1h-imidazo(4,5-c)quinoline-4-amines,their preparation and pharmaceutical compositions containing certain such compounds

Technical. Field

This invention relates to certain lH-imidazo[4,5-c]quinoline compounds, pharmaceutical compositions containing׳such compounds and process for preparing such compounds .

Certain other lH-imidazo[4,5-c]quinoline compounds and intermediates for their preparation and for the preparation of the compounds of the present invention are disclosed and claimed in IL 84537 which was divided out from the present application. :

Background of the Invention

The earliest report of an lmidazo[4,5-c]quinoline ring system was by Backeberg et al, J. Chem. Soc., 972-977 (1938). However, his report of 4-methyl-lH-imidazo[4,5-c]quinoline and 2,4-dim.ethyl-lH-imidazo[4,5-c]quinoline (named as 2-methylquin(3:4:5*:4’)iminazole and 2:2'-dimethylquin(3:4:5* :4’)iminazole)׳ is known to be erroneous in view of later work of Koenigs and Freund, Chemische Berichte 80, 143 (1947).

A further report by Backeberg, J. Chem. Soc., 1083-1089 (1938) of 2,4-dimethyl-3-phenyl-3H-imidazo[4,5-c]quinoline (named 1'-phenyl-2:2'-dimethylquin(3:4:5':4’)iminazole) is also known to be erroneous in view.of the above work of Koenigs and Freund.

The first reliable report of a lH-imidazo[4,5-c]quinoline is by Bachman et.’al., J. Org. Chem. 15, 1278-1284 (1950) who synthesized 1-(6-methoxy-8-quinolinyl)-2-methyl1H—imidazo[4,5—c]quin01׳ine as a possible antimalarial agent.

Surrey et al, J. Am. Chem. Soc. 73, 2413 (1951) synthesized certain 3-nitro- and 3-amino-4-dialkylaminoalkylaminoquinolines ^as possible antimalarial and antibacterial agents.

Jain et al., J. Med. Chem. 11, pp. 87-92, (1968), synthesized the compound [2-(4-piperidyl)ethyl]-lH-imidazo[4,5-c]quinoline as a possible anticonvulsant and cardiovascular agent.

Baranov et al., Chem. Abs. 85, 94362 (1976), reported several 2-oxoimidazo[4,5-c]quinolines.

Abbasi et al;, Monatsh. Chem. Ill (4), pp 963-969 (1980), reported certain 2H-3-hydroxyimidazo[4,5-c]quinolines. *

Berenyi et al, J. Heterocyclic Chem. 18, 1537-1540 (1981), reported certain 2-oxoimidazo[4,5-c]quinolines.

U.S. Patent No. 3,700,674 (Diehl et al.) describes certain 4-alkylamino-3-nitroquinolines as herbicidal compounds.

Detailed Description of the Invention

This invention relates to IH-imidazo [4,5-c].‘־quinolin-4-amines which are useful antiviral agents.

This invention also relates to pharmaceutical compositions containing such compounds and their preparation.

More specifically, this invention relates in one of its aspects to hovel compounds of Formula II

<img file="IL73534A_D0001.tif" />

wherein is selected from the group consisting of alkyl, cycloalkyl or cycloalkylalkyl and of up to about ten carbon atoms, hydroxyalkyl of up to about six carbon atoms,! acyloxyalkyl wherein the acyloxy moiety is alkanoyloxy of two to about four carbon atoms or benzoyloxy, and the alkyl moiety which is either straight or branched-chain, cycloalkyl or cycloalkylalkyl contains tip to about six carbon atoms, benzyl, (phenyl)ethyl or phenyl, the benzyl, (phenyl)ethyl or phenyl substituent being optionally substituted on the benzene ring by ’ , ' 73534/3 one or two moieties independently selected from , the group consisting of alkyl, cycloalkyl and cycloalkylalkyl of up to about four carbon atoms, alkoxy of one to about four carbon atoms and halogen, with the proviso that if said benzene ring is substituted by two of said moieties, then said moieties together contain no more than 6 carbon atoms; R2 is selected from the group consisting of hydrogen and alkyl, cycloalkyl or cycloalkylalkyl of up to about eight carbon atoms; and each R is independently selected from the group consisting of alkoxy of up to about four carbon atoms, cycloalkyl or cycloalkylalkyl of up to about four carbon atoms, and halogen, and n is an integer from 0 to 2, with the proviso that if n is 2, then said groups together contain no more than 6 carbon atoms; and pharmaceutically acceptable addition salts thereof. _____________..

. All of the compounds of Formula II may be used in the form of acid addition salts such as hydrochlorides, dihydrogen sulfates־, trihydrogen phosphates, hydrogen nitrates, methane sulfonates and salts of other pharmaceutically acceptable acids. Pharmaceutically acceptable acid-addition salts of compounds of Formula II are generally prepared by reaction of the respective compound with an equimolar amount of a relatively strong acid, preferably an inorganic acid such as hydrochloric, sulfuric or phosphoric acid or an organic acid such as methanesulfonic acid in a polar solvent. Isolation of the salt is facilitated by the addition of a solvent in which the salt is insoluble, an example of such a solvent being diethyl ether.

Generally, alkyl moieties!wKich may ’becontained in~ the compounds of the.invention may be straight or branchedchain or cyclic (hereinafter the term alkyl will be used to denote both alkyl, cycloalkyl or cycloalkylalkyl).

R^substituents which are alkyl preferably contain one to about eight carbon atoms, and more preferably contain about four to about six carbon atoms substituents .which are alkyl preferably contain! one to about four carbon atoms.

Hydroxyalkyl substituents which may be contained in the compounds of the invention preferably contain one to about four carbon atoms.

־ 4 The remaining substituents which may be contained in the compounds of the invention and contain an alkyl radical such as the substituents alkoxy and. alkyl (other than and R₂ as alkyl) preferably contain one or two carbon atoms in each alkyl radical.

The preferred cyclic alkyl moieties contain six or seven carbon atoms.

The halogen substituents which may be contained in the compounds of the instant invention are selected from fluorine, chlorine and bromine. Preferred halogen substituents are fluorine and chlorine.

n is preferably zero or one, and most preferably zero.

If R₁ is substituted benzyl, (phenyl)ethyl or phenyl, it is preferred that the benzene ring be monosubstituted. It is most preferred that the benzyl, (phenyl)ethyl or phenyl substituent be unsubstituted. As used in the instant specification and claims, (phenyl)ethyl denotes

1-(phenyl)ethyl or 2-(phenyl)ethyl.

It is presently preferred that R₁ be alkyl, benzyl, (phenyl)ethyl, cyclohexylmethyl or hydroxyalkyl. When R^ is :cycloalkyl, it is preferably cyclohexylmethylj

When R^ is hydroxyalkyl, the compounds of the ! invention may contain from one to three hydroxy substituents, ί Preferred hydroxyalkyl groups contain one or two hydroxy substituents.

Presently preferred antiviral compounds of Formula II are:

1-methy1-lH-imidazo[4,5-c]quinolin-4-amine, l,2,8-trimethyl-lH-imidazo[4,5-c]quinolin-4-amine,

1-(2-hydraxyethyl)-lH-imidazo[4,5-c]quinolin-4-amine,

1-benzyl-lH-imidazo[4,5-c]quinolin-4-amine/ l,2-dimethyl-lH-imidazo[4,5-c]quinolin-4-amine, . j

. ’ ׳ י ' י '1 l-benzyl-2-methyl-lH-imidazo[4,5-c]quinolin-4-amine, l,8-dimethyl-lH-imidazo[4,5-c]quinolin-4־־amine, l-cyclohexylmethyl־lH-imidazo[4,5-c]quinolin-4-amine, 1-(2,3-dihydroxypropyl)-lH־־imidazo[4,5-c]quinolin-4-amine, 1-isobutyl-lH-imidazo[4,5-c]quinolin-4-amine, 1-n-hexy1-2-methy1-lH-imidazo[4,5~c]quinolin-4-amine, and 1-n-hexyl-lH-imidazo[4,5-c]quinolin-4-amine.

The presently most preferred compounds of Formula

II are the last three mentioned above.

Compounds of the Inventionare.prepared according to reaction scheme A, below. In this reaction scheme R, R^ , R₂ and n are.as defined above».

<img file="IL73534A_D0002.tif" />

73534/3 - ר Many quinolines of Formula IV are known compounds (see, e.g., U.S. Patent 3,700,674 and references described therein). Those which are not may be prepared by known methods, for example, from 4-hydroxy-3-nitroquinolines as illustrated in step (1) of the Reaction Scheme. Step (1) may be conducted by reacting the 4-hydroxy-3-nitroquinoline of Formula III with phosphorus oxychloride. The reaction is preferably conducted in Ν,Ν-dimethylformamide and is accompanied by heating. A large molar excess of phosphorus oxychloride is preferably avoided. Employment of about a 1-2 molar ratio of phosphorus oxychloride to the 4-hydroxy-3-nitroquinoline has been found to be particularly suitable. Some compounds of Formula V are known such as those wherein is optionally substituted (phenyl)ethyl, 6-methoxy-8-quinolinyl, dialkylaminoalkyl, and phenyl. However, compounds of Formula V wherein R| is cyclohexylmethyl or hydroxyalkyl are novel.

In step (2), an optionally substituted 3-nitro-4chloroquinoline of Formula IV is reacted by heating with an amine cf the formula NH₂ in a suitable solvent such as water or tetrahydrofuran to provide a quinoline of Formula V.

Steps (1) and (2) may be combined such that the

3-nitro-4-chloroquinoline need not be isolated prior to reaction with the amine. Such a reaction is exemplified in Example 168 and Example 195 (Step A) below.

Compounds of Formula V are catalytically reduced in step (3) using a platinum catalyst such as platinum on charcoal to provide compounds of Formula VI. The reduction is conveniently carried out on a Parr apparatus in a non-reactive solvent such as toluene or a lower alkanol. Compounds of Formula VI wherein is cyclohexylmethyl or hydroxyalkyl are novel. In step (4) the intermediate compounds of Formula VI are reacted with a dialkoxyalkyl alkanoate such as diethoxymethyl acetate, or a carboxylic acid which can introduce the desired R2 group, or a trialkyl ortho ester of the formula R2C(Oalkyl)3, wherein alkyl״ is an alkyl group containing 1 to about 4 carbon atoms, or the combination of such a trialkyl ortho ester and such a carboxylic acid to provide a novel compound of Formula VII. The reaction of step (4) is carried out by heating, e.g. at about 130°C, in the presence of an acid, preferably an alkanoic acid having one more carbon atom'than R₂. Suitable acids also include haloalkanoic acids, aminoalkanoic acids, hydroxyalkanoic acids and the like. The compounds of Formula VII are active] as bronchodilators.

