Derivatives of 8-aryl-1,7-naphthiridine and a pharmaceutical composition having anti-inflammatory activity

 

(57) Abstract:

The invention relates to new derivatives naphthiridine formula I, where R1denotes phenyl, benzyl, 3-nitrophenyl, 3-chlorophenyl, 3-tianfeng, 3-(tetrazolyl)phenyl or benzofuranyl; R2denotes a hydroxy-group, tripterocalyx, allyl, alkyl, alkenyl, quinil, alkoxygroup, phenyl, phenyloxy, carboxyphenyl, carboxymethyl, carbamoylmethyl, phenylamino, diphenylamino-, amino-, elcamino, Alcaidaria, where "ALK" refers to aliphatic fragment having up to 8 carbon atoms and optionally including carboxylate, ether carboxylic acid or a hydroxy-group and/or optionally containing ether and/or ester bond, or its N-oxide in free form or in the form of pharmaceutically acceptable salts. Also described is a pharmaceutical composition having anti-inflammatory activity on the basis of these compounds. The invention can be used in medicine as a drug, for example, for the treatment of asthma. 2 S. and 4 C.p. f-crystals, 2 PL.

The invention relates to new 8-aryl-1,7-naphthirydines, to methods for their preparation, to their use as medicinal .-1,7-naphthirydines in free form or in the form of pharmaceutically acceptable salts. The term "aryl" means a mono - or bicyclic aromatic or heteroaromatic fragment, which has up to 10 aromatic atoms other than hydrogen, and which is associated with a 1.7-naphthiridine either directly (for example, phenyl, pyridyl, tetrazolyl, benzofuranyl or benzothiazolyl), or through a methylene bridge (for example, benzyl or pyridylmethyl); preferable at this monocyclic aromatic fragment, with up to six aromatic carbon atoms, of which up to 2 atoms can be replaced by nitrogen, for example phenyl, benzyl, 4-pyridyl or 4-pyridylmethyl, each of which optionally includes carboxypropyl, ether carboxylic acids or hydroxy-group. 8-aryl fragment optionally may be additionally substituted, preferably by the Deputy, which is an electron acceptor, such as nitro-, nitrilo, aminogroups, halogen or halogen containing substituent (for example, trifluoromethyl or cyano, preferably in meta-position. For example, 8-aryl fragment can be tianfei, nitrophenyl, tetrazolyl (for example, tetrazol-1-ylphenyl) or chlorophenyl. Optional double ring in naphthyridinone fragment of the molecule medroxypro, the alkyl, alkenyl, quinil, alkoxygroup, aryl, aryloxy-, amino-, arylamino, diarylamino, alkylamino, dialkylamino, arylamino or albuminurophobia, where "ALK" refers to aliphatic fragment having up to 8 carbon atoms and optionally including carboxylate, ether carboxylic acid or a hydroxy-group and/or optionally containing an ether bond and/or ester bond.

In particular, the invention proposed new 8-phenyl - 8-benzyl-1,7-naphthirydines, in which the double bond 1,7-naphthiridine optionally substituted in position 6, such as, in particular, described below in the examples, and the phenyl ring is optionally substituted by the Deputy, which is the electron acceptor, such as the nitro-group; for example, the compounds of formula I:

< / BR>
where R1denotes phenyl, benzyl, 3-nitrophenyl, 3-chlorophenyl, 3 - tianfeng, 3-(tetrazolyl) phenyl, benzofurazanyl or benzothiazolyl;

R2denotes a hydroxy-group, tripterocalyx, allyl, alkyl, alkenyl, quinil, alkoxygroup, aryl, aralkyl, aryloxy-, amino-, arylamino, diarylamino, elcamino, dialuminium, alkaryl, arylamido or Alcaidaria;

and their esters and amides in free form or in the Foch for 8-aryl-1,7-naphthirydines according to the invention.

Preferably R2selected from the group comprising hydroxy-, amino-, arylamino (e.g., phenylaminopropyl), aryl (e.g. phenyl), alkaryl [for example, (ness.)alkylphenyl], alkenyl (e.g., vinyl), quinil (for example, ethinyl), alkoxygroup containing ether and/or ester linkage (e.g., ethoxycarbonylmethoxy), alkamide(e.g., acetaminoph).

Unexpectedly, it was found that a completely new class of 6.8-aryl-1,7-naphthirydines suitable for use as pharmaceuticals, in particular as active in oral introduction of inhibitors of PDE 4, for example, for the treatment of asthma.

Thus, preferred according to the invention are 6-(carboxyphenyl or carboxymethyl)-8-(phenyl,benzo [C] thiadiazolyl or benzo[C] furutani)-1,7-naphthirydines and their esters and amides in free form or in the form of pharmaceutically acceptable salts.

More preferably the invention relates to 6-(4-carboxyphenyl - or-4-carboxymethyl)-8- (phenyl, 4-benzo [C] thiadiazolyl or 4-benzo [C] furutani)-1,7 - naphthirydines and their esters and Amida in free form or in the form of pharmaceutically acceptable salts.

Under benzo [C] toobanna preferred embodiment, the invention relates to the compound of formula II

< / BR>
where n is 0 or 1;

R7denotes a hydroxy-, amino-, C1- C4alkylamino or C1-C4alkoxygroup, preferably hydroxy or amino group;

and either

R3denotes H and R4denotes the nitrogroup, halogen (e.g. chlorine), cyano or tetrazolyl (for example, 1-tetrazolyl) and R5and R6together form an additional bond, or

R3, R4, R5and R6together denote =N-O-N= or =N-S-N=;

and their esters and Amida in free form or in the form of pharmaceutically acceptable salts.

Suitable pharmaceutically acceptable salts of 8-aryl-1,7-naphthirydines, for example, formulas I or II, for use as medicines receive conventional ways. For example, compounds having a free carboxylic acid group, for example the compounds of formula II in which R7indicates HE may be subjected to interaction with a suitable base, for example an amino sugar, such as N-methylglucamine, to obtain the corresponding salt of attaching the base. Generally, such salts joining bases are soluble in water.

