NO894189L - 4-AMINO-3-ACYLKINOLODE DERIVATIVES AND THEIR USE AS INHIBITORS OF MACHINE ACID EXPRESSION. - Google Patents

Description

Connections

The present invention relates to new substituted quinoline derivatives, methods for their preparation, intermediate products suitable for their preparation, pharmaceutical preparations containing the compounds and their therapeutic use.

Substituted quinoline derivatives with activity as facilitators of gastric acid secretion are already known. In particular, US 4343804 mentions

and EP 259174-A series of 4-phenylaminoquinoline compounds, where the phenyl ring is optionally substituted with a selection of substituents.

It has now been shown that a new class of compounds falling within the two broad indications, namely 4-phenylamino-quinolines, where the phenyl ring is substituted with a 4-hydroxy group, are particularly potent facilitators of gastric acid secretion.

According to a first aspect, the present invention provides a compound of structure (I):

where

R<1> is hydrogen, C₁₋alkyl, C₁₋galkoxy, C₁₋₋galkoxyC₋₋alkyl,

C3-6cycloalkyl, C3-gCicloalkylCi-Cgalkyl, phenylCi-ealkyl,

where the phenyl group is optionally substituted;

R<2> is hydrogen, C₁₋alkyl, C₁₋galoxy, amino, C₁₋alkylthio,

halogen, cyano, hydroxy, C 1-6 alkanoyl or trifluoromethyl; m is 1 to 3;

R<3> is hydrogen, C₁₋alkyl, phenyl, C₁₋galoxy, C₋₋alkylthio,

C₁alkanoyl, amino, C₁₄alkylamino, di-C₁₄alkylamino,

halogen, trifluoromethyl or cyano;

n is 1 or 2; and

R<4>0- is hydroxy or a bioprecursor of a hydroxy group, or a salt thereof.

Suitably, R<1> is hydrogen, C 1-6 alkyl, C 1-6 galcoxy, C 1-6 galcoxy C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 cycloalkylC 1-6 alkyl, phenylC 1-6 alkyl, where the phenyl group is optionally substituted. Preferably, R<1> is hydrogen, C₁₋alkyl or C₋₋galoxy, preferably R<1>C₋₋alkyl, especially ethyl, n-propyl or i-propyl.

Suitably m is 1 to 3, preferably m is 1 or 2; preferably m is 1.

Suitably, R<2> is hydrogen, C 1-6 alkyl, C 1-6 galcoxy, amino, C 1-6 alkylthio, halogen, cyano, hydroxy, C 1-6 galkanoyl or trifluoromethyl.

Preferably, R<2> is hydrogen, C 1-6 alkyl or C 1-6 methoxy; preferably R<2> is C 1-6 alkyl or C 1-6 methoxy, especially methyl or methoxy.

Preferably, at least one R<2->group is located in the 2-position of the phenyl ring (ie ortho to the bond that connects the ring to the nitrogen atom).

Suitably n is 1 or 2, preferably n is 1; R<3> is preferably in the 8-position of the quinoline ring.

Conveniently, R<3> is hydrogen, C 1 -g alkyl, phenyl, C 1 - 6 -alkoxy, C 1 -g alkylthio, C 1 -4 alkanoyl, amino, C 1 -g alkylamino, diC x -g alkylamino, halogen, trifluoromethyl or cyano.

Preferably, R<3> is hydrogen, C 1-6 alkyl or C 1-6 methoxy, for example methyl or methoxy.

Conveniently, R<4>0- is a bioprecursor of a hydroxy group, that is, a group that is converted to a hydroxy group after administration to a patient. Preferably, R<4>O- is for example C₁galkoxy, arylC₁galkoxy (for example OCH2Ph), C₁₁alkanoyloxy (for example OCOCH3 or OCOC(CH3)3), arylCValkanoyloxy (for example OCOCH2Ph), arylsulphonyloxy (for example toluenesulphonyloxy) or alkylsulfonyloxy (eg methanesulfonyloxy); preferably R<4>O- is hydroxy.

C 1-6 alkyl groups (either alone or as part of another group) can be straight or branched.

Phenyl C 1 -alkyl groups include, for example, the benzyl, phenylethyl, phenylpropyl and phenylbutyl groups, as well as groups in which the alkyl part is branched, e.g. 1-methylbenzyl.

Substituted phenylCi-alkyl Rx groups include, for example, phenyl groups substituted with 1 to 3 substituents R<2> as previously described.

Compounds with 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 due to the presence of the C3_6 alkyl group. Such connections will occur as two

(or more) optical isomers (enantiomers). Both the pure enantiomers, racemic mixtures (50% of each enantiomer) and various mixtures of the two fall within the scope of the present invention. All diastereomeric forms that are possible (pure enantiomers and mixtures thereof) are also covered by the invention.

