MXPA99003958A - Naphthyridine derivatives - Google Patents

Abstract

Novel 8-aryl-1,7-naphthyridines, in free or salt form, are PDE IV inhibitors and are thus useful as pharmaceuticals, e.g. for asthma therapy. Preferred compounds include compounds of formulae (I and II) wherein the R groups are as defined. Pharmaceutical compositions comprising the compounds, processes for preparation of the compounds and novel intermediates for use in the processes are disclosed.

Description

NAFTIRIDINE DERIVATIVES The present invention relates to novel 8-aryl-7-naphthyridines, to processes for their production, to their use as pharmaceuticals, and to pharmaceutical compositions comprising them. The present invention provides 8-aryl-7-naphthyridines, in free or pharmaceutically acceptable salt form. "Aryl" means an aromatic or mono- or bi-cyclic heteroaromatic moiety having up to 10 non-hydrogen aromatic atoms, and which is linked with the 1,7-naphthyridine either directly (eg, phenyl, pyridyl, tetrazolyl) , benzofurazanyl, or benzothiofurazanyl), or by means of a methylene bridge (for example, benzyl or pyridylmethyl), preferably a monoclonal aromatic fraction having up to 6 aromatic carbon atoms, up to 2 of which can be replaced by nitrogen, for example phenyl, benzyl, 4-pyridyl, or pyridylmethyl, optionally bearing a carboxyl, carboxy ester, or hydroxyl group. The 8-aryl moiety can optionally be further substituted, especially with a substituent that removes electrons, for example nitro, nitrile, imino, halogen, or a substituent containing halogen (for example trifluoromethyl), or cyano, preferably in the position goal. For example, the 8-aryl fraction can be cyanophenyl, nitrophenyl, tetrazolylphenyl (for example tetrazol-1-ylphenyl), or chlorophenyl. Optionally, the double ring of the naphthyridine moiety of the molecule can also be additionally substituted or disubstituted, especially 6-substituted, with hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, aryl, aryloxy, amino, arylamino, diarylamino, alkamino, dialkyl , arylamido, or alkamido, wherein "alk" refers to an aliphatic moiety of up to 8 carbon atoms, optionally bearing a carboxyl, or carboxy ester, or hydroxyl group, and / or optionally containing an ether linkage and / or an ester link. In particular, the invention provides novel 8-phenyl- and 8-benzyl-l, 7-naphyridines, wherein the double ring of 1,7-naphthyridine is optionally e-substituted, for example as exemplified below, and the Phenyl ring is optionally substituted by an electron-withdrawing substituent, such as nitro; for example, the compounds of the formula I: wherein: Ri is phenyl, benzyl, 3-nitrophenyl, 3-chlorophenyl, benzothiofurazanil; 2 is hydroxyl, amino, trifluoromethanesulfonyl, allyl, alkyl, alkenyl, alkynyl, alkoxy, aryl, aralkyl, aryloxy, amino, arylamino, diarylamino, alkamino, dialkamino, alkaryl, arylamido, or alcamido, and esters and amides thereof; in free or pharmaceutically acceptable salt form.

In formula I, and elsewhere in the present description, "alk" and "aryl" have the meanings given above in relation to the 8-aryl-l, 7-naphthyridines of the invention. Preferably, R 2 is selected from hydroxyl, amino, arylamino (for example phenylamino), aryl (for example phenyl), alkaryl (for example lower alkyl-phenyl), alkenyl (for example vinyl), alguinyl (for example, ethylene) , alkoxy containing an ether bond and / or an ester linkage (for example methoxycarbonylmethoxy), and alkanode (for example acetamido). In particular, it has been surprisingly discovered that an entirely new class of 6,8-aryl-1, 7-naphidines are useful as pharmaceuticals, in particular as orally active PDE-4 inhibitors, for example for the treatment of asthma.

Accordingly, in a preferred embodiment, the invention provides 6- (carboxyphenyl or carboxymethylphenyl) -8- (phenyl, benzo [c] thiadiazolyl or benzo [c] furazanyl) -1,7-naphthyridines, and esters and amides of them, in free or pharmaceutically acceptable salt form. More preferably, the invention provides 6- (4-carboxyphenyl or 4-carboxymethylphenyl) -8- (phenyl, 4-benzo [c] thiadiazolyl or 4-benzo [c] furazanyl) -1, 7 -naphthyridines, and esters and amides thereof, in free or pharmaceutically acceptable salt form. Benzo [c] thiadiazolyl and benzo [c] furazanyl mean radicals of the formula A and B, respectively: A B Therefore, in a particularly preferred embodiment, the invention provides a compound of the formula II: where: n is zero or one; R7 is hydroxy, amino, alkylamino of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms, preferably 0 hydroxyl or amino; and any of: R3 is H, and R4 is nitro, halogen (for example chloro), cyano, or tetrazolyl (for example 1-tetrazolyl), and R5 and R6 together form an additional bond, or | 5 R3, R ", R5, and Rs are together = N-0-N = or = NSN =; and esters and amides thereof; in a free or pharmaceutically acceptable salt form.

Suitable pharmaceutically acceptable salt forms of the 8-aryl-1, 7-naphthyridines, for example, of the formula I or II, for pharmaceutical use, are prepared by conventional elements 1. For example, the compounds having a free carboxylic acid group, for example the compounds of the formula II wherein R7 is OH, can be contacted with a suitable base, for example an amino sugar such as N-methyl glucamine, to provide an addition salt of the corresponding base. Conveniently, these base addition salts can be soluble in water.

The 8-aryl-l, 7-naphthyridines of the invention, for example of the formula I, can be prepared by the reaction of 2-cyano-3-pyridylacetonitrile, a) with an acid, for example HA, wherein _A is halogen, for example bromine, to obtain the compound of the formula III: which can then be further derivatized to obtain the compounds of the invention, for example with a cross-coupling reaction using metal reagents in the presence of a "palladium or nickel catalyst, to form a carbon-carbon bond, by example a reaction of Stille, Suzuki, or Heck, that is, reacting a compound of formula III with a compound Y-Rβ, wherein Y is a metal leaving group, for example B (0H) 2-, (OL. ) 3Sn- (CH3 (CH2) 3) 3Sn-, and Rβ is an 8-aryl moiety as defined above, for example benzyl or 3-n-trophenyl, to obtain the corresponding compound of formula IV: b) with a Grignard reagent, for example R8-MgBr, wherein Rβ is an 8-aryl moiety as defined above, for example benzyl or 3-nitrophenyl, to obtain the corresponding compound of formula IV; or c) with a mixture of alkali metal-alkanol, for example sodium-methanol, to obtain a compound of formula III ': wherein Alk denotes an alkyl group of 1 to 8 carbon atoms, for example methyl. The O-Alk substituent can be converted to halogen A, and the compound is subsequently derived in the 8-position as described above for the compound of formula III. The amino group of formula III, III ', or IV is susceptible to an additional reaction, for example, (i) activation with a suitable activating reagent, for example with trifluoromethanesulfonic acid and? STaN02, to obtain the triflate of the formula V: wherein Q is a halogen A as defined above, a substituent -O-Alk as defined above for the compound of the formula III ', or a fraction of 8-aryl Rβ as defined above, which is an intermediate novel and highly useful for the preparation of the compounds of the invention, for example when R2 in the formula I is bound to the rest of the molecule by means of a carbon-carbon bond, substitution can be carried out, for example, with a cross-coupling reaction using metal reagents in the presence of a palladium or nickel catalyst to form a carbon-carbon bond, for example a reaction of Stille, Suzuki, or Heck, for example by reacting a compound of the formula V wherein Q is R8, with a compound of the formula Y-R2 wherein Y is a metal leaving group as defined above, and R2 is the desired carbon substituent, for example alkyl, alkenyl, alkynyl, aryl, or alkaryl as defined above for formula I, optionally in protected form, followed by deprotection if required; or (ii) alkyl or aryl substitution (for example, by reaction with a corresponding alkyl or organometal halide) to give the desired secondary or tertiary amine, - or (iii) acylation (e.g., by reaction with a carboxylic acid or an acid anhydride) to give the corresponding amide, using conventional procedures; or (iv) conversion to hydroxyl, for example by reaction with NaN02 in the presence of a dilute acid, for example sulfuric acid, and optionally further deriving, for example, 0-algae, for example by reaction with a sodium halide. alkyl, under suitable reaction conditions.

