KR100235389B1 - 1-substituted, 2-substituted 1h-imidazo(4,5-c)quinoline-4-amine - Google Patents

Abstract

The present invention relates to 1-substituted, 2-substituted 1H-imidazo [4,5-c] quinolin-4-amine compounds of formula (I):

In formula (I), X is alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, alkyl amido, amino, substituted amino or hydroxyalkyl (substituents are alkyl, azido, chloro, hydroxy, 1-mo Polyno, 1-pyrrolidino, and alkylthio). These compounds function as antiviral agents, induce interferon biosynthesis, and inhibit tumor formation in animal models. The invention also provides an intermediate for preparing the compounds, a pharmaceutical composition containing the compounds, and a pharmacological method of using the compounds.

Description

[Name of invention]

1-substituted, 2-substituted 1H-imidazo [4,5-c] quinolin-4-amines

Detailed description of the invention

This application is part of US Patent Application Ser. No. 07 / 687,326, filed on April 18, 1991, and commonly assigned, and which is filed and filed on March 1, 1991, which is commonly pending. It is now part of the abandoned application.

[Background of invention]

[Field of Invention]

The present invention relates to 1H-imidazo [4,5-c] -quinoline compounds. In another aspect, the invention provides antiviral 1H-imidazo [4,5-c] quinolin-4-amines, intermediates for the preparation of such compounds, pharmaceutical compositions containing such compounds and pharmacology using such compounds It's about the enemy way.

[Description of Related Fields]

The first reliable report on the 1H-imidazo- [4,5-c] quinoline ring system (J. Org. Chem. 15, 1278-1284 (1950) by Baekman et al.) Contains 1- available as antimalarial agents. The synthesis of (6-methoxy-8-quinolinyl) -2-methyl-1H-imidazo [4,5-c] -quinoline is described. Subsequently, the synthesis of various substituted 1H-imidazo [4,5-c] quinolines has been reported. For example, Jane et al. (J. Med. Chem. 11, 87-92 (1968)) disclose compound 1- [2- (4-piperidyl) ethyl] -1H- that can be used as an anticonvulsant and cardiovascular agent. Imidazo [4,5-c] quinoline was synthesized. Varanof et al. (Chem. Abs. 85,94362 (1976)) reported several 2-oxoimidazo [4,5-] quinolines, and Bereny et al. (J. Heterocyclic Chem. 18,1537-1540 (1981). )) Reported certain 2-oxoimidazo [4,5-c] -quinolines.

Certain antiviral 1H-imidazo [4,5-c] quinolin-4-amines are described in US Pat. No. 4,689,338 (Guster). These compounds are substituted with alkyl, hydroxyalkyl, acyloxyalkyl, benzyl, phenylethyl or substituted phenylethyl in the 1-position and hydrogen, alkyl, benzyl or substituted benzyl, phenylethyl or phenyl in the 2-position It is. In addition, these compounds are known to induce interferon biosynthesis. Other antiviral 1H-imidazo [4,5-c] quinolin-4-amines substituted with alkenyl substituents in the 1-position are described in US Pat. No. 4,929,624 (Guster).

U.S. Pat. No. 4,698,348 (Guster) discloses 1H-imidazo [4,5-c] quinoline, for example 4-substituted 1H-imidazo [4,5-c] quinoline, which is active as a bronchodilator. Wherein the 4-substituent is especially hydrogen, chloro, alkylamino or dialkylamino and the 2-substituent is especially hydroxyalkyl, aminoalkyl or alkanamido alkyl. The patent also includes 3-amino and 3-nitroquinoline intermediates substituted with hydroxyalkylamino or cyclohexyl methylamino in the 4-position, and in particular hydroxyalkyl, aminoalkyl or alkanamidoalkyl in the 2-position. 1H-imidazo [4,5-c] quinoline N-oxide intermediates are disclosed.

Detailed description of the invention

The present invention provides a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof:

Wherein R ₁ is hydrogen; Straight or branched chain alkyl having 1 to about 10 carbon atoms and substituted straight or branched chain alkyl having 1 to about 10 carbon atoms wherein the substituent is cycloalkyl having 3 to about 6 carbon atoms, and 1 to about 4 carbon atoms Is substituted from straight or branched chain alkyl with one and selected from the group consisting of cycloalkyl having from 3 to about 6 carbon atoms; Straight or branched alkenyl having 2 to about 10 carbon atoms, and substituted straight or branched alkenyl having 2 to about 10 carbon atoms, wherein the substituent is cycloalkyl having 3 to about 6 carbon atoms, and 1 to about Selected from the group consisting of cycloalkyl having 3 to about 6 carbon atoms and substituted by straight or branched alkyl having 4 carbon atoms; Hydroxyalkyl of 1 to about 6 carbon atoms; Alkoxyalkyl wherein the alkoxy moiety has 1 to about 4 carbon atoms and the alkyl moiety has 1 to about 6 carbon atoms; Acyloxyalkyl wherein the acyloxy moiety is an alkanoyloxy or benzoyloxy of 2 to about 4 carbon atoms and the alkyl moiety has 1 to about 6 carbon atoms; benzyl; (Phenyl) ethyl; And phenyl; Benzyl unsubstituted or substituted on the benzene ring by one or two moieties independently selected from the group consisting of alkyl of 1 to about 4 carbon atoms, alkoxy of 1 to about 4 carbon atoms, and halogen. (Phenyl) ethyl or phenyl substituents provided the benzene rings are substituted by two of the moieties provided the moieties have up to 6 carbon atoms together; R ₂ and R ₃ are selected from the group consisting of hydrogen, alkyl of 1 to about 4 carbon atoms, phenyl and substituted phenyl (substituted alkyl of 1 to about 4 carbon atoms, alkoxy of 1 to about 4 carbon atoms, and halogen Independently from the group consisting of; X is alkoxy having 1 to about 4 carbon atoms, alkoxyalkyl having 1 to about 4 carbon atoms and alkyl group having 1 to about 4 carbon atoms, hydroxyalkyl of 1 to about 4 carbon atoms, Haloalkyl of 1 to about 4 carbon atoms, alkylamido, wherein the alkyl group has 1 to about 4 carbon atoms, amino, substituted amino (substituent is hydroxyalkyl or alkyl of 1 to about 4 carbon atoms), azi Chloro, hydroxy, 1-morpholino, 1-pyrrolidino, and alkylthio of 1 to about 4 carbon atoms; R is selected from the group consisting of hydrogen, straight or branched alkoxy having 1 to about 4 carbon atoms, halogen, and straight or branched chain alkyl having 1 to about 4 carbon atoms.

The present invention provides an intermediate compound of formula (Va):

Wherein R is as defined above, Y is -NO ₂ or -NH ₂ , and R ₄ is an alkoxy moiety having from 1 to about 4 carbon atoms and an alkyl moiety having from 2 to about 6 carbon atoms Alkoxyalkyl.

The present invention provides an intermediate compound of formula (VIIa):

Wherein R is as defined above in connection with formula (Va) and R ₄ is alkoxyalkyl wherein the alkoxy moiety has 1 to about 4 carbon atoms and the alkyl moiety has 1 to about 6 carbon atoms .

The present invention provides an intermediate compound of formula (VIIa):

Wherein R, R ₂ and R ₃ are as defined above; R ₅ is straight or branched chain alkyl having 1 to about 10 carbon atoms and substituted straight or branched chain alkyl having 1 to about 10 carbon atoms wherein the substituent is cycloalkyl having 3 to about 6 carbon atoms, and 1 to about Selected from the group consisting of cycloalkyl having 3 to about 6 carbon atoms and substituted by straight or branched alkyl having 4 carbon atoms; Straight or branched alkenyl having 2 to about 10 carbon atoms, and substituted straight or branched alkenyl having 2 to about 10 carbon atoms, wherein the substituent is cycloalkyl having 3 to about 6 carbon atoms, and 1 to about Selected from the group consisting of cycloalkyl having 3 to about 6 carbon atoms and substituted by straight or branched alkyl having 4 carbon atoms; Alkoxyalkyl having an alkoxy moiety having from 1 to about 4 carbon atoms and alkyl group having 1 to about 6 carbon atoms; Acyloxyalkyl wherein the acyloxy moiety is an alkanoyloxy or benzoyloxy of 2 to about 4 carbon atoms and the alkyl moiety has 1 to about 6 carbon atoms; benzyl; (Phenyl) ethyl; And phenyl; Benzyl, (phenyl) ethyl or phenyl unsubstituted or substituted on the benzene ring by one or two moieties independently selected from the group consisting of alkyl of 1 to about 4 carbon atoms, alkoxy of 1 to about 4 carbon atoms, and halogen A substituent, provided that when the benzene ring is substituted by two of the moieties, those moieties together have up to 6 carbon atoms; G is alkoxy having 1 to about 4 carbon atoms, alkoxyalkyl having 1 to about 4 carbon atoms and alkyl group having 1 to about 4 carbon atoms, alkyl group having 1 to about 4 carbon atoms Phosphorus alkylamido, azido, chloro, 1-morpholino, 1-pyrrolidino, alkylthio of 1 to about 4 carbon atoms, alkanoyloxy, alkanoyloxyalkyl (alkyl moiety having from 1 to about 4 carbon sources) And aroyloxy (provided that when G is alkylamido, then R ₅ is alkenyl, substituted alkenyl or alkoxyalkyl).

The present invention further provides a compound of formula (XIa):

Wherein R, R ₂ , R ₃ and R ₅ are as defined above, Z is an alkoxy having 1 to about 4 carbon atoms, an alkoxy moiety having 1 to about 4 carbon atoms and an alkyl moiety having 1 to Alkoxyalkyl having about 4 carbon atoms, hydroxyalkyl of 1 to about 4 carbon atoms, oxoalkyl having 2 to about 4 carbon atoms, alkanoyloxyalkyl wherein the alkyl moiety has 1 to about 4 carbon atoms Alkylamido, wherein the alkyl group has 1 to about 4 carbon atoms, substituted amino (the substituent is hydroxyalkyl or alkyl of 1 to about 4 carbon atoms), azido, chloro, 1-morpholino, 1 -Pyrrolidino, selected from the group consisting of alkylthio, hydroxy, alkanoyloxy, and aroyloxy of 1 to about 4 carbon atoms; Q is selected from the group consisting of hydrogen, chloro and R _i -E-NH-, where R _i is an organic group substantially inert to quinoline N-oxide, and E is a functional group with hydrolytic activity, wherein Q When Z is R _i -E-NH-, Z is other than hydroxy, substituted amino or hydroxyalkyl, when Q is hydrogen or chloro and Z is alkylamido or hydroxyalkyl, R ₅ is alkenyl, Subject to substituted alkenyl or alkoxyalkyl.

R ₁ in formula (I) preferably contains 2 to about 10 carbon atoms. More preferably R ₁ contains from 2 to about 8 carbon atoms, most preferably R ₁ is 2-methylpropyl or benzyl.

X in formula (I) is preferably azido, hydroxy, ethoxy, methoxy, 1-morpholino or methylthio, wherein R ₁ is 2-methylpropyl, 2-hydroxy-2-methylpropyl or benzyl This is particularly the case in phosphorus embodiments.

In the compounds of formula (I) having alkyl radicals (e.g., alkoxy or alkyl R, or alkylamidoin), the other substituents preferably have two carbon atoms in each alkyl radical, preferably having one carbon atom. More preferred.

It is preferable that R in formula (I) is hydrogen.

Most preferred compounds of formula (I) are 4-amino-α-butyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] -quinoline-2-methanol hemihydrate, 4-amino -α, α-dimethyl-2-ethoxymethyl-1H-imidazo [4,5-c] quinoline-1-ethanol, 2-ethoxymethyl-1- (2-methylpropyl) -1H-imidazo [ 4,5-c] quinolin-4-amine and 4-amino-1-phenylmethyl-1H-imidazo [4,5-c] quinolin-2-methanol.

The compounds of the present invention can be prepared as described in the following reaction scheme, wherein R, R ₁ , R ₂ , R ₃ and V are as defined above and P is a hydroxyl protecting group which can be removed later, eg For example alkanoyloxy (eg acetoxy) or aroyloxy (eg benzoyloxy) and R ₅ is as defined for R ₁ above without hydroxyalkyl and hydrogen.

Many quinolines of formula (III) are known compounds (see, eg, US Pat. No. 3,700,674). Quinoline of the unknown formula (III) can be prepared by known methods, for example, from 4-hydroxy-3-nitroquinoline illustrated in step (1) of Scheme (I) below. Step (1) may be carried out by reacting the 4-hydroxy-3-nitroquinoline of formula (II) with a chlorinating agent such as thionyl chloride or phosphorus oxychloride. In N, N-dimethylformamide, it is preferred to carry out the reaction, optionally in the presence of methylene chloride, preferably with heating. It is desirable to avoid excessive molar amounts of phosphorus oxychloride. It has been found to be particularly preferred to use about 1-2 moles of oxychloride per mole of 4-hydroxy-3-nitroquinoline of formula (II).

In step (2), the 3-nitro-4-chloroquinoline of formula (III) is combined with an amine of formula R ₅ NH ₂ (R ₅ is as described above) in a suitable solvent such as water, methane dichloride or tetrahydrofuran. The reaction was carried out by heating in the mixture to obtain quinoline of formula (IV). Steps (1) and (2) can be combined so that 3-nitro-4-chloroquinoline does not have to be separated before reacting with the compound of formula R ₅ NH ₂ . Such a reaction is illustrated in Example 134 and Example 188 (Step A) of US Pat. No. 4,689,338, which is incorporated herein by reference.

The compound of formula (IV) is reduced in step (3), preferably using a catalyst such as platinum on carbon to give the compound of formula (V). This reaction can be conveniently carried out on a Parr device in an inert solvent such as toluene or lower alkanol.

In step (4), the intermediate compound of formula (V) is either (i) a carboxylic acid of formula (OH) (R ₂ ) (R ₃ ) CCO ₂ H or (ii) formula (OH) (R ₂ ) (R ₃ ) CC (Oalkyl) ₃ is a trialkyl ortho ester, wherein ＂alkyl＂ is a straight or branched alkyl group having 1 to about 4 carbon atoms or (iii) a combination of the carboxylic acid and the trialkyl ortho ester Reaction yields a compound of formula (VI). In any case, the reaction can be carried out by heating the acid, preferably the formula (OH) (R ₃ ) (R ₂ ) CCO ₂ H, in the presence of carboxylic acid, for example at about 130 ° C.

Another method of providing a 2-substituted imidazo ring is illustrated in steps (5) and (6). Step (5) involves a reaction similar to that described with respect to step (4), but with the reaction with formic acid or trialkylorthoformate to form the intermediate of formula. Remove the protons with a strong base (e.g., alkyllithium such as n-butyllithium) with the intermediate of formula The silver compound can be reacted to form an intermediate of formula (VI).

Step 7 comprises protecting the hydroxyl group with a removable protecting group such as an alkanoyloxy group (eg acetoxy) or an aroyloxy group (eg benzoyloxy). If hydroxyl groups are present in the 1-substituent, they can also be removed as appropriate when protected in step (7) and later no longer interfere with subsequent reactions.

