DE2322350A1 - 1,8-NAPHTHYRIDIN-2 (1H) -ONE DERIVATIVES AND METHOD FOR THEIR PRODUCTION - Google Patents

Description

The present invention relates to 1,8-naphthyridin-2 (1H) -one derivatives and methods of making them.

The new compounds according to the invention have the general. Formula I.

(I)

c 7
in which R and R can be the same or different substituents and are each a hydrogen atom, a lower alkyl radical with 1 to 5 carbon atoms, a halogen-substituted C., «- -alkyl radical, preferably a trifluoromethyl or pentafluoroethyl group, or a phenyl, halophenyl (in particular

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Chlorine or fluorophenyl), benzyl, napithyl, pyridyl or thienyl group, R- * denotes a hydrogen atom or an -NHp-, -NH (C _1-5 -AlCyI) -, -N (C _1-5 -AIlCyI) ₂ -, -NHC- (C _1-3 -AIlCyI) -, pyridyl-,

-CO ₂ H- or -CO ₂ (C _1-5 -AIlCyI) -GrUpPe and R represents a hydrogen atom, an amino, -NHC- (Cj, -alkyl) -, pyridyl, imidazolyl or indolyl group or a Another mono- or "bicyclic N-heterocyclic radical, for example a diazine radical (such as a pyrimidinyl, pyridazinyl or pyrazinyl group), and at least one of the radicals R and R is a nitrogen-containing substituent of the type defined above.

The derivatives shown above as 2-oxo compounds are Keto-enol tautomers with the general formulas Ia and Ib

γ
H -, Ε «, R ^{5 5} YE ³ J-R3 N

(Ia) (Ib)

However, since the keto form is viewed as the more stable tautomer the compounds are referred to herein as 2-0xo compounds and described. However, those skilled in the art will recognize that both tautomers may exist or that any particular one Compound designated as enol - or in the manner mentioned Hydroxytautomeres can occur and the following description is to be taken to include all tautomeric forms .

Experimental glass tests have shown that the naphthyridine derivatives according to the invention increase the contents of cyclic adenosine-3 ¹ , 5 * - -mo no phosphoric acid (cyclic ATIP). Animal studies have also shown that these derivatives inhibit bronchoconstriction induced by histamine and other constricting agents. The new compounds are therefore suitable as bronchodilators. It has been found that the compounds of the invention as such

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Bronchodilators have a relatively low chronotropic effect compared to known agents of this type. In addition, the compounds have hypotonicity based on their effectiveness as peripheral vasodilators
Properties and are therefore suitable for the treatment of high blood pressure. Since the compounds according to the invention can be used both in the form of the free bases and of acid addition salts, the invention extends to both these forms.

The 1,8-naphthyridin-2 (1H) -one derivatives according to the invention are advantageously produced by one of the processes explained below:

Procedure I.

OR ⁶ O
c tt t ti 7
IT-C-CH-CR '- N. R ^5
R Vvv ³
R% A _n ^ -NH ₂ B. 7th C.
YHNO ₂
e ⁶ A \ e ³
H

3 -

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Procedure II

NH

OR ⁶ O
⁵ C-CHCR ⁷

2 (AIkO-C-CH ₂ CO ₂ AIk) + R ⁵ -C-CH-CR

CO _? Alc

R-

R-

CONHNH,

Y ° 3 ^{/ Glyko1} \ M ₂ G0 / Glycol

R ³ CH ₀ CO ₀ AIk R

CHO
2

acid

Na hydride +

Triethylphosphate

phonoacetate

In process I, the implementation of the 2,6-diaminopyridine (A) gives with the appropriate ß-diketone (B) the 2-araino-1,8-naphthyridine-. -Derivatives (C), which give the desired 2-oxo compound of the general formula I after reaction with nitrous acid.

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The first stage of the reaction is by heating to the boiling point promoted, although in practice it has been found that working conditions with lower temperatures (up to 90-95 ° C.) are useful be created.

The traditional method of converting 2-amino-1,8-naphthyridine derivatives to the corresponding 2-oxo compound using dilute sulfuric acid and sodium nitrite for the production of most 2-oxo derivatives. For the compounds according to the invention which have one on the naphthyridine nucleus bound trifluoromethyl or pentafluoroethylene have substituents, it was found to be unusable. However, it has been found that the conversion of the 2-amino group ■ to the 2-oxo group in these compounds (as well as in all C-Zwi-. selenium compounds) with the help of trifluoroacetic acid or pentafluoropropionic acid and an alkali nitrite, expediently sodium or potassium nitrite, the corresponding 2-oxo compound in good yield can be achieved. The conversion takes place rapidly at room temperature; however, you can also warm it slightly.

Process II involves reacting the appropriate β-diketone (B) with at least two equivalents of a lower-alkyl-lower-alkoxycarbonylacetimidate (D). It is not decisive which particular alkyl or alkoxy radical is present, since these radicals are then split off during the production of the end products. The resulting alkyl 2-arainonicotinate (E) is converted into the corresponding hydrazide (F) by heating with hydrazine. Reaction of the hydrazide with a sulfonyl halide such as toluenesulfonyl chloride or benzenesulfonyl chloride gives the N-sulfonyl hydrazide derivative (G). This intermediate product can be reacted with a compound of the general formula R - ^ - GH ₂ CO ₂ alkyl to give the desired end product of the general formula I in the presence of glycol, 1, A-diazabicyclo / ^, 2.2v ^{7 octane and anhydrous alkali metal carbonate.} It may sometimes be more convenient to first prepare the N-sulfonyl hydrazide (G) by heating in the presence of glycol and an alkali carbonate (M ₂ CO,), preferably

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Sodium or potassium carbonate, into the corresponding aldehyde (H) convict. The 2-aminonicotinaldehyde obtained in this way can then be converted into the desired one by one of the following two methods End product of general formula I can be converted:

A) You can the aldehyde in the presence of piperidine or another conventional base catalyst with an ester of the general. React formula R CHpGOpAlkyl, in a suitable solvent, such as ethanol, and advantageously with heating the reaction mixture operates at the reflux temperature; or

B) the aldehyde can first be obtained by combining it with sodium hydride and triethylphosphonoacetate at room temperature in the Convert alkyl 3 ~ (3-pyridyl) acrylate (J) and then the desired end product of the general formula I by boiling with concentrated mineral acid (preferably hydrochloric acid) under Generate reflux.

When R is an amino, mono- or dialkylamino or acylamino group is, the compounds in question are preferably prepared from the 3-nitro-1,8-naphthyridin-2 (1H) -one derivatives of general formula I by conventional reduction methods, which yield the 3-amino derivative. This can then be done according to known Methods are alkylated or acylated.