Compounds of structure (I) can form 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 another aspect, the present invention provides a method for producing a compound of structure (I) consisting of

(a) reacting a compound of structure (II) with a compound of structure (III)

where R<1>, R<2>, R<3>, n and m are as described for structure (I), R<5> is hydrogen or a protecting group and X is a group which is replaceable by an amine;

(b) reduction of a compound of structure (IV)

where R<1>, R<2>, R<3>, n and m are as described for structure (I), R<5> is hydrogen or a protecting group and R<6> is hydrogen or a nitrogen protecting group ; (c) for compounds of structure (I), where R<1> is different from C 1-4 alkoxy, oxidation of a compound of structure (V)

where R<2>, R<3>, n and m are as described for structure (I), R<1>' is

a R 1 group different from C 1 -6 lkoxy, and R 5 and R 5 are as described for structure (IV); after which any protecting groups are optionally removed;

<0>a group R<1> is transformed into another group R<1>;

° a salt is formed.

Suitable groups X which can be replaced by an amine include, for example, halogen moieties, aryl or alkylsulfonates, for example toluene-p-sulfonate or methanesulfonate, alkylthio, alkylsulfonyl, alkylsulfinyl, alkoxy or aryloxy groups. Preferably, X is halogen, for example chlorine or bromine, or an aryloxy moiety such as phenoxy.

Suitable hydroxy-protecting groups R<5> and nitrogen-protecting groups R<6> will be known to the person skilled in the art, see e.g. "Protective Groups in Organic Synthesis", T.W. Greene, 1981 (Wiley).

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 reduction of a compound with structure (IV) is carried out, for example, by hydrogenation over a noble metal catalyst in a suitable solvent. Conveniently, the reaction takes place over a palladium-on-charcoal catalyst in ethanol as solvent.

Compounds with structure (IV) can be prepared from the corresponding compounds with structure (VI):

where R1, R2, R3, R57R6/n and m are as previously described, for example by reaction with phosphorus oxychloride.

The oxidation of a compound with structure (V) is carried out in

a suitable solvent in the presence of an oxidizing agent. Suitable oxidizing agents include, for example, manganese dioxide or chromium trioxide.

Appropriate transformations of the groups R<1> will be known to the person skilled in the art, and thus, for example, compounds of structure (I) where R<1> is C2_6alkyl, C3_6cycloalkylC2_6alkyl or optionally substituted phenylC2_6alkyl, can be prepared by alkylation of the following compounds of structure (IA ):

where R<2>, R<3>, n and m are as described for structure (I) and R<5> and R<6> are as described for structure (IV).

The alkylation of compounds with 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), (IV), (V) and (VI) 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 on the inhibition of 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).

Accordingly, according to a further aspect, the present invention provides compounds of structure (I)

and pharmaceutically acceptable salts thereof, for therapeutic use. 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 upper intestinal bleeding, in patients with chronic and excessive alcohol consumption and in patients with GERD (gastro oesophageal reflux disease).

For therapeutic use, the compounds according to the invention are generally administered in the form of a common pharmaceutical preparation. The present invention therefore also provides a pharmaceutical preparation comprising 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 by oral administration, 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 added suspending agent, preservative , aroma 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 produced using common carriers and then filled into hard gelatin capsules. Alternatively, a dispersion or suspension can be prepared by

to use usual appropriate pharmaceutical carriers, for example aqueous gums, celluloses, silicates or oils, after which the dispersion or suspension is poured 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, such as polyethylene glycol, polyvinyl pyrrolidone, lecithin, peanut oil or sesame oil. Alternatively, the solution can be lyophilized and then reconstituted with a suitable solvent immediately before use.

A typical suppository consists of a compound with

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 free base.

The present invention also provides a method for inhibiting gastric acid secretion which consists in a mammal in need of this being given an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof; and a method for the treatment of diseases of the stomach or intestines caused by increased acid secretion, which consists in 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 dosage regimen for an adult patient may 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 free base, wherein the compound is 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.

Incidentally, 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 aminosulphonic 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).

In the following examples which illustrate the invention in more detail, temperatures are indicated in °C.

Example 1

Preparation of 3-butyryl-4-(4-hydroxyphenylamino)-8-methoxyquinoline

3-Butyryl-4-chloro-8-methoxyquinoline (2 g, 8 mmol), 4-aminophenol (1.24 g, 11 mmol) and 1,4-dioxane (50 mL) were refluxed for 2 h, after which the solid was filtered off and converted to free base. Recrystallization from ethanol and then from methanol gave 3-butyryl-4-(4-hydroxyphenyl-amino)-8-methoxyquinoline (1.6 g), m.p. 270-272°.

<C>20<H>20N2<O>3

Found: C, 71.22; H, 5.87; N, 8.26

Calculated: C, 71.41; H, 5.99; N, 8.33

Example 2

Preparation of 3-butyryl-4-(4-hydroxy-2-methylphenylamino)-8-methoxyquinoline

3-butyryl-4-chloro-8-methoxyquinoline (3.95 g, 15 mmol), 4-amino-3-methylphenol (2.46 g, 20 mmol) and 1,4-dioxane (15 mL) were given a boiled heating to the boiling point, whereupon the solid was filtered off and washed with ethyl acetate. Conversion to free base and recrystallization from ethanol gave 3-butyryl-4-(4-hydroxy-2-methylphenylamino)-8-methoxyquinoline (1.79 g, 34%), m.p. 252-253°.