The 6- (carboxy, or carboxymethyl- -phenyl) -8- (phenyl. preferred benzo [c] thiadiazolyl or benzo [c] furazanyl-1, 7-naphthyridines, or esters or amides thereof, for example-of formula II, are conveniently prepared by the following method: (A) for the preparation of 6- (carboxy- or carboxymethyl- -phenyl) -8- (phenyl, benzo [c] thiadiazolyl- or benzo [c] furazanyl) -1,7-naphthyridines, or esters or amides thereof, reacting a 6- X-8- (phenyl, benzo [c] thiadiazolyl or benzo [c] furazanyl) -1,7-naphthyridine with an X '- (carboxy, 6-carboxymethyl-phenyl) or ester or amide thereof, or reacting a β- (carboxy-carboxymethyl-phenyl) -8-Xl, 7-naphthyridine, or ester or amide thereof, with an X 1 - (phenyl, benzo [c] thiadiazolyl or benzo [c] furazanyl), wherein X and X 'are leaving groups capable of participating in a cross coupling reaction; for example, wherein X is trifluoromethanesulfonyl or halogen, for example bromine or chlorine, and X 'is a metal leaving group, for example substituted boron (eg, -B (0H) 2, -B (OAlk) 2 or -Balk2 , wherein Ale is alkyl, for example methyl or ethyl), or trialkylstannyl (for example (CH3 (CH2) 3) 3Sn-d (CH3) 3Sn-), or a Grignard radical (for example MgBr); I (B) optionally reacting a 6- (carboxy- or carboxymethyl- -phenyl) -8- (phenyl, benzo [c] thiadiazolyl or benzo [c] furazanyl -1,7-naphthyridine with a suitable amide, for example ammonia or alkyl amine (from 1 to 4 carbon atoms), to obtain the corresponding amide; I (C) optionally reacting a 6- (carboxy- or carboxymethyl- -phenyl) -8- (phenyl, benzo [c] thiadiazolyl or benzo [c] furazanyl-1, 7-naphthyridine with a suitable alcohol, for example an alcohol (from 1 to 4 carbon atoms), to obtain the corresponding ester, and recover the 6- (carboxy- or carboxymethyl- -phenyl) -8- (phenyl, benzo [c] thiadiazolyl or benzo [c] furazanil) -1 , Resulting 7-naphthyridine, or ester or amide thereof, in free form of salt.

The reaction conditions for step (A) are as known in the art for cross-coupling reactions using metal reagents, for example in the presence of a palladium or nickel catalyst, to form a carbon- carbon, - for example, as in a reaction of Stille, Suzuki, or Heck. The reaction conditions for steps (B) and (C) are as known in the art for the preparation of amides from the reaction of carboxylic acids and amines, and for the preparation of esters from of carboxylic acids and alcohols, for example under acidic or basic conditions. The recovery and purification are by usual methods, for example by chromatography or crystallization. Accordingly, in a preferred embodiment, the invention provides a process for the preparation of a compound of formula II, as defined above, which comprises reacting a compound of formula VI: wherein R3, R4, R5, *, and X are as defined above, with a compound of formula VII: wherein R7 and X 'are as defined above, and recover the compound of formula II thus obtained in free or salt form. 6-X-8- (phenyl, benzo [c] thiadiazolyl or benzo [c] furazanyl) -1,7-naphthyridines and the 6- (carboxy-carboxymethyl- -phenyl) -8-X-1, 7-naphidines, or esters or amides thereof, for use in the above reactions, are suitably prepared by the reaction of 2-cyano-3-pyridylacetonitrile with an acid, for example HA, wherein A is a halogen, for example bromine, to obtain a compound of formula III, and subsequently further derivatized as required, as previously described. The processes described above for the preparation of the 8-aryl-l, 7-naphthyridines of the invention, in particular the 6- (carboxy, or carboxymethyl- -phenyl) -8- (phenyl, benzo [c] thiadiazolyl or benzo [c] furazanyl) -1,7-naphthyridines, and esters and amides thereof, are novel, as well as the intermediates ~ of formulas IV, V, and VI, and these novel processes and intermediates are included within of the scope of the present invention. It will be appreciated that the compounds of the formula V, wherein Q is Rβ, and the compounds of the formula IV, are encompassed by the 8-aryl-l, 7-naphthyridines of the invention. Accordingly, in the further aspects, the invention provides intermediaries of the formula V: wherein Q 'is halogen, or -O-Alk, wherein Ale denotes an alkyl group of 1 to 8 carbon atoms, and of formula VI: wherein R3, R ,, R5, R_, and X are as defined above. The following examples are illustrative of the invention.

EXAMPLES EXAMPLE 1: 6-amino-8- (3-nitro-enyl) -1,7-naphthyridine A. 2-cyano-3-pyridylacetonitrile To a stirred suspension of 3-cyanomethyl pyridine N-oxide (30 grams, 0.22 moles) for the synthesis see Shigenobu Okuda, Michael M. Robinson, J. Amf Chem. Soc. 81, 740 (1959)) in dichloromethane (200 milliliters), trimethylsilanecarbonitrile (26 grams, 0.26 moles) is added. To this suspension is added dimethylcarbamyl chloride (28 grams, 0. 26 moles). The mixture is stirred for 45 hours. The solvent is removed, and the residue is dissolved in ethyl acetate. The solution is washed with 1 N NaOH, and water, and concentrated in vacuo. The product is purified by flash column chromatography on silica gel (15: 2 toluene / acetone) to provide the title compound. Mass M + H 144.1. Melting point: 62-63 ° C.

B. 6-amino-8-bromo-l, 7-naphthyridine. Through a stirred solution of 2-cyano-3-pyridylacetonitrile (3.6 grams, 0.025 mol) in toluene (80 milliliters), HBr is bubbled for 5 hours. Then 4N NaOH is carefully added, and the suspension is stirred vigorously. The mixture is filtered, and the product is washed with water and dried. Crystallization from toluene provides the title compound. Mass M + H 225. Melting point: 188 ° C, decomposition.