Step (5) provides a novel intermediate of Formula VIII through oxidation of the compound of Formula VII with a typical oxidizing agent used to form N-oxides. Suitable oxidizing agents include j

I peracids and hydrogen peroxide. The oxidation reaction is > preferably conducted in glacial acetic acid. Heating is generally employed to accelerate the rate of reaction.

Steps (4) and (5) may be combined such that the compound of Formula VII need not be isolated prior to reaction with the oxidizing agent. Such a reaction is exemplified in Example 195 (Step C) below. I

In step (6) the N-oxide of Formula VIII is ! converted to the 4-chloro intermediate of Formula IX by ן heating in the presence of a suitable chlorinating agent such as phosphorus oxychloride or thionyl chloride.

Phosphorus oxychloride is the preferred chlorinating agent and it is preferred that it be used in combination with Ν,Ν-dimethylformamide as the solvent.

In Step (7), the 4-chloro group of a compound of Formula IX is replaced by a 4-amino group to provide a compound of Formula II. The reaction of Step (7) is carried out in the presence of ammonium hydroxide or, preferably, ammonia. The intermediate of Formula IX is generally heated at 125 to 175°C under pressure for 8-24 hours. It is preferred that the reaction be conducted in a sealed reactor in the presence of either ammonium hydroxide or a solution of ammonia in an alkanol, such as, 15% ammonia in methanol.

For compounds of Formula II wherein Rj_ is hydroxyalkyl, the blocking reactions discussed above ___ may be employed to provide a compound of Formula IX wherein R^ is a protected hydroxyalkyl group. Reaction with ammonia as described in Example 140 then provides a compound of Formula II.

The antiviral activity of the compounds of

Formula II is preferably demonstrated using the method described by Kern, et al., Antimicrob. Agents Chemother.

14, 817-823 (1978).

This method uses female guinea pigs of 200 to 300 grams in weight, preferably 200 to 250 grams in weight. The preferred strain of pigs is Hartley. The pigs are anesthetized with pentobarbital or methoxyflurane, and are then infected with about 10^ plaque forming units of Type II Herpes simplex virus type intravaginally using a cotton swab. Type I Herpes simplex virus may also be used in this screening method. Drugs are prepared in saline or in water using a surfactant such as ״Tween 80 (a polyoxyethylene sorbitan monooleate commercially available from Emulsion Engineering, Inc., Elk Grove Village, Illinois). Alternatively, the compounds of Formula II may be formulated in PEG 400 (a polyethylene of average molecular weight of about 400, commercially available from Union Carbide Corporation) or in a polyethylene glycol cream. The drugs are applied intravaginally, for example, twice daily for a predetermined number of days, for example, five days. Application is initiated at a predetermined interval after infection such as one hour after infection. Virus replication can be monitored by determining the amount of virus recovered with vaginal swabs taken, for example, on days 1, 2, 3, 5 or 7 after infection. Virus is eluted from the swab in 1 ml of cell growth medium (Medium 199, Gibco Laboratories, Grand Island, New York) and virus titer is determined using cell monolayers. External lesions are scored daily for 10 days using the following scale: zero, no lesion; 1, redness or swelling; 2, a few small vesicles; 3, several large vesicles; 4, large ulcers and necrosis; 5, paralysis. Percent inhibition of lesion development is determined by comparing untreated, but infected control animals and drug treated animals. Comparison with known drugs such as phosphonacetic acid and acyclovir may also be undertaken.

Active compounds of Formula II are used to control Type I or Type Tl Herpes simplex virus by applying to a population thereof an amount of a compound sufficient to attain said control.

The compound of the invention may preferably be usedj in vivo for treating infections caused by the viruses, especially in mammals. By active virus is meant non-dormant virus. Such treatment'is generally effective when a compound of the invention or its formulation is administered topically (e.g., intravaginally or on the skin), for example, to a genital herpes infection. With some compounds of Formula II, a genital herpes infection may also be treated by oral administration. For example, the compounds of Formula II described in Examples 124, 125, and 138, may be used to treat a genital herpes infection by oral administration. Compounds of Formula II are also generally active against herpes infections by intraperitoneal administration. However, the preferred route of administration of the compounds of Formula II is topical.

The antiviral compounds of Formula II are formulated for the various routes of administration in known, pharmaceutically acceptable vehicles such as water or polyethylene glycol, generally, the compound of Formula II being present in an amount of less than about 10% by weight, and preferably about 0.1-5% by weight. Such compounds of Formula II are preferably administered in water with either a surfactant such as Tween 80 discussed above or cellulose. A 5% concentration of the surfactant has been found to be generally useful in topical, oral and intraperitoneal formulations. The presently preferred antiviral formulation for topical administration is a cream containing 1% by weight of the preferred antiviral compound 1-isobutyl-lHimidazo[4,5-c]quinolin-4-amine in micronized form (i.e., an average particle size of about 1-2 microns in diameter); 0.2% by weight of methyl paraben; 0.02% propyl paraben; 5% by weight of Avicel CL-611 (a colloidal form of microcrystalline cellulose which has been coprocessed with sodium carboxymethyl cellulose; available from EMC Corporation, Philadelphia, Pennsylvania); and 93.78% by weight of water. The formulation is prepared by dry-mixing the antiviral compound with the Avicel CL-611, and then combining that mixture with a solution containing the methyl paraben and propyl paraben in the water.

The following examples are provided to illustrate the invention and are not intended to be limiting thereof.

Example 1. Preparation of a Compound of Formula V To a stirred solution of 50.0g (0.24 mole) of

4-chloro-3-nitroquinoline in 300 ml of tetrahydrofuran was added, in small portions, 52.7g (0.72 mole) of isobutylamine. The mixture was heated at its reflux temperature for one hour and was then evaporated in vacuo. Water was added to the residue, and the solid was separated by filtration. The solid was suspended in one liter of water, and was dissolved by the gradual addition of concentrated hydrochloric acid (to pH 3 to 4) followed by filtration of the solution. The filtrate was basified (to pH 9 to 10) by the addition of concentrated ammonium hydroxide to provide bright yellow 4-(isobutylamino)-3-nitroquinoline, m.p. 119-121°C. The structural assignment was supported by infrared spectral analysis.

Example 2. Alternative Preparation of a Compound of Formula V

To a stirred solution of 40% aqueous methylamine was added, in small portions, 30.0g (0.144 mole) of 4-chloro-3-nitroquinoline. The reaction mixture was then heated at its reflux temperature for about 0.75 hour. After cooling, the mixture was poured in 300 ml of water. The solid was separated by filtration, and was then suspended in 300 ml of water. Acidification with 6N hydrochloric acid to pH 3 to 4 effected dissolution of most of the solid. Filtration was followed by basification of the filtrate with concentrated ammonium hydroxide to pH 8 to 10 to provide a yellow precipitate. The solid was separated by filtration, washed with water, and recrystallized from ethanol to provide yellow 4-methylamino-3-nitroquinoline, m.p. 168-170°C. Analysis: Calculated for C!0^H9^N3°2^: 59.1; %H, 4.5; %N, 20.7;

Found: %C, 59.0; %H, 4.2; %N, 20.8.

Using the methods of Examples 1 and 2, and starting with the indicated substituted quinolines and primary amines, the following compounds of Formula V were prepared (Table I):

<td rowspan="2"> Ex. No.</td><td colspan="3"> Table I</td>

<td> Quinoline Starting Material of Formula IV</td><td> Primary Amine Starting Material</td><td> Intermediate of Formula V (m.p. in °C)</td>

<td> 3</td><td> 4,6-dichloro-3nitroquinoline</td><td> methylamine</td><td> 6-chloro-4-me thylamino3-nitroquinoline (not taken)</td>

<td> 4</td><td> 4-chloro-3-nitroquinoline</td><td> ethanolamine</td><td> 4-(2-hydroxyethylamino)3-nitroquinoline (204-207)</td>

<td> 5</td><td> 4-chloro-3-nitro-</td><td> 2,3-dihydroxy-</td><td> 4-(2,3-dihydroxypropy1-</td>

<td></td><td> quinoline</td><td> propylamine</td><td> amino)-3-nitroquinoline (209-211)</td>

<td> 6</td><td> 4-ahloro-3-n i troquinoline</td><td> ethylamine</td><td> 4-e thylamino-3-ni troquinoline (145-148)</td>

<td> 7</td><td> 4-ahloro-6-methy13-n i troqui noline</td><td> methylamine</td><td> 6-me thy1-4-methylamino3-n i troquinoli ne (168-171)</td>

<td> 8</td><td> 4-chloro-6-me thy13-nitroquinoline</td><td> isobutylamine</td><td> 4-isobutylamino-6-me thyl3-nitroquinoline (108-110)</td>

<td> 9</td><td> 4-chloro-6-fluoro3-nitroquinoline</td><td> methylamine</td><td> 6-fluoro-4-methylamino- 3-nitroquinoline (198-202)</td>

<td> 10</td><td> 4,7-dichloro-3-</td><td> isobutylamine</td><td> 7-chloro-4-isobutylamino-</td>

<td></td><td> nitroquinoline</td><td></td><td> 3-n i troqui noline (not taken)</td>

<td> 11</td><td> 4-chloro-3-nitroquinoline</td><td> aniline</td><td> 3-nitro-4-phenylaminoquinoline (129-132)</td>

־ 15 -

<td> 12</td><td> 4-chloro-3-n i troquinoline</td><td> 4-methoxyaniline</td><td> 4-(4-methoxyphenylamino)-3nitroquinoline (136-138)</td>

<td> 13</td><td> 4-chloro-3-n i troquinoline</td><td> 4-fluoroaniline</td><td> 1 4-(4-fluorophenylamino)-3-1 nitroquinoline (147-151) 1 I</td>

