WO1993015056A1

WO1993015056A1 - Pyridone derivatives, their preparation and use as medicines

Info

Publication number: WO1993015056A1
Application number: PCT/EP1993/000175
Authority: WO
Inventors: Robert John Ife; Colin Andrew Leach; Dashyant Dhanak
Original assignee: Smithkline Beecham Intercredit B.V.
Priority date: 1992-01-27
Filing date: 1993-01-26
Publication date: 1993-08-05
Also published as: EP0625144A1; JPH07503022A; GB9201694D0; AU3352693A

Abstract

The invention relates to 2-pyridone derivatives of general formula (I) in which Ar1 is an optionally substituted phenyl ring; Ar2 is an optinally substituted phenyl ring; R1 is hydrogen or C¿1-4?alkyl; R?2¿ is hydrogen or C¿1-4?alkyl; R?3¿ is hydrogen or C¿1-4?alkyl; R?4 and R5¿ are the same or different and are each hydrogen, C¿1-4?alkyl or C1-4alkylAr?1, or R4 and R5¿ together form a group (CH=CH)¿2?; and X is CH2 or NR?6¿ in which R6 is hydrogen or C¿1-4?alkyl or a salt thereof, and their use in therapy as gastric acid secretion inhibitors.

Description

Pyridone derivatives, their preparation

and use as medicines

The present invention relates to novel substituted pyridylamidine derivatives, processes for their preparation, intermediates useful in their preparation, pharmaceutical compositions containing them, and their use in therapy, in particular as gastric acid secretion inhibitors.

The present invention, therefore, provides in a first aspect, compounds of structure (I):

in which

Ar ¹ is an optionally substituted phenyl ring;

Ar ² i.s an optionally substituted phenyl ring;

R ¹ is hydrogen or C_1-4alkyl;

R ² i.s hydrogen or C_1-4alkyl;

R ³ i.s hydrogen or C_1-4alkyl;

R ⁴ and R⁵ are the same or different and are each hydrogen, C_1-4alkyl or C_1-4alkylAr ¹, or R ⁴ and R⁵ together form a group (CH=CH)₂; and

X is CH₂ or NR⁶ in which R⁶ is hydrogen or C_1-4alkyl

and salts thereof.

Suitably, Ar is an optionally substituted phenyl ring. Suitable substituents for the phenyl ring Ar include, for example, C_1-6alkyl, C_1-6alkoxy, C_1-6alkylthio, halogen, cyano, amino, C_1-4alkylamino, diC_1-4alkylanri.no, hydroxy, carbamoyl, carboxy, C_1-6alkanoyl trifluoromethyl, and

C_1-4alkylenedioxy substituents such as methylenedioxy

(-OCH₂O-). The phenyl ring may be substituted by a single substituent, or by up to 5 substituents such as may be synthetically accessible. Preferably, the group Ar ¹ is unsubstituted phenyl or phenyl substituted by 1 to 3

substituents selected from C_1-6alkyl, C_1-6alkoxy, C₁_

₆alkylthio, halogen, cyano, amino, hydroxy, carbamoyl, carboxy, C_1-6alkanoyl or trifluoromethyl. More preferably

Ar is unsubstituted phenyl, or phenyl substituted by a single substituent selected from C_1-6alkyl, C_1-6alkoxy or halogen.

Suitably, Ar ² is an optionally substituted phenyl ring.

Suitable substituents for the phenyl ring Ar ² include, for example, C_1-6alkyl, C_1-6alkoxy, C_1-6alkylthio, halogen, cyano, amino, hydroxy, carbamoyl, carboxy, C_1-6alkanoyl trifluoromethyl, and C_1-4alkylenedioxy substituents such as methylenedioxy (-OCH₂O-). The phenyl ring may be

substituted by a single substituent, or by up to 5

substituents such as may be synthetically accessible.

Preferably, the group Ar ² is unsubstituted phenyl or phenyl substituted by 1 to 3 substituents selected from C_1-6alkyl, C_1-6alkoxy, C_1-6alkylthio, halogen, cyano, amino, hydroxy, carbamoyl, carboxy, C_1-6alkanoyl or trifluoromethyl. More preferably Ar ² is unsubstituted phenyl, or phenyl

substituted by a single substituent selected from C_1-6alkyl, C_1-6alkoxy or halogen. Suitably, R ¹ is hydrogen or C_1-4alkyl; preferably R¹ is hydrogen. Suitably, R ² is hydrogen or C_1-4alkyl; preferably R² is hydrogen.

Suitably, R³ is hydrogen or C_1-4alkyl; preferably R³ is hydrogen. Suitably, R⁴ and R⁵ are the same or different and are each, hydrogen, C_1-4alkyl or C_1-4alkylAr¹, or R⁴ and R⁵ together form a (CH=CH)₂ group; preferably R⁴ and R⁵ are both hydrogen.

Suitably, X is CH₂ or NR⁶; preferably X is CH₂ or NR⁶ in which R⁶ is C_1-4alkyl, in particular methyl.

Suitably R⁶ is hydrogen or C_1-4alkyl; preferably R⁶ is C_1-4alkyl. The compounds of structure (I) and salts thereof can be prepared by procedures analogous to those known in the art. In a further aspect, there is therefore provided, a process for preparing compounds of structure (I) and salts thereof, which comprises: a) for compounds in which X is CH₂ and R³ is hydrogen, reaction of a compound of structure (II) with a compound of structure (III):

Ar²CH₂NHR² (II)

in which Ar¹, Ar², R¹, R², R ⁴ and R⁵ are as described for structure (I); or b) for compounds in which X is CH₂ and R³ is hydrogen, reaction of a compound of structure (IV) with a compound of structure (II):

in which

Ar¹ and R¹ , R⁴ and R⁵ are as described for structure (I), and R⁶ is C_1-4alkyl,

and optionally thereafter forming a salt thereof.