C. 6-amino-8- (3-nitrophenyl) -1,7-naphthyridine To a stirred solution of 6-amino-8-bromo-l, 7-naphthyridine (4 grams, 0.018 mole) in a mixture of tetrahydrofuran (80 milliliters) and aqueous Na2CO3 (34 milliliters, 2N), is added bis (dibenzylideneacetone) palladium (0.40 grams, 0.0007 moles), triphenylphosphene (0.37 grams, 0.0014 moles), and 3-nitrophene acid nilboronic (3.7 grams, 0.022 moles). The mixture is stirred for 16 hours at 80 ° C. The mixture is filtered, ethyl acetate is added, and the mixture is washed with 2N NaOH and water. The organic solvent is removed, and the residue is suspended in ether. Filtration provides the title compound. Mass M + H 267, p. f .: 221-223 ° C.

EXAMPLE 2: 6-a ino-8- (4-benzo [c] furazanyl) -1,7-naphthyridine To a stirred solution of 6-amino-8-bromo-l, 7-naphthyridine (3.0 grams) , 13.4 mmol) in dimethyl formamide (50 milliliters), were added bis (dibenzylidenacetone) palladium (308 milligrams, 0.54 millimoles), triphenyl phosphine (565 milligrams, 2.15 millimoles) and 4-trimethylstannyl-benzo [c] furazanil (4.92 grams , 16.0 millimoles). The mixture is maintained at 125 ° C for 4 hours. Ethyl acetate (500 milliliters) is added, followed by aqueous KF (40 percent, 100 milliliters). The mixture is stirred vigorously for 45 minutes, and filtered. The organic phase is separated, washed with water, and concentrated. The residue is taken up in ether (20 milliliters), stirred for 30 minutes (0 ° C), and filtered, to give the title compound (2.8 grams). M + H = 264. P.f. 244-250 ° C.

E EMPLO 3: 6-hydroxy-8- (3-nitrophenyl) -1,7-naphyridine To a solution of 6-amino-8- (3-nitrophenyl) -1,7-naphthyridine (500 milligrams, 1.87 mmol; prepared in accordance with Example 1), in concentrated sulfuric acid and water (3 milliliters, 2: 1), sodium nitrate (155 milligrams, 2.25 millimoles) is added at 4 ° C. After 30 minutes, the ice bath is removed, and the mixture is heated at 70 ° C for 30 minutes. The reaction mixture is poured onto ice, and the solution is neutralized by the addition of sodium bicarbonate. The precipitate is filtered and washed with water to provide the title compound. P.f. 262-265 ° C.

EXAMPLE 4: 6-methoxycarbonyl rtetoxy-8- (3-nitrophenyl) -1,7-naffciridine A suspension of 6-hydroxy-8- (3-nitrophenyl) -1,7-naphthyridine (107 milligrams, 0.40 millimoles; according to the previous example, optionally without further purification), potassium carbonate (55 milligrams, 0.40 mmol), and bromoacetic acid methyl ester (37 microliters, 0.4 mmol), is stirred for 2 hours in acetone-dimethyl formamide (2). milliliters, 1: 1), at room temperature. Ethyl acetate is added, and the organic phase is washed with 2N NaOH. The solvent is removed in vacuo, and the crude product is purified by layer chromatography.

Thin preparation, to give the title compound. Mass M + H 340; P.f .: 160-162 ° C.

EXAMPLE 5: 6-Acetatni do-8- (3-nitrophenyl) -1,7-naphthyridine hydrochloride A suspension of 6-amino-8- (3-nitrophenyl) -1,7-naphthyridine (300 milligrams, 1.1 mmol; prepared according to Example 1), and acetic acid anhydride (0.12 milliliters, 1.2 mmol) in pyridine (1 milliliter) and dimethyl formamide (3 milliliters), is maintained at 80 ° C for 3 hours. Water is added, and the precipitate is filtered and washed thoroughly with water. Filtration provides the product of the title. Mass M + H 308; P.f .: 235-238 ° C.

E EMPLO 6: 6-amino-8-bßncyl-l, 7-naphthyridine To a solution of 2-cyano-3-pyridylacetonitrile (2 grams, 0.014 mol) in toluene (20 milliliters), benzyl magnesium bromide ( 8.4 milliliters, 2M in tetrahydrofuran, 0.17 moles), at room temperature. After 1 hour, the reaction is quenched with a saturated solution of ammonium chloride. The product is extracted with ethyl acetate, and the organic layer is washed with 2N NaOH and water. The product is purified by column chromatography by evaporation Flash over silica gel (10: 3 toluene / acetone) to provide the title compound. Mass M + H 236; p.f .: 113-116 ° C.

EXAMPLE 7: 6-phenylamino-8- (3-nitrofßnil) -1,7-naphyridine To a solution of triphenyl bismuth (182 milligrams, 0.41 millimoles) in dichloromethane (0.5 milliliters) and tetrahydrofuran (0.5 milliliters) is added Peracetic acid (0.083 milliliters, at 40 percent). The mixture is stirred for 1 hour. Then a solution of 6-amino-8- (3-nitrophenyl) -1,7-naphthyridine (100 milligrams, 0.37 mmol, prepared according to Example 1) in dichloromethane (0.5 milliliters) and tetrahydrofuran (0.5 milliliters) is added. . Copper (30 milligrams, 0.47 millimoles) is added, and the suspension is stirred for 40 hours. The suspension is diluted with ethyl acetate and filtered. The filtrate is washed with 2N Na2CO3 and water, and the organic layer is concentrated in vacuo. Thin layer chromatography of preparation (8: 2 of normal dichloromethane / hexane) provides the title compound.

Mass M + H 343.1; p.f .: 158-160 ° C.

EXAMPLE 8: 6-trifluoromethylsulfonyl-8- (3-nitrophenyl) -1,7-naphthyridine To a solution of 6-amino-8- (3-nitrophenyl) -1,7-naphthyridine (1.24 grams, 0.0047 moles; according to Example 1) in trifluoromethanesulfonic acid (12 milliliters), sodium nitrite is added in several portions (0.64 grams, 0.0093 moles). The solution is heated to 60 ° C, and stirred during noshe. The solution is poured onto a mixture of ethyl acetate and ice. Then 2N NaOH is added, until the aqueous phase is alkaline. The organic phase is washed with water and concentrated in vacuo. The product is purified by flash column chromatography on silica gel (7: 3 hexane / ethyl acetate) to provide the title compound. Mass M + H 400; p.f .: 106-108 ° C.

EXAMPLE 9; 6- £ enyl-8- (3-nitrofen.il) -1,7-naphthyridine To a solution of 6-trifluoromethanesulfonyl -8- (3-nitrophenyl) -1,7-naphthyridine (300 milligrams, 0.75 millimoles; according to Example 8) in tetrahydrofuran (5 milliliters), phenylboronic acid (118 milligrams, 0.97 millimoles), bis (dibenzylidene-naethane) palladium (18 milligrams, 0.03 millimoles), triphenyl phosphine (16 milligrams, 0.06 millimoles) are added, and Na2CO3 aqueous (2N, 1.44 milliliters). The solution is Hold at 60 ° C for 20 hours. The solution is diluted with ethyl acetate, filtered, and washed with IN NaOH and water. The solvent is removed in vacuo to give the pure product. Mass M + H 328. P.f. 172-175 ° C.