C21H22N2°3 • 0 / 15H2O

Found: C, 71.41; H, 6.42; N, 7.90

Calculated: C, 71.43; H, 6.37; N, 7.93

Example 3

Preparation of 3-butyryl-4-(4-hydroxy-2,6-dimethylphenylamino)-8-methoxyquinoline

4-amino-3,5-dimethylphenol (1.8 g, 1.3 mmol) and 3-butyryl-4-chloro-8-methoxyquinoline (2.6 g, 10 mmol) were boiled together under reflux for 1.4 -dioxane (50 ml) for 2 hours. The solvent was evaporated and the residue dissolved in dichloromethane, washed with water, sodium bicarbonate solution and brine and then dried and evaporated to a yellow solid, which after recrystallization from ethanol and then from methanol, gave 3-butyryl-4-(4-hydroxy -2,6-dimethylphenylamino)-8-methoxyquinoline as yellow crystals, m.p. 247-248°.

<C>22<H>24N2<0>3

Found: C, 72.28; H, 6.62; N, 7.66

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

Example 4

Preparation of 3-butyryl-4-(4-hydroxy-3-fluorophenylamino)-8-methoxyquinoline

2-Fluoro-4-amino-phenol (0.8 g, 6 mmol) and 3-butyryl-4-chloro-8-methoxyquinoline (1.5 g, 5.7 mmol) were boiled together under reflux for 1.4 -dioxane (50 ml) for 1 hour. The solvent was evaporated and the residue dissolved in dichloromethane, washed with water, sodium bicarbonate solution and brine and then dried and evaporated. The residue was recrystallized from methanol-water to give 3-butyryl-4-(3-fluoro-4-hydroxy-phenyl) -amino)-8-methoxyquinoline, m.p. 266-268°.

C 2 o H 19 FN 2 O 3 . 0 , 0 2 CH 2 C 12

Found: C, 67.34; H, 5.25; N, 7.71

Calculated: C, 67.53; H, 5.39; N, 7.87

Example 5

Preparation of 3-butyryl-4-(3-chloro-4-hydroxyphenylamino)-8-methoxyquinoline hydrochloride

3-butyryl-4-chloro-8-methoxyquinoline (2.64 g, 10 mmol), 2-chloro-4-aminophenol (1.58 g, 11 mmol) and 1,4-dioxane (20 mL) were given a briefly heated to the boiling point, and then cooled, after which the solid was filtered off. Recrystallization from pyridine gave 3-butyryl-4-(3-chloro-4-hydroxyphenylamino)-8-methoxyquinoline hydrochloride (1.40 g, 34%), m.p. 267-269°

(decomp.).

C 2 o H 19 ClN 2 O 3 .HCl

Found: C, 58.99; H, 5.03; N, 6.83; Cl" 8.40

Calculated: C, 58.98; H, 4.95; N, 6.88; Cl" 8.70

Example 6

Preparation of 3-butyryl-4-(4-hydroxy-2-methylphenylamino)-8-fluoroquinoline

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

2-fluoroaniline (25 g, 0.23 mol) and ethyl 2-butyryl-3-ethoxy acrylate (48 g, 0.23 mol) were heated to 150° for 2 h, then diluted with petroleum ether and set aside overnight . Filtration and washing gave ethyl 2-butyryl-3-(2-fluorophenylamino)-acrylate (37.5 g), m.p. 60-62°.

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

Ethyl 2-butyryl-3-(2-fluorophenylamino)acrylate (37 g,

0.13 mol) was added portionwise to boiling diphenyl ether (450 mL) and then refluxed for 1.5 hours. After some cooling, the mixture was diluted with petroleum ether (50 mL). Filtration and washing with petroleum ether gave 3-butyryl-8-fluoro-4(1H)-quinolone (26.5 g), mp 176-178°.

C. Preparation of 3-butyryl-4-chloro-8-fluoroquinoline

3-butyryl-8-fluoro-4(1H)-quinolone (2.7 g, 12 mmol) and phosphoryl chloride (40 mL) were refluxed for 3 h. Excess phosphoryl chloride was evaporated in vacuo, and the residue was poured onto ice and neutralized with aqueous ammonia. Filtration and washing with water gave 3-butyryl-4-chloro-8-fluoroquinoline (1.75 g), m.p. 57-60°.

D. Preparation of 3-butyryl-4-(4-hydroxy-2-methylphenylamino)-8-fluoroquinoline

3-Butyryl-4-chloro-8-fluoroquinoline (1.75 g, 7 mmol), 4-amino-3-methylphenol (1.3 g, 10 mmol) and 1,4-dioxane (50 mL) were boiled under reflux for 6.5 hours, after which the solvent was evaporated and the product converted to the free base. Recrystallization from methanol gave 3-butyryl-4-(4-hydroxy-2-methylphenylamino)-8-fluoroquinoline (1.2 g), m.p. 205-207°.