8-aryl-1,7-naphthirydines according to the invention, for example, will foraboschi halogen, for example bromine, to obtain the compounds of formula III:

< / BR>
which may be subjected to further derivatization with obtaining the compounds according to the invention, for example, through reaction of conjugation with the use of metal-containing reagent in the presence of palladium or Nickel catalyst to obtain carbon-carbon links, for example, by the reaction of Steele, Suzuki or Heck, i.e. the interaction of the compounds of formula III with a compound Y-R8where Y denotes a metal-containing leaving group, such as(OH)2, (CH2)3Sn-, (CH3(CH2)3)3Sn-, a R8denotes an 8-aryl fragment, as described above, for example benzyl or 3-nitrophenyl, to obtain the corresponding compounds of formula IV

< / BR>
or

b) with a Grignard reagent, for example, R8-MgBr, where R8denotes an 8-aryl fragment, as described above, for example benzyl or 3-nitrophenyl, to obtain the corresponding compounds of formula IV, or

C) with a mixture of alkali metal alcohol, for example with sodium with methanol, to obtain the compounds of formula III'

< / BR>
where Alk represents C1-C8alkyl group, for example methyl. Deputy O-Alk can be converted into a halogen and then the S="ptx2">

The amino group of compounds of formula III, III' or IV do suitable for subsequent interaction, for example,

(I) activation using suitable activating reagent, for example triftormetilfullerenov acid and NaNO2with the receipt of the triflate of the formula

< / BR>
where Q represents either a halogen And, as noted above, the Deputy-O-Alk, as indicated above for the compounds of formula III', or 8-aryl fragment R8as described above, which is a new and very important intermediate product for producing compounds according to the invention, for example, when the radical R2in the compound of formula I is connected with the rest of the molecule through a carbon-carbon bond, the substitution can be carried out, for example, through reaction of conjugation with the use of metal-containing reagent in the presence of palladium or Nickel catalyst, to obtain the carbon-carbon links, for example, by the reaction of Steele, Suzuki or Heck, i.e. the interaction of the compounds of formula V where Q denotes the R8with a compound of formula Y-R2where Y denotes a metal-containing leaving group as described above, and R2indicates the desired carbon Deputy, for example alkyl, alkenyl, quinil, aryl or alerissasasa group, or

(II) alkyl or aryl substitution (for example, by interacting with the corresponding alkylhalogenide or ORGANOMETALLIC compound) to give the desired secondary or tertiary amine, or

(III) acylation (for example, by reacting with carboxylic acid or carboxylic acid anhydride) to obtain the corresponding amide using conventional techniques or

(IV) converting the hydroxy-group, for example, interaction with NaNO2in the presence of dilute acid, for example sulfuric acid, and optionally followed by derivatization, for example, O-alkylation, for example by interaction with alkylhalogenide in a suitable reaction conditions.

Preferred 6-(carboxyphenyl or carboxymethyl)-8-(phenyl, benzo[C] thiadiazolyl or benzo[C]furutani)-1,7-naphthirydines or their esters or amides, for example, formula II, as a rule, receive the following way:

(A) to obtain 6-(carboxyphenyl or carboxymethyl)-8- (phenyl, benzo[C] thiadiazolyl or benzo[C]furutani)-1,7 - naphthirydines or their esters or amides interact 6-X-8-(phenyl, benzo[C]thiadiazolyl or benzo[C]furutani)-1,7-naphthiridine(carboxy - or carboxymethyl-phenyl)- 8-X-1,7-naphthiridine or of ester or amide with X'- (phenyl, benzo[C]thiadiazolyl or benzo[C] Puritanism), where X and X' denote a leaving group capable of participating in reactions mates, for example, where X denotes trifloromethyl or halogen, for example bromine or chlorine, and X' denotes a metal-containing leaving group, for example, substituted boron (for example, -B(OH)2, -B(OAlk)2or BAlk2where Alk denotes an alkyl, e.g. methyl or ethyl), or trialkylsilyl (e.g., (CH3(CH2)3)3Sn - or (CH3)3Sn, or a radical of the Grignard reagent (for example, MgBr), and/or

(B) carry out an optional interaction of 6-(carboxy - or carboxymethyl-phenyl)-8-(phenyl, benzo[C] thiadiazolyl or benzo[C]furutani)-1,7-naphthiridine with a suitable amine, for example, with ammonia or with C1-C4alkylamino, to obtain the corresponding amide, and/or

(C) carry out an optional interaction of 6-(carboxy - or carboxymethyl-phenyl)-8-(phenyl, benzo [C] thiadiazolyl or benzo [C] furutani)-1,7 - naphthiridine with a suitable alcohol, for example, C1-C4alcohol, to obtain the corresponding complex ether and allocate the resulting 6-(carboxy - or carboxymethyl-phenyl)-8-(phenyl, benzo [C] thiadiazolyl or benzo [C] furutani)-1,7 - naphthiridine eadie (A) are known from the reactions mates made using metal-containing reagents, for example, in the presence of palladium or Nickel catalyst, to obtain the carbon-carbon links, for example, as in the case of reactions of Steele, Suzuki or Hake. The reaction conditions for the reactions of steps (B) and (C) are known from the technology of producing amides by using the interaction of carboxylic acids with amines or receipt of esters from carboxylic acids and alcohols, for example, in acidic or alkaline conditions. Isolation and purification carried out by conventional methods, for example by chromatography or crystallization.

Thus, in a preferred embodiment, the invention relates to a method for obtaining compounds of formula II, as described above, including the interaction of the compounds of formula VI

< / BR>
where R3, R4, R5, R6and X have the above meanings, with a compound of formula VII

< / BR>
where R7and X' have the above values, and the allocation thus obtained the compounds of formula II in free form or in salt form.

6-X-8-(phenyl, benzo [C] thiadiazolyl or benzo[C]furutani)-1,7-naphthirydines and 6-(carboxyphenyl or carboxymethyl)-8-X-1,7-naphthirydines or their esters or amides, prednaznachendlya acid, for example, H-A, where a denotes halogen, such as bromine, to obtain the compounds of formula III, which may optionally be subjected to further derivatization as described above.

The above-described methods for obtaining 8-aryl-1,7-naphthirydines according to the invention, particularly preferred 6-(carboxyphenyl or carboxymethyl)-8-(phenyl, benzo [C] thiadiazolyl or benzo [C] furutani)-1,7-naphthirydines and their esters and amides, are new, as are new intermediates of the formulae IV, V and VI, and these new methods and intermediate products included in the scope of the present invention. It is obvious that the compounds of formula V in which Q denotes R8and the compounds of formula IV fall under the definition of 8-aryl-1,7-naphthirydines according to the invention.

Thus, other objects of the invention are intermediates of the formula V'

< / BR>
in which Q' represents halogen or -- O-Alk, where Alk represents C1-C8alkyl group, and formula VI

< / BR>
where R3, R4, R5, R6and X have the above values.

Below the invention is illustrated in the examples (see. table. 2).

EXAMPLES

Example 1: 6-amino-8-(3-nitrophenyl)-1.7 naftilos; synthesis see Shigenobu Okuda, Michael M. Robison, J. Am. Chem. Soc. 81, 704 (1959)) in dichloromethane (200 ml) add trimethylsilylmethyl (26 g, of 0.26 mole). To this suspension add dimethylcarbamate (28 g, of 0.26 mole). The mixture is stirred for 45 hours the Solvent is removed and the residue is dissolved in ethyl acetate. The solution was washed with 1N. NaOH and water and concentrated in vacuo. The product was then purified using column rapid chromatography on silica gel (toluene/acetone in a ratio of 15:2), receiving specified in the header connection. MS: M+H 144,1; tPL62-63oC.

