FI78088C - Process for the preparation of 1-phenyl-1,8-naphthyridine-2-one derivatives suitable for chronic lung diseases - Google Patents

Description

78088

The method prepares 1-phenyl-1,8-naphthyridin-2-one derivatives suitable for the treatment of chronic lung diseases. - For the preparation of chronically active compounds with 1-phenyl-1,8-naphthyridine-2-one derivatives.

The present invention relates to a process for the preparation of 1-phenyl-1,8-naphthyridin-2-one derivatives of the formula I which are suitable for the treatment of chronic lung diseases in which Y is hydrogen, hydroxy, benzyloxy, halogen, nitro, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms wherein S is 0 or 1, trifluoromethyl or COOA where A is hydrogen or 1- C 6 alkyl Z is hydrogen, hydroxy, halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms or alkanoyloxy of 2 to 6 carbon atoms;

R 1 is alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 5 to 7 carbon atoms, 2-, 3- or 4-pyridyl, or alkanoyl of 2 to 6 carbon atoms or alkyl of 1 to 6 carbon atoms which may be substituted by hydroxy, halogen or alkanoyloxy of 1 to 6 carbon atoms or alkyl of 1 to 4 carbon atoms substituted by phenyl, 2-, 3- or 4-pyridyl or cycloalkyl of 5 to 7 carbon atoms; R 2 is hydrogen, alkanoyl of 1 to 6 carbon atoms, hydroxyalkyl of 2 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, RaRbN * CH 2) n ~ r where n is an integer from 2 to 6 and Ra and Rb are 1 to 6 alkyl atoms, 78088 provided that when R 2 is hydrogen or alkanoyl, Y is hydrogen, alkyl, alkoxy, CF 3 or NO 2 and Z is hydrogen, halogen, alkyl or alkoxy, then there is no unsubstituted alkyl, their pharmaceutically acceptable acid addition salts, metal salts or with amines, their hydrates and solvates.

Particularly preferred compounds are: 4-acetoxy-1-phenyl-2- (2-propenyl) -1,8-naphthyridin-2 (1H) -one (melting point 195-196 ° C), 4-hydroxy-1- ( 3-methoxyphenyl) -3- (2-propenyl) -1,8-naphthyridin-1 (1H) -one (melting point 200-201 ° C) and its sodium salt; and the sodium salt of 4-hydroxy-1-phenyl-3- (n-butyl) -1,8-naphthyridin-2 (1H) -one (melting point 240-260 ° C).

The compounds of this invention are active in the treatment of allergic conditions such as asthma, bronchitis and the like. Compounds of similar structure are known from Japanese Patent Application No. 116495/77 (Kokai).

The compounds of said Japanese application have been described to have analgesic, anti-inflammatory, central nervous system depressant and diuretic activity. Nowhere in the application is it shown that the compounds have any antiallergic properties. The Japanese application referred to above does not describe or claim any compound wherein R 2 is a pharmaceutically acceptable cation derived from a metal or amine.

According to the present invention, the compounds of formula I can be prepared from known methods for preparing similar compounds, e.g., by the methods described in the above-referenced Japanese application.

3 78088

The compounds of formula I can thus be prepared by a process characterized in that a) for the preparation of a compound of formula I in which R 2 is hydrogen, a compound of general formula II is obtained

aCOOR

NH y (ID

wherein 2 Y and Z are as defined above and R is a suitable leaving group, preferably an alkoxy group, to react with a compound of general formula III

R1CH2COR4 (III) wherein

R 1 is as defined above and R 4 is a leaving group, or b) for the preparation of a compound of formula I having an alkenyl group of 3 to 6 carbon atoms in which the double bond is in the 2,3-position, Claisen is optionally reacted in the presence of an acylating agent.

όγ (IV) i R3 is an alkenyl group having 3 to 6 carbon atoms in which the double bond is in the 2,3-position, and Y and Z have the same meaning as above, and that the compound obtained by methods a or b above in which R2 is hydrogen is attached if desired. as a hydrogen group R 2 · 478088 claims any compound wherein R 2 is a pharmaceutically acceptable cation derived from a metal or amine.

The compounds of this invention can be prepared from known methods for preparing similar compounds, e.g., by the methods described in the above-referenced Japanese application.