<C>20<H>19<FN>2O2

Found: C, 70.75; H, 5.70; N, 8.21

Calculated: C, 70.99; H, 5.66; N, 8.28

Example 7

Preparation of 3-butyryl-4-(4-hydroxy-2-methylphenylamino)-8-acetylquinoline

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

A mixture of ethyl 2-butyryl-3-ethoxyacrylate (23.5 g, 0.11 mol) and 2'-aminoacetophenone (13.5 g, 0.1 mol) was heated on a steam bath for 10 minutes. Crystallization from petroleum ether gave ethyl 2-butyryl-3-(2-acetylphenylamino)acrylate as a mixture of E/Z isomers (14.9 g, 49%).

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

Ethyl 2-butyryl-3-(2-acetylphenylamino)acrylate (14.8 g,

48.8 mmol) was added to boiling diphenyl ether (50 mL) and refluxed for 3.5 h. After cooling, the solution was poured into ether and the solid filtered off and washed with ether to obtain 3-butyryl-8-acetyl-4(1H)-quinolone (8.8 g), contaminated with some diphenyl ether. This material was used without further purification.

C. Preparation of 3-butyryl-4-chloro-8-acetylquinoline

A solution of 3-butyryl-8-acetyl-4(1H)-quinolone (8.4 g)

in phosphoryl chloride (30 ml) was boiled under reflux for 1 hour, then poured onto ice and the product extracted into ether. Drying and evaporation gave crude 3-butyryl-4-chloro-8-acetyl-quinoline as a dark solid, which was used without further purification.

D. Preparation of 3-butyryl-4-(4-hydroxy-2-methylphenylamino)-8-acetylquinoline

A solution of 3-butyryl-4-chloro-8-acetylquinoline (2.0 g) and 4-amino-3-methylphenol (1.23 g, 10 mmol) in 1,4-dioxane (25 mL) was given a brief heating to the boiling point, whereupon the dioxane was evaporated. Chromatography (silica, 4-6% methanol in dichloromethane) and recrystallization from ethyl acetate gave 3-butyryl-4-(4-hydroxy-2-methylphenylamino)-8-acetylquinoline (0.65 g), m.p. 183-185°.

C 22 H 22 N 2 O 3 . 0, 2H 2 O

Found: C, 72.19; H, 6.01; N, 7.59

Calculated: C, 72.19; H, 6.17; N, 7.65

Example 8

Preparation of 3-butyryl-4-(4-acetoxy-2-methylphenylamino)-8-methoxyquinoline

3-Butyryl-4-(4-hydroxy-2-methylphenylamino)-8-methoxyquinoline (1.75 g, 5 mmol) was dissolved in a mixture of acetic anhydride (10 mL) and pyridine (10 mL) and stirred for 18 h at room temperature, whereupon the solvent was evaporated, the product dissolved in dichloromethane and washed with aqueous sodium bicarbonate. Drying, evaporation and recrystallization from ethyl acetate/petroleum ether gave 3-butyryl-4-(4-acetoxy-2-methylphenylamino)-8-methoxyquinoline (1.55 g, 79%), m.p. 167-169°.

C 23H 24N 20 4

Found: C, 70.23; H, 6.00; N, 7,10

Calculated: C, 70.39; H, 6.16; N, 7.14

Example 9

Ethyl 8- methoxy- 4-( 4- hydroxy- 2- methylphenylamino)- quinoline-3- carboxylate

Ethyl 8-methoxy-4-chloroquinoline-3-carboxylate (2.6 g,

0.0098 mol) and 4-hydroxy-2-methylaniline (2.4 g, 0.0196 mol) in ethanol (150 mL) were refluxed for 30 min. The solvent was evaporated under reduced pressure. The residue was dissolved in chloroform and extracted with 2N hydrochloric acid (3 x 100 ml). After the chloroform extracts were made basic, a solid precipitated which was filtered off and dried. Recrystallization from dimethylformamide gave the title compound.

Yield = 2.52 g, m.p. 277-279°.

C20<H>20N2<O>4

Found: C, 68.12; H, 5.84; N, 8.09

Calculated: C, 68.17; H, 5.72; N, 7.95

Example 10

Preparation of 3-butyryl-4-(4-propanoyloxy-2-methylphenylamino)-8-methoxyquinoline

3-Butyryl-4-(4-hydroxy-2-methylphenylamino)-8-methoxyquinoline (2.0 g, 5.7 mmol) was suspended in pyridine (25 mL), added propionic anhydride (25 mL) and the mixture stirred for 17 hours at room temperature, during which the solid slowly dissolved to give a clear solution. Evaporation of the pyridine and recrystallization from ethyl acetate/petroleum ether gave 3-butyryl-4-(4-propanoyloxy-2-methylphenylamino)-8-methoxy-quinoline ( 2.08 g, 90%), m.p. 163-165°.