EXAMPLE 10: 6-vinyl-8- (3-nitro-enyl) -1,7-naphthyridine To a solution of 6-trifluoromethanesulfonyl-8- (3-nitrophenyl) -1,7-naphthyridine (250 milligrams, 0.62 millimole, prepared according to example 13), in tetrahydrofuran (3 milliliters), is added vinyltributylstannane (218 milligrams, 0.68 millimoles), bis (dibenzylideneacetone) palladium (14 milligrams, 0.025 millimoles), triphenyl phosphine (13 milligrams, 0.049 millimoles) , and lithium chloride (78 milligrams, 1.86 millimoles). The mixture is maintained at 70 ° C overnight. The solution is diluted with ethyl acetate, filtered and washed with water. Thin layer chromatography (8: 2 dichloromethane / normal hexane) yields the title compound. Mass M + H 278; p.f. 145-151 ° C.

EXAMPLE 11: 6-ethynyl-8- (3-nitrophenyl) -1,7-naphthyridine A. 6-Trimethylsilylethynyl-8- (3-nitrophenyl) -1,7-naphthyridine is prepared as follows: To a solution of 6-trifluoromethanesulfonyl-8- (3-nitrophenyl) -1,7-naphthyridine (200 milligrams, 0.50 mmol, -prepared according to Example 13) in dimethyl formamide (1 milliliter) and triethyl amine (0.5 milliliter) ), ethynyltrimethylsilane (0.078 milliliter, 0.56 millimole), bis (di-benzylidenacetone) palladium (5.8 milligrams, 0.020 millimole), triphenyl phosphine (5.3 milligrams, 0.020 millimole), and copper iodide (3.8 milligrams, 0.020 millimole) are added. . The mixture is maintained at 60 ° C for 2 hours. The solution is diluted with ethyl acetate and washed with water. The product is purified by flash column chromatography on 20: 0.2 silica gel toluene / acetone), yielding 6-trimethylsilylethynyl-8- (3-nitrophenyl) -1,7-naphthyridine. (Mass M + H 348, mp 160-163 ° C).

B. To a solution of 6-trimethylsilylethynyl-8- (3-nitrofe-nyl) -1,7-naphthyridine (77 milligrams, 0.22 mmol) in methanol (0.5 milliliters) and toluene (0.5 milliliters) is added hydroxide. potassium IN (0.22 milliliters). The mixture is stirred for 2 hours. The suspension is filtered, and the product is washed with water and ether, yielding the title compound. Mass M + H 275; p.f.215 ° C, decomposition.

EXAMPLE 12: 6- (4-carboxyphenyl) -8- (3-cyanophenyl) -1,7-naphthyridine To a solution of 6-trifluoromethanesulfonyl-8- (3-cyanophenyl) -1,7-naphthyridine (2.15 grams, 5.67 millimoles) in dimethyl formamide (21.5 milliliters), 4-carboxy-phenylbordnic acid (1.13 grams, 6.81 millimoles), bis (dibenzylidenacetone) aladium (131 milligrams, 0.23 millimoles), triphenyl phosphine (95 milligrams, 0.36 millimoles), and aqueous K2CO3 (2N, 17 milliliters). The reaction mixture is stirred at 80 ° C for 2.5 hours. The hot solution is filtered through Celite, and the crude product is precipitated by carefully adding water (10 milliliters) and aqueous HCl (2N, 8 milliliters). The suspension is filtered, and the crude product is stirred in hot tetrahydrofuran (30 milliliters). The cold suspension is filtered again to give the title compound (1.12 grams). M + H = 352. Melting point > 300 ° C. Retention time by high performance liquid chromatography = 7.58 minutes (column: LiChroCart 125-4, Supersphere 60 RP-selection B, 40 ° C, eluent: acetonitrile-water (0.1% TFA) = 45:55; milliliter / minute, detection at 254 nanometers).

EXAMPLE 13: 6- (4-carbamoylfnsyl) -8- (3-cyanophenyl) -1,7-naphthyridine To a suspension of 6- (4-carboxyphenyl) -8- (3-cyanophe-nyl) -1, 7- Naphthyridine (100 milligrams, 0.28 millimoles) in toluene (2 milliliters), thionyl chloride (0.1 milliliters, 1.37 millimoles) is added. The reaction mixture is refluxed for 3 hours. The solvent is evaporated, and the residue is taken up in tetrahydrofuran (2 milliliters). Aqueous ammonia is added, and the solution is stirred for 2 hours at room temperature. Ethyl acetate is added, and the organic layer is washed with water, to give the pure title compound having a melting point of 237-240 ° C.

EXAMPLE 14: 6- (4-carb? - ifenyl) -8- (4-benzo [c] furazanyl) -1,7-naphyridine A. 6-amino-8-methoxy-l, 7-naphthyridine A sodium solution (3.2 grams, 0.139 moles) in methanol (1,400 milliliters), 2-cyano-3-pyridylaceto-nitrile (20 grams, 0.139 moles) was added, and the reaction mixture was stirred for 17 hours at the temperature ambient. Then water (700 milliliters) was added, and as most of the methanol evaporated, the title compound crystallized. Melting point: 178-180 ° C.

B. 6-trifluoromethanesulfonyl-8-methoxy-1,7-naphthyridine To a solution of 6-amino-8-methoxy-1, 7-naphthyridine (19 grams, 0.108 moles), in a 1: 1 mixture of water and trifluoromethanesulfadic acid (380 milliliters), a solution of sodium nitrite (11.2 grams, 0.162 moles) in water (40 milliliters) at 0 ° C is carefully added. After 1 hour, the cooling bath is removed, and the reaction mixture is stirred for another hour at room temperature. Then ethyl acetate (500 milliliters) is added, and the solution is neutralized by the addition of sodium bicarbonate (4N, 1 liter). The water phase is extracted again with ethyl acetate (3 x 500 milliliters). The organic solvent is evaporated, and the crude product is purified by flash column chromatography on silica gel (20: 3 toluene / acetone) to provide the title compound. M + 308; melting point 99-101 ° C.

C. 6- (4-carboxyphenyl) -8-methoxy-l, 7-na thyridine To a solution of 6-trifluoromethanesulfonyl-8-methoxy-1,7-naphthyridine (1.5 grams, 4.86 mmol) in dimethyl formamide (40 milliliters) ), 4-carboxy-phenylbordnic acid (0.866 grams, 5.34 millimoles), bis (dibenzylidenacetone) palladium (112 milligrams, 0.167) is added. millimoles), tri-o-tolytic phosphine 96 milligrams, 0.32 millimoles), and aqueous Na 2 CO 3 (14.6 milliliters, 2N). The reaction mixture is stirred at 110 ° C for 3 hours. The hot solution is filtered through celite, and the solution is evaporated to dryness. The crude product is dissolved in hot water (60 milliliters), and the water phase is washed with ethyl acetate (3 x 50 milliliters). The product is precipitated from the water phase, carefully adding aqueous HCl (2N, 6 milliliters). The suspension is filtered, and the crude product is stirred again in hot ethyl acetate (50 milliliters). The cold suspension is filtered to give the title compound (1.10 grams). M + 280; melting point > 300 ° C.

