1h-imidazoû4,5-c¨quinolines and 1h-imidazoû4,5-c¨quinolin-4-amines

(74) Agent

Riker Laboratories Inc, 3M Center, Saint Paul, MN 55144, US John Franklin Gerster, Saint Paul, MN, US Tandberg Patent Office AS, Oslo (54) Designation 3-nitroquinoines.

(56) Published publications None (57) Summary

Compounds of formula

<img file="NO168705B_D0001.tif" />

wherein each group R 9 is independently selected from alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms and halogen, and n is an integer O-2, provided that if n is 2, the R 2 substituents together contain no more than 6 carbon atoms; R 9 is selected from hydroxyalkyl of 1 to 6 carbon atoms and cyclohexylmethyl; and R? is selected from alkyl of 1 to 4 carbon atoms and hydrogen is useful in the preparation of therapeutically active compounds.

The present invention relates to 3-nitroquinolines useful for the preparation of certain 1H-imidazo [4,5-c] quinoline compounds which are useful as bronchodilators and / or as antiviral agents.

The invention relates to novel compounds of formula XX which are characterized in that they have the formula

<img file="NO168705B_D0002.tif" />

<img file="NO168705B_D0003.tif" />

wherein each group R₅ is independently selected from alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms and halogen, and n is an integer 0-2, provided that if n is 2, R₅the substituents together do not exceed 6 carbon atoms; R₆ is selected from hydroxyalkyl of 1 to 6 carbon atoms, dihydroxyalkyl of 1 to 6 carbon atoms and cyclohexylmethyl; and R₇ is selected from alkyl of 1 to 4 carbon atoms and hydrogen.

The compounds are useful as intermediates in the preparation of therapeutically active 1H-imidazo [4,5-c] quinoline compounds as described in Norwegian Patent Application 844565 (Laid-Open 163,819).

The compounds can be prepared as shown in the following reaction nucleus:

<img file="NO168705B_D0004.tif" />

In the step, an optionally substituted 3-nitro 4-chloroquinoline of formula IV is reacted wherein R₇ is as defined above by heating with an amine of formula NH-R₆ in a suitable solvent, such as water or tetrahydrofuran, to give a quinoline of formula V.

The invention is further illustrated in the following examples.

Example 1

Preparation of a Compound of Formula V⁵ To a solution of 50.0 g (0.24 mole) of 4-chloro-3-hydroquinoline in 300 ml of tetrahydrofuran was added in small portions 52.7 g (0.72 mole) of isobutylamine. The mixture was heated to reflux for 1 hour and then evaporated in vacuo. Water was added to the residue and there¹⁰ solids were separated by filtration. The solid was suspended in 1 liter of water and dissolved by the gradual addition of concentrated hydrochloric acid (to pH 3 - 4) followed by filtration of the solution. The filtrate was made basic (to pH 9 - 10) by the addition of concentrated ammonium hydride¹⁵ Roxide Forming pale yellow 4- (isobutylamino) -3-nitroquinoline, m.p. 119-121 ° C.) The structural confirmation was supported by infrared spectral analysis.

Using the methods described in Example 1 from the indicated substituted quinolines and

20 primary amines, the following compounds of formula V were prepared (Table I).

Table I

<td>25 Ex. No..</td><td>Quinoline starting material of formula IV</td><td>Primary amine (starting material)</td>

<td> 2</td><td>4-chloro-3-nitro- quinoline</td><td>ethanolamine</td>

<td> 30 3</td><td>4-chloro-3-nitroquinoline</td><td>2,3-dihydroxypropylamine</td>

<td> 4</td><td>4-chloro-3-nitro- quinoline</td><td>3-hydroxypro- pylamin</td>

<td> 35 5</td><td>4-chloro-6-fluor2-methyl-3-nitroquinoline</td><td>2,3-dihydroxypropylamine</td>

Intermediate of Formula V (m.p. ^QC)

4- (2-hydroxyethylamino)

3-Nitroquinoline (204-207)

4- (2,3-dihydroxypropylamino) -3-nitroquinoline (209-211)

- (3-hydroxypropylamino) -3-nitroquinoline (159-162)

4- (2,3-Dihydroxypropylamino) -6-fluoro-2-methyl 3-nitroquinoline (187-189)

Example 6

Preparation of a Compound of Formula VI

To a solution of 57.3 g (0.23 mol) of 4- (isobutylamino) -3-nitroquinoline (from Example 1) in 600 ml of ethanol was added 2 g of platinum-on-carbon and the resulting mixture was hydrogenated in a Parr apparatus for 3 hours. Filtration followed by evaporation in vacuo gave a residue which gradually solidified to a yellow solid, 3-amino-4- (isobutylamino) quinoline.