Suitable protecting groups and their placement and removal reactions are well known to those skilled in the art. See, eg, Examples 115-123 of US Pat. No. 4,689,338 (Guster).

Step (8) oxidizes the compound of formula (IV) with a conventional oxidant capable of forming an N-oxide to provide an intermediate of formula (VII). Preferred oxidizing agents are acids peroxide and hydrogen peroxide. Heating is generally used to accelerate the reaction rate.

In step (9), the N-oxide of formula (VII) is heated in the presence of a suitable chlorinating agent such as phosphorus oxychloride to obtain the chlorinated intermediate of formula (VII).

In step (10), the 4-chloro group is replaced with a 4-amino group and the protecting group (p) is removed to give a compound of formula (XII) (subclass of formula (I)). The amination reaction is carried out in the presence of ammonium hydroxide or preferably ammonia. It is preferable to heat the intermediate of formula (V) for 6-24 hours at 125 ° C to 175 ° C under pressure. Preferably, the reaction is carried out in a closed reactor in the presence of ammonium hydroxide, or ammonia solution in alkanol (eg, about 5 to about 15% in methanol is preferably ammonia).

Compounds of formula (XII) may also be prepared by step 9a of the reaction scheme. Step 9a comprises: (i) reacting a compound of formula (iii) with an acylating agent; (ii) reacting the product with an amination agent; Consisting of separating the compound of formula (XII). Detail step (i) of step 9a consists of reacting the N-oxide with an acylating agent. Suitable acylating agents are alkylsulfonyl chlorides or arylsulfonyl chlorides such as benzenesulfonyl chloride, methanesulfonyl chloride, p-toluenesulfonyl chloride. Preference is given to arylsulfonyl chloride. Most preferred is p-toluenesulfonyl chloride. Substep (ii) of step (9a) consists of reacting the product of substep (i) with an amination agent excess. Suitable amination agents include ammonia (eg in the form of ammonium hydroxide) and ammonium salts (eg ammonium carbonate, ammonium bicarbonate and ammonium phosphate). Ammonium hydroxide is preferred. The reaction of step 9a is preferably carried out by dissolving the N-oxide of formula in an inert solvent such as methylene chloride, adding the amination agent to the solution and then adding the acylation agent. Preferred conditions include cooling to about 0 ° C. to about 5 ° C. during the addition of the acylating agent. Heating or cooling can be used to control the reaction rate. Step 9a also includes the removal of the protecting group P discussed above in connection with step 7. Another method for preparing the compound of formula (iii) is shown in steps (11) and (12).

Step 11 involves reacting an N-oxide with an isocyanate, where the isocyanate group is bound to a functional group with hydrolytic activity. The term “functional group with hydrolytic activity” means any functional group capable of carrying out a nucleophilic substitution reaction in step 12 of the reaction scheme. Examples of functional groups having hydrolytic activity include carbonyl ( There is). A particular class of said isocyanates is an isocyanate of the formula R _i -E-NCO, wherein R _i is an organic group that is substantially inert to quinoline N-oxide under the conditions of step (11), and E is a functional group with hydrolytic activity to be. Suitable R _i groups are readily selected by those skilled in the art. Preferred R _i groups are alkyl, aryl, alkenyl and combinations thereof. Particularly preferred isocyanates include aroyl isocyanates such as benzoyl isocyanate. The reaction of the isocyanate with the N-oxide is carried out under substantially anhydrous state by adding the isocyanate to a solution of the N-oxide in an inert solvent such as carbon dichloride. The resulting 4-substituted compound of formula (XI) can be separated by removal of the solvent.

Reaction Scheme

Step 12 of the reaction scheme involves hydrolysis of the compound of formula (XI). As used herein, the term “hydrolysis” means not only nucleophilic substitution with water, but also substitution with other nucleophilic compounds. Such reactions can be carried out in a general manner well known to those skilled in the art, for example by heating in the presence of a nucleophilic solvent such as water or lower alkanol in the presence of an optional catalyst such as alkali metal hydroxide or lower alkoxide.

In step (9a), (10) or (12), the compound containing a protecting group such as acetoxy, benzoyloxy and the like is removed to become a compound containing a hydroxyl group. The hydroxyl-containing compound of formula (I) may be converted or processed by methods well known to those skilled in the art to further provide a compound of formula (I). For example, reaction with thionyl chloride will provide a compound of formula (I) wherein X is chloro. The reaction of this compound with a nucleophilic group such as sodium azide, pyrrolidine, methanethiol or morpholine results in a compound of formula (I) wherein X is azido, 1-pyrrolidino, thiomethyl or 1-morpholino, respectively. Will provide. Reducing the azido compound provides a compound of formula (I) wherein X is amino. Such amino compounds may be acylated to give compounds wherein X is alkylamido.

Some compounds of formula (I) may be prepared by analogous reaction schemes in which the X group is introduced directly in step (4) and the hydroxy alkyl substituents may be allowed in the 1-position with the proper use of various protection and deprotection steps. Can be.

Substituents at the 2-position are introduced by reacting a compound of formula (XIII) with a lithiating agent such as lithium diisopropylamide or n-butyllithium in a polar aprotic solvent to be lithiated on a 2-methyl group. To provide.

Wherein R and R ₅ are as defined above.

The lithiated compound is then reacted with a suitable reagent containing a leaving group that may be substituted by a lithiated 2-methyl group (e.g. chloromethylmethylether or N-methoxy-N-methyl acetamide) to form a 2-methyl group Can be processed. The compound can then be maintained as suitable for the compound of formula (I).

While not all compounds of formula (I) can be prepared by the illustrated reaction schemes, known schemes may be readily applied to those skilled in the art to prepare compounds other than those exemplified herein. For example, compounds in which R ₁ is alkenyl can be prepared using the general scheme set forth in US Pat. No. 4,929,624 (Guster et al.) Or variations thereof, and compounds in which R ₁ is hydrogen are commonly transferred and simultaneously It may be prepared using the general scheme presented in pending application 07 / 484,761 (Guster) or a variant thereof, the two patents of which are incorporated herein by reference. Another synthetic scheme that can be used by those skilled in the art in the preparation of some of the compounds of the present invention is disclosed in US Pat. No. 4,988,815 to Andre et al., Which is incorporated herein by reference. Those skilled in the art will also recognize that upon modification of the reaction sequence and use of conventional synthetic alternatives, the preparation of the compounds of the present invention will not follow the illustrated scheme.

The resulting compound of formula (I) can be removed and recrystallized by, for example, conventional means as disclosed in US Pat. No. 4,689,338 (Guster), from a suitable solvent such as N, N-dimethylformamide or a solvent mixture. By separation or by dissolution in a suitable solvent such as methanol and by reprecipitation by addition of a second solvent in which the compound is insoluble.

The compounds of formula (I) can be used as antiviral agents themselves or in the form of pharmaceutically acceptable acid-addition salts such as hydrochloride, sulfate, phosphate, nitrate, methanesulfonate or other salts of pharmaceutically acceptable acids. Can be. Pharmaceutically acceptable acid-addition salts of the compounds of formula (I) generally allow the compounds to be dissolved in polar solvent in an equal molar amount of relatively strong acids, preferably inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, or organic acids such as methanesulfonic acid. It can manufacture by reaction of. Separation of the salt is facilitated by the addition of a solvent, such as diethyl ether, where the salt is insoluble.

The compounds of the present invention may be formulated in pharmaceutically acceptable carriers such as water or polyethylene glycol with additives, excipients and the like suitable for various routes of administration. Certain formulations can be readily selected by one of ordinary skill in the art. Suitable formulations for topical administration include preparations such as creams, ointments and the like known to those skilled in the art. The formulations generally contain up to 10% by weight of the compound of formula (I), preferably about 0.1 to 5% by weight of the compound of formula (I).

Compounds of formula (I) exhibit antiviral activity in mammals. Therefore, these compounds can be used to control viral infections. For example, the compound of formula (I) can be used as an agent to control mammalian infection caused by type II herpes simplex virus. Compounds of formula (I) can also be used to treat a herpes infection by oral, topical or intraperitoneal administration.

Many compounds of formula (I) were tested and found to induce interferon biosynthesis in human cells and in mice. In addition, many compounds of formula (I) were tested to find that they inhibit tumors in mice. Test methods and results are shown below. These results indicate that at least certain compounds of the invention treat other diseases such as rheumatoid arthritis, warts, eczema, hepatitis B, psoriasis, multiple sclerosis, essential thrombocytopenia, cancer (eg, basal cell carcinoma) and other tumor diseases. Imply that it can be used to.

In the examples below, all reactions are carried out with stirring under a dry nitrogen atmosphere unless otherwise indicated. The specific materials recited in the examples and amounts thereof, as well as other conditions and details, should not be construed as unduly limiting the present invention.

Example 1

[1- (2-Methylpropyl) -1H-imidazo [4,5-c] -quinoline-2-methanol]

3-nitro-4- (2-methylpropylamino) quinoline (36.8 g; 0.15 mole) was added to a mixture of ethyl acetate (300 mL), 5% Pt / C (about 1 g) and magnesium sulfate (30 g). The mixture was hydrogenated at about 50 psi at an initial pressure. When the hydrogenation reaction was complete, the solid was filtered out of the mixture and ethyl acetate was evaporated. The resulting intermediate diamine was mixed with glycolic acid (26.9 g; 0.35 mole) and the mixture was heated at 150-160 ° C. for about 3 hours with manual stirring from time to time. The reaction mixture was then dissolved in dilute hydrochloric acid and treated with decolorized carbon, and the solid was filtered from the mixture. The filtrate was made basic with ammonium hydroxide to precipitate the product as a green solid. The solid was filtered and dried to give 34.3 g (89.6%) of crude product. The solid was reprecipitated again as above and the product was recrystallized from ethyl acetate to give green crystals.

Melting Point: 165-168 ℃

Assay: calcd: C, 70.6; H, 6.7; N, 16.5.

Found: C, 70.4; H, 6.7; N, 16.3.

Example 2

[1- (2-Methylpropyl) -1H-imidazo [4,5-c] -quinoline-2-methyl acetate]

1- (2-methylpropyl) -1H-imidazo [4,5-c] -quinoline-2-methanol (51.4 g; 0.2 mol, Example 1); triethylamine (30.9 ml; 0.22 mol) It was dissolved in containing methane dichloride (500 mL). The solution was stirred at room temperature while acetyl chloride was added dropwise. The resulting solution was stirred at room temperature for about 24 hours and washed with water and aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and evaporated to give 58.1 g (97%) of acetate as a brown solid. The product was recrystallized from ethyl acetate to give a tan solid.

Melting point: 147-154 deg.

Assay: calcd: C, 68.7; H, 6.4; N, 14.1.

Found: C, 68.1; H, 6.4; N, 13.8.

Example 3

[1- (2-Methylpropyl) -1H-imidazo [4,5-c] -quinoline-2-methyl benzoate]

Example 2 prepared the title compound from 1- (2-methylpropyl) -1H-imidazo [4,5-c] -quinoline-2-methanol using benzoyl chloride in the general method.

Example 4

[2-acetoxymethyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline 5N oxide]

1- (2-Methylpropyl) -1H-imidazo [4,5-c] -quinoline-2-methylacetate (63.0 g; 0.21 mol, Example 2) was suspended in ethanol (475 mL) and 32% Acetic peroxide (89 mL; 0.42 mol) was added to the mixture. The mixture was heated at 50 ° C. for 2 hours with stirring. Upon heating the solid dissolved and a heavy precipitate formed after 1.5 hours. The precipitate was filtered from the mixture and dried to give 33.7 g of N-oxide. The filtrate was concentrated to 100 ml and a further 15.2 g collected solid. A total crude yield of 48.9 g (74.3%) was obtained. The material was recrystallized from ethanol to give light yellow crystals.

Melting point: 233-240 ° C.

Assay: calcd: C, 65.1; H, 6.1; N, 13.4.

Found: C, 64.6; H, 6.1; N, 13.2.

Example 5

[2-benzoyloxymethyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline 5N oxide]

Example 4 prepared the title compound using 1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline-2-methylbenzoate (Example 3) in the process and ethyl acetate Recrystallization from gave pure product.

Melting point: 192-195 ° C.

Assay: calcd: C, 70.4; H, 5.6; N, 11.2.

Found: C, 70.6; H, 5.7; N, 11.2.

Example 6

4-chloro-1- (2-methylpropyl) -1H-imidazo- [4,5-c] quinoline-2-methyl acetate

2-acetoxymethyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline 5N oxide (48.9 g; 0.156 moles, Example 4) was suspended in methane dichloride (500 mL) Phosphorus oxychloride (17.5 mL; 0.187 mol) was added dropwise to the stirred suspension. The reaction rate was controlled by adjusting the rate of addition. At the end of the addition, the mixture was stirred at reflux for 1 hour. The mixture was then carefully neutralized with sodium bicarbonate. All solids were dissolved in methane dichloride. The organic layer was separated, dried over magnesium sulfate and evaporated to afford 43.6 g (84.2%) of crude product. A small amount was purified by silica gel flash chromatography (using ethyl acetate as eluent) and recrystallized from ethyl acetate to give a pure sample.

Melting point: 182-188 deg.

Assay: calcd: C, 61.5; H, 5.5; N, 12.7.

Found: C, 61.5; H, 5.4; N, 12.6.

Example 7

[4-Chloro-1- (2-methylpropyl) -1H-imidazo- [4,5-c] quinoline-2-methyl benzoate]

In the method of Example 6 the title compound was prepared using 2-benzoyloxymethyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline-5N-oxide and ethyl acetate / Recrystallization from hexanes was analyzed and characterized.

Melting point: 143-150 ° C.

Assay: calcd: C, 67.1; H, 5.1; N, 10.7.

Found: C, 67.2; H, 5.1; N, 10.6.

Example 8

[4-Chloro-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline-2-methanol]

4-Chloro-1- (2-methylpropyl) -1H-imidazo- [4,5-c] quinoline-2-methylbenzoate (14.3 g; 0.36 mol, Example 7) was dried over methanol (350 mL). Suspended in. The mixture was made basic (pH 10) with 25% sodium methoxide. The mixture was stirred at room temperature for 5 hours, after which only a very small amount of starting material was identified by silica gel TLC (ethyl acetate as eluent). The mixture was acidified with acetic acid and concentrated to dryness. The residue was slurried in ether. The solid was filtered from the mixture and suspended in an aqueous sodium hydroxide solution. The product was filtered from the mixture, washed with water and dried to yield 7.5 g (71.4%) of a tan solid. The product was recrystallized from ethanol to yield 4.8 g of pure product.

Melting point: 162-166 ° C.

Assay: calcd: C, 62.2; H, 5.6; N, 14.5.

Found: C, 62.2; H, 5.6; N, 14.3.