<td> 14</td><td> 4-chloro-3-n i troquinoline</td><td> ammonia</td><td> 1 4-amino-3-nitroquinoline j (263-265)</td>

<td> 15</td><td> 4-chloro-3-nitroquinoline</td><td> n-butylamine</td><td> 4-(n-butylamino)-3nitroquinoline (81-83)</td>

<td> 16</td><td> 4-chloro3־-nitroquinoline</td><td> 3-hydroxypropylamine</td><td> 4-(3-hydroxypropylamino)-¹3-nitroquinoline (159-162)</td>

<td> 17</td><td> 4-chloro-3-n i troquinoline</td><td colspan="2"> 4-chlorobenzylamine 4-(4-chlorobenzylamino)-3-nitroquinoline (not taken)</td>

<td> out of ambit</td><td> ‘ 118 4-chloro-3-nitro- 1 quinoline</td><td> 2-me thoxye thylamine 4-(2-me thoxyethylamino)3-nitroquinoline (115-118) .</td>

<td></td><td> 4 19־-chloro-6-methyl-</td><td> n-butylamine 4-(n-butylamino)-6-</td>

<td> ־</td><td> 3-n i troqui noline</td><td> methyl-3-nitroquinoline ׳’</td>

<td></td><td></td><td> (not taken) !</td>

Example 20. Preparation of a Compound of Formula VI To a solution of 57.3g (0.23 mole) of

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

Using the method of Example 20, and starting with the indicated intermediates of Formula V, the intermediates of Formula VI shown in Table II were prepared. In those cases where the hydrochloride is listed, it was obtained by first bubbling hydrogen chloride through an ethanol solution of the free amine and then separating the solid product by filtration.

<td colspan="3"> Table II</td>

<td rowspan="2"> Ex. No.</td><td colspan="2"> Intermediate of</td>

<td> Formula V (Example No.)</td><td> Intermediate of Formula VI (m.p. in °C)</td>

<td> 21</td><td> 2</td><td> 3-amino-4-(me thylamino)quinoline hydrochloride (294-296)</td>

<td> 22</td><td> 3</td><td> 3-amino-6-chloro-4-(methylamino)quinoline (not taken)</td>

<td> 23</td><td> 4</td><td> 3-amino-4-(2-hydroxyethylamino)quinoline dihydrochloride (282-283)</td>

<td> 24</td><td> 5</td><td> 3-amino-4-(2,3-dihydroxypropylamino)quinoline hydrochloride (201-204)</td>

<td> 25</td><td> 6</td><td> 3-amino-4-(ethylamino)quinoline hydrochloride (226-229)</td>

<td> 26</td><td> 7</td><td> 3-amino-6-methy1-4-(me thylamino)quinoline hydrochloride (&gt;300)</td>

<td> 27</td><td> 8</td><td> 3-amino-4-isobutylamino-6-methy1quinoline (not taken)</td>

<td> 28</td><td> 9</td><td> 3-amino-6-fluoro-4-(methylamino)quinoline (not taken)</td>

<td> 29</td><td> 10</td><td> 3-amino-7-chloro-4-(isobutylamino)quinoline (not taken)</td>

<td> 30</td><td> 11</td><td> 3-amino-4-phenylaminoquinoline (not taken)</td>

- .

12 3-amino-4-(4-methoxyphenylamino)- quinoline (not taken)

13 3-amino-4-(4-fluorophenylamino)- quinoline (not taken)

14 3,4-diaminoquinoline (170-174)

15 3-amino-4-(n-butylamino)quinoline (80-83)

16 3-amino-4-(3-hydroxypropylamino)- quinoline (not taken)

17 3-amino-4-(4-chlorobenzylamino)- quinoline (not taken)

Example 37. Preparation of a Compound of Formula VII Crude 3-amino-4-(methylamino)quinoline (0.207 mole) obtained by the method of Example 20 was mixed with 500 ml of glacial acetic acid and 76 ml of triethyl orthoacetate, and the resulting mixture was heated at reflux for two hours. Evaporation provided a residue which was dissolved in 800 ml of water. The solution was basified with concentrated ammonium hydroxide. The solid was separated by filtration and washed with water to provide l,2-dimethyl-lH-imidazo[4,5-c]quinoline. When a sample of this product was recrystallized from diethyl ether, it had a melting point of 194-196°C. Analysis: Calculated for C12H11N3: %C, 73.1; %H, 5.6; %N, 21.3; Found: %C, 73.4; %H, 5.7; %N, 21.5.

Using the method of Example 37 and starting with the indicated intermediates, carboxylic acids and trialkyl orthoesters, the compounds of Formula VII shown in Table III were prepared.

Table III

<td></td><td> Intermediate</td><td> Ortho Ester;</td><td></td>

<td> Ex.</td><td> of Formula VI</td><td> Carboxylic</td><td> Compound of</td>

<td> No.</td><td> (Example No.)</td><td> Acid</td><td> Formula VII (m.p. in °C)</td>

<td> 38</td><td> 20</td><td> triethyl</td><td> l-isobutyl-lH-imidazo[4,5-c]quinoline</td>

orthofornate; (92-95) formic acid

22 triethyl 8-chloro-l,2-dimethyl-lH-imidazo[4,5- orthoacetate; cjquinoline (not taken) acetic acid

23 triethyl l-(2-hydroxyethyl)-lH-imidazo[4,5-c]- orthoformate; quinoline (170-172) formic acid

24 triethyl l-(2,3-dihydroxypropyl)-2-methyl-lH- orthoacetate; imidazo[4,5-c]quinoline (232-234) acetic acid

25 triethyl l-ethyl-2-methyl-lH-imidazo[4,5-c]- orthoacetate; quinoline (126-129) acetic acid

26 triethyl l8_׳-dimethyl-lH-imidazo[4,5-c]- orthdformate; quinoline hydrate (180-184) formic acid

26 triethyl l,28_׳-trimethyl-lH-imidazo[4,5-c]- orthoacetate; quinoline (220-221) acetic acid

25 triethyl l-ethyl-lH-imidazo[4,5-c]quinoline orthoformate; (80-82) formic acid

<td></td><td> ־</td>

<td> 46</td><td> 27 triethyl l-isobutyl-8-methyl-lH-imidazo[4,5- orthoformate: cjquinoline (160-163) formic acid</td>

<td> 47</td><td> 28 triethyl 8-fluoro-l-methyl-lH-imidazo[4,5-c]- orthoformate: quinoline hydrate (201-205) formic acid</td>

<td> 48</td><td> 29 triethyl 7-chloro-l-isobutyl-lH-imidazo[4,5-c]- orthoformate: quinoline (not taken) formic acid</td>

<td> 49</td><td> 30 triethyl l-phenyl-lH-imidazo[4,5-c]quinoline orthoformate; (137-139) formic acid</td>

<td> 5.0</td><td> 31 triethyl l-(4-methoxyphenyl)-lH-imidazo[4,5-c]- orthoformate; quinoline (150-152) formic acid</td>

<td> 51_k</td><td> 32 triethyl l-(4-fluorophenyl)-2-methyl-lH-imidazo- orthoacetate; [4,5-c]quinoline (191-193) acetic acid</td>

<td>_;</td><td> .31 triethyl l-(4-methoxyphenyl)-2-methyl-lH-imidazo- orthoacetate; [4,5-c]quinoline (174-176) acetic acid</td>

<td> ' 53 '</td><td> 32 triethyl l-(4-fluorophenyl)-lH-imidazo[4,5-c]- orthoformate; quinoline (159-161) formic acid</td>

<td> 54</td><td> 33 triethyl lH-imidazo[4,5-c]quinoline hydrate orthoformate; (&gt;250) formic acid</td>

<td> 55 i</td><td> 34־</td><td> triethyl orthoformate; formic acid</td><td> 1- (n-butyl )-lH-imidazo[4,5-c]quinoline (not taken)</td>

<td> 56</td><td> ' 35</td><td> triethyl orthoformate; formic acid</td><td> 1- (3-hydroxypropyl )-lH-imidazo[4,5-c]quinoline (not taken)</td>

<td> 57</td><td> 21</td><td> triethyl orthoformate; formic acid</td><td> 1-methyl-lH-imidazo[4,5-c]quinoline (143-145)</td>

<td> 58</td><td> 24</td><td> triethyl orthoformateן formic acid</td><td> 1-(2,3-di hydroxypropyl)-lH-imidazo[4,5-c]quinoline (228-230)</td>

<td> ־59</td><td> 20</td><td> triethyl orthoacetate; acetic acid</td><td> l-isobutyl-2-methyl-lH-imidazo- [4,5-c]quinoline hydrate (85-88)</td>

<td> 60</td><td> 28</td><td> triethyl orthoacetate; acetic acid</td><td> 1,2-dimethyl-8-fluoro-lHimidazo[4,5-c]quinoline (234-239)</td>

Example 61. Preparation of a Compound of Formula VIII. | To a solution of 9.3g (0.0413 mole) of !

l-isobutyl-lH-imidazo[4,5-c]quinoline (from Example 35) in 150 ml of acetic acid was added 1.5 equivalents (0.062 mole) of 30% hydrogen peroxide. The mixture was heated ati 65-70’C for one day, and was then evaporated. The residuej was neutralized with saturated sodium bicarbonate solution ן and the resulting mixture was extracted with dichloromethane. The extracts were dried, then evaporated to provide a residue which solidified gradually to yellow solid l-isobutyl-lH-imidazo[4,5-c]quinolin-5-oxide. This product was recrystallized twice from ethyl acetate to give a green solid, m.p. 211-213’C. Analysis: Calculated for C14H15N3O: %C, 69.7: %H, 6.3; %N, 17.4; Found: %C, 69.7; %H, 6.3; %N, 17.1.

Using the method of Example 61, and starting with the indicated intermediates, the compounds of Formula VIII shown in Table IV were prepared.

