NO166082B - INTERMEDIATES FOR USE IN THE PREPARATION OF IMIDAZOKINOLINON DERIVATIVES. - Google Patents

Description

The present invention generally relates to heterocyclic hydrocarbon compounds.

More specifically, the present invention relates to a number of hitherto unknown 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-thione derivatives which are characterized by the general formula XIV

there

R^ means halogen, C1_4~<a>alkyl, C1_4~alkyl or trifluoromethyl,

R 2 means hydrogen, halogen, C 1 -4 alkyl or C 1 -4 alkoxy,

R 3 means hydrogen, halogen, C1-4 alkyl or Cj_4<a>lkoxy,

R 4 means hydrogen or C 1-6 alkyl,

or a pharmaceutically acceptable salt thereof.

The present application is separated from NO application no. 861617.

The compounds of formula XIV according to the present application are used in the preparation of the therapeutically active imidazoquinolinone derivatives of the general formula XII as described in more detail below.

The 1,3-dihydro-2H-Imidazo[4,5-b]quinolin-2-thiones of the invention

with formula XIV can be produced by the following conversions:

Method E;

In step 1 of method E, the aldehyde (XVII, where R^, R2 and R3 have the meaning given in connection with XIV) is condensed with R4-2-thiohydantoin (XVIII, where R4 is hydrogen or lower alkyl) in aqueous ethanol or morpholine or piperidine at steam bath temperature. In step 2, the protection for the amine function in XIX is removed by dissolving the material in pure trifluoroacetic acid in the presence of anlsol to form the aniline intermediate XX. Cyclization of XIX was accomplished by treatment with pyridine lumtosylate in diphenyl ether at 180°C to form the thione XIV.

As indicated above, compounds of formula XII according to NO application no. 861617 can be prepared by

a) alkylates a thio compound of formula XIV according to the invention

where R]_, R2. R3 and R4 have the meaning given above, with R5X, where R5X is lower alkyl and X means a leaving group such as mesylate, tosylate, phosphate, sulfate and halogen, preferably chlorine or bromine, forming an alkylated thio compound of formula XV

b) and then hydrolyzes the compound of formula XV, preferably under acidic conditions, to form

the compound of formula XII.

The following examples shall illustrate the invention in more detail.

The following examples illustrate:

example 1 the preparation of output compounds which used in the production of the intermediate product According to

present application;

example 2 the preparation of the present invention

intermediate products; and

example 3 the use of the intermediate products of the present invention for the production of the therapeutically active compounds described in NO application no. 861617.

Example 1

1. 1- Dimethylethyl- r2- formyl- 5-( trifluoromethyl) phenylcarbamate (a) 1. 1- Dimethylethyl- r5-( trifluoromethyl)- phenylcarbamate

A mixture of 3-aminobenzotrifluoride (16 g, 0.1 mol) and di-tert-butyl dicarbonate (32 g, 0.15 mol) and 25 mL of tetrahydrofuran (THF) was stirred at room temperature for 90 minutes and heated to reflux. for 90 minutes. The mixture was diluted with 10 ml of water, left overnight and concentrated in vacuo. The residue was dissolved in 100 ml of hexane under reflux, treated with activated carbon, filtered and cooled to C<P>C for 16 hours. Filtration gave 1,1-dimethylethyl-[5-(trifluoromethyl)phenyl]carbamate (75-80% yield in several preparation trials), mp 75-76°C.

Analysis calculated for C12<H>14F3N02: C 55.17 H 5.40 N 5.36

Found: C 55.13 H 5.45 N 5.33

(b) 1. 1-Dimethylethyl-r2-formyl-5-(trifluoromethylphenylcarbamate)

s-Butyllithium (15 mL of a 1.45 M solution in THF) (22 mmol) was added dropwise to a stirred solution of 1,1-dimethylethyl-[5-trifluoromethyl)phenyl]carbamate (2.61 g, 10 mmol) in 40 ml of dry THF at -40*C under argon. After 40 min, N,N-dimethylformamide (1.15 mL, 15 mmol) was added and the mixture was stirred at -40°C for 10 min before being diluted with 30 mL of diethyl ether. The mixture was washed with 30 ml of 10 µg acetic acid solution and saturated with 30 ml of sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a silica gel column using a mixture of hexane:ethyl acetate (95:5) as eluent to give 1,1-dimethylethyl-2-formyl-5-(trifluoromethyl)phenyl]carbamate, yield 70-84% .

Analysis calculated for Ci3<H>14F3N03: C 53.98 H 4.87 N 4 .84

Found: C 53.67 H 4.87 N 4.85

Example 2

Method E Preparation of imidoazo[4,5-b]kInolin-2-thiones of formula XIV

(a) 1 . 3-dihydro-6-(trifluoromethyl)-2H-imidazol4. 5-blquinoline- 2-tlon

(XIV, R 1 -6-CF 3 , R 2 = R 3 = R 4 = H).

Step 1. 1 . 1-Dimethylethyl-r2-r(5-oxo-2-thioxo-4-imidazolidinevlidene)methyl5-(trifluoromethyl)phenylcarbamate A mixture of 1,1-dimethylethyl[2-formyl-5-(trifluoromethyl)-phenyl ]carbamate (20 g, 60 mmol) and 2-thiohydantoin (8.02 g, 60 mmol), 60 mL of ethanol, 60 mL of water, and 6 mL of morphol in were heated on a steam bath. After 90 min the mixture was cooled, left overnight and the precipitate filtered off and dried in vacuo to give 1,1-dimethylethyl-[2-[(5-oxo-2-thioxo-4-Imidazolidinylidene)methyl]-5 -(trifluoromethyl)phenyl]carbamate (20.65 g, 77%) m.p. 21b°C (dec.).