C24H26N2O4. 0.25H2O

Found: C, 70.11; H, 6.43; N, 6.74

Calculated: C, 70.14; H, 6.50; N, 6.82

Example 11

Preparation of 3-butyryl-4-(4-isobutyryloxy-2-methylphenylamino)-8-methoxyquinoline

3-Butyryl-4-(4-hydroxy-2-methylphenylamino)-8-methoxyquinoline (2.0 g, 5.7 mmol) was suspended in pyridine (25 mL), added isobutyryl chloride (5 mL) and the mixture stirred for 17 hours at room temperature, during which the solid quickly dissolved to form a clear solution. The pyridine was evaporated and the residue taken up in dichloromethane and washed with aqueous sodium bicarbonate and brine, dried and evaporated. Recrystallization from isopropyl ether gave 3-butyryl-4-(4-isobutyryloxy-2-methylphenyl-amino)-8-methoxyquinoline (0.87 g, 36%), m.p. 123-125°.

C25H28N2O4.0, 5H2O

Found: C, 69.83; H, 6.59; N, 6.41

Calcd: C, 69.91; H, 6.80; N, 6.52

Example 12

Preparation of 3-isobutyryl-4-(4-hydroxy-2-methylphenylamino)-8-methoxyquinoline

A solution of 3-isobutyryl-4-chloro-8-methoxyquinoline

(1.32 g, 5 mmol) and 4-amino-3-methylphenol (0.62 g, 5 mmol) in dioxane (50 mL) were refluxed for 1 h, then cooled and the solid filtered off. It was recorded in

a hot mixture of ethanol and tributylamine and cooled, after which the solid was filtered off. Recrystallization from ethanol gave 3-isobutyryl-4-(4-hydroxy-2-methylphenylamino)-8-methoxyquinoline (0.97 g, 55%), m.p. 243-245°.

C21<H>22<N>2O3.0.15H2O

Found: C, 71.49; H, 6.06; N, 7.95

Calculated: C, 71.43; H, 6.36; N, 7.93

Example 13

Preparation of 3-butyryl-4-(4-hydroxy-3,5-dimethylphenylamino)-8-methoxyquinoline

A. Preparation of 2,6-dimethyl-4-aminophenol

Sulphanilic acid (43.3 g, 0.25 mol) and sodium carbonate

(13.25 g, 0.125 mol) was dissolved in water (250 mL) and cooled to 15°C. Sodium nitrite (18.63 g, 0.27 mol) in water (100 mL) was added in one portion and the mixture immediately added to concentrated hydrochloric acid (53 mL) and ice (300 g) with stirring.

After 30 minutes, the resulting suspension was added to an ice-cold solution of 2,6-dimethylphenol (30.54 g, 0.25 mol) and sodium hydroxide (55 g) in water (550 mL) with vigorous stirring. After 2 hours, the temperature was raised to 50° and sodium dithionite (115 g, 0.66 mol) was added portionwise. After heating to 75°, the red color disappeared, and after a further 10 minutes the solution was cooled to room temperature. The resulting white solid was filtered off, washed and dried to give the title compound (27.33 g), m.p. 135-137°.

B. Preparation of 3-butyryl-4-(3,5-dimethyl-4-hydroxyphenyl-amino)-8-methoxyquinoline

2,6-dimethyl-4-aminophenol (0.78 g, 5.69 mmol) and 3-butyryl-4-chloro-8-methoxyquinoline (1.0 g, 3.79 mmol) in dioxane (35 mL)

was refluxed under nitrogen for 2.5 hours. The solvent was evaporated and the residue treated with

saturated sodium bicarbonate solution and chloroform. The resulting solid was filtered off, washed with chloroform and water, boiled in methanol and filtered again to give the title compound (0.84 g), m.p. 287-289° (decomp.).

Found: C, 71.01; H, 6.49; N, 7.43

Calculated: C, 71.00; H, 6.50; N, 7.50

Example 14

Preparation of 3-butyryl-4-(4-hydroxy-3,5-difluorophenylamino)-8-methoxyquinoline

A. Preparation of 2,6-difluoro-4-aminophenol

2,6-difluoro-4-nitrophenol (1.75 g, 10 mmol) and 10% palladium on carbon catalyst (0.3 g) in ethanol (100 mL) were shaken in a closed vessel at an initial hydrogen pressure of 3 .5 bar. After hydrogen uptake was complete, the catalyst was filtered off and the filtrate evaporated to a solid, triturated with petroleum ether, filtered, washed and dried to give the title compound (1.31 g), m.p. indeterminate.