Example 9

[4-amino-1- (2-methylpropyl) -1H-imidazo- [4,5-c] quinoline-2-methanol]

4-chloro-1- (2-methylpropyl) -1Himidazo- [4,5-c] quinoline-2-methylbenzoate (5.0 g; 0.13 moles, Example 7) was added 15% methanol containing ammonia ( 50 ml). The mixture was heated at 175 ° C. for 7 hours in Parr bomb. The resulting solution was evaporated to reduce volume. Sticky solid crystallized from the solution. The solid was filtered from the mixture and slurried in aqueous sodium bicarbonate solution. The resulting solid was filtered from the mixture, washed with water and dried to give 2.1 g (62.7%) of crude product, which was recrystallized from ethanol several times to give pure product.

Melting point: 226-231 ° C.

Assay: calcd: C, 66.6; H, 6.7; N, 20.7.

Found: C, 66.4; H, 6.5; N, 20.4.

Example 10

[2-Chloromethyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinolin-4-amine hydrochloride]

4-amino-1- (2-methylpropyl) -1H-imidazo- [4,5-c] quinoline-2-methanol (5.0 g; 0.0185 mol, Example 9) was prepared by vigorously stirring thionyl chloride ( 25 ml). The resulting mixture was stirred at rt overnight. The mixture was diluted with 100 mL of ether and the solid was filtered from the mixture and dried thoroughly. The product was pure enough for the subsequent reaction. The sample was recrystallized from ethanol to give pure product.

Melting point: 279-292 ° C.

Assay: calcd: C, 55.4; H, 5.6; N, 17.2.

Found: C, 55.3; H, 5.5; N, 17.1.

Example 11

[2-azidomethyl-1- (2-methylpropyl) -1H-imidazo- [4,5-c] quinolin-4-amine]

2-Chloromethyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinolin-4-amine hydrochloride (2.5 g; 0.0077 moles, Example 10) was treated with N-methylpyrrolidone ( 15 ml). A solution of lithium azide (2.3 g) in water (45 mL) was added to the suspension. The resulting mixture was heated in a steam bath for 2 hours and diluted with water (about 45 mL). The tan solid was washed with water and dried to afford 1.4 g (60.9%) of crude product. The solid was recrystallized from ethanol to give pure product.

Melting point: 174-178 ° C.

Assay: calcd: C, 61.0; H, 5.8; N, 33.2.

Found: C, 60.9; H, 5.6; N, 32.6.

Example 12

[1- (2-Methylpropyl) -2-morpholinomethyl-1H-imidazo- [4,5-c] quinolin-4-amine]

2-chloromethyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinolin-4-amine hydrochloride (Example 10, prepared from 2.0 g of the corresponding alcohol) )). The mixture was refluxed for 4 hours. The resulting solution was cooled to room temperature. A solid precipitated out. The solid was filtered from the mixture and slurried in aqueous sodium bicarbonate solution. The product was filtered from the mixture, washed with water and dried to give 1.7 g (68.0%) of solid, which was recrystallized from ethanol to give pure product.

Melting point: 228-234 ° C.

Assay: calcd: C, 67.2; H, 7.4; N, 20.6.

Found: C, 67.3; H, 7.9; N, 20.6.

Example 13

[1- (2-Methylpropyl) -2-pyrrolidinomethyl-1H-imidazo [4,5-c] quinolin-4-amine]

2-chloromethyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinolin-4-amine hydrochloride by using pyrrolidine in place of morpholine in the method of Example 12 (Example The pyrrolidinomethyl compound was prepared from 10). 1.90 g (63.0%) of crude product were obtained. The crude solid was recrystallized from ethanol to give pure product.

Melting point: 172-187 ° C.

Assay: calcd: C, 70.6; H, 7.8; N, 21.7.

Found: C, 70.6; H, 7.8; N, 21.5.

Example 14

[4-Amino-1- (2-methylpropyl) -1 H-imidazo- [4,5-c] quinoline-2methanamine]

2-Azidomethyl-1- (2-methylpropyl) -1H-imidazo- [4,5-c] quinolin-4-amine (3.2 g, 0.0108 mol, Example 11) in ethanol (300 mL) 5% Pd / C (about 1 g) was added to the mixture. The mixture was hydrogenated in a fire apparatus until hydrogen absorption stopped. The catalyst was regenerated by removing hydrogen and filling the mixture with hydrogen. The hydrogenation reaction occurred again. This procedure was repeated until hydrogen was no longer absorbed. The catalyst was filtered from the mixture and the filtrate was evaporated. The residue was recrystallized several times from ethanol to give yellow crystals.

Melting point: 287-291 ° C.

Assay: calcd: C, 66.9; H, 7.1; N, 26.0.

Found: C, 66.5; H, 7.2; N, 25.1.

Example 15

[N-acetyl-4-amino-1- (2-methylpropyl) -1H-imidazo- [4,5-c] quinoline-2-methanamine]

4-Amino-1- (2-methylpropyl) -1H-imidazo- [4,5-c] quinoline-2-methanamine (1.1 g; 0.004 moles, Example 14) was added to acetic anhydride (3 mL). Added. The mixture was stirred at rt for 5 h. The solution was diluted with methanol (50 mL) and refluxed for 1 hour. The solution was concentrated and the residue was made basic with aqueous sodium bicarbonate solution. The oily residue was extracted into methane dichloride. The extract was dried over magnesium sulfate and evaporated to dryness completely. The residue was recrystallized from ethyl acetate to give pure product.

Melting point: 214-218 ° C.

Assay: calcd: C, 65.6; H, 6.8; N, 22.5.

Found: C, 65.1; H, 6.6; N, 22.0.

Example 16

[α-methyl-1- (2-methylpropyl) -1H-imidazo- [4,5-c] quinoline-2-methanol]

3-amino-4- (2-methylpropylamino) quinoline (29.0 g; 0.135 mol) and lactic acid (36 mL; 0.48 mol) were mixed and heated at 140 ° C. for 6 hours. The mixture was then dissolved in dilute hydrochloric acid and treated with charcoal. The solid was filtered out of the mixture. The filtrate was made basic with ammonium hydroxide to precipitate the product as an oil. The oil was extracted into ethyl acetate. The ethyl acetate solution was treated with decolorized carbon and the solids were filtered out of the mixture. The filtrate was evaporated to dryness to give a green oil, which was pure enough for the subsequent reaction. A small amount of the sample was distributed with hexane to give a solid which was analyzed by recrystallization from ethyl acetate.

Melting Point: 152-166 ℃ .0

Assay: calcd: C, 71.4; H, 7. 11; N, 15.6.

Found: C, 71.1; H. 7.33; N. 15.4.

Example 17

[α-methyl-1- (2-methylpropyl) -1H-imidazo- [4,5-c] quinoline-2-methyl benzoate]

α-methyl-1- (2-methylpropyl) -1H-imidazo- [4,5-c] quinoline-2-methanol (20.0 g; 0.074 mol, Example 16) was dissolved in methane dichloride (200 mL). Was dissolved and triethylamine (11.4 mL; 0.082 mol) was added to the solution. Benzoyl chloride (9.5 mL; 0.082 mol) was added dropwise to the stirred solution. The mixture was stirred at rt for 6 h. The solution was washed with water and aqueous sodium bicarbonate solution, dried over magnesium sulfate and evaporated to give 26.6 g of green viscous oil. The product was pure enough for the subsequent N-oxidation reaction, but a small amount of the sample was purified by silica gel flash chromatography (ethyl acetate as eluent) for analysis and characterization.

Melting point: 158-163 ° C.

Assay: calcd: C, 74.0; H, 6.2; N, 11.3.

Found: C, 73.7; H, 6.2; N, 11.2.

Example 18

[α-Methyl-1- (2-methylpropyl) -1H-imidazo- [4,5-c] quinoline-2-methyl benzoate 5N oxide]

α-methyl-1- (2-methylpropyl) -1H-imidazo- [4,5-c] quinoline-2-methylbenzoate (11.7 g; 0.031 mol, Example 17) was added to ethanol, 32 % Acetic acid peroxide (11.1 mL; 0.0092 mol) was added to the solution. The mixture was heated at 65 ° C. for 5 hours. The solution was then evaporated to dryness. The residue was treated with aqueous sodium bicarbonate solution. The product was extracted into ethyl acetate, dried over magnesium sulfate and evaporated to give an oily residue containing trace amounts of starting material. The crude product was used in the subsequent reaction.

Example 19

[4-Chloro-α-methyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline-2-methyl benzoate]

α-methyl-1- (2-methylpropyl) -1H-imidazo- [4,5-c] quinoline-2-methyl benzoate 5N oxide (9.2 g; 0.0236 mol, Example 18) 200 ml). Phosphorous oxychloride (2.6 mL; 0.0283 moles) was added to the solution. The reaction mixture was stirred at rt for 2.5 h. The solution was evaporated and the residue was mixed with water and ammonium hydroxide. The oil was extracted into ethyl acetate. The extract was dried over magnesium sulfate and evaporated to dryness completely. 7.6 g (79.2%) of product was obtained as a glassy solid which was used as such in the subsequent reaction.

Example 20

[4-amino-α-methyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline-2-methanol]

15% of 4-chloro-α-methyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline-2-methyl benzoate (3.7 g; 0.009 mol, Example 19) It was added to methanol containing ammonia (50 mL). The mixture was heated at 165 ° C. for 6 h in spring. The resulting reaction mixture was evaporated and the residue slurried in aqueous sodium bicarbonate solution. The product was extracted into methane dichloride and the extract was washed with aqueous sodium bicarbonate solution and dried over magnesium sulfate. The organic extract was evaporated to dryness to yield an oily solid. The solid was purified by silica gel column chromatography to give two products, the intended product and 4- (N-methyl) derivative. The intended product (Rf = 0.36 silica gel TLC, ethyl acetate is the eluent) was recrystallized from ethanol to give a solid.

Melting point: 190-195 ° C.

Assay: calcd: C, 67.6; H, 7.1; N, 19.7.

Found: C, 67.6; H, 7.1; N, 19.7.

4- (N-methyl) derivative was recrystallized from ethyl acetate to give a solid.

Melting point: 145-149 ° C.

Assay: calcd: C, 68.4; H, 7.4; N, 18.8.

Found: C, 68.3; H, 7.4; N, 18.7.

Example 21

[α, α-dimethyl-1- (2-methylpropyl) -1H-imidazo- [4,5-c] quinoline-2-methanol]

3-amino-4- (2-methylpropyl amino) quinoline (28.7 g; 0.133 mol) and 2-hydroxyisobutyric acid (27.8 g; 0.267 mol) were mixed and the mixture was heated at 160 ° C. for 5 hours. Add to water and cloudy mixture to produce green oil. The oil was extracted with ether to yield 8.6 g of oil containing both products. The mixture was purified by silica gel column chromatography to yield 3.2 g of the intended product. Small amounts were analyzed and characterized by recrystallization from ethyl acetate.

Melting point: 156-164 ° C.

Assay: calcd: C, 72.1; H, 7.5; N, 14.8.

Found: C, 71.9; H, 7.4; N, 14.6.

Example 22

[4-Chloro-α, α-dimethyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline-2-methanol]

α, α-dimethyl-1- (2-methylpropyl) -1H-imidazo- [4,5-c] quinoline-2-methanol (3.0 g; 0.0106 mol, Example 21) in ethanol (30 mL) Dissolved and added 32% acetic acid peroxide (3.8 mL; 0.0108 moles). The mixture was heated at 65 ° C. for 4 hours. The solution was concentrated and the residue slurried in aqueous sodium bicarbonate solution. The oily product was extracted into ethyl acetate. The extract was dried over magnesium sulfate and evaporated to dryness. Yield of 2.8 g of N oxide was obtained as a yellow solid. Intermediate N oxide was added to methane dichloride and 1.1 equivalents of phosphorus oxychloride was added to the vigorously stirred mixture. The mixture was stirred overnight at room temperature and concentrated. The residue was slurried in aqueous sodium bicarbonate solution and extracted into ethyl acetate. The product was purified by silica gel flash chromatography (10% ethyl acetate in methane dichloride). A small amount was recrystallized from ethyl acetate to give a solid.

Melting point: 205-210 ° C.

Assay: calcd: C, 64.2; H, 6.3; N, 13.2.

Found: C, 64.2; H, 6.3; N, 13.1.

Example 23

[4-amino-α, α-dimethyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline-2-methanol]

4-chloro-α, α-dimethyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline-2-methanol (Example 22) using 15% methanol containing ammonia And amination at 150 ° C. in vaccum. The product was purified by silica gel column chromatography (5% methanol in ethyl acetate as eluent). The product was then recrystallized from ethyl acetate / hexanes to give a solid.

Melting point: 214-217 ° C.

Assay: calcd: C, 66.4; H, 7.4; N, 18.8.

Found: C, 68.2; H, 7.4; N, 18.7.

Example 24

[1-phenylmethyl-1H-imidazo [4,5-c] -quinoline-2-methanol]

3-amino-4- (benzylamino) quinoline (9.5 g; 0.038 mol) and glycolic acid (6.8 g; 0.089 mol) were mixed and the mixture was heated at 150 ° C. for about 4 hours. The cloudy mixture was dissolved in dilute hydrochloric acid while heating. On cooling a precipitate formed and filtered from the mixture. The solid was dissolved in hot water. The solution was then made basic with ammonium hydroxide to precipitate the product. From the original filtrate it was made basic with ammonium hydroxide to obtain a second, less pure, small amount of product. The solid was dispersed in ethyl acetate to give a green powder. Overall yield was 82%. The product was recrystallized from methanol to give a pure sample.

Melting point: 211-213 ° C.

Assay: calcd: C, 74.7; H, 5.2; N, 14.5.

Found: C, 74.4; H, 5.1; N, 14.4.

Example 25

[1-phenylmethyl-1H-imidazo [4,5-c] -quinoline-2-methyl acetate]

1-phenylmethyl-1H-imidazo [4,5-c] -quinoline-2-methanol (7.5 g; 0.026 moles, Example 24) was added to methane dichloride (70 mL). Acetic anhydride (5.7 mL) and pyridine (3.1 mL) were added to the mixture. The mixture was refluxed for about 6 hours and the solids were filtered from the mixture. The filtrate was evaporated and the residue was filtered and then slurried in water and methanol / water. The solid was then filtered from the mixture and dried to yield 6.7 g (74.4%) of product. The solid was recrystallized from methanol.

Melting point: 216-218 ° C.

Assay: calcd: C, 72.5; H, 5.2; N, 12.7.

Found: C, 72.1; H, 5.1; N, 12.6.

Example 26

[1-phenylmethyl-1H-imidazo [4,5-c] -quinoline-2-methyl acetate 5N oxide]

1-phenylmethyl-1H-imidazo [4,5-c] -quinoline-2-methyl acetate (6.7 g; 0.019 mol, Example 25) and 32% acetic acid peroxide (4.6 ml; 0.0214 mol) ethyl acetate (125 mL) and ethanol (250 mL) were added. The mixture was refluxed for 6 hours. The solution was evaporated to dryness and the residue slurried with aqueous sodium bicarbonate solution. The solid was filtered from the mixture, washed with water and dried to give 7.2 g of crude product. The crude product was recrystallized from ethyl acetate.

Melting point: 229-232 ° C.

Assay: calcd: C, 69.2; H, 4.9; N, 12.1.

Found: C, 69.1; H, 4.9; N, 12.0.