The reaction between compounds of structure (II) and compounds of structure (III) can be carried out in a

suitable solvent such as ethanolic hydrochloric acid at ambient temperature or, more preferably, by first treating the compound of structure (II) with trimethylaluminium in a suitable solvent such as toluene or tetrahydrofuran and then adding the compound of structure (III) in a suitable solvent such as tetrahydrofuran to the reaction mixture, and heating at elevated temperature until the reaction is complete.

The reaction between compounds of structure (IV) and structure (II) can be carried out in a suitable solvent, such as, for example, dichloromethane, at ambient

temperature, for as long as is necessary until the reaction is complete.

The intermediates of structures (II) , (III) and (IV) are commercially available or can be prepared by standard techniques as hereinafter described.

The compounds of structure (I) and their

pharmaceutically acceptable salts exert an anti-secretory effect by inhibition of the gastrointestinal H K ATPase enzyme (Fellenius, E., Berglindh, T., Sachs, G., Olke, L., Elander, B., Sjostrand, S.E., and Wallmark, B., 1981, Nature, 290, 159-61 ) .

In a further aspect therefore the present invention provides compounds of structure (I) and pharmaceutically acceptable salts thereof for use in therapy. 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, in particular humans. Such diseases include, for example, gastric and duodenal ulcers, aspiration pneumonitis and Zollinger-Ellison

Syndrome.

Further, the compounds of structure (I) can be used in the treatment of other disorders where an anti-secretory effect is desirable for example in patients with gastritis, NSAID induced gastritis, acute upper intestinal bleeding, in patients with a history of chronic and excessive alcohol consumption, and in patients with gastro oesophageal reflux disease (GERD).

In therapeutic use, the compounds of the present invention are usually administered in a standard

pharmaceutical composition. The present invention

therefore provides in a further aspect pharmaceutical compositions 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 active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.

A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier (s) for example. ethanol, glycerine, non-aqueous solvent, for example

polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent. A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier (s) routinely used for preparing solid formulations. Examples of such

carriers include magnesium stearate, starch, lactose, sucrose and cellulose.

A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.

Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.

A typical suppository formulation comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent such as polymeric glycols, gelatins or cocoa butter or other low melting vegetable or synthetic waxes or fats.

Preferably the composition is in unit dose form such as a tablet or capsule. Each dosage unit for oral administration contains suitably from 1 to 1000 mg, preferably from 1 to 500 mg (and for parenteral administration contains preferably from 0.1 to 25 mg) of a compound of the formula (I) or a

pharmaceutically acceptable salt thereof calculated as the free base.

The present invention also provides a method of

inhibiting gastric acid secretion which comprises

administering to a mammal in need thereof an effective amount of a compound of the formula (I) or a

pharmaceutically acceptable salt thereof; and a method of treatment of diseases of the stomach or intestine based on increased acid secretion which comprises administering to a mammal in need thereof an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof.

The pharmaceutically acceptable compounds of the invention will normally be administered to a subject for the treatment of gastrointestinal diseases and other conditions caused or exacerbated by gastric acidity. The daily dosage regimen for an adult patient may be, for example, an oral dose of between 1 mg and 1000 mg, preferably between 1 mg and 500 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 the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day. Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more.

In addition, the compounds of the present invention can be co-administered with further active ingredients, such as antacids (for example magnesium carbonate or hydroxide and aluminium hydroxide), non-steroidal anti-flammatory drugs (for example indomethacin, aspirin or naproxen), steroids, or nitrite scavengers (for example ascorbic acid or

aminosulphonic acid), or other drugs used for treating gastric ulcers (for example histamine H₂-antagonists such as cimetidine), or agents capable of inhibiting the

Helicobacter pylori organisms, for example antibiotics such as amoxicillin.

The following examples illustrate the invention.

Temperatures are recorded in degrees centigrade.

Example 1

1-Benzyl-3-(N-benzylamidino)-2-pyridone hydrochloride

A) 1-Benzyl-3-cyano-2-pyridone

Petrol-washed sodium hydride (1.92 g, 80 mmol) was suspended in dry DMF (200 ml), 3-cyano-2-pyridone (9.0 g, 75 mmol) added portionwise, and the mixture stirred until evolution of hydrogen ceased. Benzyl bromide (13.7 g, 80 mmol) was then added slowly, keeping the temperature below 30°C. The mixture was stirred for a further 5 hours, then poured onto ice-water. The precipitate formed was filtered off and dried to give 1-benzyl-3-cyano-2-pyridone (11.68 g, 72%),

m.p. 120-121°C.

B) 1-Benzyl-3-(N-benzylamidino)-2-pyridone hydrochloride 1-Benzyl-3-cyano-2-pyridone (6.0 g, 28.8 mmol) was dissolved in ethanolic HCl (250 ml) and allowed to stand at room temperature for 1 week. The solvent was evaporated and the residue dissolved in dry dichloromethane, cooled in ice, and a solution of benzylamine (50 ml, excess) in dichloromethane added slowly. Cooling was removed and the mixture stirred 2 hours at room temperature, then washed with water and aqueous bicarbonate, dried, and the solvent evaporated.

Chromatography (silica gel, 4% methanol in chloroform), conversion to the hydrochloride and crystallisation from ethanol-ether gave the product (0.45 g), m.p. 186-188°C.