<td> Ex. No. 62</td><td> Compound of Formula VII (Example No.) 39</td><td> Table IV Compound of Formula VIII (m.p. in.»C) 8-chloro-l,2-dimethyl-lH-imidazo[4,5-c]- quinolin-5-oxide (not taken)</td>

<td> 63</td><td> 113 (Part C)</td><td> l-benzyl-lH-imidazo[4,5-c]quinolin-5oxide (241-251)</td>

<td> 64</td><td> 114 (Part C)</td><td> l-cyclohexylmethyl-lH-imidazo[4,5-c]quinolin-5-oxide (224-226, dec.)</td>

<td> 65</td><td> 42</td><td> l-ethyl-2-methyl-lH-imidazo[4,5-c]quinolin-5-oxide (220-222)</td>

<td> 66</td><td> 43</td><td> 1,8-dimethy1-lH-imidazo[4,5-c]quinolin5-oxide (265-268)</td>

<td> 67</td><td> 44</td><td> 1,2,8-trimethyl-lH-imidazo[4,5-c]quinolin-5-oxide (not taken)</td>

<td> 68</td><td> 45</td><td> l-ethyl-lH-imidazo[4,5-c]quinolin-5oxide (not taken)</td>

<td> 69</td><td> 46</td><td> l-isobutyl-8-methyl-lH-imidazo[4,5-c]quinolin-5-oxide (not taken)</td>

8-fluoro-l-methyl-lH-imidazo[4,5-c]- quinolin-r-5-oxide (not taken)

7-chloro-l-isobutyl-lH-imidazo[4,5-c]- quinolin-5-oxide (not taken)

1-phenyl-lH-imidazo[4,5-c]quinolin-5oxide (222-225)

1-(4-methoxyphenyl)-lH-imidazo[4,5-c]quinolin-5-oxide (245-247)

1-(4-fluorophenyl)-2-methyl-lH-imidazo[4,5-c]quinolin-5-oxide (245-248) l-(4-methoxyphenyl)-2-methyl-lH-imidazo-

[4,5-c]quinolin-5-oxide (211-213)

1-(4-fluorophenyl)-IH-imidazo[4,5-c]quinolin-5-oxide (257-259) lH-imidazo[4,5-c]quinolin-5-oxide (not taken)

122 2-methyl-l-[2-(phenyl)ethyl]-lH-imidazo[4,5-c]quinolin-5-oxide (204-206) l,2-dimethyl-lH-imidazo[4,5-c]quinolin-

5-oxide (234-237)

1-methyl-lH-imidazo[4,5-c]quinolin-5oxide (241-244) _{859 ו} l-isobutyl-2-methyl-lH-imidazo[4,5-e]quinolin-5-oxide (214-216) g₂ 60 1,2-dimethyl-8-fluoro-lH-imidazo[4,5-c]quinolin-5-oxide (not taken)

Example 83. Preparation of a Compound of Formula IX A mixture of 9.95 g (0.0412 mole) of l-lsobutyl-lH-imidazo[4,5-c]quinolin-5-oxide (from Example 61). and 100 ml of phosphorus oxychloride was heated at its reflux temperature for 2.5 hours, and was then cooled and poured into ice with stirring. Basification (to pH 9-10) with 50% aqueous sodium hydroxide solution was followed by extraction with dichloromethane. The extracts were dried over sodium chloride and sodium bicarbonate, and then evaporated to provide a solid residue. A sample of the residue was recrystallized from diethyl ether to provide 4־chloro-l-isobutyl-lH-imidazo[4,5-c]quinoline, m.p. 134-136’C. Analysis: Calculated for C₁4H₁₄C1N₃: %C, 64.7: %H, 5.4; %N, 16.2; Found: %C, 64.3; %H, 5.3; %N, 16.3.

Using the method of Example 83, and starting with the indicated compounds of Formula VIII, the compounds of Formula IX were prepared.

<td></td><td> Table V</td>

<td> Compound of Ex. Formula VIII No. (Example No.)</td><td> Compound of Formula IX (m.p. in °C)</td>

<td> 84 79</td><td> 4-chloro-l, 2-dimethyl-lH-imidazo[4,5-c]quinoline (198-200)</td>

<td> 85 62</td><td> 4,8-dichloro-l, 2-dimethyl-lH-imidazo[4,5-c]quinoline (not taken)</td>

<td> 86 63</td><td> l-benzyl-4-chloro-lH-imidazo[4,5-c]~ quinoline (160-167)</td>

<td> 87 64</td><td> 4-chloro-l-cyclohexylmethyl-lHimidazo[4,5-c]quinoline (176-179)</td>

<td> 88 65</td><td> 4-chloro-l-ethy1-2-methyl-lH-imidazo[4,5-c]quinoline (170-172)</td>

<td> 89 66</td><td> 4-chloro-l, 8-dimethyl-lH-imidazo[4,5-c]quinoline (233-237)</td>

<td> 90 67</td><td> 4-chloro-l, 2,8-trimethyl-lH-imidazo- [4,5-c]quinoline (243-247)</td>

<td> 91 68</td><td> 4-chloro-l-ethyl-lH-imidazo[4,5-c]quinoline (not taken)</td>

<td> 92 69</td><td> 4-chloro-1-isobutyl-8-methy1-1H-imidazo[4,5-c]quinoline (202-205)</td>

<td> 93 70</td><td> 4-chloro-8-fluoro-l-methyl-lH-imidazo[4,5-c]quinoline (not taken)</td>

<td> 94 71</td><td> 4,7-dichloro-l-isobutyl-lH-imidazo[4,5clquinoline (not taken)</td>

/ 73534/3

<td> 95</td><td> 72 '</td><td> 4-chloro-l-phenyl-lH-imidazo[4,5-c]quinoline (not taken)</td>

<td> 96</td><td> Ί3</td><td> 4-chloro-1-(4-methoxyphenyl)-1H-imidazo[4,5-c]quinoline (210-212)</td>

<td> 97</td><td> 74</td><td> 4-chloro-l-(4-fluorophenyl)-2-methyl-lHimidazo[4,5-c]quinoline (295-297) t.</td>

<td> 98</td><td> 75</td><td> 4-chloro-l-(4-methoxyphenyl)-2-methy1-1H-</td>

<td></td><td></td><td> imidazo[4,5-c]quinoline . (211-213)</td>

<td> 99</td><td> 76</td><td> 4-chloro-l-(4-fluorophenyl)-lH-imidazo[4,5-c]quinoline (248-250)</td>

<td> 100</td><td> 116.</td><td> 4-chloro-1-[2-( phenyl)ethyl]-lH-imidazo-</td>

<td></td><td> Part D</td><td> [4,5-c]quinoline (176-188)</td>

<td> 101</td><td> 80</td><td> 4-chloro-l-methyl-lH-imidazo[4,5-c]-</td>

<td></td><td></td><td> quinoline (179-181)</td>

<td> 102</td><td> 81</td><td> 4-chloro-l-isobutyl-2-methyl-lH-imidazo-</td>

<td> .</td><td></td><td> [4,5-c]quinoline (152-155)</td>

<td> 103'</td><td> 82 .</td><td> 4-chloro-l, 2-dimethyl-8-fluoro-lHimidazo-[4,5-c]quinoline (not taken)</td>

<td> Example</td><td> 1.04 '</td><td></td>

To a stirred, cold (5°C) mixture of 29.1 g (0.136 mole) of l-(2-hydroxyethyl)-lH-imidazo[4,5-c]quinoline (from Example 40) and 500 ml of pyridine was added, in small portions, 23.9 g (0.17 mole) of benzoyl chloride.

The mixture was permitted to warm to about 20°C slowly, and was then stirred for eighteen hours at 20°C. The solution was. evaporated, and water was added, to the residue. The solid was separated by filtration, washed with water and recrystallized from a 50:50 ethyl acetate/hexane mixture. Recrystallization from ethyl acetate and again from ethanol provided white crystals of l-(2-benzoyl0xyethyl)-lH-imidazo[4,5-c]quinoline, m.p. 149-151°C. Analysis: Calculated for C19H15N3O2: %C, 71.9; %H, 4.8; %N, 13.2; Found: %C, 71.8: %H, 4.6; %N, 13.2.

Example 105

A mixture of 67.5 g (0.213 mole) of 1-(2-benzoyloxyethyl)-lH-imidazo[4,5-c]quinoline ( from Example 104'), 36.3 g (0.32 mole) of 30% hydrogen peroxide and 450 ml of glacial acetic acid was heated at 65®C for two days with stirring . The solution was then evaporated in vacuo, and the residue was added to water. The mixture was neutralized with aqueous sodium hydroxide solution and sodium bicarbonate. The solid was separated by filtration, washed with water and recrystallized from methanol to provide tan solid l-(2-benzoyloxyethyl)-lH-imidazo[4,5-c]quinolin-5-oxide.

Example .106

A mixture of 50g (0.15 mole) of 1-(2-benzoyloxyethy1)-lH-imidazo[4,5-c]quinolin-5-oxide (from Example 105) and 200 ml of phosphorus oxychloride was heated for two hours on a steam bath. The mixture was then partially evaporated in vacuo. The mixture was then poured over ice and the solution was neutralized with sodium hydroxide. The product was separated by filtration, dissolved in dichloromethane, and the solution was washed with aqueous sodium bicarbonate solution and then dried. Evaporation provided a solid which was recrystallized from a 50:50 methanol:dichloromethane solution to provide white 1-(2-benzoyloxyethyl)-4-chloro-lH-imidazo[4,5-c]quinoline, m.p. 186-190’C., Analysis: Calculated for C19H14CIN3O2: %C, 64.9; %H, 4.0; %N, 12.0; Found: %C, 64.8; %H, 3.8; %N, 12.1.

Example 107

A mixture of 25.3 g (0.072 mole) of l-(2-benzoyloxyethyl)-4-chloro-lH-imidazo[4,5-c]quinoline (from Example 106) and 500 ml of 10% ammonia in methanol was stirred at about 20*C for three days, and was filtered and then evaporated to low volume. The slurry was mixed with diethyl ether, and the solid was separated by filtration, washed with ether and recrystallized from methanol to provide white crystals of 4-chloro-1-(2-hydroxyethyl)-IH-imidazo[4,5-c]quinoline, m.p. 185-187^OC. Analysis: Calculated for C!2^H10^C1N3^{0! %c}׳ 58.2; %H, 4.1; %N, 17.0; Found: %C, 58.0; %H, 4.0; %N, 17.3.