Example 27

[4-amino-1-phenylmethyl-1H-imidazo [4,5-c] -quinoline-2-methanol]

1-phenylmethyl-1H-imidazo [4,5-c] -quinoline-2-methyl acetate 5N oxide (5.6 g; 0.0162 mol, Example 26) was dissolved in methane dichloride (150 mL) and ammonium hydroxide (55 mL). Suspended in a mixture of; The mixture was cooled to 0-5 ° C. A solution of p-toluenesulfonyl chloride (3.4 g; 0.0178 mol) in methane dichloride (25 mL) was added dropwise to the stirred mixture vigorously while the temperature was maintained at 0-5 ° C. At the end of the addition, stirred overnight at room temperature. Methane dichloride was then evaporated from the mixture and the solids were filtered out of the mixture. The tan solid was washed with water and dried to give 5.5 g of product, which was observed to be the acetate of the intended product. Acetic acid was added to a mixture of methanol (300 mL) and methane dichloride (100 mL). The mixture was made basic with sodium methoxide containing 25% methanol. After 1/2 hour, the product began to precipitate out of solution. The solid was filtered from the mixture, washed successively with water and methanol and dried to give 3.1 g (64.6%). Samples were recrystallized from methanol / methane dichloride.

Melting point:> 300 ° C.

Assay: calcd: C, 71.0; H, 5.3; N, 18.4.

Found: C, 71.1; H, 5.0; N, 18.1.

Example 28

[2-Chloromethyl-1-phenylmethyl-1H-imidazo- [4,5-c] -quinolin-4-amine hydrochloride]

4-amino-1-phenylmethyl-1H-imidazo [4,5-c] -quinoline-2-methanol (2.0 g; 0.0066 mol, Example 27) was added in small amounts to thionyl chloride (10 mL). . After stirring for 30 minutes at room temperature the product crystallized out of solution. The mixture was diluted with dry ether (75 mL). The solid was filtered from the mixture, washed with ether and dried thoroughly. The product was used as is without further characterization or purification.

Example 29

[2-morpholinomethyl-1-phenylmethyl-1H-imidazo- [4,5-c] quinolin-4-amine]

2-Chloromethyl-1-phenylmethyl-1H-imidazo- [4,5-c] quinolin-4-amine hydrochloride (Example 28, prepared from 2.0 g of alcohol) was added to morpholine (5.0 mL) and The mixture was refluxed for 4 hours. The mixture was cooled to room temperature and the solids were filtered out of the mixture. The solid was slurried in aqueous sodium bicarbonate solution, filtered from the mixture and dried. 2.0 g of crude yield product was obtained as a white solid. The crude product was recrystallized from methanol / methane dichloride.

Melting point: 300 ° C.

Assay: calcd: C, 70.7; H, 6.2; N, 18.8.

Found: C, 70.4; H, 6.2; N, 18.6.

Example 30

[4-Amino-N-hydroxyethyl-N-methyl-1-phenylmethyl-1H-imidazo- [4,5-c] -quinolin-2-methanamine hemihydrate]

2-chloromethyl-1-phenylmethyl-1H-imidazo- [4,5-c] quinolin-4-amine hydrochloride (prepared from Example 28, 1.4 g of alcohol) was added N-methylethanolamine (20 mL The mixture was heated at about 130 ° C. for 3 hours in an oil bath. The solution was diluted with water and the mixture was extracted with diethyl ether (7 x 200 mL). The combined extracts were washed with saturated sodium chloride solution and evaporated to dryness to yield an orange solid. The crude product was recrystallized from methanol / methane dichloride.

Melting Point: 188-195 ℃

Assay: calcd: C, 68.1; H, 6.5; N, 18.9.

Found: C, 68.4; H, 6.5; N, 18.7.

Example 31

[2-Methylthiomethyl-1-phenylmethyl-1H-imidazo- [4,5-c] quinolin-4-amine]

2-Chloromethyl-1-phenylmethyl-1H-imidazo- [4,5-c] quinolin-4-amine hydrochloride (prepared from alcohol of Example 28, 2.11 g) was prepared with methanethiol (1.33 g) in methanol. ; 0.028 mol) and sodium methoxide (1.5 g; 0.028 mol) solution. Solids dissolved upon addition and a creamy solid precipitated out. After stirring for several hours at room temperature, the mixture was diluted with water. The solid was filtered from the mixture, washed with water and dried. A crude yield of 2.3 g was obtained. The product was purified by silica gel flash chromatography (10% ethanol in ethyl acetate eluent) and recrystallized from methanol / methane dichloride to give a cream solid.

Melting point: 217-219 ° C.

Assay: calcd: C, 68.2; H, 5.4; N, 16.8.

Found: C, 67.5; H, 5.3; N, 16.6.

Example 32

[2-methoxymethyl-1- (2-methylpropyl) -1H-imidazo- [4,5-c] -quinoline]

3-amino-4- (2-methylpropylamino) quinoline (5.0 g; 0.023 mol) and methoxyacetic acid (20 mL) were mixed and heated at about 200 ° C. until all bubbling ceased. Heating was continued for 5-10 more minutes and the cloudy solution was allowed to cool to room temperature. The solution was diluted with water, made strong base with 50% sodium hydroxide and extracted with ether. The combined extracts were dried over magnesium sulfate and evaporated to dryness to yield 5.2 g of crude product. The crude product was used as is for subsequent reactions. A small amount of sample was recrystallized from ether to give almost colorless crystals.

Melting point: 96-99 ° C.

Assay: calcd: C, 71.4; H, 7.1; N, 15.6.

Found: C, 71.1; H, 7.0; N, 15.6.

Example 33

[2-methoxymethyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline-5N-oxide monohydrate]

2-methoxymethyl-1- (2-methylpropyl) -1H-imidazo- [4,5-c] -quinoline (5.0 g; 0.0186 mol, Example 32) was added 32% acetic acid peroxide (4.9 g; 0.0206 mol)) to ethyl acetate (100 mL). The solution was refluxed for about 15 minutes. The solution was then evaporated. The residue was slurried in aqueous sodium bicarbonate solution and the solids were filtered out of the mixture. The filtrate was allowed to stand overnight at room temperature to give a second product. The combined yield of crude product was 4.6 g (86.8%). Recrystallization from isopropyl alcohol gave a pure sample.

Melting point: broad.

Assay: calcd: C, 63.5; H, 7.0; N, 13.8.

Found: C, 63.5; H, 6.7; N, 13.8.

Example 34

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

2-methoxymethyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline-5N-oxide (4.0; 0.014 mol, Example 33) was dissolved in methane dichloride (80 mL). Dissolved. Concentrated ammonium hydroxide (30 mL) was added to the solution. The mixture was cooled to 0-5 ° C. and vigorously stirred with a dropwise addition of a solution of p-toluenesulfonyl chloride (2.9 g; 0.015 moles) in methane dichloride (15 mL). The temperature was maintained at 0-5 ° C. upon addition. At the end of the addition, the mixture was stirred at room temperature for 1 hour. Methane dichloride was separated from the aqueous layer, dried over magnesium sulfate and evaporated to dryness to yield 1.7 g of a tan powder. Recrystallization twice from isopropyl alcohol yielded an analytically pure sample with a melting point of 157-160 ° C. and analysis of the form containing 1/4 mole of water.

Assay: calcd: C, 66.5; H, 7.2; N, 19.4.

Found: C, 66.9; H, 6.9; N, 19.0.

Example 35

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

4- (2-methoxyethylamino) -3-nitroquinoline (16.24 g; 0.066 mol) was added to a mixture of ethyl acetate (1500 mL), 5% platinum on carbon (1 g) and magnesium sulfate (6 g). . The mixture was hydrogenated on a fire apparatus at an initial pressure of 30 psi. At the end of the hydrogenation reaction, the solid was filtered off and ethyl acetate was evaporated. The resulting diamine intermediate was heated with methoxyacetic acid (70 mL) at 150 ° C. for 2-3 hours and at 120 ° C. for 2-3 hours. The reaction mixture was poured into water (400 mL), made strong with 6N sodium hydroxide and extracted with ether (3 x 200 mL). The ether extracts were combined, washed with brine and evaporated to yield 9.9 g of oil which was left to crystallize. The aqueous layer was reextracted with ether (4 x 200 mL). The extracts were combined, washed with brine and evaporated. The residue was recrystallized from ethyl acetate to give 1.5 g of yellow needles.

Assay: calcd: C, 66.4; H, 6.3; N, 15.5.

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

Example 36

[1- (2-methoxyethyl) -2-methoxymethyl-1H-imidazo [4,5-c] quinoline 5N oxide]

1- (2-methoxyethyl) -2-methoxymethyl-1H-imidazo [4,5-c] quinoline (13.3 g; 0.044 mol, Example 35) was dissolved in hot ethyl acetate (150 mL) , 32% acetic acid peroxide (12.0 mL) was added slowly to the solution. The mixture was heated at reflux for 2-3 hours and left overnight at room temperature. The resulting precipitate was collected, washed with ethyl acetate and evaporated together with toluene to give 2.6 g of solid. Ethyl acetate filtrate was evaporated. The resulting residue was collected in about 300 mL of water and made basic with concentrated ammonium hydroxide. The resulting precipitate was collected, washed with water, evaporated together with toluene and dried to give 5.6 g of solid. A total crude yield of 8.2 g was obtained and the material used in the subsequent reaction.

Example 37

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

Dissolve 1- (2-methoxyethyl) -2-methoxymethyl-1H-imidazo [4,5-c] quinoline 5N oxide (7.67 g; 0.027 mol, Example 36) in methylene chloride (100 mL) And cooled to 0-5 ° C. Cold concentrated ammonium hydroxide (75 mL) was added with stirring, cooling continued and a precipitate formed. A solution of p-toluene sulfonyl chloride (5.59 g; 0.029 mol) in methylene chloride (20 mL) was added slowly with continued stirring and cooling. After addition the mixture was kept at 0-5 ° C. for about 30 minutes and stirred overnight at room temperature. Methylene chloride was evaporated from the mixture and the solid was filtered from the mixture. The volume of the aqueous filtrate was reduced under a stream of nitrogen and the resulting precipitate collected, washed with water and dried to give 5.1 g of solid. The solids were collected in water, acidified with concentrated hydrochloric acid and filtered. The filtrate was basified with 6N sodium hydroxide. The resulting precipitate was collected, washed with water and dried to give colorless needles.

Melting point: 126-127 ° C.

Assay: calcd: C, 62.9; H, 6.3; N, 19.6.

Found: C, 62.9; H, 6.05; N, 19.3.

Example 38

[2-Ethoxymethyl-1- (2-methylpropyl) -1H-imidazo- [4,5-c] quinoline]

4- (2-methylpropylamino) -3-nitroquinoline (30.5 g; 0.12 mol) was added to a mixture of ethyl acetate (800 mL), 5% platinum on carbon (1.5 g) and magnesium sulfate (10 g). . The mixture was hydrogenated in a perm plant at an initial hydrogen pressure of 30 psi. At the end of the hydrogenation reaction, the solids were removed and ethyl acetate was evaporated. The resulting intermediate, diamine, was mixed with ethoxyacetic acid (80.5 mL) and heated with stirring at 130 ° C. for 2-3 hours. The reaction mixture was cooled down, poured into 400 mL of water and made basic with 6N ammonium hydroxide. The green solids were combined and dried to give 8.8 g of the title product. The structure was confirmed by nuclear magnetic resonance spectroscopy. The filtrate was extracted with ether (4 x 150 mL). The ether extracts were then combined and evaporated to yield 11.2 g of green solid. The solids were combined and used for the subsequent reaction.

Example 39

[2-Ethoxymethyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline 5N oxide]

2-ethoxymethyl-1- (2-methylpropyl) -1H-imidazo- [4,5-c] quinoline (17.4 g; 0.061 mol, Example 38) was dissolved in hot ethyl acetate (150 mL) , 32% peroxide acetic acid (14.5 mL) was added slowly to the solution. The mixture was refluxed for 2-3 hours and cooled to room temperature. The precipitate was collected, washed with a small amount of ethyl acetate and dried to give 6.3 g of a white solid. The structure was confirmed by nuclear magnetic resonance spectroscopy. This material was used in the subsequent reaction.

Example 40

[2-ethoxymethyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinolin-4-amine]

2-ethoxymethyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline 5N oxide (6.0 g; 0.02 mol, Example 39) was suspended in methylene chloride (150 mL) And cooled to 0-5 ° C. Concentrated ammonium hydroxide (60 mL) was cooled to 0-5 ° C and added to the suspension. A solution of p-toluenesulfonyl chloride in methylene chloride (20 mL) was added slowly to the mixture with stirring. The mixture was stirred overnight at room temperature. Methylene chloride was evaporated and the resulting precipitate was collected and washed with water to yield 6.3 g of crude material. The crude material was dispersed with ether. The solids were combined, washed with ether and dried to give an analytically pure sample.

Melting point: 133-137 ° C. Analyzed for forms containing 0.5 mol of water.

Assay: calcd: C, 66.5; H, 7.4; N, 18.2.

Found: C, 67.0; H, 7.3; N, 18.2.

Example 41

[4- (3-methoxypropylamino) -3-nitroquinoline]

4-hydroxy-3-nitroquinoline (19.0 g; 0.10 mol) was suspended in methylene chloride (250 mL). Thionyl chloride (8.0 mL, 0.11 mole) was combined with dimethylformamide (8.5 mL, 0.11 mole) and added slowly to the suspension. The resulting mixture was stirred and heated at reflux for about 2 hours. 3-methoxypropylamine (10.25 g, 0.115 mol) was combined with triethylamine (15 mL, 0.20 mol) and slowly added to the mixture with stirring. Intense heat of reaction was measured. The mixture was evaporated and the residue suspended in water. The suspension was acidified with concentrated hydrochloric acid. A hazy solid was collected. The filtrate was made basic with concentrated ammonium hydroxide. The precipitates were collected, washed with water and dried to give 8.4 g of a yellow solid. Melting point: 93-95 ° C. The cloudy solid was suspended in 2 L of water and acidified with concentrated hydrochloric acid, heated in a steam bath for 2-3 hours and filtered when hot. The filtrate was made basic with concentrated ammonium hydroxide. The precipitates were collected, washed with water and dried to yield 9.2 g of a yellow solid.

Melting point: 93-95 ° C.

Assay: calcd: C, 59.8; H, 5.8; N, 16.1.

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

Example 42

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

4- (3-methoxypropylamino) -3-nitroquinoline (14.6 g; 0.056 mol, Example 41) was diluted with ethyl acetate (1300 mL), 5% platinum on carbon (1.0 g), and magnesium sulfate (5.0 to the mixture of g). The mixture was hydrogenated at an initial hydrogen pressure of 30 psi in the digging apparatus. At the end of the hydrogenation reaction, the solids were removed and ethyl acetate was evaporated. The remaining intermediate diamine was mixed with ethoxyacetic acid (60 mL) 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 and extracted with ether (5 × 100 mL). The ether extracts were combined, dried over magnesium sulfate and evaporated. The residue was purified by silica gel chromatography (20% methanol in ethyl acetate as eluent) to afford 13.3 g of green oil. This material was used in the subsequent reaction.