For the preparation of the acid addition salts of the 1,8-naphthyridine-2 (iH) - obtained by any of the aforementioned methods -On derivatives one dissolves either the free base in a corresponding one Acid-containing aqueous or aqueous-alcoholic solution and isolates the salt by evaporating the solution. Man can also react the free base with the acid in question in an organic solvent, the salt separating out directly or can be obtained by concentrating the solution. The preferred salts are pharmacologically acceptable salts, which are mainly from mineral acids, such as hydrochloric, hydrobromic, hydroiodic, phosphoric or sulfamic acid, or from organic acids such as vinegar, lemon, wine, methanesulfone, Benzenesulfonic or p-toluenesulfonic acid, derive. Although medical compatible salts are preferred, extends the

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Invention on all acid addition salts, since salt forms of the most varied kinds are used for the purpose of purification or identification produce or sometimes use a salt as an intermediate in the production of a medically acceptable salt Can use ion exchange processes.

The following examples provide a more detailed explanation of the reaction conditions used in the various processes are used for the preparation of the compounds according to the invention, and describe the preparation of certain compounds the invention.

example 1

6-Amino-5 ^ -dimethyl-1 »8-naphthyridin-2 (iH) -one Stage A: Production of ethyl-amino-S-acetamido- ^ fi-dimethyl nicotinate

One erhitet a mixture of 67.7 g (0.431 mol) of 3-Ac et amidop entan-2,4-dione and 137.1 g (0.862 mol) Äthyläthoxycarbonylacetimidat overnight at 100 ⁰ C. The reaction mixture solidified upon cooling partially · The solids are isolated, suspended in 40 ml of isopropanol and filtered again. The filter cake is washed with 20 ml of isopropanol. This gives 45.3 g (yield 41.8 j>) of a product of mp. 168.5 bie 170 ⁰ C. This gives a product after recrystallization from chloroform, mp. 169-170 ⁰ C.

C. H N ber .: 57.36 6.82 16.72 found: 57.02 6.90 16.81

Level B; Production of 2-alnino-5-acetamido-4t6-dimethylnico-

tic acid hydrazide

One erhitBt a mixture of 45.3 g (0.18 mol) of ethyl 2-amino-5-acetamido ^ je-dimethylnicotinate and 100 ml of hydrazine hydrate at an oil bath with stirring for 2 hours at 120 ⁰ C. The mixture is cooled and the mixture isolates the solid parts. A second yield of solid is obtained by bringing the mother liquor to about

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constricts half of its initial volume. The combined solids melt at 293 ° C. (decomposition); yield 38.1 g (89 <fi) . The analytically pure compound is obtained by dissolving the solid product in about 6.5 parts (parts by weight / parts by volume) of hot water and the filtered solution is diluted with methanol and the purified product decomposes at about 309 ° C. with only partial melting.

50 C. 6th H N 51 ber .: 50 , 62 6th , 37 29 60 found: , 84 , 60 29

Step C: Preparation of N - (2-Amino-5-acetamido-4,6-dimethyl-

nicotinoyl) -N -benzo! sulfonylhydrazine

31.1 g (0.16 Moles) benzenesulfonyl chloride. After about 45 minutes the acid chloride disappears; the maximum temperature reached by the reaction mixture is 36 C. The product is caused to precipitate by pouring the reaction mixture into a stirred solution of 8.3 ml of acetic acid in 250 ml of water. The product is isolated, slurried in 150 ml of Y / water, filtered again and dried. 49.52 g (yield 90 fo) of crude product of melting point 216 to 218 ^° C. (evolution of gas) are obtained. After purification by dissolving in hot (100 ° C.) dimethylformamide, filtering and diluting with methanol (1 part) and water (3 parts), the product melts at 233 to 234 ° C. (decomposition).

CHNS

C ₁₅ H ₁₉ N ₅ O ₄ S; calc .: 50.92 5.07 18.56 8.48 found: 51.24 4.97 18.76 "8.75

Stage D: Preparation of 2-amino-5-acetamido-4,6-dimethyl-

nicotinaldehyde

The mixture is heated 80 ml ethylene glycol in an oil bath at 17O ⁰ C for as long reaches 16O ⁰ C until the internal temperature. Then 8 g (21.2 mmol) of N - (2-amino-5-acetamido-4,6-dimethylnicotinoyl) - -N -benzenesulfonylhydrazine are added and the mixture is stirred so long

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until the internal temperature has again reached a value of 16O ⁰ , then 5.6 g of anhydrous sodium carbonate are added all at once, the mixture is heated for a further 30 seconds and the reaction mixture is then rapidly cooled and poured into 320 ml of Y / ater a. The product is isolated by continuous extraction with methylene dichloride for about 24 hours, after which 2.9 g (yield 66 fo) of crude product are obtained. After purification by crystallization from ethanol, the pure compound melts at 270 to 275 ° C (decomposition) with rapid heating.

CHN 0

C ₁₀ H ₁₃ N ₃ O ₂ ; calc .: 57.96 6.32 20.28 15.44 found: 57.83 6.46 20.44 15.26

Stage Et Preparation of ethyl 3- (2-amino-5-acetamido-4,6-

-dimethylpyrid-3-, yl) acrylate

A suspension of 600 mg (25 mmol) of NaH in 40 ml of anhydrous ethylene glycol / hemethyl ether is added dropwise with stirring and Cooling in an ice bath with a mixture of 5.6 g (25 mmol) of triethylphosphonoacetate in 10 ml of anhydrous ÄiiiylengTykoldimethylä-üier. When the addition is complete, the reaction mixture is stirred at room temperature until all of the sodium hydride reacts Has. 4.14 g (20 mmol) of finely powdered 2-amino-5-acetamido-4,6-dimethylnicotinaldehyde are then added in the form of small portions over the course of 30 minutes with stirring and cooling. The mixture is then stirred for 72 hours at room temperature, after which time the crude product is isolated, washed with a small amount of a 1: I ethanol / acetonitrile mixture and dried. You get 4.93 g (yield $ 90.5) of product of pp. 204 bis 2O5 ° C. After recrystallization from acetonitrile, the pure Compound obtained at bp 204.5-205.5 ° C.