D. 6- (4-carboxyphenyl) -8-bromo-l, 7-naphthyridine To a solution of 6- (4-carboxyphenyl) -8-methoxy-l, 7-naphthyridine (250 milligrams, 0.892 mmol) in dimethyl formamide (10 milliliters), PBr3 (0.63 milliliters, 6.63 millimoles) is added. The reaction mixture is heated at 100 ° C for 30 minutes. The suspension is then poured into water (50 milliliters), and the solution is washed with ethyl acetate (2 x 50 milliliters). The organic solvent is removed, and the crude product is stirred in ether. The suspension is filtered to give the title compound (215 milligrams). Melting point: 248- 250 ° C, decomposition.

E. 4-Benzo [c] furazanylboronic acid - To a solution of 4-benzo [c] furazanyl bromide (4 grams, 0.020 moles) in tetrahydrofuran (80 milliliters) and normal pentane (20 milliliters), borate is added. of triethyl (3.8 milliliters, 0.022 moles) and N, N, N, N-tetraethylenic diamine (3 milliliters, 0.02 moles). Then normal butyl lithium (8.8 milliliters, 2.5N in hexane, 0.022 moles) is added dropwise at -100 ° C, and the solution is stirred for an additional 5 minutes. The reaction mixture is poured into an aqueous solution of saturated ammonium chloride, and the water phase is extracted with ethyl acetate. The organic solvent is removed, and the crude product is recovered in normal dichloromethane / hexane (5: 6). The suspension is filtered to give the title compound (1.05 grams), which is used without further purification.

F. 6- (4-carboxyphenyl) -8- (4-benzo [c] furazanyl) -1,7-naphthyridine To a solution of 6- (4-carboxyphenyl) -8-bromo-l, 7-naphthyridine (100 milligrams, 0.304 millimoles) in dimethyl formamide (2.5 milliliters), 4-benzo [c] furazanilboronic acid (60 milligrams, 0.36 millimoles), bis (dibenzylideneacetone) palladium (7 milligrams, 0.0122 millimoles), tri-o-tolytic phosphine (7.4 milligrams, 0.024 millimoles), and aqueous Na 2 CO 3 (0.9 milliliters, 2N). The reaction mixture is stirred at 80 ° C for 2 hours. The hot solution is filtered through Celite, and the solution is evaporated to dryness, the residue is stirred in ethyl acetate (20 milliliters), the suspension is filtered, and the organic solvent is removed, the residue is dissolved in formamide. warm dimethyl (7 milliliters), and the crude product is precipitated by the careful addition of aqueous HCl (2N, 1 milliliter) .The crude product is recrystallized from hot dimethyl formamide, to give the title compound (68 milligrams). MH + 369; Melting point> 300 ° C. M + H = 369. Retention time by high performance liquid chromatography = 10.40 minutes (column: LiChroCart 125-4, Supersphere 60 RP-selection B, 40 ° C eluent : acetonitrile-water (0.1 percent TFA) = 45:55; 1 milliliter / minute; detection at 254 nanometers).

By repeating the procedure described in the appropriate previous example, and using appropriate starting materials, the following compounds of the formula I are obtained, as identified in Table 1 below.

Table 1 Base addition salts of the compounds having free carboxyl groups can be prepared, for example as described above, by contacting the compound with an appropriate ammoazugar, for example D-glucamine N-methyl. The following example is illustrative of the preparation of these base addition salts.

EXAMPLE 34: 6- (4-carboxyphenyl) -8- (4-benzo [c] furazanyl) -1,7-naphthyridine; salt with N-methyl D-glucamine To a hot solution of 6- (4-carboxyphenyl) -8- (4-benzo [c] furazanyl) -1,7-naphthyridine (1 gram, 2.72 mmol) in dimethyl formamide (100 g. milliliters), N-methyl D-glucamine (0.53 grams, 2.72 millimoles) is added. The solvent is removed under reduced pressure, and the residue is recrystallized from hot methanol (approximately 50 milliliters) to give the pure product (1.11 grams). Melting point: 230 ° C, decomposition. Retention time by high performance liquid chromatography = 6.65 minutes (column: LiChroCart 125.4, Supersphere 60 RP-sort B, 50 ° C, eluent: gradient from 0 percent B / 100 percent A to 70 percent B / 30 percent of A in 15 minutes, A: 2.7 grams of Na2HP0t grams in 900 milliliters of water / 100 milliliters of acetonitrile, and B: 100 milliliters of water / 900 milliliters of acetonitrile, detection at 220 nanometers). The product is soluble in water. The 8-aryl-l, 7-naphthyridines of the invention, for example of the formula I, and in particular the 6-carboxy, or carboxymethyl- -phenyl) -8- (phenyl, benzo [c] thiadiazolyl or benzo [c] furazanil) -1,7-naphthyridines, and esters and amides thereof, in free or salt form (hereinafter referred to as "AGENTS OF THE INVENTION"), exhibit pharmacological activity, and are useful as pharmaceuticals , for example for therapy, in the treatment of diseases and conditions as described hereinafter. In particular, the AGENTS OF THE INVENTION exhibit inhibitory activity of cyclic nucledide phosphodiesterase (PDE) isoenzyme, selective for type 4 isoenzyme. The AGENTS OF THE INVENTION possess anti-inflammatory, anti-hyperreactivity properties of the airways, and bronchodilators. They also possess immunosuppressive activities, inhibitors of the secretion of tumor necrosis factor-a, and other pharmacological activities, as can be demonstrated in conventional test methods, for example, as follows: A. Inhibition of PDE4: Isozyme inhibition assays PDE4A, PDE4B, PDE4C, and recombinant PDE4D Cloning and expression: The PDE4 cDNA, which codes for the four enzymes, human PDE4A (as described by Sullivan et al., Cel Signal 1994; 6: 793-812), rat PDE4B (as described by Colicelli et al., Proc. Nati, Acad. Sci. USA 1989; 86: 3599-3903), human PDE4C (as described by Engels et al., FEBS Lett, 1995; 358: 305-310), human PDE4D (as described by Baecker et al., Gene 1994; 138: 253-256), is cloned into either a yeast extrachromosomal expression vector (PDE4C, PDE4D), or is integrated (PDE4A, PDE4B; a single copy) into the pep4 locus of a Saccharoiayces cerevisiae strain that lacks both wild type yeast PDE genes. Yeast strains expressing the PDE4 isoenzymes are cultured in 1 liter cultures at 30 ° C, granulated, and frozen until homogenization. Homogenization: The yeast in granule (5 millili tros) is suspended in 50 milliliters of regulator (10 mM tris-hydroxymethylamminomethane, 1 mM ethylenediaminetetraacetic acid, 1 milligram / milliliter each of leupeptin and pepstatin A, 175 milligrams / milliliter of phenylmethylsulfonyl fluoride, 1 mM dithiothreitol , pH 7.4 with HCl). After centrifugation, 15 grams of glass beads (from 425 to 600 millimeters, washed with acid, Sigma Chemical Co.) washed with a regulator, are added to the granule. To this paste, 1 milliliter of regulator and 60 milligrams of colamidopropanesulfonic acid are added, and the pulp is stirred vigorously for 4 hours at 4 ° C. The yeast cells disintegrate, as seen microscopically (phase contrast optics) as dark cells, and it is >; 3D percent (usually 50 percent). The paste is transferred to a thick glass funnel, and the homogenate is collected by suction and washed from the glass beads with a total of 15 milliliters of regulator. Cell fragments are separated from the cytosol by centrifugation (2000xg, 10 minutes, 4 ° C). The granule is resuspended in 15 milliliters of regulator, and assayed to determine PDE activity, together with the cytosol. Isoenzyme preparations are derived in another way from human sources. Type 3 and 4 preparations are obtained taking advantage of the predominance of type 3 isoenzymes in platelets, and of type 4 isoenzymes in neutrophils, applying the following techniques: cells and tissues are homogenized on ice in_Tris-HC1, 10 mM, pH 7.4, containing: sucrose (250 M, 1 mM EDTA, dithiothreitol (1 mM), leupeptin and pepstatin A (1 microgram / -mililiter of each), and phenyl-methyl-sulfonyl fluoride (PMSF, 0.17 milligrams / milliliter added just before homogenization). Neutrophils (type 4) and platelets (types 2 and 3) are obtained from human blood , and sonified (Branson's probe, 4 x 15 seconds) Human lung (types 1 and 5) are obtained from patients who undergo surgery, and homogenized using a Polytron homogenizer (two 30-second bursts). of isoenzyme: preparations of PDE 3 and 4 (1 μM cAMP substrates) consist of low-speed supernatants of platelet homogenates and neutrophils, respectively Type 1 (substrates cAMP 1 μM, Ca2 * 0.5 mM, calmodulin 125 nM) , 2 (cAMP 100 μM), and 5 (cGMP 1 μM), separated using anion exchange chromatography (Q-Sepharose) using a gradient of NaCl in the homogenization regulator without sucrose, and PMSF (NaCl from 0 to 0.1 M in 2.5 column volumes, from 0.1 to 0.45 M in 24 column volumes) . PDE 1: the fractions where the hydrolysis of 1 μM cAMP can be stimulated by Ca2 * plus calmodulin (0.5 mM and 125 nM, respectively); eluting in NaCl at 0.17-0.18 M. PDE 2: the fractions showing substantial hydrolytic activity of cAMP at 100 μM, but not at 1 μM; eluting in NaCl 0.31-0.32 M. PDE 5: the fractions that selectively hydrolyse 1 μM cGMP on 1 μM cAMP; eluting in NaCl 0.20-0.24 M.