C20H19N3O ·HCl

Found C 68.05, H 5.71, N 11.81 Requires C 67.90, H 5.70, N 11.90 Example 2

1-(4-Chlorobenzyl)-3-(N-benzylamidino)-2-pyridone

hydrochloride A) Preparation of 1-(4-chlorobenzyl)-3-cyano-2-pyridone

Substituting 4-chlorobenzyl chloride (6.44 g, 0.04 mol) for benzyl bromide and using corresponding molar proportions of the other reagents in example 1A gave 1-(4-chlorobenzyl)-3-cyano-2-pyridone (8.06 g, 82%), m.p. 139-140°C.

B) Preparation of 1-(4-chlorobenzyl)-3-(N-benzylamidino)-2-pyridone hydrochloride To a stirred suspension of benzylamine hydrochloride in dry toluene (10 ml) at 5°C under nitrogen, was added dropwise a solution of 2M trimethylaluminium in toluene ( 6 ml,

0.012 mol) such that the temperature did not exceed 5°C . The mixture was allowed to reach room temperature and treated with 1-(4-chlorobenzyl)-3-cyano-2-pyridone (1 g,

0.004 mol) in tetrahydrofuran (20 ml) and left for 3 hours at 65°C. After cooling, the supernatant was decanted off and the residue treated with chloroform. The resulting solid was dissolved in a methanol/silica slurry, the suspension filtered, evaporated, and the residue triturated with ethanol. The resulting solid on recrystallisation from ethanol/ether gave 1-(4-chlorobenzyl)-3-(N-benzylamidino)-2-pyridone hydrochloride (0.15 g, 10.5%), m.p. 207-209°C.

C₂₀H₁₈N₃Cl ·HCl

Found C 61.93, H 4.95, N 11.16, Cl 18.18

Requires C 61.86, H 4.93, N 10.82, Cl 18.26 Example 3

1-(2-Methylbenzyl)-3-(N-benzylamidino)-2-pyridone

hydrochloride A) Preparation of 1-(2-methylbenzyl)-3-cyano-2-pyridone

Substituting 2-methylbenzyl bromide (7.4g , 0.04 mol) for benzyl bromide and using corresponding molar proportions of the other reagents in example 1A gave 1-(2-methylbenzyl)-3-cyano-2-pyridone (6.45g , 73%), m.p. 140-141°C.

B) Preparation of 1-(2-methylbenzyl)-3-(N-benzylamidino)-2-pyridone hydrochloride Benzylamine hydrochloride (1.06 g, 0.006 mol) was suspended in dry toluene to which 2M trimethylaluminium in toluene (2.9 ml, 0.006 mol) was added dropwise at 5°C under

nitrogen. After allowing to reach 50°C, the mixture was treated with 1-(2-methylbenzyl)-3-cyano-2-pyridone (1.35 g, 0.006 mol) in dry tetrahydrofuran (20 ml) and left for 16 hours. After cooling, the mixture was poured onto a

chloroform/silica slurry, washed with chloroform and then methanol. The methanol wash was evaporated and the residue partitioned between 2N NaOH/chloroform. The organic layer was separated, evaporated and distilled at 100°C (0.02 mm Hg) . The residue was triturated with ethanol, causing crystallisation of unreacted cyanopyridone, which was filtered off. The filtrate was treated with ethanolic HCl to form crystals of 1-(2-methylbenzyl)-3-(benzylamidino)-2-pyridone hydrochloride (0.65 g, 29%), m.p. 230-231°C.

C₂₁H₂₁N₃O ·HCl

Found C 68.63, H 6.09, N 11.73, Cl 9.62 Requires C 68.56, H 6.03, N 11.42, Cl 9.64 Example 4

1-(4-Fluorobenzyl)-3-(N-benzylamidino)-2-pyridone

hydrochloride A) Preparation of 1-(4-fluorobenzyl)-3-cyano-2-pyridone

Substituting 4-fluorobenzyl chloride (5 g, 0.04 mol) for benzyl bromide and using corresponding molar proportions of the other reagents in example 1A gave 1-(4-fluorobenzyl)-3-cyano-2-pyridone (2.38 g, 26%), m.p. 118-120°C.

B) Preparation of 1-(4-fluorobenzyl)-3-(N-benzylamidino)-2-pyridone hydrochloride Substituting 1-(4-fluorobenzyl)-3-cyano-2-pyridone (1.36 g, 0.006 mol) for 1-(2-methylbenzyl)-3-cyano-2-pyridone and using the corresponding molar proportions of the other reagents in example 3B gave 1-(4-fluorobenzyl)-3-(N-benzylamidino)-2-pyridone hydrochloride (0.83 g, 35%) from ethanolic hydrogen chloride/ether, m.p. 186-187°C.

C₂₀H₁₈FN₃O ·HCl

Found C 64.29, H 5.33, N 11.41, Cl 9.53

Requires C 64.60, H 5.15, N 11.30, Cl 9.53 Example 5

1-(4-Nitrobenzyl)-3-(N-benzylamidino)-2-pyridone hydrochloride

A) Preparation of 1-(4-nitrobenzyl)-3-cyano-2-pyridone Substituting 4-nitrobenzyl bromide (10 g, 0.08 mol) for benzyl bromide and using corresponding molar proportions of the other reagents in example 1A gave 1-(4-nitrobenzyl)-3-cyano-2-pyridone (18.98 g, 93%), m.p. 148-150°C. B) Preparation of 1-(4-nitrobenzyl)-3-(N-benzylamidino)-2-pyridone hydrochloride

Substituting 1-(4-nitrobenzyl)-3-cyano-2-pyridone (1 g, 0.004 mol) for 1-(4-chlorobenzyl)-3-cyano-2-pyridone and using corresponding molar proportions of the other reagents in example 2B gave 1-(4-nitrobenzyl)-3-(N-benzylamidino)-2-pyridone hydrochloride ( 0.15 g, 10%), m.p. 188-190°C.