B. 6-amino-8-bromo-1,7-naphthiridine

Mix a solution of 2-cyan-3-pyridylacetonitrile (3.6 g, 0,025 mol) in toluene (80 ml) bubbled HBr for 5 hours Then carefully add 4n. NaOH and the suspension is intensively stirred. The mixture is filtered and the product washed with water and dried. Crystallization from toluene receive specified in the header connection. MS: M+H 225; tPL188oC, decomposition.

Century 6-amino-8-(3-nitrophenyl)-1.7-naphthiridine

To a stirred solution of 6-amino-8-bromo-1,7-naphthiridine (4 g, 0,018 mole) in a mixture of tetrahydrofuran (80 ml) and water Na2CO3(34 ml, 2n.) add bis(dibenzylideneacetone)palladium (0.40 g, 0,0007 mol), triphenylphosphine (0,37 g, 0,0014 mol) and 3-nitro the t ethyl acetate and the mixture washed with 2n. NaOH and water. The organic solvent is removed and the residue suspended in a simple ether. After filtering receive specified in the header connection. MS: M+H 267; tPL221-223oC.

Example 2: 6-amino-8-(4-benzo[C]furutani)-1,7-naphthiridine

To a stirred solution of 6-amino-8-bromo-1,7-naphthiridine (3.0 g, a 13.4 mmole) in DMF (50 ml) is added bis(dibenzylideneacetone)palladium (308 mg, 0.54 mmole), triphenylphosphine (565 mg, of 2.15 mmole) and 4-tributylstannyl - benzo[C]furutani (4,92 g, 16.0 mmol). The mixture was kept at 125oC for 4 h Add ethyl acetate (500 ml), then aqueous KF (40%, 100 ml). The mixture is intensively stirred for 45 min and filtered. The organic phase is separated, washed with water and concentrated. The residue is dissolved in a simple ether (20 ml), stirred for 30 min (0oC) and filtered, obtaining mentioned in the title compound (2.8 g). MS: M+H 264; tPL244-250oC.

Example 3: 6-hydroxy-8-(3-nitrophenyl)-1,7-naphthiridine

To a stirred solution of 6-amino-8-(3-nitrophenyl)-1,7-naphthiridine (500 mg, of 1.87 mmole, obtained according to example 1) in concentrated sulfuric acid and water (3 ml, 2:1), add at the 4oC sodium nitrate (155 mg, 2.25 mmole). After 30 min the ice bath removed and the mixture is heated up to me. The precipitate is filtered and washed with water, getting mentioned in the title compound, tPL262-265oC.

Example 4: 6-ethoxycarbonylmethoxy-8- (3-nitrophenyl)-1,7-naphthiridine

The suspension containing 6-hydroxy-8-(3-nitrophenyl)-1,7-naphthiridine (107 mg, 0.40 mmole, obtained according to the preceding example, it is not necessarily without additional purification), potassium carbonate (55 mg, 0.40 mmole) and methyl ether bromoxynil acid (37 μl, 0.4 mmole), stirred for 2 h in a mixture of acetone and dimethylformamide (2 ml, 1:1) at room temperature. Add ethyl acetate and the organic phase is washed with 2n. NaOH. The solvent is removed in vacuum and the crude product purified preparative thin-layer chromatography, receiving specified in the header connection. MS: M+H 340; tPL160-162oC.

Example 5: the Hydrochloride of 6-acetamido-8-(3-nitrophenyl)-1,7-naphthiridine

The suspension containing 6-amino-8-(3-nitrophenyl)-1,7-naphthiridine (300 mg, 1.1 mmole, obtained according to example 1) and acetic anhydride (0,12 ml, 1.2 mmole) in pyridine (1 ml) and dimethylformamide (3 ml), incubated at 80oC for 3 hours, water is Added and the precipitate was filtered and thoroughly washed with water. After filtering receive specified in the header of the product. MS: M+H is lonitrile (2 g, of 0.014 mol) in toluene (20 ml) is added at ambient temperature benzylacrylamide (8,4 ml, 2M in tetrahydrofuran, to 0.17 mol). After 1 h the reaction stopped with saturated solution of ammonium chloride. The product is extracted with ethyl acetate and the organic layer washed with 2n. NaOH and water. The product was then purified using column rapid chromatography on silica gel (10:3 toluene/acetone) to give specified in the header connection. MS: M+H 236; tPL113-116oC.

Example 7: 6-phenylamino-8-(3-nitrophenyl)-1,7-naphthiridine

To a solution of triphenylbismuth (182 mg, 0,41 mmole) in dichloromethane (0.5 ml) and tetrahydrofuran (0.5 ml) is added peracetic acid (0,083 ml, 40%). The mixture is stirred for 1 h Then add a solution of 6-amino-8-(3-nitrophenyl)-1,7-naphthiridine (100 mg, 0.37 mmole, obtained according to example 1) in dichloromethane (0.5 ml) and THF (0.5 ml). Add copper (30 mg, of 0.47 mmole) and the suspension is stirred for 40 hours, the Suspension is diluted with ethyl acetate and filtered. The filtrate was washed with 2n. Na2CO3and water and the organic layer was concentrated in vacuo. Using preparative thin-layer chromatography (dichloromethane/n-hexane in the ratio 8:2) get the specified header connection. MS: M+H 343,1; tPL158-160oC.

oC and stirred overnight. The solution was poured onto a mixture of ethyl acetate and ice. Then add 2n. NaOH up until the pH of the aqueous phase does not become alkaline. The organic phase is washed with water and concentrated in vacuo. The product was then purified using column rapid chromatography on silica gel (hexane/ethyl acetate in the ratio 7:3), receiving specified in the header connection. MS: M+H 400; tPL106-108oC.

Example 9: 6-phenyl-8-(3-nitrophenyl)-1,7-naphthiridine

To a solution of 6-trifloromethyl-8-(3-nitrophenyl) -1,7-naphthiridine (300 mg, 0.75 mmole, obtained according to example 8) in tetrahydrofuran (5 ml), add phenylboronic acid (118 mg, 0.97 mmole), bis(dibenzylideneacetone)palladium (18 mg, 0.03 mmole), triphenylphosphine (16 mg, 0.06 to mmole) and an aqueous solution of Na2CO3(2H., the 1.44 ml). The solution is maintained at 60oC for 20 h the Solution was diluted with ethyl acetate, filtered and washed with 1N. NaOH and water. The solvent is evaporated in vacuum, obtaining a pure product. MC: M+H 328;PL172-175oC.