C ₁₄ H ₁₉ N ₃ O ₃ ; ber .:
found:

Stage P: Preparation of 6-amino-5,7-dimethyl-1,8-naphthyridine

-2 (1H) -one

The mixture is heated 2.48 g (8.95 mmol) of ethyl 3- (2-amino-5-acetamido-

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C. 63 H 91 1 N 1 5 60, 85 6, 90 1 5, 1 2 60, 6, 5,

JO

-4,6-dimethylpyrid-3-yl) acrylate, which is dissolved in 24.8 ml of 6 η hydrochloric acid, under reflux for 6 days. The reaction mixture is then filtered through a glass fiber filter disc and the piltrate is slowly diluted within 15 minutes with 75 ml of ethanol. Then 1.043 g (yield 51.7 %) of a product in the form of the hydrochloride (melting point 325 ° C.; decomposition) crystallize out of the solution. The yield increases by a second product fraction obtained to 79 ° C. After recirculation of the crude product from a mixture of dilute hydrochloric acid and isopropanol, the pure compound is obtained with a melting point of 325 ° C. (decomposition).

ber. •
• B. C. H 2 1 Cl N .HCl; found •
• 53.22 5.36 1 5.71 18.61 53.28 5.80 5.79 18.62 e i s ρ i e 1

3-Amino-5 «7-dimethyl-1,8-naphthyridin-2 (1H) -one hydrochloride, stage A; Preparation of 2-amino-4 »6-dimethylnicotinic acid hydrazide 42.5 g (0.219 mol) of ethyl 2-amino-4,6-dimethyl nicotinate and 62 g of 85 percent hydrazine hydrate are stirred together at 120 to 130 ° C. overnight. The excess hydrazine hydrate is distilled off under reduced pressure, the residue is suspended in isopropanol and filtered off. This gives 35.8 g (yield, 90 56) of a product of mp. 170 to 175 ⁰ C. The Umkristaliisation from isopropanol to provide a compound of mp. 174 to 176 ° C.

53 C. H 71 N 09 ber .: 53 , 32 6, 87 31, 94 found: , 37 6, 30,

1 2

Stage B: Preparation of N - (2-Amino-4,6-dimethylnicotinoyl) -N -

-benzo1sulfonylhydrazine

A solution of 127 g (0.69 mol) of 2-amino-4,6-dimethylnicotinic acid hydrazide in 1.655 liters of 1 η sodium hydroxide solution is treated with 134 g (0.76 mol) of benzenesulfonyl chloride and the mixture is stirred at room temperature up to Formation of a clear yellow solution. Then pouring the reaction mixture into a stirred solution of 41.5 ml of acetic acid in 1.73 liters of water and adjusts the _pH value of the overall

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mix by adding more acetic acid to about 6.5 em. The solid fractions are isolated, washed with water and dried. 203 g (yield 92 fo) of a product with a melting point of 162 ° to 166 ° C. are obtained. After recrystallization from isopropanol, a product is obtained which contains 1 mol of isopropanol from the crystallization and partially ^{melts at about 105 °} C .; the final melting point is 165 to 167 ° C.

The same product is obtained if the reaction with benzenesulf onyl chloride in pyridine.

CHNS

C ₁₄ H ₁₆ N ₄ O ₃ SC ₃ H ₈ O; calc .: 53.67 6.36 14.72 8.42

found: 53.50 6.16 15.11 8.52

Step C: Preparation of 2-amino-4 _t 6-dimethylnicotinaldehyde

62 g (0.163 mol) of N - (2-amino-4,6-dimethylnicotinoyl) - are divided

2
-N -benzenesulfonyl-hydrazine-isopropa.nolate in two halves.

300 ml of ethylene glycol are added to each half and the resulting mixture is heated to 160 ° C. Then 30 g of anhydrous sodium carbonate are added all at once with vigorous stirring. The mixture is allowed to cool and then poured into water. The two batches are combined and the product is isolated by extraction with chloroform. After recrystallization from carbon tetrachloride, 152 a product is obtained, mp. 158 to ⁰ C. A further recrystallisation from the same solvent of the melting point to 162-166 ⁰ C is increased.

C. 98 H 71 N 65 ; ber .: 63, 69 6, 69 18 54 found: 63, 6, 18

Step D: Preparation of 3-nitro-5,7-dimethyl-1,8-naphthyridine

-2 (1H) -one

A mixture of 2.4 g (16 mmol) of 2-amino-4,6-dimethylnicotinaldehyde is boiled, 5.12 g (32 mmol) of ethyl nitroacetate, 336 mg (4 mmol) of piperidine and 4 ml of ethanol for 1 hour with stirring and Reflux. The mixture is then cooled and treated with petroleum ether. The solid fractions are filtered off and

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Jt

recrystallized from methanol. One gets hurt-c 1.55 g (yield 44 $) of a product from the Pp. 270-272 ⁰ C (decomposition). After recrystallization from the same solvent, a product of pp. 272 to 274 ^° C. (decomposition) is obtained.

C HN

C ₁₀ H ₉ N ₃ O ₃ ; calc .: 54.79 4.14 19.17 f.r 54.68 4.26 19.11

Stage Et Preparation of 3-Amino-5t7-dimethyl-1,8-naphthyridine

-2 (1H) -one hydrochloride

6 g (27.4 mmol) of 3-nitro-5,7-dimethyl-1,8-naphthyridin-2 (1H) -one are suspended in 250 ml of acetic acid and hydrogenated the compound at a pressure of about 3.5 kg / cm in the presence of 250 mg Platinum oxide. After the theoretical amount or a slight excess of hydrogen has been absorbed, the Catalyst off, the piltrate is boiled with activated charcoal and filtered again. The solvent is then under reduced pressure evaporated and the residue converted into the hydrochloride by treatment with ethanolic hydrochloric acid. By recrystallization of the product from methanol containing activated carbon is obtained 6.3 g (theoretical yield) of a product, which after further Recrystallization from methanol at 306 to 3O9 ° C melts.

C. 22nd H 36 Cl 71 N 61 ber .: 53 18th 5, 58 15, 45 18 82 found: 53 5, 15, 18

The compounds listed in Table I are by the method of Example 1 (stage A), using the equivalent instead of the 3-acetamidopentane-2,4-dione used there Amount of the ß-diketone indicated in Table I was used. By using the nicotinate obtained in this way instead of the in example 2 (step A) used nicotinate is used and then according to the in example 2 (steps A to E) described

If 7 methods work, the 3-amino-5-R-7-R -1,8-naphthyridin-2 (1H) -one compounds are obtained with those shown in Table I.

5 7
Substituents R and R.

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Tabel

NH 2-CO ₂ C ₂ H ₅ ) + t
H R ⁵ 0 0 2 (C ₂ H ₅ OC-CH R ⁵ p-pluo rphenyl _Ώ 5 Ά „ττ Ά τ> 7 Example K. Isopropyl H- 2-naphthyl VJl R ⁷ - Xthyl / Example 2 HT ^ lKJO _n C _n Ht: Xthyl Wen AE _H 7-L Jl _1n / ⁵
ti c. Example no. Isopropyl 3 n-propyl 4th Phenyl p-pluo rphenyl VJl Benzyl Isopropyl 6th tert-butyl 2-naphthyl 7th Xthyl Xthyl 8th Isobutyl methyl 9 Isopropyl Xthyl 10 2-naphthyl n-propyl 11 Isopentyl methyl 12th Phenyl methyl 13th 3-pyridyl Trifluoromethyl 14th 2-thienyl Trifluoromethyl —Ι
VJl By S Trifluoromethyl 16 3-acetamido-5,7-dimethyl-1, Trifluoromethyl 17th Trifluoromethyl 18th Trifluoromethyl 19th Trifluoromethyl 20th Trifluoromethyl Trifluoromethyl ρ i e 1 21 8-naphthyridin-2 (1H) -one