Example 108

To a solution of 3.0 g (0.013 mole) of l-isobutyl-lH-imidazo[4,5-c]quinoline (from Example 3-8) in 150 ml of wet ethanol was added hydrogen chloride gas. After stirring for about one hour the solid 1-isobutyl-lHimidazo[4,5-c]quinoline hydrochloride hydrate was separated by filtration and recrystallized from ethanol to provide off-white crystals, m.p. 227-229°C. Analysis: Calculated for C14H15N3-HC1״H2O: %C,60.1: %H, 6.5; %H, 15.0; Found: %C, 60.2; %H, 6.2; %N, 15.4.

Example Part A Using the method of Example benzoyl chloride was reacted with l-(2,3-dihydroxypropyl)-lH-imidazo[4,5-c]quinoline (from Example 58) to provide 1-(2,3-dibenzoyloxypropyl)-IH-imidazo[4,5-c]quinoline. Part B

The crude product from Part A was reacted with hydrogen peroxide according to the method of Example 105' to provide 1-(2,3-dibenzoyloxypropyl)-lH-imidazo[4,5-c]quinolin-5-oxide as a pale yellow solid, the melting point of crude material being 73-B2°C.

Part C

The product from Part B was reacted with phosphorus oxychloride according to the method of Example 106 to provide 4-chloro-l-(2,3-dibenzoyloxypropyl)-lHimidazo[4,5-c]quinoline, m.p. 162-165’C after recrystallization from ethanol. Analysis: Calculated for C27H20CIN3O4: %C, 66.7; %H, 4.1; %N, 8.6; Found: %C, 66.3; %H, 3.9; %N, 8.4.

Part D

Hydrolysis of the product from Part C according to the method of Example 107. provides 4-chloro-l-(2,3dihydroxypropyl )-1H-imidazo[4,5-c]quinoline.

Example Part A 1-(2,β-Dihydroxypropyl)-lH-imidazo[4,5-c]quinoline (from Example 58) was reacted with excess acetic anydride to provide l-(2,3-diacetoxypropyl)-lH-imidazo[4,5-c]quinoline. Part B

The product of Part A was reacted with hydrogen peroxide according to the method of Example 105 to provide l-(2,3-diacetoxypropyl)-lH-imidazo[4,5-c]quinoline-5-oxide as a brownish-yellow solid, the melting point of the crude material being 84-96’C. Part C

The product of Part B was reacted with phosphorus oxychloride according to the method of Example 106 to provide 4-chloro-l-(2,3-diacetoxypropyl)-lH-imidazo[4,5-c]-quinoline. Part D

The product of Part C was hydrolyzed according to the method of Example 107 to provide 4-chloro-l-(2,3-dihydroxypropyl)-lH-imidazo[4,5-c]quinoline. Recrystallization from ethanol provided product, m.p. 223-225°C. Analysis: Calculated for C13H12CIN3O2: %C, 56.2, %H, 4.4; %N, 15.1; Found: %C, 55.8, %H, 4.3; %N, 15.1.

Example !!!

To a stirred solution of 4,0g (0.0117 mole) of 1-(2,3-diacetoxypropyl)-lH-imidazo[4,5-c]quinolin-5-oxide (from Example 110, Part B) in 50 ml of methanol was added about 12 drops of 25% sodium methoxide solution. After one hour the product was collected by filtration, washed with methanol and recrystallized from ethanol to provide l-(2,3-dihydroxypropyl)-lH-imidazo[4,5-c]quinolin-5-oxide, m.p. 240-242°C. Analysis: Calculated for C13H13N3O3: %C, 60.2: %H, 5.1; 16.2; Found: %C, 60.0; %H, 5.0; %N,

15.8.

Example 112

Excess acetic anhydride (100 ml) was refluxed for 0.5 hour with l-(2,3-dihydroxypropyl)-2-methyl-lH-xmidazo[4,5-c]quinoline (from Example 41 ) to provide 1-(2,3-diacetoxypropyl)-2-methyl-lH-imidazo[4,5-c]quinoline. This product was reacted with hydrogen peroxide using the method of Example 105 to provide l-(2,3-diacetoxypropyl)-2methyl-lH-imidazo[4,5-c]quinolin-5-oxide as a yellow solid. This crude product was reacted with phosphorus oxychloride according to the method of Example 106 to provide the product 4-chlor0-(2,3-diacetoxypropyl)-2-methy1-1H-imidazo[4,5-c]quinoline. This product was dissolved in methanol saturated with ammonia, and the solution was stirred for three days. The product obtained was 4-chloro-l-(2,3dihydroxypropyl)-2-methyl-lH-imidazo[4,5-c]quinoline.

Example Part A

Using the method of Example 1, benzylamine and 4-chloro-3-nitroquinoline were reacted to provide 4-benzylamino-3-nitroquinoline. The structural assignment for the crude product (m.p. 178-196’C) was supported by infrared spectral analysis.

Part B

Using the method of Example 20, 42.2g (0.15 mole) of 4-benzylamino-3-nitroquinoline was reduced to provide

3- amino-4-(benzylamino)quinoline as a tan solid. Part C

To the product from Part B was added 48.7g (0.5 mole) of diethoxymethyi acetate and the mixture was heated on a steam bath for one hour, and was then maintained at reflux for 0.5 hour. The solution was added to a stirred excess of concentrated ammonium hydroxide. The solid was separated by filtration and washed sequentially with water, 10:1 diethyl ether: ethanol and 1:1 hexane:diethyl ether. Recrystallization from isopropanol provided pale yellow needles of l-benzyl-lH-imidazo[4,5-c]quinoline, m.p. 179-181°C. Analysis: Calculated for C17H13N3: %C, 78.7; %H, 5.1; %N, 16.2; Found: %C, 78.6; %H, 4.8; %N, 16.3.

Example

Part A

A mixture of 26.1g (0.125 mole) of

4- chloro-3-nitroquinoline, 16.4g (0.1275 mole) of 95% cyclohexylmethylamine and 16.5 g (0.125 mole) of 95% diisopropyl ethylamine in 300 ml of tetrahydrofuran was heated on a steam bath for 0.5 hour. The solution was evaporated and the residue was slurried in methanol, filtered and washed with methanol. Recrystallization from methanol provided yellow platelets of 4-cyclohexylmethylamino-3-nitroquinoline, m.p. 140-142’C. Analysis: Calculated for C16H19N3O2: %C, 67.3: %H, 6.7; %N, 14.7; Found: %C, 67.3; %H, 6.6; %N, 14.7.

Part B

Using the method of Example 20, 17 g (0.60 mole) of 4-cyclohexylmethylamino-3-nitroquinoline was reduced to provide 3-amino-4-cyclohexylmethylaminoquinoline. Part C

The crude product from Part B was heated at reflux for 2.5 hours in 250 ml of 98% formic acid to provide 1-cyclohexylmethyl-lH-imidazo[4,5-c]quinoline as a pale yellow solid.

Example 115

Using the method of Example 1, 4-chloro-3-nitroquinoline was reacted with 4-chlorobenzylamine to provide yellow solid 4-(4-chlorobenzylamino)-3-nitroquinoline, melting point of crude product 168-173°C.

Example Part A

Using the method of Example 1, 4-chloro-3-nitroquinoline was reacted with

2- (phenyl)ethylamine to provide yellow solid

3- n1tro-4-[2-(phenyl)ethylamino]quinoline, the melting point of the crude product being 174-180^eC.

Part B

Using the method of Example 20,

3-nitro-4-[2-(phenyl)ethylamino]quinoline from Part A was reduced to provide 3-amino-4-[2-(phenyl)ethylaminojquinoline. Part C

Using the method of Example 37 , 3-amino-4-[2(phenyl)ethylaminojquinoline was reacted with triethyl orthoformate and formic acid to provide l-[2-(phenyl)ethyl]-lH-imidazo[4,5-c]quinoline, m.p. 105-108’C. Part D

Using the method of Example 61, l-[2-(phenyl)ethylamino]-lH-imidazo[4,5-c]quinoline was converted to yellow solid 1-[2-(phenyl)ethyl]-lH-imidazo[4,5-c]quinolin-

5-oxide, melting point of crude product, 73-95’C.

REFERENCE EXAMPLE A

! ״ “—ד7ד־—־

A mixture of 5.8 g (0.026 mole) of

3-amino-6-methyl-4-(methylamino)quinoline (the hydro- j chloride salt of which having been obtained in Example 26j, ! 4.1g (0.040 mole) of 4-aminobutyric acid and 100 ml of 4N j hydrochloric acid was heated at its reflux temperature for ¹ about 65 hours. The solution was cooled and diluted to 500 ml total volume with isopropanol. The precipitate was separated by filtration, and then recrystallized from aqueous isopropanol to provide yellow crystals of

2-(3-aminopropyl)-1,8-dimethyl-lH-imidazo[4,5-c]quinoline j dihydrochloride, m.p. >300°C. Analysis: Calculated for , C15H1gN4*2HCl: %C, 55.0; %H, 6.2; %N, 17.1; Found: %C, 54.3; %H, 6.2: %N, 17.1.

Example 117-. 1

Using the method of Reference. Example A,. 3,4-diamino! quinoline (from Example 3:3) was reacted with glacial acetic j acid to provide 2-methyl-lH-imidazo[4,5-c]quinoline as a j white solid, crude m.p. 119-123^eC. j

Example 118

Using the method of Reference 'Example A, 3-amino-4. (methylamino)quinoline (the hydrochloride salt of which having been obtained in Exmple 21) was reacted with isobutyric acid to provide 2-isopropyl-l-methyllH-imidazo[4/5-c]quinoline. The crude product was dissolved in ethyl acetate and an excess of concentrated j hydrochloric acid was added. The precipitate was separated | by filtration and recrystallized from ethanol to provide

2-isopropyl-l-methy1-lH-imidazo[4,5-c]quinoline hydrochloride, m.p. 260-263’C. This salt was suspended in water and the mixture was basified (pH 8-Ϊ0) with 50% aqueous sodium hydroxide. The solid was separated by filtration, washed with water and recrystallized from 1 hexane to provide the free base as the hydrate, m.p. 76-81’C. Analysis: Calculated for C14H!5N30.25״H20: %C, 73.2; %H, 6.8; %N, 18.3; Found: %C, 73.0 %H, 7.0; %N, 18.4.:

-

Example

Part A

Using the method of Example 37,

3- amino-4-(benzylamino)quinoline (from Example 113 , Part

B), was reacted with triethyl orthoacetate and acetic acid to provide l-benzyl-2-methyl-lH-imidazo[4,5-c]quinoline hydrate, m.p. 145-147°C. Analysis: Calculated for ^C18^H15^N3*²’^25H2^{O: %c}68.9 ׳; %H, 6.3, %N, 13.4; Found: %C, 69.2: %H, 6.0; %N 13.4.