Example 43

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

2-ethoxymethyl-1- (3-methoxypropyl) -1H-imidazo [4,5-c] quinoline (13.3 g; 0.044 mol, Example 42) was dissolved in ethyl acetate (150 mL), 32% acetic acid peroxide (12 mL) was added slowly to the solution. The reaction mixture was heated at reflux for 3-4 hours and cooled to room temperature. The mixture was evaporated. The residue was diluted with water (300 mL), basified with concentrated ammonium hydroxide and extracted with ether (7 × 100 mL). The ether extracts were combined, dried over magnesium sulfate and evaporated to give a small amount of yellow oil. The aqueous base layer was then extracted with ethyl acetate (6 x 100 mL). The ethyl acetate extracts were combined, washed with brine, dried over magnesium sulfate and evaporated to give a yellow solid. The solids were evaporated together with toluene to give 3.56 g of yellow crystals solid. The structure was confirmed by nuclear magnetic resonance spectroscopy. The material was used for the subsequent reaction.

Example 44

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

2-ethoxymethyl-1- (3-methoxypropyl) -1H-imidazo [4,5-c] quinoline 5N oxide (3.5 g; 0.011 mol, Example 43) was dissolved in methylene chloride (25 mL) And cooled to 0-5 ° C. Concentrated ammonium hydroxide (35 mL) was cooled to 0-5 ° C and added to the solution. The resulting mixture was stirred for about 15 minutes. A solution of p-toluenesulfonyl chloride in methylene chloride (10 mL) was added slowly with stirring. The reaction mixture was stirred for an additional 30 minutes at 0-5 ° C. and at room temperature overnight. Methylene chloride was evaporated. The resulting precipitate was collected, washed with water and recrystallized first from ethyl acetate and from ethane dichloride to give a crystalline solid.

Melting point: 123.5-125 ° C.

Assay: calcd: C, 64.95; H, 7.05; N, 17.8.

Found: C, 65.0; H, 7.0; N, 17.7.

Example 45

[1- (2-Methylpropyl) -α-phenyl-1H-imidazo [4,5-c] quinoline-2-methanol]

3-amino-4- (2-methylpropylamino) quinoline (43.5 g; 0.20 mole) and formic acid (300 mL) were combined and heated in a steam bath for several hours. The reaction mixture was concentrated in vacuo, diluted with water, basified with ammonium hydroxide and extracted twice with ether. Ether extracts were treated with activated charcoal and combined to a total volume of 1200 ml. The volume was reduced to 500 ml, cooled and filtered to afford 31.1 g of 1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline, a light green crystalline solid.

1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline (4 g; 0.017 mol) was dissolved in tetrahydrofuran (50 mL) and cooled to -78 ° C. 7.75 mL fractions of n-butyl lithium (2.5 M in hexane) were added dropwise to the cooled solution. After 15 minutes of addition, benzaldehyde (2.7 mL; 0.027 mol) was added and the reaction mixture was allowed to warm slightly. The reaction was quenched with water and diluted with ethyl ether. The ether was separated, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel chromatography using 5% methanol in methylene chloride as eluent to afford an oily yellow solid. This material was recrystallized from methylene chloride / hexanes to give a white crystalline solid.

Melting point: 160-166 ° C.

Assay: calcd: C, 76.1; H, 6.4; N, 12.7.

Found: C, 75.9; H, 6.3; N, 12.7.

Example 46

[1- (2-Methylpropyl) -α-phenyl-1H-imidazo [4,5-c] quinoline-2-methyl acetate]

1- (2-methylpropyl) -α-phenyl-1H-imidazo [4,5-c] quinoline-2-methanol (3 g; 9 mmol, Example 45) was dissolved in methylene chloride (50 mL), Combined with acetic anhydride (1.3 mL; 13.5 mmol) and triethylamine (1.6 mL; 11.8 mol) and stirred overnight at room temperature. The reaction mixture was diluted with methylene chloride and washed successively with water and saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography (50% ethyl acetate in methylene chloride as eluent) to give a white solid. The structure was confirmed by nuclear magnetic resonance spectroscopy.

Example 47

[2- (α-Acetoxybenzyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline 5N oxide]

Dissolve 1- (2-methylpropyl) -α-phenyl-1H-imidazo [4,5-c] quinoline-2-methyl acetate (3 g; 8 mmol, Example 46) in ethyl acetate (50 mL) Combined with acetic acid peroxide (2.2 g; 8.8 mmol) and heated at reflux for about 1 hour. The reaction mixture was cooled down and stirred for several days at room temperature. The resulting precipitate was collected, washed with ethyl acetate and dried to give 2.6 g of solid. The structure was confirmed by nuclear magnetic resonance spectroscopy.

Example 48

[4-amino-1- (2-methylpropyl) -α-phenyl-1H-imidazo [4,5-c] quinoline-2-methanol]

Methylene chloride (40 mL) in 2- (α-acetoxybenzyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline 5N oxide (2.6 g; 6.7 mmol, Example 47) ) And combined with benzoyl isocyanate (1.2 g; 7.3 mmol) and heated at reflux for about 1 hour. The reaction mixture was diluted with methylene chloride, washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was collected in methanol, combined with the catalytic amount of 25% sodium methoxide in methanol and heated at reflux for several hours. The reaction product was purified by silica gel chromatography using 2-5% methanol in methylene chloride and recrystallized from ethyl acetate-hexane. The recrystallized material was evaporated twice together with methylene chloride to yield about 0.5 g of solid.

Melting point: 125-140 ° C.

Assay: calcd: C, 72.8; H, 6.4; N, 16.2.

Found: C, 71.9; H, 5.6; N, 15.6.

Mass spectrum m / z = 347.

Example 49

[2- (α-methoxybenzyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline]

1- (2-methylpropyl) -α-phenyl-1H-imidazo [4,5-c] quinoline-2-methanol (5.0 g; 15 mmol, Example 45) was converted to N, N-dimethylformamide (25 ML) and added to a cooled (0-5 ° C.) suspension of sodium hydride (0.5 g; 16.6 mmol) in N, N-dimethylformamide (100 mL). The reaction mixture was stirred at rt for about 1 h and combined with methyl iodide (1.4 mL; 22.6 mmol). Stirring was continued until the reaction was complete as indicated by thin layer chromatography. The reaction mixture was diluted with ether and quenched with water. The ether layer was separated, washed twice with water, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with methylene chloride / hexanes to yield 4.5 g of solid. The structure was confirmed by nuclear magnetic resonance spectroscopy.

Example 50

[2- (α-methoxybenzyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline 5N oxide]

2- (α-methoxybenzyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline (4.5 g; 13 mmol, Example 49) was diluted with ethyl acetate (70 mL). Dissolved in acetic acid, combined with acetic acid peroxide (3.4 g; 14 mmol) and heated under reflux for several hours. The reaction mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (1-5% methanol in methylene chloride as eluent) to yield 3.9 g of oil, which was allowed to stand and solidify. The structure was confirmed by nuclear magnetic resonance spectroscopy.

Example 51

[2- (α-methoxybenzyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinolin-4-amine]

Methylene chloride (60 mL) in 2- (α-methoxybenzyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline 5N oxide (3.9 g; 10.8 mmol, Example 50) ) And mixed with ammonium hydroxide (20 mL). The mixture was cooled in an ice bath, during which a solution of p-toluenesulfonyl chloride (2.2 g; 11.85 mmol) in methylene chloride (20 mL) was added. The reaction mixture was allowed to warm up to room temperature and stirred for several hours. The organic phase was separated, washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was recrystallized from ethyl acetate / hexanes to give 2.5 g of solid.

Melting point: 183-184 ° C.

Assay: calcd: C, 73.3; H, 6.7; N, 15.5.

Found: C, 73.1; H, 6.7; N, 15.3.

Example 52

α- (4-chlorophenyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline-2-methanol

Using the method of Example 45, 1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline (2.5 g) was reacted with 4-chlorobenzaldehyde to yield 3.1 g of a yellow solid. . The structure was confirmed by nuclear magnetic resonance spectroscopy.

Example 53

[α- (4-chlorophenyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline-2-methyl acetate]

Using the method of Example 46, α- (4-chlorophenyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline-2-methanol (2.6 g; 7.1 mmol, Example 52) was reacted with acetic anhydride to afford the title product as a thick oil. The structure was confirmed by nuclear magnetic resonance spectroscopy.

Example 54

[2- (α-Acetoxy-4-chlorobenzyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline 5N oxide]

Using the method of Example 47, α- (4-chlorophenyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline-2-methyl acetate (2.9 g, 7.1 mmol) Example 53) was oxidized with acetic acid to give 5N oxide as an oil.

Example 55

[4-amino-α- (4-chlorophenyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline-2-methanol]

Using the method of Example 48, Example 2- (α-acetoxy-4-chlorobenzyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline 5N oxide (3.3 g, 7.8 mmol, Example 54) was reacted with benzoyl isocyanate and hydrolyzed to yield 0.8 g of the title product as a solid.

Melting point: 140-145 ° C.

Assay: calcd: C, 66.2; H, 5.6; N, 14.7.

Found: C, 65.6; H, 5.5; N, 14.4.

Example 56

[α-butyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline-2-methanol]

Using the method of Example 45, 1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline (20 g; 89 mmol) was reacted with valericaldehyde to give 11.6 g of the title product as a solid. Obtained as

Example 57

[2- (1-acetoxypentyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline]

Α-butyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline-2-methanol (11.6 g; 37 mmol, Example 56) using the general method of Example 46 Was reacted with acetic anhydride to afford the title product.

Example 58

[2- (1-acetoxypentyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline 5N oxide]

Using the general method of Example 47, 2- (1-acetoxypentyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline (11.5 g; 32 mmol, Example 57) was oxidized with acetic acid to give the title 5N oxide.

Example 59

[2- (1-acetoxypentyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinolin-4-amine]

Using the general method of Example 51, 2- (1-acetoxypentyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline 5N oxide (12 g; 32 mmol, Example) Example 58) was reacted with tosyl chloride and ammonium hydroxide to afford the title amine.

Example 60

[4-Amino-α-butyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline-2-methanol hemihydrate]

A drop of 25% sodium methoxide in methanol was added to 2- (1-acetoxypentyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinolin-4-amine (12 g) in methanol. ; 32 mmol, Example 59) and the resulting mixture was heated to reflux for about 1 hour. The reaction was concentrated in vacuo to give a solid. A portion of this solid was collected in a large volume of methylene chloride, washed with water, dried over magnesium sulfate and reduced to a volume of about 50 ml. The resulting precipitate was collected and dried to give 2.6 g white crystalline solid.

Melting point: 208-211 ° C.

Assay: calcd: C, 68.0; H, 8.1; N, 16.7.

Found: C, 67.8; H, 7.7; N, 16.6.

Example 61

[2- (1-methoxypentyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinolin-4-amine]

Sodium hydride (0.32 g; 10.0 mmol) with 4-amino-α-butyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline-2-methanol (3 g; 9.2 mmol) To the suspension of Example 60) and the resulting mixture was stirred for about 2 hours. Methyl iodide (0.82 mL; 13.8 mmol) was added to the mixture and stirring continued overnight. Thin layer chromatography showed incomplete reaction, so sodium hydride (0.25 g) was added, followed by methyl iodide (1 mL) after 2 hours. The reaction was further stirred for several hours, quenched with water and diluted with ethyl acetate. The organic layer was separated, washed with water, dried over magnesium sulfate and concentrated in vacuo to afford an oil. The oil was purified by silica gel chromatography (1-3% methanol in methylene chloride as eluent) to yield 0.5 g of solid.

Melting point: 125-128 ° C.

Assay: calcd: C, 70.55; H, 8.3; N, 16.5.

Found: C, 70.2; H, 8.3; N, 16.0.

Example 62

[2- [1- (1-morpholino) pentyl] -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinolin-4-amine]

Thionyl chloride (1 mL; 13.8 mmol) was diluted with 4-amino-α-butyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline-2- in methylene chloride (30 mL). Methanol (3 g; 9.2 mmol, Example 60) was added to the cooled (0-5 ° C.) suspension. The resulting mixture was stirred for several hours. The morpholine (8 mL; 90 mL mole) was added and the reaction mixture was heated to reflux until thin layer chromatography indicated the reaction was complete. The reaction mixture was diluted with additional methylene chloride and water and ammonium hydroxide were added. The organic layer was separated, washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by continuous silica gel chromatography using ethyl acetate as eluent in the first column and 1-4% methanol in methylene chloride as the eluent in the second column to give about 1 g of the title product as a solid.

Melting point: 95-100 ° C. Analyzes were made for forms containing 1/3 mole of water.

Assay: calcd: C, 68.8; H, 8. 45; N, 17.4.

Found: C, 68.7; H, 8.1; N, 17.4.

Example 63

[α-methyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline-2-methanol]

Using the general method of Example 45, 1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline (20 g; 89 mmol) was reacted with acetaldehyde to afford the title product. The structure was confirmed by nuclear magnetic resonance spectroscopy.

Example 64

[2- (1-methoxyethyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] -quinoline]

Using the general method of Example 49, α-methyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline-2-methanol (3 g; 11 mmol, Example 63) was prepared. Reaction with methyl iodide afforded 2,4 g of the title compound. The structure was confirmed by nuclear magnetic resonance spectroscopy.

Example 65

[2- (1-methoxyethyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline 5N oxide]

Using the general method of Example 50, 2- (1-methoxyethyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] -quinoline (2,4 g, 8.5 mmol, Example 64) was oxidized with acetic acid to give the title 5N oxide.

Example 66

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

Using the general method of Example 51, 2- (1-methoxyethyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline 5N oxide (2.4 g; 8 mmol, Example 65) was aminated to yield 1 g of the title product as a crystalline solid.

Melting point: 185-189 ° C. Analyzes were made for forms containing 1/4 mole of water.

Assay: calcd: C, 67.4; H, 7.5; N, 18.5.

Found: C, 67.7; H, 7.4; N, 18.1.

Example 67

[α-methyl-1- (2-methylpropyl) -1H-imidazo- [4,5-c] quinoline-2-methyl acetate]

Using the general method of Example 46, α-methyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] -quinoline-2-methanol (5.8 g, 0.02 mol, Example 16) ) Was reacted with anhydrous acetic acid to give the title product.

Example 68

[2- (1-acetoxyethyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline 5N oxide]

Using the general method of example 47, α-methyl-1- (2-methylpropyl) -1H-imidazo- [4,5-c] quinoline-2-methyl acetate (6.3 g; 0.02 mol, Example 67) was oxidized with acetic acid to give the title 5N oxide as a solid. The structure was confirmed by nuclear magnetic resonance spectroscopy.

Example 69

[4-Amino-α-methyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline-2-methyl acetate hydrate]

Using the general method of Example 51, 2- (1-acetoxyethyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline 5N oxide (4.1 g; 2.5 mmol, Example 68) was aminated to afford the title product as a solid. Melting point: 152-155 ° C. Analyze for forms containing 1/4 mole of water.

Assay: calcd:% C, 65.3; % H, 6.8; % N, 16.9.