C₂₀H₁₈N₄O₃ ·HCl ·0.2H₂O

Found C 59.50, H 4.76, N 13.76, Cl 8.82

Requires C 59.59, H 4.86, N 13.90, Cl 8.84

Example 6

1-(4-Methoxybenzyl)-3-(N-benzylamidino)-2-pyridone

hydrochloride

A) Preparation of 1-(4-methoxybenzyl)-3-cyano-2-pyridone

Substituting 4-methoxybenzyl chloride (3.13 g, 0.02 mol) for benzyl bromide and using corresponding molar proportions of the other reagents in example 1A gave 1-(4-methoxybenzyl)-3-cyano-2-pyridone (1.49 g, 31%), m.p. 132-133°C.

B) Preparation of 1-(4-methoxybenzyl)-3-(N-benzylamidino)-2-pyridone hydrochloride

Substituting 1-(4-methoxybenzyl)-3-cyano-2-pyridone (1.49 g, 0.006 mol) for 1-(4-chlorobenzyl)-3-cyano-2-pyridone and using corresponding molar proportions of the other reagents in example 2B gave 1-(4-methoxybenzyl)-3-(N-benzylamidino)-2-pyridone hydrochloride (0.24 g, 10%), m.p. 218-220°C

C₂₁H₂₁N₃O₂ ·HCl

Found C 65.33, H 5.76, N 10.83, Cl 9.16 Requires C 65.71, H 5.78, N 10.95, Cl 9.24 Example 7

1-(4-Benzyloxybenzyl)-3-(N-benzylamidino)-2-pyridone hydrochloride A) Preparation of 4-(benzyloxybenzyl)-3-cyano-2-pyridone

Substituting 4-benzyloxybenzyl chloride (5 g, 0.02 mol) for benzyl bromide and using corresponding molar proportions of the other reagents in example 1A gave 1-(4-benzyloxybenzyl)-3-cyano-2-pyridone (6.56 g, 93%), m.p. 109-110°C.

B) Preparation of 1-(4-benzyloxybenzyl)-3-(N-benzylamidino)-2-pyridone hydrochloride Substituting 1-(4-benzyloxybenzyl)-3-cyano-2-pyridone

(4.74 g, 0.015 mol) for 1-(2-methylbenzyl)-3-cyano-2-pyridone and using corresponding molar proportions of the other reagents in example 3B gave 1-(4-benzyloxybenzyl)-3- (N-benzylamidino)-2-pyridone hydrochloride (1.22 g, 17%) from ethanolic hydrogen chloride/ether, m.p. 208-209°C.

C₂₇H₂₅N₃O₂ ·HCl

Found C 70.50, H 5.70, N 9.14 , Cl 7.71 Requires C 70.32, H 5.75, N 9.08 , Cl 7.78 Example 8

1-(2,6-Dichlorobenzyl)-3-(N-benzylamidino)-2-pyridone hydrochloride

A) Preparation of 1-(2,6-dichlorobenzyl)-3-cyano-2-pyridone

Substituting 2,6-dichlorobenzyl bromide for benzyl bromide (5 g, 0.04 mol) and using corresponding molar proportions of the other reagents in example 1A gave 1-(2,6-dichlorobenzyl)-3-cyano-2-pyridone (5.0 g, 44%), m.p. 181-182°C. B) Preparation of 1-(2,6-dichlorobenzyl)-3-(N-benzylamidino)-2-pyridone hydrochloride

Substituting 1-(2,6-dichlorobenzyl)-3-(N-benzylamidino)-2-pyridone (1.67 g, 0.006 mol) for 1-(2-methylbenzyl)-3-cyano-2-pyridone and using corresponding molar proportions of the other reagents in example 3B gave 1-(2,6-dichlorobenzyl)-3- (N-benzylamidino)-2-pyridone hydrochloride (0.09 g, 4%) from ethanolic hydrogen chloride/ether, m.p. 179-180°C.

C₂₀H₁₇N₃CI₂O ·1.2HCl ·0.17H₂O

Found C 55.22, H 4.10, N 9.48, Cl 25.80 Requires C 55.47, H 4.31, N 9.70, Cl 26.19

Example 9

1-(2-Methylbenzyl)-3-(N-(2-methylbenzyl)amidino)-2-pyridone hydrochloride

Substituting 2-methylbenzylamine hydrochloride (0.95 g, 0.006 mol) for benzylamine hydrochloride and using

corresponding molar proportions of the other reagents in example 3B gave 1-(2-methylbenzyl)-3-(N-(2-methylbenzyl)-amidino)-2-pyridone hydrochloride (0.33 g, 14%) from

ethanolic hydrogen chloride/ether, m.p. 212-213°C.

