Derivatives naphthiridine containing pharmaceutical composition

 

(57) Abstract:

Describes derivatives naphthiridine General formula (I) or their pharmaceutically acceptable salts of the formula

where R1: -R0or lower alkylbenzoates; R0: lower alkyl; R2: -R0, halogen, lower alkylene-HE-S-R0-THE OTHER0or-CH=N-OR9that may be the same or different from each other; R3and R4: -H, R9: -H;

R5: cyclohexyl; thienyl or phenyl which may be substituted by a group selected from lower alkyl and halogen;

R6: -OH, -OR7, -COOH, -CONH2, -CON(R7)2, -O-COR7, -O-COOR7, -COR7, -NH2, -N(R7)2, -N(R7)COR7, -N(R7)SO2R7, -C(NH)NH2, -NHC(NH)NH2or a group of the formula-Y-R8;

R7: lower alkyl which may be substituted by a group-CO2R0;

R8: phenyl which may be substituted by a group selected from R10or heterocyclic group selected from morpholinyl, tetrazolyl, imidazolyl, pyridyl, piperidyl, thiazolyl, piperazine, pyrrolidine or imidazo[1,2-a]pyridyl, which may be substituted by a group selected from Ra bond or-CO - and X: link or lowest alkylen. These compounds may be used as preventive or therapeutic agents for respiratory diseases associated with inhibition of PDE type IV. 2 s and 5 C.p. f-crystals, 6 PL.

THE TECHNICAL FIELD

This invention relates to the derivatives of naphthiridine used as a medicine, in particular as inhibitors of phosphodiesterase type IV.

Asthma is a respiratory disease that causes wheezing and asthma in spasm of the respiratory tract. The number of patients is constantly increasing and is forecast to increase further.

Currently, for the treatment of asthma as bronchodilators are mainly used xanthine derivatives, such as aminophylline and theophylline, and stimulants, such as procaterol.

The functional mechanism of these compounds aimed at alleviating spasms of smooth muscles of the respiratory tract by increasing the concentration of intracellular cyclic adenosine-3',5'-monophosphate (camp) through the activation of the enzyme adenylate cyclase, which generates intracellular camp, or inhibition of the enzyme phosphodiesterase (PDE), gidrolizuemye camp, in chap who AMF causes inhibition spasms of smooth muscles of respiratory ways (Clin. Exp. Allergy, 22, 337-344 (1992), Drugs of the Future, 17, 799-807 (1992)), which contributes to improvement in asthma patients.

However, it is known that derivatives of xanthine cause systemic side effects such as hypotension and cardiotonic action (J. Cyclic Nucleotide and Protein Phosphorylation Res., 10, 551-564 (1985), J. Pharmacol. Exp. Ther., 257, 741-747 (1991)), and stimulants can cause hypocholesterolemia and, at higher doses, can cause side effects such as trembling fingers and palpitations.

On the other hand, it was found that PDE is divided in at least five different types from I to V, and each of them has a different distribution or function (Pharmacol. Ther., 51, 13-33 (1991)). In particular, PDE type IV has no effect on cyclic guanosine-3',5'-monophosphate (cGMP), but provides specific hydrolysis of camp among nucleotides, and its presence is detected in the smooth muscle of the Airways and infiltra cells.

It was also described that inhibitors of PDE type IV demonstrate inhibitory effect on the infiltration of eosinophils at the expense of antigens and factors of platelet aggregation in Guinea pigs (Eur. J. Pharmacol., 255, 253-256 (1994)) and inhibit the release of harmful proteins (basal protein of the myelin sheath, which provide inhibitory effect on spasms of smooth muscles by reducing substances (histamine, metafolin, LTD4) (Br. J. Pharmacol., 113, 1423-1431 (1994)), inhibit the production of IL-4 is a cytokine that is known to be heavily involved in asthma (J. Invest., Dermatol., 100, 681-684 (1993)), have inhibitory effect on the increase of vascular permeability of the respiratory tract (Fundam. Clin. Pharmacol., 6, 247-249 (1992)) and have an inhibitory effect on hypersensitivity of the respiratory tract (Eur. J. Pharmacol., 275, 75-82 (1995)). Thus, it is expected that the inhibitor of PDE type IV can become an agent for the treatment of asthma, with fewer side effects.

As inhibitors of PDE type IV is known to many compounds, including derivatives naphthiridine. The authors of this invention previously described derivative naphthiridine, represented by the following formula, in which position 4 (R6) is cyclic Deputy, such as aryl, heteroaryl or cycloalkyl, and in position 3 (R5is unsubstituted or substituted lower alkyl group

where R5is a hydrogen atom or a lower alkyl group and R6is an aryl group having Deputy, heteroaryl group, with the Deputy, cycloalkyl group or Adamantine group.

the market of this invention have conducted studies with the aim of obtaining a new connection, which effectively and selectively inhibited would PDE type IV and it would be useful for the prevention and treatment of respiratory diseases such as bronchial asthma, it would have fewer side effects, and medicinal products containing the specified connection.

The authors of this invention have also conducted extensive studies of compounds that have an inhibitory effect on PDE type IV, and as a result have found that a compound in which a specific substituent (-X-R6is entered in position 3 of the previously described compounds (WO 96/06843), is a novel compound and has a strong inhibitory effect on PDE type IV, and has excellent oral absorbiruyaci and metabolically stable. Therefore, it was found that this compound is very useful as an inhibitor of PDE type IV, which amounted to the invention.

Accordingly, this invention relates to a new derived naphthiridine represented by the following General formula (I) or its pharmaceutically acceptable salts, and pharmaceutical preparation containing the specified connection as the active ingredient.

where R1: -R0, NISS is UP>: -H, -R0, halogen, lower alkylene-HE,

lowest alkylen-SH, -lower alkylene-O-R0-the inferior alkylen-3-R0- the inferior alkylen-O-CO-R0-the inferior alkylen-S-CO-R0, -OH, -O-R0, -S-R0, -SO-R0, -SO2-R0, -NH2-THE OTHER0, -NR02-cycloalkyl, -CO-R0or-CH=N-OR9and they can be the same or different from each other;

R9: -H, -R0or lowest alkylen-aryl;

R5: cycloalkyl, which may be substituted by a group selected from R10, cycloalkenyl, which may be substituted by a group selected from R10, heterocyclic group which may be substituted by a group selected from R10or phenyl which may be substituted by a group selected from R10;

R6: -OH, -OR7, -COOH, -COOR7, -CONH2, -CONHR7, -CON(R7)2,

-O-COR7, -O-COOR7, -CHO, -COR7, -NH2-THE OTHER7, -N(R7)2, -NHCOR7,

-N(R7)COR7, -NHSO2R7, -N(R7)SO2R7, -CN, -NHCOOR7, -N(R7)COOR7,

-C(NH)NH2, -NHC(NH)NH2or-N(R7)C(NH)NH2or a group of the formula

-Y-R8;

R7, -CO2H, -CO2R0, -NH2-THE OTHER0, -NR02, -NO2, -CN and-COR0;

R8: cycloalkyl, which may be substituted by a group selected from R10, aryl which may be substituted by a group selected from R10or heterocyclic group which may be substituted by a group selected from R10;

R10: -OH, -phenyl, -halogen, -OR0, -CO2H, -CO2R0, -NH2,

-OTHER0, -NR02, -NR2, -CN or-COR0or group described in R7;

Y is: a bond, -O-, -COO-, -CONH-, -CON(R7)-, -O-CO-, -O-COO-, -CO-, -NH-, -N(R7)-, -NHCO-, -N(R7)CO-, -NHCOO-, -N(R7)COO-, -NHSO2- or-N(R7)SO2- and

X: link or lowest alkylene, or lower albaniles (hereinafter accept the same values).

Also, in accordance with this invention, presents the medicinal product, in particular an inhibitor of PDE type IV, which contains a derivative naphthiridine or its salt.

Hereinafter the invention is described in more detail.

In the context of this description, the term "lower" means a straight or branched hydrocarbon chain having from 1 to 6 carbon atoms. Examples of "lower alkylidene. Preferred are alkyl having from 1 to 4 carbon atoms, and particularly preferred is methyl or ethyl. The term "lower alkylene" means a divalent group formed by removing any one of hydrogen atoms of the above "lower alkyl", and is preferred alkylene having from 1 to 4 carbon atoms, especially preferred is methylene, ethylene or propylene. "Lower albaniles" means a group having one or more double bonds at any position of the lower alkylene" having two or more carbon atoms, and preferably is Alcanena having from 2 to 4 carbon atoms.

"Cycloalkyl" preferably is cycloalkyl having from 3 to 8 carbon atoms, particularly preferably cyclopropyl or cyclohexyl. "Cycloalkenyl" preferably is zilouchian having from 5 to 8 carbon atoms, particularly preferably cyclohexenyl. The term "aryl" means an aromatic hydrocarbon group having 6 to 14 carbon atoms, preferably phenyl. "Heterocyclic group" is a monocyclic - tricyclic heterocyclic group having from 1 to 4 heteroatoms, selected from the group vkluchaya ring with the benzene ring. This heterocycle is preferably a five - semifinal saturated or unsaturated monocyclic heterocyclic group, especially preferably a pyridine, piperidine, morpholine, thiophene, thiazole, imidazole, tetrazole, pyrazino or piperazine.

The term "halogen" means F, Cl, Br or I.

The phrase "which may be substituted" means unsubstituted or having from 1 to 5 substituents which may be the same or different from each other."

Deputy in cycloalkyl, which may be substituted", "cycloalkenyl, which may be substituted", "heterocyclic group which may has to be substituted, phenyl which may be substituted" and the "aryl which may be substituted", is not specifically limited as long as it can be used as a substituent in the rings of these compounds, which can be used to obtain drugs, in particular an inhibitor of PDE type IV, but preferably it is HE, -phenyl, -halogen, -OR0, -CO2H, -CO2R0, -NH2-THE OTHER0, -NR02, -NO2, -CN or-COR0or lower alkyl which may be substituted by a group selected from these groups.

the I group, with the same number of carbon atoms. For example, X is preferably a bond or lower alkylene and R6preferably a is-OH, -COOH, -COOR7, -O-COR7, -NH2-THE OTHER7, -N(R7)2, -C(NH)NH2, -NHC(NH)NH2or-N(R7)C(NH)NH2or a group represented by the formula-Y-R8. R8preferably an aryl or heterocyclic group. These groups may be substituted by a group selected from the group comprising-OH, -phenyl, -halogen, -OR0, -CO2H, -CO2R0, -NH2-THE OTHER0, -NR02, -NO2, -CN and-COR0.

The group R5in position 4 naphthiridine preferably is cycloalkyl, phenyl which may be substituted in position 3, or the like. Deputy preferably is halogen, lower alkyl or the like. Group R3and R4in positions 5 and 6 naphthiridine each preferably is lower alkyl or hydrogen atom, more preferably a hydrogen atom. The group R2in position 7 naphthiridine preferably is lower alkyl, halogen, lower alkylene HE or a group represented by the formula-CH=N-OH.

