EP0539418A1 - Imidazopyridine paf antagonists - Google Patents

Imidazopyridine paf antagonists

Info

Publication number
EP0539418A1
EP0539418A1 EP91912594A EP91912594A EP0539418A1 EP 0539418 A1 EP0539418 A1 EP 0539418A1 EP 91912594 A EP91912594 A EP 91912594A EP 91912594 A EP91912594 A EP 91912594A EP 0539418 A1 EP0539418 A1 EP 0539418A1
Authority
EP
European Patent Office
Prior art keywords
formula
compound
pyrid
methylimidazo
phenyl
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.)
Ceased
Application number
EP91912594A
Other languages
German (de)
French (fr)
Inventor
Kelvin Cooper
Michael Jonathan Fray
John Steele
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.)
Pfizer Ltd
Pfizer Inc
Original Assignee
Pfizer Ltd
Pfizer Inc
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 Pfizer Ltd, Pfizer Inc filed Critical Pfizer Ltd
Publication of EP0539418A1 publication Critical patent/EP0539418A1/en
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • This invention relates to imidazopyridine, specifically to certain 4-substituted-1-(2-methaylinidazo[4,5-c]pyrid-1-yl)-benzene derivatives.
  • the compounds are potent and selective antagonists of platelet activating factor having clinical utility in the treatmant of allergic and inflammatory conditions in humans and animals.
  • Platelet activating factor (PAF, 1-0-alkyl-2-acetyl-snglyceryl-3-phosphorylcholine) is an ether phopholipid whose structure was first elucidated in 1979. It is produced by, released fr ⁇ n and interacts with many pro-inflamaatory cells, platelets and the kidney.
  • PAF In addition to potent platelet aggregating activity, PAF exhibits a wide spectrum of biological activities elicited either directly or via ths release of othsr powerful mediators such as thromboxane A 2 or the leukotrienes, which make PAF inhibitors of potential value in the treatment of a variety of conditions including allergic, inflammatory and hypersecretory conditions such as asthma, arthritis, rhinitis, bronchitis and urticaria, the treatment of circulatory shock, gastric ulceration, psoriasis and cardiovascular conditions, including angina, thrombosis and stroke.
  • allergic, inflammatory and hypersecretory conditions such as asthma, arthritis, rhinitis, bronchitis and urticaria
  • the treatment of circulatory shock gastric ulceration, psoriasis and cardiovascular conditions, including angina, thrombosis and stroke.
  • PAF antagonists having the formula:
  • R 3 are each H or methyl
  • R 4 is hydrogen, halo, C 1 -C 4 alkyl or
  • n is an integer of from 1 to 3.
  • halo means fluoro, chloro, bromo or iodo.
  • Alkyl and alkoxy groups of 3 or more carbon atoms may be straight or branched-chain.
  • R 1 , R 2 and R 3 are
  • R 4 is preferably chlorine and n is 1 or 2.
  • the compounds of the formula (I) may contain at least one asymmetric centre and exist as a pair of enantiomers.
  • Such isomers may be separable by physical methods, e.g. by fractional crystallisation or chromatography of the parent compounds or of a suitable salt or derivatives thereof.
  • the invention includes all the enantiomers whether separated or not.
  • the pharmaceutically acceptable acid addition salts of the compounds of the formula (I) which form such salts are those farmed from acids which form non-toxic acid addition salts, for example the hydrochloride, hydrobronide, sulphate or bisulphate, phosphate or acid phosphate, acetate, citrate, fumerate,
  • the compound of formula I may be obtained by cyclisation of a compound of the formula:
  • R 1 , R 2 , R 3 , R 4 and n are as previously defined.
  • This reaction is achieved by either reacting the anhydride with the amine (III) in water or an aqueous organic solvent in the presence of a base (e.g. sodi ⁇ xn carbonate), or by reacting the benzoic acid with the amine using a diimide coupling reagent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.