C₂₂H₂₃N₃O ·HCl

Found C 68.75, H 6.42, N 10.95, Cl 9.23

Requires C 69.19, H 6.33, N 11.00, Cl 9.28

Example 10

1-Benzyl-3-(N-(4-fluorobenzyl)amidino)-2-pyridone

hydrochloride

4-Fluorobenzylamine hydrochloride (1.37 g, 0.0085 mol) was suspended in dry toluene to which 2M trimethylaluminium in toluene (4.5 ml, 0.0085 mol) was added dropwise at 5°C under nitrogen. After allowing to reach 50°C, the mixture was treated with 1-benzyl-3-cyano-2-pyridone (1.8 g, 0.0085 mol) in dry tetrahydrofuran (20 ml) and left for 16 hours. After cooling, the mixture was poured onto a chloroform/silica slurry, washed with chloroform and then methanol. The methanol wash was evaporated and the residue partitioned between 2N NaOH and chloroform. The organic layer was separated, evaporated and distilled at 100°C (0.02 mm Hg). The residue was triturated with ethanol causing

crystallisation of unreacted cyanopyridone, which was filtered off. The filtrate was treated with ethanolic hydrogen chloride to form crystals of 1-benzyl-3-(N-(4-fluorobenzyl)amidino)-2-pyridone hydrochloride (0.33 g, 10%), m.p. 199-200°C.

C₂₀H₁₀FN₃O ·HCl

Found C 64.65, H 5.19, N 11.38, Cl 9.53 Requires C 64.60, H 5.15, N 11.30, Cl 9.53 Example 11

1-Benzyl-3-(N-(2-methylbenzyl)amidino)-2-pyridone

hydrochloride

Substituting 2-methylbenzylamine hydrochloride (1.34 g, 0.0085 mol) for 4-fluorobenzylamine hydrochloride and using corresponding molar proportions of the other reagents in example 10 gave 1-benzy1-3-(N-(2-methybenzyl)amidino)-2-pyridone hydrochloride (0.47 g, 15%) from ethanolic hydrogen chloride/ether, m.p. 155-156°C.

C₂₁H₂₁N₃O ·1.15HCl

Found C 67.26, H 5.98, N 11.30, Cl 10.53 Requires C 67.56, H 5.98, N 11.26, Cl 10.92

Example 12

1-(4-Methoxybenzyl)-3-(N-(2-methylbenzyl)amidino)-2-pyridone hydrochloride

Substituting 1-(4-methoxybenzyl)-3-cyano-2-pyridone (2.8 g, 0.012 mol) for 1-benzyl-3-cyano-2-pyridone and using

corresponding molar proportions of the other reagents in example 11 gave 1-(4-methoxybenzyl)-3-(N-(2-methylbenzyl)-amidino)-2-pyridone hydrochloride (0.28 g, 6%) from

ethanolic hydrogen chloride/ether, m.p. 182-183°C. C₂₂H₂₃N₃O ·HCl

Found C 66.29, H 6.08, N 10.54, Cl 9.03

Requires C 66.41, H 6.08, N 10.56, Cl 8.91 Example 13

1-Benzyl-3-(N-(4-chlorobenzyl)amidino)-2-pyridone

hydrochloride

4-Chlorobenzylamine hydrochloride (2.5 g, 0.014 mol) was suspended in dry toluene to which 2M trimethylaluminium in toluene (7 ml, 0.014 mol) was added dropwise at 5°C under nitrogen. After allowing to reach 50°C, the mixture was treated with 1-benzyl-3-cyano-2-pyridone (1 g, 0.0047 mol) in dry tetrahydrofuran (20 ml) and left for 16 hours. After cooling, the supernatent was decanted off and the residue treated with chloroform. This caused formation o.f a solid which was dissolved in a methanol/silica slurry. The suspension was filtered, evaporated and triturated with ethanol, causing crystallization of 1-benzyl-(N-(4-chlorobenzyl)amidino)-2-pyridone hydrochloride (0.15 g, 10.5%), m.p. 207-209°C.

C₂₀H₁₈N₃CIO ·HCl

Found C 61.46, H 4.85, N 10.83, Cl 18.57 Requires C 61.87, H 4.93, N 10.82, Cl 18.26

Example 14

1-Benzyl-3-(N-(4-trifluoromethylbenzyl)amidino)-2-pyridone hydrochloride Substituting 4-trifluoromethylbenzylamine hydrochloride

(1.26 g, 0.06 mol) for 4-fluorobenzylamine hydrochloride and using corresponding molar proportions of the other reagents in example 10 gave 1-benzyl-3-(N-(4-trifluoromethylbenzyl)amidino)-2-pyridone hydrochloride (0.32 g, 13%) from ethanolic hydrogen chloride/ether, m.p. 179-180°C. C₂₁H₁₈N₃F₃O ·HCl

Found C 59.42, H 4.68, N 9.72, Cl 8.41

Requires C 59.79, H 4.54, N 9.96, Cl 8.40 Example 15

1-Benzyl-3-(N-(4-methoxybenzyl)amidino)-2-pyridone hydrochloride

Substituting 4-methoxybenzylamine hydrochloride (1.47 g, 0.0085 mol) for 4-fluorobenzylamine hydrochloride and using corresponding molar proportions of the other reagents in example 10 gave 1-benzyl-3-(N-(4-methoxybenzyl)amidino)-2-pyridone hydrochloride (0.31 g, 9.5%) from ethanolic hydrogen chloride/ether, m.p. 175-176°C.

C₂₁H₂₁N₃O₂ ·HCl

Found C 65.51, H 5.84, N 11.02, Cl 9.18 Requires C 65.71, H 5.78, N 10.95, Cl 9.24

Example 16

1-Benzyl-3-(N-(4-methylbenzyl)amidino)-2-pyridone

hydrochloride

Substituting 4-methylbenzylamine hydrochloride (0.95 g, 0.006 mol) for 4-fluorobenzylamine hydrochloride and using corresponding molar proportions of the other reagents in example 10 gave 1-benzyl-3-(N-(4-methylbenzyl)amidino)-2-pyridone hydrochloride (0.16 g, 7%) from ethanolic hydrogen chloride/ether, m.p. 193-194°C.