660 mg (3 mmol) of according to Example 2 (steps A to D) produced 3-nitro-5,7-dimethyl-1,8-naphthyridine

-2 (1H) -one in 25 ml acetic acid at a pressure of about 3 »5 kg / cm

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in the presence of 30 mg of platinum oxide, the hydrogenation is after. finished about 90 minutes. Acetic acid is added to the solution of the white pesticide suspended in the reaction mixture and the solution is heated until the solid fraction has completely dissolved. The catalyst is then filtered off and the filtrate, after treatment with activated charcoal, is filtered again while hot. After evaporation of the Piltrats obtained 400 mg of a product which after recrystallization from ethyl acetate at 244-246 ⁰ C melt (after sintering at 224 ⁰ C). The solid product is redissolved in hot ethyl acetate, a small amount of anhydrous potassium carbonate is added to neutralize the acetic acid, and the mixture is filtered. After cooling, 220 mg of a product with a p.p. 248 to 251 ^° C. is obtained.

CH N

C ₁₂ H ₁₃ N ₃ O ₂ ; calc .: 62.33 5.67 18.17 found: 62.26 6.00 18.03

By replacing the 3-nitro-5,7-climethyl -— 1 _t 8-naphthyridin-2 (1H) -one used in Example 21 with the equivalent amount of the 3-nitro intermediates of the compounds of Examples 3 to 20 (in each case replaced by the methods of example 1, stage A, and example 2, stages A to D), the 3-acetamido derivatives of the compounds of example 3 to 20 are obtained in each case.

Example 22

3-Isopropylamino-5 »7-dimethyl-1,8-naphthyridin-2 (1H) -one hydrochloride

378 mg (2 mmol) of 3-amino--5,7-dimethyl-1,8-naphthyridin-2 (1H) -one obtained according to Example 2 are dissolved in 50 ml of acetic acid with an acetone content of 1.2 ml and hydrogenated the mixture at a pressure of about 3.5 kg / cm in the presence of 55 mg of platinum oxide. The reaction mixture is filtered, the piltrate is evaporated to dryness and the residue is treated with ammonium hydroxide. This gives 340 mg (yield 74 ° C.) of a product which is converted into the hydrochloride by treatment with ethanolic hydrochloric acid. After recrystallization of the product from isopropanol, 240 mg (yield 45 $>) of the product are obtained in the form of the hydro-

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/ Γ

chloridsi pp. 238 to 24O ⁰ C (after sintering >> ei 205 ⁰ C).

C H Cl N ■

C ₁₃ H ₁₇ N ₃ O.HCl; calc .: 55.31 6.78 13.24 15.69 - found: 57.98 6.88 12.99 16.04

By using the 3-amino-5,7-dimethyl-1,8-naphthyridin-2 (1H) -one used according to Example 22 replaced in each case by the equivalent amount of the compounds from Example 3 to 20 and after If the method of Example 22 works, the 3-isopropylamino derivative of the compounds of Example 3 is obtained in each case until 20.

Example 23

3-dimethylamino-5 , 7-dimethyl-1,8-naphthyridin-2 (1H) -one hydrochloride

438 mg (2 mmol) of 3-nitro-5,7-dimethyl-1,8-naphthyridin-2 (1H) - -one obtained according to Example 2 (steps A to D) are suspended in a mixture of 5 ml of ethanol and 25 ml of acetic acid. 0.9 ml (10 mmol) of formaldehyde solution are added and the mixture is hydrogenated at a pressure of about 3.5 kg / cm in the presence of 10 # palladium on activated carbon (300 mg) until no more hydrogen is absorbed. The solution is filtered and evaporated to dryness and the residue is dissolved in a small amount of methanol. A small excess of ethanolic hydrochloric acid is added to the solution obtained. By anhydrous ether, the hydrochloride of the product (mp. 230 bie 235 ⁰ C) brought to precipitation}, the yield is 400 mg (79 ¹ Pl. After recrystallization from isopropanol the monohydrochloride melt of the product at 232 to 235 ° C

C H Cl N

C ₁₂ H ₁₅ N ₃ CHCl; calc .: 56.80 6.36 16.56 13.97

found: 57.24 6.43 16.12 13.71

By using the 3-nitro-5,7-dimethyT-1,8-naphthyridin-2 (1H) -one used according to Example 23 in each case by the equivalent amount of the 3-nitro intermediate of the compounds of Example 3 to 20 and following the method of Example 23

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works, one receives in each case the 3-üimexnylarainodexuvat of the compounds of Example 3 to 20.

Example 24

6- (4-pyridyl) -1 _t 8-naphthyridin-2 (1H) -one hydrochloride Stage A: Production of 2-amino-6- (4-pyridyl) -1 _t 8-naphthyridine dihydrochloride

The mixture is stirred a mixture of 4 "76 mM 2,6-diaminopyridine, 4.8 mmol 2- (4-pyridyl) -propan-1,3-dione and 50 ml of phosphoric acid 85prozentiger 6 hours oil bath at 90 to 95 ⁰ C and then let it stand overnight at room temperature. The mixture is then poured into ice water and neutralized with ammonium hydroxide to a p n value of 7. The solid components are isolated, washed with water and dried. A product is obtained (yield 57 #), that of the Dihydrochloride from methanol to 35O ⁰ C does not melt by crystallization in shape.

C. 89 H 09 N 98 Cl 02 ber .: 52, 01 4, 34 18 85 24, 06 found: 53 4, 18 24,

Stage Bt Production of 6- (4-pyridyl) -1,8-naphthyridin-2 (1H) -

-on-hydrochloride

16.95 mmol of 2-amino-6- (4-pyridyl) -1,8-naphthyridine are dissolved in 50 ml of trifluoroacetic acid and the stirred solution, cooled in an ice bath, is treated with 3 g (43.5 mmol) of finely powdered sodium nitrite in the form of small portions . Stirring is continued for one hour at room temperature, the mixture is then poured into water containing pieces of ice (about 500 ml), the solid product is filtered off and dried in an oven at 50 C. 1.7 g are obtained (yield 39 #) ) Product which melts in the form of the hydrochloride above 35O ⁰ C (after crystallization from methanol).

C H Cl N

C ₁ , H ₉ N ₃ O.HCl; calc .: 60.12 3.88 13.65 16.18 found: 60.29 4.28 13.87 16.32

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Example 25

3- (4-Pyridyl) -5 , 7-dimethyl-1, 8-naphthyridin-2 (1H) -one hydrochloride Using the procedure of Example 2 (Step D), but using the equivalent amount of methyl instead of the ethyl nitroacetate -4-pyridylacetate employed and the boiling under stirring and reflux continued for 48 hours, a product is obtained, which of the hydrochloride from methanol at 306 melts after recrystallization in the form of 31o C ⁰ in 55prozentiger yield.