Among the compounds according to Dr. who chlorophenyl)-1-ethyl-7-methyl-1,8-naphthiridine-2(1H)-he,

4-(3-chlorophenyl)-1-ethyl-3-(2-guanidinate)-7-methyl-1,8-naphthiridine-2(1H)-he,

4-cyclohexyl-1-ethyl-7-methyl-3-[2-(1H-tetrazol-5-yl)ethyl]-1,8-naphthiridine-2(1H)-he,

4-(3-chlorophenyl)-1-ethyl-7-methyl-3-[3-(1H-tetrazol-5-yl)propyl]-1,8-naphthiridine-2(1H)-he,

4-(3-bromophenyl)-1-ethyl-7-methyl-3-[2-(1H-tetrazol-5-yl)ethyl]-1,8-naphthiridine-2(1H)-he,

3-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]propanoic acid,

3-(4-cyclohexyl-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]propanoic acid,

3-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]benzoic acid,

3-[4-(3-chlorophenyl)-1-ethyl-7-(gidroksilaminami)-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]propanoic acid,

3-[7-chloro-4-(3-chlorophenyl)-1-ethyl-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]propanoic acid,

3-[1-ethyl-7-methyl-4-(3-were)-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]propanoic acid,

4-(3-chlorophenyl)-1-ethyl-7-methyl-3-(piperidine-4-yl)-1.8-naphthiridine-2(1H)-he

1-{2-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]ethyl}piperidine-4-carboxylic acid and their salts.

Depending on the kinds of the substituents of the compounds in accordance with this invention mod the frame of the invention.

Connections, in accordance with this invention in some cases may have asymmetric carbon atoms and these atoms can be (R)- and (S)-form optical isomers. The invention encompasses all such optical isomers in mixed and separated form.

In the compounds in accordance with this invention also includes pharmaceutically acceptable prodrugs. Pharmaceutically acceptable prodrugs are compounds having groups which can be converted into certain groups in accordance with this invention, such as NH2HE and CO2N, by dissolving or under certain physiological conditions. Examples of groups that can form prodrugs include those described in Prog. Med.", 5, 2157-2161 (1985) and "Pharmaceutical Research and Development" (Hirokawa Publishing Co., 1990), volume 7, Drug Design, 163-198.

Compounds in accordance with this invention can form acid-salt or additive, depending on the kinds of substituents, salts with bases. Such salts are pharmaceutically acceptable salts, and their illustrative examples include acid additive salts with inorganic acids, such as chloride and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonate, econsultation, aspartic acid and glutamic acid, salts with inorganic bases, such as, for example, salts with sodium, potassium, magnesium, calcium and aluminum, and organic bases such as methylamine, ethylamine, ethanolamine, lysine and ornithine, and ammonium salt.

In addition, this invention also includes various hydrates, solvate and polymorphic substances of the compound (I) in accordance with this invention and their salts.

The way to obtain

Connection in accordance with this invention and its pharmaceutically acceptable salts can be obtained by various known methods of synthesis taking into account the properties of the connection based on basic (primary) link structure or the types of the substituents. In this case, depending on the type of functional group, it is sometimes effective, from the industrial point of view, the substitution of functional groups in the original soedineniya to the functional group. Then, the target compound can be obtained by removing the protective group as required by each specific case. Examples of such functional groups can be hydroxyl and carboxyl groups, and these protective groups, which are optionally used, depending on the reaction conditions, can be protective group described, for example, in "Protective Groups in Organic Synthesis" (2nd ed.), published in Green and Wuts.

(1) the First way to obtain

where L1is a leaving group (the same is applied hereinafter).

In this method of producing compound (Ia) in accordance with this invention is produced by interaction of the aminopyridine derivative (II) with allermuir agent represented by the General formula (III), to obtain the amide derivative (IV) and then directly by the reaction of ring closure.

Preferred examples of the leaving group represented by L1include halogen atoms, acyloxy, carbonates, such as allyloxycarbonyl, and the remains of organic sulfonic acids, such as methanesulfonic and p-toluensulfonate. Also, through Association Deputy on XR6with L1the compound of General formula (III) can form in hold in an organic solvent, inert to the reaction, selected from halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran (THF) or dioxane; N,N-dimethylformamide (DMF) or without solvent, at a temperature of from cooling to heating. If the reaction aminopyridine derivative (II) and allerease agent (III) may be used in equivalent amounts or one of them may be used in excess, and sometimes, for a smoother passage of the reaction, it is useful to carry out the reaction in the presence of an organic base (preferably triethylamine, pyridine or 4-(N,N-dimethylamino)pyridine), inorganic base (preferably sodium hydroxide or potassium carbonate) or metal base (preferably sodium hydride, sodium methylate or of potassium tert-butylate).

In this method of obtaining the allocation of amide derivative (IV) and the reaction ring closure can be carried out Paladino. In this case, given solvent, temperature, substrate and so on, the above conditions may apply in each reaction.

(2) the Second way obtained the abuser the amino group, produced from compound (Ib) in accordance with this invention having a carboxyl group. Connection carbamate (Ic) obtained as an intermediate connection is a connection in accordance with this invention.

The compound (Ic) in accordance with this invention can be obtained by the interaction of the compounds of isocyanate, which is obtained by rearrangement of kurzius acid azide obtained by the interaction of the reactive derivative of the carboxyl group derived from the compound (Ib), such as an acid anhydride, azide salt, such as sodium azide, or method of interaction with diphenylphosphorylacetate (DFA), or which is obtained by rearrangement of Hoffman's primary amide derived from the compound (Ib) conventional amidation reaction with a compound of alcohol.

The reaction is carried out in an organic solvent inert to the reaction, selected from halogenated hydrocarbons, aromatic hydrocarbons, ethers, DMF, or without solvent, at a temperature of from cooling to heating. When carrying out the reaction of the compound of alcohol can be used in an equivalent amount or in excess relative to the compound (Ib).

(3) the Third way to obtain

The compound having a carboxyl group at R8the compound (I) can be obtained by hydrolysis triptorelin group on R8.

The reaction is carried out in an organic solvent inert to the reaction, selected from halogenated hydrocarbons, aromatic hydrocarbons, ethers, DMF, or without solvent, in the presence of acid (hydrochloric acid, sulfuric acid or the like) or a base (sodium hydroxide, sodium methylate or the like) at a temperature of from cooling to heating.

(4) the Fourth way to obtain

In this method of obtaining the compound (If), (Ig) and (Ih) in accordance with this invention is produced from compound (Ie) in accordance with this invention mentioned above synthesis.

The compound (If) in accordance with this invention can be obtained by dehydration of the compound (Ie) in accordance with this invention. Can be used the usual method of dehydration, such The compound (Ig) in accordance with this invention can be obtained by the interaction of the compound (If) in accordance with this invention with salt azide, such as sodium azide. The reaction is carried out in an organic solvent inert to the reaction, selected from halogenated hydrocarbons, aromatic hydrocarbons, ethers, alcohols, such as methanol and ethanol, DMF and water, or without solvent at a temperature of from cooling to heating.

If the reaction of the azide salt can be used in an equivalent amount or in excess relative to the compound (If), and in some cases for the smooth conduct of the reaction, it is useful to carry out the reaction in the presence of acid (acetic acid, triperoxonane acid, triethylamine hydrochloride, hydrochloric acid, aluminum chloride or the like) or a base (pyridine, triethylamine, sodium hydroxide, potassium hydroxide, sodium methylate, of potassium tert-butylate or the like).

The compound (Ih) in accordance with this invention can be obtained by the interaction of the compound (If) in accordance with this invention with ammonia, ammonium salt, such as ammonium chloride, or Amida metal, such as sodium amide. Also it can be obtained by the interaction of imidocloprid obtained by the interaction of the compound (If) with hydrogen chloride, ammonium salt, generowania hydrocarbons, aromatic hydrocarbons, ethers, alcohols, DMF and water, or without solvent at a temperature of from cooling to heating and at a pressure of from normal to high. If the reaction miniraise agent may be used in an equivalent amount or in excess relative to the compound (If).

(5) the Fifth way to obtain

In this way we obtain the compound (Ii) from the compound (Id) in accordance with this invention by the reaction of obtaining guanidine.

Examples guanidinopropionic agents used in this reaction include cyanamide, amdinocillin, 1-amidinopropane and S-methylisothiazoline. The reaction is carried out in an organic solvent inert to the reaction, selected from halogenated hydrocarbons, aromatic hydrocarbons, ethers, alcohols, DMF and water, or without solvent at a temperature of from cooling to heating. If the reaction guanidinopropionic agent may be used in an equivalent amount or in excess relative to the compound (Id), and in some cases for the smooth conduct of the reaction, it is useful to carry out the reaction in the presence of acid (acetic acid, triperoxonane acid, is filamina, sodium hydroxide, potassium hydroxide, sodium methylate, of potassium tert-butylate or the like).

(6) the Sixth way to obtain

where Raand Rbmay be the same or different and each is H or a group represented by R7or R8(the same values used below).

In this method of obtaining the derivative of thiazole (Ik) is produced from compound (Ij) in accordance with this invention.

The target compound can be obtained by the interaction with thioamides (V) bromine compounds, which is obtained by the interaction of the compound (Ij) with brainwashin agent such as bromine, N-bromosuccinimide or benzyltrimethylammonium, after isolation or without isolation. The reaction is carried out in an organic solvent inert to the reaction, selected from halogenated hydrocarbons, aromatic hydrocarbons, ethers, alcohols, acetic acid, DMF and water, or without solvent at a temperature of from cooling to heating. When carrying out the reaction of the compound (Ij) and pomeroyi agent or compound of bromine and thioamide (V) can be used in equivalent amounts or one of them may be used in excess, and in some cases, d ptx2">(7) the Seventh way to obtain

In this method of obtaining the chlorine atom is introduced into the pyridine ring of compound (II) according to the present invention.

The target compound can be obtained by the interaction of the compound oxide of pyridine, obtained by the interaction of the compound (Il) with an oxidizing agent such as m-chloroperbenzoic acid, peracetic acid or hydrogen peroxide, with gloriouse agent such as phosphorus oxychloride, pentachloride phosphorus or thionyl chloride, after isolation or without isolation. The reaction is carried out in an organic solvent inert to the reaction, selected from halogenated hydrocarbons, aromatic hydrocarbons, ethers, alcohols, acetic acid, DMF and water, or without solvent at a temperature of from cooling to heating. When carrying out the reaction of the compound (Il) and oxidizing agent or a compound oxide of pyridine and gloriouse agent can be used in equivalent amounts or one of them may be used in excess, and in some cases for the smooth conduct of the reaction, it is useful to carry out the reaction in the presence of acid or base.

The chlorine atom can be converted into different substituents p is, as described in the publication WO 97/19078 and so on

(8) Synthesis of starting materials

where L2is a leaving group, such as L1and M is H or metal salt (the same values used below).

The original compound (II) in which the substituent R2and the pyridine ring is combined with the bond carbon-carbon parent compound (VI) having a leaving group in position 2 and position 6 of the pyridine ring, can be synthesized by the method described on pages 19-21 publication WO 97/19078.

The original compound (II) in which the substituent R2and the pyridine ring is not merged with the bond carbon-carbon can be synthesized by carrying out substitution reactions of starting compound (VI) with amine compound (VII) with R1group and the nucleophilic reagent R2M (VIII) sequentially. The procedure for replacement is suitable for the substituents R1NH and R2and leaving groups (L1and L2). The reaction is carried out in an organic solvent inert to the reaction, selected from water, aromatic hydrocarbons, ethers, DMF, or without solvent at a temperature of from cooling to heating. In some cases, for more than the who Foundation (preferably, sodium hydroxide or potassium carbonate) or base metal.