The compounds of formula I can thus be prepared by a process characterized in that A: A compound of general formula II

-C0R

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UL

z 5 78088 wherein Y and Z are as defined above and R is any suitable leaving group, preferably an alkoxy group, is reacted with a compound of general formula III

r1ch2cor III

wherein R 1 and R 2 are as defined above; or B: for the preparation of a compound of formula I wherein R 1 is an alkenyl group of 3 to 6 carbon atoms in which the double bond is in the 2,3-position Claisen is converted to a compound of general formula IV wherein R 3 is an alkenyl group of 2 to 6 carbon atoms in which the double bond is 2, In the 3-position, and Y and Z have the same meaning as above, and that the non-hydrogen group R2-6 78088 is optionally added to the compound obtained by Methods A or B above in which R2 is hydrogen.

Reaction A is best carried out by bringing together the reaction components in the presence of a base such as a metal alkoxide, e.g. potassium tert-butoxide, at an elevated temperature, e.g. 60-160 ° C. The reaction is best carried out under an inert atmosphere such as nitrogen. Alternatively, the reaction may be carried out unreacted in the presence of a solvent such as toluene, xylene, etc.

The starting compounds of formulas II and III are either known compounds or can be obtained by methods well known in the art. Compounds of formula II may be prepared by standard methods, e.g. as described in U.S. Patent No. 26,655 (Reissue):

^ n ^ S.h, W

2-Anilino-3-pyrazinecarboxylic acid is a known compound /C.A. 7_5 '20154e (1971) /, and its esters can be prepared by standard methods. Likewise, the compounds of formula III are generally known.

Claisen rearrangement (Method B) can be carried out simply by heating the alkenyl ether of formula IV used as starting material. However, the reaction can also be carried out in an unreacted, high-boiling solvent such as cymene. The compound obtained is then a compound of formula I in which R 2 is hydrogen. However, if the rearrangement is carried out in the presence of a carboxylic acid anhydride, a compound of formula I in which R 2 is a carboxylacyl group is obtained directly.

The conversion of a compound of Scheme I wherein R 2 is hydrogen to a compound wherein R 2 is other than hydrogen can be accomplished by standard methods such as acylation, alkylation, and salt formation. Thus, for example, a compound in which R 2 is 2-propenyl can be prepared by reacting a 4-hydroxy compound with allyl bromide. The acylation can be carried out by generally known methods, e.g. by reacting a 4-hydroxy compound under standard conditions with a reactive derivative of a carboxylic acid (anhydride, halide).

It will be apparent to one skilled in the art that certain groups denoted by groups Y and Z and certain substituents of groups and R 2, etc. may be converted to each other after methods A and B, if desired. For example, the hydroxy group can be converted to halogen by treatment with a halogenating agent, e.g., thionyl halide, etc.

Likewise, a compound in which the acyl, ether or salt function is in the 4-position can be converted by standard reactions to the corresponding compound having a 4-hydroxy group. Thus, for example, a compound having a 4-acyl group can be treated with sodium hydroxide to give a compound in which R 2 is sodium. Further treatment of such a compound with hydrochloric acid affords the 4-hydroxy compound.

Compounds in which R 2 is a cation can be readily obtained by reacting a 4-hydroxy compound with a suitable base or amine or its reactive derivatives.

Example 1 4-Acetoxy-1-phenyl-3- (2-propenyl) -1,8-naphthyridin-2 (1H) -one (A) 4- (2-Propenyloxy) -1-phenyl-1,8-naphthyridine -2 (1H) -one: 37.5 g of allyl bromide are added dropwise with stirring to a mixture of 62 g of 4-hydroxy-1-phenyl-1,8-naphthyridin-2 (1H) -one, 39.6 g of anhydrous potassium carbonate and 1800 ml of acetone. The reaction mixture is refluxed for 22 hours, concentrated in vacuo and the residue is extracted with 600 ml of chloroform. The organic extract is washed with water, 1N sodium hydroxide solution and again with water, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude solid is rotated with 3 x 400 mL of boiling isopropyl ether and filtered to give an insoluble product, 38.5 g, mp 171-174 ° C. Recrystallization from methanol gives the product as a colorless solid, m.p. 176-177 ° C.

(B) 4-Acetoxy-1-phenyl-3- (2-propenyl) -1,8-naphthyridin-2 (1H) -one

A mixture of 33.8 g of 4- (2-propenyloxy) -1-phenyl-1,8-naphthyridin-2 (1H) -one and 35 ml of acetic anhydride is refluxed for 4 hours. The reaction mixture solidifies on cooling. Trituration with isopropyl ether and filtration gives 36.1 g of product as a colorless solid, m.p. 189-195 ° C. Recrystallization from ethanol gives the product of this example, m.p. 195-196 ° C.