•
• B. C. 61 H 26th 1 Cl 1 N 60 ber. •
• 62, 30th 4.90 1 2.32 1 4, 72 found 62, P i 4.50 2.08 4, ice cream e 1

3- (3-Pyridyl) -5,7-dimethyl-1,8-naphthyridin-2 (1H) -one hydrochloride Using the procedure of Example 2 (step D), but instead of ethyl nitroacetate, ethyl 3- pyridyl acetate is used and the refluxing continues for 72 hours, a product is obtained in 35 percent yield which, after purification, melts ^{in the form of the hydrochloride by recrystallization from a methanol / diethyl ether mixture at 297 to 301 ° C.}

C H Cl N

C ₁₅ H ₁₃ N ₃ O-HCl; calc .: 62.61 4.90 12.32 14.60

Found: 62.43 4.88 12.45 14.76

Example 27

3- (2-pyridyl) -5,7-dimethyl-1,8-naphthyridin-2 (1H) -one-hydro chloride Using the procedure of Example 2 (stage D), but using ethyl instead of the nitroacetate used there -2- pyridyl acetate is used and the refluxing continues for 72 hours, a product is obtained in 37 percent yield which, after purification, melts in the form of the hydrochloride by recrystallization from methanol at 270 to 273 ° C.

C ₁ , -H ₁₃ N ₃ O.HCl; calc .: 62.61

found: 62.38

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H 90 1 Cl 1 N 60 4, 07 1 2.32 1 4, 53 5, 2.16 4,

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Example 28

Ethyl ^ -acetamido-S ^ -dimethyl-i, 8-naphthyridin-2 (1H) -one-3- ~ carboxylate

By according to Example 2 (stage D) the 2-amino-4,6-dimethylnicotinaldehyde or the ethyl nitroacetate by the equivalent amounts of 2-araino-5-acetamido-4,6-dimethylnicotinaldehyde (prepared according to Example 1, stage D) or Replacing diethyl malonate and otherwise working essentially according to the method described in stage D of Example 2, after 17 hours of refluxing under reflux in 87 percent yield, a product is obtained which separates out after recrystallization from a chloroform / carbon tetrachloride mixture with 1 mol of water of crystallization; Mp. 231 to 232 ⁰ C.

CHN

C ₁ 5 H ₁₇ N ₃ O ₄ .H ₂ O; calc .: 56.02 5 _? 63 13.31

found: 56.06 5.93 13.08

Example 29

6-Acetamido-5 _t 7-dimethyl-1 _t 8-naphthyridin-2 (1H) -one-3-carboxylic acid 321 mg (1 mmol) of ethyl 6-acetamido-5,7-dimethyl prepared according to Example 28 are dissolved 1,8-naphthyridin-2 (1H) -one-3-carboxylate in 2 ml of water to which 0.28 ml of 40 percent (w / w) potassium hydroxide solution was added. The clear solution is heated in a steam bath for 2 hours, cooled and acidified with dilute acetic acid up to a Ρττ value of 5.5. At the beginning a gelatinous precipitate is formed, which becomes denser and more crystalline when standing at room temperature. The product is isolated, washed with water and dried. This gives 195 mg (yield $ 66) of product with a melting point of 305 ^° C. (decomposition), which is purified by dissolving in dilute ammonium hydroxide solution, treating with activated charcoal and reprecipitation with acetic acid; the melting point does not change.

C ₁₃ H ₁₃ N ₃ O ₄ ; ber .: found .:

56, 72 18th 4th , 76 1 5 , 27 56, 53 4th , 72 1 5 ,H _

309847/1 129

/ R

Example 30

3-C4-pyridyl) -5,7-di- (trifluoromethyl) -1,8-naphthyridin-2 (1H) -.on Level A; Production of ethyl-2-amino-4,6-di- (trifluoromethyl) - nicotinate

59.6 g (0.375 mol) of ethyl ethoxycar bo nylac et imidate are added slowly within 15 minutes with 39 g (0.188 mol) of 1,1,1,5,5,5-hexafluoroacetylacetone while stirring and cooling in an ice bath. The mixture is stirred for 15 minutes at room temperature and then in an oil bath at 105 to 110 ° C. for 20 hours. The contents of the flask are then distilled and the fraction with a boiling point of 65 to 88 ° C./0.5 mm is collected. The product fraction that solidifies in the cooler and in the upper part of the bladder can be scraped out and added to the semi-solid product in the receiver. The solid product is freed from the oily components by filtration, washed on the filter with a little cold ethanol and collected. This gives 10.44 g (yield 18.6 $>) of product of melting point 84 to 86 ⁰ C. After purification by recrystallization from a 2:. 1 methanol / water mixture, followed by sublimation at 45 ° C / O, OO5 mm one obtains a connection of m.p. 87 to 88 ⁰ C.

C. H F. N 39.75 2.67 37.72 9.27 39.61 2.96 37.80 9.66

^C 10 ^H 8 ^P 6 ^N 2 ° 2 ^i.d.

found:

Level B; Production of 2-amino-4,6-di - (trif luo methyl) -nico-

tic acid hydrazide

The mixture is stirred a mixture of 2.55 g (8.45 mmol) of ethyl 2-amino-4,6-di- (trifluoromethyl) nicotinate, 5 ml 85prozentigem hydrazine hydrate and 5 ml of isopropanol for 3 hours an oil bath at 110 ⁰ C On cooling, colorless crystals separate from the dark red solution, which are filtered off and washed with a little isopropanol. A second crop of solids is obtained by evaporating the mother liquors. The total yield is 1.45 g (59.6 g of a product with a melting point of 240 ° to 243 ° C. (decomposition). After recirculation from 25 ml of isopropanol, 1.05 g (yield 42.8 %) of a product of Mp. 244 to 245 ⁰ C (decomposition).

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C H F N

C ₈ H ₆ F ₆ N ₄ Oj calc .: 33.35 2.10 39.56 19.44 found: 33.27 2.20 39.48 19.50

Stage Ct Manufacture of. N - / 2-amino-4,6-di (trifluoromethyl) -

-nicotinoyl7-N - "benzo! sulfonylhydrazine

4.35 g (15.1 mmoles) of 2-amino-4,6-di- (trifluoromethyl) nicotinic acid hydrazide are stirred in 36.3 ml of 1 n sodium hydroxide solution until a clear solution is obtained. 2.94 g (16.6 mmol) of benzenesulfonyl chloride are then added all at once, and the resulting mixture is rapidly stirred until it is completely dissolved. When this solution is poured into a stirred solution of 0.9 g (15 mmol) of acetic acid in 40 ml of water, a fine precipitate forms. The p "value of the suspension is adjusted to about 6.5 with acetic acid, the product is isolated, washed with water and dried. 6.52 g (theoretical yield) of a product are obtained which sinters at about 230 ° C. and has a melting point of 235 to 238 ^° C. (decomposition). The pure compound is obtained by precipitation from a filtered solution of the crude product in ethyl acetate (4 parts by volume per part by weight), to which chloroform (10 parts by volume per part by weight) is added; the pure compound melts at 243 to 245 ^° C. (decomposition).

