HU220667B1 - Quinolin derivatives for producing 1- and 2-substituted 1h-imidazo[4,5-c]quinolin-4-amines - Google Patents

Abstract

The present invention relates to novel quinoline derivatives of formula (Va) wherein Y is nitro or amino; R4 is alkoxyalkyl, wherein the alkoxy moiety has a carbon number of from 1 to 4, and an alkyl moiety has from 1 to 6 carbon atoms. The compounds of the present invention are useful as intermediates in the preparation of novel antiviral (1,2-substituted) -1H-imidazo [4,5-c] quinoline derivatives. ŕ

Description

FIELD OF THE INVENTION The present invention relates to compounds of formula (Va) which are useful as intermediates in the preparation of new 1- and 2-substituted-1 Himidazo [4,5-c] quinolin-4-amines.

In formula (Va), Y is nitro or amino;

R4 is an alkoxyalkyl group in which the alkoxy moiety has a carbon number of 1 to 4 and the alkyl moiety has a carbon number of 1 to 6.

Preferred compounds of formula (Va) are those wherein R _{4 is} methoxyethyl or 3-methoxypropyl.

The quinoline derivatives of formula (Va) of the present invention are important intermediates in the preparation of 1-imidazo [4,5-c] quinolin-4-amine substituted at 1- and 2-positions. The latter compounds and their pharmaceutically acceptable acid addition salts have antiviral activity and are thus useful in combating viral infections.

The first reliable report on the 1H-imidazo [4,5-c] quinoline ring system is from Backman et al. Org. Chem. 75, 1278-1284 (1951)], who have described the synthesis and possible use of 1- (6-methoxy-8-quinolinyl) -2-methyl-1H-imidazo [4,5-c] quinoline against malaria. Subsequently, the synthesis of various substituted 1H-imidazo [4,5-c] quinoline derivatives is described. For example, Jain et al., J. Med. Med. Chem. 77, 87-92 (1968)] synthesized 1- [2- (4-piperidinyl) ethyl] -1H-imidazo [4,5-c] quinoline, which has potent anticonvulsant and cardiovascular effects. compound. Baranov et al., Chem. Abs. 85, 94362 (1976)] disclose numerous 2-oxoimidazo [4,5-c] quinoline derivatives; Berenyi et al., J. Med. Heterocyclic Chem., 18, 1537-1540 (1980)] also discloses certain 2-oxoimidazo [4,5-c] quinoline compounds.

Gerster, U.S. Patent 4,689,338, discloses 1H-imidazo [4,5-c] quinolin-4-amine compounds having antiviral activity. These compounds are 1-alkyl, hydroxyalkyl, acyloxyalkyl, benzyl, phenyl, ethyl or substituted phenylethyl, and in the 2-position they are hydrogen, alkyl, benzyl, substituted benzyl, phenyl. substituted with ethyl or phenyl. It is also known that these compounds induce the biosynthesis of interferon. Further 1H-imidazo [4,5-c] quinolin-4-amines substituted at the 1-position with an alkenyl group are disclosed by Gerster in U.S. Patent No. 4,929,624.

In U.S. Patent No. 4,698,348, Gerster discloses bronchodilator 1H-imidazo [4,5-c] quinoline derivatives which, for example, have a hydrogen or chlorine, alkylamino or dialkylamino at the 4-position. and are substituted in the 2-position with, among others, hydroxyalkyl, aminoalkyl or alkanamidoalkyl. The latter patent further discloses 3-amino and 3-nitroquinoline intermediates substituted at the 4-position with hydroxyalkylamino or cyclohexylmethylamino, and 2-positions, inter alia, with hydroxyalkyl, aminoalkyl or also discloses 1H-imidazo [4,5-c] quinoline-N-oxide intermediates substituted with alkanamidoalkyl.

