NO176712B - Analogous Process for Preparing Therapeutically Active 4-Amino-3-Acylquinoline Derivatives - Google Patents

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The present invention relates to a process for the production of new substituted quinoline derivatives for therapeutic use.

Substituted quinoline derivatives which inhibit gastric acid secretion are already known. For example, US 4343804 and EP 259174-A mention series of 4-phenylaminoquinoline compounds, where the quinoline ring is substituted with e.g. one or more alkyl, phenyl, alkoxy, alkylthio or halogen groups. The present invention relates to substituted quinoline derivatives which comprise a new selection of substituents on the quinoline ring, which have also been shown to be suitable for inhibiting gastric acid secretion.

According to the present invention, a method for producing a compound with structure is provided

(I) :

where

R<1> is hydrogen or C1-4 alkyl;

R<2> is hydrogen, C 1-4 alkyl, halogen or hydroxy;

m is 1, 2 or 3; and

R 3 is hydroxyC 1-6 alkyl, polyhydroxyC 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, hydroxyC 1-6 alkoxy, polyhydroxyC 1-6 alkoxy,

C 1-6 alkoxyC 1-6 alkoxy or hydroxyC 1-6 alkoxyC 1-6 alkoxy; or a salt thereof.

Preferably, R<3> is hydroxyC 1-6 alkyl, hydroxyC 1-6 alkoxy or C 1-6 alkoxyC 1-6 alkoxy; preferably R 3 is hydroxyC 1-6 alkoxy or C 1-6 alkoxyC 1-6 haloxy, especially hydroxyethoxy or methoxyethoxy. C 1-4 alkyl groups (either by themselves or as part of another group) can be straight or branched.

HydroxyCx-ealkyl groups include, for example, hydroxymethyl, 2-hydroxyethyl groups and groups where the hydroxy group is not located at the chain end, e.g. 1-hydroxyethyl.

PolyhydroxyC 1-6 alkyl groups are alkyl groups substituted with more than a single hydroxy group, for example a 2,3-dihydroxypropyl or 2,3-dihydroxybutyl group. C 1 -C 6 -C 1 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 -C 6 alkyl groups include, for example, methoxymethyl and methoxyethyl groups.

HydroxyC1-galcoxy groups include, for example

2 hydroxypropyloxy groups with structure -OCH2CH(OH)CH3.

PolyhydroxyC 1 -alkoxy groups include alkoxy groups substituted with more than a single hydroxy group, for example a 1,3-dihydroxybutyloxy group of structure

OCH2CH(OH)CH2CHOH.

C 1 -galcoxy C 1 -alcoxy groups especially include methoxy-ethoxy groups.

HydroxyC 1-6 alkoxy C 1-6 alkoxy groups include, for example, 2-hydroxyethoxyethoxy groups.

Compounds of structure (I) where one or more of R<1 >to R<3> is a C3.6 alkyl group (either by itself or as part of another group, for example a benzyl or phenethyl group), may contain an asymmetric center as a result of the presence of the C3_6alkyl group. Likewise, compounds of structure (I), where R<3> contains a secondary hydroxy group, such as an -OCH2CH(OH)CH3 group, will also contain an asymmetric center. Such compounds will occur as optical isomers (enantiomers).

Compounds of structure (I) can form salts, in particular pharmaceutically acceptable acid addition salts, with suitable organic and inorganic acids, the nature of which will be known to those skilled in the art. For example, pharmaceutically acceptable salts can be formed by reaction with hydrochloric, sulfuric or phosphoric acids; aliphatic, aromatic or heterocyclic sulphonic acids or carboxylic acids, such as citric acid, maleic acid or fumaric acid.

According to the present invention, a compound with structure (I) is prepared by

(a) reaction of a compound of structure (II) and a compound of structure (III):

where R<1>, R2 and m are as described for structure (I), R<3>' is an optionally protected R<3> group, and X is halogen; or

(b) alkylation of a compound of structure (VII)

where R<1>, R2 and m are as described for structure (I), and R<5> is nitrogen-protecting group; after which if desired

° any protective groups are removed;

° a group R<1> is converted into another group R<1>;

° a group R<3> is converted into another group R<3>;

° a salt is formed.

Suitable nitrogen-protecting groups R<5> and groups to protect the hydroxy group(s) in R<3>', which will be known to those skilled in the art, are, for example, as described in "Protective Groups in Organic Synthesis", T.W. Greene, 1981 (Wiley).

Suitable protected R<3->groups are those where the hydroxy group(s) are in protected form. Such groups will be known to the person skilled in the art, as described in the above reference, for example acetylated groups, such as acetyl and benzoyl, or if applicable, acetonides.

The reaction between compounds with structure (II) and compounds with structure (III) is carried out in an organic solvent at a temperature between room temperature and the boiling point of the solvent used. Suitable solvents include, for example, tetrahydrofuran, dioxane or anisole. The reaction is preferably carried out at reflux temperature in dioxane as solvent.

The alkylation of a compound of structure (VII) is carried out in the presence of an alkylating agent in a suitable organic solvent, preferably at the boiling point of the solvent used, in the presence of a strong base. Suitable alkylating agents include, for example, an epoxide, for example epichlorohydrin, chlorohydroxyalkane or an alkoxyalkylbenzene sulfate. Suitable strong bases and solvents include, for example, potassium t-butoxide in tetrahydrofuran, or potassium carbonate in acetone.

Appropriate transformations of the groups R<1> will be known to the person skilled in the art, and thus, for example, compounds with structure (I) where R<1> is C2.6alkyl can be prepared by alkylation of the following compounds with structure (IA):

where R<2>, R<3> and m are as described for structure (I) and R<5> is as described above.

The alkylation of compounds of structure (IA) is carried out in the presence of an alkylating agent in a suitable organic solvent at a temperature between room temperature and the boiling point of the solvent, in the presence of a strong base. Suitable alkylating agents include, for example, alkyl or aralkyl halides, such as methyl or benzyl iodide, and dialkyl sulfates, such as dimethyl or diethyl sulfate. Suitable strong bases include, for example, sodium hydride, lithium diisopropylamide or dimsyl sodium (the sodium salt of dimethyl sulfoxide). Subsequent removal of any protective groups that may occur leads to the desired compounds with structure (I).

The intermediates with structure (II) and (VII) are new and can be prepared according to standard techniques.

The intermediates of structure (III) are commercially available, or they can be prepared by standard techniques.

Compounds of structure (I) and their pharmaceutically acceptable salts have an antisecretory effect by inhibiting the gastrointestinal H<+>K<+>ATPase enzyme (Fellenius, E., Berglindh, T., Sachs, G., Olke, L., Elander, B., Sjostrand, S.E., & Wallmark, B., 1981, Nature, 290. 159-161).

The compounds of structure (I) and their pharmaceutically acceptable salts inhibit exogenously and endogenously stimulated gastric acid secretion and are useful in the treatment of gastrointestinal diseases in mammals, especially humans. Such diseases include, for example, gastric and duodenal ulcers, aspiration pneumonia and Zollinger-Ellison syndrome.

The compounds with structure (I) can also be used in the treatment of other disorders, where an antisecretory effect is desirable, for example in patients with gastritis, an NSAID-induced gastritis, acute bleeding in the upper part of the intestine, in patients with chronic and excessive alcohol consumption and in patients with GERD (gastro oesophageal reflux disease).

For therapeutic use, the compounds produced according to the invention are generally administered in the form of a common pharmaceutical preparation. A pharmaceutical preparation comprises a compound of structure (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The compounds of structure (I) and their pharmaceutically acceptable salts, which are effective when administered orally, can be prepared as liquids, for example syrups, suspensions or emulsions, as well as tablets, capsules and lozenges.

A liquid formulation will usually consist of a suspension or solution of the compound or of a pharmaceutically acceptable salt, in a suitable liquid carrier, for example ethanol, glycerol, non-aqueous solvents, for example polyethylene glycol or oils, or water with a suspending agent added , preservative, flavoring or coloring matter.

A preparation in the form of a tablet can be prepared by using any suitable pharmaceutical carrier which is usually used for the preparation of solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.

A preparation in the form of a capsule can be prepared by using normal capsule preparation routines. For example, pellets containing the active ingredient can be prepared using common carriers and then filled into hard gelatin capsules. Alternatively, a dispersion or suspension can be prepared by using usual suitable pharmaceutical carriers, for example aqueous gums, celluloses, silicates or oils, after which the dispersion or suspension is filled onto a soft gelatin capsule.

Typically, parenteral preparations consist of a solution or suspension of the compound, or a pharmaceutically acceptable salt, in a sterile aqueous vehicle or in a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil or sesame oil. Alternatively, the solution may be lyophilized and then reconstituted with an appropriate solvent immediately prior to administration.

A typical suppository consists of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is effective in this type of administration, together with a binding and/or smoothing agent, such as polymeric glycols, gelatins or cocoa butter or other low melting vegetable or synthetic waxes or fats.

Preferably, the preparations are produced in unit dose form, such as a tablet or capsule.