CHNS

C ₁₄ H ₁₀ F ₆ N ₄ O ₃ Si calcd .: 39.26 2.35 13.08 7.49

found: 39.72 2.78 13.20 7.55

Stage Dt Production of 3- (4-pyridyl) -5,7-di- (trifluoromethyl) -

-1,8-naphthyridin-2 (1H) -one

30 ml of glycol are heated to 175 ° C. in an oil bath. 1.28 g are added (3 mmol) N - / 2-amino-4,6-di- (trifluoromethyl) -nicotinoyl7-N -benzenesulfonylhydrazine and immediately afterwards a solution of 453 mg (3 nffaol)

Methyl 4-pyridyl acetate and 336 mg (3 mmol) 1,4-diazabicyclo- / 2,2,27octane in 6 ml ethylene glycol were added. The mixture is stirred vigorously so long reaches 16O ⁰ C to the temperature. Then it is mixed with 900 mg of anhydrous sodium carbonate. Heating on the oil bath is continued for 1 minute and then the reaction mixture is allowed to cool and then poured into 200 ml

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Poured water. The product is precipitated by adding a single drop of acetic acid. A fine, ocher-colored solid crystallizes out overnight and is isolated. This gives 639 mg of product, mp. 235-236 ⁰ C. By neutralization of the mother liquors with acetic acid up to a value of 7 PJJ is obtained a further 51 mg of product melting at about 250 to 270 ⁰ C. The purification of the combined crude products by Soxhlet extraction with acetonitrile gives 328 mg (yield 30 %) of a compound which melts at 282 to 285 ^° C., with some decomposition.

CHN

C ₁₅ H ₇ F ₆ N ₃ O; calc .: 50.15 1.96 11.69

Found: 49.61 2.19 11.87

Example 31

3- (2-Pyridyl) -5,7-di- (trifluoromethyl) -1,8-naphthyridin-2 (1H) -one By mixing the methyl 4- pyridyl acetate used according to Example 12 (stage D) with the equivalent amount of ethyl 2-pyridylacetate and otherwise going replaced essentially by the procedure described in step D of example 12 operation, a product is obtained which melts after crystallization from acetonitrile at 298-300 ⁰ C in 31prozentiger yield.

CHN

C ₁₅ H ₇ F ₅ N ₃ O; calc .: 50.15 1.96 11.69

Found: 49.89 2.15 11.48

Example 32

6- (2-imidazolyl) -1,8-naphthyridin-2 (1H) -one Stage A: Preparation of / 3- (dirnethylamino) -2- (imidazo 1-2-yl) -

allylid en7-dimethylammonium hexafluorpho sphat The Vilsmeier-Haack reagent is prepared using 140 ml (1.8 mol) of dimethylformamide and 500 ml of 3 η phosgene in chloroform. Is reacted within 1 hour 30.8 g (0.375 mol) of 2-methylimidazole in the form of subsets added, keeping the temperature at or below 1O ⁰ C. The mixture is then stirred at room temperature overnight. The reaction mixture is then poured onto 490 g of ice, shaken and separated

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Phases from each other. The chloroform solution is extracted with 35 ml of water, the combined aqueous solutions are treated with 63 g (0.375 mol) of sodium hexafluorophosphate and filtered. The filtrate is cooled in an ice bath, with 139 g of 0.13 mol) of anhydrous sodium carbonate being added in the form of small portions. 50.7 g (yield 39 °) of a crystalline precipitate with a melting point of 185 ° to 187 ° C. are obtained. After TJmkri st alii sat ion of the crude product from water (5 parts by volume per part by weight) gives the pure compound as colorless crystals, mp. 191-192 ⁰ C.

C "H 'N

C ₁₀ H ₁₇ N ₄ .PF ₆ .1 / 2H ₂ O; calc .: 34.51 4.97 16.15

found: 34.59 5.22 16.14

Stage B: Preparation of 2- (2-imidazolyl) propane-1,3-dione A solution of 23.6 g (0.068 mol) of the product obtained in Stage A in 70 ml of 2 η sodium hydroxide solution is kept at up to 70 for 1 hour C. Then 6 η hydrochloric acid is added dropwise to the hot solution while stirring. When the p _R value is 7.0 to 7.5, the mixture is cooled to 5 ° C. 7.88 g (yield 81.5% ) of product are obtained. The crude product is purified by suspending it in hot water (5 parts by volume per part by weight), adding solid sodium carbonate to dissolve it, filtering and finally precipitating the product by neutralization with acetic acid; the pure compound melts (decomposition) at 278 to 28O ⁰ C.

C H N

C ₆ H ₆ N ₂ O ₂ ; calc .: 52.17 4.38 20.28 found: 51.96 4.62 20.10

Stage C: Preparation of 2-Amino-6- (2-imidazolyl) -1 _t 8-naphthyridine By carrying out the 2- (4-pyridyl) - -propane-1,3-dione used in Example 24 (Stage A) replacing the equivalent amount of 2- (2-imidazolyl) propane-1,3-dione and otherwise working essentially according to the method described in step A of Example 24, a product is obtained in 70 percent yield which, after recrystallization from water, is obtained 34O ⁰ C (decomposition) melts.

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14 677 232235Q

Stage D; Preparation of 6- (2-imidazolyl) -l, 8-naphthyridin-2 (iH) -one A mixture of 211 mg (1 mmol) of 2-amino-6- (2-imidazolyl) -1,8-naphthyridine is added in 2.5 ml 40prozentiger sulfuric acid at 5 ⁰ C under stirring with 69 mg (1 mmol) of sodium nitrite. The solution is allowed to warm to room temperature and then heated to 50 ° C. for 4 hours. Then cool the reaction mixture to 5 ⁰ G and mixes it with an additional 40 mg (0.57 mmol) of sodium nitrite to the completion of the reaction ensured. The mixture is then heated to 50 ^° C. for 2 hours, cooled to room temperature, diluted with water and neutralized with ammonium hydroxide. 140 mg of a solid product are obtained, which is purified by dissolving it in 5 ml of dilute acetic acid, treating the solution with activated charcoal and neutralizing the filtered solution with a few drops of ammonium hydroxide. The pure compound (100 mg; yield $ 47) 'melts below

35O ⁰ C not. C. s ρ H 80 N 40 62.25 3. » 84 26, 41 C ₁₁ HgN-O; ber .: 62.40 3, e 1 26, found: at i 33