The compounds of formula (Va) of the present invention are useful in the preparation of compounds of formula (I) and pharmaceutically acceptable acid addition salts thereof, wherein:

R [is] hydrogen; C 1 -C 10 linear or branched substituted alkyl having from 3 to 6 carbon atoms, cycloalkyl or 3 to 6 carbon atoms, substituted with 1 to 4 carbon atoms, linear or branched; cycloalkyl containing branched alkyl; C2 -C10 linear or branched alkenyl, or C2 -C10 linear or branched substituted alkenyl substituted with 3 to 6 cycloalkyl groups, or 3 to 6 cycloalkyl groups; cycloalkyl having from 1 to 4 carbon atoms having from 1 to 4 carbon atoms and having from 1 to 4 carbon atoms; Hydroxyalkyl having from 1 to 6 carbon atoms; an alkoxy group having from 1 to 4 carbon atoms in the alkoxy moiety and an alkoxyalkyl group having from 1 to 6 carbon atoms in the alkyl moiety; an acyloxyalkyl group in which the acyloxy unit is an alkanoyloxy group having from 2 to 4 carbon atoms or a benzoyloxy group and the alkyl number of the alkyl moiety is from 1 to 6; benzyl; (Phenylethyl) group; or phenyl; and the latter benzyl, (phenylethyl) or phenyl optionally independently substituted on the benzene ring with one or two C 1-4 alkyl, C 1-4 alkoxy or halogen atoms, with the proviso that when the benzene ring has two substituents as defined above, these substituents may contain up to 6 carbon atoms in total;

R ₂ and R ₃ are each independently hydrogen; C 1 -C 4 alkyl; phenyl; or substituted phenyl substituted with from 1 to 4 carbon atoms, from 1 to 4 carbon atoms or halogen;

X is C 1 -C 4 alkoxy; alkoxyalkyl having 1 to 4 carbon atoms in the alkoxy moiety and alkoxyalkyl having 1 to 4 carbon atoms in the alkyl moiety; Hydroxyalkyl having from 1 to 4 carbon atoms; Haloalkyl of 1 to 4 carbon atoms; alkylamido having from 1 to 4 carbon atoms in the alkyl moiety; amino; a substituted amino group having from 1 to 4 alkyl or hydroxyalkyl substituents; azide; chloro; hydroxy; 4-morpholinyl;

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1-pyrrolidinyl; and (1-4C) alkylthio; and

R is hydrogen; Linear or branched alkoxy having from 1 to 4 carbon atoms; halogen; or a linear or branched alkyl group having from 1 to 4 carbon atoms.

In the compounds of formula (Va), when R 4 is an alkoxyalkyl group, preferably each alkyl group contains 2 carbon atoms, more preferably 1 carbon atom.

The most preferred compounds of formula I are: 4-amino-a-butyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline-2-methanol hemihydrate; 4-amino-a, a-dimethyl-2- (ethoxymethyl) -lH-imidazo [4,5-c] quinoline-l-ethanol; 2- (ethoxymethyl) -l- (2-methylpropyl) -lH-imidazo [4,5-c] quinolin-4-amine; and 4-amino-1- (phenylmethyl) -1H-imidazo [4,5-c] quinoline-2-methanol.

For example, a compound of the invention may be prepared according to Scheme 1, Steps (1) to (3). In the formulas, R, R _b, R ₂ , R ₃ and X are as defined above and P is a hydroxyl protecting group which may be removed later; such as alkanoyloxy groups (such as acetoxy); or aroyloxy groups (such as benzoyloxy); and _R5 is - except for the hydroxyalkyl group and the hydrogen atom - the same meaning as R _t.

Many quinoline derivatives of formula (III) are known (see, for example, U.S. Patent No. 3,700,674 and references cited therein). Quinoline derivatives which are not yet known can be prepared in a known manner, for example from 4-hydroxy-3-nitroquinoline derivatives as shown in Scheme 1, step (I). This step can be carried out by reacting the 4-hydroxy-3-nitroquinoline derivative of formula (II) with a chlorinating carbon such as thionyl chloride or phosphorus oxychloride. This reaction is preferably carried out in Ν, Ν-dimethylformamide (hereinafter DMF), optionally in the presence of methylene chloride, preferably by heating. The use of excess phosphorus oxychloride is preferably avoided; it has been found particularly advantageous to use about 1 to 2 moles of phosphorus oxychloride per mole of the 4-hydroxy-3-nitroquinoline derivative.