Each dosage unit for oral administration preferably contains from 1 to 250 mg (and for parenteral administration, preferably from 0.1 to 25 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base.

Gastric acid secretion can be inhibited by administering to a mammal in need of treatment an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Diseases in the stomach or intestines which are due to increased acid secretion can be treated in the same way by animals in need of this being given an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

The pharmaceutically acceptable compounds of the invention will normally be administered to a patient for the treatment of gastrointestinal diseases and other conditions caused or aggravated by stomach acid. The daily dosing regimen for an adult patient can for example consist of an oral dose of between 1 mg and 500 mg, preferably between 1 mg and 250 mg, or an intravenous, subcutaneous or intramuscular dose of between 0.1 mg and 100 mg , preferably between 0.1 mg and 25 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base, the compound being administered 1 to 4 times per day. It would be appropriate for the connections to be given over a continuous period of time, for example a week or more.

Furthermore, the compounds according to the invention can be given together with other active substances, such as antacids (for example magnesium carbonate or -hydroxide and aluminum hydroxide), non-steroidal anti-inflammatory drugs (for example indomethacin, aspirin or naproxen), steroids or nitrite-consuming compounds (for example ascorbic acid or aminosulfonic acid) or other drugs used to treat stomach ulcers (for example pirenzepine), prostanoids, for example 16,16-dimethyl-PGE2, or histamine H2 antagonists (for example cimetidine).

The following examples illustrate the invention. Temperatures are indicated in °C.

Example 1

Preparation<g> of 3-butyryl-4-(2-methylphenylamino)-8-(hydroxymethyl)quinoline

A. Preparation of ethyl 2-butyryl-3-(2-hydroxymethyl)phenylamino)acrylate.

A mixture of ethyl 2-butyryl-3-ethoxyacrylate (23.5 g, 0.11 mol) and 2-aminobenzyl alcohol (12.3 g, 0.1 mol) was heated to 100° for 10 minutes and then diluted with petroleum ether . After cooling, ethyl 2-butyryl-3-(2-(hydroxymethyl)phenylamino)acrylate (24.9 g, 85%) crystallized as a mixture of E/Z isomers, which was filtered off and washed with petroleum ether.

B. Preparation of ethyl 2-butyryl-3-(2-(4-methoxy-benzoyloxymethyl)phenylamino)acrylate

Ethyl 2-butyryl-3-(2-(hydroxymethyl)phenylamino)acrylate (14.6 g, 50 mmol) was dissolved in pyridine (50 mL), cooled on ice and p-anisoyl chloride (12.8 g, 75 mmol). The mixture was stirred for 16 hours while warming to room temperature, then evaporated, taken up in dichloromethane, washed with aqueous sodium bicarbonate, dried and evaporated. Crystallization from ether gave ethyl 2-butyryl-3-(2-(4-methoxybenzoyloxyethyl)phenylamino)acrylate (12.3 g, 58%).

C. Preparation of 3-butyryl-8-(4-methoxybenzoyloxymethyl)-4(1H)-quinolone

Ethyl 2-butyryl-3-(2-(4-methoxybenzoyloxymethyl)phenylamino)acrylate (12.2 g, 28.7 mmol) was added portionwise to boiling diphenyl ether (200 mL) and then refluxed for 30 minutes. . Most of the diphenyl ether was distilled off in vacuo and the residue triturated with ether to give 3-butyryl-8-(4-methoxybenzoyloxymethyl)-4(1H)-quinolone (5.85 g, 54%), m.p. 156-162°.

D. Preparation of 3-butyryl-4-chloro-8-(4-methoxybenzoyl-oxymethyl)quinoline

A solution of 3-butyryl-8-(4-methoxybenzoyloxymethyl)-4(1H)-quinolone (5.75 g, 15.1 mmol) in phosphoryl chloride (75 mL) was refluxed for 30 minutes, the phosphoryl chloride was evaporated in vacuum, the residue poured onto ice, neutralized with sodium bicarbonate and extracted into dichloromethane. Drying, evaporation and trituration with ether gave crude 3-butyryl-4-chloro-8-(4-methoxy-benzoyloxymethyl)quinoline, which was used without further purification.

E. Preparation of 3-butyryl-4-(2-methylphenylamino)-8-(4-methoxybenzoyloxymethyl)quinoline

A solution of 3-butyryl-4-chloro-8-(4-methoxybenzoyl-oxymethyl)quinoline (3.3 g, 8.3 mmol) and 2-methylaniline (1.33 mL, 12.4 mmol) in 1, 4-Dioxane (30 mL) was refluxed for 2 hours, whereupon the dioxane was evaporated and the product converted to the free base. Recrystallization from ethanol gave 3-butyryl-4-(2-methylphenylamino)-8-(4-methoxybenzoyloxymethyl)-quinoline (3.5 g, 90%), m.p. 135-137°.

F. Preparation of 3-butyryl-4-(2-methylphenylamino)-8-(hydroxymethyl)quinoline

A solution of 3-butyryl-4-(2-methylphenylamino)-8-(4-methoxybenzoyloxymethyl)quinoline (3.44 g, 7.3 mmol) and potassium hydroxide (0.56 g, 10 mmol) in ethanol ( 100 ml) was boiled under reflux for 30 minutes, whereupon the solvent was evaporated, water added and the product extracted into dichloromethane. Chromatography (silica gel, 1-2% methanol in dichloromethane) and recrystallization from methanol gave 3-butyryl-4-(2-methylphenylamino)-8-(hydroxymethyl)quinoline (0.48 g, 20%), m.p. 148-150°.

Found: C, 75.40; H, 6.73; N, 8.42

Calculated: C, 75.42; H, 6.63; N, 8.38

Example 2

Preparation of 3-butyryl-4-(2-methylphenylamino)-8-(2-methoxyethoxy)quinoline

A. Preparation of 3-butyryl-4-chloro-8-hydroxyquinoline

3-Butyryl-4-chloro-8-methoxyquinoline (26.3 g, 0.1 mol) in dichloromethane (250 mL) was cooled to -78° under nitrogen and slowly added boron tribromide (75 g, 0.3 mol). The solution was stirred overnight while gradually warming to room temperature, after which the reaction was quenched with water. The organic solution was separated and evaporated to give the crude product, which was used immediately without further purification.

B. Preparation of 3-butyryl-4-(2-methylphenylamino)-8-hydroxyquinoline

The product from the above step was dissolved in dioxane

(250 ml), added 2-methylaniline (10.7 ml, 0.15 mol) and the solution refluxed for 1 hour. The solvent was

evaporated, the residue taken up in dichloromethane, washed with aqueous sodium bicarbonate, dried and evaporated.

Recrystallization from methanol gave 3-butyryl-4-(2-methylphenylamino)-8-hydroxyquinoline (20.9 g), m.p. 113-115°.

C. Preparation of 3-butyryl-4-(2-methylphenylamino)-8-(2-methoxyethoxy)quinoline

A solution of 3-butyryl-4-(2-methylphenylamino)-8-hydroxyquinoline (3.20 g, 10 mmol) and potassium t -butoxide (1.47 g, 12 mmol) in dry tetrahydrofuran (100 mL) was refluxed for 5 min, after which 2-methoxyethylbenzenesulfonate (4.33 g, 20 mmol) was added and heating continued for 18 h. Evaporation of the solvent, chromatography (silica gel, 1-2% methanol in dichloromethane) and recrystallization from ethyl acetate gave 3-butyryl-4-(2-methylphenylamino)-8-(2-methoxyethoxy)quinoline (1.42 g, 38 %), m.p. 75-77°.

C23<H>26N203. 0.1H 2 O

Found: C, 72.55; H, 6.82; N, 7.33

Calculated: C, 72.64; H, 6.94; N, 7.37

Example 3

Preparation of 3-butyrvl-4-(4-hydroxy-2-methylphenylamino)-8-(hydroxymethyl)quinoline hydrochloride

A. Preparation of 3-butyryl-4-(4-hydroxy-2-methylphenylamino)-8-(4-methoxybenzoyloxymethyl)quinoline

A solution of 3-butyryl-4-chloro-8-(4-methoxybenzoyl-oxymethyl)quinoline (2.56 g, 6.4 mmol) and 4-amino-3-methylphenol (1.18 g, 9.6 mmol) ) in 1,4-dioxane (30 mL) was refluxed for 2 h and then evaporated. Chromatography (silica gel, 1% methanol in dichloromethane) and recrystallization from ethanol gave 3-butyryl-4-(4-hydroxy-2-methylphenylamino)-8-(4-methoxybenzoyloxymethyl)quinoline (2.36 g, 76%), m.p. . 171-175°.

B. Preparation of 3-butyryl-4-(4-hydroxy-2-methylphenylamino)-8-(hydroxymethyl)quinoline hydrochloride

A solution of 3-butyryl-4-(4-hydroxy-2-methylphenylamino)-8-(4-methoxybenzoyloxymethyl)quinoline (2.34 g, 4.8 mmol) and sodium hydroxide (0.38 g, 9.6 mmol ) in methanol (50 mL) was refluxed for 30 min, then diluted with water and neutralized with dilute hydrochloric acid. The solid was filtered off and washed with water and then converted to the hydrochloride. Recrystallization from aqueous ethanol gave 3-butyryl-4-(4-hydroxy-2-methylphenylamino)-8-(hydroxymethyl)quinoline hydrochloride (1.16 g, 62%), m.p. 167-171°.