Example 2 4-Hydroxy-1-phenyl-2- (2-propenyl) -1,8-naphthyridin-2 (1H) -one

A mixture of 6.0 g of 4-acetoxy-1-phenyl-3- (2-propenyl) -1,8-naphthyridin-2 (1H) -one, 200 ml of ethanol and 40 ml of 1N sodium hydroxide solution is stirred at room temperature. 22 hours. The ethanol is removed in vacuo and the remaining aqueous solution is acidified with 1N hydrochloric acid. The product is filtered, washed with water and dried, 5.3 g, melting point 248-250 ° C. Recrystallization from chloroform gives the product of this example as a colorless solid, mp 250-252 ° C.

9,78088 3- (2-Hydroxyethyl) -4-hydroxy-1-phenyl-1/8-naphthyridin-2 (1H) -one

Under nitrogen, 13.4 g of potassium tert-butoxide are added to a solution of 6.8 g of methyl 2-phenylamino-3-pyridinecarboxylate in 60 ml of ω-butyrolactone. The reaction mixture is heated and stirred for 1 hour at 95 ° C, poured onto ice and stirred overnight. The mixture is extracted with ether, the aqueous layer is acidified with acetic acid to pH 4.5 and the product is recovered by filtration. Recrystallization from chloroform / acetone / isopropanol gives the product of this example as a colorless solid; melting point 235-236 ° C.

Example 3 Sodium and Potassium Salt of 3- (N-butyl) -4-hydroxy-1-phenyl-1,8-naphthyridin-2 (1H) -one A; 3- (n-Butyl) -4-hydroxy-1-phenyl-1,8-naftyridln-2 (1H) -one

To a stirred solution of 9 g of methyl 2- (phenylamino) -3-pyridinecarboxylate in 90 ml of ethyl caproate is added very 7.26 g of potassium tert-butoxide under a nitrogen atmosphere. The reaction mixture is heated for 2 hours at an internal temperature of 140-142 ° C, cooled and the potassium salt is collected by filtration. The crude potassium salt is dissolved in 150 ml of water, acidified with 10% hydrochloric acid and the product is filtered off and dried; weight 9.8 g, melting point 238-239 ° C.

B: 3- (n-Butyl) -4-hydroxy-1-phenyl-1,8-naphthyridin-2 (1H) -one sodium salt 57.9 ml of 1N aqueous sodium hydroxide solution are added to a stirred suspension containing 17.05 g of 3 - (n-butyl) -4-hydroxy-1-phenyl-1,8-naphthyridin-2 (1H) -one and 140 ml of water. Stir for 1 hour at room temperature, cool in an ice bath and filter. The clear filtrate is lyophilized overnight to give the title compound as a monohydrate. It is a cream-colored powder, melting point 240-260 ° C (decomposes).

The corresponding potassium salt is prepared by the method of Example 1 as a monohydrate by replacing the aqueous sodium hydroxide solution with an equivalent amount of aqueous potassium hydroxide solution. The lyophilized potassium salt has a melting point of 215-225 ° C.

Example 5 3- (n-Butyl) -4-hydroxy-1-phenyl-1,8-naphthyridin-2 (1H) -one ethanolamine salt 0.65 g of ethanolamine is added to 3- (n-butyl) -4-hydroxyamine. 1-phenyl-1,8-naphthyridin-2 (1H) -one (2.95 g) in 100 ml of methanol.

The solvent is removed in vacuo and the title compound is precipitated as a colorless salt by the addition of ethyl acetate, mp 228-234 ° C.

The following amine salts are prepared by replacing ethanolamine with the corresponding amine: 3- (n-Butyl) -4-hydroxy-1-phenyl-1,8-naphthyridin-2 (1H) -one-N-methylglucamine salt, m.p. 181-206 ° C.

3- (n-Butyl) -4-hydroxy-1-phenyl-1,8-naphthyridin-2 (1H) -one-diethanolamine salt, m.p. 160-190 ° C.

3- (n-Butyl) -4-hydroxy-1-phenyl-1,8-naphthyridin-2 (1H) -one ethylenediamine salt, m.p. 158-171 ° C.

Example 6 3- (n-Butyl) -4-hydroxy-1-phenyl-1,8-naphthyridin-2 (1H) -one calcium salt 11,780 88

A solution containing 1 g (3 mmol) of the compound of Example 5a is treated with 1.5 ml of 1N calcium chloride solution (1.5 mmol). The resulting cloudy solution is filtered and allowed to stand to form a precipitate. Filter and wash with acetone. The title compound is recovered from water or acetone-water as a pentahydrate, which is a colorless powder, m.p. 350 ° C.