C₂₁H₂₁N₃O ·HCl

Found C 68.26, H 6.03, N 11.39, Cl 9.77

Requires C 68.56, H 6.03, N 11.42, Cl 9.64

Example 17

1- (4-Methylbenzyl)-3-(N-benzylamidino)-2-pyridone hydrochloride

A) 1-(4-Methylbenzyl)-3-cyano-2-pyridone Substituting 4-methylbenzyl bromide (7.4 g, 0.04 mol) for benzyl bromide and using corresponding molar proportions of the other reagents in example 1A gave 1-(4-methylbenzyl)-3-cyano-2-pyridone (6.67 g, 73%), m.p. 144-145°C.

B) 1-(4-Methylbenzyl)-3-(N-benzylamidino)-2-pyridone hydrochloride

Benzylamine hydrochloride (1.06 g, 0.006 mol) was suspended in dry tetrahydrofuran (20 ml), to which 2M trimethylaluminium in toluene (2.9 ml, 0.006 mol) was added dropwise at 5°C under nitrogen. The mixture was warmed to 50 °C, then treated with 1-(4-methylbenzyl)-3-cyano-2-pyridone (1.35 g, 0.006 mol) in dry tetrahydrofuran (20 ml) and left for 16 hours. After cooling, the mixture was poured onto a chloroform/silica slurry, washed with chloroform and then methanol. The methanol wash was evaporated and the residue partitioned between 2N NaOH and chloroform. The organic layer was separated, evaporated and distilled at 100°C (0.002 mm Hg). The residue was treated with ethanolic hydrogen chloride to form crystals of 1-(4-methylbenzyl)-3- (N-benzylamidino)-2-pyridone hydrochloride (0.73 g, 33%), m.p. 209-210°C.

C₂₁H₂₁N₃O ·1.0HCl

Found C 68.08, H 6.00, N 11.39, Cl 9.91

Requires C 68.56, H 6.03, N 11.42, Cl 9.64

Example 18

1-(4-Dimethylaminobenzyl)-3-(N-benzylamidino)-2-pyridone dihydrochloride

A) 1-(4-Dimethylaminobenzyl)-3-cyano-2-pyridone

Substituting 4-dimethylaminobenzyl chloride (8.5 g, 0.04 mol) for benzyl bromide and using corresponding molar proportions of the other reagents in example 1A gave 1-(4-dimethylamino)-3-cyano-2-pyridone (0.65 g, 6.4%),

m.p. 153-155°C. B) 1-(4-Dimethylaminobenzyl)-3-(N-benzylamidino)-2-pyridone dihydrochloride

Substituting 4-(dimethylaminobenzyl)-3-cyano-2-pyridone (1.37 g, 0.005 mol) for 1-benzyl-3-cyano-2-pyridone and using corresponding molar proportions of the other reagents in example 11 gave 1-(4-dimethylaminobenzyl)-3-(N-benzylamidino)-2-pyridone dihydrochloride (0.2 g, 9.2%), m.p. 210-211°C.

C₂₂H₂₄N₄O ·2HCl

Found C 60.17, H 6.10, N 12.64, Cl 15.83 Requires C 60.11, H 6.13, N 12.75, Cl 16.04

Example 19

1-(4-Methoxybenzyl)-3-(N-(2-methylbenzyl)amidino)-2- quinolone hydrochloride

A) 1-(4-Methoxybenzyl)-3-cyano-2-quinolone To a solution of sodium ethoxide (made from 0.81g of sodium and ethanol) in ethanol (200 ml) was added 3-cyano-2- quinolone (6 g, 0.035 mol) and the mixture stirred overnight at room temperature. The reaction mixture was poured into diethyl ether (200 ml) and the solid obtained was collected by filtration and air dried. To a slurry of the sodium salt in dimethylformamide (50 ml) was added 4-methoxybenzyl chloride (5 ml, 0.037 mol) and the reaction mixture stirred at room temperature overnight. The reaction mixture was poured onto ice/water and the solid obtained was collected by filtration and dried. The solid was purified by flash chromatography using chloroform as eluant. The fractions containing the pure product were combined and evaporated under reduced pressure to give the title compound

(4.5g, 44%), m.p. 178-180°C.

B) 1-(4-Methoxybenzyl)-3-(N-(2-methylbenzyl)amidino)-2-quinolone hydrochloride. Substituting 1-(4-methoxybenzyl)-3-cyano-2-quinolone

(2 g, 0.0069 mol) for 1-(2-methylbenzyl)-3-cyano-2-pyridone and using corresponding molar proportions of the other reagents in example 3B gave the title compound

(0.12 g, 4.2%). m.p. >250°C.

C₂₆H₂₅N₃O₂ ·HCl

Found C 69.80, H 5.91, N 9.46, Cl- 7.81

Requires C 69.71, H 5.85, N 9.38, Cl- 7.91 Example 20

1-Benzyl-3-(N-benzylamidino)-2-quinolone hydrochloride

A) 1-Benzyl-3-cyano-2-quinolone To a slurry of sodium hydride (2 g, 0.05 mol) in

dimethylformamide (50 ml) was added a slurry of 3-cyano-2- quinolone (8.5 g, 0.05 mol) in dimethylformamide (100 ml) dropwise. On completion of the addition the mixture was stirred for 30 minutes, then benzyl bromide (8.6 g, 0.05 mol) was added dropwise keeping the temperature below 20°C using an ice/salt bath. Stirring was continued at room temperature overnight, the mixture was poured onto ice/water (500 ml), and the solid obtained was collected by filtration and dried (8.5 g, 65%), m.p. 193-195°C.