Found:% C, 65.5; % H, 6.8; % N, 16.9.

Example 70

[2- (2-methoxyethyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline]

Using the general method of Example 45, 2-methyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline (2 g; 8.4 mmol) was dissolved in 2-chloroethylmethyl ether (0.76 ML, 10 mmol) to give the title product. The structure was confirmed by nuclear magnetic resonance spectroscopy.

Example 71

[2- (2-methoxyethyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline 5N oxide]

Using the general method of Example 47, 2- (2-methoxyethyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline (1 g, 3.5 mmol, Example 70 ) Was oxidized with acetic acid to yield 0.75 g of 5N oxide as a yellow solid. The structure was confirmed by nuclear magnetic resonance spectroscopy.

Example 72

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

Using the general method of Example 51, 2- (2-methoxyethyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline 5N oxide (0.75 g, Example 71 ) Was aminated to yield 0.4 g of the title product as a solid.

Melting point: 168-170 ° C.

Assay: calcd:% C, 68.4; % H, 7.4; % N, 18.8.

Found:% C, 68.4; % H, 7.4; % N, 18.6.

Example 73

[1- [1- (2-methylpropyl) -1H-imidazo [4,5-c] quinolin-2-yl] propan-2-one]

2-methyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline (1 g, 4.2 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) and cooled to -78 ° C. . A fraction of lithium diisopropyl amide (2.8 mL, 4.2 mmol) was added dropwise to the cooled solution. Ten minutes after addition, T.A. Oster T.M. N-methoxy-N-methylacetamide (0.45 g, 4.4 mmol) prepared according to the method of Harris's Tetrahedron Letters, 24,1851 (1983) was added. After 15 minutes the reaction was quenched with water and the resulting precipitate was collected and dried to give the title product as a solid. The structure was confirmed by nuclear magnetic resonance spectroscopy.

Example 74

[α-methyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline-2-ethanol]

1- [1- (2-methylpropyl) -1H-imidazo [4,5-c] quinolin-2-yl] propan-2-one (8 g, 28.4 mmol, Example 73) was diluted with ethanol (400 mL). Suspended in. Sodium borohydride (1.64 g, 43.3 mmol) was added and the reaction mixture was stirred at room temperature for about 2 hours. Methanol (about 20 mL) was added and stirring continued overnight. Water was added and the solvent removed in vacuo. The residue was partitioned between methylene chloride and water. The methylene chloride layer was separated, dried over magnesium sulfate and concentrated in vacuo to afford the title product. The structure was confirmed by nuclear magnetic resonance spectroscopy.

Example 75

[2- (2-methoxypropyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline]

α-methyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline-2-ethanol (6.5 g, 23 mmol, Example 74) was prepared with N, N-dimethylformamide (50 ML) and cooled to 0 ° C. Sodium hydride (0.8 g, 25 mmol, 80% dispersion in mineral oil) was added and the resulting mixture was stirred at 0 ° C. for about 1 hour. Methyl iodide (2.2 mL, 34 mmol) was added and the resulting mixture was stirred at 0 ° C. for about 1 h and then allowed to cool to room temperature. The reaction was quenched with water and diluted with ethyl acetate. The organic layer was separated, washed several times with water, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel chromatography using 2-5% methanol in methylene chloride to afford 3 g of the title product. The structure was confirmed by nuclear magnetic resonance spectroscopy.

Example 76

[2- (2-methoxypropyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline 5N oxide]

Using the general method of Example 47, 2- (2-methoxypropyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline (3 g, 10 mmol, Example 75 ) Was oxidized with acetic acid to yield 2.1 g of the title 5N oxide as a solid. The structure was confirmed by nuclear magnetic resonance spectroscopy.

Example 77

[2- (2-methoxypropyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinolin-4-amine]

Using the general method of Example 51, 2- (2-methoxypropyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline 5N oxide (2 g, 6.4 mmol, implementation) Example 76) was aminated to yield 1.3 g of the title compound as a solid.

Melting point: 139-141 ° C.

Assay: calcd:% C, 69.2; % H, 7.7; % N, 17.9.

Found:% C, 69.1; % H, 7.8; % N, 17.8.

Example 78

[α-methyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline-2-ethyl acetate]

Α-methyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline-2-ethanol (9.4 g, 33 mmol, Example 74) using the general method of Example 46 Was reacted with acetic anhydride to afford the title product. The structure was confirmed by nuclear magnetic resonance spectroscopy.

Example 79

[2- (2-acetoxypropyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline 5N oxide]

Using the general method of Example 47, α-methyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline-2-ethyl acetate (10.7 g, 33 mmol, Example 78 ) Was oxidized with acetic acid to give the title 5N oxide. The structure was confirmed by nuclear magnetic resonance spectroscopy.

Example 80

[4-Amino-α-methyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline-2-ethyl acetate]

Using the general method of Example 51, 2- (2-acetoxypropyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline 5N oxide (10.5 g, 30 mmol, Example 79) was aminated to afford the title product. The structure was confirmed by nuclear magnetic resonance spectroscopy.

Example 81

[4-Amino-α-methyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline-2-ethanol]

Using the general method of Example 60, 4-amino-α-methyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline-2-ethyl acetate (10.2 g, 30 mmol) Example 80) was hydrolyzed to give 2 g of the title product as a solid.

Melting point: 196-197 ° C.

Assay: calcd:% C, 68.4; % H, 7.4; % N, 18.8.

Found:% C, 68.6; % H, 7.5; % N, 18.9.

Example 82

[7-Chloro-4- (2-hydroxy-2-methylpropylamino) -3-nitroquinoline]

Using the general method of Example 41, 7-chloro-4-hydroxy-3-nitroquinoline (18 g, 80 mmol) was subjected to chlorine addition reaction using thionyl chloride. After the chlorination reaction was terminated as confirmed by thin layer chromatography, the reaction mixture was cooled to room temperature. Triethylamine (28 mL, 200 mmol) and 2-amino-2-methyl-2-propanol (10.3 g, 96 mmol) were added and the reaction mixture was heated to reflux for about 1 hour. The reaction mixture was cooled in an ice bath and the resulting precipitate was collected and dried to give the title product as a solid. The structure was confirmed by nuclear magnetic resonance spectroscopy.

Example 83

[7-Chloro-α, α-dimethyl-2-ethoxymethyl-1H-imidazo [4,5-c] quinoline-1-ethanol]

Using the general method of Example 42, 7-chloro-4- (2-hydroxy-2-methylpropylamino) -3-nitroquinoline (18.5 g, 63 mmol, Example 82) was reduced and the resultant Diamine was reacted with ethoxyacetic acid to give the title product as a thick green oil.

Example 84

[7-chloro-2-ethoxymethyl-1- (2-hydroxy-2-methylpropyl) -1H-imidazo [4,5-c] quinoline 5N oxide]

Using the general method of Example 47, 7-chloro-α, α-dimethyl-2-ethoxymethyl-1H-imidazo [4,5-c] quinoline-1-ethanol (20.9 g, 63 mmol, Example) Example 83) was oxidized with acetic acid to yield 14.8 g of the title oxide as a solid.

Example 85

[4-amino-7-chloro-α, α-dimethyl-2-ethoxymethyl-1H-imidazo [4,5-c] quinoline-1-ethanol]

Using the general method of Example 51, 7-chloro-2-ethoxymethyl-1- (2-hydroxy-2-methylpropyl) -1H-imidazo [4,5-c] quinoline 5N oxide (14.8 g, 42 mmol, Example 84) were aminated to yield 8.6 g of the title product as a solid.

Melting point: 238-240 ° C.

Assay: calcd:% C, 58.5; % H, 6.1; % N, 16.1.

Found:% C, 58.4; % H, 6.0; % N, 16.0.

Example 86

[α, α-dimethyl-2-hydroxymethyl-1H-imidazo [4,5-c] quinoline-1-ethanol]

Using the general method of Example 24, 3-amino-4- (2-hydroxy-2-methylpropyl amino) quinoline (45 g, 0.19 mol) was reacted with glycolic acid to give 35.7 g of the title product as a tan solid. Obtained. The structure was confirmed by nuclear magnetic resonance spectroscopy.

Example 87

[1- (2-hydroxy-2-methylpropyl) -1H-imidazo [4,5-c] quinoline-2-methyl acetate]

Using the general method of Example 2, α, α-dimethyl-2-hydroxymethyl-1H-imidazo [4,5-c] quinoline-1-ethanol (35.0 g, 0.13 mol, Example 86) was prepared. Reaction with acetyl chloride gave 32.3 g of a tan solid. Nuclear magnetic resonance spectroscopy showed that the tan solid contained the title product and about 10% diester. The material was used without further purification.

Example 88

[2-acetoxymethyl-1- (2-hydroxy-2-methylpropyl) -1H-imidazo [4,5-c] quinoline 5N oxide]

Using the general method of Example 47, peroxidized 1- (2-hydroxy-2-methylpropyl) -1H-imidazo [4,5-c] quinoline-2-methyl acetate (31 g, Example 87) Oxidation with acetic acid gave 19.6 g of crude 5N oxide.

Example 89

[4-Chloro-1- (2-hydroxy-2-methylpropyl) -1H-imidazo [4,5-c] quinoline-2-methyl acetate]

A 16.7 g fraction of crude 5N oxide prepared in Example 88 was suspended in methylene chloride (1200 mL). Phosphorous oxychloride (3.5 mL) was added to the suspension with vigorous stirring over about 5 minutes. After about 1.5 hours, the reaction mixture was filtered to remove 7.9 g of solids. The methylene chloride filtrate was combined with phosphorus oxychloride (1.2 mL) and stirred at room temperature for about 20 hours. Saturated sodium bicarbonate solution (250 mL) was added to the reaction mixture with stirring. The layers were separated. The aqueous layer was extracted with methylene chloride. The methylene chloride layers were combined, dried over magnesium sulfate and concentrated in vacuo to give 10.2 g of the title product as a tan solid. The structure was confirmed by nuclear magnetic resonance spectroscopy.

Example 90

[4-amino-α, α-dimethyl-2-hydroxymethyl-1H-imidazo [4,5-c] quinoline-1-ethanol]

Using the general method of Example 9, 4-chloro-1- (2-hydroxy-2-methylpropyl) -1H-imidazo [4,5-c] quinoline-2-methyl acetate (8.3 g, 24 Ammonia, mmol 89) gave 2.3 g of the title product as a solid.

Melting point: 264-271 ° C.

Assay: calcd:% C, 62.9; % H, 6.3; % N, 19.6.

Found:% C, 62.9; % H, 6.3; % N, 19.3.

Example 91

[2-ethoxymethyl-1-phenylmethyl-1H-imidazo [4,5-c] quinoline]

3-amino-4- (phenylmethylamino) quinoline (4 g, 16 mmol) was combined with ethoxyacetic acid (4.5 mL, 48 mmol) and heated at 120 ° C. for about 3 hours. The reaction mixture was cooled to room temperature, diluted with water and made basic with ammonium hydroxide. The resulting precipitate was collected to give 5.3 g of the title compound as a solid. The structure was confirmed by nuclear magnetic resonance spectroscopy.

Example 92

[2-Ethoxymethyl-1-phenylmethyl-1H-imidazo [4,5-c] quinoline 5N oxide]

Using the general method of Example 47, 2-ethoxymethyl-1-phenylmethyl-1H-imidazo [4,5-c] quinoline (4.5 g, 14 mmol, Example 91) was oxidized with acetic acid peroxide. 3.2 g of the titled 5N oxide were obtained as a solid.

Example 93

[2-ethoxymethyl-1-phenylmethyl-1H-imidazo [4,5-c] quinolin-4-amine]

Using the general method of Example 51, 2-ethoxymethyl-1-phenylmethyl-1H-imidazo [4,5-c] quinoline 5N oxide (3.2 g, 9.6 mmol, Example 92) was aminated 1.1 g of the title product were obtained as a solid.

Melting point: 204-205 캜.

Assay: calcd:% C, 72.3; % H, 6.1; % N, 16.9.

Found:% C, 72.1; % H, 5.7; % N, 16.6.

Example 94

[α, α-dimethyl-2-methoxymethyl-1H-imidazo [4,5-c] quinoline-1-ethanol]

3-amino-4- (2-hydroxy-2-methylpropylamino) quinoline (7.5 g, 32 mmol) was combined with methoxyacetic acid (7.5 mL, 97 mmol) and heated at about 170 ° C. for about 3 hours. . The resulting solid residue was dissolved in ethyl acetate (150 mL). The ethyl acetate solution was extracted twice with 0.2 N sodium hydroxide, washed with water, dried over magnesium sulfate, treated with activated charcoal and concentrated to a volume of about 50 ml. Hexane was added to ethyl acetate and the resulting precipitate was collected and dried to yield 0.9 g of the title product as crystalline solid.

Melting Point: 145-148 ° C.

Assay: calcd:% C, 67.3; % H, 6.7; % N, 14.7.

Found:% C, 67.2; % H, 6.6; % N, 14.6.

Example 95

[1- (2-hydroxy-2-methylpropyl) -2-methoxymethyl-1H-imidazo [4,5-c] quinoline 5N oxide]

Α, α-dimethyl-2-methoxymethyl-1H-imidazo [4,5-c] -quinoline-1-ethanol (6.6 g, 23 mmol, Example 94) using the general method of Example 47 Was oxidized with acetic acid to yield 5.7 g of the title 5N oxide. A small amount of sample was recrystallized from ethyl acetate to obtain an analytical sample.

Melting Point: 175-197 ° C.

Assay: calcd:% C, 63.8; % H, 6.4; % N, 14.0.

Found:% C, 63.8; % H, 6.4; % N, 13.8.

Example 96

4-amino-α, α-dimethyl-2-methoxymethyl-1H-imidazo [4,5-c] quinoline-1-ethanol

Using the general method of Example 51, 1- (2-hydroxy-2-methylpropyl) -2-methoxymethyl-1H-imidazo [4,5-c] quinoline 5N oxide (4.7 g, 16 mmol) Example 95) was aminated to yield 2.4 g of the title product as a solid.

Melting point: 204-207 ° C.

Assay: calcd:% C, 64.0; % H, 6.7; % N, 18.6.

Found:% C, 64.1; % H, 6.8; % N, 18.6.

Example 97

[α, α-dimethyl-2-ethoxymethyl-1H-imidazo [4,5-c] quinoline-1-ethanol]

Using the general method of Example 91, 3-amino-4- (2-hydroxy-2-methylpropylamino) quinoline (46.2 g, 0.20 mol) was reacted with ethoxyacetic acid (62.5 g, 0.6 mol) 53.6 g of crude product was obtained as a gray solid. A small amount was recrystallized from toluene to yield 3.6 g of a colorless solid.

Melting point: 117-120 ° C.

Assay: calcd:% C, 68.2; % H, 7.1; % N, 14.0.

Found:% C, 68.5; % H, 7.1; % N, 14.0.