Analysis calculated for Ci6H16F3<N>3°3<S:>

C 49.60 H 4.16 N 10.85 S 8.27

Found: C 49.56 H 4.10 N 10.92 S 7.96

Step 2. 5- T r2- amlno-4- ( trifluoromethyl ) phenyl~ l methylene!- 2-thioxo- 4- lmidazolidinone. 90 ml of trifluoroacetic acid was added to a mixture of 1,1-dimethylethyl [2-[(5-oxo-2-thioxo-4-imidazolidinylidene)methyl]-5-(trifluoromethyl)phenyl]carbamate (18 g, 46 mmol) and anisole (36 g, 0.3 mol). After dissolution, the solvent was evaporated off and the residue crystallized from a mixture of 65 ml of ethanol and 135 ml of chloroform, which gave 5-[[2-amino-4-(trifluoromethyl)-phenyl]methylene]-2-thioxo-4- imidazolidinone (9.85 g, 73%) with melting point 240°C.

Analysis calculated for C11<H>18<F>3N30S: C 45.99 H 2.81 N 14.63

Found: C 46.00 H 2.81 N 14.54

Step 3. 1. 3-dihydro-6-(trifluoromethyl)-2H-imldazor4. 5-blklnolln- 2- tion

A mixture of 5-[[2-amino-4-(trifluoromethyl)phenyl]methylene]-2-thioceo-4-imidazolidinone (3.63 g, 12 mmol), 1.8 g pyridinium tosylate and 5.4 g diphenyl ether was heated to 180<*>C under argon. After 18 minutes, the mixture was cooled, 60 ml of chloroform was added and the whole was boiled under reflux. After 30 minutes, the solid was filtered off and dissolved in a mixture of 80 ml of water and 5 ml of 10% sodium hydroxide solution while heating. Addition of acetic acid gave a heavy precipitate which was filtered off, washed with water and dried in vacuo to give 1,3-dihydro-6-(trifluoromethyl)-2H-imidazo[4,5-b]quinolin-2-thione (1.79 g, 53%) with m.p

>320<*>C.

Analysis calculated for CUH5F3N3S: C 49.07 H 2.25 N 15.61 Found: C 48.92 H 2.23 N 15.58

(b) 1. 3- dihydro- 7. 8- dimetvl- 2H- imidazor4 . 5-b1quinolin-2-thione

(XIV, R-t - R4 - H, R2 - 7-CH3, R3 - 8-CH3).

The product prepared according to method E as described in example 31(a) above after 2-amino-4-trifluorobenzaldehyde was replaced by 2-amino-5,6-dimethylbenzaldehyde.

Example 3

1. 3- dlhydro- 6-( trifluoromethyl)- 2H- imidazo 4. 5- b1klnolin- 2-one

(a) 2-( methylthio )- 6-( tr ifluoromethyl)- 1H- lm idazof 4. 5-blklnolln

A suspension of 1,3-dihydro-6-(trifluoromethyl)-2H-imidazo-[4,5-b]quinolin-2-thione (0.53 g, 2 mmol) in 5 mL of methanol was treated with 0.18 g of 50% aqueous sodium hydroxide, which gave a solution that was cooled in an ice bath. Methyl iodide (0.3 g, 0.13 mL, 2.1 mmol) was added and the mixture stirred for 90 min before filtration. The solid was washed with methanol and dried in air to give 2-(methylthio)-6-(trifluoromethyl)-1H-imidazo[4,5-b]quinoline (0.34 g, 61%), mp >270° C.

Analysis calculated for C12H8F3N3S: C 50.88 H 2.85 N 14.83 Found: C 50.50 H 2.83 N 15.01

NMR (DMS0-d6): S 2.81 (3H, s, S-CH3), 7.70 (1H, dd, J-8.5Hz, J'=2Hz, aromatic H ortho to CF3), 8.29 (2H, m,

aromatic H), 8.46 (1H, s, aromatic H ortho to N-C-SMe) and 13.30 (1H, bs, NH).

(b ) 1. 3-Dihydro-6-(trifluoromethyl)-2H-imidazoT4. 5-blklnoline-2-one

A mixture of 2-(methylthio)-6-(trifluoromethyl)-1H-imidazo[4,5-b]quinoline (1.77 g, 6 mmol), 25 ml of acetic acid, and 25 ml of 3N hydrochloric acid solution was heated on a steam bath for 4 hours. The solution was diluted with 250 ml of hot water, cooled and filtered. The filtrate was concentrated, giving a second yield. The solids were mixed with 25 ml of acetic acid and 25 ml of 3N hydrochloric acid solution and the mixture was heated on a steam bath overnight. The mixture was diluted with 250 mL of hot water, cooled, the solid collected and dried in vacuo to give 1,3-dihydro-6-(trifluoromethyl)-2H-imidazo[4,5-b]quino-lin-2- on (1.38 g, 83%), m.p. >250°C.

Analysis calculated for C1;LH6F3N30: C 52.18 H 2.39 N 16.60 Found: C 52.04 H 2.43 N 16.64

Claims (1)

1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-1 ion derivatives, characterized by formula (XIV) where R1 means halogen, C1_4-alkyl, C1_4-alkyl or trifluoromethyl, R2 means hydrogen, halogen, C1_4 -alkyl or C1_4-<a>lkoxy, R3 means hydrogen, halogen, C1_4-alkyl or C1_4-<a>lkoxy, R4 means hydrogen or C1-4alkyl, or a pharmaceutically acceptable salt thereof.