Example 10: 6-vinyl-8-(3-nitrouse according to example 8) in tetrahydrofuran (3 ml) add vinyltrimethylsilane (218 mg, 0.68 mmole), bis(dibenzylideneacetone)palladium (14 mg, of 0.025 mmole), triphenylphosphine (13 mg, 0,049 mmole) and lithium chloride (78 mg, of 1.86 mmole). The mixture was kept at 70oC during the night. The solution is diluted with ethyl acetate, filtered and washed with water. Using preparative thin-layer chromatography (dichloromethane/n-hexane in the ratio 8:2) get the specified header connection. MS: M+H 278; tPL145-151oC.

Example 11: 6-ethinyl-8-(3-nitrophenyl)-1,7-naphthiridine

A. 6-trimethylsilylethynyl-8-(3-nitrophenyl)-1,7-naphthiridine receive the following way:

To a solution of 6 - trifloromethyl-8-(3-nitrophenyl)-1,7-naphthiridine (200 mg, of 0.50 mmole, obtained according to example 8) in dimethylformamide (1 ml) and triethylamine (0.5 ml) add amenitieseven (0,078 ml of 0.56 mmole), bis(dibenzylideneacetone)palladium (5,8 mg, at 0.020 mmole), triphenylphosphine (5.3 mg, at 0.020 mmole) and copper iodide (3.8 mg, at 0.020 mmole). The mixture was kept at 60oC for 2 h the Solution was diluted with ethyl acetate and washed with water. The product was then purified column rapid chromatography on silica gel (toluene/acetone in a ratio of 20:0,2), receiving 6-trimethylsilylethynyl-8-(3-nitrophenyl)-1,7-naphthiridine. MS: M+H 348; tPL160-163oC.

B. To a solution of 6-trimethylsilylethynyl-8-(the l). The mixture is stirred for 2 hours, the Suspension is filtered and the product washed with water and simple ether, receiving specified in the header connection. MS: M+H 276; tPL215oC, decomposition.

Example 12: 6-(4-carboxyphenyl)-8-(3-tianfeng)-1,7-naphthiridine

To a solution of 6-trifloromethyl-8-(3-tianfeng) -1,7-naphthiridine (2.15 g, 5,67 mmole) in DMF (21,5 ml) is added 4-carboxybenzeneboronic acid (1.13 g, for 6.81 mmole), bis(dibenzylideneacetone)palladium (131 mg, of 0.23 mmole), triphenylphosphine (95 mg, of 0.36 mmole) and water TO a2CO3(2H., 17 ml). The reaction mixture was stirred at 80oC for 2.5 hours, the Hot solution is filtered through celite and the crude product is precipitated by carefully adding water (10 ml) and aqueous HCl solution (2n., 8 ml). The suspension is filtered and the crude product is stirred in hot THF (30 ml). The cold suspension is filtered again, getting mentioned in the title compound (1.12 g). M+H 352; tPL> 300oC. retention Time using GHUR is 7,58 min (column LiChroCart 125-4, Supersphere 60 RP-select B, 40oC; eluent acetonitrile/water (with 0.1% TFA) in a ratio of 45:55; flow rate 1 ml/min, detection at 254 nm).

Example 13: 6-(4-carbamoylphenoxy)-8-(3-tianfeng)-1,7-naphthiridine

To a suspension of 6-(4-carbox clonney the mixture was kept at the temperature of reflux distilled for 3 hours The solvent is evaporated and the residue is dissolved in THF (2 ml). Add aqueous ammonia and the solution stirred for 2 h at ambient temperature. Add ethyl acetate and the organic layer washed with water, getting clean is specified in the header connection with tPL237-240oC.

Example 14: 6-(4-carboxyphenyl)-8-(4-benzo[C]furutani)- 1,7-naphthiridine

A. 6-amino-8-methoxy-1,7-naphthiridine

To a solution of sodium (3.2 g, 0,139 mol) in methanol (1400 ml) is added 2-cyan-3-pyridylacetonitrile (20 g, 0,139 mol) and the reaction mixture stirred for 17 h at ambient temperature. Then add water (700 ml) and after evaporation of the greater part of the methanol is produced by crystallization specified in the title compound, tPL178-180oC.

B. 6 tripterocalyx-8-methoxy-1,7-naphthiridine

To a solution of 6-amino-8-methoxy-1,7-naphthiridine (19 g, to 0.108 mol) in a mixture 1: 1 of water and triftormetilfullerenov acid (380 ml) was carefully added a solution of sodium nitrite (11.2 g, rate £ 0.162 mol) in water (40 ml) at 0oC. After 1 h the cooling bath removed and the reaction mixture was stirred for 1 h at ambient temperature. Then add ethyl acetate and the solution is neutralized by adding bicarbonate and the crude product is purified column rapid chromatography on silica gel (toluene/acetone in a ratio of 20:3), receiving specified in the header connection. M+308; tPL99-101oC.

Century 6-(4-carboxyphenyl)-8-methoxy-1,7-naphthiridine

To a solution of 6-trifloromethyl-8-methoxy-1,7-naphthiridine (1.5 g, a 4.86 mmole) in DMF (40 ml) is added 4-carboxybenzeneboronic acid (0,866 g, 5,34 mmole), bis(dibenzylideneacetone)palladium (112 mg, 0,167 mmole), tri-ortho-tolylphosphino (96 mg, of 0.32 mmole) and an aqueous solution of Na2CO3(14.6 ml, 2n.). The reaction mixture was stirred at 110oC for 3 hours, the Hot solution is filtered through celite and the solution evaporated to dryness. The crude product is dissolved in hot water (60 ml) and the aqueous phase washed with ethyl acetate (CH ml). The product precipitated from the aqueous phase by gently adding an aqueous solution of HCl (2n. , 6 ml). The suspension is filtered and the crude product is again stirred in hot ethyl acetate (50 ml). The cold suspension was filtered, getting mentioned in the title compound (1.10 g). M+280; tPL> 300oC.

G 6-(4-carboxyphenyl)-8-bromo-1,7-naphthiridine.

To a solution of 6-(4-carboxyphenyl)-8-methoxy-1,7-naphthiridine (250 mg, 0,892 mmole) in DMF (10 ml) add PBr3(0.63 ml, 6,63 mmole). The reaction mixture is heated to 100oC for 30 minutes and Then the suspension was poured onto water (50 ml) and the solution about the Ira. The suspension is filtered, getting mentioned in the title compound (215 mg). tPL248-250oC, decomposition.