Connection in accordance with this invention, obtained by each of the above methods may be further converted to various compounds in accordance with this invention, by amidation reactions, sulfonmethane, esterification, hydrolysis, alkylation, recovery of ester or nucleophilic substitution. The amidation, sulfenamidovy and etherification can be carried out according to the methods described in "JIKKEN CALLED KOZA" (4th edition), published by the Chemical society of Japan, vol. 22 (1992) (Maruzen), the hydrolysis can be carried out according to the method described in the paragraph dedicated to the removal of the carboxyl protecting group, in the aforementioned "Protective Groups in Organic Synthesis" (2nd edition), the alkylation can be carried out according to the method described in "JIKKEN CALLED KOZA" (4th edition), published by the Chemical society of Japan, volume 20 (1992) (Maruzen), and recovery of ester can be carried out according to the method described in "JIKKEN CALLED KOZA" (4th edition), published by the Chemical society of Japan, 20 (1992) (Maruzen). Nucleophilic substitution can be carried out by the interaction of the compounds with alkyl group, substituted HE Ridom or p-toluensulfonate obtaining complex organic ether sulfonate, subsequent interaction with the nucleophile. Alternative specified substitution can be achieved by conducting the reaction of Mitsunobu. The reaction is carried out in an organic solvent inert to the reaction, selected from halogenated hydrocarbons, aromatic hydrocarbons, ethers, DMF, or without solvent at a temperature of from cooling to heating. In some cases, to smooth the reaction is useful to carry out the reaction in the presence of a base.

The reaction product obtained in each of the above methods of preparation, is isolated and purified as a free compound, a salt or a variety of salagou, such as hydrate. Salt can be obtained by conventional reactions obtain salt.

Isolation and purification are carried out using commonly used chemical methods, such as extraction, concentration, evaporation, crystallization, filtration, recrystallization and various kinds of chromatography.

Various isomers can be isolated by usual method using the difference in physico-chemical properties of the respective isomers. For example, optical isomers can be separated by the usual method of optical separation, such as F. the Cesky active parent compound.

INDUSTRIAL APPLICABILITY

With regard to the inhibition of PDE, it is now known that at least five types I through V, and the connection in accordance with this invention has a particularly excellent effect on the inhibition of PDE type IV and, therefore, can be used as an agent for prevention and/or treatment of respiratory diseases (for example, bronchial asthma (including reinfection-allergic bronchial asthma), chronic bronchitis, lung disease and respiratory distress syndrome in adults (rdsw)) involving PDE type IV. In particular, a compound in accordance with this invention may be regarded as an agent for prevention and/or treatment of bronchial asthma.

In addition, the connection in accordance with this invention can also be used as an agent for prevention and/or treatment of other diseases, which are known to participate PDE type IV, such as disease, are involved in cytokine (IL-1, IL-4, IL-6 and TNF (tumor necrosis factor) or similar (for example, rheumatoid arthritis, ulcerative colitis, Crohn's disease, sepsis, septic shock, endotoxic shock, gramatically dostatochnosti circulatory (heart failure, atherosclerosis, myocardial infarction, stroke and the like)). Also, because the connection is in accordance with this invention is well metabolized by the enzyme P450 metabolizing drugs in microsome liver, and has good oral absorbiruyaci and duration, it can be used as a drug long acting with a good pharmacokinetic profile.

The availability of a connection in accordance with this invention by the following tests.

Experimental example 1. Inhibitory effect on PDE type IV.

1) a Solution containing PDE type IV, isolated from the muscle tissue of the ventricle of the rat heart following way. Heart carved in male Wistar rats under anesthesia with ether, washed with saline solution and then separated from the ventricle. Separated ventricle finely cut with scissors and suspended in buffer A (20 mm Bis-Tris, 50 mm sodium acetate, 2 mm etc, 5 mm 2-mercaptoethanol, 2 mm benzamidine, 0.05 mm of phenylmethylsulfonyl, pH 6.5) containing 1% PROTEASE INHIBITOR COCKTAIL For Mammalian Cell Extracts (Sigraa). The cells are then destroy using the transmitter station, and subjected to ultracentrifugation (100000 G, 60 minutes, 4&#m) Q-separate, equilibrated with buffer A. the column Then washed with 1200 ml of buffer to remove unattached protein. Protein attached to the column, elute 750 ml of a buffer containing a linear gradient of sodium acetate solution from 0.05 to 1.00 M, and is divided into 110 tubes containing 7 ml fractions. Examine the action of PDE, aimed at the utilization of camp in each fraction obtained in the presence or in the absence of cGMP and calcium/calmoduline. Each fraction, which demonstrates the camp-metabolizing activity and influenced by the presence of cGMP or calcium/calmoduline on camp-metabolizing action, is used as initial solution for testing inhibitory effect against PDE type IV.

3) Each test compound in a preset concentration is subjected to 10-minute interaction at a temperature of 30°C in a reaction mixture containing 40 mm Tris-Hcl (pH 8.0), 5 mm magnesium chloride, 4 mm 2-mercaptoethanol, 1 μm camp, 1 µci/ml of [3H]camp and the original solution of PDE type IV. The reaction stopped by the addition of 1/2 volume of 20 mg/ml suspension SPA beads yttrium silicate coated polylysine (Amersham) containing 18 mm zinc sulfate and 5 μm 3-isobutyl-1-methylxanthines (IBMC)ingibirovanii 50% of the metabolic activity of PDE type IV is defined as IC50 and expect for each connection.

Using the above test and the method described in WO 97/19078, in the same way, measure the inhibitory effect on PDE types I, II, III and V.

As a result of the above test inhibitory effect was confirmed that the compounds of examples 2, 7, 16, 21, 28, 38, 39, 40, 41, 43, 47, 58, 65, 66, 67 and 68 have the IC5011 nm or less for PDE type IV, including connections with the powerful action of 0.002 nm.

Experimental example 2. Testing of drug metabolism in vitro using liver microsomes.

1) a Suspension of liver microsomes of human and rat (microsome person: Xenotech, microsome rats: Charles River) were diluted 100 mm Na-K phosphate buffer (pH 7.4) to a protein concentration of 0.5 mg/ml To portions of 100 μl of the resulting suspension is added 2 μl of a solution of test compound (10 mg/ml solution in acetonitrile), 500 µl of 200 mm Na-K phosphate buffer (pH 7.4), 50 μl of 1 mm add-NaOH (pH 7.4) and 200 μl of purified water, receiving the substrate solution (concentration in the reaction solution: microsomal liver (as a protein component) 0.05 mg/ml, test the connection, 20 ng/ml, 100 mm Na-K phosphate buffer, 0.1 mm add-NaOH).

2) the Working environment is the addition of 57 μl GF-dehydrogenase (1750 U/5 mg/ml) to the mixture. The resulting mixture is heated at a temperature of 37°C for 5 minutes and then cooled on ice before use.

3) 900 μl portion of a solution of substrate pre-incubated at 37 ° °C for 5 minutes and then add 100 ál of the working system restored NADP, followed by conducting the reaction at a temperature of 37°C for 10, 20 and 30 minutes. After terminating the reaction by adding 2 ml of ethyl acetate entire mixture is cooled on ice.

Control sample is prepared by adding 100 ál of the working system restored NADP after adding 2 ml of ethyl acetate (reaction time 0 minutes).

4) In the reaction solution add 100 ál of internal standard having a predetermined concentration (solution of acetonitrile), 1 ml of 0.5 M phosphoric acid and 2 ml of ethyl acetate, followed by shaking for 10 minutes. After 10 minutes centrifugation at 2500 rpm and the ethyl acetate layer is separated and evaporated to dryness, and the residue is dissolved in 100 µl of solvent HPLC with mobile phase. Test the connection elute in approximately 12 minutes, and the internal standard after about 16 minutes under the following conditions. Conditions of HPLC with mobile phase: acetonitrile/20 mm most condensed ANM>

5) Calculate the ratio (residual ratio) of the peak height in 10, 20 or 30 minutes the reaction to the peak height of each of the tested compounds in the control group (ratio of the height of the peak to the internal standard).

As a result of the above test, it was confirmed that the compounds of examples 2, 21, 28, 41, 43, 47, 65 67 well metabolized by the enzyme P450 metabolizing drugs present in microsomes liver.

Experimental example 3. Assessment oral namely, and pharmacokinetic profile using inhibitory effect of PDE type IV as an indicator.

This study was conducted to assess oral namely, and pharmacokinetic profiles of compounds inhibiting PDE type IV in accordance with this invention.

1) Each test compound suspended in purified water containing 0.5% methylcellulose, orally administered seven male Fisher rats at a dose of 3 mg/kg In the control group in the same way enter the solvent (0.5% of methylcellulose in purified water, 3 ml/kg). After oral administration periodically taken samples of blood in the presence of heparin from the tail veins of the Torah were administered the test compound or solvent, add to the measuring system of PDE type IV, as described in experimental example 1, so that the final concentration was 0.1%, and measure the inhibitory activity against PDE type IV.

The result of this test it was found that the compounds of examples 2, 21, 28, 41, 43, 47, 65 and 67 have good oral absorbiruyaci and metabolic stability compared with the compound of the comparison (connection comparison: 4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo - 1,2-dihydro-1,8-naphthiridine).

Experimental example 4. Inhibition of antigen-induced infiltration of eosinophils in the Airways.

In experiments on the inhibition of antigen-induced infiltration of eosinophils in the Airways in vivo, which are indicative of the activity of compounds against asthma, used a modified method described in J. Pharmacol.Exp.Ther., 2000 Dec; 295(3): 1149-55.

The sensitized female rats BN caused inflammation of the respiratory tract by inhalation of 1% aerosol of albumin for 20 minutes Each connection (at a dose of 3 mg/kg) was administered orally 1 h before the beginning of the inhalation of the antigen. As the normal control group used the group isobutylene path for the control group and normal control group were taken at 0 and 100%, respectively, and thereby assessed the activity of the test compounds as inhibitors.

The results obtained for some compounds according to the invention, showing their applicability for the treatment of asthma, below.

Connection example No. Inhibition of infiltration

eosinophils (%)

2 90

28 72

43 62

47 85

65 77

67 80

Based on the results of experimental examples 1-4 can be said that the compounds in accordance with this invention have ingibiruet action against PDE type IV and, therefore, can be used as an agent for the prevention and treatment of diseases involving PDE type IV.

Pharmaceutical compositions containing one, two or more compounds in accordance with this invention or their salts as active ingredient, obtained using carriers, fillers and other additives that are commonly used in pharmaceuticals production.

The introduction can be either orally, in the form of, for example, tablets, pills, capsules, granules, powders or liquids, or parenterally in the form of, for example, intravenous or intramuscular injections, suppositories, percutaneous preparative forms, the nasal prsti from symptoms, age and sex of each patient, but is usually from 0.001 to 100 mg/kg / day for an adult patient with a dose, and this dose can be administered once a day or be divided into 2-4 servings per day. Also, if in accordance with the symptoms is intravenous administration, the dose is administered once or several times a day, usually in amounts of from 0.001 to 10 mg/kg / day for an adult patient. Inhalations are made once or several times a day, usually in a dose of from 0.0001 to 1 mg/kg / day for an adult patient, percutaneous forms cause one or more times a day in amounts of from 0.0001 to 1 mg/kg / day for an adult patient.

Solid compositions for oral administration in accordance with this invention using, for example, in the form of tablets, powders or granules. In such solid compositions one or more active substances are mixed with at least one inert filler such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone or magnesium aluminosilicate. Typically, the composition may contain inert additives, including lubricating agents such as magnesium stearate, disintegrating agents such as carboxymethylcelluose or connection, soluble in the stomach or intestinal tract.