Part B

Using the method of Example 61, l-benzyl-2-methyl-lH-imidazo[4,5-c]quinoline was converted to l-benzyl-2-methyl-lH-imidazo[4,5-c]quinolin-5-oxide hydrate, m.p. 193-196°C. Analysis: Calculated for ^c18^h15ⁿ3°*2.25H2O: %C, 65.6; %H, 6.0; %N, 12.7; Found: %C, 65.4; %H, 5.7; %N, 12.5.

Example 120

To a solution of 5.7 g (0.30 mole) of 3-hydroxy-

4- nitroquinoline in 50 ml of Ν,Ν-dimethylformamide was added 9.3 g (0.60 mole) of phosphorus oxychloride. The solution was heated on a steam bath for 5 minutes, then poured with stirring into 200 ml of 40% aqueous methylamine. The mixture was heated on a steam bath for fifteen minutes, then diluted with 200 ml of water. The solid was separated by filtration, then dissolved in dilute hydrochloric acid. The solution was filtered and the filtrate was basified with ammonium hydroxide. The solid precipitate was separated by filtration, washed with water and dried to provide yellow solid 4-methylamino-3-nitroquinoline, m.p. 167-171’C.

Example 121

To a solution of 4.8 g (0.0311 mole) of phosphorus oxychloride in 20 ml of N,N-dimethylformamide was added, in small portions, 5.0 g (0.207 mole) of

1-isobutyl-lH-imidazo[4,5-c]quinoline-5-oxide. The solution was stirred for 15 minutes at 20°C, then heated on a steam bath for 15 minutes. The solution was cooled to 20°C, then poured into stirred ice. The solution was basified to pH 8 with concentrated ammonium hydroxide. The yellow solid precipitate was separated by filtration, washed sequentially with water and diethyl ether, and dried to provide 4-chloro-l-isobutyl-lH-imidazo[4,5-c]quinoline hydrate, m.p. 103-107°C. Recrystallization twice from ethyl acetate with drying provided 4-chloro-l-isobutyl-lHimidazo[4,5-c]quinoline, m.p. 135-137’C. Analysis: Calculated for C₁₄H₁₄C1N₃: %C, 64.7; %H, 5.4; %N, 16.2; Found: %C, 64.6; %H, 5.5; %N, 16.1.

Example 12 2

Using the method of Example 37, 3—amino-4—[2— (phenyl)ethylaminojquinoline (from Example 116, Part B) was reacted with triethyl orthoacetate and acetic acid to provide 2-methyl-l-[2-(phenyl)ethyl]-lH-imidazo[4,5-cjquinoline.

Example Part A

Using the method of Example 20,

4-(4-chlorobenzylamino)-3-nitroquinoline (from Example 17) was reduced to provide 3-amino-4-(4-chlorobenzylamino)quinoline.

Part B

The product from Part A was reacted with triethyl orthoacetate and acetic acid using the method of Example 37 to provide l-(4-chlorobenzyl)-2-me.thyl-lH-imidazo[4,5-c]quinoline, m.p. 183-185°C.

Example 124. Preparation of a Compound of Formula II A mixture of 4.0 g (0.0154 mole) of

4-chloro-l-isobutyl-lH-imidazo[4,5-c]quinoline (from Example 83) and 25 cc of concentrated ammonium hydroxide was placed in a metal bomb and heated at 150°C for about 16 hours. After cooling the solid was separated by filtration, washed with water and recrystallized from ethanol to provide white crystals of l-isobutyl-lH-imidazo[4,5-c]quinolin-4-amine, m.p. 288-291’C. Recrystallization from N,N-dimethylformamide is preferred. Analysis: Calculated for C14H15N4: %C, 70.0;

%H, 6.7; %H, 23.3; Found: %C, 69.3; %H, 6.6; %N, 23.2.

Example 125; Alternative Preparation of a Compound of Formula II

A mixture of 2.0 g (0.00863 mole) of 4-chloro-l, 2-dimethyl-lH-imidazo[4,5-c]quinoline (from Example 84) and 30 ml of 15% ammonia in methanol was heated in a steel bomb for 18 hours at 155’C. The bomb was cooled, and the solid was separated by filtration, washed with ethanol and recrystallized from ethanol to provide white needles of l,2-dimethyl-lH-imidazo[4,5-c]quinolin4-amine, m.p. 288-290°c. Analysis: Calculated for ^C12^H12^N4^:. %C, 67.9; %H, 5.7; %N, 26.4; Found: %C, 67.6; %H, 5.4; %N, 26.3.

Using the general method exemplified in Examples 124 and 125 compounds of the invention of Formula II shown in Table VII were prepared.

<td></td><td> Intermediate</td><td> Table VI!</td>

<td> Ex. No.</td><td> Formula XI (Example No.)</td><td> Product of formula II (m.p. £_n ־_c)</td>

<td> 126</td><td> 89</td><td> l,8-dimethyl-lH-imidazo[4,5-c]quinolin-4-amine (305-309)</td>

<td> 127</td><td> . ,׳110 Part D</td><td> (2,3-dihydroxypropyl)-1Himidazo[4,5-c]quinolin-4-amine (228-230)</td>

<td> 128</td><td> 90</td><td> l,2,8-trimethyl-lH-imidazo[4,5c]quinolin-4-amine (&gt;250)</td>

<td> 129</td><td> 92</td><td> l-isobutyl-8-methyl-lH-imidazo[4,5-c]quinolin-4-amine hydrate (206-208)</td>

<td> 130</td><td> 101</td><td> l־methyl-lH-imidazo[4,5-c]quinolin4-amine (270-272)</td>

<td> 131</td><td> 95</td><td> l-phenyl-lH-imidazo[4,5-c]quinolin4-amine (278-280)</td>

<td> 132</td><td> 96</td><td> l-(4-methoxyphenyl)-lH-imidazo[4,5c]quinolin-4-amine (286-288)</td>

<td> 133</td><td> 98</td><td> l-(4-methoxyphenyl)-2-methyl-lH- imidazo[4,5-c]quinolin-4-amine (263-265)</td>

<td> 134</td><td> 97</td><td> 1-(4-fluorophenyl)-2-methyl-lHimidazo[4,5-c]quinolin-4-amine (296-299)</td>

<td> 135 99</td><td> 1-(4-fluorophenyl)-lH-imidazo[4,5-c]quinolin-4-amine (290-293)</td>

<td> .136 85</td><td> 8-chloro-l, 2-dimethyl-lH-imidazo[4,5-c]quinolin-4-amine (283-286)</td>

<td> 137 94</td><td> 7-chloro-l-isobutyl-lH-imidazo[4,5-c]quinolin-4-amine hydrate (211-214)</td>

<td> 138 102</td><td> l-isobutyl-2-methyl-lH-imidazo- [4,5-c]quinolin*4־-amine (200-202)</td>

<td> 139 103</td><td> 1,2-dimethyl-8-fluoro-lH-imidazo[4,5-c]quinolin-4-amine hydrate (262-264)</td>

Example 140

A mixture of 1.3 g (0.0037 mole) of

1-(2-benzoyloxyethy1)-4-chloro-lH-imidazo[4,5-c]quinoline (from Example 106) in 60 ml of methanol was saturated with about 10g of ammonia gas. The mixture was heated at 150°C in a steel bomb for ten hours. The mixture was evaporated, and the residue was slurried in diethyl ether and filtered. The solid obtained was slurried in methanolic hydrochloric acid to provide off-white solid l-(2-hydroxyethyl)lH-imidazo[4,5-c]quinolin-4-amine hydrochloride hydrate, m.p. >25O’C. Analysis: Calculated for C12H12ⁿ4°*^hc^*1«25H2O: %C, 50.2; %H, 5.4; %N, 19.5; Found: %C, 50.2; %H, 5.2; %N, 19.1.

Example .141

Using the method of Example 125, l-benzyl-4chloro-lH-imidazo[4,5-c]quinoline (from Example 86) was reacted with ammonia to provide white solid l-benzyl-lH-imidazo[4,5-c]quinolin-4-amine after recrystallization from Ν,Ν-dimethylformamide, m.p. 257-259°C. Analysis: Calculated for C17H14N4: %C, 74.4; %H, 5.1; %N, 20.4; Found: %C, 74.3; %H, 5.4; %N, 20.5.

Example 142

Using the method of Example 125, 4-chloro-l-cyclohexylmethyl-lH-imidazo[4,5-c]quinoline (from Example 87) was aminated to provide solid 1-cyclohexylmethyl-lH-imidazo[4,5-c]quinolin-4-amine hydrate. Analysis: Calculated for ¹C17H₂0N4*H₂O: %C, 68.4; %H, 7.4; %N, 18.8; Found; %C, 68.2; %H, 7.4; %N, 18.5.

Example 14 3. ' j

A mixture of 4.0 g (0.016 mole) of 4—chloro—1— | (2-hydroxyethyl)-lH-imidazo[4,5-c]quinoline (from Example 107) and 30 ml of 10% ammonia in methanol was heated in a i steel bomb for 12 hours at 150^ec. The resulting solid was separated from the cooled mixture by filtration, and was washed sequentially with water and methanol. The air-dried solid was recrystallized from Ν,Ν-dimethylformamide to provide white solid l-(2-hydroxyethyl)-lH-imidazo[4,5-c]quinolin-4-amine, m.p. 260-262°C. Analysis: Calculated for; ^c12^H12^N4°i *C63.1 ׳; %H, 5.3; %N, 24.5; Found: %C, 63.0; ן %H, 5.2; %N, 24.3. i

I

Example 144 Alternative Preparation of a Compound of Formula II

A mixture of 6.0 g (0.023 mole) of 4-chloro-lisobutyl-lH-imidazo[4,5-c]quinoline (from Example 83) and ml of 20% ammonia in methanol was heated in a steel bomb!

for 18 hours at 150״C. The bomb was cooled, and the solid was separated by filtration, washed with methanol and recrystallized from N,N-dimethylformamide to provide

1-1sobuty1—lH-imidazo[4,5—cJquinolin—4—amine, m.p.