C21H22N2O3. HC1. 0.5H2O

Found: C, 63.60; H, 5.86; N, 7.00; Cl, 8.69

Calculated: C, 63.71; H, 6.11; N, 7.08; Cl, 8.95

Example 4

Preparation<g> of 3-butyryl-4-(2-methylphenylamino)-8-(1-hydroxyethyl)quinoline

A. Preparation of 3-butyryl-4-(2-methylphenylamino)quinoline-8-carbaldehyde

Oxalyl chloride (18.22 g, 0.144 mol) in dichloromethane (180 mL, dried over molecular sieve) was cooled to -70°C and with stirring under nitrogen added dropwise a solution of dimethyl sulfoxide (13.08 g, 0.168 mol) in dry dichloromethane (20 ml), while the temperature was kept lower than -60°C. After 30 minutes, a solution of 3-butyryl-4-(2-methylphenylamino)-8-hydroxymethylquinoline (40 g, 0.12 mol) in dry dichloromethane (700 ml) was added at a temperature lower than -60°. After a further 30 minutes, triethylamine (102 ml) was added dropwise, after which the mixture was allowed to warm to room temperature, before washing with water and drying (Na 2 SO<.). The filtered solution was evaporated to a yellow oil which crystallized on trituration with ether to give the title compound (33.02 g), m.p. 142-144°.

B. Preparation of 3-butyryl-4-(2-methylphenylamino)-8-(1-hydroxyethyl)quinoline

A solution of 3-butyryl-4-(2-methylphenylamino)quinoline-8-carbaldehyde (2.0 g, 6 mmol) in dichloromethane (100 mL) was stirred at 0-5° and treated with a solution of methylmagnesium iodide in ether until TLC (2% methanol in dichloromethane) showed that essentially a new product had formed. The mixture was washed with ammonium chloride solution, dried and evaporated. Chromatography (silica gel, 0.5% methanol in dichloromethane) afforded the desired 3-butyryl-4-(2-methylphenylamino)-8-(1-hydroxyethyl)quinoline (0.28 g) as yellow crystals, m.p. 140-142°.

<C>22<H>24N2<O>2

Found: C, 75.81; H, 7.04; N, 8.01

Calculated: C, 75.83; H, 6.94; N, 8.04

Example 5

Preparation of 3-butyryl-4-(2-methylphenylamino)-6-(hydroxymethyl)quinoline

A. Preparation of ethyl 2-butyryl-3-(4-hydroxymethyl-phenylamino)acrylate

4-Aminobenzyl alcohol (25 g) and ethyl 2-butyryl-3-ethoxy-acrylate (61 g) were heated together in a rotary evaporator (bath temperature 100°) for 30 minutes. Ethyl 2-butyryl-3-(4-(hydroxymethyl)phenylamino)acrylate (49.5 g, 84%) crystallized on standing, was filtered off, washed with a little petroleum ether and vacuum dried, m.p. 44-46°.

B. Preparation of ethyl 2-butyryl-3-(4-benzoyloxymethyl-phenylamino)acrylate

A solution of ethyl 2-butyryl-3-(4-hydroxymethylphenyl-amino) acrylate (49.5 g, 0.17 mol) and pyridine (50 mL) in chloroform (250 mL) was stirred at 0-5° (ice -bath). Benzoyl chloride

(22 mL, 0.19 mol) in chloroform (250 mL) was added dropwise while maintaining the reaction temperature below 10°. The cooling bath was removed and the mixture stirred overnight at room temperature. The mixture was washed with 2M HCl, sodium bicarbonate solution and brine, dried (anhydrous MgSOA), filtered and evaporated to an oil which crystallized at

grace period. The product was slurried with petroleum ether, filtered off and washed with petroleum ether to give ethyl 2-butyryl-3-(4-benzoyl-oxymethylphenylamino)acrylate as white crystals (61.8 g, 92%), m.p. 73-75°.

C. Preparation of 3-butyryl-6-(benzoyloxymethyl)-4(1H)-quinolone

Ethyl 2-butyryl-3-(4-benzoyloxymethylphenylamino)acrylate (50 g) was added portionwise to boiling diphenyl ether (500 ml) and boiling continued under reflux for 30 minutes. On cooling, crystals appeared and the mixture was diluted with petroleum ether to give 3-butyryl-6-(benzoyl-oxymethyl)-4(1H)-quinolone (39.7 g, 96%) as light brown crystals, m.p. 220-223°.

D. Preparation of 3-butyryl-4-chloro-6-(benzoyloxymethyl)-quinoline

3-Butyryl-6-(benzoyloxymethyl)-4(1H)-quinolone (30 g) was refluxed in phosphorus oxychloride (200 mL) for 30 minutes. The solvent was evaporated and the residue partitioned between dichloromethane and ammonia solution. The organic layer was washed successively with sodium bicarbonate solution and 50% brine. It was dried (anhydrous MgSO4 , filtered and evaporated to an oily solid which crystallized on trituration with petroleum ether to give 3-butyryl-4-chloro-6-(benzoyloxymethyl)quinoline (21.2 g, 67%), mp 85 -86°.

E. Preparation of 3-butyryl-4-(2-methylphenylamino)-6-benzoyloxymethylquinoline

3-Butyryl-4-chloro-6-benzoyloxymethylquinoline (10 g, 30 mmol) and o-toluidine (3.7 mL, 35 mmol) were refluxed in 1,4-dioxane (150 mL) in 1.5 hours. The solvent was evaporated and the residue dissolved in chloroform, washed with 2M HCl, sodium bicarbonate solution (x 2) and brine, dried, filtered and evaporated to an oil which readily crystallized to give 3-butyryl-4-(2-methylphenylamino) -6-benzoyloxymethyl-quinoline (8.6 g, 66%), m.p. 142-144°.

F. Preparation of 3-butyryl-4-(2-methylphenylamino)-6-hydroxymethylquinoline

3-Butyryl-4-(2-methylphenylamino)-6-benzoyloxymethylquinoline (3.0 g, 6.8 mmol) was dissolved in methanol (50 mL) and 2M sodium hydroxide solution (50 mL) was added. The mixture was refluxed for 45 minutes until a clear solution was obtained. The mixture was partitioned between chloroform and water, the aqueous layer re-extracted with chloroform and the combined organic solutions washed with brine, dried, filtered and evaporated. Crystallization from ether gave 3-butyryl-4-(2-methylphenylamino)-6-hydroxymethylquinoline (1.9 g, 83%), m.p. 139-141°.

Found: C, 75.32; H, 6.52; N, 8.37

Calculated: C, 75.42; H, 6.63; N, 8.36

Example 6

Preparation of 3-butyryl-4-(2-methylphenylamino)-7-(hydroxymethyl)quinoline

A. Preparation of ethyl 2-butyryl-3-(3-hydroxymethyl-phenylamino)acrylate

3-Aminobenzyl alcohol (2 4.63 g, 0.2 mol) and ethyl butyryl acetate (53.56 g, 0.2 mol) were heated at 150° for 2 hours, then cooled, diluted with petroleum ether (bp. 60-80°) and allowed to crystallize at 0°C. Filtration and washing gave the title compound (58.27 g) as a mixture of Z and E isomers.

B. Preparation of ethyl 2-butyryl-3-(3-benzoyloxymethyl-phenylamino)acrylate

To a stirred and cooled (ice-bath) solution of ethyl 2-butyryl-3-(3-hydroxymethylphenylamino)acrylate (29.13 g,

0.1 mol) in pyridine, benzoyl chloride (21.09 g, 0.15 mol) was added dropwise. The ice bath was removed and the mixture set aside for 16 hours, after which it was evaporated, treated with chloroform (200 ml) and washed with saturated aqueous sodium bicarbonate (200 ml), water (200 ml) and ;.W hydrochloric acid (2 x 150 ml) .

After drying (Na2SO4 and stirring with charcoal), the solution was filtered and evaporated to an oil which crystallized slowly under petroleum ether (bp 40-60°) to give the title compound (34.5 g), mp 59-63°.

C. Preparation of 3-butyryl-7-benzoyloxymethyl-4-(1H)-quinolone

Ethyl 2-butyryl-3-(3-benzoyloxymethylphenylamino)acrylate (34.37 g, 86.9 mmol) was added portionwise to refluxing diphenyl ether (300 mL) and then refluxed for 1 hour. After cooling, petroleum ether (b.p. 40-60°) was added and the precipitated solid was filtered off. Purification by column chromatography (silica, methanol-chloroform) gave the title compound as a solid (10.52 g), m.p. 228-231°C, from dichloromethane.