B) 1-Benzyl-3-(N-benzylamidino)-2-quinolone hydrochloride

Substituting 1-benzyl-3-cyano-2-quinolone (2 g, 0.008 mol) for 1-(2-methylbenzyl)-3-cyano-2-pyridone and using

corresponding molar proportions of the other reagents in example 3B gave 1-benzyl-3-(N-benzylamidino)-2-quinolone hydrochloride (0.25 g, 8.8%), m.p. >250°C

C₂₄H₂₀N₃O ·HCl

Found C 71.28, H 5.56, N 10.41, Cl- 8.59 Requires C 71.55, H 5.25, N 10.43, Cl- 8.80 Example 21

1-Benzyl-3-(N-benzylamidino)-6-methyl-2-pyridone

hydrochloride A) 1-Benzyl-3-cyano-6-methyl-2-pyridone

To a slurry of sodium hydride (6 g, 0.15 mol) in

dimethylformamide (150 ml) was added 6-methyl-3-cyano-2-pyridone (20 g, 0.149 mol) portionwise. On completion of the addition the reaction mixture was stirred for 30

minutes, warming to 40°C to dissolve the pyridone, then cooled to below 20°C and benzyl bromide (17.2 ml, 0.145 mol) added dropwise. Stirring was continued overnight, the mixture was poured onto ice/water and extracted with diethyl ether (3×200 ml). The ether extracts were combined, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified by flash

chromatography using chloroform as eluant. Fractions containing the product were combined and evaporated under reduced pressure to give an oil, which crystallized on addition of hexane. The solid was collected by filtration to give the title compound (13.8 g, 41%), m.p. 101-103°C.

B) 1-Benzyl-3-(N-benzylamidino)-6-methyl-2-pyridone

hydrochloride

Substituting 1-benzyl-3-cyano-6-methyl-2-pyridone (2 g, 0.009 mol) for 1-(2-methylbenzyl)-3-cyano-2-pyridone and using corresponding molar proportions of the other reagents in example 3B gave the title compound (0.72 g, 22%), m.p. 183-185°C.

C₂₁H₂₉N₃O ·HCl

Found C 68.35, H 5.98, N 11.49, Cl- 9.47

Requires C 68.56, H 6.03, N 11.42, Cl- 9.64 Example 22

1-Benzyl-3-(N-(N-phenyl)amidino)-2-pyridone hydrochloride

A stirred solution of phenylhydrazine (1.5 g, 14 mmol) in dry THF (20 ml) was treated at 0°C with a 1.0M solution of dimethylaluminium chloride in hexane (14.4 ml. 14.4 mmol). When effervescence ceased, a solution of 1-benzyl-3-cyano-2-pyridone (1.0 g, 4.8 mmol) in dry THF (20 ml) was added and the mixture warmed to 40°C, then poured onto a silica gel/ chloroform slurry. Non-polar materials were removed by washing the gel with chloroform. The product was eluted with methanol, which was evaporated and the residue

recrystallised from an isopropyl alcohol/ether mixture to give the title compound as an orange/yellow solid (90 mg, 5%) m.p. 185-6°C.

C₁₉H₁₉N₄O · 1.3HCl

Found C 61.98, H 5.21, N 15.10 Requires C 62.38, H 5.32, N 15.32

Example 23

1-Benzyl-3-(N-(N-methyl-N-phenyl)amidino)-2-pyridone hydrochloride Substituting 1-methyl-1-phenylhydrazine hydrochloride

(0.95g, 0.006 mol) for benzylamine hydrochloride and using corresponding molar proportions of the other reagents in example 3B gave 1-benzyl-3-(N-(N-methyl-N-phenyl)amidino)-2-pyridone hydrochloride (0.18g, 8%), m.p. 147-149°C.

C₂₀H₂₀N₄O. 1. 0 HCl. 0.2 H₂O

Found C 64.51, H 5.70, N 15.22, Cl 9.41

Requires C 64.49, H 5.79, N 15.04, Cl 9.51 Example 24

1-Benzyl-3-(N-benzylamidino)-5-methyl-2-pyridone

hydrochloride A) 1-Benzyl-3-cyano-5-methyl-2-pyridone

To a solution of sodium ethoxide (prepared from 1.37g of sodium and ethanol) in ethanol (200 ml) was added 3-cyano-5-methyl-2-pyridone (8.0g, 0.06 mol) and the mixture stirred overnight at room temperature. The reaction mixture was poured into ether (200 ml) and the solid obtained collected by filtration and air dried. A slurry of the sodium salt in dimethylformamide (100 ml) was treated with benzyl bromide (10.2g, 0.06 mol) and the reaction mixture stirred at room temperature overnight. The reaction was poured into ice/water and the solid collected by filtration, washed with a little ether and dried to give 1-benzyl-3-cyano-5-methyl-2-pyridone (11.75g, 88%), m.p. 179-182°C. B) 1-Benzyl-3-(N-benzylamidino)-5-methyl-2-pyridone

hydrochloride.

Substituting 1-benzyl-3-cyano-5-methyl-2-pyridone (2.0g, 0.009 mol) for 1-(2-methylbenzyl)-3-cyano-2-pyridone and using corresponding molar proportions of the other reagents in example 3B gave 1-benzyl-3-(N-benzylamidino)-5-methyl-2-pyridone hydrochloride (1.71g, 52%). m.p. 155-156°C.