In step (2) with (III) 3-nitro-4-quinoline by heating the formula with an amine of formula R ₅ NH ₂ - wherein R ₅ is as defined above in a suitable solvent such as water, methylene chloride or tetrahydrofuran (hereinafter briefly THF) to give a quinoline derivative of formula IV. Steps (1) and (2) can also be combined by reacting the 3-nitro-4-chloroquinoline derivative with an amine of formula R ₅ NH ₂ without prior isolation. Such a reaction is described, for example, in Examples 134 and 188 (Step A) of U.S. Patent 4,689,338; this description is incorporated herein by reference.

Compounds of formula (IV) are generally reduced in step (3) using a catalyst such as platinum on charcoal to give compounds of formula (V). The hydrogenation reduction is conveniently carried out in a Parr apparatus, in an inert solvent such as toluene or lower alkanol.

Compounds of formula (Va) of the present invention wherein Y is -NH ₂ may be converted to the 1- and 2-substituted 1H-imidazo [4.5] of formula (I) in steps (4) to (12) of Scheme 1. c] quinolin-4-amine derivatives. This procedure is described below.

In step (4), the intermediate of formula (V) is (i) (OH) (R ₂ ) (R ₃ ) CCO ₂ H, or (ii) (OH) (R ₂ ) (R ₃ ) CC. Reacting with a trialkyl orthoester of (O-alkyl) ₃ wherein "alkyl" is a linear or branched alkyl group having from 1 to 4 carbon atoms; or (iii) reacting a combination of the above carboxylic acid and a trialkyl ortho ester above to give a compound of formula VI. In each case, the reaction is carried out by heating, for example at about 130 ° C, in the presence of an acid, preferably a carboxylic acid of the formula (OHXR ₃ ) (R ₂ ) CCO ₂ H.

Another method of forming the 2-substituted imidazole ring is shown in steps (5) and (6). The reaction of Step (5) is similar to that of Step (4), except that an intermediate of formula (VII) is obtained using formic acid or trialkyl orthoformate; the latter with the aid of a strong base (e.g., alkyl lithium such as n-butyllithium)

It is deprotonated with II and reacted with R ₂ CR _{3 to} give a compound of formula VI.

In step (7), the hydroxyl group is provided with a cleavable protecting group; for this purpose, the hydroxy group is converted to an alkanoyloxy such as acetoxy or an aroyloxy such as benzoyloxy. In cases where the hydroxy group is present in the 1-position substituent, it may also be deprotected in step (7) and subsequently removed if no longer required in subsequent reactions. Suitable protecting groups and appropriate reactions for their introduction and removal are well known to those of skill in the art; see, for example, U.S. Patent Nos. 115-123, U.S. Patent 4,689,338. examples.

In Step (8), an intermediate of formula (IX) is prepared by oxidizing a compound of formula (VIII) with a common oxidant suitable for the formation of N-oxides. Preferred oxidizing agents for this purpose are, for example, peroxyacids and hydrogen peroxide. Generally, heating is used to increase the reaction rate.

In step (9), an N-oxide of formula (IX) is a suitable chlorinating agent, such as phosphorus oxychloride.

Heating in the presence of B1 667 B1 yields intermediate X.

In step (10), the 4-chloro atom is replaced by a 4-amino group and the P protecting group is deprotected. There is thus obtained a compound of formula (XII), which represents a narrower subset of compounds of formula (I). The amination is carried out with ammonium hydroxide or more preferably with ammonia. Preferably, the intermediate of formula (X) is heated at a temperature of 120 to 175 ° C for 6 to 24 hours under pressure. This reaction is preferably carried out in a closed reactor with ammonium hydroxide or an alkanolic solution of ammonia (e.g., preferably methanolic solution containing from about 5% to about 15% ammonia).