D. Preparation of 3-butyryl-4-chloro-7-benzoyloxymethyl-quinoline

3-Butyryl-7-benzoyloxymethyl-4(1H)-quinolone (10.42 g, 29.8 mmol) and phosphoryl chloride (60 mL) were refluxed for 1 h, then evaporated and the residue poured onto ice (300 g) under stirring. After neutralization with concentrated ammonia, the product was extracted into chloroform and the solution dried (Na2SOA) and evaporated to a solid. Trituration with ether gave the title compound (9.76 g), m.p. 66-68°.

E. Preparation of 3-butyryl-4-(2-methylphenylamino)-7-benzoyloxymethylquinoline

3-butyryl-4-chloro-7-benzoyloxymethylquinoline (3.68 g,

10 mmol) and o-toluidine (1.61 g, 15 mmol) in dioxane (100 mL) were refluxed for 2.5 h, then allowed to cool and stand for 16 h. The solvent was evaporated and the product converted to the free base and recrystallized from ethanol to give the title compound (1.8 g), m.p. 110-112°.

F. Preparation of 3-butyryl-4-(2-methylphenylamino)-7-hydroxymethylquinoline

To a stirred suspension of 3-butyryl-4-(2-methylphenylamino)-7-benzoylmethylquinoline (2.74 g, 6.25 mmol) in methanol (25 mL) was added 2N sodium hydroxide (6.24 mL). Stirring was continued for 18 hours, the solvent then evaporated in vacuo and the residue treated with water and extracted with chloroform. The combined extracts were dried (Na2SO4) and evaporated to a solid, which was purified by column chromatography (silica, chloroform-methanol) to give the title compound (1.31 g), mp 176-178°, from methanol.

<C>22<H>22N2<O>3

Found: C, 75.17; H, 6.56; N, 8.31

Calculated: C, 75.42; H, 6.63; N, 8.38

Example 7

Preparation of 3-isobutyryl-4-(2-methylphenylamino)-8-(hydroxymethyl)quinoline

A. Preparation of ethyl 2-isobutyryl-3-ethoxyacrylate

A mixture of ethyl isobutyryl acetate (60.5 g, 0.38 mol), triethyl orthoformate (12 6 mL, 0.76 mol) and acetic anhydride (36 mL, 0.38 mol) was refluxed for 24 h, after which volatile components were removed in vacuo, finally at 100°/0.5 mm. The residue consisted mainly of ethyl 2-isobutyryl-3-ethoxyacrylate as a mixture of E/Z isomers, and was used without further purification.

B. Preparation of ethyl 2-isobutyryl-3-(2-(hydroxymethyl)-phenylamino)acrylate

2-Aminobenzyl alcohol (12.32 g, 0.1 mol) was dissolved in ethyl 2-isobutyryl-3-ethoxyacrylate (23.57 g, 0.11 mol), stirred for 2 hours at room temperature and then briefly boiled . Cooling and trituration with petroleum ether gave ethyl 2-isobutyryl-3-(2-(hydroxymethyl)phenylamino)acrylate (22.29 g, 77%) as a mixture of E/Z isomers, m.p. 72-84°.

C. Preparation of ethyl 2-isobutyryl-3-(2-benzoyloxymethyl)-phenylamino)acrylate

Ethyl 2-isobutyryl-3-(2-(hydroxymethyl)phenylamino)acrylate (22.14 g, 76 mmol) was dissolved in pyridine (150 mL), cooled on ice, added benzoyl chloride (13.9 mL, 120 mmol), whereupon the mixture was stirred overnight. The pyridine was evaporated, aqueous sodium bicarbonate added, the product extracted into dichloromethane, dried, evaporated and crystallized from methanol to give ethyl 2-isobutyryl-3-(2-(benzoyloxymethyl)phenylamino)-acrylate (29.40 g, 98%) , m.p. 76-84°. D. Preparation of 3-isobutyryl-8-(benzoyloxymethyl)-4(1H)-quinolone.

Diphenyl ether (500 mL) was heated to boiling, ethyl 2-isobutyryl-3-(2-(benzoyloxymethyl)phenylamino acrylate (29.3 g, 74.1 mmol) was added and heating continued for 15 min. Most of the diphenyl ether was removed by vacuum distillation and the residue chromatographed (silica gel, 1-2.5% methanol in dichloromethane) and recrystallized from ethyl acetate to give 3-isobutyryl-8-(benzoyloxymethyl)-4(1H)-quinolone (11.9 g, 46% ), mp 158-160°

E. Preparation of 3-isobutyryl-4-chloro-8-(benzoyloxymethyl)quinoline.

A solution of 3-isobutyryl-8-(benzoyloxymethyl)-4(1H)-quinolone (11.81 g, 29.9 mmol) in phosphoryl chloride (100 mL) was refluxed for 2.5 h, after which the excess phosphoryl chloride was evaporated. Water was added and the product was extracted into a mixture of dichloromethane and isopropyl alcohol. Drying and evaporation of the organic layer gave crude 3-isobutyryl-4-chloro-8-(benzoyloxymethyl)quinoline (12.0 g), contaminated with isopropyl alcohol. This was used without further purification.

F. Preparation of 3-isobutyryl-4-(2-methylphenylamino)-8-(hydroxymethyl)quinoline.

A solution of 3-isobutyryl-4-chloro-8-(benzoyloxymethyl)quinoline (3.68 g, 10 mmol) and 2-methylaniline (2.13 mL, 20 mmol) in dioxane (50 mL) was boiled under reflux for 2 hours, then evaporated, taken up in dichloromethane, washed with aqueous sodium bicarbonate, water and brine, dried and evaporated to an oil. The oil was taken up in 1% methanolic sodium hydroxide solution (100 mL) and stirred vigorously for 1 hour. The methanol was evaporated, water and dichloromethane added and the aqueous phase adjusted to pH 10 and extracted with dichloromethane. The organic extracts were dried, evaporated and chromatographed (silica gel, 1-2% methanol in dichloromethane). Trituration of product fractions with ether, followed by recrystallization from aqueous methanol gave 3-isobutyryl-4-(2-methylphenylamino)-8-(hydroxymethyl)quinoline (1.46 g, 44%), m.p. 116-118°.

C21H22N2O2

Found: C, 75.31; H, 6.53; N, 8.40

Calculated: C, 75.42; H, 6.63; N, 8.38

Example 8

Preparation of 3-isobutyl-4-(4-fluoro-2-methylphenylamino)-8-(hydroxymethyl)quinoline

A solution of 3-isobutyryl-4-chloro-8-(benzoyloxymethyl)quinoline (1.84 g, 5 mmol) and 4-fluoro-2-methylaniline (0.78 mL, 7 mmol) in dioxane (25 mL) was boiled under reflux for 2 hours, after which the solvent was evaporated. A solution of sodium hydroxide (0.8 g, 20 mmol) in methanol (50 mL) was added and the mixture stirred at room temperature for 1.5 h. The resulting precipitate was filtered off and recrystallized from methanol to give (0.48 g, 27%), m.p. 139-140°.

^21^20^ N202

Found: C, 71.24; H, 5.99; N, 7.84

Calculated: C, 71.57; H, 6.01; N, 7.95

Example 9

Preparation of 3-butyryl-4-(4-fluoro-2-methylphenylamino)-8-(hydroxymethyl)quinoline

A. Preparation of ethyl 2-butyryl-3-(2-(benzoyloxymethyl)-phenylamino)acrylate.

A solution of ethyl 2-butyryl-3-(2-hydroxymethyl)phenylaminoacrylate (51.1 g, 0.175 mol) in pyridine (400 mL) was cooled in ice, added benzoyl chloride (29 mL, 0.25 mol) and the mixture was stirred for 2 days at room temperature. The pyridine was evaporated and aqueous sodium bicarbonate added, whereupon the mixture was extracted with dichloromethane and the organic layers dried and evaporated. Trituration with petroleum ether and washing with cold methanol gave ethyl 2-butyryl-3-(2-(benzoyloxymethyl)phenylamino)acrylate (60.8 g, 88%), m.p. 78-82°.

B. Preparation of 3-butyryl-8-(benzoyloxymethyl)-4(1H)-quinolone.

Diphenyl ether (500 ml) was heated to the boiling point, ethyl 2-butyryl-3-(2-(benzoyloxymethyl)phenylamino)-acrylate (60.5 g, 0.15 mol) was added and the reflux continued for 25 minutes. Most of the diphenyl ether was removed by vacuum distillation. Chromatography (silica gel, 0-3% methanol in dichloromethane) and recrystallization from methanol gave 3-butyryl-8-(benzoyloxymethyl)-4(1H)-quinolone (24.1 g, 45%), m.p. 115-117°. C. Preparation of 3-butyryl-4-chloro-8-(benzoyloxymethyl)-quinoline.

A solution of 3-butyryl-8-(benzoyloxymethyl)-4(1H)-quinolone (17.93 g) in phosphoryl chloride (150 ml) was refluxed for 1.5 hours, after which the excess phosphoryl chloride was evaporated. The residue was poured onto ice, extracted with dichloromethane, dried and evaporated to give 3-butyryl-4-chloro-8-(benzoyloxymethyl)quinoline. The crude product was used without further purification.