Example 98

[2- (Ethoxymethyl-1- (2-hydroxy-2-methylpropyl) -1H-imidazo [4,5-c] quinoline 5N oxide]

Using the general method of Example 47, α, α-dimethyl-2-ethoxymethyl-1H-imidazo [4,5-c] quinoline-1-ethanol (59.9 g, 0.2 mol, Example 97) was prepared. Oxidation with acetic acid gave 59.9 g of crude 5N oxide as a solid.

Example 99

[4-amino-α, α-dimethyl-2-ethoxymethyl-1H-imidazo [4,5-c] quinoline-1-ethanol]

Using the general method of Example 51, 2-ethoxymethyl-1- (2-hydroxy-2-methylpropyl) -1H-imidazo [4,5-c] quinoline 5N oxide (30.0 g, 0.095 mol) Example 98) was aminated to yield 25.7 g of crude product as off-white solid. A portion (20.3 g) of crude product was suspended in methanol (125 mL) and methylene chloride (60 mL) was added to the suspension. The resulting solution was treated with charcoal and filtered. The filtrate was heated to evaporate to remove methylene chloride and the total volume was reduced to about 110 ml. The solution was cooled to room temperature. The resulting precipitate was collected, washed with methanol and dried to give 12.1 g of the title product as a colorless crystalline solid.

Melting point: 190-192 ° C.

Assay: calcd:% C, 65.0; % H, 7.1; % N, 17.8.

Found:% C, 64.8; % H, 7.1; % N, 17.9.

Example 100

[4-Chloro-α, α-dimethyl-2-ethoxymethyl-1H-imidazo [4,5-c] quinoline-1-ethanol]

3-amino-2-chloro-4- (2-hydroxy-2-methylpropylamino) quinoline (2.0 g, 7.5 mmol) was combined with acetonitrile (80 mL). Ethoxyacetyl chloride (0.92 g, 7.5 mmol) was added to the reaction mixture. After about 5 minutes a yellow precipitate formed. p-toluenesulfonic acid (0.1 g) was added and the reaction mixture was heated to reflux temperature. Reflux was continued for about 120 hours, at which time the reaction mixture was homogeneous. The reaction mixture was cooled down and the acetonitrile was removed under vacuum. The resulting residue was dissolved in methylene chloride and washed with dilute ammonium hydroxide. The aqueous phase was extracted with methylene chloride (3 x 25 mL). The organic phases were combined, dried over magnesium sulfate and concentrated to give 2.6 g of crude product as a dark yellow solid. The crude product was recrystallized from t-butylmethyl ether to give 1.8 g of solid. The structure was confirmed by nuclear magnetic resonance spectroscopy.

Example 101

[4-amino-α, α-dimethyl-2-ethoxymethyl-1H-imidazo [4,5-c] quinoline-1-ethanol]

4-Chloro-α, α-dimethyl-2-ethoxymethyl-1H-imidazo [4,5-c] quinoline-1-ethanol (1.0 g, 3 mmol, Example 100) and 7% methanol containing ammonia (30 mL) was placed in a steel pressure vessel at about 150-160 ° C. for 6 hours. The vessel was cooled to room temperature or lower, the reaction solution was removed and treated with methanol containing potassium hydroxide. The solution was then evaporated to low volume and diluted with water. The resulting precipitate was collected, washed with water and dried to yield 0.7 g of crude product as a solid. The crude product was recrystallized from a mixture of ethyl acetate and methanol to give a colorless solid.

Example 102

[2-methoxymethyl-1-phenylmethyl-1H-amidazo [4,5-c] quinoline]

Using the general method of Example 91, 3-amino-4- (phenylmethylamino) quinoline (4.0 g, 16 mmol) was reacted with methoxyacetic acid (3.7 mL) to yield 4.4 g of the title product as a solid. It was. The structure was confirmed by nuclear magnetic resonance spectroscopy.

Example 103

[2-methoxymethyl-1-phenylmethyl-1H-amidazo [4,5-c] quinoline 5N oxide]

Using the general method of Example 47, 2-methoxymethyl-1-phenylmethyl-1H-amidazo [4,5-c] quinoline (4.4 g, 14.5 mmol, Example 102) was oxidized with acetic acid peroxide. 3 g of the titled 5N oxide were obtained as a solid.

Example 104

[2-methoxymethyl-1-phenylmethyl-1H-amidazo [4,5-c] quinolin-4-amine]

Using the general method of Example 51, 2-methoxymethyl-1-phenylmethyl-1H-amidazo [4,5-c] quinoline 5N oxide (3 g, 9 mmol, Example 103) was aminated to 2.0 g of the title product were obtained as a solid.

Melting point: 202-204 ° C.

Assay: calcd:% C, 71.7; % H, 5.7; % N, 17.6.

Found:% C, 71.4; % H, 5.7; % N, 17.4.

[Antiviral Activity and Interferon Induction in Guinea Pick]

In the following test methods, the compounds of the present invention show the ability to reduce the number and depth of lesions caused by guinea pigs infected with type II herpes simplex virus and induce the biosynthesis of interferon in guinea pigs.

Heartley guinea pick females weighing 200-250 g were anesthetized with methoxyflurane (available from Pittman-Moor Inc., Washington Crossing, NJ under the trade name METAFANE ^™ ), followed by Wipe with a dry cotton swab. The guinea pigs are then infected with vagina by a cotton swab moistened with Herpes simplex virus type II strain 333 (1 × 10 ⁵ plaque forming units / ml). Guinea picks are divided into seven groups of animals divided into one group for each treatment and one control group (treated with excipients). Compounds of the invention are formulated in water containing 5% Tween 80 (polyoxyethylene sorbitan monooleate available from Aldrich Chemical Company, Milwaukee, Wis.). Guinea picks are administered orally for four consecutive days, once daily, starting 24 hours after infection.

[Antiviral activity]

Antiviral activity is assessed by comparing lesion development in compound-treated guinea pigs and excipient-treated guinea pigs. External lesions are recorded 4,7,8 and 9 days after infection using the following criteria: 0-no lesion, 1-redness and swelling, 2-several small vesicles, 3-several large vesicles, 4-necrosis Calculate% lesion inhibition using a large ulcer and 5-paralysis, the maximum lesion record for each guinea pig. % Lesion inhibition is calculated as follows. :

[Interferon induction]

24 hours after the administration of the initial dose of the test compound, three guinea pig blood is collected from each treatment group by cardiac puncture of an anesthetized animal with methoxyflurane. The blood is congested and allowed to coagulate at room temperature. After low speed centrifugation, serum is collected and stored at -70 ° C until analysis.

Interferon levels in guinea pig serum are determined in standard microtiter assays using transformed guinea pig cells (ATCCCRL 1405). Interferon analysis is performed on 96 well microtiter plates. Confluent monolayers of transformed guinea pig cells are treated with dilutions of guinea pig serum made from Medium 199 (GIBC0, Grand Island, NY). Cell and serum dilutions are incubated overnight at 37 ° C. The next day the medium and serum are removed and about 10 plaque forming units of mengovirus are added to each well. Controls consist of wells that do not receive guinea pick serum (virus positive controls) and wells that do not accept viruses (virus negative controls). Cells and viruses are incubated for 2 to 3 days at 37 ° C. to quantify the cytopathic effects of viruses. Virus cell pathology effect is stained with 0.05% crystal violet and quantitated by absorbance measurement by spectrometer. The titer of interferon in serum is expressed in units / ml and is the reciprocal of the highest dilution rate that protects cells from viruses.

The results are shown in the table below.

The results indicate that the tested compounds of the present invention inhibit Herpes simplex virus type II lesions in guinea pigs. The compounds tested also appeared to induce interferon biosynthesis in guinea pigs.

[Interferon-α Induction in Human Cells]

In the following test methods, the compounds of the present invention show the ability to induce the biosynthesis of interferon-α in human cells.

The in vivo human blood cell system was used to assess interferon-α induction by the compounds of the present invention. Activity is based on the measurement of interferon secreted into the culture medium.

[Preparation of Blood Cells for Culture]

Whole blood is collected by venipuncture into EDTA vactainer tubes. Peripheral blood mononuclear cells (PBMs) were prepared by LeucoPREP ^™ brand cell separation tubes (available from Beckton Dickinson) and L-glutamine (1% penicillin-streptomycin solution with 10% autologous serum) was added. Cultured in RPMI 1640 medium (available from GIBCO, Grand Island, NY) containing 25 mM HEPES 4- (2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid) or 1% Whole blood diluted to 1: 10 can be used with RPMI 1640 medium containing L-glutamine and 25 mM HEPES added to the penicillin-streptomycin solution of 200. A 200 μL fraction of PBM or diluted whole blood in the medium is used in 96 wells (bottom). This flat) is added to the MicroTest ^™ III tissue culture plate.

Compound Formulation

The compound is dissolved in water, ethanol or dimethyl sulfoxide and diluted with distilled water, 0.01 N sodium hydroxide or 0.01 N hydrochloric acid (the choice of solvent depends on the chemical properties of the compound to be tested). The compound is initially tested at a concentration range of about 0.1 μg / ml to about 5 μg / ml. Compounds showing induction at a concentration of 0.5 μg / ml are tested in the concentration range of 0.01 μg / ml to 5.0 μg / ml.

[Incubation]

A solution of the test compound is added to a well containing 200 μl of PBM or diluted whole blood in the medium (to a volume of 50 μl or less). The solvent, medium or both are added to the control well (i.e. well without test compound) In addition, it is necessary to adjust so that the final volume of each well is 250 µl. The plates are covered with a plastic lid, gently vortexed and incubated for 24 hours at 37 ° C. in a 5% carbon dioxide atmosphere.

[detach]

After incubation, the plates were covered with PARAFILM ^™ and centrifuged for 15 minutes at 1000 ° C. at 4 ° C. in a Damon IEC model CRU-5000 centrifuge. Medium (about 175 μl) is removed from 4-8 wells and collected into 2 ml sterile freezing vials. The sample is kept at -70 ° C until analysis.

[Interferon Analysis / Calculation]

Interferon is measured by biological analysis using A549 human lung cancer cells administered with brain myocarditis antigen. For details on biological assays, see G.L. Brennan and L.H. Autonated Bioassay of Interferons in Microtest Plates, Biotechnics, June / July; 78,1983., Incorporated herein by reference. The method is briefly described as follows: Interferon dilution and A549 cells are incubated at 37 ° C. for 12-24 hours. The incubated cells are infected by inoculation of the brain myocarditis virus. Infected cells are incubated at 37 ° C. for an additional period of time and quantitated for viral cell pathological effects. The cytopathic effect of the virus is quantitatively analyzed by staining and then absorbance measurements by spectrometer. Results are expressed in α interferon reference units / ml based on the values obtained for the NIH HU IF-L standard. Interferon was identified as almost all interferon a by testing with a checkerboard neutralization assay for anti-human interferon (beta) and goat anti-human interferon (alpha) in rabbits using an A549 cell monolayer administered with brain myocarditis virus. . The results are shown in the table below, where not listed in the table indicates that the compound was not tested at the particular dosage concentration.

Results less than a certain number (＂<＂) indicate that interferon is not identified in amounts above the lower sensitivity of the assay.

Interferon-α Induction in Human Cells

The results indicate that the tested compounds of the present invention induce interferon biosynthesis at identifiable levels in human whole blood cells, PBM cells or both over a wide range of dosage concentrations.

[Interferon Induction in Mice]

In the following test methods, the compounds of the invention measure the ability to induce interferon biosynthesis in mice.

For each dose level to be tested, the compound is orally administered to three groups (3 per group) of CFW male mice (unfastened: body weight 23-28 g). After 1 hour, blood samples are taken from the first group. Samples are congested and centrifuged. Serum is removed from the centrifuge tube, divided into two fractions, placed in a freezing vial and maintained at -70 ° C until analysis. This procedure is repeated 2 hours for group 2 mice and 4 hours for group 3 mice.

[Interferon Analysis / Calculation]

Samples are analyzed as described above with respect to the interferon induction assay in human cells. The results are shown in the table below as α / β reference units / ml based on the values obtained for the mouse MU-1-IF standard. The results, indicated as less than a certain number in the table below (＂<＂), indicate that interferon is not identified in amounts above the lower sensitivity of the assay.

The results indicate that the compounds tested induce interferon biosynthesis at levels identifiable in mice.

[Inhibition of MC-26 Tumors in Mice]

In the following test methods, the compounds of the present invention are measured for their ability to inhibit tumor proliferation in mice.

Initially (day 0) CDF1 mouse females are inoculated intravenously with 4 × 10 ⁴ MC-26 colon tumor cells in a volume of 0.2 ml saline per mouse. Mice are killed after 14 days. The lungs are removed, fixed with WARF (containing 24% ethanol, 10% formalin and 2% acetic acid in water) and left to stand for 30 minutes. Isolate the lobes and count the colonies. Five mice are assigned to each treatment group and a control is made.

Mice in the treatment group were orally administered suspensions of the compound (30 mg / kg) in water (10 mL / kg) on days 3,4,5,6,7,10,11,12,13 and 14.

Mice in the control group were orally administered saline (10 mL / kg) on days 3, 4, 5, 6 and 7 and water (10 mL / kg) on days 10, 11, 12, 13 and 14.

The results are shown in the table below.

Initially CDF1 mouse females are intravenously inoculated with 1 × 10 ⁴ MC-26 colon tumor cells in a volume of 0.2 ml saline per mouse. Mice are killed after 21 days. The lungs are removed, fixed in WARF and left to stand for 30 minutes. Separate the leaves and count the colonies. Ten mice are assigned to each treatment group and control group.

Mice in the control group were orally administered water (10 mL / kg) on days 0, 1, 2, 3 and 4. Four mice in this group died before 21 days.

Mice in the first treatment group were orally administered a suspension of the compound of Example 99 (1 mL / kg) in water (10 mL / kg) on days 0, 1, 2, 3 and 4. One mouse in this group died before 21 days.

Mice in the second treatment group were orally administered suspensions of the compound of Example 99 (3 mg / kg) in water (10 mL / kg) on days 0, 1, 2, 3 and 4. All mice in this treatment group survived for up to 21 days.

The results are shown in the table below.

The results indicate that the compounds tested inhibited MC-26 tumor formation in mice.

[In Vitro Indirect Antiviral Activity]

In the following test methods, the compounds of the present invention are measured for their ability to inhibit the progression of virus infection.