In a similar manner there are obtained: 4-hydroxy-3- (n-pentyl) -1-phenyl-1,8-naphthyridin-2 (1H) -one sodium salt; hydrate (1H2o), mp 245-270 ° C.

3- (n-Butyl) -1- (2,6-dimethylphenyl) -4-hydroxy-1,8-naphthyridin-2 (1H) -one sodium salt, m.p. 270-280 ° C.

Example 7 4-Acetoxy-3- (n-butyl) -1- (4-methylthiophenyl) -1,8-naphthyridin-2 (1H) -one

To a solution of 11.5 g (0.034 mol) of 3- (n-butyl) -4-hydroxy-1- (4-methylthiophenyl) -1,8-naphthyridin-2 (1H) -one (Compound 41 in the table) 150 in 1 ml of acetic anhydride was refluxed for 4 hours and then concentrated to a solid residue which was recrystallized from acetonitrile to give the pure final product (compound 48 in the following table). Yield 9.8 g (75%), melting point: 208-210 ° C.

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Yhd 22 7 8 0 8 8 The compounds of this invention are useful in the treatment of chronic obstructive pulmonary diseases such as asthma, bronchitis and the like, as these compounds have been shown in standard tests to inhibit the release of intermediates such as SRS-A (slow reacting substance of anaphylaxis) and histamine. antagonists of the effect of SRS-A on respiratory tissue. These chronic obstructive pulmonary diseases may be the result of allergic reactions or may have non-allergic causes. The compounds can thus be used to treat allergic diseases and are best used in the treatment of allergic chronic obstructive pulmonary disease. As used herein, chronic obstructive pulmonary disease refers to disease states in which the passage of air through the lungs is blocked or reduced, such as asthma, bronchitis, and the like.

Anti-allergenic activity is identified by assays that measure the extent to which the compound inhibits anaphylactic bronchospasm in sensitized guinea pigs whose SRS-A bronchoconstriction is induced by the antigen. These compounds are orally effective non-adrenergic, non-anticholinergic antianaphylactic agents. When administered orally, they are active at a dosage of about 2 to 100 mg / kg body weight; when administered parenterally, e.g. intravenously, the compounds are active at a dosage of about 1-10 mg / kg body weight.

In in vitro tests, the compounds are antagonistic of leukotriene-induced contractions of lung parenchymal bands. They have been found to be active in these tests as in other tests, as well as in comparison to compounds known to be effective in the treatment of chronic obstructive pulmonary diseases such as asthma or bronchitis. In a preferred antiallergic use, the compound of this invention is used to treat allergic patients by administering an antiallergically effective amount thereof. The allergy treated may be, for example, asthma or some other chronic obstructive pulmonary disease.

Some of the compounds described herein have cytoprotective effects in the gastrointestinal tract.

23 78088

The test results are given below. The effect of some compounds releases the medium SRS-A from the lungs of sensitized guinea pigs in vitro. In experiments, compounds 1-6 correspond to compounds of the invention, compound 7 and 8 correspond essentially to compound IID of U.S. Patent 4,128,694. However, the preparation of this compound is not described in the referenced publication, so two compounds resembling these known substances having a COOR group in the 3-position in the side chain are included in this comparative experiment. In addition, a well-known phenidone compound has been used as a reference.

a5c 6, SRS-A release from the lungs of sensitized guinea pigs in vitro

Inhibition of allergic bronchospasm

Compound Inhi- (%) in vivo (orange. YR 1 R 2 boiling% dose 25 mg / kg) 1 H CH 2 CH 3 H 74 2 H CH 2 CH 2 OH H 58 3 OCH 3 COCH 3 H 58 4 H C 4 H 9 H 70 61 5 H CH 2 CH = CH2 COCH3 59 65 6 OCH3 CH2CH = CH2 H 79 90 7 H CH2COOCH3 H 12

8 H CH2COOH HO

__9 _____________ Phenidone ____________ 41 _____________-_______ 24 7 8 0 8 8

The experimental results show that the potency of compounds 1-6 is considerably higher than that of the reference compounds. The results also show the adverse effect of the C00R group on the effect of the compounds contained in the compounds of U.S. Patent No. 4,128,649.