D. 4-benzo[C]furazolidona acid

To a solution of 4-benzo[C] furosemide (4 g, at 0.020 mole) in tetrahydrofuran (80 ml) and n-pentane (20 ml) add triethylborane (3.8 ml of 0.022 mol) and N,N,N,N-tetramethylaniline (3 ml of 0.02 mol). Then dropwise at -100oC add n-BuLi (8,8 ml, 2.5 N. in hexane, to 0.022 mole) and the solution stirred for another 5 minutes, the Reaction mixture was poured onto an aqueous saturated solution of ammonium chloride and the aqueous phase extracted with ethyl acetate. The organic solvent is removed and the crude product is dissolved in a mixture of dichloromethane/n-hexane (ratio 5:6). The suspension is filtered, getting mentioned in the title compound (1,05 g), which is used without further purification.

E. 6-(4-carboxyphenyl)-8-(4-benzo[C]furutani)-1,7-naphthiridine

To a solution of 6-(4-carboxyphenyl)-8-bromo-1,7-naphthiridine (100 mg, 0,304 mmole) in DMF (2.5 ml) is added 4-benzo [C] furosemidebuy acid (60 mg, of 0.36 mmole), bis(dibenzylideneacetone)palladium (7 mg, 0,0122 mmole), tri-ortho-tolylphosphino (7.4 mg, 0,024 mmole) and an aqueous solution of Na2CO3(0.9 ml, 2n.). The reaction mixture was stirred at 80oC for 2 h, the suspension is filtered and the organic layer removed. The residue is dissolved in hot DMF (7 ml) and the crude product is precipitated by gently adding an aqueous solution of HCl (2n., 1 ml). The crude product is recrystallized from hot DMF, getting mentioned in the title compound (68 mg). MH+369; tPL> 300oC. M+N=369. Retention time using GHUR is the 10.40 min (column LiChroCart 125-4, Supersphere 60 RP-select B, 40oC; eluent acetonitrile/water (with 0.1% TFA) in a ratio of 45:55; flow rate 1 ml/min, detection at 254 nm).

According to the method described above in the corresponding example and using the appropriate initial products will receive the following compounds of formula 1, are listed in table 1.

Salt accession grounds compounds having free carboxyl groups, for example compounds described above can be obtained by the interaction of the compounds with the corresponding amino sugar, for example, N-methyl-O-glucamine. The following example illustrates the receipt of such salts accession grounds.

Example 34: 6-(4-carboxyphenyl)-8-(4-benzo[C]furutani)-1,7-naphthiridine: salt with N-methyl-D-glucamine

To a hot solution of 6-(4 - carboxyphenyl)-8-(4-benzo[C]furutani)-1,7-naphthiridine (1 g, of 2.72 mmole) in DMF (100 ml) is added N-methyl-D-gluco methanol (about 50 ml), getting a pure product (1,11 g).PL230oC, decomposition. Retention time using GHUR is of 6.65 min (column LiChroCart 125-4, Supersphere 60 RP-select B, 50oC; eluent: gradient from 0% B 100% a to 70% W/30% And for 15 min; And means 2.7 g KHPO4/0,027 g Na2HPO4in 900 ml of water/100 ml of acetonitrile, and B denotes 100 ml of water/900 ml of acetonitrile; detection at 220 nm). The product is soluble in water.

8-Aryl-1,7-naphthirydines according to the invention, e.g. of formula I, particularly preferably 6-(carboxyphenyl or carboxymethyl)-8- (phenyl,benzo[C] thiadiazolyl or benzo[C] furutani)-1,7-naphthirydines and their esters and amides in free form or in salt form (designated hereinafter in the present description as "agents of the invention") exhibit pharmacological activity and are useful as pharmaceuticals, e.g. for therapy in the treatment of the following in the present description of diseases and conditions.

In particular, the agents according to the invention show inhibitory activity against inhibitory cyclic nucleotide phosphodiesterase (PDE), the election in respect of isoenzyme type 4.

The agents according to the invention have anti-inflammatory, prevents increased, inhibiting the secretion of TNF and other pharmacological activities that may be shown by standard methods of testing are described in the following examples.

A. Inhibition of PDE4: analysis of the inhibition of recombinant isoenzyme PDE4A, PDE4B, PDE4C and PDE4D.

Cloning and expression: cDNA PDE4, encoding four isoenzyme: human PDE4A (as described by Sullivan and others, Cell Signal 1994; 6: 793-812), rat PDE4B (as described in Colicelli and others, Proc. Natl. Acad. Sci. USA 1989; 86: 3599-3903), human PDE4C (as described by Engels and others, FEBS Lett. 1995; 358: 305-310) and human PDE4D (as described by Baecker and others , Gene, 1994; 138: 253-256), clone or extrachromosomal expressing the yeast vector (PDE4C, PDE4D), or by integrating (PDE4A, PDE4B; one copy) in the locus RAR strain of Saccharomyces cerevisiae lacking both genes PDE yeast wild type. Yeast strains expressing the PDE4 isoenzymes are grown in 1 l cultures at 30oC, pellitero (precipitated by centrifugation and stored frozen until homogenization.

Homogenization: Pelletierine yeast (5 ml) are suspended in 50 ml buffer (10 mm Tris-hydroxyethylaminomethyl, 1 mm Ethylenediamine-tetraoxane acid, 1 mg/ml leupeptin and pepstatin And 175 mg/ml phenylmethylsulfonyl granules (diameter 425-600 mm, the washed acid, firms Sigma Chemical Co.). To this suspension was added 1 ml of buffer and 60 mg cholamidopropyl acid and the suspension is intensively stirred for 4 h at 4oC. Yeast cells break down (disintegrate), evaluating microscopy (phase-contrast optics), when the number of dark cells will exceed 30% (usually 50%). The suspension is transferred into a coarse glass funnel, the homogenate was collected by suction and glass granules are washed with buffer to a total volume of 15 ml of Cell fragments are separated from cytosol by centrifugation (2000xg, 10 min, 4oC). Debris resuspended in 15 ml of buffer and evaluated for PDE activity together with the cytosol.

Other drugs isoenzymes get, using as sources of cells and organs. Drugs isoenzymes type 3 and 4 receive the following method, using the fact that platelets are dominated by isoenzymes type 3 and neutrophil - isoenzymes type 4.