Whole blood is collected by venipuncture into the EDTA documenter tube. Peripheral blood mononuclear cells (PBM) are isolated using Ficoll-Paque ^R solution (available from Pharmacia LKB Biotechnology Inc., Piscatway, NJ). PBM was washed with phosphate buffered saline and diluted with RPMI 1640 medium (available from GIBCO, Grand Island, NY) to give a final concentration of 2.5 × 10 ⁶ cells / ml. 1 ml fraction of PBM in medium is placed in 15 ml polypropylene test tube. 100 μl fractions of autologous serum are added to each test tube. Test compounds are dissolved in dimethyl sulfoxide and diluted with RPMI 1640 medium. Test compound solutions are added to test tubes containing PBM to obtain a final concentration range of 0.1 μg / ml to 10 μg / ml. The control test tube does not receive any test compound. The tubes are then incubated for 24 hours at 37 ° C. in a 5% carbon dioxide atmosphere. After incubation, the tubes are centrifuged at 400 × g for 5 minutes. Remove the supernatant. PBMs are grown in 100 μl RPMI 1640 medium and infected with 100 μl containing 10 ⁵ tissue culture 50% infectious dose of vesicular stomatitis virus (VSV). The tubes are incubated at 37 ° C. for 30 minutes to allow the virus to adsorb. 1 ml of RPMI 1640 medium is added to each test tube and the tubes are incubated at 37 ° C. for 48 hours. The tubes are frozen and thawed to lyse the cells. Test tubes are centrifuged at 400 × g for 5 minutes to remove cell debris, and supernatants are analyzed by serial 10-fold dilution on Vero cells in 96 well microtiter plates. Infected cells are incubated at 37 ° C. for 24 hours before quantitative analysis of the cytopathic effects of viruses. The cytopathic effect of the virus is quantitatively analyzed by staining with 0.05% crystal violet. The results are shown as VSV inhibition defined as log ₁₀ (control VSV production rate / experimental VSV production rate). The results are shown in the table below and not listed indicate that the compound was not tested at the particular dosage concentration. Control tubes have a value of zero.

The results indicate that the compounds tested are active against VSV.

Claims (8)

Compounds of the formula or pharmaceutically acceptable acid addition salts thereof: Wherein R ₁ is hydrogen; Straight or branched chain alkyl having 1 to about 10 carbon atoms and substituted straight or branched chain alkyl having 1 to about 10 carbon atoms, wherein the substituents are cycloalkyl having 3 to about 6 carbon atoms, and 1 to about 4 carbon atoms Is substituted from straight or branched chain alkyl with one and selected from the group consisting of cycloalkyl having from 3 to about 6 carbon atoms; Straight or branched alkenyl having 2 to about 10 carbon atoms, and substituted straight or branched alkenyl having 2 to about 10 carbon atoms, wherein the substituent is cycloalkyl having 3 to about 6 carbon atoms, and 1 to about Selected from the group consisting of cycloalkyl having 3 to about 6 carbon atoms and substituted by straight or branched alkyl having 4 carbon atoms; Hydroxyalkyl of 1 to about 6 carbon atoms; Alkoxyalkyl wherein the alkoxy moiety has 1 to about 4 carbon atoms and the alkyl moiety has 1 to about 6 carbon atoms; Acyloxyalkyl wherein the acyloxy moiety is an alkanoyloxy or benzoyloxy of 2 to about 4 carbon atoms and the alkyl moiety has 1 to about 6 carbon atoms; benzyl; (Phenyl) ethyl; And phenyl; Benzyl, (phenyl) ethyl or phenyl unsubstituted or substituted on the benzene ring by one or two moieties independently selected from the group consisting of alkyl of 1 to about 4 carbon atoms, alkoxy of 1 to about 4 carbon atoms, and halogen Substituents, provided that the benzene ring is substituted by two of the moieties, provided that the moieties together have up to 6 carbon atoms; R ₂ and R ₃ are selected from the group consisting of hydrogen, alkyl of 1 to about 4 carbon atoms, phenyl and substituted phenyl (substituted alkyl of 1 to about 4 carbon atoms, alkoxy of 1 to about 4 carbon atoms, and halogen Independently from the group consisting of; X is an alkoxy, alkoxy moiety having 1 to about 4 carbon atoms, alkoxy alkyl having 1 to about 4 carbon atoms and the alkyl moiety having 1 to about 4 carbon atoms, haloalkyl of 1 to about 4 carbon atoms, 1 Hydroxyalkyl of from about 4 carbon atoms, alkylamido, wherein the alkyl group has from 1 to about 4 carbon atoms, amino, substituted amino (substituent is hydroxyalkyl or alkyl of 1 to about 4 carbon atoms), azi Fig. 2 is selected from the group consisting of chloro, hydroxy, 1-morpholino, 1-pyrrolidino, and alkylthio of 1 to about 4 carbon atoms; R is selected from the group consisting of hydrogen, straight or branched alkoxy having 1 to about 4 carbon atoms, halogen, and straight or branched chain alkyl having 1 to about 4 carbon atoms. The compound of claim 1, wherein R ₁ is 2-hydroxy-2-methylpropyl or 2-methylpropyl. The compound of claim 1, wherein X is azido, ethoxy, hydroxy, methoxy, 1-morpholino or methylthio. The compound of claim 1, wherein R ₂ and R ₃ are hydrogen. The compound of claim 1, further comprising: N-acetyl-4-amino-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinolin-2-methanamine; 4-amino-7-chloro-α, α-dimethyl-2-ethoxymethyl-1H-imidazo [4,5-c] quinoline-1-ethanol; 4-amino-α- (4-chlorophenyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline-2-methanol; 4-amino-α, α-dimethyl-2-hydroxymethyl-1H-imidazo [4,5-c] quinoline-1-ethanol; 4-amino-α, α-dimethyl-2-methoxymethyl-1H-imidazo [4,5-c] quinoline-1-ethanol; 4-amino-α, α-dimethyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline-2-methanol; 4-amino-N-hydroxyethyl-N-methyl-1-phenylmethyl-1H-imidazo [4,5-c] quinoline-2-methanamine hemihydrate; 4-amino-α-methyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline-2-ethanol; 4-amino-α-methyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline-2-methanol; 4-amino-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinoline-2-methanol; 4-amino-1- (2-methylpropyl) -α-phenyl-1H-imidazo [4,5-c] quinoline-2-methanol; 2-azidomethyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinolin-4-amine; 2-chloromethyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinolin-4-amine hydrochloride; 2-ethoxymethyl-1- (3-methoxypropyl) -1H-imidazo [4,5-c] quinolin-4-amine; 2-ethoxymethyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinolin-4-amine; 2-ethoxymethyl-1-phenylmethyl-1H-imidazo [4,5-c] quinolin-4-amine; 2- (α-methoxybenzyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinolin-4-amine; 1- (2-methoxyethyl) -2-methoxymethyl-1H-imidazo [4,5-c] quinolin-4-amine; 2- (2-methoxyethyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinolin-4-amine; 2- (1-methoxyethyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinolin-4-amine; 2-methoxymethyl-1- (2-methylpropyl) -1H-imidazo [4,5-c] quinolin-4-amine; 2-methoxymethyl-1-phenylmethyl-1H-imidazo [4,5-c] quinolin-4-amine; 2- (1-methoxypentyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinolin-4-amine; 2- (2-methoxypropyl) -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinolin-4-amine; 1- (2-methylpropyl) -2-morpholinomethyl-1H-imidazo [4,5-c] quinolin-4-amine; 1- (2-methylpropyl) -2-pyrrolidinomethyl-1H-imidazo [4,5-c] quinolin-4-amine; 2-methylthiomethyl-1-phenylmethyl-1H-imidazo [4,5-c] quinolin-4-amine; 2-morpholinomethyl-1-phenylmethyl-1H-imidazo [4,5-c] quinolin-4-amine; And 2- [1- (1-morpholino) pentyl] -1- (2-methylpropyl) -1H-imidazo [4,5-c] quinolin-4-amine. Compound of the formula Wherein R ₅ is straight or branched chain alkyl having from 1 to about 10 carbon atoms and substituted straight or branched chain alkyl having from 1 to about 10 carbon atoms, wherein the substituent is cycloalkyl having from 3 to about 6 carbon atoms, and Selected from the group consisting of cycloalkyl having 3 to about 6 carbon atoms and substituted by straight or branched alkyl having 1 to about 4 carbon atoms; Straight or branched alkenyl having 2 to about 10 carbon atoms, and substituted straight or branched alkenyl having 2 to about 10 carbon atoms, wherein the substituent is cycloalkyl having 3 to about 6 carbon atoms, and 1 to about Selected from the group consisting of cycloalkyl having 3 to about 6 carbon atoms and substituted by straight or branched alkyl having 4 carbon atoms; The alkoxy moiety is selected from the group consisting of 1 to about 4 carbon atoms; Alkoxyalkyl wherein the alkoxy moiety has 1 to about 4 carbon atoms and the alkyl moiety has 1 to about 6 carbon atoms; Acyloxyalkyl wherein the acyloxy moiety is an alkanoyloxy or benzoyloxy of 2 to about 4 carbon atoms and the alkyl moiety has 1 to about 6 carbon atoms; benzyl; (Phenyl) ethyl; And phenyl; Benzyl, (phenyl) ethyl or phenyl unsubstituted or substituted on the benzene ring by one or two moieties independently selected from the group consisting of alkyl of 1 to about 4 carbon atoms, alkoxy of 1 to about 4 carbon atoms, and halogen A substituent, provided that when the benzene ring is substituted by two of the moieties, those moieties are subject to having up to 6 carbon atoms together; R ₂ and R ₃ are hydrogen, alkyl of 1 to about 4 carbon atoms, phenyl and substituted phenyl, wherein the substituents are alkyl of 1 to about 4 carbon atoms, alkoxy of 1 to about 4 carbon atoms, and halogen Independently selected from the group consisting of; P is selected from the group consisting of alkanoyloxy, alkanoyloxyalkyl, wherein the alkyl moiety has from 1 to about 4 carbon atoms and aroyloxy; R is selected from the group consisting of hydrogen, straight or branched chain alkoxy having 1 to about 4 carbon atoms, halogen, and straight or branched chain alkyl having 1 to about 4 carbon atoms. Compound of the formula Wherein R ₅ is straight or branched chain alkyl having 1 to about 10 carbon atoms and substituted straight or branched chain alkyl having 1 to about 10 carbon atoms, wherein the substituent is cycloalkyl having 3 to about 6 carbon atoms, and Selected from the group consisting of cycloalkyl having 3 to about 6 carbon atoms and substituted by straight or branched alkyl having 1 to about 4 carbon atoms; Straight or branched alkenyl having 2 to about 10 carbon atoms, and substituted straight or branched alkenyl having 2 to about 10 carbon atoms, wherein the substituent is cycloalkyl having 3 to about 6 carbon atoms, and 1 to about Selected from the group consisting of cycloalkyl having 3 to about 6 carbon atoms and substituted by straight or branched alkyl having 4 carbon atoms; Alkoxyalkyl wherein the alkoxy moiety has 1 to about 4 carbon atoms and the alkyl moiety has 1 to about 6 carbon atoms; Acyloxyalkyl wherein the acyloxy moiety is an alkanoyloxy or benzoyloxy of 2 to about 4 carbon atoms and the alkyl moiety has 1 to about 6 carbon atoms; benzyl; (Phenyl) ethyl; And phenyl; Benzyl, (phenyl) ethyl or phenyl unsubstituted or substituted on the benzene ring by one or two moieties independently selected from the group consisting of alkyl of 1 to about 4 carbon atoms, alkoxy of 1 to about 4 carbon atoms, and halogen A substituent, provided that when the benzene ring is substituted by two of the moieties, those moieties are subject to having up to 6 carbon atoms together; R ₂ and R ₃ are hydrogen, alkyl of 1 to about 4 carbon atoms, phenyl and substituted phenyl, wherein the substituents are alkyl of 1 to about 4 carbon atoms, alkoxy of 1 to about 4 carbon atoms, and halogen Independently selected from the group consisting of; G is an alkoxy having 1 to about 4 carbon atoms, an alkoxy moiety having 1 to about 4 carbon atoms and an alkyl moiety having 1 to about 4 carbon atoms, an alkyl group having 1 to about 4 carbon atoms Amido, azido, chloro, 1-morpholino, 1-pyrrolidino, alkylthio of 1 to about 4 carbon atoms, alkanoyloxy, alkanoyloxyalkyl (the alkyl moiety having from 1 to about 4 carbon atoms) ). And aroyloxy, provided that when R is alkylamido, then R ₅ is alkenyl, substituted alkenyl, or alkoxyalkyl; R is hydrogen, straight or branched chain alkoxy having 1 to about 4 carbon atoms, halogen, and straight or branched chain alkyl having 1 to about 4 carbon atoms. Compound of the formula Wherein R ₅ is straight or branched chain alkyl having from 1 to about 10 carbon atoms and substituted straight or branched chain alkyl having from 1 to about 10 carbon atoms, wherein the substituent is cycloalkyl having from 3 to about 6 carbon atoms, and Selected from the group consisting of cycloalkyl having 3 to about 6 carbon atoms and substituted by straight or branched alkyl having 1 to about 4 carbon atoms; Straight or branched alkenyl having 2 to about 10 carbon atoms, and substituted straight or branched alkenyl having 2 to about 6 carbon atoms, wherein the substituent is cycloalkyl having 3 to about 6 carbon atoms, and 1 to about Selected from the group consisting of cycloalkyl having 3 to about 6 carbon atoms and substituted by straight or branched alkyl having 4 carbon atoms; Alkoxyalkyl wherein the alkoxy moiety has 1 to about 4 carbon atoms and the alkyl moiety has 1 to about 6 carbon atoms; Acyloxyalkyl wherein the acyloxy moiety is an alkanoyloxy or benzoyloxy of 2 to about 4 carbon atoms and the alkyl moiety has 1 to about 6 carbon atoms; benzyl; (Phenyl) ethyl; And phenyl; Benzyl, (phenyl) ethyl or phenyl unsubstituted or substituted on the benzene ring by one or two moieties independently selected from the group consisting of alkyl of 1 to about 4 carbon atoms, alkoxy of 1 to about 4 carbon atoms, and halogen Substituents, provided that the benzene ring is substituted by two of the moieties, provided that the moieties together have up to 6 carbon atoms; R ₂ and R ₃ are hydrogen, alkyl of 1 to about 4 carbon atoms, phenyl and substituted phenyl, wherein the substituents are alkyl of 1 to about 4 carbon atoms, alkoxy of 1 to about 4 carbon atoms, and halogen Independently selected from the group consisting of; Z is alkoxy having 1 to about 4 carbon atoms, alkoxyalkyl having 1 to about 4 carbon atoms and alkoxy moiety having 1 to about 4 carbon atoms, hydroxyalkyl of 1 to about 4 carbon atoms, Oxoalkyl having 2 to about 4 carbon atoms, alkanoyloxyalkyl wherein the alkyl moiety has 1 to about 4 carbon atoms, alkylamido, wherein the alkyl group has 1 to about 4 carbon atoms, substituted amino (substituents Is 1 to about 4 carbon atoms of hydroxyalkyl or alkyl), azido, chloro, 1-morpholino, 1-pyrrolidino, alkylthio of 1 to about 4 carbon atoms, hydroxy, alkanoyloxy, And aroyloxy; Q is selected from the group consisting of hydrogen, chloro and R _i -E-NH-, wherein R _i is an organic group substantially inert to quinoline N-oxide, and E is a functional group with hydrolytic activity, provided that When Q is R _i -E-NH-, Z is other than hydroxy, substituted amino or hydroxyalkyl as defined above, and when Q is hydrogen or chloro and Z is alkylamido or hydroxyalkyl, Provided that R ₅ is alkenyl, substituted alkenyl or alkoxyalkyl; R is selected from the group consisting of hydrogen, straight or branched alkoxy having 1 to about 4 carbon atoms, halogen, and straight or branched chain alkyl having 1 to about 4 carbon atoms.