  • a base e.g. sodi ⁇ xn carbonate
  • a diimide coupling reagent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.
  • the activity of the compounds of the invention is shown by their ability to inhibit the platelet aggregating activity of PAF in vitro. Testing is performed as follows:
  • Blood samples are taken from either rabbit or man into 0.1 vol disodium ethylenediamine tetraacetic acid buffer and the sa ⁇ ples centrifuged for 15 minutes to obtain platelet rich plasma.
  • the plasma is further centrifuged to give a platelet pellet which is washed with a buffer solution (4 mM KH 2 PO 4 , 6mM Na 2 HPO 4 , 100 mM NaCl, 0.1% glucose and 0.1% bovine serum albumin, pH 7.25) and finally resuspended in buffer solution to a concentration of 2 ⁇
  • the activity of the compounds of formula (I) is also demonstrated in vivo by their ability to protect mice from the lethal effect of an injection of PAF.
  • a mixture of PAF (50 ⁇ g/kg) and DL-propranolol (5 mg/kg) in 0.9% w/v sodium chloride is injected (0.2 ml) via a tail vein into mice.
  • the compounds under test are either injected into the tail vein immediately prior to the PAF/propranolol injection or administered orally by gavage two hours earlier.
  • the compounds are tested at several doses in groups of 5 mice and the dose which reduces mortality to 50% is recorded as the PD 50 value.
  • the compounds of the formula (I) will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of
  • ком ⁇ онентs for example, they may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavouring or colouring agents. They may be injected parenterally, far example, intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueouu solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
  • oral dosages of the compounds will generally be in the range of from 2-1000 mg daily for an average adult patient (70 kg).
  • individual tablets or capsules will contain from 1 to 500 mg of active compound, in a suitable
  • Dosages for intravenous administration would typically be within the range 1 to 10 mg per single dose as required.
  • inhalation via a nebuliser or aerosol may be the preferred route of drug
  • Dose levels by this route would be within the range 0.1 to 50 mg per single dose as required.
  • the physician will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age. weight and response of the particular patient.
  • the above dosages are exemplary of the average case but there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • the invention provides a
  • composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.
  • the invention also includes a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for use in medicine, in particular in the treatment of allergic, inflammatory and hypersecretory conditions in a human being.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pulmonology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Immunology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composés de formule (I), dans laquelle R1 et R2 représentent chacun H ou méthyle, R4 représente de l'hydrogène, un halo, un alkyle C1-C4, ou un alcoxy C1-C4 et n représente un nombre entier compris entre 1 et 3, lesdits composés étant des antagonistes du facteur d'activation plaquettaire utiles pour le traitement de conditions allergiques et inflammatoires.Compounds of formula (I), in which R1 and R2 each represent H or methyl, R4 represents hydrogen, a halo, a C1-C4 alkyl, or a C1-C4 alkoxy and n represents an integer between 1 and 3, said compounds being antagonists of the platelet activating factor useful for the treatment of allergic and inflammatory conditions.

Description

Imidazopyridine PAF Antagonists
This invention relates to imidazopyridine, specifically to certain 4-substituted-1-(2-methaylinidazo[4,5-c]pyrid-1-yl)-benzene derivatives. The compounds are potent and selective antagonists of platelet activating factor having clinical utility in the treatmant of allergic and inflammatory conditions in humans and animals.
Platelet activating factor (PAF, 1-0-alkyl-2-acetyl-snglyceryl-3-phosphorylcholine) is an ether phopholipid whose structure was first elucidated in 1979. It is produced by, released frαn and interacts with many pro-inflamaatory cells, platelets and the kidney. In addition to potent platelet aggregating activity, PAF exhibits a wide spectrum of biological activities elicited either directly or via ths release of othsr powerful mediators such as thromboxane A2 or the leukotrienes, which make PAF inhibitors of potential value in the treatment of a variety of conditions including allergic, inflammatory and hypersecretory conditions such as asthma, arthritis, rhinitis, bronchitis and urticaria, the treatment of circulatory shock, gastric ulceration, psoriasis and cardiovascular conditions, including angina, thrombosis and stroke.