Using the method described in Example 6 from the indicated intermediates of formula V, the intermediates of formula VI were prepared as shown in Table

II. In those instances where the hydrochloride is indicated, this was achieved by first bubbling hydrogen chloride through an ethanol solution of the free amine and then separating the solid product by filtration.

Table II

Ex. No..

Intermediate of Formula V Intermediate of Formula VI (Example No. in strain) (m.p. ° C)

3-Amino-4- (2-hydroxyethylamino) quinoline dihydrochloride (282-293)

3-Amino-4- (2,3-dihydroxypropylamino) quinoline hydrochloride (201-204)

3-amino-4- (3-hydroxypropylamino) quinoline (not determined)

3-Amino-4- (2,3-dihydroxypropylamino) -6-fluoro-2-methylquinoline (brown solid) (undetermined)

Example 11

0.207 moles of crude 3-amino-4- (methylamino) quinoline obtained by the procedure of Example 6 were mixed with 500 ml of glacial acetic acid and 76 ml of triethyl orthoacetate, and the resulting mixture was heated under reflux for 2 hours. Evaporation gave a residue which was dissolved in 800 ml of water. The solution was made basic with concentrated ammonium hydroxide. The solid was separated by filtration and washed with water to give 1,2-dimethyl-1H168705 imidazo. [4,5-c] quinoline. When a sample of this product was recrystallized from diethyl ether, it had a melting point of

<td> 194 -</td><td>196 ° C.</td><td colspan="2"></td>

<td>5 Ex.</td><td>Intermediate of Formula VI</td><td>Table III ortho ester, carboxyl</td><td>Compounds of Formula VII</td>

<td>No..</td><td>(example nof)</td><td>acid</td><td>(m.p. ° C)</td>

<td> 12</td><td> 29</td><td>triethyl-</td><td>1- (2-hydroxyethyl) -1H-</td>

<td> 10</td><td></td><td>orthoformate;</td><td>imidazo [4,5-cJkinolin</td>

<td> 13</td><td> 30</td><td>formic acid triethyl-</td><td>(170-172) 1- (2,3-dihydroxypropyl) -2-</td>

<td></td><td></td><td>orthoacetat;</td><td>methyl-lH-imidazo [4,5-c] -</td>

<td> 14</td><td> 41</td><td>acetic acid triethyl-</td><td>quinoline (232-234) 1- (3-hydroxypropyl) -1H-</td>

<td> 15</td><td></td><td>orthoformate; formic acid</td><td>imidazo [4,5-c] quinoline (not determined)</td>

<td> 15</td><td> 30</td><td>triethyl-</td><td>1- (2,3-dihydroxypropyl) -</td>

orthoformate; 1H-imidazo [4,5-c) quinoline formic acid (228-230) * in strain.

Example 16

Part A

A mixture of 26.1 g (0.125 mole) of 4-chloro-3-nitroquinoline, 16.4 g (0.1275 mole) of 95% cyclohexylmethylamine and 16.5 g (0.125 mole) of 95% diisopropylethylamine in 300 ml of tetrahydrofuran was heated on a steam bath for 1/2 hour. The solution was evaporated and the residue was suspended in methanol, filtered and washed with methanol. Recrystallization from methanol gave yellow patches of 4-cyclohexylmethylamino-3-nitroquinoline, m.p. 140 - 142 ° C.

Analysis for C

Calculated: C 67.3 H 6.7 N 14.7%

Found: C 67.3 H 6.6 N 14.7%

Part B

Using the method of Example 26, g (0.60 mol) of 4-cyclohexylmethylamino-3-nitroquinoline was reduced to 3-amino-4-cyclohexylmethylaminoquinoline.

Part C

The crude product from Part B was heated under reflux for 2 1/2 hours in 250 ml of 98% formic acid to give 1-cyclohexylmethyl-1H-imidazo [4,5-c] quinoline as a pale yellow solid.