3-Amino-5,7-di- (pentafluoroethyl) -1,8-naphthyridin-2 (1H) -one, Stage A; Production of 1.1 _t 1 _t 2 «2.6.6 _t 7» 7i7-decafluoroheptane -3 »5-dione

A stirred suspension of 44.8 g (0.4 mol) of potassium tert-butoxide in 400 ml of anhydrous ether is added within of about 15 minutes with 76.8 g (0.4 mol) of ethyl pentafluoropropionate. The majority of the solid goes into solution. A solution of 64.8 g (0.4 mol) of pentaf is then slowly added luo räthylmethylketon in 60 ml of anhydrous ether is added, the mixture is stirred for 2 hours at room temperature and then leaves it over Standing at night. Then it is added with stirring and external cooling (ice bath) with a solution of 27.2 ml of glacial acetic acid in 120 ml of water. A warm solution of 56 g (0.28 mol) of copper acetate is then gradually added with stirring and cooling Add 532 ml of water. The ether is distilled off and the copper salt of the product is filtered off, washed with water,

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thoroughly drained and then washed with petroleum ether. Man then suspends the copper derivative in 200 ml of ether and decomposes it by treatment with 450 ml of 15 percent sulfuric acid, Die Aqueous layer is separated and washed with more ether (3 χ 50 ml) extracted. The combined ether extracts are dried first over anhydrous sodium sulfate and then over anhydrous Calcium sulfate. After evaporation of the ether, the product is obtained, which is obtained by fractional distillation at atmospheric pressure is cleaned.

Stage Bt Production of ethyl-2-amino-4,6-di ~ (pentafluoroethyl) -

nicotinate

By replacing that used in Example 1 (Step, A) 3-Acetamidoρentane-2,4-dione the equivalent amount of 1,1,1,2,2,6,6, -7,7,7-decafluoroheptane-3,5-dione uses and otherwise works according to the method of Example 1 (stage A), one obtains ethyl-2- -amino-4,6-di- (pentafluoroethyl) nicotinate.

Stage G: Preparation of 3-amine o-5 ^ 7 -di-fpentafluoroethyl) -1,8- -naphthyridin-2 (1H) -one

This compound is prepared by replacing the nicotinate used in step A of Example 2 with the equivalent Amount of ethyl 2-amino-4,6-di (pentafluoroethyl) nicotinate used and then according to the methods of stages A to Ξ of Example 2 works.

Example 34

3-Amino-5-methyl-7-pentafluoroethyl-1,8-naphthyridin-2 (1H) -one Stage At Preparation of (1) ethyl-2-amino-4-] 3entafluoro-t> -me thylnicotinate and (2) ethyl ^ -amino ^ -methyl ^ -penta- fluo räthylni cot inat

It is heated 7.1 g (28.3 mmol) Äthoxycarbonylacetimidat and 2.86 g (14 mmol) of 5,5,6,6,6-Pentafluorhexan-2,4-dione together overnight at 100 ⁰ C. Distillation of the Mixture at about 0.03 mm gives 4.75 g of distillate with a boiling point of 71 to 102 ^° C. Chromatography of the distillate on silica gel using methylene dichloride as solvent gives the two isomers of

- .24 -

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Pp. 98 to 10O ⁰ C or 77 to 81 ⁰ C.

Level B; Production of 3-amino-5-pentafluoroethyl-7-methyl-

-1 _t 8-naphthyridin-2 (1H) -one

The ethyl 2-amino-4-pentafluoroethyl-6-methylnicotinate is used containing fraction essentially according to the method described in Example 2 (stage A) with hydrazine hydrate and works then obtained according to the methods of levels B to Ej one 3-amino-5-pentafluoroethyl-7-methyl-1,8-naphthyridin- -2 (1H) -one.

Stage C; Production of 3-amino-5-methyl-7-pentafluoroethyl

-1 _t 8-naphthyridin-2 (1H) -one

It also provides the connection to in Example 2 (Steps A to E) procedures described here, by, instead of the nicotinate used in Step A of Example 2, the equivalent amount of ethyl-2-araino-4-methyl-6-pentafluoräthylnicotinat used.

Example 35

6- (3-IndoIyI) -I, 8-naphthyridin-2 (1H) -one hydrochloride Stage At production of / 3- (Dimethylamine) -2- (1-formylindole-

-3-yl) allylidene-7-dimethylammonium tetrafluoroborate 132 g (1.8 mol) of ice bath-cooled anhydrous N, N-dimethylformamide are added dropwise with stirring with 55.2 g (0.36 mol) of phosphoryl chloride. 21 g (0.12 mol) of indole-3-acetic acid are added to the cold mixture. The mixture obtained is gradually heated to 90 ^° C. and kept at this temperature for 3 hours. The excess dimethylformamide is distilled off at the water pump and the residue is quenched with 100 g of ice. The aqueous solution is treated with activated charcoal and filtered. The crude trimethinium salt is precipitated by adding a solution of 14.5 g (0.132 mol) of sodium tetrafluoroborate in a small amount of water (about 30 ml). After crystallization from 400 ml of a 3: 1 ethanol / methanol mixture, this yields 16 g of a black pesticide. This gives after three recrystallization from methanol with treatment with

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309847/1129

H 1 N 08 6th , 59 1 3, 68 6th , 84 2,

Activated carbon is the pure compound which crystallizes in the form of colorless platelets} pp. 202 to 204 ° C; Yield 8.86 g ( $ 20.6)

CHNF

C ₁₆ H ₂₀ BP ₃ N ₃ O; calc .: 53.80 5.64-11.98 21.27 found: 53.00 5.83 11.76 20.91

Stage B: Preparation of 3-dimethylamino-2- (3-indolyl) acrolein. 990 mg (3 mmol) of the trimethinium salt obtained in Stage A are stirred for 1 hour at 70 ° C. with 1 n sodium hydroxide solution. The pesticide is filtered off and washed with water; 564 mg (yield 88 $) of a crude compound of Pp .. 188 to 190 ⁰ C (decomposition) are obtained. Recrystallization of the crude product from 11.5 ml of ethanol gives the pure compound, which crystallizes in the form of cream-colored prisms; P.p. 191 to 192 ° C (slight darkening).

C ₁₃ H ₁₄ N ₂ O; calc .: 72.87 'found: 72.41

Step. C: Preparation of 3-indolylmalondialdehyde A suspension of 1.07 g (5 mmol) of the enaminoaldehyde from stage B in 15 ml of ethanol is treated with 0.6 ml of 10% sodium hydroxide solution and the mixture is refluxed and under nitrogen for 9 hours. The ethanol is distilled off under reduced pressure and the residue is slurried with about 10 ml of 1 η sodium hydroxide solution and filtered. Is added to the Piltrat with 5 ml of methanol, and represents the p _H ~ of the mixture by a dropwise addition of 6 η hydrochloric acid to about 3.5. The product is isolated and washed with water; 565 mg (yield 61 #) of crude product with a boiling point of 166 to 167 ^° C. (decomposition) are obtained. After recrystallization of the solid crude product from 5.5 ml of nitromethane, to which a drop of water has been added, the pure compound is obtained with a p.p. 170.5 to 171.5 ° C. (pale dark color above 165 ° C.).