Cells and tissues are homogenized on ice in 10 mm Tris-HCI buffer, pH 7,4 containing sucrose (250 mm), add (1 mm), dithiothreitol (1 mm), leupeptin and pepstatin a (1 µg/ml each) and phenylmethylsulfonyl (PMSF, 0.17 mg/ml, add nelovka and treated with ultrasound (probe type Branson, H with). Obtained during the operation of the sick lung samples (types 1 and 5), homogenized using a homogenizer transmitter station (two pulse 30 C). Drugs isoenzymes:

Drugs PDE3 and 4 (the substrate of camp, 1 μm) are respectively from the supernatant of homogenates of platelets and neutrophils obtained at low rotation speed. Isoenzymes type 1 (the substrate of camp, 1 micron, Ca2+0, 5 mm, calmodulin, 125 nm), type 2 (camp, 100 μm) and type 5 (cGMP, 1 µm) was separated using anion exchange chromatography (Q-Sepharose), using a gradient of NaCI in buffer for homogenization without sucrose and PMSF (from 0 to 0.1 M NaCI, 2.5 column volumes, from 0.1 to 0.45 M in 24 column volumes). PDE1: fractions, in which the hydrolysis of 1 μm camp can be stimulated Ca2+calmodulin (0.5 mm and 125 nm, respectively); elution at a concentration of NaCI To 0.17 To 0.18 M PDE2: factions, mainly exhibiting hydrolytic activity towards camp when substrate concentration of 100 μm, but is inactive at 1 μm; elution at a concentration of NaCI 0,31-0,32 M PDE5: fractions, selectively gidrolizuemye cGMP, 1 μm, but does not have activity against camp, 1 μm; elution at a concentration of NaCI 0,20-0,24 M

Analysis of PDE: Protocol analysis based on the two-stage method described Thomp the TOD mostly is what enzyme is dissolved in a buffer for homogenization (see above) to the total hydrolysis of the substrate in the process of analysis was 10-30%. To initiate the reaction, 25 ml of the diluted enzyme is added to 25 ml of substrate ([3H]-cyclic amp, 1.25 mm 740 Bq) and 75 ml of inhibitor (see below). After incubation for 30 min at 37oC reaction stop using baths with hot water (65oC, 5 min). Tablets cooled on ice and incubated for 10 min at 37oC with 25 ml of 5'-nucleotidase (from the venom of the snake, from oiophaghus hannah, the company Sigma Chemical Co., 0.1 mg/ml in water). Unreacted substrate is separated from [3H] - adenosine by successively adding the aliquot volume (100+50+50 ml with 5-minute intervals) about 30. % suspension of Dowex 1x2 (acetate form) in 0.2 vol.%-Noah acetic acid. Dowex precipitated by centrifugation (150xg, 5 min). Aliquots of the supernatant liquids transferred to 96-well tablets with scintillation solid phase (LumaPlate, Canberra Packard), using an automatic pipette (type Hamilton MicroLab 2200), dried (at least 4 h at 50oC) and count radioactivity (counter type, Canberra Packard TopCount).

Inhibitors: Royal solutions of inhibitors are prepared in dimethyl sulfoxide (DMSO) and diluted with water/DMSO, receiving 7 concentrations, E. analysis support constant at 50 ml/ml.

Determination of the parameters of inhibition: the Concentration at which inhibition occurs by 50% (IC50), and the slope of the dose-response (hill coefficient) determined from the graphs of the dependence of inhibition on the concentration using nonlinear equalization using the least squares method using logarithmic equations with two parameters. The results are expressed as the negative logarithm of the concentration of inhibitor at which there is 50% inhibition (IC50) (in moles/l; pIC50). Estimate 95% confidence intervals and expressed as pL and pU (negative decimal logarithm of the lower and upper confidence limits, respectively). Concentrations that cause significant sedimentation in the study, excluded from the analyzed data.

In the study by this method, the agents according to the invention mainly inhibit PDE isoenzymes type 4, showing a slight effect in respect of the isoenzymes of types 1, 2, 3 and 7. In the group of PDE isoenzymes type 4 (i.e., the PDE isoenzymes type 4 from a to D) agents according to the invention is mainly manifested by selective inhibition of the isoenzyme D PDE type 4 compared with inhibition of isozymes 4A, 4B and 4C PDE type 4.4/well in 0.2 ml HBSS) stimulate fMLP (1 μm) in the presence of lucigenin (25 μm). Inhibition of the oxidation potential (as measured by the changes in chemiluminescence) is determined by the curve dose-response, using a logarithmic equation.

The agents according to the invention are active when testing the above method in concentrations of from 0.001 to 5 μm, typically in concentrations in the range of small nanomolar concentrations. For example, when evaluating this method is IC50the compound of example 2 is 0,006 mm.

Given their anti-inflammatory activity, the impact of increased airway reactivity and profile in relation to the inhibition of PDE isoenzymes, in particular their activity as selective inhibitors of PDE type 4, the agents according to the invention are suitable for treating, in particular for prophylactic treatment of obstructive or inflammatory Airways disease. So, with constant and regular administration over extended periods of time the agents according to the invention are suitable for successful protection from recurrent bronchostenosis or other symptomatic effects that accompany obstructing development of the basic status of such disease.

Given their bronchodilatory activity, the agents according to the invention is suitable as bronchodilators, for example, for the treatment of chronic or acute bronchostenosis, for example, for symptomatic treatment of obstructive or inflammatory Airways disease.

The term "treating" or "treatment" in the context of the present description and claims refers to obstructive or inflammatory airway disease, and so they include both prophylactic and symptomatic therapies.

In accordance with the foregoing objects of the present invention are the following.

A. the Way

a) treatment increased airway responsiveness,

b) increasing the lumen of the bronchi or bronchioles or, in particular,

in the treatment of obstructive or inflammatory Airways disease in a patient, ordaudio for such treatment, and this method includes the introduction to the patient an effective amount of an agent according to the invention.

Obstructive or inflammatory airway disease, which fall under the scope of the present invention include asthma, pneumoconiosis, HRO is rum adults (ARDS), as well as exacerbation of increased reactivity of the Airways in the treatment of other medication, such as aspirin, or therapy with the use of-agonists.

The present invention is applicable for the treatment of asthma of any type or origin, including congenital and primarily purchased asthma. It is applicable for treatment of allergic (atopic/lgE mediated) asthma. It is also applicable to the treatment diatopically asthma, including bronchial, purchased and occupational asthma, asthma induced by bacterial infection, and other types of non-allergic asthma. It is also applicable for the treatment of syndrome startrange breathing children (children, early asthma).

The invention is applicable to treatment of pneumoconiosis any type or origin, including, for example, aluminas, antraks, asbestosis, helicos, Philos, sideros, silicosis, tabacos and bissines.

The invention is applicable to treatment OSDP or OSL, including chronic bronchitis, emphysema or related shortness of breath.

The invention is also applicable to the treatment of bronchitis of any type or origin, including acute, arachidonyl, catarrhal, chronic, lobar or purulent t the coefficients according to the invention is also suitable for down-regulation or inhibition of the excretion of TNF-, for example, for the treatment of diseases or conditions that are caused by the release of TNF - or TNF - a plays the role of a mediator, such as diseases or conditions, the etiology of which includes or contains a pathology, for example, spam, excessive or unregulated secretion of TNF-, in particular, for the treatment of cachexia or endotoxic shock and for the treatment of AIDS [cf. data Sharief and others, Mediators of Inflammation, 1, 323-338 (1992)].

