EP0625144A1 - Pyridone derivatives, their preparation and use as medicines - Google Patents

Pyridone derivatives, their preparation and use as medicines

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Publication number
EP0625144A1
EP0625144A1 EP93902251A EP93902251A EP0625144A1 EP 0625144 A1 EP0625144 A1 EP 0625144A1 EP 93902251 A EP93902251 A EP 93902251A EP 93902251 A EP93902251 A EP 93902251A EP 0625144 A1 EP0625144 A1 EP 0625144A1
Authority
EP
European Patent Office
Prior art keywords
pyridone
hydrochloride
benzylamidino
benzyl
amidino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP93902251A
Other languages
German (de)
French (fr)
Inventor
Robert John Ife
Colin Andrew Leach
Dashyant Dhanak
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Intercredit BV
Original Assignee
SmithKline Beecham Intercredit BV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SmithKline Beecham Intercredit BV filed Critical SmithKline Beecham Intercredit BV
Publication of EP0625144A1 publication Critical patent/EP0625144A1/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3

Definitions

  • Ar 1 is an optionally substituted phenyl ring
  • Ar 2 i.s an optionally substituted phenyl ring
  • R 1 is hydrogen or C 1-4 alkyl
  • R 2 i.s hydrogen or C 1-4 alkyl
  • R 3 i.s hydrogen or C 1-4 alkyl
  • X is CH 2 or NR 6 in which R 6 is hydrogen or C 1-4 alkyl
  • Ar is an optionally substituted phenyl ring.
  • Suitable substituents for the phenyl ring Ar include, for example, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, halogen, cyano, amino, C 1-4 alkylamino, diC 1-4 alkylanri.no, hydroxy, carbamoyl, carboxy, C 1-6 alkanoyl trifluoromethyl, and
  • Ar is unsubstituted phenyl, or phenyl substituted by a single substituent selected from C 1-6 alkyl, C 1-6 alkoxy or halogen.
  • X is CH 2 or NR 6 ; preferably X is CH 2 or NR 6 in which R 6 is C 1-4 alkyl, in particular methyl.
  • reaction between compounds of structure (II) and compounds of structure (III) can be carried out in a
  • 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 ) .
  • 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
  • the compounds of the present invention are usually administered in a standard
  • 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.
  • a binding and/or lubricating agent such as polymeric glycols, gelatins or cocoa butter or other low melting vegetable or synthetic waxes or fats.
  • the present invention also provides a method of
  • 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.
  • the compounds will be administered for a period of continuous therapy, for example for a week or more.
  • Helicobacter pylori organisms for example antibiotics such as amoxicillin.
  • the compounds of examples 1 to 23 had IC 50 values of less than 20 ⁇ M.

Abstract

L'invention se rapporte à des dérivés de 2-pyridone de formule générale (I) dans laquelle Ar1 représente un cycle de phényle éventuellement substitué; Ar2 représente un cycle de phényle éventuellement substitué; R1 représente hydrogène ou alkyleC1-4; R2 représente hydrogène ou alkyleC1-4; R3 représente hydrogène ou alkyleC1-4; R4 et R5 sont identiques ou différents et représentent chacun hydrogène, alkyleC1-4 ou alkyleC1-4 Arl, ou R4 et R5 forment conjointement un groupe (CH=CH)2; et X représente CH2 ou NR6 dans lequel R6 représente hydrogène au alkyleC1-4. L'invention concerne également un sel desdits dérivés ainsi que l'utilisation de ceux-ci comme inhibiteurs de sécrétion d'acide gastrique.The invention relates to 2-pyridone derivatives of general formula (I) in which Ar1 represents an optionally substituted phenyl ring; Ar2 represents an optionally substituted phenyl ring; R1 represents hydrogen or C1-4alkyl; R2 represents hydrogen or C1-4alkyl; R3 represents hydrogen or C1-4alkyl; R4 and R5 are the same or different and each represents hydrogen, C1-4alkyl or C1-4alkyl Arl, or R4 and R5 jointly form a group (CH = CH) 2; and X represents CH2 or NR6 in which R6 represents hydrogen to C1-4alkyl. The invention also relates to a salt of said derivatives as well as the use thereof as inhibitors of gastric acid secretion.