PDE Assay: The assay protocol is based on the two-step method described by Thompson et al. (Adv. Second Messenger Phosphoprotein Res. 1979; 10: 69-92), modified for 96-well microtiter plates. Briefly, the enzyme is diluted with homogenization buffer (see above) in order to obtain between 10 percent and 30 percent total substrate hydrolysis during the assay. To start the reaction, add 25 milliliters of diluted enzyme to 25 milliliters of substrate ([3 H] -cAMP, 1.25 mM, 740 Bq), and 75 milliliters of inhibitory solution (see below). After 30 minutes at 37 ° C, the reaction is stopped in a hot water bath (at 65 ° C, for 5 minutes). The plates are cooled on ice, and incubated for 10 minutes at 37 ° C with 25 milliliters of 5'-nucleotidase (viper venom, from Oiophagus hannah,, Sigma Chemical Co., 0.1 milligrams / milliliter in water). The unreacted substrate is separated from [3H] -adenosine by adding in sequence (100 + 50 + 50 milliliters, at 5 minute intervals) of Dowex 1x2 paste at 30 percent (volume / volume) (acetate form) in 0.2 percent (volume / volume) acetic acid. The Dowex is granulated by centrifugation (150xg, 5 minutes). The aliquots of the supernatants are transferred to 96-well solid phase scintillation plates (LumaPlate, Canberra Packard) using an automated pipette device (Hamilton MicroLab 2200), dried (at least 4 hours at 50 ° C), and are counted (Canberra Packard TopCount).

Inhibitors: Solutions of dimethyl sulfoxide inhibitor (DM? O) are prepared, and diluted with water / dimethyl sulfoxide to reach seven selected concentrations to cover the range of 30 percent to 70 percent inhibition. The concentration of dimethyl sulfoxide is kept constant at 50 milliliters / milliliter throughout the entire assay. Determination of the inhibition parameters: The concentration in which the maximum mean inhibition (IC50) and the inclination of the dose response curve (Hill coefficient) are presented are determined from the concentration-inhibition curves by means of adjustment of non-linear least squares to the two-parameter logistic equation. The results are expressed as the negative decimal logarithm of concentration inhibitor in which the maximum average inhibition (IC50) is observed (in moles / liter, pIC50). Confidence intervals of 95 percent were estimated, and were expressed as pL and pU (negative decimal logarithms of the lower and upper confidence limits, respectively). The concentrations that cause a visible precipitation in the test are excluded from the analysis. In this test method, the AGENTS OF THE INVENTION predominantly inhibit the type 4 PDE isoenzymes which have a relatively small effect in relation to types 1, 2, 3, and. Within the group of PDE isoenzymes type 4 (ie PDE types 4 A to D) the AGENTS OF THE INVENTION generally exhibit a selectivity for the inhibition of the PDE isoenzyme type 4 D compared to the PDE isoenzymes type 4A, 4B, and 4C.

Anti-inflammatory activity: Inhibition of eosinophil activation by formyl-MetLeuPhe (fMLP) Purified human eosinophils are stimulated (10 / cavity in 0.2 milliliters of HBSS) with fMLP (lμM) in the presence of lucigenin (25μM). Inhibition of oxidative burst (measured as changes in chemiluminescence) is determined from the dose response curves, using the logistic equation. The AGENTS OF THE INVENTION are active in the above test method in concentrations of the order of 0.001 to 5 μM, generally in the low nM range. The compound of Example 2, for example, has an IC 50 in this test of 0.006 μM. Considering its anti-inflammatory activity, its influence on the airway hyperreactivity, and its profile in relation to the inhibition of PDE, in particular as selective inhibitors of type 4, the AGENTS OF THE INVENTION are useful for the treatment , in particular the prophylactic treatment, of the obstructive or inflammatory disease of the airways. Accordingly, by continuous and regular administration for prolonged periods of time, the AGENTS OF THE INVENTION are useful to provide early protection against the recurrence of bronchoconstrictor attack or other symptomatic attack consequential to obstructive or inflammatory airway disease, or for the control, decrease, or reversal of the basal state of this disease. Considering their bronchodilator activity, the AGENTS OF THE INVENTION are useful as bronchodilators, for example for the treatment of chronic or acute bronchoconstriction, for example for the symptomatic treatment of obstructive or inflammatory airways disease.

The words "treatment" and "treating", as used throughout the present specification and in the claims in relation to obstructive or inflammatory airway disease, should be understood in accordance with the same as encompassing both the Prophylactic therapy mode as symptomatic. In accordance with the foregoing, the present invention further provides: A. One method: a) for the treatment of airway hyperreactivity, b) to effect bronchodilatation, or in particular, c) for the treatment of obstructive or inflammatory airway disease, in a subject in need thereof, which method comprises administering to this subject an effective amount of an AGENT OF THE INVENTION. Obstructive or inflammatory diseases of the airways to which the present invention is applied include asthma, pneumoconiosis, chronic obstructive airway or pulmonary disease (COAD or COPD), and insufficiency syndrome. adult respiratory syndrome (ARDS), as well as exacerbation of airway hyperreactivity as a result of another drug therapy, for example, aspirin or β-agonist therapy. The present invention is applicable to the treatment of asthma of any type or genesis, including intrinsic asthma, and especially extrinsic asthma. It is applicable to the treatment of allergic asthma (atdico / mediated by IgE). It is also applicable to the treatment of non-atypical asthma, including, for example, bronchitic asthma, induced by exercise, and occupational asthma, asthma "induced immediately after a bacterial infection, and other non-allergic asthma." It is also applicable to the treatment of panting baby syndrome (infant asthma). invention is applicable to the treatment "of pneumoconiosis of any type or genesis, including, for example, aluminosis, anthracosis, asbestosis, calicosis, ptilosis, siderosis, silicosis, tobacosis, and byssinosis. The invention is applicable to the treatment of COPD or COAD, including chronic bronchitis, pulmonary emphysema, or dyspnea associated therewith. The invention is also applicable to the treatment of bronchitis of any type or genesis, including, for example, acute, arachidic, catarrhal, chronic, croupus, or phthinoid bronchitis, etcetera.