The method according to the invention is applicable for the treatment of cachexia associated with pathological secretion of TNF - or with pathological levels of TNF - a in serum, regardless of origin, including cachexia, resulting, for example, bacterial, viral or parasitic infection or the result of deprivation or exhaustion humoral or other organic, such as the kidney function. He, for example, is applicable for the treatment of cancer, malaria and permalloy cachexia, cachexia resulting from dysfunction of the pituitary, thyroid or thymus, and uremic cachexia. He, in particular, is effective for the treatment of AIDS-related cachexia, for example, cachexia resulting from or associated with HIV infection.

The method according to the invention is also applicable to the treatment which should be noted, what the present invention relates to a method of treating septic shock, and conditions resulting from or have symptoms of septic shock, such as ARDS (respiratory distress syndrome adults).

The method according to the invention, moreover, is applicable for the treatment of diseases resulting from HIV infection, such as AIDS, with the aim of reducing the intensity or control the development of such disease.

Given their profile in relation to the inhibition of PDE isoenzymes and/or inhibiting the excretion of TNF- , as well as their immunosuppressive activity, the agents according to the invention are also suitable as immunosuppressants, for example, for the treatment of autoimmune diseases, in particular for the treatment of autoimmune diseases in which inflammatory processes or that have an inflammatory component or aetiology, or as anti-inflammatory agents for the treatment of inflammatory diseases, in particular for the treatment of inflammatory disease are autoimmune reaction or which has an autoimmune component or aetiology.

Examples of such diseases to which the present invention is applicable, include autoimmu the erythrocytes and idiopathic thrombocytopenia), systemic lupus erythematosus, polyhedric, scleroderma, granulomatous's granulomatosis, dermatomyositis, chronic active hepatitis, severe pseudoparalysis myasthenia syndrome Stevens-Johnson, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), endocrine ophthalmopathy, graves disease, sarcoidosis, alveolitis, chronic hypersensitive pneumonitis, multiple sclerosis, primary biliary cirrhosis, juvenile diabetes (diabetes mellitus type I), uveitis (anterior and posterior), keratoconjunctivitis sicca and vernally keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with nephrotic syndrome or without it, e.g. including idiopathic nephrotic syndrome or nephropathy minimal change), as well as inflammatory and/or hyperproliferative skin diseases, such as psoriatic atopic dermatitis, pemphigoid and, in particular, contact dermatitis, for example, allergic contact dermatitis.

The agents according to the invention is particularly suitable for the treatment of arthritis and other rheumatic or inflammatory diseases, primarily for the treatment of rheumatoid arthritis.

Given their anti-inflammatory activity, in particular? in relation to inhibition of activation of eosinophils, the agents according to the invention is also suitable for the treatment associated with eosinophils diseases, such as eosinophilia, and are primarily associated with eosinophilia diseases of the Airways (e.g. involving abnormal eosinophil infiltration of lung tissue), including hypereosinophilia, affecting the respiratory tract and/or lungs, as well as, for example, associated with eosinophilia of respiratory diseases that are caused or accompanied by the syndrome Leffler, eosinophilic pneumonia, parasitic (in particular matatalino) infestation (including tropical eosinophilia), bronchopulmonary Aspergillus, polyarthritis nodosa (including syndrome Churg-Strauss), eosinophilic granuloma and associated with eosinophilia disorders of the respiratory tract caused by a reaction to medication.

Given their profile in relation to the inhibition of PDE isoenzymes, in particular p is inhibitorof PDE type 4, for example, for the treatment of diseases associated with decrease of calcium in the tissues, especially degenerative diseases of bones and joints, caused by the reduction of calcium, in particular osteoporosis. In this respect, they are also suitable for the treatment of allergic inflammatory diseases, such as rhinitis, conjunctivitis, atopic dermatitis, urticaria and gastrointestinal allergies, as vasodilating agents, for example, for the treatment of angina, hypertension, congestive heart failure and multi-infarct dementia, and to treat other conditions, which shows the inhibition of PDE type 4, for example depression, conditions and disorders characterized by impairment in cognitive function, including Alzheimer's disease, Parkinson's disease and stroke.

Because of their synergistic ability to interact with immunosuppressants and/or anti-inflammatory drugs, the agents according to the invention are also suitable as Serpentina agents for use in combination with these drugs, such as amplifiers therapeutic activity of these drugs or as a means to reduce the required size is n conjunction with the agents according to the invention include, for example, cyclopeptide, cyclopeptide or macrolide immunosuppressants or anti-inflammatory medicines, such as medicines from the class of cyclosporine, such as cyclosporine a or G, drugs such as tacrolimus (also known as FK 506), ascomycin and rapamycin, and various well-known related tools and their derivatives, as well as drugs from the class of corticosteroids. Diseases for which it may be applied such combined therapy include, for example, any disease or condition that requires immunosuppressive or anti-inflammatory drug therapy, for example, above in the present description. In particular, the agents according to the invention is suitable for use in the above joint therapy, for example, for the purposes of immunosuppressive, anti-inflammatory or anti-asthma treatment, for example, to achieve the effects of cyclosporine, for example, moderate impacts caused by cyclosporine a, macrolides or steroids.

In accordance with the foregoing, another object of the present invention is the following.

B. the Way

a) pangeometry immunosuppression,

g) treatment of inflammatory diseases or

d) the treatment of any specific condition or disease specified above,

in a patient in need of such treatment, and this method includes the introduction to the patient an effective amount of an agent according to the invention.

The present invention also refers to:

C. the agent according to the invention, intended for use as a drug, for example, for use in accordance with any of the above method or for the treatment of any of the above diseases or conditions, such as specified above in sections a and B.

The dose used in the practical implementation of the present invention, as obviously vary depending on, for example, from a particular disease or condition to be treated, in particular? from concretely applied agent according to the invention, the route of administration and the desired therapy. In General, however, satisfactory results, for example, in the treatment of the above diseases can be obtained through oral dose comprising from 0.01 to 2.0 mg/kg For larger mammals, for example humans, the recommended daily dose for oral administration should sootvetstvovala double or quadruple the introduction or in the form of a continuous release. Thus, suitable standard dosage forms for oral administration comprise from about 0.2 to 75 or 150, for example, from about 0.2 or 2.0 to 50, 75 or 100 mg of the agent according to the invention together with a pharmaceutical acceptable diluent or carrier.