Claims (1)

A process for the preparation of 1-phenyl-1,8-naphthyridin-2-one derivatives of the formula I which are suitable for the treatment of chronic lung diseases: wherein Y is hydrogen, hydroxy, benzyloxy, halogen, nitro, 1 - alkyl of 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyl of 2 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms-S (O) m in which m is 0 or 1, trifluoromethyl or COOA in which A is hydrogen or alkyl of 1 to 6 carbon atoms Z is hydrogen, hydroxy, halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms or alkanoyloxy of 2 to 6 carbon atoms; R 1 is alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 5 to 7 carbon atoms, 2-, 3- or 4-pyridyl, or alkanoyl of 2 to 6 carbon atoms or alkyl of 1 to 6 carbon atoms which may be substituted by hydroxy11a , halogen or alkanoyloxy of 1 to 6 carbon atoms or alkyl of 1 to 4 carbon atoms substituted by phenyl, 2-, 3- or 4-pyridyl or cycloalkyl of 5 to 7 carbon atoms; R 2 is hydrogen, alkanoyl of 1 to 6 carbon atoms, hydroxyalkyl of 2 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, RaRbNtcH 2> n '' where n is an integer from 2 to 6 and Ra and Rjj are alkyl of 1 to 6 carbon atoms, provided that when R 2 is hydrogen or alkanoyl, Y is hydrogen, alkyl, alkoxy, CP 3 or NO 2 and Z is hydrogen, halogen, alkyl or alkoxy, then R 1 is not unsubstituted alkyl and their pharmaceutically acceptable acid addition salts , salts with metallic or amines, their hydrates and solvates, characterized in that a) for the preparation of a compound of formula I in which R 2 is hydrogen, a compound of general formula II - COOR N j ^ v (II) in which z Y and Z have the same meaning as above and R is a suitable leaving group, preferably an alkoxy group, to react with a compound of general formula III R 1 CH 2 COR 4 (III) wherein R 1 is as defined above and R 4 is a leaving group, or b) a compound of formula I wherein R 1 is 3 -6 carbon atoms to prepare an alkenyl group in which the double bond is in the 2,3-position, Claisen is optionally reacted in the presence of an acylating agent with a compound of general formula IV 78088 OR 1 -NN 0 (IV) wherein R 3 is an alkenyl group of 3 to 6 carbon atoms in which the double bond is in the 2,3-position, and Y and Z have the same meaning as above, and that the compound obtained by methods a or b above wherein »2 is hydrogen is esterified or etherified, if desired, to add a non-hydrogen group R2, and that the compound of formula (I) is optionally isolated with a pharmaceutically acceptable salt . 28 78088 For the preparation of a chlorine, a compound of the formula 1-phenyl-1,8-naphthyridin-2-one derivative with the formula 1-phenyl, benzylloxy, halogen, nitro, 1 -6 kolatoms a.lky.1, 1-6 kolatoms alkoxy, 2-6 kolatoms alkanoyl, 1-6 kolatoms alkyl-S (0) m, from 0 to 1, 1 from trifluoromethyl or CooA, from A to 1 -6 collations alkyl; For example, hydroxy, halogen, 1-6 carbon atoms alkyl, 1-6 kolatoms alkoxy, 1-6 kolatoms hydroxyalkyl or 2-6 kolatoms alkanoyloxy; R 2 is 2-10 kolatoms alkenyl, 2-6 kolatoms alkynyl, 5-7 kolatoms cycloalkyl, 2-, 3- or 4-pyridyl, or 2-6 kolatoms alkanoyl •: or 1-6 kolatoms alkyl, which may be substituted with hydroxy, halogen or 1-6 carbon atoms with alkanoyl.i or 1-4 carbon atoms with substituents on phenyl, 2-, 3- or 4-pyridyl or 5-7 · ': cycloalkyl; R2 is a derivative, 1-6 kolatoms alkanoyl, 2-4 kolatoms hydroxyalkyl, 2-6 kolatoms alkenyl, 2-4 kolatoms alkynyl, RqR ^ N (C1-4) n, där n är ett helt or 2-6 och Ra and Rb är 1-6 kolatoms alkyler, förutsa11, atr. and R 2 is an alkanoyl, Y is an alkyl, alkoxy, CF 2 or NC> 2 and Z is a halogen, alkyl or alkoxy, R 7 is 78088 alkyl; in the case of a pharmaceutical compound with a heat transfer medium, a salt with a metallic or an amine, a hydrate or a salt, an entry for the purpose of Figure I, a mixture of the compounds of formula II, (II) wherein Y and Z are selected from the group consisting of the same group of compounds as the group consisting of reactants with the same group of formulas III R1CH2COR4 (III) of the same group with the same group of R a group, or b) for the preparation of a compound of formula I, having a value of 3-6 carbon atoms in the group, of which the double-stranded mixture is 2,3-membered, and> all form IV