In our European patent application no 0258033 we disclose a series of 2-substituted 1,4-dihydropyridine derivatives as PAF antagonists. In our later European patent application no 0310386 we disclose a further series of dihydropyridirie PAF antagonistswherein the 2-position substituent includes in particular a
2-methyl-imidazo[4,5-c]pyrid-1-yl-phenyl group. The present invention provides further PAF antagonists having the formula:
and their pharmaceutically acceptable salts, wherein R1, R2 and
R3 are each H or methyl, R4 is hydrogen, halo, C1-C4 alkyl or
C1-C4 alkoxy and n is an integer of from 1 to 3.
In the above definition, the term halo means fluoro, chloro, bromo or iodo. Alkyl and alkoxy groups of 3 or more carbon atoms may be straight or branched-chain.
In preferred embodiments of the invention R1, R2 and R3 are
H, R4 is preferably chlorine and n is 1 or 2.
When R4 is a branched alkyl or alkoxy group having 4 carbon atoms, the compounds of the formula (I) may contain at least one asymmetric centre and exist as a pair of enantiomers. Such isomers may be separable by physical methods, e.g. by fractional crystallisation or chromatography of the parent compounds or of a suitable salt or derivatives thereof. The invention includes all the enantiomers whether separated or not.
The pharmaceutically acceptable acid addition salts of the compounds of the formula (I) which form such salts are those farmed from acids which form non-toxic acid addition salts, for example the hydrochloride, hydrobronide, sulphate or bisulphate, phosphate or acid phosphate, acetate, citrate, fumerate,
gluconate, lactate, maleate, succinate and tartrate salts.
The compound of formula I may be obtained by cyclisation of a compound of the formula:
wherein R1, R2, R3, R4 and n are as previously defined.
In a typical procedure the compound of formula II is simply heated in a high-boiling organic solvent (for example toluene or xylene) at a temperature above 100°C for a period of several hours. The solvent is evaporated and the product recovered and purified by conventional procedures. The intermediates of formula II are prepared by reaction of an amine of formula-:
with a benzoic acid or anhydride derivative of formula-:
This reaction is achieved by either reacting the anhydride with the amine (III) in water or an aqueous organic solvent in the presence of a base (e.g. sodiτxn carbonate), or by reacting the benzoic acid with the amine using a diimide coupling reagent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.
Appropriate reagents and conditions for these steps may be readily established by reference to standard text books and to the examples provided hereafter.
The activity of the compounds of the invention is shown by their ability to inhibit the platelet aggregating activity of PAF in vitro. Testing is performed as follows:
Blood samples are taken from either rabbit or man into 0.1 vol disodium ethylenediamine tetraacetic acid buffer and the saπples centrifuged for 15 minutes to obtain platelet rich plasma. The plasma is further centrifuged to give a platelet pellet which is washed with a buffer solution (4 mM KH2PO4, 6mM Na2HPO4, 100 mM NaCl, 0.1% glucose and 0.1% bovine serum albumin, pH 7.25) and finally resuspended in buffer solution to a concentration of 2 ×
108 platelets/ml. A sample (0.5 ml) is pre-incubated with stirring for two minutes at 37ºC in a Paton aggregometer, either with vehicle alone, or with vehicle containing the particular compound under test. PAF is added at a sufficient concentration to give a maximum aggregating response in the absence of test coπpound (10-8 to 10-9 molar), and the platelet aggregation is measured by following the increase in light transmission of the solution. The experiment is repeated in the presence of test compound at a range of concentrations and the concentration of compound required to reduce the response to 50% of its maximm value in recorded as the IC50 value.
