR3, NR3R4, OSO2R5, and NR3SO2R4; or two Y together may form O-(CH2)n-O or O-(CF2)n-O, wherein n is 1 or 2: or Y is condensed C5-C6-aryl group; X is 1-3 substituents independently selected from hydrogen, halogen, hydroxyl, C1-C6-alkoxy, and C1-C4-alkyl; R1 is hydrogen, C1-C4-alkyl, or C6-C12-aryl; R2, R3, and R4 are independently hydrogen or C1-C4-alkyl; R5 is C6-C12-aryl. Also disclosed are pharmaceutical compositions including said derivatives and having activity in relation to CNS.

EFFECT: new compounds with valuable pharmacological action.

9 cl, 1 tbl, 83 ex

The invention relates to new derivatives of galantamine General formula I:

where R1-R5, G1-G3and W have the meanings indicated in the claims, and the invention relates to a method for producing these compounds, medicinal product and the method of its production

The invention relates to a derivative phthalazine General formula (I) or their pharmaceutically acceptable salts, or hydrates, where R1and R2are the same or different from each other and each represents a halogen atom, a C1-C4alkyl group which may be substituted by a halogen atom, a hydroxyl group or a C1-C4alkoxygroup, which may be substituted by a halogen atom, or cyano; X represents a cyano, a halogen atom, hydroxyimino, optional O-substituted C1-C4alkyl group, or a heteroaryl group selected from thiazoline, thienyl, pyrazolidine, triazolinones and tetrazolyl groups that may be substituted WITH1-C4alkyl group; Y represents a cyclic amino group (i) - (v) described in paragraph 1 of the claims; (vi) etinilnoy or ethyl group substituted WITH1-C4alkyl group, which, in turn, replaced by a number of deputies referred to in paragraph 1 of the claims; (vii) optionally substituted phenyl group; (viii) pyridyloxy or thiazolidine group

The invention relates to new spirochetes formula I

< / BR>
where Ar is phenyl, substituted phenyl where the substituents are: alkoxy, alkyl, alkoxyalkyl, phenoxy, halogen, pyridyloxy, alkoxyalkane, halogenfree; R1- H; R2- H1-C4alkyl; W represents O or one or more1-C4alkyl fragments; Y is independently one or more members of the group consisting of H2, SR3, alkoxy; R3- H, alkyl; Z is a carbocyclic or heterocyclic Spiro-fragment with a 3-7 member ring system, where the heterocyclic fragment includes 2 oxygen atom or sulfur, or one nitrogen atom and spirits may be unsubstituted or substituted by hydroxy, C1-C4the alkyl, benzyloxy; n=1-3; optical isomers, diastereomers or enantiomers or pharmaceutically acceptable salts

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to alkylated (1H-benzimidazol-5-yl)-(-4-substituted phenyl)-amine derivatives, in particular compound of formula and pharmaceutically acceptable salts or solvates thereof, wherein R1, R2, and R9, are independently hydrogen, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluorimethoxy, azido, etc.; R7 is optionally substituted C1-C10-alkyl, C3-C10-cycloalkyl, etc.; A is-OR3 or NR4R3; R8 is hydrogen, -Cl, -Br, -F, cyano, nitro, etc.; and meanings of the rest substituents are as defined in specification. Also disclosed is composition for MEK inhibition and uses of benzinidazole compounds.

EFFECT: new compounds with value biological properties.

32 cl, 56 ex

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: Described are derivatives of general formula I (all symbols are as described in specification), pharmaceutically acceptable salts thereof or cyclodextrin clathrates. Such compounds hardly bind of EP2 subtype of PGE receptor and are useful in prophylaxis of immune diseases, allergy, death of neuronal cells, liver or kidney insufficiency, etc.

EFFECT: new agent for prophylaxis of various diseases.