Compounds of formula (XII) may also be prepared according to step (9a) by (i) reacting a compound of formula (IX) with an acylating agent; (ii) reacting the product thus obtained with an aminating agent; and (iii) isolating the compound of formula XII. In step (i) of step 9a, an N-oxide is reacted with an acylating agent. Suitable acylating agents include alkyl or arylsulfonyl chlorides such as benzenesulfonyl chloride, methanesulfonyl chloride and p-toluenesulfonyl chloride. Arylsulfonyl chlorides are preferably used. Most preferred is p-toluenesulfonyl chloride. In step (ii) of step (9a), the product of step (i) is reacted with an excess of an aminating agent. Suitable aminating agents are, for example, ammonia (e.g. in the form of ammonium hydroxide) and various ammonium salts (e.g., ammonium carbonate, ammonium bicarbonate and ammonium phosphate). Preferably, ammonium hydroxide is employed. Thus, in step 9a, it is preferred to dissolve an N-oxide of formula IX in an inert solvent such as dichloromethane, to which is added the amine and then the acylating agent. Preferred reaction conditions include: cooling the solution to about 0-5 ° C during the addition of the acylating agent; the rate of the reaction can be controlled by heating or cooling. Step 9a, as explained above in connection with step 7, involves the removal of the protecting group in P.

A further process for preparing compounds of formula (XII) is illustrated in steps (11) and (12). In step (11), an N-oxide is reacted with an isocyanate, wherein the isocyanate group is bound to a "hydrolytically reactive functional group". "Hydrolyzically reactive functional group" means a functional group which can be subjected to the nucleophilic exchange reaction in step (12) of the reaction scheme. Such a reactive functional group is 0

Case II contains, for example, the -C-carbonyl group. A particular class of such isocyanate compounds are the isocyanates of the formula R 1 -E-NCO, wherein R; is an organic group substantially inactive with respect to quinoline NOx under the conditions of step (11), and E is the said hydrolyzically reactive functional group. The person skilled in the art can easily select the appropriate Rj groups. Preferred R 1 groups include alkyl, aryl, alkenyl, and combinations thereof. For example, aroyl isocyanates such as benzoyl isocyanate are particularly preferred. The N-oxide is reacted with the isocyanate compound under substantially anhydrous conditions by adding the isocyanate compound to a solution of the N-oxide in an inert solvent such as dichloromethane.

In step 12, the compound of formula XI is hydrolyzed. In this case, the term "hydrolysis" is understood to mean not only the exchange of nucleophiles with the water molecule, but also the reaction with other nucleophilic compounds. These reactions may be carried out by methods well known to those skilled in the art, for example, by heating the compound of formula XI in the presence of a nucleophilic solvent, for example water or lower alkanol, optionally in the presence of a catalyst such as alkali metal hydroxide or lower alkanolate.

In Steps 9a, 10, or 12, a protecting group, such as an acetoxy or benzoyloxy derivative, is deprotected to provide a hydroxyl-containing compound. A hydroxy-containing compound of formula (I) may be converted to other compounds of formula (I) by methods well known to those skilled in the art. For example, a reaction with thionyl chloride gives a compound of formula I wherein X is chlorine. Interaction of the latter chloro compound with a nucleophilic reagent such as sodium azide, pyrrolidine, methanethiol or morpholine yields compounds of formula I wherein X (in the above order) is azido, 1-pyrrolidinyl, thiomethyl, or Represents a 4-morpholinyl group. The resulting azido compound can be reduced to a compound of formula I wherein X is amino. Acylation of such an amino compound may yield a compound wherein X is an acid amide group.

The compounds of formula (I) may be used as antiviral agents alone or in the form of their pharmaceutically acceptable acid addition salts.

The invention is illustrated by the following examples. It is noted that all reactions, unless specifically noted in a dry nitrogen atmosphere, were carried out by stirring.

Example 1

Preparation of 4 - [(3-Methoxypropyl) amino] -3-methroquinoline

19.0 g (0.10 mol) of 4-hydroxy-3-nitroquinoline are suspended in 250 ml of DKM and 8.0 ml (0.11 mol) of thionyl chloride and 8.5 ml (0.11 mol) of dimethyl are added. -formamide (DMF for short) is added slowly to the above suspension. The reaction mixture was stirred at reflux for about 2 hours. 10.25 g (0.115 mol) of (3-methoxypropyl) amine are obtained

A mixture of triethylamine (15 ml, 0.20 mole) and 15 ml (0.20 mol) was added dropwise with stirring. Strong heat evolution is observed. The mixture was evaporated and the residue suspended in water and acidified with concentrated hydrochloric acid. The dark solid precipitate was filtered and the filtrate was basified with concentrated ammonium hydroxide. The resulting precipitate was filtered, washed with water and dried to give 8.4 g of a yellow solid, m.p. 93-95 ° C. The dark solid product was suspended in water (2 L), acidified with concentrated hydrochloric acid, heated on a steam bath for 2-3 hours and then filtered while hot. The filtrate was basified with concentrated ammonium hydroxide, and the precipitate was filtered off, washed with water and dried to give 9.2 g of the title compound as a yellow solid, m.p. 93-95 ° C.