B. Preparation of 3-butyryl-4-(3,5-difluoro-4-hydroxyphenyl-amino)-8-methoxyquinoline

2,6-difluoro-4-aminophenol (1.49 g, 5.65 mmol) and 3-butyryl-4-chloro-8-methoxyquinoline (1.23 g, 8.48 mmol) in dioxane (50 mL) were boiled under reflux under nitrogen for 2.5 hours. The solvent was evaporated and the product converted to the free base, purified by flash chromatography (silica, methanol-ammonia/chloroform), triturated with methanol, filtered, washed and dried to give the title compound (0.58 g), m.p. 274-275°

(decomp.).

C 20 H 28 F 2 N 2 O 3 . 0 , 15 CHCl 3

Found: C, 61.87; H, 4.67; N, 7.18

Calculated: C, 62.01; H, 4.69; N, 7.18

Example 15

Preparation of 3-butyryl-4-(3,4-dihydroxy-2,6-dimethylphenyl-amino)-8-methoxyquinoline

A. Preparation of cyclohexanone 4-amino-3,5-dimethyl-1,2-phenylene ketal

Cyclohexanone 4-nitro-3,5-dimethyl-1,2-phenylene ketal

(10.0 g) and 10% palladium on charcoal (1.0 g) in ethanol (200 ml) were shaken under a hydrogen atmosphere (3.5 kg/cm<2>) at 45°C for 3 hours. The mixture was filtered through celite and evaporated, which

left cyclohexanone 4-amino-3,5-dimethyl-1,2-phenylene ketal (8.0 g, 90%) as a brown oil.

B. Preparation of the cyclohexanone ketal of 3-butyryl-4-(3,4-dihydroxy-2,6-dimethylphenylamino)-8-methoxyquinoline

Cyclohexanone 4-amino-3,5-dimethyl-1,2-phenylene acetal

(3.1 g, 13 mmol) and 3-butyryl-4-chloro-8-methoxyquinoline (2.75 g, 12 mmol) were refluxed together in 1,4-dioxane (50 mL) for 1.5 h . The solvent was evaporated and the residue dissolved in chloroform, washed with 2M HCl, sodium bicarbonate solution and brine. Evaporation and crystallization from ether gave 3-butyryl-4-(cyclohexanone-1-amino-2,6-dimethyl-3,4-phenylene-acetal)-8-methoxyquinoline (2.2 g) as light brown crystals. Chromatography of the mother liquor gave an additional 1.0 g of the title compound (total 3.2 g, 57%), m.p. 151-153°.

C. Preparation of 3-butyryl-4-(3,4-dihydroxy-2,6-dimethyl-phenylamino)-8-methoxyquinoline

The product from B (1.0 g) in 5M hydrochloric acid (50 mL) was refluxed for 10 minutes to ensure that all solids had dissolved. The mixture was cooled and carefully brought to pH 7 by addition of sodium hydrogen carbonate solution. The resulting yellow solid was filtered off, washed with water, dichloromethane and ether and dried in vacuo to give 3-butyryl-4-(3,4-dihydroxy-2,6-dimethylphenyl-amino)-8-methoxyquinoline (0, 75 g, 90%), m.p. 288-290°C.

C 22H 24N 20 4

Found: C, 69.32; H, 6.40; N, 7.21

Calcd: C, 69.46; H, 6.36; N, 7.36

Example 16

Preparation of 3-butyryl-4-(4-hydroxy-2-methylphenylamino)-6-hydroxyquinoline

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

4-Methoxyaniline (25 g) and ethyl 2-butyryl-3-ethoxyacrylate (57 g) were heated together on a rotary evaporator (bath

temperature 100°) for 1 hour to give ethyl 2-butyryl-3-(4-rnetoxy-phenylamino)acrylate (78 g) as an orange oil.

B. Preparation of 3-butyryl-6-methoxy-4(1H)-quinolone

Ethyl 2-butyryl-3-(4-methoxyphenylamino)acrylate (78 g) was added dropwise to boiling diphenyl ether (600 ml) and reflux continued for 45 minutes. After cooling, the mixture was diluted with petroleum ether and the precipitate filtered off, washed with petroleum ether and dried to give 3-butyryl-6-methoxy-4(1H)-quinolone (24 g, 49%) as a light brown solid, m.p. 252-254°.

C. Preparation of 3-butyryl-4-chloro-6-methoxyquinoline

3-Butyryl-6-methoxy-4(1H)-quinolone (20 g) was refluxed in phosphorus oxychloride for 1 hour. The mixture was cooled, poured onto ice and carefully neutralized with ammonia solution. The mixture was extracted with dichloromethane and the combined extracts washed with sodium bicarbonate solution (x 2) and brine. The organic solution was dried, filtered and evaporated to give 3-butyryl-4-chloro-6-methoxyquinoline (13.3 g, 62%) as an oil which crystallized from ether/petroleum ether; m.p. 73-75°.