Liquid compositions for oral administration include, for example, pharmaceutically acceptable emulsions, liquids, suspensions, syrups and elixirs, and contain conventional inert solvents such as purified water or ethanol. In addition to the inert solvent data composition may also contain auxiliary agents, such as solubilizers agent, wetting agent and suspendisse agent, as well as sweeteners, flavoring additives, flavorings and preservatives.

Injections for parenteral administration include aseptic aqueous or non-aqueous liquids, suspensions and emulsions. Examples of aqueous solvents include distilled water for injection and physiological saline. Examples of nonaqueous solvents include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, alcohol such as ethanol, and Polysorbate 80 (trade mark). Such compositions may also contain an agent that regulates toychest (osmotic pressure), antiseptics, wetting agent, emulsifying agent, dispersing agent, stabilizing agent and solubilizers agent. These compositions are sterilized, for example, filtration is about, they can be in the form of the initial sterile solid compositions dissolved in sterile water or a sterile solvent for injection immediately before the introduction.

THE OPTIMAL VARIANT OF THE INVENTION

The invention is illustrated by the following examples, which however do not limit the scope of the present invention. Methods of obtaining the source of the compounds shown in the reference examples. In this case, 3-(3-chlorobenzoyl)-2-ethylamino-6-dimethoxypyrimidine receive in accordance with the method of reference example 44 publication WO 97/19078 and 3-substituted derivatives of 2-ethylamino-6-methylpyridine, such as 3-(3-chlorobenzoyl)-2-ethylamino-6-methylpyridine and 3-cyclohexanecarbonyl-2-ethylamino-6-methylpyridin receive according to the procedures described in the reference examples 45, 48 and 51 publication WO 97/19078 respectively.

In the reference examples and tables the following abbreviations are used. PR.: the number of the example, AB.: the number of reference example No.: the connection number. Data: physicochemical data (MS: mass spectrometry with fast atom bombardment (M+H)+So pl.: the melting temperature (°C), decomp.: decomposition, AMR: (M. D.) characteristic peaks1H-NMR in Dl3the salad, FUM: fumarate, clean column: loose coupling, the number in front of the component, for example 1 Hcl, means monohydrochloride), SYN.: the method of obtaining (each number refers to the number of the sample or a reference sample with a similar method of obtaining), Me: methyl, Et: ethyl, AWG: cyclopropyl, snekh: cyclohexyl, Ph: phenyl. AC: acetyl, Py2: pyridine-2-yl and Ru: pyridine-4-yl. In addition, the number in front of each Deputy shows the position of the substitution, for example, 2-CL-Ru means 2-chloropyridin-4-yl and 3l-PH means 3-chlorophenyl.

Reference example 1

A solution of 3-(3-chlorobenzoyl)-2-ethylamino-6-methylpyridine in DMF is treated with 60% sodium hydride and then subjected to interaction with monoacylglycerol when heated. Then solution treated and purified in the usual method of obtaining ethyl-4-{N-[3-(3-chlorobenzoyl)-6-methylpyridin-2-yl]-N-ethyl-carbarnoyl}butanoate. The compound obtained is subjected to interaction with sodium methylate in ethanol under heating, and then to the reaction mixture concentrated sulfuric acid, followed by interaction when heated for 2 days. Then the reaction mixture was treated and purified in the usual method of obtaining ethyl-3-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthiridine-3-[4-(3 - chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]acetate. AMR: 6,91 (1H, d, J=8.1 Hz), of 4.13 (2H, q, J=7,1 Hz), 3.43 points (2N, C).

Reference example 3

According to the method of reference example 1 are methyl-4-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]butanoate. AMR: TO 6.88 (1H, d, J=7.8 Hz), of 4.67 (2H, q, J=7.0 Hz), and 2.27 (2H, t, J=7,6 Hz).

Reference example 4

After the interaction of 3-(3-chlorobenzoyl)-2-ethylamino-6-methylpyridine with isochroman-1,3-dione (75%) by heating the compound obtained after conventional treatment, is subjected to the interaction with methyliodide in 2-butanone in the presence of potassium carbonate. Then the reaction mixture was treated and purified in the usual method of obtaining methyl-2-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]benzoate as a yellow solid. MS: 433.

Reference example 5

After processing 4-cyanobutane acid sodium methylate in methanol-treated compound is subjected to interaction with revalorisation in THF. Thus obtained compound is subjected to interaction with 3-(3-chlorobenzoyl)-2-ethylamino-6-methylpyridine when heated. Then the connection is received conventional treatment, treated in ethanol in the presence of sodium methylate when heated. Then the reaction mixture of the process is as pale yellow solid. MS: 352.

Reference example 6

The compound obtained by the interaction of the 3'-triftormetilfullerenov acid with revalorisation in THF in the presence of triethylamine is stirred while adding 3-(3-chlorobenzoyl)-2-ethylamino-6-methylpyridine at a temperature of 150°C for 15 hours. Then the reaction mixture was treated and purified in the usual method of obtaining 4-(3-chlorophenyl)-1-ethyl-7-methyl-3-(3-triptoreline)-1.8-naphthiridine-2(1H)-it is in the form of a colorless solid. MS: 443.

Reference example 7

According to the method of reference example 6 to obtain 4-(3-chlorophenyl)-1-ethyl-7-methyl-3-(4-triptoreline)-1.8-naphthiridine-2(1H)-he. MS: 443.

Reference example 8

Ethyl-2-(2-aminothiazol-4-yl)acetate is subjected to interaction with acetylchloride in dichloroethane in the presence of triethylamine, and then the reaction mixture was treated and purified in the usual method to obtain ethyl-2-(2-acetylaminophenol-4-yl)acetate as a colorless solid. MS: 229.

Reference example 9

Ethyl-2-(2-acetylaminophenol-4-yl)acetate is subjected to interaction with a mixture of ethanol -1 M aqueous solution of sodium hydroxide (1:1) at room temperature, then the reaction mixture was treated and acasta. MS: 201.

Reference example 10

Using 2-(2-acetylaminophenol-4-yl)acetic acid according to the method of reference example 6 N get-{4-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]thiazol-2-yl}ndimethylacetamide. MS: 439.

Reference example 11

Utilizedabated subjected to interaction with benzylbromide in acetonitrile in the presence of cesium carbonate and then the reaction mixture was treated and purified in the usual method of obtaining ethyl-1-(benzyloxycarbonylamino)isonipecotate in the form of a colorless oily substance. MS: 306.

Reference example 12

Ethyl-1-(benzyloxycarbonylamino)isonipecotate subjected to catalytic recovery in hydrogen atmosphere of 1 ATM in ethanol in the presence of 10% palladium on coal. The compound obtained is treated with sodium methylate in ethanol and then subjected to interaction with revalorisation in THF.

The compound obtained is subjected to interaction with 3-(3-chlorobenzoyl)-2-ethylamino-6-methylpyridine when heated and then treated with sodium methylate in ethanol. Then the reaction mixture was treated and purified in the usual method of obtaining ethyl-1-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-natteri the

The solution Diisopropylamine in THF is treated with 1.6 M solution of utility/hexane. Then to the mixture are added dropwise 2,6-dichloropyridine with THF and left to interact, then added dropwise 3-chlorobenzaldehyde. The reaction mixture was treated and purified in the usual method and the compound obtained is subjected to interaction with manganese dioxide in toluene by heating. The reaction mixture was treated and purified in the usual method of obtaining 3-(3-chlorobenzoyl)-2,6-dichloropyridine. MS: 286.

Reference example 14

To a solution of 2,6-dichloro-3-(3-chlorobenzoyl)pyridine in THF added 70% aqueous solution of ethylamine with subsequent interaction at room temperature. Then the reaction mixture was treated and purified in the usual method of obtaining 6-chloro-3-(3-chlorobenzoyl)-2-Ethylenediamine. AMR: 8,95 (1H, Shir.C), 6,48 (1H, d, J=7.8 Hz), is 1.31 (3H, t, J=7,1 Hz).

Reference example 15

Glutaric anhydride and 6-chloro-3-(3-chlorobenzoyl)-2-ethylaminomethyl subjected to interaction when heated at a temperature of 150°C and then treated and purified in the usual method. The compound obtained is subjected to interaction with methyliodide in 2-butanone in the presence of potassium carbonate at a temperature of 60°C. the ZAT is co-1,2-dihydro-1,8-naphthiridine-3-yl]propanoate in the form of a colorless solid. MS: 405.

Reference example 16

3-(3-Chlorobenzoyl)-2-ethylamino-6-dimethoxypyrimidine in DMF is treated with 60% sodium hydride, followed by interaction with monoacylglycerol. Then the reaction mixture was treated and purified in the usual method. The compound obtained is subjected to interaction with ethanol in the presence of sodium methylate when heated and the reaction mixture was treated and purified in the usual method. Then the obtained compound is treated with a solution of 6 M hydrochloric acid - dioxane (1:1) under heating, and then the reaction mixture was treated and purified in the usual method. The compound obtained is further subjected to interaction with methyliodide in DMF in the presence of potassium carbonate, and then the reaction mixture was treated and purified in the usual method of obtaining methyl-3-[4-(3-chlorophenyl)-1-ethyl-7-formyl-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]propanoate. AMR: 10,11 (1H, d, J=0.6 Hz), 2,45-2,95 (4H, m), USD 1.43 (3H, t, J=7,1 Hz).

Reference example 17

15% aqueous solution of timedelta sodium added dropwise to a solution of 2,6-dichloro-3-(3-chlorobenzoyl)pyridine in DMF under cooling on ice. After completion of the reaction, the reaction mixture was treated and purified in the usual method. Received soedinenii temperature 110°C. Then the reaction mixture was treated and purified in the usual method of obtaining 3-(3-chlorobenzoyl)-2-ethylamino-6-methylsulfonylamino. AMR: 6,36 (1H, DD, J=8,2, 0.7 Hz), 2,58 (3H, s) of 1.32 (3H, t, J=7,1 Hz).

Reference example 18

To a solution of 4-(3-chlorophenyl)-1-ethyl-7-methyl-3-(pyridin-4 - yl)-1,8-naphthiridine-2(1H)-it is in dichloromethane add m-chloroperbenzoic acid at room temperature, followed by stirring for 5 hours. Then the reaction mixture was treated and purified in the usual method of obtaining 4-(3-chlorophenyl)-1-ethyl-7-methyl-3-(1-oxypyridine-4-yl)-1,8-naphthiridine-2(1H)-it is in the form of a colorless solid. MS: 392.

Reference example 19

To a solution of 3-(3-chlorobenzoyl)-2-ethylamino-6-methylpyridine in DMF add chlorocatechol and pyridine, followed by interaction at room temperature. Then the reaction mixture was treated and purified in the usual method of obtaining N-[3-(3-chlorobenzoyl)-6-methylpyridin-2-yl]-N-ethylchloride. To a solution of the compound in acetonitrile added N-tert-butoxycarbonylmethyl and potassium carbonate with subsequent interaction when heated. Then the reaction mixture was treated and purified in the usual method of obtaining 2-[4-tert-butoxycarbonylamino the Yu with sodium methylate in methanol under heating. Then the reaction mixture was treated and purified in the usual method of obtaining 3-(1-tert-butoxycarbonyl-piperazine-4-yl)-4-(3-chlorophenyl)-1-ethyl-7-methyl-1,8-naphthiridine-2(1H)-she. AMR: TO 4.73 (2H, q, J=7,3 Hz), 3,15-to 3.35 (2H, m), 1,38 (N, C).