292-294’C. Analysis: Calculated for C14H16N4: %C, 70.0;

%H, 6.7; %N, 23.3; Found: %C, 69.9; %H, 6.7; %N, 23.6.

Example

Step (1)

To a solution of 22.5 g (0.0823 mole) of 4-(n-hexyl)amino-3-nitroquinoline in 300 ml of toluene was added about 1.0 g of 5% platinum on charcoal and the mixture was hydrogenated on a Paar apparatus for 1.5 hours. Filtration followed by evaporation in vacuo provided a residue of 3-amino**4-(n-hexyl)aminoquinoline as an orange solid. Thin layer chromatographic analysis of the product on silica gel, eluting with methanol, showed one spot at Rf=0.73 and a trace at Rf=0.35. Step (2)

The crude reaction product obtained by the method of Step (1) above from 22.5 g of 4-(n-hexyl)amino-3-nitroquinoline was mixed with 17.1 (0.1152 mole) of triethyl orthoformate and the mixture was heated at 130°c. for 2.5 hours. Evaporation provided a residue which was analyzed by thin layer chromatography on a silica gel plate, eluting with methanol. One spot was detected at R_f=0.8. A small sample of the residue was recrystallized once from diethyl ether to provide solid 1-(n-hexyl)-IH-imidazo[4,5-c]quinoline, m.p. 75-77°C. Analysis: Calculated for ^16^19^3^:%0, 75.85; %H, 7.55; %N, 16.6; Found:%C, 75.7; %H, 7.7; %N, 16.7

Step (3)

The crude reaction product from Step (2) above was diluted with 125 ml of glacial acetic acid and 14.0 g (0.1235 mole) of 30% hydrogen peroxide, and the mixture was heated at a bath temperature of 70°C for 22 hours. The glacial acetic acid was removed by adding heptane and by then effecting an azeotropic distillation. The residue was diluted and neutralized with saturated sodium bicarbonate solution. The solid obtained was separated by filtration, washed with water, slurried in diethyl ether, separated by filtration and dried. Recrystallization from ethyl acetate provided 11.8 g of solid 1-(n-hexyl)-lH-imidazo[4,5-c]quinolin-5-oxide, m.p. 153-158“C. Step (4)

To a mixture of 6.1 ml (0.0657 mole) of phosphorus oxychloride and 80 ml of Ν,Ν-dimethylformamide was added gradually, with cooling to 10-20’C, 11.8 g (0.0438 mole) of l-(n-hexyl)-lH-imidazo[l,5-c]quinolin-5-oxide. The solution was allowed to stand at 20°C for 15 minutes, and was then heated on a steam bath for 30 minutes. The solution was cooled and poured over ice with stirring. To the mixture was added concentrated ammonium hydroxide to adjust the pH to 8 to 9. The solid was separated by filtration, washed sequentially with water and diethyl ether, and dried. Recrystallization of a small portion of product from 1:1 ethyl acetate:hexane provided white solid 4-chloro-1-(n-hexyl)-lH-imidazo[4,5-c]quinoline, m.p. 106-108^oC. Analysis: Calculated for C!gH|gClN3; %c 66.8: %H, 6.3: %N, 14.6; Found %C, 66.8; %H, 6.1; %N, 14.4.

Step (5)

A mixture of 8.9 g (0.0308 mole) of 4-chloro-l(n-hexyl)-lH-imidazo[4,5-c]quinoline and 75 ml of 20% ammonia in methanol was placed in a metal bomb and heated at 150״C for about 8 hours. After cooling, the solid was separated by filtration, washed with methanol and recrystallized from ethanol. The product was white solid 1-(n-hexyl)-lH-imidazo[4,5—c]quinolin-4—amine, m.p. 189-191°C. Analysis: Calculated for C!gH2QN₄: %C, 71.6; %H, 7.5; %N, 20.9; Found: %C, 71.4; %H, 7.4; %N, 21.0.

Using the method of Example 1 and/or 2, and starting with the indicated substituted quinolines and primary amines, the following compounds of Formula V were prepared (Table VIII)

TABLE VIII

<td> Ex. No.</td><td> Quinoline Starting Material ____________of Formula IV______________</td><td> Primary Amine Starting Material</td><td> Intermediate of Formula V (m.p. in.’C)</td>

<td> 146</td><td> 4־chloro־3־nitroquinoline</td><td> 4-chlorobenzylamine</td><td> 4־4)־chlorobenzylamino)-3־nitroquinoline (175-177)</td>

<td> 147</td><td> 4־chloro־3־nitroquinoline</td><td> n-octylamine</td><td> 4־(n־octylamino)־3״ni troquinoline (5052־)</td>

<td> 148</td><td> 4-chloro־3־nitroquinoline</td><td> !-(phenyl)ethylamine</td><td> 4-[l-(phenyl)ethylamino]־3־nitroquinoline (138141־)</td>

<td> 149</td><td> 4-chloro3־-nitroquinoline</td><td> 1,3-dimethylbutylamine</td><td> 4־(l־3_׳dimethylbutylamino)־3־nitroquinoline (66-68)</td>

<td> 150</td><td> 4-chloro־6,7־dimethoxy3־-nitroquinoline</td><td> isobutylamine</td><td> 6,7־dimethoxy-4־isobutylamino־3־nitro-</td>

quinoline kJ

GJ 01 to £

M

Example 151

Using the method of Example 145, Step (1),

6,7-dimethoxy-4-isobutylamino-3־-nitroquinoline was reduced to 3-amino-6,7-dimethoxy-4-isobutylaminoquinoline, m.p. 159-161’C.

Using the method of Example 145, Step (1), various intermediates of Formula V were reduced to provide

3-aminoquinolines of Formula VI. These intermediates of Formula VI (usually crude) were cyclized using the method of Example 145, Step (2), to provide the intermediates of Formula VII shown in Table IX.

TABLE IX

<td> Intermediate</td>

<td> Ex. of Formula V</td>

<td> No. (Example) Intermediate of Formula VI Ortho Eater __</td>

<td> 152 146 3-amno-4-(4'-chlorobenzyl- triethyl orthoacetate</td>

<td> amino)quinoline</td>

<td> 153 1451 Step (2) 3-amino-4-(n-hexylamlno)־ triethyl orthoacetate</td>

<td> quinoline</td>

<td> 154 2 3-amino-4־(methylat1ino)־ triethyl orthoisobutyrate</td>

<td> quinoline</td>

<td> 155 14.7 3-amino4-(n־octylamino) triethyl orthoformate</td>

<td> quinoline</td>

<td>₁₅₆ 3 ן-amincr4-(isobutylan1ino) triethyl orthoisobutyrate</td>

<td> quinoline</td>

<td> .₁₅₇ 116,Part B 3-amino4-[2-(phenyl)ethyl- triethyl orthiosobutyrate</td>

<td> andnolquinoline</td>

<td> !58 148 3-amino-4-[l-(phenyl)ethyl- triethyl orthoformate</td>

<td> amino]quinoline</td>

<td> 159־ W J-arino-HbWiiBttyl. triethyl orthoformate</td>

<td> butylamino)quinoline</td>

<td> 160 151 3-amino-6,7-direthoxy-4. triethyl orthofomate</td>

<td> (isobutylanino)quinoline (a few drops of formic acid)</td>

Intermediate of Formula VII ____________(m.p. in °C)________________ l-(4-chlorobenzyl)-2-methyl-lHimidazo[4,5-c]quinoline (178-180)

1- (n-hexyl)2־-methyl-lH-imidazo[4,5-c]quinoline (88-90)

2- isobutyl-l־methyl-lH-imidazo[4,5-c]quinoline (125-127)

1- (n-octyl )-lH-in!idazo[4,5-c] quinoline (not taken)

112-diisobutyl-lH-imidazo[45 _׳-c]quinoline (93-95)ן

2- isobutyl-l-[2-(phenyl)ethyl]-lH-J imidazo[4,5-c]quinoline (92-94)ן l-[l-(phenyl)ethyl]־lH-imidazo[4,5-c]quinoline (172-174) l-(l,3-din1ethylbutyl)-lH-in1idazo[415־c]quinoline (83-85) 7/8^imethoxy-l-isobutyl-lH-imidazo[4,5־c]quinoline (163-165) s I c I s G

Using the method of Example 145, step (3), intermediate compounds of Formula VIII shown in Table X were prepared.

TABLE X

Intermediate of Formula VII (Example No.) ____________Intermediate of Formula VIII (m.p. in *C)__

152 l-(4־chlorobenzyl)־2־methyl־lH-imidazo[4,5־c]quinolin־5־oxide (251253־) l־(n־butyl)-lH-imidazo[4,5־c]quinolin־5־oxide (161163־)

153 1־(n-hexyl)־2־methyl-lH־imida20[4־5_׳c]quinolin־5־oxide (138148־ crude)

154; 2־isobutyl־l־methyl־lH־imidazo[4,5־c]quinolin־5־oxide (202204־)

155 l־(n־octyl)־lH־imidazo[4,5־c]quinolin5־-oxide (8690־)

156_? l,2־diisobutyl־lH־imidazo[4₍5־c]quinolin־5־oxide (153-156)

157. 2־isobutyl־l־2]־(phenyl)ethyl]-lH-imidazo[4₎5־c]quinolin־5־oxide (158160־)

158: , i־[l-(phenyl)ethyl]־lH־imidazo[45_׳-c]quinolin-5־oxide (not taken), yellow solid, satisfactory elemental analysis,

159 1-(1,3-dimethylbutyl)־lH־imidazo[4־5_׳c]quinolin־5־oxide (not taken),t light orange solid1

160.1 7,8־dimethoxy־l־isobutyl־lH־imidazo[4,5־c]quinolin־5־oxide (not taken) si w

ω

Using the method of Example 145, Step (4), intermediate compounds of Formula IX shown in Table XI were prepared.