CHN

C _1. , H ₉ NO ₂ .1 / 3H ₂ O; calc .: 68.38 5.04 7.25

Found: 68.18 4.95 7.49

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Stage D; Production of 6- (3-indolyl) -1,8-naphthyridin-2UH) -

-on-hydrochloride

This compound is prepared by instead of the 2- (4-pyridyl) propane-1,3 - "- dione used in Step A of Example 24 the equimolar amount of 3-indolylmalondialdehyde is used and then essentially following the method described in Steps A and B of Example 24 operates.

Example 36

6- (4-Pyrimidinyl) -1,8-naphthyridin-2 (1H) -one hydrochloride This compound is prepared by the methods described in Example 35 (steps A to D), using instead of the in step A of Example 35 indole-3-acetic acid used the equimolar amount of pyrimidine-4-acetic acid.

When the compounds according to the invention were tested on anesthetized dogs according to standard test procedures, it was found that these compounds inhibit the bronchoconstriction caused by one or more bronchoconstrictor agonists; During the testing, known methods for investigating the bronchodilation effect of test substances were used. In addition, it has been found that the compounds of the invention have hypotonic properties which are believed to be due to their action as peripheral vasodilators. There is therefore the possibility that the compounds of the invention will be useful as antihypertensive agents. Intravenous or intraduodenal doses in the range from about 5 to about 75 mg / kg ensured protection (measured by ED ^ ₀ ) against the bronchoconstriction induced in the case of most of the experimental animals used. Those compounds which also showed hypotonic properties were effective B am within the same dose range.

The invention also provides medicaments which contain at least one of the compounds according to the invention as active ingredient (s) as well as combined with a carrier suitable for pharmaceutical purposes or a corresponding binder (excipient)

- 27 -

309847/1129

4P

contain. The substance (s) can be in a suitable form for oral administration (preferably as capsules, tablets or liquid preparations) or for parenteral administration (as solutions or suspensions) or in conventional Methods produced aerosols are provided. One can, for example, in a conventional manner using lactose .as Excipiens produce capsules which each contain 10 to 25 mg of active ingredient as a unit dose. The unit doses know in terms of administration according to the medical one Prescription is around 5 to 100 mg.

The invention has been made with reference to very specific, prepared by special methods and for special administration, Forms of processing processed representatives of the new 1,8-naphthyridine derivatives explained. However, this does not mean that the invention is limited by or to the specific embodiments described. Rather, it also extends to others Representatives of the new compounds falling within the scope of the general disclosure including the claims as well as other methods or modifications of the procedures explained for their production and other medicinal products, all of which are readily accessible to the person skilled in the art on the basis of the above technical teaching.

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309847/1129

Claims (14)

Patent claims 1. Process for the preparation of 1,8-naphthyridin-2 (1H) -ones of general formula I. and their pharmacologically acceptable salts, thereby characterized in that a 2-aminopyridine -3-aldehyde of the general formula II converted in a manner known per se into the corresponding compound of the general formula I and, if necessary, produces its pharmacologically acceptable salt, where in each of the aforementioned general formulas R is a hydrogen atom, an amino, C, ^ -alkanoylamino, Cjc-alkylamino, ( C ,, - alkyl) ₀ -amino or pyridyl group or a -CO ₀ X-ReSt (X = what- 5 7 hydrogen atom or C 1 - alkyl radical), R and R are the same or are different and each have a hydrogen atom, a trifluoromethyl, pentafluoroethyl, phenyl, chlorophenyl, Fluorophenyl ,. Benzyl, naphthyl, pyridyl or thienyl group or a Cj _, - alkyl radical and R a hydrogen atom, an amino, C. ^ - alkanoylamino, pyridyl, imidazolyl or indolyl group or a diazine radical and where at least one of the radicals R ^ and R is one of those defined above nitrogen-containing substituents. 2. The method according to claim 1, characterized in that R 3t, R ⁵ - 29 - is a pyridyl group, R and R 'are each a methyl 3098A7 / 1129 ¹⁴⁶⁷⁷ 232235Q represent a group and R is a hydrogen atom. 3. The method according to claim 1, characterized in that R represents a pyridyl group and R- *, R ^ and R 'each represent a Represent hydrogen atom. 4. The method according to claim 1, characterized in that R c 7 means an amino group, R and R each represent a methyl group represent and R is a hydrogen atom. 5. The method according to claim 1, characterized in that R ^ 5 7 a -COgC ^ c group, R and R 'each represent a methyl group represent and R is an acetylamino group. 6. 1,8-Iiaphthyridin-2 (1H) -one of the general formula Ia or Ib ~ v 11 "* f— ^
¹ R ¹ ' (Ia) (Ib) and their pharmacologically active salts, where R is a hydrogen atom, an amino, C-J -alkanoylamino, C ._ [- alkylamino, (C ₁ , - alkyl) ₀ -amino or pyridyl group or a -CO ₀ X-ReSt 5 7 (X = hydrogen atom or Cj ^ -alkyl radical) means R and R are identical or different and are each a hydrogen atom, a trifluoromethyl, pentafluoroethyl, phenyl, chlorophenyl, Pluophenyl, benzyl, naphthyl, pyridyl or thienyl group or a C., - alkyl radical and R is a hydrogen atom, an amino, Cj _.> - alkanoylamino, pyridyl, imidazolyl or indolyl group or a diazine radical and where at least one of the radicals R ^ and R is one of those defined above nitrogen-containing substituents. 7. Compounds according to claim 6, characterized in that R and R 'each have an identical or different Cj _ ^ - - 30 - 309847/1 129 Η 677 rest mean. - »ο -» ^ -5 r η 232Z3DU 8. Compounds according to claim 6, characterized in that R and R each represent a methyl group. 9. Compounds according to claim 6, characterized in that R 7 ß and R each represent a methyl group and R an amino group represents. 10. Compounds according to claim 6, characterized in that R 7 λ and R each represent a methyl group and R ^{J is} an amino group represents. 11. Compounds according to claim 6, characterized in that R 7 λ and R each represent a methyl group, R ^{J represents} a -COpCoH, - group and R is an acetylamino group. 12. Compounds according to claim 6, characterized in that R 7 "\ and R each represent a methyl group and R ^{J is} a pyridyl group represents. 13. Compounds according to claim 6, characterized in that R 7 ■ ^ and R each represent a trifluoromethyl group, R a Represents pyridyl group and R is hydrogen atom. 14. Compounds according to claim 6, characterized in that R ^ 5 7
represents a 4-pyridyl group and R, R ^ and R ¹ each represent a Represent hydrogen atom. - 31 3098Λ7 / 1129