Reference example 20

To a solution of 4-(3-chlorophenyl)-1-ethyl-3-(3-hydroxypropyl)-7-methyl-1,8-naphthiridine-2(1H)-she's in THF add triethylamine and methanesulfonanilide with subsequent interaction when heated. Then the reaction mixture was treated and purified in the usual method of obtaining 4-(3-chlorophenyl)-1-ethyl-3-(3-methanesulfonylaminoethyl)-7-methyl-1,8-naphthiridine-2(1H)-she. AMR: 4,67 (2H, q, J=7,1 Hz), 4,18 (2H, t, J=6.3 Hz), with 2.93 (3H, s).

Reference example 21

To a solution of 4-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]butane acid in THF add oxalicacid and one drop of DMF, followed by stirring at room temperature. The reaction mixture was added dropwise to a cooled on ice to a solution of concentrated aqueous ammonia in THF and the mixture is then stirred for 30 minutes. Then the reaction mixture was treated and purified in the usual method of obtaining 4-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]butanamide. To the solution obtained m at room temperature. Then the reaction mixture was treated and purified in the usual method of obtaining 4-(3-chlorophenyl)-3-(3-cyanopropyl)-1-ethyl-7-methyl-1,8 - naphthiridine-2(1H)-she. AMR: 6,90 (1H, d, J=8,2 Hz), of 4.67 (2H, q, J=7,1 Hz), 1.70 to 2,10 (2H, m).

Reference example 22

To a suspension of magnesium in diethyl ether are added dropwise 2-bromothiophene at room temperature and the resulting mixture is allowed to react. After cooling to a temperature of 0°C the reaction mixture was added 2-chloro-6-methylnicotinic acid and, after heating to room temperature, the mixture is stirred for 12 hours. Then the reaction mixture was treated and purified in the usual method of obtaining 2-chloro-6-methyl-3-(thiophene-2-carbonyl)pyridine. AMR: 7,79 (1H, DD, J=5,0; 1,1 Hz), 7,78 (1H, d, J=7,7 Hz), 2.63 in (3H, s).

Reference example 23

In a sealed tube is heated and stirred 2-chloro-6-methyl-3-(thiophene-2-carbonyl)pyridine and 70% aqueous solution of ethylamine. Then the reaction mixture was treated and purified in the usual method of obtaining 2-ethylamino-6-methyl-3-(thiophene-2-carbonyl)pyridine. AMR: OF 7.97 (1H, d, J=8.1 Hz), a 7.62 (1H, DD, J=5,0; 1,1 Hz) of 1.28 (3H, t, J=7,3 Hz).

Reference example 24

A solution of 3-(3-chlorobenzoyl)-6-dimethoxymethyl-2-Ethylenediamine in DMF is treated with heridatary 80°C under stirring. Then the reaction mixture was treated and purified in the usual method. The compound obtained is dissolved in ethanol and the resulting solution was added sodium methylate at a temperature of 0°C, followed by heating under reflux for 1 hour. The reaction mixture is cooled to a temperature of 0°C and then add concentrated sulfuric acid followed by heating under reflux for 1 hour. Then the reaction mixture is treated with a conventional method. The compound obtained is dissolved in dioxane and the resulting solution was added 6 M hydrochloric acid at a temperature of 0°C, after heating to room temperature, the mixture is stirred for 3 hours. Then the reaction mixture is treated in the usual method of obtaining 3-[4-(3-chlorophenyl)-1-ethyl-7-formyl-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]propanoic acid. AMR: 10,12 (1H, s), of 7.70 (1H, d, J=8.1 Hz), the 1.44 (3H, t, J=6.9 Hz).

Reference example 25

To a solution of 3-(3-chlorobenzoyl)-6-dimethoxymethyl-2-Ethylenediamine in acetone add 6 M hydrochloric acid and the mixture is left to interact at room temperature for 5 hours. After removal of solvent by evaporation of the propylene oxide and chlorocatechol daywalt at a temperature of 60°C for 14 hours. Then the reaction mixture was treated and purified in the usual method of obtaining 2-chloro-N-[3-(3-chlorobenzoyl)-6-formylpyridine-2-yl]-N-ethylacetamide in the form of a yellow oily substance. AMR: 10,1 (1H, d, J=0.6 Hz), 7,95 (2H, Shir.C) 1.0 to 1.5 (3H, m).

Reference example 26

To a solution of 2-chloro-N-[3-(3-chlorobenzoyl)-6-formylpyridine - 2-yl]-N-ethylacetamide in acetonitrile added cesium carbonate and utilizedabated, followed by stirring at 60°C for 3 hours. After removal of inorganic substances by filtration and the solvent is evaporated, the obtained residue is dissolved in ethanol, add sodium methylate and heated under reflux for 15 minutes. Then the reaction mixture was treated and purified in the usual method of obtaining ethyl-1-[4-(3-chlorophenyl)-1-ethyl-7-formyl-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]piperidine-4-carboxylate as a yellow oily substance. MS: 468.

Reference example 27

To a solution of ethyl-1-[4-(3-chlorophenyl)-1-ethyl-7-formyl-2 - oxo-1,2-dihydro-1,8-naphthiridine-3-yl]piperidine-4-carboxylate in ethanol add borohydride sodium while cooling on ice and stirred for 15 minutes. Then the reaction mixture was treated and purified in the usual method of obtaining these is th oily substance. MS: 470.

Reference example 28

To a solution of (1-acetylpiperidine-4-yl)acetic acid in THF at room temperature is added triethylamine and pivaloyloxy and stirred at room temperature for 1 hour. The reaction mixture is filtered and concentrated. Then to the residue add 3-cyclohexanecarbonyl-2-ethylamino-6-methylpyridin, followed by stirring at a temperature of 150°C for 14 hours. To the product obtained by treating the reaction mixture, add ethanol and sodium methylate and the mixture was heated under reflux for 1 hour. Then the reaction mixture was treated and purified in the usual method of obtaining 3-(1-acetylpyridine-4-yl)-4-cyclohexyl-1-ethyl-7-methyl-1,8-naphthiridine-2(1H)-it is in the form of a colorless solid. MS: 396.

Reference example 29

To a solution of 3-(3-bromobenzoyl)-2-ethylamino-6-methylpyridine in dichloroethane add p-toluensulfonate, (1-ethoxycarbonylpyrimidine-4-yl)acetic acid and 4-dimethylaminopyridine, followed by stirring at a temperature of 80°C for 12 hours. To the product obtained by treating the reaction mixture, add ethanol and sodium methylate, the resulting mixture is heated with reverse holodilnik)-3-(1-ethoxycarbonylpyrimidine-4-yl)-1-ethyl-7-methyl-1,8-naphthiridine-2(1H)-it is in the form of a pale brown solid. MS: 498.

Reference example 30

4-(3-Bromophenyl)-3-(2-cyanoethyl)-1-ethyl-7-methyl-1,8-naphthiridine-2(1H)-he synthesized according to the method of reference example 5. MS: 396.

Reference example 31

4-Cyclohexyl-3-(2-cyanoethyl)-1-ethyl-7-methyl-1,8-naphthiridine-2(1H)-he synthesized according to the method of reference example 5. MS: 324.

Reference example 32

4-(3-Chlorophenyl)-1-ethyl-3-(2-hydroxyethyl)-7-methyl-1,8-naphthiridine-2(1H)-he synthesized according to the method presented below in example 16. AMR: 6,92 (1H, d, J=8,2 Hz), of 4.67 (2H, q, J=7.0 Hz), 3,74 (2H, t, J=5.8 Hz).

Reference example 33

5-(3-Chlorophenyl)-8-ethyl-6-[3-(morpholine-4-yl)-3-oxopropyl]-7-oxo-7,8-dihydro-1,8-naphthiridine-2-carbaldehyde synthesized by the method shown below in example 6. AMR: OF 7.69 (1H, d, J=8.1 Hz), 3,51-to 3.67 (8H, m) of 1.44 (3H, t, J=7,0 Hz).

Reference example 34

To 50 ml of a dichloroethane solution containing 7.5 g of 3-(3 - chlorobenzoyl)-2-ethylamino-6-methylpyridine, add 5 ml of monoethylfumarate and 6.5 g of 4-dimethylaminopyridine. The mixture is stirred at room temperature for 30 minutes and then heated at an oil bath at a temperature of 80°C for 30 minutes. The reaction mixture is cooled to room temperature and after adding 1 M chloritoid oritel is evaporated. The resulting residue is purified by chromatography on a column of silica gel (hexane-ethyl acetate to chloroform-ethyl acetate) to obtain 7,10 g ethyl-4-(3-chlorophenyl)-1-ethyl - 7-methyl-2-oxo-1,2-dihydro-1,8-naphthiridine-3-carboxylate as colorless crystals.

Example 2

15 ml of 1 M aqueous sodium hydroxide solution is added to 15 ml of THF-methanol (1;1) containing 2.70 g ethyl-3-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]propanoate, followed by stirring under heating at an oil bath at a temperature of 80°C for 2 hours. After cooling to room temperature the mixture is brought to pH 3 by addition of 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated salt solution and then the solvent is evaporated. The resulting residue is purified by chromatography on a column of silica gel (chloroform-methanol) and then recrystallized from diisopropyl ether-ethyl acetate to obtain 1.27 g of 3-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]propanoic acid as colorless crystals.

Example 3

A mixture of 1.00 g of 3-(3-chlorobenzoyl)-2-ethylamino-6-methylpyridine and 5.17 g of 2,2-dimethylglutaric anhydride premesis is of 0.5 M hydrochloric acid is heated under reflux for 2 hours. Then the reaction mixture is cooled to room temperature and extracted with ethyl acetate. The organic layer was washed with saturated salt solution and then the solvent is evaporated. The resulting residue is purified by chromatography on a column of silica gel (hexane-ethyl acetate) and then recrystallized from ethanol-water to obtain 198 mg of 3-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]-2,2-dimethylpropanoate acid in the form of orange crystals.

Reference example 35

10 ml of polyphosphoric acid added to 320 mg of 4-(3-chlorophenyl)-3-cyano-1-ethyl-1,8-naphthiridine-2(1H)-it, followed by stirring under heating at an oil bath at a temperature of 130°C for 2 hours. The reaction mixture was poured into ice water, adjusted to pH 6 by addition of 1 M aqueous sodium hydroxide solution and extracted with chloroform. The organic layer was washed with saturated salt solution and then the solvent is evaporated. The resulting residue is purified by chromatography on a column of silica gel (chloroform-ethyl acetate) and then recrystallized from ethanol to obtain 180 mg of 4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthiridine-3-carboxamide as colorless crystals.

Example 5

ethyl-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]propanoic acid, followed by stirring at room temperature for another 30 minutes. The reaction mixture was added dropwise to 10 ml of chilled on ice THF solution containing 1.0 ml of the research, followed by stirring for 30 minutes. To the reaction mixture was added 1 M hydrochloric acid and the mixture extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution and then the solvent is evaporated. The resulting residue is purified by chromatography on a column of silica gel (chloroform-methanol) and then recrystallized from diisopropyl ether-ethyl acetate to obtain 780 mg of 4-(3-chlorophenyl)-1-ethyl-7-methyl-3-[3-(morpholine-4-yl)-3-oxopropyl]-1,8-naphthiridine-2(1H)-it is in the form of colorless crystals.

Example 6

While cooling on ice, 630 mg of 1-ethyl-3-(3-dimethyl - aminopropyl)carbodiimide hydrochloride, 154 mg of dimethylamine hydrochloride and of 0.53 ml of triethylamine are sequentially added to 10 ml of DMF solution containing 700 mg of 3-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]propanoic acid. The reaction mixture is heated to room temperature and stirred for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated salt solution and then the solvent is evaporated. Proceviat from diisopropyl ether to obtain 262 mg of 3-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]-N,N-dimethylpropanamide in the form of colorless crystals.