Analysis :

Calculated: C, 59.8; H5,8; N, 16.1%;

Found: C, 59.6; H, 5.7; N, 16.0%.

Reference Example 1

Preparation of 2- (Ethoxymethyl) -1- (3-methoxypropyl) -1H-imidazo [4,5-c] quinoline

To 1300 ml of ethyl acetate containing 1.0 g of 5% platinum carbon in charcoal and 5.0 g of magnesium sulfate was added 14.6 g (0.056 mol) of the 4 - [(3-methoxypropyl) amino] -3 Nitroquinoline is added and the reaction mixture is hydrogenated on a Parr apparatus under an initial hydrogen pressure of 210 kPa. Upon completion, the solid precipitate was removed and the ethyl acetate was evaporated. The remaining diamine (i.e., intermediate) was stirred with 60 ml of ethoxyacetic acid and heated at 120 ° C for about 8 hours. The reaction mixture was cooled to room temperature, poured into water, basified with 6N sodium hydroxide solution and extracted five times with 100 ml of ether. The combined ethereal extracts were dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (20% methanol / ethyl acetate) to give the title compound (13.3 g, green oil) which was used in the following reactions.

Reference Example 2 Preparation of 1- (2-methoxyethyl) -2- (2-methoxymethyl) -1H-imidazo [4,5-c] quinoline

To a mixture of 1500 ml of ethyl acetate, 1 g of 5% carbon platinum catalyst and 6 g of magnesium sulfate is added 16.24 g (0.066 mol) of 4 - [(2-methoxyethyl) amino] -3-nitroquinoline, and hydrogenating the reaction mixture in a Parr apparatus at an initial pressure of 210 kPa. After hydrogenation, the solid precipitate was filtered off and the filtrate was evaporated to give ethyl acetate. The resulting diamine (as an intermediate) was heated with methoxyacetic acid (70 mL) at 150 ° C for 2-3 hours and then at 120 ° C for 2-3 hours. The reaction mixture was poured into water (400 mL), made strongly basic with 6N sodium hydroxide solution and extracted three times with 200 mL of ether. The combined ethereal extracts were washed with brine and evaporated to give 9.9 g of an oil which crystallized on standing. The aqueous layers were repeatedly extracted four times with 200 mL of ether, and the combined organic extracts were washed with brine and evaporated. The residue was recrystallized from ethyl acetate to give the title compound as yellow needle crystals (1.5 g).

Analysis:

Calculated: C, 66.4; H, 6.3; N, 15.5%;

Found: C, 66.6; H, 6.4; N, 16.1%.

Reference Example 3 Preparation of 1- (2-methoxyethyl) -2- (methoxymethyl) -1H-imidazo [4,5-c] quinoline-5-N-oxide

To a warm solution of 13.3 g (0.044 mol) of 1- (2-methoxyethyl) -2- (methoxymethyl) -1H-imidazo [4,5-c] quinoline prepared by the procedure of Reference Example 2 and 150 ml of ethyl acetate. 12.0 ml of 32% peracetic acid are added slowly and carefully. The reaction mixture was refluxed for 2-3 hours and then allowed to stand at room temperature overnight. The precipitate was collected, rinsed with ethyl acetate and evaporated; toluene is used as a co-solvent. 2.6 g of solid are obtained. The ethyl acetate filtrate was evaporated and the residue was taken up in about 300 ml of water and basified with concentrated ammonium hydroxide. The resulting precipitate was collected on a filter, rinsed with water, evaporated with toluene and dried. 5.6 g of a solid product are obtained. The total crude yield was 8.2 g, and the product was obtained for further reaction.