D. Preparation of 3-butyryl-4-(2-methyl-4-fluorophenylamino)-8-(hydroxymethyl)quinoline. A solution of 3-butyryl-4-chloro-8-(benzoyloxymethyl)-quinoline (3.68 g, 10 mmol) and 4-fluoro-2-methylaniline (1.67 mL, 15 mmol) in dioxane (40 mL) was refluxed for 3 hours, cooled and filtered, after which the solid was discarded. The solution was evaporated and the residue taken up in 1% methanolic sodium hydroxide (100 ml) and stirred for 2 hours at room temperature. The solid was filtered off and recrystallized from methanol to give 3-butyryl-4-(2-methyl-4-fluorophenylamino)-8-(hydroxymethyl)quinoline (1.56 g, 44%), m.p. 168-170°.

C21H21FN2O2

Found: C, 71.40; H, 5.78; N, 7.80

Calculated: C, 71.57; H, 6.01; N, 7.95

Example 10

Preparation of 3-butyryl-4-(2-methylphenylamino)-8-(2-hydroxyethoxy)quinoline

3-Butyryl-4-(2-methylphenylamino)-8-hydroxyquinoline (3.2 g, 10 mmol) was dissolved in tetrahydrofuran (150 mL), potassium t-butoxide (1.83 g, 15 mmol) was added and stirred until dissolved, whereupon 2-chloroethanol (1.3 mL, 20 mmol) was added and the mixture refluxed overnight. A further portion of potassium t-butoxide (1.83 g) and 2-chloroethanol (1.3 ml) was added and boiling continued for 2 days. The tetrahydrofuran was evaporated, the residue taken up in dichloromethane, washed with water and brine, dried and evaporated. Recrystallization from ethyl acetate/petroleum ether gave 3-butyryl-4-(2-methylphenylamino)-8-(2-hydroxyethoxy)quinoline (1.18 g, 32%), m.p. 125-127°.

C22H2i,N2O3

Found: C, 72.23; H, 6.61; N, 7.52

Calculated: C, 72.50; H, 6.64; N, 7.69

Example 11

Preparation<g> of 3-butyryl-4-(2-methylphenylamino)-8-(2-(2-hydroxyethoxy)ethoxy)quinoline

3-butyryl-4-(2-methylphenylamino)-8-hydroxyquinoline

(2.40 g, 7.5 mmol) and potassium t -butoxide (1.22 g, 10 mmol) were dissolved in tetrahydrofuran (40 mL), added 2-(2-chloroethoxy)-ethanol (1.58 mL , 15 mmol) and the mixture boiled under reflux for 18 hours. The solvent was evaporated, the residue taken up in dichloromethane, washed with water and brine, dried and evaporated. Chromatography (silica gel, 3-5% methanol in dichloromethane) and recrystallization from ethyl acetate gave 3-butyryl-4-(2-methylphenylamino)-8-(2-(2-hydroxyethoxy)ethoxy)-quinoline (1.77 g, 60 %), m.p. 144-146°.

<C>24<H>28<N>2<O>4

Found: C, 70.51; H, 6.72; N, 6.72

Calculated: C, 7 0.57; H, 6.91; N, 6.86

Example 12

Preparation of 3-butyryl-4-(2-methylphenylamino)-8-(2-(2-(2-hydroxyvetoxy)ethoxy)ethoxy)quinoline

A mixture of 3-butyryl-4-(2-methylphenylamino)-8-hydroxyquinoline (2.40 g, 7.5 mmol), potassium t-butoxide (1.22 g, 10 mmol) and 2-(2- (2-chloroethoxy)ethoxy)ethanol (2.18 g, 15 mmol) in tetrahydrofuran (40 mL) was refluxed for 3 days. The solvent was evaporated, the residue taken up in dichloromethane, washed with water and brine, dried and evaporated. Chromatography (silica gel, 0-10% methanol in ethyl acetate) and crystallization from ether gave 3-butyryl-4-(2-methylphenylamino)-8-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)quinoline (2, 32 g, 68%) as a hygroscopic solid, m.p. 102-104°.

C26H32N2O5.0,1H2O

Found: C, 68.61; H, 7.17; N, 6.04

Calculated: C, 68.73; H, 7.14; N, 6.17

Example 13

Preparation of 3-butyryl-4-(4-fluoro-2-methylphenylamino)-8-(2-

( 2- hydroxyethoxy) ethoxy) quinoline

A. Preparation of 3-butyryl-4-(4-fluoro-2-methylphenylamino)-8-hydroxyquinoline.

A solution of 3-butyryl-4-chloro-8-methoxyquinoline (131.9 g, 0.5 mol) in dichloromethane (1 liter) was cooled to -78° and then boron tribromide (142 ml, 1.5 mol). The mixture was slowly warmed to 0°, stirred for 2 hours and then allowed to warm to room temperature overnight. After cooling again in ice, the reaction was carefully quenched with water, whereupon the resulting solid was filtered off and dried. This was heavily contaminated with boron-containing impurities, but was used without purification. Crude 3-butyryl-4-chloro-8-hydroxyquinoline (64 g) and 4-fluoro-2-methylaniline (16.7 mL, 0.15 mol) were dissolved in dioxane (300 mL), heated on a steam bath for 2 hours and then set aside overnight. The dioxane was evaporated, dichloromethane and aqueous sodium bicarbonate were added and the mixture was stirred until all solids had dissolved, after which the organic layer was dried and evaporated. Recrystallization from methanol gave 3-butyryl-4-(4-fluoro-2-methylphenylamino)-8-hydroxyquinoline (37 g), m.p. 121-122°.

B. Preparation of 3-butyryl-4-(4-fluoro-2-methylphenylamino)-8-(2-(2-hydroxyethoxy)ethoxy)quinoline

A solution of 3-butyryl-4-(4-fluoro-2-methylphenylamino)-8-hydroxyquinoline (3.2 g, 10 mmol) and potassium t-butoxide

(1.83 g, 15 mmol) in tetrahydrofuran (70 mL) was boiled under reflux, added 2-chloroethoxyethanol (2.11 mL,

20 mmol) and the heating continued for 17 hours. The solvent was evaporated, the residue taken up in dichloromethane, washed with water and brine, dried and evaporated. Chromatography (silica gel, 3-6% methanol in dichloromethane), after elution of large amounts of unchanged starting material, gave product-containing fractions which were recrystallized from methanol to give 3-butyryl-4-(4-fluoro-2-methylphenylamino)- 8-(2-(2-hydroxyethoxy)-ethoxy)quinoline (0.38 g, 9%), m.p. 144-145°.

<C>24<H>27<FN>2<0>A

Found: C, 67.68; H, 6.43; N, 6.59

Calculated: C, 67.59; H, 6.38; N, 6.57

Example 14

Preparation of 3-butyryl-4-(4-fluoro-2-methylphenylamino)-8-(2-hydroxyethoxy)quinoline

A solution of 3-butyryl-4-(4-fluoro-2-methylphenylamino)-8-hydroxyquinoline (3.2 g, 9.4 mmol) and potassium t -butoxide (1.83 g, 15 mmol) in tetrahydrofuran (75 mL) was heated to reflux, 2-chloroethanol (1.3 mL, 20 mmol) was added and heating continued for 2 days. The solvent was evaporated, the residue taken up in dichloromethane, washed with water and brine, dried and evaporated. Chromatography (silica gel, 5% methanol in dichloromethane) led first to the recovery of starting material followed by product fractions, which were recrystallized from ethyl acetate/petroleum ether and then from methanol to give 3-butyryl-4-(4-fluoro-2-methylphenylamino) -8-(2-hydroxyethoxy)-quinoline as a hygroscopic solid (0.82 g, 23%), m.p. 130-133°.

C22H23FN2O3. 0.8HzO

Found: C, 66.69; H, 6.20; N, 7.07

Calculated: C, 66.58; H, 6.25; N, 7.06

Example. 15

Preparation of 3-butyryl-4-(4-hydroxy-2-methylphenylamino)-8-(1-hydroxyethyl)quinoline

A. Preparation of 2-(1-Hydroxyethyl)aniline.

Sodium borohydride (40 g, 1.0 mol) was added portionwise to a stirred solution of o-aminoacetophenone (80 g) in methanol (800 ml) at 0°, the effervescence being allowed to subside between each addition. The cooling was removed and the mixture was allowed to heat to the boiling point to complete the reaction. After cooling, the solvent was evaporated and the residue partitioned between dichloromethane-water. The organic solution was washed successively with water and brine, dried (anhydrous MgSO 4 ), filtered and evaporated to a pale yellow oil which crystallized from petroleum ether (40-60°) to give white crystals (52 g, 64%), m.p. 50-52°.

B. Preparation of ethyl 2-butyryl-3-(2-(1-hydroxyethyl)-phenylamino)acrylate.

2-(1-Hydroxyethyl)aniline (30 g, 0.32 mol) and ethyl 2-butyryl-3-ethoxyacrylate (47.3 g, 0.22 mol) were heated together in a rotary evaporator (bath temperature 100°C ) for 1 h to give ethyl 2-butyryl-3-(2-(1-hydroxyethyl)phenylamino)-acrylate as an oil (65 g, 96%). C. Preparation of ethyl 2-butyryl-3-(2-(1-benzoyloxyethyl)-phenylamino)acrylate.