Reference example 38

To 10 ml of toluene containing of 1.00 g of 4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthiridine-3-carboxylic acid add 900 mg diphenylphosphinite (DFA) and 0.5 ml of triethylamine, followed by heating on an oil bath at a temperature of 100°C for 1 hour. Then the reaction mixture was added 10 ml of ethanol and the mixture is stirred under heating for 30 minutes. After cooling to room temperature the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated salt solution and then the solvent is evaporated. The resulting residue is purified by chromatography on a column of silica gel (toluene-ethyl acetate) and then recrystallized from ethyl acetate to obtain 590 mg of ethyl-N-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]carbamate in the form of colorless crystals.

Reference example 39

720 mg of ethyl-N-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo - 1,2-dihydro-1,8-naphthiridine-3-yl]carbamate is stirred in 40 ml of ethanol - 3 M aqueous sodium hydroxide solution (1:1) and heated at an oil bath at a temperature of 100°C for 4 hours. After cooling to room temperature the reaction mixture was rastvoritel is evaporated. The resulting residue is purified by chromatography on a column of silica gel (toluene-ethyl acetate) and then recrystallized from diisopropyl ether-ethyl acetate to obtain 298 mg of 3-amino-4-(3-chlorophenyl)-1-ethyl-7-methyl-1,8-naphthiridine-2(1H)-it is in the form of colorless crystals.

Example 12

To 15 ml of dichloroethane containing 1,38 g 3-(2-amino-ethyl)-4-(3-chlorophenyl)-1-ethyl-7-methyl-1,8-naphthiridine-2(1H)-she added 720 mg of 37% aqueous formalin solution and 0.55 ml of acetic acid under cooling at a temperature of 0°C, followed by stirring for 30 minutes. Then in a mixture of 2.05 g of triacetoxyborohydride sodium and the mixture is heated to room temperature, then stirred for 2 hours. The reaction mixture is cooled to a temperature of 0°C, adjusted to pH 8 by addition of 1 M aqueous sodium hydroxide solution and extracted with chloroform. From the organic layer, the solvent is evaporated and the residue purified by chromatography on a column of silica gel (chloroform-methanol). To the obtained oily substance in 5 ml of methanol added 194 mg of oxalic acid and then the solvent is evaporated. The crude crystals are recrystallized from acetonitrile to obtain 300 mg of 4-(3-chlorophenyl)-3-(2-dime"ptx2"> Reference example 40

To 5 ml of DMF solution containing of 1.00 g of 3-amino-4-(3 - chlorophenyl)-1-ethyl-7-methyl-1,8-naphthiridine-2(1H)-it adds 191 mg of 60% sodium hydride followed by heating to a temperature of 60°C. To the reaction mixture 551 mg of N-(2-chloroethyl)dimethylamine hydrochloride and 1.08 ml of triethylamine with 5 ml DMF and the reaction mixture is stirred for 1 hour. After cooling to a temperature of 0°C, the reaction mixture was diluted with 5 ml of water and extracted with ethyl acetate. The organic layer was washed with saturated salt solution and the solvent is evaporated. The residue is purified by chromatography on a column of silica gel (chloroform-methanol). To the obtained oily substance in 5 ml of methanol added 83 mg of oxalic acid and then the solvent is evaporated. The crude crystals are recrystallized from methanol to obtain 93 mg of 4-(3-chlorophenyl)-3-(2-diethylaminoethylamine)-1-ethyl-7-methyl-1,8-naphthiridine-2(1H)-it monoacetate hemihydrate in the form of colorless crystals.

Example 14

To 10 ml of dichloroethane containing 630 mg of 3-(3-aminopropyl)-4-(3-chlorophenyl)-1-ethyl-7-methyl-1,8-naphthiridine-2(1H)-it adds 243 mg methanesulfonanilide and 0.30 ml of triethylamine while cooling on ice with Aut with ethyl acetate and washed with saturated aqueous sodium bicarbonate and saturated salt solution. From the organic layer, the solvent is evaporated, the obtained residue is purified by chromatography on a column of silica gel (hexane-ethyl acetate) and then recrystallized from ethanol-water to obtain 204 mg of N-{3-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]propyl}methanesulfonamide in the form of colorless crystals.

Example 16

A mixture of 1.00 g of 3-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]propanoic acid, 20 ml of methanol and 0.5 ml of concentrated sulfuric acid is heated under reflux for a whole day and night. After cooling to room temperature the mixture was added saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated salt solution and then the solvent is evaporated. The residue is purified by chromatography on a column of silica gel (hexane-ethyl acetate). The compound obtained was dissolved in 20 ml of THF and added 500 mg of sodium borohydride. When heated with reflux condenser are added dropwise 3 ml of methanol and the mixture then continue to heat under reflux for 3 hours. After cooling to room temperature, add 1 M hydrochloric acid and the mixture is extra is. The residue is purified by chromatography on a column of silica gel (hexane-ethyl acetate) and then recrystallized from diisopropyl ether to obtain 497 mg of 4-(3-chlorophenyl)-1-ethyl-3-(3-hydroxypropyl)-7-methyl-1,8-naphthiridine-2(1H)-it is in the form of colorless crystals.

Example 17

While cooling on ice ceiling of 5.60 ml of triethylamine and the 4.90 ml pualeilani add 80 ml of THF solution containing 5,08 g 5-ketohexose acid, followed by stirring at room temperature for 1 hour. The reaction mixture is filtered and the solvent is evaporated. To the residue obtained by evaporation of the solvent, add a 2.00 g of 3-(3-chloro-benzoyl)-2-ethylamino-6-methylpyridine and the mixture is stirred under heating at 150°C for 2 days. After cooling to room temperature the reaction mixture was diluted with ethyl acetate and washed with 1 M aqueous sodium hydroxide solution and saturated salt solution. The solvent of the organic layer is evaporated, the obtained residue is purified by chromatography on a column of silica gel (hexane-ethyl acetate) and then recrystallized from ethanol to obtain 774 mg of 4-(3-chlorophenyl)-1-ethyl-7-methyl-3-(3-oxobutyl)-1.8-naphthiridine-2(1H)-it is in the form of yellow crystals.

Example 18

Example 19

To 10 ml of a THF solution containing 500 mg of 4-(3-chlorophenyl)-1-ethyl-3-(3-hydroxypropyl)-7-methyl-1,8-naphthiridine-2(1H)-she added 300 mg of p-toluensulfonate, 0.15 ml of triethylamine and a catalytic amount of 4-dimethylaminopyridine followed by heating under reflux for 2 hours. Then add 300 mg of p-toluensulfonate, 0.15 ml of triethylamine and a catalytic amount of 4-dimethylaminopyridine followed by heating under reflux for 2 hours. After cooling to room temperature, water is added and the mixture extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution and the solvent is evaporated pnoe connection is stirred with 300 ml of imidazole, 250 mg of potassium carbonate and 10 ml of DMF and heated at an oil bath at a temperature of 80°C for 2 hours. Then add 300 mg of potassium iodide, followed by stirring under heating at an oil bath at a temperature of 80°C for another 2 hours. After cooling to room temperature the reaction mixture was diluted with water and then extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution and then the solvent is evaporated. The resulting residue is purified by chromatography on a column of silica gel (chloroform-methanol-aqueous ammonia) and then dissolved in ethyl acetate. To the solution was added a 4 M solution of hydrogen chloride in ethyl acetate and then the solvent is evaporated under reduced pressure. The residue is recrystallized from acetonitrile-ethyl acetate to obtain 447 mg of 4-(3-chlorophenyl)-1-ethyl-3-[3-(imidazol-1-yl)propyl]-7-methyl-1,8-naphthiridine-2(1H)-it monohydrochloride 0.2 hydrate in the form of a colorless crystalline solid.

Example 20

1.40 g of methyl 2-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo - 1,2-dihydro-1,8-naphthiridine-3-yl]benzoate was stirred in 20 ml of methanol and 10 ml of 1 M aqueous sodium hydroxide solution at 60°C for 15 hours. The reaction mixture is cooled is on and recrystallized from ethyl acetate-diisopropyl ether to obtain 540 mg of 2-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]benzoic acid 0.6 hydrate in the form of a colorless crystalline solid.

Example 21

A mixture of 700 mg of 4-(3-chlorophenyl)-1-ethyl-7-methyl-3-(3-tri - formationl)-1.8-naphthiridine-2(1H)-it and 5 ml of concentrated sulfuric acid is stirred at a temperature of 120°C for 2 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution and then the solvent is evaporated. The crude crystals are recrystallized from acetonitrile to obtain 459 mg of 3-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]benzoic acid as pale yellow crystals.

Example 22

While cooling on ice 897 mg of sodium methylate is added to 40 ml of methanol containing of 3.45 g of 3-(4-ethoxycarbonylphenyl)propanoic acid, followed by stirring for 30 minutes. After concentration of the reaction mixture, the resulting residue is diluted with 50 ml THF. After cooling on ice to the mixture of 3.07 ml pualeilani, followed by stirring at room temperature for 1 hour. To the residue obtained by concentration of the reaction mixture after filtering, add 800 mg 3-(3-chlorobenzoyl)-2-ethylamino-6-methylpyridine, followed by stirring at a temperature of 150 washed with 1 M aqueous sodium hydroxide solution and saturated salt solution. The solvent is evaporated from the organic layer and to the residue are added 50 ml of methanol and 900 mg of sodium methylate, followed by heating under reflux for 3 hours. Then add 40 ml of 1 M aqueous sodium hydroxide solution and the mixture is stirred at a temperature of 60°C for 16 hours. Then to the reaction mixture are added 50 ml of 1 M hydrochloric acid. After concentration under reduced pressure the resulting residue was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and saturated salt solution. After evaporation of the solvent the crude crystals are recrystallized from ethanol to obtain 764 mg of 4-{[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]methyl}benzoic acid as pale yellow crystals.

Example 23

To 20 ml of dioxane containing 783 mg of 3-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]benzoic acid, add to 0.48 ml DFFA, at 0.31 ml of triethylamine and of 0.89 ml of tert-butanol, followed by heating under reflux for 18 hours. After cooling to room temperature and concentrating the reaction mixture under reduced pressure, to the obtained residue deathworm salt. The organic layer is concentrated under reduced pressure and the resulting residue purified by chromatography on a column of silica gel (hexane-ethyl acetate). To 680 mg of 680 mg of the obtained compound in 5 ml of ethyl acetate add 5 ml of 4 M hydrogen chloride-ethyl acetate while cooling on ice, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated and the obtained crude crystals are recrystallized from ethanol-ethyl acetate to obtain 486 mg of 3-(3-AMINOPHENYL)-4-(3-chlorophenyl)-1-ethyl-7-methyl-1,8-naphthiridine-2(1H)-it monohydrochloride in the form of pale brown crystals.

Example 26

To 50 ml of methanol containing and 3.16 g of 4-pyridyloxy acid monohydrochloride add of 1.97 g of sodium methylate under cooling on ice and the mixture is stirred for 1 hour. The reaction mixture was concentrated and to the residue are added 50 ml of THF. While cooling on ice to the mixture of 2.24 ml pualeilani. Then the mixture is treated according to the method of example 17 and then treated according to the method of obtaining salt to obtain 98 mg of 4-(3-chlorophenyl)-1-ethyl-7-methyl-3-(pyridin-4-yl)-1.8-naphthiridine-2(1H)-it monohydrochloride in the form of pale yellow crystals.