Reference Example 4

Preparation of 1- (2-methoxyethyl) -2- (methoxymethyl) -1H-imidazo [4,5-c] quinolin-4-amine

1.61 g (0.027 mol) of 1- (2-methoxyethyl) -2-methoxymethyl-1H-imidazo [4,5-c] quinoline-5-N-oxide prepared according to the procedure of Reference Example 3 and After cooling to 0-5 ° C, DKM solution (75 ml) was added with ice-cold concentrated ammonium hydroxide (75 ml) while stirring. Meanwhile, a precipitate forms. 5.59 g (0.029 mol) of p-toluenesulfonyl chloride dissolved in 20 ml of DKM are slowly added with stirring and cooling. The mixture is kept at 0-5 ° C for about 30 minutes (after addition) and stirred at room temperature the next day. DKM was evaporated from the reaction mixture and the solid was filtered off. The aqueous filtrate was concentrated under a stream of nitrogen, and the resulting precipitate was collected on a filter, washed with water, dried to give 5.1 g of a solid. The latter is taken up in water, acidified with concentrated hydrochloric acid and filtered. The filtrate was basified with 6N sodium hydroxide solution and the resulting precipitate was collected, rinsed with water and dried. This gave the title compound as colorless needle crystals, mp 126-127 ° C.

Analysis:

calcd: C, 62.9; H6,3; N, 19.6%;

Found: C, 62.9; H6,05; N, 19.3%.

Reference Example 5

Preparation of 2- (Ethoxymethyl) -1- (3-methoxypropyl) -1H-imidazo [4,5-c] quinoline-5-N-oxide

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2-Ethoxymethyl-1- (3-methoxypropyl) -1H-imidazo [4,5-c] quinoline (13.3 g, 0.044 mol) prepared in Reference Example 1 is dissolved in 150 ml of ethyl acetate, and 12 ml of 32% peracetic acid is added slowly to this solution. The reaction mixture was refluxed for 3-4 hours and then cooled to room temperature. The mixture was evaporated and the residue was diluted with water (300 mL), basified with concentrated ammonium hydroxide and extracted with ether (100 mL). The combined ether extract was dried over anhydrous magnesium sulfate and evaporated. This gives a small amount of a yellow, oily product. Therefore, the aqueous basic phase was extracted six times with 100 ml of ethyl acetate each time, and the combined extract was washed with brine, dried over anhydrous magnesium sulfate and evaporated to give a yellow solid residue, to which toluene was added and evaporated again. 3.56 g of the title compound are obtained in the form of a yellow crystalline solid which is confirmed by its nuclear magnetic resonance spectrum. The product was used as such in further reactions.

Reference Example 6

Preparation of 2- (Ethoxymethyl) -1- (3-methoxypropyl) -1H-imidazo [4,5-c] quinolin-4-amine

3.5 g (0.011 mol) of 2- (ethoxymethyl) -1- (3-methoxypropyl) -1H-imidazo [4,5-c] quinoline-5-N-oxide prepared in Reference Example 5 and 25 ml of DKM solution

After cooling to 0-5 ° C, 35 ml of concentrated ammonium hydroxide, previously cooled to 0-5 ° C, are added. The resulting mixture is stirred for about 15 minutes and a solution of 2.33 g (0.012 mol) of p-toluenesulfonyl chloride in 10 mL of DKM is added slowly with stirring. The reaction mixture was stirred for another 30 minutes at 0-5 ° C and then at room temperature for the next day and then the DKM was evaporated. The precipitate was collected on a filter, washed with water and recrystallized first from ethyl acetate then dichloroethane. The title compound is thus obtained in crystalline solid form. Mp 123.5-125 ° C.

Analysis:

Calculated: C, 64.95; H, 7.05; N, 17.8%; Found: C, 65.0; H, 7.0; N, 17.7%.

Claims (2)

PATENT CLAIMS CLAIMS 1. Compounds of formula (Va) wherein: Y is nitro or amino; R ₄ is an alkoxyalkyl group in which the alkoxy moiety has a carbon number of 1 to 4 and the alkyl moiety has a carbon number of 1 to 6. Compounds according to claim 1, wherein R 1 methoxyethyl or 3-methoxypropyl.