TABLE XI

<td></td><td colspan="2"> Intermediate</td>

<td> Ex.</td><td> of Formula VIII</td><td></td>

<td> No.</td><td> (Example No.)</td><td> Intermediate of Formula IX (m.p. in °C)</td>

<td> •171</td><td> 78.</td><td> 4-chloro-2-methyl-l-[2-(phenyl)ethyl]-m-imidazo[45_׳-c]quinoline (138-140)</td>

<td> 172</td><td> 161</td><td> l-(4-chlorobenzyl)-4־chloro-2-methyl-lH־imidazo[4|5-c]quinoline (240-242)</td>

<td> 173</td><td> 162</td><td> l-(n-butyl)-4-chloro-lH-imidazo[4,5-c]quinoline (122-124)</td>

<td> 174</td><td> 163</td><td> 4-chloro-l-(n-hexyl)-2-methyl־lH-i1nidazo[4,5-c]quinoline (119-121)</td>

<td> 175</td><td> 164</td><td> 4-chloro-2-isobutyl-l־n1ethyl-lH־i1nidazo[4₍5-c]quinollne (158-160) »</td>

<td> 176</td><td> 165</td><td> 4-chloro-l-(n-octyl)-lH-imidazo[4;5-c]quinoline (86-90)</td>

<td> 177</td><td> 166</td><td> 4-chloro-l;2-diisobutyl-lH-imidazo[4;5-c]quinoline (137-139)</td>

<td> 178</td><td> 167</td><td> 4-chloro-2-isobutyl-l-[2-(phenyl)ethyl]-lH-imidazo[4,5-c]quinoline (151-153)</td>

<td> 179</td><td> 168</td><td> 4-chloro-l-[l-(phenyl)ethyl]-lH-imidazo[4;5-c]quinoline (not taken);</td>

<td></td><td></td><td> white solid; satisfactory elemental analysis</td>

<td> 180</td><td> 169</td><td> 4-chloro-l-(l;3-dimethylbutyl)-lH-imidazo[4;5-c]quinoline (111-114)</td>

<td> 181</td><td> 170 .</td><td> 4-chloro-7,8-dimethoxy-l-isobutyl-lH-imidazo[4,5-c]quinoline (185-188)</td>

Ϊ⁷

GJ

U1

GJ £

hj

Using the general method exemplified in Example 145, Step (5), compounds of the invention of Formula II shown in Table XII were prepared.

Table XII

Intermediate of Formula IX

<td> (Example No.)</td><td> ____________________Product of Formula II (m.p. in °C)_______________________</td>

<td> 88</td><td> l־ethyl־2־methyl־lH־in1idazo[4,5־c]quinolin־4־a111ine (274276־)</td>

<td> 171</td><td> 2-1i1ethyl-l2]־-(phenyl)ethyl]־lH-in1idazo[4־5_׳c]quinolin-4-a111ine (168190־)</td>

<td> 172</td><td> l4)־-chlorobenzyl)2־-methyl־lH־imidazo[4₍5־c]quinolin4־-amine (&gt;300)</td>

<td> 173</td><td> l־(n־butyl)־lH־imidazo[4₍5־c]quinolin־4־at11ine (274276־)</td>

<td> 100 174</td><td> l-[2־(phenyl)ethyl]-lH-i111idazo[4|5־c]quinolin4־-amine (199201־) l־(n־hexyl)־2־uethyl־lH־in1idazo[4₍5־c]quinolin־4־a1nine (189191־)</td>

<td> 175</td><td> 2־isobutyl-l־methyl-lH-i1nidazo[4 ־5_׳c]quinolin-4־an1ine (222-224)</td>

<td> 176 177</td><td> l־(n־octyl)־lH-imidazo[4־5_׳c]quinolin־4־amine (127129־) l־2_׳diisobutyl־m־imidazo[4,5־c]quinolin־4־an1ine (1911 (193־</td>

<td> 178</td><td> 2-i3obutyl-l-[2-(phenyl)ethyl]־lH־ii1idazo[45_׳-c]quinolin־4־a1ine hydrate μ (232-235) 1</td>

<td> 179</td><td> l־[l־(phenyl)ethyl]־lH־imidazo[4,5־c]quinolin־4־amine (217221־)</td>

<td> 180</td><td> l-(113־di1nethylbutyl)-lH־imidazo[4|5־c]quinolin־4־an1ine (158161־)</td>

X

UJ

U1 u £

X hJ

Example 194

To a solution of 3.5 g (0.0116 mole) of

2-methy1-1-[2-(phenyl)ethyl]-lH-imidazo[4,5-c]quinolin-4amine in 30 ml of ethanol was added 1.2 g (0.0127 mole) of methanesulfonic acid. The mixture was heated on a steam bath for 30 minutes, the ethanol was removed by evaporation in vacuo and the residue was recrystallized from ethanol. The product was white solid 2-methyl-l-[2-(phenyl)ethyl]lH-imidazo[4,5-c]quinolin-4-amine methanesulfonate, m.p. 287-289°C. Analysis: Calculated for C1gH1gN4*CH3SO3H: %C, 60.3; %H, 5.6; %N, 14.1; Found; %C, 60.1; %H, 5.3; %N, 14.0.

Additional salts of the invention prepared by reaction of the amine with acids in ethanol as described above were: l-isobutyl-lH-imidazo[4,5-c]quinolin-4-amine hydrochloride, m.p. >300״C. l-isobutyl-lH-imidazo[4,5-c]quinolin-4-amine nitrate salt, m.p. 260-262°C (dec.) l-isobutyl-lH-imidazo[4,5-c]quinolin-4-amine methanesulfonate hydrate, m.p. 203-205°C. l-n-hexyl-lH-imidazo[4,5-c]quinolin-4-amine hydrochloride, m.p. 288-291’C.

1,2-diisobutyl-lH-imidazo[4,5-c]quinoline-4-amine hydrochloride hydrate.

Example

Step (A)

To 50.0 g (0.269 mole) of 4-hydroxy-3-nitroquinoline in 300 ml of N,N-dimethylformamide in a 500 ml erlenmeyer flask was added, gradually, 44.3 g (0.2892 mole) of phosphorus oxychloride. The resulting mixture was heated on a steam bath for about 15 minutes, and was then poured onto ice with stirring. After neutralization with saturated sodium bicarbonate solution, the resulting light-colored solid was separated by filtration and washed sequentially with a saturated sodium bicarbonate solution and water. The solid was dissolved in methylene chloride and the solution obtained was dried over sodium chloride, filtered and transferred to a 2 1 erlenmeyer flask. Triethylamine (159.6 g, 1.577 moles) was added at one time, followed by the slow addition of 21.2 g (0.2892 mole) of isobutylamine. After the isobutylamine had been added, the mixture was heated on a steam bath for about 30 minutes. J The methylene chloride was removed by rotary evaporation. Water was added to the residue obtained, and concentrated ״ hydrochloric acid was subsequently added to dissolve the residue. The solution was filtered, and the filtrate was brought to pH 8-9 with concentrated ammonium hydroxide. The resulting yellow solid was filtered, washed with water, and dried to provide 73.4 g of crude 4-isobutylamino-3nitroquinoline, m.p. 114-118°C. The product was further purified by recrystallization from ethanol.

Step (B)

4-isobutylamino-3-nitroquinoline (31.5 g, 0.1284 moles) from Step (A) above, was dissolved in 300 ml of toluene, and 1 g of 5% platinum on carbon was added thereto. The resulting mixture was hydrogenated on a Parr apparatus for one and one-half hours. The mixture was then heated and filtered. Toluene was removed from the filtrate by rotary evaporation to provide 27.8 g of crude

3-amino-4-(isobutylamino)quinoline. Recrystallization twice from ethyl acetate/hexane provided 18.8 g of purified product, m.p. 98-100°C. Analysis: Calculated for ^C13^H17^N3^{: %c}ל⁵.⁷² ׳ %H, 8.0; %N, 19.5; Found: %C, 73.2; %H, 7.8; %N, 19.7.

Step (C)

To 10.0 g (0.0464 mole) of 3-amino-4(isobutylamino)quinoline (from Step (B) above) was added 9.0 g (0.0604 mole) of triethyl orthoformate, and the mixture was heated at 125-130°C for three hours. The mixture was then allowed to cool to room temperature, and 30 ml of glacial acetic acid and 7.9 g (0.0696 mole) of 30% hydrogen peroxide solution were added thereto. The resulting mixture was heated at 68-70’C in an oil bath for about 24 hours. The glacial acetic acid was removed by azetropic distillation using heptane as the co-solvent. Saturated sodium bicarbonate solution was added to the residue to bring it to neutrality. The beige solid which precipitated was filtered, washed with water, and dried to provide 10.0 g of crude product 1-isobutyl-lH-imidazo[4,5-c]quinolin-5-oxide. This solid was slurried in a small amount of cold acetone, and was then separated by filtration, washed and dried to provide 6.2 g of purified product having a m.p. of 205-209״c.

Step (D)

To 40 ml of cold N,N-dimethylformamide (10-20’C) was added slowly 5.9 g (0.0385 mole) of phosphorus oxychloride with swirling, the temperature of the mixture being maintained at 10-20°C. l-isobutyl-lH-imidazo[4,5-c]quinolin-5-oxide (6.2 g; 0.0257 mole) from Step (C) above was added gradually with swirling and cooling. After addition was complete, the solution was allowed to stand at room temperature for about 30 minutes with occasional swirling. The solution was then heated on a steam bath for thirty minutes. After allowing it to cool, the solution was poured onto ice with stirring, and the resulting mixture was brought to pH 8-9 with concentrated ammonium hydroxide. The resulting off-white solid was filtered, washed with water, rinsed with ether, and dried to provide 6.0 g of crude 4-chloro-l-isobutyl-lH-imidazo[4,5-c]quinoline having a m.p. of 135-138״C.

Step (Ε)

A mixture of 6.0 g (0.0231 mole) of 4-chloro-l— isobutyl-lH-imidazo[4,5-c]quinoline from Step (D) above and 30 ml of 20% ammonia in methanol was heated in a steel bomb for about 8 hours at about 145°C. The bomb was allowed to stand overnight at room temperature. The bomb was then cooled in an ice bath, and the solid therein was filtered, washed with methanol, and dried. Recrystallization from Ν,Ν-dimethylformamide provided 4.1 g of 1-isobutyl-lHimidazo[4,5-c]quinolin-4-amine, m.p. 288-291 °C.