D. Preparation of 3-butyryl-4-chloro-6-hydroxyquinoline

3-butyryl-4-chloro-6-methoxyquinoline (7.9 g) was stirred in

dry dichloromethane (150 mL) under nitrogen and via a syringe added boron tribromide (8.5 mL). The mixture was stirred overnight and then carefully added to a large volume of ice. The mixture was brought to pH 14 with sodium hydroxide solution, washed with dichloromethane, neutralized with hydrochloric acid and extracted several times with dichloromethane. The combined extracts were washed with brine, dried, filtered and evaporated to give 3-butyryl-4-chloro-6-hydroxyquinoline as a yellow powder (1.5 g,

20%), m.p. 157-160°.

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

3-butyryl-4-chloro-6-hydroxyquinoline (4.0 g) and 4-amino-m-cresol (2.0 g) were boiled together under reflux in 1,4-dioxane (60 ml) for 2 hours. The solvent was evaporated and the residue was dissolved in chloroform and washed successively with 2M HCl, sodium bicarbonate solution (x 2) and brine. The organic solution was dried, filtered and evaporated to a brown oil. A portion of the solid material which appeared insoluble in chloroform was combined with the oil and the mixture chromatographed (silica gel, 2-4% methanol in chloroform) to give 3-butyryl-4-(4-hydroxy-2-methylphenylamino)-6 -hydroxyquinoline (1.3 g, 24%), as orange crystals, m.p. 242-244°.

C2oH2ON2O3.0.3<H>2O

Found: C, 70.26; H, 5.89; N, 8.21

Calculated: C, 7 0.28; H, 6.07; N, 8.24

Example 17

Preparation of 3-butyryl-4-(4-hydroxy-2-methylphenylamino)-6-hydroxy-8-methoxyquinoline

A. Preparation of 4-amino-3-methoxyphenol

Sulfanilic acid (43.3 g) and anhydrous sodium carbonate (13.25 g) were dissolved in water (250 ml) and cooled to 15°C. Sodium nitrite (18.5 g) in water (100 ml) was added and the mixture immediately poured into a mixture of ice (300 ml) and hydrochloric acid (54 ml) and stirred at 0° for 20 minutes. The suspension was then added to a cooled solution of 3-methoxyphenol (31 g) and sodium hydroxide (55 g) in water (300 ml). The resulting deep red solution was stirred for 1 hour and then heated to 70°. Sodium dithionite was added in portions until the color disappeared after cooling. Crystals of 4-amino-3-methoxyphenol (23 g, 66%) formed which were filtered, washed with water and dried, m.p. 168-170°.

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

4-amino-3-methoxyphenol (21 g) and ethyl 2-butyryl-3-ethoxy acrylate (36 g) were heated together to 90-110° for 30 minutes

to give ethyl 2-butyryl-3-(4-hydroxy-2-methoxyphenylamino)acrylate (46.1 g, 77%) as a brown solid, m.p. 140-142°.

C. Preparation of ethyl 2-butyryl-3-(4-benzoyloxy-2-methoxy-phenylamino)acrylate

Ethyl 2-butyryl-3-(4-hydroxy-2-methoxyphenylamino)acrylate (34.5 g) and pyridine (100 mL) were stirred in dichloromethane (500 mL) at 0-5°. Benzoyl chloride (20 mL) in dichloromethane (100 mL) was added dropwise (less than 10°) and the mixture stirred overnight at room temperature. The reaction mixture was washed successively with water, 2M HCl (x 2) and sodium bicarbonate solution (x 2). The organic layer was dried, filtered and evaporated to an oil which crystallized on standing to give ethyl 2-butyryl-3-(4-benzoyloxy-2-methoxyphenylamino))acrylate (24 g, 52%), m.p. 85-87°D. Preparation of 3-butyryl-6-benzoyloxy-8-methoxy-4(1H)-quinolone

Ethyl 2-butyryl-3-(4-benzoyloxy-2-methoxyphenylamino)acrylate (22 g) was added portionwise to boiling diphenyl ether and refluxed for 45 minutes. After cooling, the mixture was chromatographed (silica gel, 2% methanol in dichloromethane) to give 3-butyryl-6-benzoyloxy-8-methoxy-4(1H)-quinolone as a light brown solid (18.1 g, 92%), m.p. 102-104°.

E. Preparation of 3-butyryl-6-benzoyloxy-4-chloro-8-methoxy-quinoline

3-Butyryl-6-benzoyloxy-8-methoxy-4(1H)-quinolone (18.0 g) was refluxed in phosphorus oxychloride (100 mL) for 40 minutes. The solvent was evaporated and the residue dissolved in dichloromethane and poured into a vigorously stirred mixture of ice and sodium bicarbonate solution. The organic phase was washed with sodium bicarbonate solution, dried, filtered and evaporated to give 3-butyryl-6-benzyloxy-4-chloro-8-methoxy-quinoline as a brown oil (25 g).