Considering their activity as selective inhibitors of the release of tumor necrosis factor-a, the AGENTS OF THE INVENTION are also useful to decrease or inhibit the release of tumor necrosis factor-a, for example for the treatment of diseases or conditions where the release of tumor necrosis factor-a, or having a mediating role, is implied, for example diseases or conditions having an etiology involving or understanding the release of tumor necrosis factor-to morbid, for example undesirable, excessive, or unregulated, in particular for the treatment of cachexia or endotoxin shock, and in the treatment of AIDS [cf. Sharief et al., Mediators of Inflammation, 1 323-338 (1992)]. The method of the invention is applicable to the treatment of cachexia associated with the morbid release of tumor necrosis factor-a, or with levels in the blood serum of tumor necrosis factor-a of any origin, including cachexia as a result of, for example , bacterial, viral, or parasitic infection, or to the deprivation or deterioration of humoral function or other organic function, for example renal. For example, it is applicable to the treatment of cancerous cachexia, for malaria, and dermal, cachexia resulting from the malfunctioning of the pituitary, thyroid, or thymus glands, as well as cachexia uremic In particular, it is applicable to the treatment of AIDS-related cachexia, ie, cachexia as a consequence of, or associated with, HIV infection. The method of the invention is also applicable to the treatment of septic shock, for example shock conditions resulting from bacterial infection. In this regard, it should be noted that the present invention provides a method for treating septic chogue as such, as well as conditions resulting from, or symptomatic of, septic shock, for example ARDS (adult respiratory distress syndrome). The method of the invention is also applicable to the treatment of the disease as a result of HIV infection, for example AIDS, for example to reduce or control the progression of this disease. Considering its profile in relation to the inhibition of PDE isoenzymes and / or the inhibition of the tumor necrosis factor-a release, as well as its immunosuppressive activity, the AGENTS OF THE INVENTION are also useful as immunosuppressive agents, for example for the treatment of autoimmune diseases, in particular for the treatment of autoimmune diseases where the inflammatory processes are involved, or which have an inflammatory component or etiology, or as anti-inflammatory agents for the treatment of inflammatory disease, in particular for the treatment of inflammatory disease in which auto-immune reactions are involved, or which has an autoimmune component or etiology. Examples of these diseases to which the present invention is applicable include autoimmune hematological disorders (e.g., hemolytic anemia, aplastic anemia, anemia of pure red blood cells, and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic stomatitis, autoimmune inflammatory bowel disease (eg, ulcerative colitis and Crohn's disease), endocrine ophthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumoñitis , multiple sclerosis, primary biliary cirrhosis, juvenile diabetes (diabetes mellitus type I), uveitis (anterior and posterior), keratoconjunctivitis sicca, and vernal gueratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis, and glomerulonephritis (with and without nephrotic syndrome, for example including ne syndrome idiopathic cold or minimal change nephropathy), as well as inflammatory and / or hyperproliferative diseases of the skin, such as atopic psoriasis dermatitis, pemphigus, and in particular dermatitiscontact, for example allergic contact dermatitis. The AGENTS OF THE INVENTION are in particular useful for the treatment of arthritis and other rheumatic or inflammatory diseases, especially for the treatment of rheumatoid arthritis. As immunosuppressants, the AGENTS OF THE INVENTION are further indicated for use in the prevention of graft rejection, for example for the maintenance of transplants of halogenic or similar organs, for example in connection with transplantation of kidney, liver, lung, heart, heart - lung, intestine, bone marrow, skin, or cornea. Considering its anti-inflammatory activity, in particular in relation to the inhibition of the activation of eosindfils, the AGENTS OF THE INVENTION are also useful for the treatment of disorders related to eosinophils, for example eosinophilia, in particular disorders related to the eosindhyl airways (for example, involving morbid eosinophilic infiltration of lung tissues), including hypereosinophilia, how it affects the airways and / or the lungs, and / or, for example, disorders related to eosinophils of the airways resulting from, or concomitantly with, Ldffler syndrome, eosinophilic pneumonia, parasitic infestation (in particular metazoa-rios) (including tropical eosinophilia), aspergillosis bronchopulmonary, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma, and eosinophil-related disorders that affect the airways, caused by the reaction to drugs. Considering its profile in relation to the inhibition of PDE isoenzymes, in particular its profile as selective inhibitors of type 4, the AGENTS OF THE INVENTION are also useful as inhibitors of PDE type 4, for example for the treatment of the disease involving the calcium depletion in the tissue, in particular bone and joint degenerative diseases involving calcium depletion, especially osteoporosis. In this aspect, they are also useful for the treatment of allergic inflammatory diseases, such as rhinitis, conjunctivitis, atopic dermatitis, urticaria, and gastrointestinal allergies; as vasodilators, for example for the treatment of angina, hypertension, congestive heart failure, and dementia by multiple infarcts; and for the treatment of other conditions wherein the PDE 4 inhibition is indicated, for example depression, conditions and diseases characterized by impaired cognitive function, including Alzheimer's disease, Parkinson's disease, and embolism. Considering your ability to interact synergistically with immunosuppressant and / or antiinflammatory drugs, the AGENTS OF THE INVENTION are also useful as co-therapeutic agents to be used in conjunction with these drugs, for example as enhancers of the therapeutic activity of these drugs, or as a means to reduce the dosage required or the potential side effects of these drugs. The drug substances with which the AGENTS OF THE INVENTION can be co-administered include, for example, immunosuppressive or anti-inflammatory drugs of cyclopeptide, cyclopeptolide, or macrodexid, for example drugs belonging to the class of cyclosporin, example cyclosporin A or G, substances tacrolimus (also known as FK 506), ascomycin and rapamycin, and their different congeners and known derivatives, as well as glucocorticosteroid drugs. The diseases to which this co-therapy can be applied include, for example, any disease or condition requiring therapy with immunosuppressive or anti-inflammatory drugs, for example as described hereinabove. In particular, the AGENTS OF THE INVENTION are suitable for use in co-therapy as mentioned above, for example for the purposes of immunosuppressive, anti-inflammatory, or anti-asthmatic treatment, for example to achieve a cyclosporin-dispersing effect, for example cyclosporin A, macrolide, or steroid. In accordance with the foregoing, the present invention also provides: B. A Method: a) to decrease or inhibit the release of tumor necrosis factor-a, b) to inhibit the activity of the PDE 4 isoenzyme, c) to perform immunosuppression, d) for the treatment of inflammatory disease, e) for the treatment of any particular condition or disease as described hereinabove, in a subject in need thereof, which method comprises administering to this subject an effective amount of a AGENT OF THE INVENTION. The present invention also provides: C. AN AGENT OF THE INVENTION for use as a pharmaceutical product, for example for use in any method or in the treatment of any disease or condition as described hereinabove, for example as defined in A d B above.