C₂₁H₂₉N₃O. HCl

Found C 67.97, H 6.00, N 11.21, Cl 9.48 Requires C 68.56, H 6.03, N 11.42, Cl 9.64 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 lyophilised gastric vesicles was determined. Preferred compounds of structure (I) were also tested over a range of concentrations to determine IC₅₀ values.

(i) Preparation of lyophilised gastric vesicles

(H/K-ATPase). Lyophilised gastric vesicles were prepared from pig fundic mucosa after 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 MgSO₄, 1 mM KCl, 2 mM Na₂ATP and 3-6 μg protein/ml lyophilised gastric vesicles. After incubation for 30 minutes, the inorganic phosphate hydrolysed from ATP was determined by the method of

Yoda and Hokin (Biochem. Biophys. Res. Commun. 40, 880, 1970).

Compounds of structure (I) were dissolved in

dimethylsulphoxide which up to the highest

ccoonncceennttrraattiioonn uused 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. Results

The compounds of examples 1 to 23 had IC₅₀ values of less than 20 μM.

Claims

Claims :

1. A compound of structure (I):

in which

Ar ¹ is an optionally substituted phenyl ring;

Ar ² is an optionally substituted phenyl ring;

R¹ is hydrogen or C_1-4alkyl;

R² is hydrogen or C_1-4alkyl;

R ³ is hydrogen or C_1-4alkyl;

R ⁴ and R⁵ are the same or different and are each hydrogen, C_1-4alkyl or C_1-4alkylAr¹, or R ⁴ and R⁵ together form a group (CH=CH)₂; and

X is CH₂ or NR⁶ in which R⁶ is hydrogen or C_1-4alkyl

or a salt thereof.

2. A compound according to claim 1 in which Ar ¹ is phenyl, X is CH₂ and Ar ² is phenyl.

3. A compound according to claim 2 in which R ¹ to R³ are all hydrogen.

4. A compound according to claim 1 which is:

1-benzyl-3-(N-benzylamidino)-2-pyridone hydrochloride;

1-(4-chlorobenzyl)-3-(N-benzylamidino)-2-pyridone

hydrochloride;

1-(2-methylbenzyl)-3-(N-benzylamidino)-2-pyridone

hydrochloride;

1-(4-fluorobenzyl)-3-(N-benzylamidino)-2-pyridone

hydrochloride; 1-(4-nitrobenzyl)-3-(N-benzylamidino)-2-pyridone

hydrochloride; 1-(4-methoxybenzyl)-3-(N-benzylamidino)-2-pyridone hydrochloride;

1-(4-benzyloxybenzyl)-3-(N-benzylamidino)-2-pyridone

hydrochloride;

1-(2,6-dichlorobenzyl)-3-(N-benzylamidino)-2-pyridone hydrochloride;

1-(2-methylbenzyl)-3-(N-(2-methylbenzyl)amidino)-2-pyridone hydrochloride;

1-benzyl-3-(N-(4-fluorobenzyl)amidino)-2-pyridone

hydrochloride;

1-benzyl-3-(N-(2-methylbenzyl)amidino)-2-pyridone

hydrochloride;

1-(4-methoxybenzyl)-3-(N-(2-methylbenzyl)amidino)-2-pyridone hydrochloride;

1-benzyl-3-(N-(4-chlorobenzyl)amidino)-2-pyridone

hydrochloride;

1-benzyl-3-(N-(4-trifluoromethylbenzyl)amidino)-2-pyridone hydrochloride;

1-benzyl-3-(N-(4-methoxybenzyl)amidino)-2-pyridone

hydrochloride;

1-benzyl-3-(N-(4-methylbenzyl)amidino)-2-pyridone

hydrochloride;

1-(4-methylbenzyl)-3-(N-benzylamidino)-2-ρyridone

hydrochloride;

1-(4-dimethylaminobenzyl)-3-(N-benzylamidino)-2-pyridone dihydrochloride;

1-(4-methoxybenzyl)-3-(N-(2-methylbenzyl)amidino)-2-quinolone hydrochloride;

1-benzy1-3-(N-benzylamidino)-2-quinolone hydrochloride;

1-benzyl-3-(N-benzylamidino)-6-methyl-2-pyridone

hydrochloride;

1-benzyl-3-(N-(N-phenyl)amidino)-2-pyridone hydrochloride; 1-benzyl-3-(N-(N-methyl-N-phenyl)amidino)-2-pyridone hydrochloride; or

1-benzyl-3-(N-benzylamidino)-5-methyl-2-pyridone

hydrochloride.

5. A process for preparing a compound according to claim 1 which comprises: a) for compounds in which X is CH₂ and R³ is hydrogen, reaction of a compound of structure (II) with a compound of structure (III):

Ar²CH₂NHR² (II)

in which Ar¹, Ar², R¹, R², R⁴ and R⁵ are as described for structure (I); or b) for compounds in which X is CH₂ and R³ is hydrogen, reaction of a compound of structure (IV) with a compound of structure (II) :

in which

Ar¹ and R¹, R⁴ and R⁵ are as described for structure (I), and R⁶ is C_1-4alkyl.

6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, in association with a

pharmaceutically acceptable carrier.

7. A compound according to any one of claims 1 to 4 for use in therapy, in particular as gastric acid secretion inhibitors.

8. A compound of structure (III) as described in claim 5.

9. A compound of structure (IV) as described in claim 5.