Example in-2(1H)-he 5 ml ethanol and 5 ml of 6 M hydrochloric acid is heated under reflux for 15 hours. The reaction mixture was concentrated and, after addition of saturated aqueous sodium bicarbonate solution extracted with chloroform. The organic layer is washed with water and saturated salt solution, then the solvent is evaporated. The residue is purified by chromatography on a column of silica gel (chloroform-methanol-aqueous ammonia) and the resulting yellow oily substance was dissolved in 5 ml of methanol, to which successively added 1 ml of methanol containing 45 mg of fumaric acid. The solvent is evaporated and the resulting residue is recrystallized from ethanol-ethyl acetate to obtain 187 mg of 4-(3-chlorophenyl)-1-ethyl-7-methyl-3-(piperidine-4-yl)-1.8-naphthiridine-2(1H)-it monopolarity in the form of pale yellow crystals.

Example 29

To 20 ml of chloroform containing 510 mg of 4-(3 - chlorophenyl)-1-ethyl-3-(3-oxobutyl)-7-methyl-1,8-naphthiridine-2(1H)-she added dropwise to 1.03 ml of bromine while cooling on ice. After adding to the reaction mixture is added saturated aqueous sodium thiosulfate solution, the mixture is extracted with chloroform and the organic layer was washed with a saturated solution of salt. Organic St. 10 ml of ethanol, add 104 mg of thioacetamide and stirred at a temperature of 70°C for 2 hours. The solvent of the reaction mixture is evaporated and to the obtained residue is added chloroform. The solution is washed with water and saturated salt solution and dried over anhydrous magnesium sulfate. The solvent of the organic layer is evaporated, the residue is purified by chromatography on a column of silica gel (ethyl acetate-hexane) and then recrystallized from acetonitrile to obtain 301 mg of 4-(3-chlorophenyl)-3-[(2,4-dimethylthiazol-5-yl)methyl]-1-ethyl-7-methyl-1,8-naphthiridine-2(1H)-it is in the form of colorless crystals.

Example 30

To 670 mg of 4-(3-chlorophenyl)-1-ethyl-7-methyl-3-(1-oxypyridine-4-yl)-1,6-naphthiridine-2(1H)-it add 1.6 ml of phosphorus oxychloride and 2.4 ml of triethylamine, followed by stirring at 60°C for 1 hour. The solvent is evaporated and to the obtained residue, add water. The mixture is extracted with ethyl acetate, the organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated, the obtained residue is purified by chromatography on a column of silica gel (ethyl acetate-hexane) and then recrystallized from ethanol-water to obtain 175 mg of 4-(3-chlorophenyl)-3-(2-chloropyridin-4-yl)-1-ethylacetate, containing 570 mg of 3-(1-tert-butoxycarbonylmethyl-4-yl)-4-(3-chlorophenyl)-1-ethyl-7-methyl-1,8-naphthiridine-2(1H)-it, add 10 ml of 4 M hydrogen chloride-ethyl acetate, followed by stirring at room temperature for 1 hour. After adding water, the reaction mixture is neutralized 1 M aqueous solution of sodium hydroxide and then extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated, the obtained residue is purified by chromatography on a column of silica gel (chloroform-methanol-aqueous ammonia) and then recrystallized from diisopropyl ether to obtain 115 mg of 4-(3-chlorophenyl)-1-ethyl-7-methyl-3-(piperazine-1-yl)-1.8-naphthiridine-2(1H)-it is in the form of pale yellow crystals.

Example 34

To 10 ml of DMF solution containing 500 mg of 4-(3-chlorophenyl)-1-ethyl-3-(3-hydroxypropyl)-7-methyl-1,8-naphthiridine-2(1H)-it is added 500 mg of potassium carbonate and 0.5 ml under the conditions, followed by stirring under heating at an oil bath at a temperature of 80°C for 2 hours. Then add 1.0 g of potassium carbonate and 1.0 ml under the conditions, followed by stirring under heating at an oil bath at a temperature of 80°C for celog is by ethyl acetate. The organic layer is washed with water and saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated, the obtained residue is purified by chromatography on a column of silica gel (hexane-ethyl acetate) and then recrystallized from hexane-diisopropyl ether to obtain 160 mg of 4-(3-chlorophenyl)-1-ethyl-3-[3-(methoxycarbonylamino)propyl]-7-methyl-1,8-naphthiridine-2(1H)-it is in the form of colorless crystals.

Example 35

To 10 ml of tert-butanol, containing 500 mg of 4-(3-chlorophenyl)-1-ethyl-3-(3-hydroxypropyl)-7-methyl-1,8-naphthiridine-2(1H)-she consistently add 300 mg of tert-butyl sodium and 0.2 ml under the conditions, followed by stirring under heating at an oil bath at a temperature of 60°C for 2 hours. After cooling the reaction mixture to room temperature it was added water and 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated, the obtained residue is purified by chromatography on a column of silica gel (hexane-ethyl acetate) and then recrystallized from diisopropyl ether to obtain 180 mg of 4-(3-chlorophenyl)-1-ethyl-3-(3-methoxypropyl)-the Ola, containing of 3.54 g of ethyl- (8-methyl-8-azabicyclo[3.2.1]Octan-3-yl)acetate, add 30 ml of 1 M aqueous sodium hydroxide solution, followed by stirring at room temperature for 14 hours. Then to the reaction mixture is added 30 ml of 1 M hydrochloric acid and the solvent is evaporated. To the obtained residue, add ethanol and after removing insoluble substances by filtration, the solvent is again evaporated to obtain 3.55 g of the crude product. 3.50 g of the compound dissolved in 40 ml of methanol and 837 mg of sodium methylate with obtaining a sodium salt. After evaporation of methanol, the resulting residue is suspended in 40 ml of THF are 2.87 ml pualeilani, followed by stirring at room temperature for 2 hours. To the reaction mixture is added diethyl ether, and after removing insoluble substances by filtration, the solvent is evaporated. To the obtained residue, add 800 mg 3-(3-bromobenzoyl)-2-ethylamino-6-methylpyridine, followed by stirring at 150°C for 14 hours. To the reaction mixture are added ethyl acetate and the solution washed with 1 M aqueous sodium hydroxide solution, water and saturated salt solution and then dried over anhydrous magnesium sulfate. After evaporation ramratnam refrigerator for 1 hour. After evaporation of the solvent added ethyl acetate, the solution washed with water and saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent is evaporated and the resulting residue purified by chromatography on a column of silica gel (chloroform-methanol-29% aqueous ammonia) to obtain 150 mg of the product. The connection is treated with 4 M hydrogen chloride to obtain the hydrochloride, which is then recrystallized from ethanol-ethyl acetate to obtain 69 mg of 4-(3-chlorophenyl)-1-ethyl-7-methyl-3-(8-methyl-8-azabicyclo[3.2.1]Octan-3-yl)-1.8-naphthiridine-2(1H)-it monohydrochloride in the form of colorless crystals.

Example 37

To 10 ml of a THF solution containing 700 mg of 4-(3-chlorophenyl)-1-ethyl-3-(3-methanesulfonylaminoethyl)-7-methyl-1,8-naphthiridine-2(1H)-it, add 0.5 ml of pyrrolidine and 300 mg of potassium iodide, followed by stirring under heating at an oil bath at a temperature of 60°C for 1.5 hours. After cooling to room temperature, to the mixture are added water and 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. Then the solvent is evaporated and the residue purified by chromatography on a column with silicagel hydrogen chloride-ethyl acetate. Then the residue obtained by evaporation of the solvent is recrystallized from ethyl acetate-acetonitrile to obtain 133 mg of 4-(3-chlorophenyl)-1-ethyl-7-methyl-3-[3-(pyrrolidin-1-yl)propyl]-1,8-naphthiridine-2(1H)-it monohydrochloride in the form of colorless crystals.

Example 38

To a mixture of 2.00 g of 4-(3-chlorophenyl)-1-ethyl-3-(2-hydroxyethyl)-7-methyl-1,8-naphthiridine-2(1H)-she, 1.0 ml of triethylamine and 20 ml of THF are added dropwise 0.5 ml of methanesulfonanilide, followed by stirring at room temperature for 30 minutes. To the reaction mixture, water is added and the mixture extracted with ethyl acetate. The organic layer is successively washed with 1 M hydrochloric acid, saturated aqueous sodium bicarbonate and saturated salt solution and then dried over anhydrous magnesium sulfate. To 20 ml of a solution of the residue obtained by evaporation of the solvent, THF, add 1.0 ml of triethylamine, and 1.0 ml of utilisedictated and 500 mg of potassium iodide, followed by stirring under heating at an oil bath at a temperature of 60°C for the whole nights. After cooling the reaction mixture to room temperature it was added water and extracted with ethyl acetate. The organic layer was washed with a saturated solution of zoographies on a column of silica gel (chloroform-methanol) to give 1.70 g of the compound of ester. Then by the method of example 2 receive 593 mg 1-{2-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]ethyl}piperidine-4-carboxylic acid as colorless crystals.

Example 39

To 15 ml of 1,4-dioxane containing 314 mg of 3-(2-amino-ethyl)-4-(3-chlorophenyl)-1-ethyl-7-methyl-1,8-naphthiridine-2(1H)-she added 404 mg of 1-amidinopropane of monohydrochloride and of 0.48 ml diisopropylethylamine, followed by stirring for 122 hours. The reaction solution is evaporated, the obtained solid is removed by filtration and the solid is then washed with chloroform. The combined filtrate and washings are concentrated and the residue purified by chromatography on a column of silica gel (chloroform-methanol-aqueous ammonia). The obtained oily substance was dissolved in 5 ml of ethanol and there successively added 4 M hydrogen chloride-ethyl acetate and acetonitrile. The solvent is evaporated to obtain 347 mg of 4-(3-chlorophenyl)-1-ethyl-3-(2-guanidinate)-7-methyl-1,8-naphthiridine-2(1H)-it monohydrochloride monohydrate in the form of a colorless solid.

Example 40

Hydrogen chloride bubbled in 20 ml ethanol-chloroform (1:1) containing 461 mg of 4-(3-chlorophenyl)-3-(2 - cyanoethyl)-1-ethyl-7-methyl-1,8-naphthiridine-2(1H)-it, PR is a promotional solution evaporated. To the obtained solid substance is added 15 ml of ethanol and 505 mg of ammonium acetate, followed by stirring for 90 hours. The reaction solution is evaporated and the residue purified by chromatography on a column of silica gel (chloroform-methanol-aqueous ammonia). 0.4 ml of 4 M hydrogen chloride-ethyl acetate is added to the obtained oily substance in 5 ml of ethanol. After evaporation of the solvent, the obtained residue is recrystallized from ethanol-ethyl acetate to obtain 268 mg of 3-(2-amidaniel)-4-(3-chlorophenyl)-1-ethyl-7-methyl-1,8-naphthiridine-2(1H)-it monohydrochloride in the form of colorless crystals.