The dosages used in the practice of present invention will, of course, vary depending on, for example, the particular disease or condition to be treated, the particular AGENT OF THE INVENTION used, the mode of administration, and the desired therapy. However, it is generally indicated that satisfactory results are obtained, for example for the treatment of diseases as mentioned hereinabove, after oral administration in dosages in the order of approximately 0.01 to 2.0 milligrams / kilogram. In older mammals, for example humans, a daily dosage indicated for oral administration, according to the above, will be on the scale of approximately 0.75 to 150 milligrams, conveniently administered once, or in divided doses of 2 to 4 times at day, or in a sustained release form. The unit dosage forms for oral administration, therefore, suitably comprise from about 0.2 to 75 or 150, eg, from about 0.2 or 2.0 to 50, 75, or 100 milligrams of the AGENT OF THE INVENTION, together with a diluent or a pharmaceutically acceptable vehicle for the same. For use in the treatment of chronic or obstructive airway disease, for example asthma, the AGENTS OF THE INVENTION may also be administered by the inhaled route. Again, the dosages used will vary, for example, depending on the particular disease or condition, the AGENT OF THE INVENTION particular employed, the particular mode of administration (for example, whether by inhalation of dry powder or otherwise), and the desired effect. However, in general an inhaled daily dosage indicated will be in the range of about 2.5 to about 130.0 microgrammes / kilogram / day, for example from about 13.0 to about 60.0 micrograms / kilogram / day. For older mammals, for example humans, a daily dosage indicated to be administered by inhalation, for example in the treatment of asthma, will be on the scale of from about 0.2 to about 10.0 milligrams, for example from about 1 to about 5 milligrams, conveniently given in a single administration, or 2 or 3 separate administrations throughout the day. An appropriate dosage per administration, therefore, will be of the order of about 200 micrograms to about 3.3 milligrams, with administration up to 3 times a day, suitably administered from a dry powder inhalation delivery device in a series of 2. to 8 aspirations in each administration.

The AGENTS OF THE INVENTION can also be administered by any other appropriate route, for example by infusion, for example for the treatment of chogue by endotoxin; nasally, for example for the treatment of rhinitis; ocularly, for example for the treatment of autoimmune diseases of the eyes; dermally, that is, topically to the skin, for example for the treatment of dermatosis or psoriasis; or rectally, for example by means of enema or suppository, for example for the treatment of inflammatory bowel disease. Suitable dosages to be applied by these routes will generally be of the order of 10 to 100 times less than those prescribed for oral administration. Pharmaceutical compositions comprising the AGENTS OF THE INVENTION can be prepared using conventional diluents or excipients and techniques known in the galenical matter. Therefore, oral dosage forms may include tablets, capsules, and the like. Formulations for dermal administration may take the form of creams, ointments, gels, or transdermal delivery systems, for example patches, and in addition to diluents or inert carriers, may adequately contain skin penetration enhancing agents, again as described above. know in the technique. Compositions for inhalation may comprise aerosol formulations or other sprayable formulations, as well as inhalable dry powder formulations, with or without diluent, to be administered by any suitable dry powder inhalation system as is known in the art. For the preparation of dry powder forms for inhalation, the AGENTS OF THE INVENTION are suitably employed in a pharmaceutically acceptable acid addition salt form. This salt form is suitably milled, for example using an air jet or ceramic mill, to provide a finely divided inhalable powder, for example having an average particle diameter of about 2 to 3 microns. Suitably, at least 90 percent of the material will have an average particle diameter of less than 7.8 millimeters, more preferably less than 4.8 microns. In order to ensure obtaining an appropriate and consistent particulate product suitable for administration by inhalation in the form of dry powder, it may be preferable to effect grinding of the active ingredient previously mixed with an appropriate inhalable vehicle medium, for example lactose, under conditions of reduced temperature. Accordingly, the present invention also provides: a pharmaceutical composition comprising an AGENT OF THE INVENTION together with a pharmaceutically acceptable diluent or carrier therefor, for example for use in any method as defined hereinbefore.

Claims (11)

1. An 8-aryl-l, 7-naphthyridine or an N-oxide thereof, in free or salt form.

2. A compound according to claim 1 of formula I: wherein: R. is phenyl, benzyl, 3-nitrophenyl, 3-chlorophenyl, 3-cyanophenyl, 3- (tetrazolyl) phenyl, benzofurazanyl, or benzothiofurazanyl; R 2 is hydroxyl, amino, trifluoromethanesulfonyl, allyl, alkyl, alkenyl, alkynyl, alkoxyl, aryl, aralguilo, aryloxyl, amino, arylamino, diarylamino, alkamino, dialkamino, aralkyl, arylamido, or alcamido, and esters and amides thereof; in free form or salt.

3. A compound according to claim 1, which is a 6- (carboxyphenyl or carboxymethylphenyl) -8- (phenyl, benzo [c] thiadiazolyl d benzo [c] urazanyl) -1,7-naphthyridines, and esters and amides thereof, in free or pharmaceutically acceptable salt form.

4. A compound according to claim 3 of formula II: where: n is zero or one; R7 is hydroxyl, amino, alkenyl of 1 to 4 carbon-amino atoms, or alkoxy of 1 to 4 carbon atoms, preferably hydroxyl or amino; and any of: R3 is H, and R < is nitro, halogen (for example chloro), cyano, or tetrazolyl (for example 1-tetrazolyl), and R5 and R6 together form an additional bond, or R3, R ,, R5, and R6 are together = N-0- N = d = NSN =; and esters and amides thereof; in a free or pharmaceutically acceptable salt form.

5. A compound according to claim 1 or 3 of any of the examples 1 to 33.

6. A compound according to claim 1, for use as a pharmaceutical product. "

7. Pharmaceutical compositions comprising a compound according to claim I.

8. The use of a compound according to claim 1, in the manufacture of a medicament for the treatment of inflammation, particularly inflammatory or obstructive diseases of the airways, for example asthma

9. A process for the preparation of a compound of the formula II, as defined in claim 4, which comprises reacting a compound of formula VI: wherein R3, R4, R1, Rs are as defined in claim 4, and X is a leaving group, with a compound of formula VII: wherein R7 is as defined in claim 4, and X 'is a leaving group, and recovering the compound of the formula II thus obtained in free or salt form.

10. A compound of the formula V: wherein Q 'is halogen, or -O-Alk, wherein Alk denotes an alkyl group of 1 to 8 carbon atoms,

11. A compound of formula VI: wherein R3, R4, R5, R6 are as defined in claim 4, and X is a leaving group. The novel 8-aryl-l, 7-naphthyridines, in free or salt form, are inhibitors of PDE IV, and therefore, they are useful as pharmaceuticals, for example for asthma therapy. Preferred compounds include the compounds of formulas I and II: where the R groups are as defined. Pharmaceutical compositions comprising the compounds, processes for the preparation of the compounds, and novel intermediates for use in the processes are disclosed.