18 cl, 388 ex, 68 tbl, 3 dwg

Novel benzodioxols // 2304580

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzodioxol of the formula (I): wherein R1, R2, R3, R4, R5, R6, R7 and X are given in the description and the invention claim, and to their pharmaceutically acceptable salts. Also, invention relates to pharmaceutical compositions based on compounds of the formula (I) and their using for preparing medicinal agents used in treatment and/or prophylaxis of diseases associated with modulation of CB1 receptors.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

19 cl, 279 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds represented by the general formula (I): and their pharmaceutically acceptable salts and esters possessing agonistic activity with respect to peroxisome proliferator receptors PPARα and/or PPARγ, to a pharmaceutical composition based on thereof and their using for preparing medicines wherein R1 means thiophenyl or phenyl optionally substituted with from one to three substitutes chosen independently from halogen atom, (C1-C8)-alkoxy-group, (C1-C8)-alkyl and (C1-C8)-alkyl substituted with one-three halogen atoms; R2 means hydrogen atom or (C1-C8)-alkyl; R3 means phenoxy-, (C2-C8)-alkenyloxy- or (C1-C8)-alkoxy-group; R4 means hydrogen atom or (C1-C8)-alkyl wherein one of substitutes R5 and R6 means compound of the formula and another one means hydrogen atom and wherein the bond between carbon atoms Ca and Cb means a carbon-carbon simple or double bond; R7 means hydrogen atom or (C1-C8)-alkyl; R8 means hydrogen atom or (C1-C8)-alkyl being any of A and A1 means nitrogen atom and another means oxygen or sulfur atom; n means 1, 2 or 3.

EFFECT: valuable medicinal properties of compound and pharmaceutical composition.

30 cl, 1 tbl, 14 sch, 86 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzimidazole of the general formula (I): wherein A represents -CH2- or -C(O)-; Y represents -S- or -NH-; R1 and R2 represent independently hydrogen atom, (C1-C8)-alkyl, (C5-C9)-bicycloalkyl optionally substituted with one or some similar or different (C1-C6)-alkyl radicals, or radical of the formula -(CH2)n-X wherein X represents amino-group, (C3-C7)-cycloalkyl and other values of radicals also given in the invention claim; R3 represents -(CH2)p-W-(CH2)p'-Z3 wherein W3 represents a covalent bond, -CH(O)- or -C(O)-; Z3 represents (C1-C6)-alkyl, aryl radical, heteroaryl and other values of radical also; V3 represents -O-, -S-, -C(O)-, -C(O)-O-, -SO2- or a covalent bond; Y3 represents (C1-C6)-alkyl radical optionally substituted with one or some halogen-radicals, amino-group, di-((C1-C6)-alkyl)-amino-group, phenylcarbonylmethyl, heterocycloalkyl or aryl radicals; p, p' and p'' represent independently a whole number from 0 to 4; R4 represents radical of the formula: -(CH2)s-R''4 wherein R''4 represents heterocycle comprising at least one nitrogen atom and optionally substituted with (C1-C6)-alkyl or aralkyl, and other values of radicals given in the invention claim also. Also, invention relates to a pharmaceutical composition showing antagonistic property with respect to GnRH and based on these compounds. Also, using above proposed compounds for preparing a medicament is considered. Invention provides synthesis of novel compounds, preparing pharmaceutical composition and medicament based on thereof in aims for treatment of such diseases as endometriosis, fibroma, polycystic ovary, breast, ovary and endometrium cancer, gonadotropic hypophysis desensitization in medicinal stimulation of ovary in fertility treatment in females.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

18 cl, 2 tbl, 538 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes a compound of the formula (I):

wherein R1 is chosen from the following group: (C1-C6)-alkyl, (C2-C6)-alkylidene, (C2-C6)-alkenyl, (C2-C6)-alkynyl, -O-(C1-C6)-alkyl, -O-(C2-C6)-alkenyl; m = 1; C3-C4 mean -CH2-CH or -CH=C, or C4 represents -CH and C3 absents; R2 and R3 represent hydrogen atom (H); or R2, R3, m and C3-C4 form compound of the formula:

; each among R4 and R5 is chosen independently from group comprising H, halogen atom, hydroxy-group, (C1-C6)-alkyl, -O-(C1-C6)-alkyl; L1 and L2 represent biradicals chosen from group comprising -(CR6)=C(R7), -C(R6)=N and -N=C(R6)-, -S-; Y is chosen from group consisting of oxygen atom (O) and two hydrogen atoms; X is chosen from group comprising -C(R6)(R7)-C(R6)(R7)-, -C(R6)=C(R7)-, -O-C(R6)(R7)-, -C(R6)(R7-O-, -S-C(R6)(R7)-, -C(R6)(R7)-S- and -S-. Invention describes compositions comprising compounds of the formula (I), method for enhancing activity of muscarinic receptors of subtype M1, method for treatment of diseases associated with muscarinic receptors.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 2 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a compound of the formula (I): or its pharmaceutically acceptable salt wherein X is chosen from the group consisting of carbon (C), oxygen (O), nitrogen (N) and sulfur (S) atoms; Z represents nitrogen atom (N); Y is chosen from the group consisting of =O, =S or their tautomers; SPU means a spacer element providing distance d between Z and N atom wherein -SPU- represents bi-radical -(CR6R7)n- wherein n means 1, 2, 3, 4 or 5; N atom in common with R1 and R2 forms heterocyclic ring wherein indicated heterocyclic ring is chosen from the group consisting of piperidine and 8-azabicyclo[3.2.1]octane and wherein heterocyclic ring is substituted with one or more substitutes R4 chosen from the group consisting of hydrogen atom, (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (C1-C8)-alkoxy-group, (C1-C8)-alkylidene, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C6)-alkyloxyimino-group each of them is substituted optionally with a substitute R5 and wherein at least with one of indicated substitutes R4 is represented by R4' chosen from the group consisting of (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (C1-C8)-alkoxy-group and (C1-C8)-alkylidene wherein each of them is substituted optionally with a substitute R5 wherein R5 is chosen from the group consisting of hydrogen, halogen atom, hydroxy-group, (C1-C8)-alkyl, (C1-C8)-alkoxy-group, (C3-C8)-cycloalkyl, (C2-C8)-alkenyl and (C2-C8)-alkynyl; RX can absent or can be chosen from the group consisting of hydrogen atom and optionally substituted (C1-C8)-alkyl; R3 can be represented in 0-4-fold range and chosen from the group consisting of halogen atom, optionally substituted (C1-C8)-alkyl and (C1-C8)-alkoxy-group; each R6 and R7 is chosen optionally and independently among the group consisting of hydrogen atom, hydroxy-group and optionally substituted (C-C8)-alkyl. Also, invention relates to a pharmaceutical composition possessing the selective activity with respect to M and/or M4-subtypes of muscarinic receptors and antagonism with respect to D2-dopamine receptors and comprising compound of the formula (I) by claim 1 in common with pharmaceutically acceptable carriers or excipients. Also, invention relates to a method for enhancing activity of cholinergic receptor comprising interaction of cholinergic receptor and system comprising cholinergic receptor with the effective amount of at least one compound of the formula (I) by claim 1. Also, invention relates to using the compound according to any claim among 1-11 or its pharmaceutically acceptable salt, or pharmaceutical composition containing any base for preparing a medicinal preparation used in prophylaxis aim or treatment of psychosis or for attenuation of symptoms associated with psychosis.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

27 cl, 3 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new 2-arylimino-2,3-dihydrothiazole derivatives of formula described in claims having affinity and selectivity to somatostatin receptors and useful as drugs for treatment of pathological conditions or diseases mediated by one or more somatostatin receptors, such as acromegalia, chromophone adenoma, endocrine pancreatic tumor, argentaffinoma syndrome, gastrointestinal hemorrhage, etc.

EFFECT: new agent for treatment of pathological conditions or diseases mediated by somatostatin receptors.

6 cl, 2836 ex

FIELD: organic chemistry, chemical technology, pesticides.