Example 42

To 7 ml of THF-ethanol (5:2), containing 300 mg of methyl 3-[4-(3-chlorophenyl)-1-ethyl-7-formyl-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]propionate add 9 mg of sodium borohydride while cooling on ice. After stirring for 1 hour to the reaction mixture are added water and extracted with ethyl acetate. The organic layer was washed with saturated salt solution and then the solvent is evaporated. The residue is purified by chromatography on a column of silica gel (hexane-ethyl acetate). Using 200 mg of 210 mg of the obtained compound, the compound is treated by the method of example 2 to obtain 130 mg of 3-[4-(3-chlorophenyl)-1-ethyl-7-hiteker 43

To 33 ml methanol-pyridine (10:1), containing 1.50 g of methyl-3-[4-(3-chlorophenyl)-1-ethyl-7-formyl-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]propanoate add 300 mg of hydroxylamine hydrochloride under cooling on ice. After stirring for 1 hour the reaction mixture is diluted with water and extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution and then the solvent evaporated. The resulting residue is treated according to the method of example 2 to obtain 72 mg of 3-[4-(3-chlorophenyl)-1-ethyl-7-gidroksilaminami-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]propanoic acid as colorless crystals.

Example 44

In a sealed tube a mixture of 4.4 g of 6-chloro-3-(3-chlorobenzoyl)-2-Ethylenediamine, 5 ml of THF and 10 ml of 40% aqueous solution of methylamine was stirred under heating at an oil bath at a temperature of 100°C for 2 hours. After cooling to room temperature, add chloroform. The organic layer is washed with water and saturated salt solution and then the solvent evaporated. To the residue add 2 ml of benzoyl chloride, 2 g of 4-dimethylaminopyridine and 100 ml of dichloroethane, followed by heating on an oil bath at a temperature of 80°C for 2 hours. Then add the temperature value 100°C for 1 hour. After cooling to room temperature, add water to the mixture and extracted with chloroform. The organic layer is washed with water and saturated salt solution and then the solvent is evaporated. The residue is purified by chromatography on a column of silica gel (hexane-ethyl acetate). To 50 ml of a solution of the obtained compound in DMF added 700 mg of 60% sodium hydride while cooling on ice, followed by stirring for 30 minutes. Then there is added to 2.7 ml of monoethylfumarate, followed by stirring under heating at an oil bath at a temperature of 80°C for 1 hour. Then to the mixture is added to 2.7 ml of monoethylfumarate, followed by stirring under heating at an oil bath at a temperature of 80°C for another 1 hour. After cooling to room temperature the mixture is diluted with water and extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution and then the solvent is evaporated. The residue is purified by chromatography on a column of silica gel (hexane-ethyl acetate). The compound obtained is heated under reflux together with 1.5 g of sodium methylate and 50 ml of ethanol for 1 hour. After cooling to room temperature, to the reaction mixture add 2 ml conc the mixture is cooled to room temperature and after adding saturated aqueous sodium bicarbonate solution extracted with ethyl acetate. The organic layer was washed with saturated salt solution and then the solvent is evaporated. The residue is purified by chromatography on a column of silica gel (hexane-ethyl acetate). The compound obtained is stirred with 10 ml of THF-methanol (1:1) and 20 ml of 1 M aqueous sodium hydroxide solution and heated at an oil bath at a temperature of 80°C for 1 hour. After cooling to room temperature the reaction mixture is brought to pH 2 by adding 1 M hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with saturated salt solution and then the solvent is evaporated. The obtained residue is recrystallized from acetonitrile to obtain 1,43 g of 3-[4-(3-chlorophenyl)-1-ethyl-7-methylamino-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]propanoic acid as pale yellow crystals.

Example 46

A mixture of 1.2 g of 3-(3-bromobenzoyl)-2-ethylamino-6-methylpyridine and 2.1 g of glutaric anhydride was stirred under heating at a temperature of 150°C for 15 hours. After cooling to room temperature, add 10 ml of 1 M hydrochloric acid and heated under reflux for 1 hour. After cooling to room temperature the reaction mixture was diluted with water and extracted with the weave add 50 ml of ethanol and 0.5 ml of concentrated sulfuric acid followed by heating under reflux for 1 hour. The reaction mixture is cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated salt solution and then the solvent is evaporated. The residue is purified by chromatography on a column of silica gel (chloroform). Then the connection process by the method of example 2 with the receipt of 1.00 g of 3-[4-(3-bromophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]propanoic acid as pale yellow crystals.

Example 47

To 20 ml of a THF solution containing 2,34 g 3-cyclohexanecarbonyl-2-ethylamino-6-methylpyridine, add 3 ml of monoethylfumarate and 2.8 ml of 2,6-lutidine followed by stirring under heating at an oil bath at a temperature of 60°C for 1 hour. After cooling the reaction mixture to room temperature it was added water and extracted with ethyl acetate. The organic layer was washed with 3 M hydrochloric acid, saturated aqueous sodium bicarbonate and saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated and 1.00 g of sodium methylate is added to 20 ml of a solution of the obtained residue in ethanol followed by heating under reflux for 1 hour. Then to reaction what rinicom for another 1 hour. After cooling the mixture to room temperature it was added water, the mixture is neutralized 1 M hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated and the residue is recrystallized from ethanol-water to obtain 764 mg of 3-(4-cyclohexyl-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl)propionic acid as colorless crystals.

Example 52

To 370 mg of ethyl-{4-[4-(3-bromophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]piperidine-1-yl}acetate add 5 ml of 6 M hydrochloric acid, followed by stirring at a temperature of 100°C for 15 hours. After removal of solvent the crude crystals are recrystallized from ethanol-acetonitrile to obtain 185 mg of {4-[4-(3-bromophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]piperidine-1-yl}acetic acid monohydrochloride in the form of colorless crystals.

Example 55

To 1.28 g of 4-(3-bromophenyl)-3-(1-ethoxycarbonylpyrimidine-4 - yl)-1-ethyl-7-methyl-1,8-naphthiridine-2(1H)-it add 20 ml of concentrated hydrochloric acid, followed by stirring at temperatures ammonia, the mixture is extracted with ethyl acetate. The organic layer was washed with saturated salt solution and then dried over anhydrous sodium sulfate. After removal of the solvent from the organic layer obtained crude crystals are recrystallized from acetonitrile and then recrystallized from ethanol-water to obtain 357 mg of 4-(3-bromophenyl)-1-ethyl-7-methyl-3-(piperidine-4-yl)-1.8-naphthiridine-2(1H)-it is in the form of colorless crystals.

Example 56

To 30 ml of methanol containing 2,56 g imidazo[1,2-a]pyridine-3-luxusni acid, add 783 mg of sodium methylate, followed by stirring at room temperature for 30 minutes. The solvent is evaporated and to the obtained residue, add 15 ml of N-methylpyrrolidone and 2.15 ml of pivaloate, followed by stirring at room temperature for 2 hours. Then added to the mixture of 900 mg of 3-(3-bromobenzoyl)-2-ethylamino-6-methylpyridine and the mixture is stirred at a temperature of 150°C for 16 hours. To the reaction solution was added water and the mixture extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution and dried over anhydrous magnesium sulfate. After removal of solvent the residue is purified by chromatography on Bromphenol)-1-ethyl-3-(imidazo[1,2-a]pyridine-3-yl)-7-methyl-1,8-naphthiridine-2(1H)-it is in the form of yellow crystals.

Example 57

To 5 ml of acetonitrile, containing 400 mg of 4-(3-bromophenyl)-1-ethyl-7-methyl-3-(piperidine-4-yl)-1.8-naphthiridine-2(1H)-it type of 0.11 ml of ethylbromoacetate and 0.13 ml of triethylamine, followed by stirring at room temperature for 13 hours. To the reaction solution was added ethyl acetate, the solution washed with aqueous sodium bicarbonate solution and saturated salt solution and dried over anhydrous magnesium sulfate. After removal of the organic layer of the solvent, the obtained residue is purified by chromatography on a column of silica gel (hexane-ethyl acetate) and then recrystallized from ethyl acetate-diisopropyl ether to obtain 120 mg of ethyl-{4-[4-(3-bromophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]piperidine-1-yl}acetate as colorless crystals.

According to the method of the above examples or reference examples get compound in examples and reference examples listed in tables 1-4, respectively. Structures and physicochemical data of the compounds of reference examples 34 and 45 and examples 1-69 shown in tables 1-4.

In addition, the structures of other compounds of this invention are shown in tables 5 and 6. They can be easily synthesized by odnoi engineering, or modified methods.

1. Derived naphthiridine General formula (I) or its pharmaceutically acceptable salt

where R1- R0or lowest alkylen-cycloalkyl;

R0is lower alkyl;

R2- R0, -halogen, -lower alkylene-HE-S-R0-THE OTHER0or-CH=N-OR9that may be the same or different from each other;

R3and R4MR.

R9N;

R5- cyclohexyl, thienyl or phenyl which may be substituted by a group selected from lower alkyl and halogen;

R6- OH, -OR7, -COOH, -CONH2, -CON(R7)2, -O-COR7, -O-COOR7, -COR7, -NH2, -N(R7)2, -N(R7)COR7, -N(R7)SO2R7, -C(NH)NH2, -NHC(NH)NH2or a group of the formula-Y-R8;

R7- a lower alkyl which may be substituted by a group-CO2R0;

R8is phenyl which may be substituted by a group selected from R10or heterocyclic group selected from morpholinyl, tetrazolyl, imidazolyl, pyridyloxy, selected from R10;

R10- halogen, -CO2H, -NH2or-COR0or a group described as R7;

Y is a bond or-CO-;

X is a bond or lower alkylene.

2. Derived naphthiridine or its pharmaceutically acceptable salt p. 1, where X is a bond or lower alkylene and R6is-OH, -COOH, -O-COR7, -NH2, -N(R7)2, -C(NH)NH2, -NHC(NH)NH2or a group of the formula-Y-R8.

3. Derived naphthiridine or its pharmaceutically acceptable salt p. 1, where R5is cyclohexyl or phenyl, substituted by halogen.

4. Derived naphthiridine or its pharmaceutically acceptable salt p. 1, which is chosen from the group comprising 3-(2-amidaniel)-4-(3-chlorophenyl)-1-ethyl-7-methyl-1,8-naphthiridine-2(1H)-he, 4-(3-chlorophenyl)-1-ethyl-3-(2-guanidinate)-7-methyl-1,8-naphthiridine-2(1H)-he 4-cyclohexyl-1-ethyl-7-methyl-3-[2-(1H-tetrazol-5-yl)ethyl]-1,8-naphthiridine-2(1H)-he, 4-(3-chlorophenyl)-1-ethyl-7-methyl-3-[3-(1H-tetrazol-5-yl)propyl]-1,8-naphthiridine-2(1H)-he, 4-(3-bromophenyl)-1-ethyl-7-methyl-3-[2-(1H-tetrazol-5-yl)ethyl]-1,8-naphthiridine-2(1H)-he, 3-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]propanoic acid, 3-(4-cyclohexyl-1-ethyl-7-methyl-2-oxo-1,2-digilog acid, 3-[4-(3-chlorophenyl)-1-ethyl-7-(gidroksilaminami)-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]propanoic acid, 3-[7-chloro-4-(3-chlorophenyl)-1-ethyl-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]propanoic acid, 3-[1-ethyl-7-methyl-4-(3-were)-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]propanoic acid, 4-(3-chlorophenyl)-1-ethyl-7-methyl-3-(piperidine-4-yl)-1.8-naphthiridine-2(1H)-he 1-{2-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthiridine-3-yl]ethyl}piperidine-4-carboxylic acid.

5. Pharmaceutical composition having inhibitory activity against phosphodiesterase type IV containing the derived naphthiridine General formula (I) or its pharmaceutically acceptable salt p. 1 and a pharmaceutically acceptable carrier.

6. The pharmaceutical composition under item 5, which is an agent for prevention or treatment of respiratory diseases.

7. The pharmaceutical composition according to p. 6, which is an agent for the prophylaxis or treatment of bronchial asthma.



 

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