The activity of the compounds of formula (I) is also demonstrated in vivo by their ability to protect mice from the lethal effect of an injection of PAF. A mixture of PAF (50μg/kg) and DL-propranolol (5 mg/kg) in 0.9% w/v sodium chloride is injected (0.2 ml) via a tail vein into mice. The compounds under test are either injected into the tail vein immediately prior to the PAF/propranolol injection or administered orally by gavage two hours earlier. The compounds are tested at several doses in groups of 5 mice and the dose which reduces mortality to 50% is recorded as the PD50 value. For therapeutic use the compounds of the formula (I) will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of
administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavouring or colouring agents. They may be injected parenterally, far example, intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueouu solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
For administration to man in the curative or prophylactic treatment of allergic bronchial conditions and arthritis, oral dosages of the compounds will generally be in the range of from 2-1000 mg daily for an average adult patient (70 kg). Thus for a typical adult patient, individual tablets or capsules will contain from 1 to 500 mg of active compound, in a suitable
pharmaceutically acceptable vehicle or carrier. Dosages for intravenous administration would typically be within the range 1 to 10 mg per single dose as required. For the treatment of allergic and bronchial, hyper-reactive conditions, inhalation via a nebuliser or aerosol may be the preferred route of drug
administration. Dose levels by this route would be within the range 0.1 to 50 mg per single dose as required. In practice the physician will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age. weight and response of the particular patient. The above dosages are exemplary of the average case but there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
Thus in a further aspect the invention provides a
pharmaceutical composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.
The invention also includes a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for use in medicine, in particular in the treatment of allergic, inflammatory and hypersecretory conditions in a human being.
The preparation of the intermediates of formula (II) and the compounds of formula (I) will now be more particularly illustrated by reference to the following experimental Examples. The purity of compounds was routinely monitored by thin layer chromatography using Merck Kieselgel 60 F254 plates. 1H-Nuclear magnetic reasonance spectra were recorded using either a Nicolet QE-300 or a Bruker AC-300 spectrometer and were in all cases consistent with the proposed structures. Chemical shifts are given in parts-perntillion downfield from tetramethylsilane using conventional abbreviations for designation of major peaks: s, singlet; d, doublet; t, triplet; m, multiplet and br, broad. EXAMPLE 1
7-Chloro-3,4-dihydro-2-[4'-(2-methylimidazo[4,5-c]pyrid-1-yl)- phenyl]-5H-1,4-benzodiazepin-5-one
a) 4-Chloroisatoic anhydride (0.32 g, 1.6 mmol) was added to a solution of 2-amino-4'-(2-methylimidazo[4,5-c]pryrid-1-yl)-acetophenone (0.57 g, 1.45 mmol) in water (6 ml). After stirring to uniform consistency, a solution of sodium carbonate (0.19 g, 1.8 mmol) was added. After 1 hour, dichloromethane (12 ml) was added and two phase stirring was resulted for 66 hours. The mixture was partitioned between saturated aqueous sodium hydrogen carbonate and dichloronethane. The organic phase was separated, dried (MgSO4) and evaporated to an amorphous solid. Flash chromatography on silica, eluting with 15 then 25% methanol in ethyl acetate afforded 2-amino-5-chloro-N-{2-[4-(2-methylimidazo- [4,5-c]pyrid-1-yl)phenyl]-2-oxoethyl}benzamide as a solid (0.14 g, 23%), m.p. H6-118°C. 1 H NMR (CD3SOCD3): 2.52(3H,s), 4.79(2H,d,J 5.4Hz), 6.58hr exch (2H,s), 6.76(1H,d,J 8.9Hz), 7.21(1H,dd,J 8.9,2.2Hz), 7.28(1H,d,J 5.4Hz), 7.67(1H,d,J 2.2Hz), 7.82 and 8.28 (each 2H,d,J 8.4Hz), 8.35(1H,d,J 5.5Hz), 8.85 hr exch (1H,t,J 5.4Hz) and 8.94(1H,s).
b) A suspension of the benzamide from part (a) (0.11 g, 0.26 mmol) in xylene (5 ml, containing 2-3 drops ethanol to aid solubility) was heated to 140ºC for 5 hours. The solvent was evaporated and the residue purified by flash chromatography on silica, eluting with 10 then 20% methanol in ethyl acetate to afford the title product as a pale-yellow amorphous solid (0.041 g, 40%), m.p. 225-227°C. Found: C,63.52; H,4.14; N,16.61.