A solution of ethyl 2-butyryl-3-(2-(1-hydroxyethyl)-phenylamino)acrylate (63 g, 0.2 mol) and pyridine (50 mL) in dichloromethane (400 mL) was stirred at 0°C. and treated with benzoyl chloride (50 mL) in dichloromethane (100 mL), added at such a rate that the reaction temperature was kept below 10°C. The cooling bath was removed and the mixture stirred at room temperature for 2 hours. The solution was washed with 2M hydrochloric acid (x 2), saturated sodium hydrogen carbonate solution, water and brine, dried (anhydrous MgSO4, filtered and evaporated to an orange oil (70 g, 83%).

D. Preparation of 3-butyryl-8-vinyl-4(1H)-quinolone.

Ethyl 2-butyryl-3-(2-(1-benzoyloxyethyl)phenylamino)acrylate (70 g, 0.17 mol) was added dropwise to boiling diphenyl ether (700 mL) while maintaining the reaction temperature above 240°C. The mixture was refluxed for 1 hour and then rapidly cooled. The mixture was chromatographed (silica gel, dichloromethane + methanol (2-4%)) to give the desired compound as a light solid (23.2 g, 56%), m.p. 206-208°C.

E. Preparation of 3-butyryl-4-chloro-8-vinylquinoline.

3-Butyryl-8-vinylquinolone (23 g, 95 mmol) was refluxed in a mixture of phosphoryl chloride (100 mL) and chloroform (100 mL) for 45 min. The solvent was evaporated and the residue mixed with ice, neutralized with ammonia solution and extracted into dichloromethane. The organic solution was washed successively with sodium hydrogen carbonate solution and brine, dried (anhydrous MgSO4 , filtered and evaporated. Chromatography (silica gel, 2% methanol in dichloromethane) afforded 3-butyryl-4-chloro-8-vinylquinoline as a brown oil ( 9.5 g, 38.5%).

F. Preparation of 3-butyryl-4-(4-hydroxy-2-methylphenylamino)-8-vinylquinoline.

3-Butyryl-4-chloro-8-vinylquinoline (20.0 g, 77 mmol) and 4-amino-m-cresol (9.5 g, 77 mmol) were boiled together under reflux in 1,4-dioxane (150 ml) for 2.5 hours. The solvent was evaporated and the residue dissolved in dichloromethane, washed with water, 2M hydrochloric acid, sodium bicarbonate solution and brine. The solution was dried (anhydrous MgSO4 , filtered and evaporated to an oil, which was chromatographed (silica gel, 1% methanol in dichloromethane) to give 3-butyryl-4-(4-hydroxy-2-methylphenylamino)-8-vinylquinoline as orange crystals (9.0 g, 32%), mp 150-152°.

G. Preparation of 3-butyryl-4-(4-hydroxy-2-methylphenylamino)-quinoline-8-carbaldehyde

3-Butyryl-4-(4-hydroxy-2-methylphenylamino)-8-vinylquinoline (5.0 g, 14.4 mmol) was stirred at -60 °C in a mixture of methanol (100 mL) and dichloromethane (200 ml) and bubbled through with ozone for 15 minutes. The ozone mixture was purged with nitrogen. Dimethyl sulfide (2.5 mL) was added and the mixture was allowed to warm to room temperature. The solvent was evaporated and the residue chromatographed (silica gel, methanol 1% in dichloromethane) to give 3-butyryl-4-(4-hydroxy-2-methylphenylamino)quinoline-8-carbaldehyde (2.1 g, 42%) as an oil .

H. Preparation of 3-butyryl-4-(4-hydroxy-2-methylphenylamino)-8-(1-hydroxyethyl)quinoline.

3-Butyryl-4-(4-hydroxy-2-methylphenylamino)quinoline-8-carbaldehyde (2.0 g, 6 mmol) was stirred in dry tetrahydrofuran (200 mL) at -30 °C and treated with a solution of methylmagnesium iodide in ether. The cooling was removed and the mixture was allowed to warm to room temperature. The mixture was washed with saturated ammonium chloride solution (x 2) and the aqueous layer extracted with dichloromethane. The combined organic layers were dried and evaporated to give a brown oil, which was chromatographed (silica gel, 1% methanol in dichloromethane) to give the starting aldehyde (0.16 g) and 3-butyryl-4-(4-hydroxy -2-methylphenylamino)-8-(1-hydroxyethyl)quinoline as yellow crystals from ether-petroleum ether (0.45 g, 21.5%), m.p. 182-184°C.

C22<H>2AN2O3.0.15H2O

Found: C, 72.00; H, 6.71; N, 7.48

Calculated: C, 71.97; H, 6.67; N, 7.63

Example 16

Preparation<g> of 3- isobutyryl- 4-( 4- hydroxyz- 2- methylphenylamino)-8-( hydroxymethyl) quinoline hydrochloride

A solution of 3-isobutyryl-4-chloro-8-(benzoyloxymethyl)quinoline (3.68 g, 10 mmol) and 4-hydroxy-2-methylaniline (1.35 g, 11 mmol) in dioxane (50 mL ) was boiled under reflux for 2 hours, after which the dioxane was evaporated and the residue taken up in 1% methanolic sodium hydroxide (100 ml) and stirred for 1.5 hours at room temperature. The methanol was evaporated, the residue taken up in water, adjusted to pH 7, and the solid filtered off. This was converted to the salt with ethanolic hydrogen chloride, then recrystallized from aqueous ethanol to give 3-isobutyryl-4-(2-methylphenylamino)-8-(hydroxymethyl)-quinoline hydrochloride (1.15 g, 30%), m.p. 225-255° (decomp.).

C 21 H 22 N 2 O 3 .HCl

Found: C, 65.19; H, 5.98; N, 7.24; Cl, 8.77

Calculated: C, 65.19; H, 5.99; N, 7.24; Cl, 9.16

Example 17

Preparation of 3-butyl-4-(4-fluoro-2-methylphenylamino)-8-(2-methoxysvetoxy)quinoline

A solution of 3-butyryl-4-(4-fluoro-2-methylphenylamino)-8-hydroxyquinoline (3.38 g, 10 mmol) and potassium t -butoxide (1.68 g, 15 mmol) in tetrahydrofuran (75 mL) was heated almost to boiling point and chloroethyl methyl ether (1.83 mL, 20 mmol) was added and the mixture was refluxed for 3 days. The solvent was evaporated and the product was then taken up in dichloromethane, washed with water and brine, dried and evaporated. Chromatography (silica gel, ethyl acetate/2% acetic acid/0-5% methanol) and recrystallization from ethyl acetate/petroleum ether gave 3-butyryl-4-(4-fluoro-2-methylphenylamino)-8-(2-methoxyethoxy)-quinoline (0 .41 g), m.p. 124-125°.

<C>23<H>25<FN>2<O>2

Found: C, 69.71; H, 6.52; N, 7.02

Calculated: C, 69.68; H, 6.36; N, 7.07

Example 18

Preparation of 3-isobutyryl-4-(2-methylphenylamino)-8-(2-hydroxybutoxy)quinoline

A. Preparation of 3-isobutyryl-4-chloro-8-methoxyquinoline

3-Isobutyryl-8-methoxy-4(1H)-quinolone (39.4 g, 0.16 mol) and phosphoryl chloride (315 mL) were stirred at room temperature for 10 minutes and then ether (700 mL) was added. After a further 16 hours, the yellow precipitate was filtered off, washed with ether and, with stirring, added to crushed ice. The mixture was neutralized with 10% aqueous sodium carbonate and the product extracted into dichloromethane (3 x 250 ml), dried and evaporated to an oil. Treatment with petroleum ether (60-80°) gave 3-isobutyryl-4-chloro-8-methoxyquinoline (34.8 g) as a white crystalline solid, m.p. 90-92°.

B. Preparation of 3-isobutyryl-4-chloro-8-hydroxyquinoline

A solution of 3-isobutyryl-4-chloro-8-methoxyquinoline (21.1 g, 80 mmol) in dichloromethane (320 mL) was cooled to -10° and boron tribromide (60.13 g, 240 mmol) was added dropwise under nitrogen . The solution was allowed to warm to room temperature, whereupon after 16 hours it was poured onto crushed ice (500 g). The layers were separated and the aqueous layer extracted with dichloromethane. The combined extracts were washed with brine, dried and evaporated to a yellow solid (29.75 g). This complex of 3-isobutyryl-4-chloro-8-hydroxyquinoline was used without further purification.

C. Preparation of 3-isobutyryl-4-(2-methylphenylamino)-8-hydroxyquinoline

The 3-isobutyryl-4-chloro-8-hydroxyquinoline complex

(14.88 g) and 2-methylaniline (6.43 g, 60 mmol) in dioxane (250 mL) were refluxed for 3 h. The solvent was evaporated and the residue treated with aqueous sodium bicarbonate solution and extracted into dichloromethane. The combined extracts were dried (Na 2 SO 4 ) and evaporated to a solid, which was boiled with methanol, cooled, filtered, washed with methanol and dried to give 3-isobutyryl-4-(2-methylphenylamino)-8-hydroxyquinoline (8, 72 g), m.p. 131-133°.