SUBSTANCE: invention relates to a method for synthesis of compound of the formula (I): wherein Q means nitrogen atom (N); Y means nitro-group (-NO2); Z means -NR3; R1 and R2 mean in common alkylene bridge that comprises two or three carbon atoms and, optionally, a heteroatom chosen from the group comprising -NR5 and oxygen atom (O); R3 means unsubstituted (C1-C12)-alkyl; R5 means hydrogen atom (H) or (C1-C12)-alkyl. Method involves the following steps: (a) interaction of compound of the formula (II): wherein X means a leaving group with a halogenated agent to yield compound of the formula (III): wherein W means halogen atom and wherein treatment of compound of the formula (III) involves extraction of compound of the formula (III) with hydrochloric acid taken in the concentration 10-50 wt.-%, and (b) interaction of the synthesized compound of the formula (III) with compound of the formula (IV): wherein R1, R2, Y, Z and Q have above given values. In the process for synthesis of compound of the formula (III) the stage (a) involves purification stage wherein formed crude product is treated with water at acid range of pH values.

EFFECT: improved method of synthesis.

3 cl, 6 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention proposes compounds of the general formula (1): wherein X is chosen from sulfur atom and methylene group; X1 is chosen from sulfur atom and methylene group; X2 is chosen from oxygen (O), sulfur (S) atoms and methylene group; X3 means -NR5 or carbonyl group; R1 means hydrogen atom or nitrile group; R and R3 are chosen independently from hydrogen atom (H) and (C1-C6)-alkyl; R4 means R4A when X3 means -NR5 and R4B when X3 means carbonyl group; R4A is chosen from -R6R7NC(=O), -R6R7NC(=S), -R8(CH2)qC(=O), -R8(CH2)qC(=S), -R8(CH2)qSO2 and -R8(CH2)qOC(=O); R4B means -R6R7N; R5 means hydrogen atom (H); R6 and R7 are chosen independently from -R8(CH2)q, or they form in common -(CH2)2-Z1-(CH2)2- or -CHR9-X2-CH2-CHR10-; R8 is chosen from hydrogen atom (H), (C1-C4)-alkyl, cycloalkyl group condensed with benzene ring, acyl, dialkylcarbamoyl, dialkylamino-group, N-alkylpiperidyl, optionally substituted aryl, optionally substituted α-alkylbenzyl, optionally substituted aroyl, optionally substituted arylsulfonyl and optionally substituted heteroaryl representing monocyclic 5- and 6-membered ring aromatic group with one or two heteroatoms chosen from nitrogen, oxygen and sulfur atoms, and derivatives of abovementioned rings condensed with benzene; R9 and R10 are chosen independently from hydrogen atom (H), hydroxymethyl and cyanomethyl groups; Z1 is chosen from -(CH2)r-, -O-, and -N((CH2)q)R8)-; Z2 means optionally the substituted ortho-phenylene group; m = 1-3; n = 0-4; p = 2-5; q = 0-3, and r = 1 or 3. Proposed compounds are inhibitors of dipeptidyl-peptidase IV and can be used in preparing pharmaceutical compositions designated for treatment of different diseases, among them, diabetes mellitus of type 2.

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

22 cl, 8 tbl, 453 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes derivatives of aminotetraline of the formula (I) wherein R1 means (C1-C6)-alkyl; R2 means halogen atom or -OR'; R3 means hydrogen atom (H) or -OR' wherein R' means (C1-C6)-alkyl or -SO2R'' wherein R'' means phenyl, thienyl, isoxazolyl; R4 means (C1-C6)-alkyl, phenyl, piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, diazepinyl, furanyl, isoxazolyl, imidazolyl and pyrazolyl that can be substituted optionally, and pharmaceutical compositions containing derivatives of aminotetraline. Proposed compounds are selective antagonists of M2/M3 muscarinic receptors and designated for treatment and prophylaxis of diseases associated with smooth muscle disorder.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 1 tbl, 16 ex

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