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 C1-4alkyl;
R 2 i.s hydrogen or C1-4alkyl;
R 3 i.s hydrogen or C1-4alkyl;
R 4 and R5 are the same or different and are each hydrogen, C1-4alkyl or C1-4alkylAr 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 C1-4alkyl
and salts thereof.
Suitably, Ar is an optionally substituted phenyl ring. Suitable substituents for the phenyl ring Ar include, for example, C1-6alkyl, C1-6alkoxy, C1-6alkylthio, halogen, cyano, amino, C1-4alkylamino, diC1-4alkylanri.no, hydroxy, carbamoyl, carboxy, C1-6alkanoyl trifluoromethyl, and
C1-4alkylenedioxy 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 C1-6alkyl, C1-6alkoxy, C1_
6alkylthio, halogen, cyano, amino, hydroxy, carbamoyl, carboxy, C1-6alkanoyl or trifluoromethyl. More preferably
Ar is unsubstituted phenyl, or phenyl substituted by a single substituent selected from C1-6alkyl, C1-6alkoxy or halogen.
Suitably, Ar 2 is an optionally substituted phenyl ring.
Suitable substituents for the phenyl ring Ar 2 include, for example, C1-6alkyl, C1-6alkoxy, C1-6alkylthio, halogen, cyano, amino, hydroxy, carbamoyl, carboxy, C1-6alkanoyl trifluoromethyl, and C1-4alkylenedioxy 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 C1-6alkyl, C1-6alkoxy, C1-6alkylthio, halogen, cyano, amino, hydroxy, carbamoyl, carboxy, C1-6alkanoyl or trifluoromethyl. More preferably Ar 2 is unsubstituted phenyl, or phenyl
substituted by a single substituent selected from C1-6alkyl, C1-6alkoxy or halogen. Suitably, R 1 is hydrogen or C1-4alkyl; preferably R1 is hydrogen. Suitably, R 2 is hydrogen or C1-4alkyl; preferably R2 is hydrogen.
Suitably, R3 is hydrogen or C1-4alkyl; preferably R3 is hydrogen. Suitably, R4 and R5 are the same or different and are each, hydrogen, C1-4alkyl or C1-4alkylAr1, 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 C1-4alkyl, in particular methyl.
Suitably R6 is hydrogen or C1-4alkyl; preferably R6 is C1-4alkyl. 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 C1-4alkyl,
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 C1-4alkyl;
R2 is hydrogen or C1-4alkyl;
R 3 is hydrogen or C1-4alkyl;
R 4 and R5 are the same or different and are each hydrogen, C1-4alkyl or C1-4alkylAr1, or R 4 and R5 together form a group (CH=CH)2; and
X is CH2 or NR6 in which R6 is hydrogen or C1-4alkyl
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 C1-4alkyl.
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.
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Families Citing this family (18)

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Publication number Priority date Publication date Assignee Title
UA80393C2 (en) 2000-12-07 2007-09-25 Алтана Фарма Аг Pharmaceutical preparation comprising an pde inhibitor dispersed on a matrix
MY140561A (en) 2002-02-20 2009-12-31 Nycomed Gmbh Dosage form containing pde 4 inhibitor as active ingredient
TWI417095B (en) 2006-03-15 2013-12-01 Janssen Pharmaceuticals Inc 1,4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of mglur2-receptors
TW200900065A (en) 2007-03-07 2009-01-01 Janssen Pharmaceutica Nv 3-cyano-4-(4-pyridinyloxy-phenyl)-pyridin-2-one derivatives
TW200845978A (en) 2007-03-07 2008-12-01 Janssen Pharmaceutica Nv 3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives
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CA2735764C (en) 2008-09-02 2016-06-14 Ortho-Mcneil-Janssen Pharmaceuticals, Inc. 3-azabicyclo[3.1.0]hexyl derivatives as modulators of metabotropic glutamate receptors
WO2010060589A1 (en) 2008-11-28 2010-06-03 Ortho-Mcneil-Janssen Pharmaceuticals, Inc. Indole and benzoxazine derivatives as modulators of metabotropic glutamate receptors
SG176018A1 (en) 2009-05-12 2011-12-29 Janssen Pharmaceuticals Inc 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors
MY153913A (en) 2009-05-12 2015-04-15 Janssen Pharmaceuticals Inc 7-aryl-1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors
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ES2536433T3 (en) 2010-11-08 2015-05-25 Janssen Pharmaceuticals, Inc. 1,2,4-Triazolo [4,3-a] pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
PL2649069T3 (en) 2010-11-08 2016-01-29 Janssen Pharmaceuticals Inc 1,2,4-TRIAZOLO[4,3-a]PYRIDINE DERIVATIVES AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS
JO3368B1 (en) 2013-06-04 2019-03-13 Janssen Pharmaceutica Nv 6,7-DIHYDROPYRAZOLO[1,5-a]PYRAZIN-4(5H)-ONE COMPOUNDS AND THEIR USE AS NEGATIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS
JO3367B1 (en) 2013-09-06 2019-03-13 Janssen Pharmaceutica Nv 1,2,4-TRIAZOLO[4,3-a]PYRIDINE COMPOUNDS AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS
DK3096790T3 (en) 2014-01-21 2019-10-07 Janssen Pharmaceutica Nv COMBINATIONS INCLUDING POSITIVE ALLOSTERIC MODULATORS OR ORTHOSTERIC AGONISTS OF METABOTROP GLUTAMATERG SUBTYPE 2 RECEPTOR AND APPLICATION OF THESE
UA127921C2 (en) 2014-01-21 2024-02-14 Янссен Фармацевтика Нв Combinations containing positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3299081A (en) * 1963-09-13 1967-01-17 Merck & Co Inc Chemical processes for preparing nu-substituted amidines
US4028084A (en) * 1974-10-11 1977-06-07 Rohm And Haas Company Derivatives of 3-carboxy pyrid-2-ones
US4284768A (en) * 1980-07-02 1981-08-18 American Home Products Corporation 1,2-Dihydro-4-amino-2-oxo-3-quinoline-carboxylic acid derivatives
GB8804445D0 (en) * 1988-02-25 1988-03-23 Smithkline Beckman Intercredit Compounds
IL100917A0 (en) * 1991-02-16 1992-11-15 Fisons Plc Pyridinone and pyrimidinone derivatives,their preparation and pharmaceutical compositions containing them

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9315056A1 *

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