D. Preparation of 3-isobutyryl-4-(2-methylphenylamino)-8-(2-hydroxyethoxy)quinoline

To a solution of 3-isobutyryl-4-(2-methylphenylamino)-8-hydroxyquinoline (5 g, 15.6 mmol) in dry tetrahydrofuran (250 mL) was added potassium t-butoxide (2.63 g,

2 3.4 mmol), and then 2-bromoethanol (3.9 g, 31.2 mmol). The stirred mixture was refluxed for 16 hours, after which a new portion of potassium t-butoxide (2.63 g, 2 3.4 mmol) and 2-bromoethanol (3.9 g, 31.2 mmol) were added and the heating continued for 2 days. The solvent was evaporated and

the residue treated with aqueous sodium bicarbonate and extracted into dichloromethane. The extracts were dried and evaporated to an oil which was purified by flash chromatography (silica gel, dichloro-

methane/methanol) and recrystallized from 40-60 petroleum ether to give 3-isobutyryl-4-(2-methylphenylamino)-8-(2-hydroxyethoxy)-quinoline (2.25 g), m.p. 154-156°.

C22H2AN203. 0.4H2O. 0.06CH2C12

Found: C, 70.55; H, 6.61; N, 7.31

Calculated: C, 60.33; H, 6.67; N, 7.44

Example 19

Preparation of 3- isobutyryl- 4-( 4- fluoro- 2- methylphenylamino)- 8-( 2- hydroxyethoxy) quinoline

A. Preparation of 3-isobutyryl-4-(4-fluoro-2-methylphenylamino)-8-hydroxyquinoline

The 3-isobutyryl-4-chloro-8-hydroxyquinoline complex

(14.88 g) and 4-fluoro-2-methylaniline (7.53 g, 60 mmol) in dioxane (250 mL) were refluxed for 3 h. The solvent was evaporated and the residue treated with aqueous sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried and evaporated to a solid which was boiled with methanol, cooled, filtered off, washed with methanol and dried to give 3-isobutyryl-4-(2-methylphenylamino)-8-(2-hydroxyethoxy)quinoline (9 .07 g), m.p. 138-140°.

B. Preparation of 3-isobutyryl-4-(4-fluoro-2-methylphenylamino-8-(2-hydroxyethoxy)quinoline

To a solution of 3-isobutyryl-4-(4-fluoro-2-methylphenylamino)-8-hydroxyquinoline (5 g, 14.8 mmol) in dry tetrahydrofuran (250 mL) was added potassium t-butoxide (2, 49 g, 22.2 mmol). The stirred mixture was refluxed for 16 h, then a new portion of potassium t-butoxide (2.49 g, 22.2 mmol) and 2-bromoethanol (3.69 g,

29.6 mmol) and the heating continued for 2 days. The solvent was evaporated and the residue treated with aqueous sodium bicarbonate and extracted into dichloromethane. The extracts were dried and evaporated to an oil, which was purified by flash chromatography (silica gel, dichloromethane/methanol) and recrystallized from ether to give 3-isobutyryl-4-(4-fluoro-2-methyl-

phenylamino)-8-(2-hydroxyethoxy)quinoline (1.97 g), m.p. 183-185°.

<C>22H23FN203. 0, 07H2O. 0.04Et2O

Found: C, 68.59; H, 5.96; N, 7.14

Calcd: C, 68.79; H, 6.11; N, 7.27

Example 20

Preparation of 3-isobutvryl-4-(2-methylphenylamino)-8-(2-methoxyvethoxy)quinoline

A mixture of 3-isobutyryl-4-(2-methylphenylamino)-8-hydroxyquinoline (5.0 g, 15.6 mmol), potassium t-butoxide (2.63 g, 23.4 mmol) and 2-chloroethyl -methyl ether (2.85 mL, 31.2 mmol) in tetrahydrofuran (250 mL) was refluxed for 3 days, after which the solvent was evaporated. Water was added and the product extracted into dichloromethane, after which the organic extracts were dried and evaporated. Chromatography (silica gel, ethyl acetate/2% acetic acid/0-5% methanol) removed unchanged starting material, after which more chromatography (silica gel, 1-1.5% methanol in dichloromethane) and recrystallization from petroleum ether (40-60) gave 3-isobutyryl- 4-(2-methylphenylamino)-8-(2-methoxyethoxy)quinoline (0.67 g), m.p. 68-70°.

^-23H2éN203

Found: C, 73.10; H, 6.97; N, 7.23

Calculated: C, 72.99; H, 6.92; N, 7.40

Example 21

Preparation of 3-propanoyl-4-(2-methylphenylamino)-8-(2-hydroxyethoxy)quinoline

A. Preparation of methyl 2-propanoyl-3-methoxyacrylate

A mixture of methyl propionyl acetate (112.2 g, 0.86 mol), trimethyl orthoformate (188 mL, 1.72 mol) and acetic anhydride (81 mL, 0.86 mol) was refluxed for 17 h, after which volatile material was removed in vacuo, finally at 70°/0.3 mm. The residue was mainly methyl 2-propanoyl-3-methoxyacrylate, and was used without further purification.

B. Preparation of methyl 2-propanoyl-3-(2-methoxyphenyl-amino) acrylate

A mixture of methyl 2-propanoyl-3-methoxyacrylate (70 g) and 2-methoxyaniline (45 ml) was boiled on a steam bath for 30 minutes and then diluted with petroleum ether and set aside to crystallize. Filtration and washing with ether gave methyl 2-propanoyl-3-(2-methoxyphenylamino)acrylate (78.2 g) as a mixture of E/Z isomers.

C. Preparation of 3-propanoyl-8-methoxy-4(1H)-quinolone

Methyl 2-propanoyl-3-(2-methoxyphenylamino)acrylate (77.7 g, 0.29 mol) was added to boiling diphenyl ether (500 mL) and then refluxed for 1 hour. The solution was partially cooled and poured into high-boiling petroleum ether, whereupon the solid was filtered off and washed with 40-60 petroleum ether to give 3-propanoyl-8-methoxy-4(1H)-quinolone (35.6 g, 52%), m.p. . 260-263°.

D. Preparation of 3-propanoyl-4-chloro-8-methoxyquinoline

3-Propanoyl-8-methoxy-4(1H)-quinolone (35.4 g, 0.15 mol) was dissolved in phosphoryl chloride (400 mL) and refluxed for 1 hour, whereupon the excess phosphoryl chloride evaporated. The residue was mixed with ice and then diluted with water and extracted into dichloromethane. Drying and evaporation gave 3-propanoyl-4-chloro-8-methoxyquinoline (39.7 g) as a dark oil, which was used without further purification.

E. Preparation of 3-propanoyl-4-chloro-8-hydroxyquinoline

3-Propanoyl-4-chloro-8-methoxyquinoline (32 g) was dissolved in dichloromethane (250 ml), cooled to -78° and boron tribromide (37 ml) added slowly. The solution was allowed to slowly warm to room temperature overnight and was then cooled again in ice and the reaction carefully quenched with water. The resulting solid was filtered off and washed with water to give crude 3-propanoyl-4-chloro-8-hydroxyquinoline (115 g crude weight), which was used without further purification.

F. Preparation of 3-propanoyl-4-(2-methylphenylamino)-8-hydroxyquinoline

Crude 3-propanoyl-4-chloro-8-hydroxyquinoline (86 g) and 2-methylaniline (10.7 mL) in dioxane (200 mL) were heated on a steam bath for 30 minutes and then set aside overnight. After evaporation of the dioxane, dichloromethane and aqueous sodium bicarbonate were added and the organic layer was washed with water and brine, dried and evaporated to a yellow solid. Recrystallization from methanol gave 3-propanoyl-4-(2-methylphenylamino)-8-hydroxyquinoline (11.6 g), m.p. 125-128°.

G. Preparation of 3-propanoyl-4-(2-methylphenylamino)-8-(2-hydroxyethoxy)quinoline

A solution of 3-propanoyl-4-(2-methylphenylamino)-8-hydroxyquinoline (3.06 g, 10 mmol) and potassium t -butoxide (1.68 g, 15 mmol) in diglyme (50 mL) was heated to 150° and added dropwise a solution of 2-bromoethanol (0.85 ml, 12 mmol) in diglyme (25 ml), whereupon the temperature of the mixture was raised to the boiling point with vigorous stirring. After 1 hour, a new portion of 2-bromoethanol (0.85 ml) was added and refluxing continued for 2 hours. Diglyme was evaporated, the residue taken up in dichloromethane, washed with water and brine, dried and evaporated. Chromatography (silica gel, ethyl acetate/2% acetic acid/2-5% methanol) and recrystallization from aqueous isobutyl alcohol gave 3-propanoyl-4-(2-methylphenylamino)-8-(2-hydroxyethoxy)quinoline (0.48 g), m.p. . 174-176°.