F. Preparation of 3-butyryl-4-(4-hydroxy-2-methylphenylamino)-6-hydroxy-8-methoxyquinoline

3-Butyryl-4-chloro-6-benzoyloxy-8-methoxyquinoline (6.0 g) and 4-amino-m-cresol (2.0 g) were boiled together under reflux in 1,4-dioxane (100 ml) for 2 hours. The solvent was evaporated and the residue heated in 10% methanolic potassium hydroxide for 10 minutes on a steam bath. The solution was neutralized with 5M HCl and extracted several times with dichloromethane. The combined extracts were dried and evaporated to give 3-butyryl-4-(4-hydroxy-2-methylphenylamino)-6-hydroxy-8-methoxyquinoline (4.0 g, 70%), m.p. 251-253°.

Example A

A tablet for oral administration is prepared by combining

to a 9 mm tablet.

Example B

An injection solution for parenteral administration is prepared from the following

The compound with structure (I) is dissolved in the citric acid and the pH is slowly adjusted to pH 3.2 with the sodium hydroxide solution. The solution is then brought up to 100 ml with water, sterilized and sealed in ampoules and glasses of suitable size.

Biological data

H+K+ ATPase activity

The effects of a single high concentration (100M) 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 i

presence of the following: 10 mMPipes/Tris buffer pH 7.0, 2 mM MgSO4,

1 mM KCl, 2 mM Na2ATP and 3-6 g protein/ml 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 K<+->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 results obtained are as follows:

Claims (12)

1. Connection with structure (I): where R<1> is hydrogen, C 1-6 alkyl, C 1 -6 alkoxy, C 1 -galoxyC 1 -g alkyl, C 3 -6 cycloalkyl, C 1 -C 6 cycloalkylC 1 -C 6 alkyl, phenylC 6 -C 6 cycloalkyl, where the phenyl group is optionally substituted; R <2> is hydrogen, C 1 -g alkyl, C 1 -gal oxy, amino C 1 -g alkylthio, halogen, cyano, hydroxy, C 1 -galkanoyl or trifluoromethyl; m is 1 to 3; R <3> is hydrogen, C 1 -g alkyl, phenyl, C 1 -gal oxy, C 1 -g alkylthio, C 1 -galkanoyl, amino, C 1 -C 8 alkylamino, di-C 1 -C 8 alkylamino, halogen, trifluoromethyl or cyano; n is 1 or 2; and R <4> 0- is hydroxy or a bioprecursor of a hydroxy group, or a salt thereof. 2. Compound according to claim 1, where m is 1. 3. Compound according to claim 2, where R <2> is a C 1 -g alkyl group in the 2-position of the phenyl ring. 4. Compound according to claim 3, where n is 1 and R<3> is a C 1 gal oxy group. 5. Compound according to claim 4, where the group R <3> is in the 8-position. 6. Compound according to claim 1, which is 3-butyryl-4-(4-hydroxyphenylamino)-8-methoxyquinoline, 3-butyryl-4-(4-hydroxy-2-methylphenylamino)-8-methoxyquinoline, 3-butyryl-4 -(4-hydroxy-2,6-dimethylphenylamino)-8-methoxyquinoline, 3-butyryl-4-(4-hydroxy-3-fluorophenylamino)-8-methoxyquinoline, 3-butyryl-4-(3-chloro-4- hydroxyphenylamino)-8-methoxyquinoline hydrochloride, 3-butyryl-4-(4-hydroxy-2-methylphenylamino)-8-fluoroquinoline, 3-butyryl-4-(4-hydroxy-2-methylphenylamino)-8-acetylquinoline, 3 -butyryl-4-(4-acetoxy-2-methylphenylamino)-8-methoxyquinoline. 7. Pharmaceutical preparation comprising a compound according to claims 1-6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 8. Compound according to claims 1-6, for therapeutic use. 9. Compound according to claims 1-6, for use in inhibiting gastric acid secretion. 10. Method for producing a compound according to claim 1, characterized by (a) turnover of a compound with structure (II) with a compound of structure (III) wherein R 1 , R 2 , R 3 , n and m are as described for structure (I), R 5 is hydrogen or a protecting group and X is a group replaceable by an amine; (b) reduction of a compound of structure (IV) where R 1 , R 2 , R 3 , n and m are as described for structure (I), R 5 is hydrogen or a protecting group and R < 6 > is hydrogen or a nitrogen protecting group; (c) for compounds of structure (I), where R <1> is different from C₁ galcoxy, oxidation of a compound of structure (V) where R <2> , R <3> , n and m are as described for structure (I), R <1> ' is an R! group different from C 1 gal oxy, and R < 5 > and R < 6> is as described for structure (IV ); after which, if applicable ° any protective groups are removed; ° a group R <1> is converted into another group R <1> ; ° a salt is produced. 11. Connection with structure (IV) where R<1> , R2, R<3> , n and m are as described for structure (I), R<5> is hydrogen or a protecting group and R<6> is hydrogen or a nitrogen-protecting group. 12. Connection with structure (V) where R <2> , R <3> , n and m are as described for structure (I), R <1>' is an Rx group which is different from Ci-galcoxy and R 5 and R 6 are as described for structure ( IV).