When applying for the treatment of chronic or obstructive diseases of the Airways such as asthma, the agents according to the invention can also be administered in this way, as the inhalation. And in this case, the applied dose should vary, for example, depending on the specific disease or condition, a particular agent used according to the invention, the specific route of administration (for example, by using either a dry powder form for inhalation, or other method) and the desired action. However, in General, the recommended daily dose for inhalation ranges from approximately 2.5 to approximately 130,0 µg/kg/day, for example, from about 13.0 to about 60,0 mg/kg/day. For larger mammals, for example humans, the recommended daily dose for administration by inhalation, for example, for the treatment of asthma should be in the range of from about 0.2 to 10.0 mg, for example from 1 to 5 mg, and it is usually applied for one is edenia, thus, should range from about 200 μg to approximately 3.3 mg with the introduction of 3 times a day, preferably with the introduction of using the device for inhalation of a dry powder in the form of a series consisting of 2-8 dowani with each introduction.

The agents according to the invention can also be administered by other suitable for this purpose method, for example by infusion, for example, for the treatment of endotoxic shock; nasal, for example, for the treatment of rhinitis; instillation in the eye, for example, for the treatment of autoimmune diseases of the eyes; dermal, i.e., topically on the skin, for example, for the treatment of dermatitis, or psoriasis; or rectally, for example, using an enema or suppository, for example, for the treatment of inflammatory bowel disease. Acceptable dose for administration by such routes should normally be 10-100 times lower than the doses required for oral administration.

Pharmaceutical compositions comprising the agents according to the invention, can be obtained using conventional diluents or excipients, or using methods well known in the field of preparation of herbal medicines. For example, dosage forms for oral administration may be tablets, capsules, etc. Whom the ical systems, for example, plaques, and in addition to inert diluents or carriers can also contain agents that enhance penetration through the skin, also known in this field.

Compositions for inhalation may be an aerosol or other intended for spraying shapes and forms intended for inhalation dry powders, with a diluent or without it, for the introduction using any known in the field of acceptable system of inhalation dry powder. To obtain forms for inhalation in the form of a dry powder agents according to the invention can be applied in the form of a pharmaceutically acceptable acid salt additive. This compound in salt form is usually pulverized, for example, using an air nozzle or a ceramic mill to obtain fine powder for inhalation, for example, with an average particle diameter of approximately 2-3 microns. Preferably, at least 90% of the product had an average particle diameter less than 7.8 μm, more preferably less than 4.8 μm. To obtain an acceptable and appropriate to the product, suitable for administration via inhalation in the form of a dry powder, it may be preferable to implement change is inhalation, for example, lactose, at low temperatures.

In accordance with the foregoing the present invention also relates to pharmaceutical compositions containing the agent according to the invention together with a pharmaceutically acceptable diluent or carrier, for example, for use in any of the methods described above.

1. Derivatives of 8-aryl-1,7-naphthiridine formula I

< / BR>
where R1denotes phenyl, benzyl, 3-nitrophenyl, 3-chlorophenyl, 3-tianfeng, 3-(tetrazolyl)phenyl or benzofuranyl;

R2denotes a hydroxy-group, tripterocalyx, allyl, alkyl, alkenyl, quinil, alkoxygroup, phenyl, phenyloxy, carboxyphenyl, carboxymethyl, carbamoylmethyl, phenylamino, diphenylamino-, amino-, alkaline or Alcaidaria, where "ALK" refers to aliphatic fragment having up to 8 carbon atoms and optionally including carboxylate, ether carboxylic acid or a hydroxy-group and/or optionally containing an ether bond and/or ester bond,

or its N-oxide in free form or in the form of pharmaceutically acceptable salts.

2. Connection on p. 1, representing 6-(carboxyphenyl or carboxymethyl)-8-(phenyl or benzo [the

3. Connection on p. 2 of the formula II

< / BR>
where n is 0 or 1;

R7denotes a hydroxy-, amino-, WITH1-C4alkylamino or1-C4alkoxy group, preferably hydroxy or amino group;

or R3denotes hydrogen and R4denotes the nitrogroup, chlorine, cyano or tetrazolyl (for example, 1-tetrazolyl) and R5and R6together form an additional bond,

or R3, R4, R5and R6together denote =N-O-N=,

or its ester in free form or in the form of pharmaceutically acceptable salts.

4. Connection on p. 1 representing:

6-amino-8-(3-nitrophenyl)-1,7-naphthiridine,

6-amino-8-(4-benzo[C]furutani)-1,7-naphthiridine,

6-hydroxy-8-(3-nitrophenyl)-1,7-naphthiridine,

6 ethoxycarbonylmethoxy-8-(3-nitrophenyl)-1,7-naphthiridine,

the hydrochloride of 6-acetamido-8-(3-nitrophenyl)-1,7-naphthiridine,

6-amino-8-benzyl-1,7-naphthiridine,

6 phenylamino-8-(3-nitrophenyl)-1,7-naphthiridine,

6 tripterocalyx-8-(3-nitrophenyl)-1,7-naphthiridine,

6-phenyl-8-(3-nitrophenyl)-1,7-naphthiridine,

6-vinyl-8-(3-nitrophenyl)-1,7-naphthiridine,

6-ethinyl-8-(3-nitrophenyl)-1,7-naphthiridine,

6-(4-carboxyphenyl)-8-(3-tianfeng)-1,7-naphtalimide,

N-methyl-D-glucagonoma salt of 6-(4-carboxyphenyl)-8-(4-benzo[C] furutani)-1,7-naphthiridine

or the compounds of formula I, in which

R1denotes 3-chlorophenyl and R2denotes amino,

R1denotes 3-tianfei and R2denotes amino,

R1refers to 4-(5-tetrazolyl)phenyl and R2denotes amino,

R1denotes benzyl and R2indicates phenylamino,

R1denotes benzyl and R2indicates diphenylamino,

R1denotes benzyl and R2indicates tripterocalyx,

R1denotes 3-chlorophenyl and R2indicates tripterocalyx,

R1denotes 3-tianfei and R2indicates tripterocalyx,

R1denotes 4-benzo[C] furutani and R2indicates tripterocalyx,

R1refers to 4-(5-tetrazolyl)phenyl and R2indicates tripterocalyx,

R1denotes benzyl and R2denotes phenyl,

R1denotes benzyl and R2denotes vinyl,

R1denotes benzyl and R2denotes ethinyl,

R1denotes 3-chlorophenyl and R2denotes 4-carboxyphenyl,

R1will obstacal 4-aminocarbonylmethyl,

R1denotes 3-nitrophenyl and R2denotes 4-aminocarbonylmethyl,

R1denotes 3-chlorophenyl and R2denotes 4-ethoxycarbonylphenyl or

R1denotes 3-nitrophenyl and R2denotes 4-ethoxycarbonylphenyl.

5. The compound according to any one of paragraphs.1-4, possessing anti-inflammatory activity.

6. Pharmaceutical composition having anti-inflammatory activity and containing the compound according to any one of paragraphs.1-4 together with a pharmaceutically acceptable diluent and/or carrier.

 

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< / BR>
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