<C>2i<H>22<N>2<0>3

Found: C, 71.92; H, 6.20; N, 7.88

Calculated: C, 71.98; H, 6.33; N, 7.99

Example 22

Preparation of 3-propanoyl-4-(4-fluoro-2-methylphenylamino)-8-(2-hydroxyethoxy)quinoline

A. Preparation of 3-propanoyl-4-(4-fluoro-2-methylphenylamino)-8-hydroxyquinoline

Crude 3-propanoyl-4-chloro-8-hydroxyquinoline (28 g) and 2-methylaniline (3.1 mL) in dioxane (100 mL) were heated on a steam bath for 30 min and then set aside overnight. After evaporation of the dioxane, dichloromethane and aqueous sodium bicarbonate were added, the organic layer was washed with water and brine, dried and evaporated to a yellow solid. Recrystallization from methanol gave 3-propanoyl-4-(4-fluoro-2-methylphenylamino)-8-hydroxyquinoline (4.0 g), m.p. 143-146°.

B. Preparation of 3-propanoyl-4-(4-fluoro-2-methylphenylamino)-8-(2-hydroxyethoxy)quinoline

A solution of 2-bromoethanol (5.75 mL, 42 mmol) in acetone (25 mL) was added dropwise to a refluxing mixture of 3-propanoyl-4-(4-fluoro-2-methylphenylamino)-8-hydroxyquinoline (1 .62 g, 5 mmol), anhydrous potassium carbonate (6.9 g, 50 mmol) and acetone (25 mL) with vigorous stirring. The heating was continued for 18 hours, then water was added and the product was extracted into dichloromethane, dried and evaporated. Chromatography (silica gel, 2-5% methanol in dichloromethane) and recrystallization from methanol afforded 3-propanoyl-4-(4-fluoro-2-methylphenylamino)-8-(2-hydroxyethoxy)quinoline (0.89 g), m.p. . 170-172°.

C21H21FN2O3

Found: C, 68.32; H, 5.90; N, 7.37

Calcd: C, 68.46; H, 5.75; N, 7.60

Example A

A tablet for oral administration was prepared by combining

Example B

An injectable solution for parenteral administration was prepared from the following

The compound of structure (I) was dissolved in the citric acid and the pH slowly adjusted to 3.2 with the sodium hydroxide solution. The solution was then added to water to a volume of 100 ml, sterile filtered and sealed in ampoules and glasses of appropriate size.

Biological data

H+K+ ATPase activity

The effects of a single high concentration (100 µM) of a compound of structure (I) on K-stimulated ATPase activity in lyophilized gastric vesicles were determined. Preferred compounds of structure (I) were also screened at a series of concentrations to determine IC 50 values.

(i) Preparation of lyophilized gastric vesicles (H/K-ATPase)

Lyophilized gastric vesicles were prepared from porcine fundic mucosa by the method of Keeling et al., (Biochem. Pharmacol., 34, 2967, 1985).

(ii) K+-stimulated ATPase activity

K<+->stimulated ATPase activity was determined at 37°C in the presence of the following: 10 mM Pipes/Tris buffer pH 7.0, 2 mM MgSOA, 1 mM KCl, 2 mM Na2ATP and 3-6 g protein/ ml of lyophilized gastric vesicles. After incubation for 30 minutes, inorganic phosphate, hydrolyzed from ATP, was determined according to the method of Yoda & Hokin (Biochem. Biophys. Res. Commun. 40, 880, 1970).

Compounds of structure (I) were dissolved in dimethylsulfoxide which, up to the highest concentration, had no effect on iC-stimulated ATPase activity.

The effect of the highest concentration of each compound of structure (I) on the recovery of a standard amount of inorganic phosphate was also determined.

The IC50 values obtained are given in the following table:

B. Perfused stomach lumen from rat (pentakastrin-stimulated gastric acid secretion).

Using a modification of the method described by Ghosh & Schild (Br. J. Pharmacology, 13, 54, 1958), after i.v. administration, the following compounds at a concentration of 10 µmol/kg were found to inhibit pentagastrin-stimulated gastric acid secretion:

The biological properties of the compounds produced according to the invention compared to known compounds are given in the table below. The IC50 values were obtained using the assay methods described above.

A comparison of the previously known compound A with the compound in examples 3 and 15, which are the most closely related compounds produced according to the invention, shows that the compounds produced according to the invention are 5-15 times more active than the known compound. These values become even higher when examples 3 and 15 are compared with compound B from EPA 259,174 (respectively 7 and 22 times more active).

Claims (7)

1. Analogy method for the preparation of a therapeutic active compound with structure (I) where R<1> is hydrogen or C1-6 alkyl; R 2 is hydrogen, C 1-6 alkyl, halogen or hydroxy; m is 1, 2 or 3; and R 3 is hydroxyC 1-6 alkyl, polyhydroxyC 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, hydroxyC 1-6 alkoxy, polyhydroxyC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy or hydroxyC 1-6 alkoxyC 1-6 alkoxy; or a salt thereof, characterized by (a) reaction of a compound with structure (II) and a compound with structure (III): where R<1>, R2 and m are as described for structure (I), R<3>' is an optionally protected R<3> group, and X is halogen; or (b) alkylating a compound of structure (VII) where R<1>, R<2> and m are as described for structure (I), and R<5> is nitrogen-protecting group; after which if desired ° any protective groups are removed; ° a group R<1> is converted into another group R<1>; ° a group R<3> is converted into another group R<3>; ° a salt is formed. 2. Process according to claim 1 for the preparation of a compound where m is 1, and the group R<2> is located in the 2-position of the phenyl ring, characterized by the use of corresponding starting materials. 3. Process according to claim 1 for the production of a compound according to claim 1, where m is 2, and the two groups R<2> are in the 2- and 4-positions of the ring, characterized in that corresponding starting materials are used. 4. Process according to one of claims 1-3 for the preparation of a compound where the group R<3> is located in the 8-position of the quinoline ring, characterized by the use of corresponding starting materials. 5. Method according to one of claims 1-4 for the production of 3-butyryl-4-(2-methylphenylamino)-8-(hydroxymethyl)quinoline, 3-butyryl-4-(2-methylphenylamino)-8-(2-methoxyethoxy ) quinoline, 3-butyryl-4-(4-hydroxy-2-methyl phenylamino)-8-(hydroxymethyl)-quinoline hydrochloride, 3-butyryl-4-(2-methylphenylamino)-8-(1-hydroxyethyl) quinoline, 3-butyryl-4-(2-methylphenylamino)-6-(hydroxyethyl)quinoline, 3-butyryl-4-(2-methylphenylamino)-7-(hydroxymethyl)quinoline, 3-isobutyry 1-4-(2- methylphenylamino)-8-(hydroxymethyl)quinoline, 3-isobutyryl-4-(4-fluoro-2-methylphenylamino)-8-(hydroxymethyl)-quinoline, 3-butyryl-4-(4-fluoro-2-methylphenylamino) -8-(hydroxymethyl)-quinoline, 3-butyryl-4-(2-methylphenylamino)-8-(2-hydroxyethoxy)quinoline, 3-butyryl-4-(2-methylphenylamino)-8-(2-(2- hydroxyethoxy)-ethoxy)quinoline, 3-butyryl-4-(2-methylphenylamino)-8-(2-(2-(2-hydroxy etoxy)-ethoxy)ethoxy)quinoline, 3-butyryl-4-(4-fluoro-2-methylphenylamino ) -8-(2-(2-hydroxyethoxy)ethoxy)quinoline, 3-butyryl-4-(4-fluoro-2-methylphenylamino)-8-(2-hydroxyethoxy)-quinoline, 3-butyryl-4- (4-hydroxy-2-methylphenylamino)-8-(1-hydroxyethyl)-quinoline, 3-isobutyryl-4-(4-hydroxy-2-methylphenylamino)-8-(hydroxymethyl)quinoline hydrochloride, 3-butyryl-4 - (4-fluoro-2-methylphenylamino)-8-(2-methoxyethoxy)-quinoline, 3-isobutyryl-4-(2-methylphenylamino)-8-(2-hydroxyethoxy)-quinoline, 3-isobutyryl -4-(4-fluoro-2-methylphenylamino)-8-(2-hydroxyethoxy)quinoline, 3-isobutyryl-4-(2-methylphenylamino)-8-(2-methoxyethoxy)quinoline, 3-propanoyl-4-(2-methylphenylamino)-8-(2-hydroxyethoxy)quinoline, or 3-propanoyl-4-(4-fluoro-2-methylphenylamino)-8-(2-hydroxyethoxy)quinoline, or a salt thereof, characterized by the use of corresponding starting materials. 6. Chemical compound, characterized by structure (II): where R<1> is as described for structure (I), R3 is an optionally protected R<3> group, and X is halogen. 7. Chemical compound, characterized by formula (VII): where R<1>, R<2> and m are as described for structure (I), and R<5> is hydrogen or a nitrogen-protecting group.