C22H16ClN5O, 0.75 H2O requires C,63.62; H,4.25; N,16.86%. EXAMPLE 2
7,8-Dichloro-3,4-dihydro-2-[4'-(2-methylimidazo[4,5-c]pyrid-c-yl)-phenyl]-5H-1,4-benzodiazepin-5-one
a) The procedure of Exanple 1 part (a) was followed but starting with 4,5-dichloroisatoic anhydride to yield 2-amino-4,5-dichloroN-{2-[4-(2-methylimidazo[4,5-c]pyrid-a-yl)phenyl]-2-oxoethyl}-benzamide.
1H NMR (CDCl3): 2.63(3H,s), 5.00(2H,d,J 4.2Hz) , 5.69br exch. (2H,s), 6.83(1H,s), 7.18(2H,m), 7.62(3H,m), 8.33(2H,d,J 8.4Hz), 8.42(1H,d,J 5.5Hz), 9.11(1H,s).
b) The above product was cyclised following the procedure of Exanple 1(b) to give the title product in 58% yield, m.p.
174-177°C. Found: C,58.08; H,3.41; N,14.94. C22H15Cl2N5O .H2O requires C,58.16; H,3.77; N,15.40%.
EXAMPLE 3
7,9-Dichloro-3,4-dihydro-2-[4'-(2-methylimidazo[4,5-c]pyrid-c-yl)-phenyl]-5H-1,4-benzodiazepin-5-one
a) A solution of 2-amino-4'-(2-methylimidazo[4,5-c]pyrid-1-yl)-acetophencaie hydrochloride (0.7 g, 1.8 mmol), 3,5-dichloro-2-amdnobenzoic acid (0.48 g, 2.3 mmol), N-hydroxybenzotriazole (0.34 g, 2.4 nmol), HHaethylmorphnline (1.61 ml, 16 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarhodiimide hydrochloride (0.89 g, 4.7 πmole) in dichloromethane (25 ml) was stirred at 25ºC for 3 hours. All volatiles were evaporated and the residue was partitioned between ethyl acetate and water buffered to pH 5. The organic layer was separated, dried (MgSO4) and evaporated. Flash chromatography of the residue on silica, eluting with 10% methanol in ethyl acetate afforded 2-amino-3,5-dichloro-N-{2-[4 -(2-methylimidazo[4,5-c]pyrid-1-yl)phenyl]-2-oxoethyl}benzamide as a pale-yellow gum (0.21 g, 26%). 1H NMR (CDCl3): 2.62(3H,s), 4.98(2H,d,J 5.7Hz), 6.10 br exch. (3H,m), 7.13(1H,d,J 5.7Hz), 7.39(1H,d,J 2Hz), 7.48(1H,d,J 2Hz), 7.57 and 8.30 (each 2H,d,J 8.4Hz), 8.43(1H,d,J 5.7Hz) and 9.07(1H,s).
b) p-Toluenesulphonic acid hydrate (0.1 g, 0.5 nmol) was added to a refluxing solution of the ketoamine from part (a) (0.21 g, 0.47 nmol) in dichloromethane (14 ml). After 6 hours, the mixture was partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate. The organic layer was dried (MgSO4) and evaporated to a yellow foam. Flash chromatography on silica, eluting with 5% methanol in ethyl acetate afforded the title product as an off white solid (0.065 g, 33%), m.p. 165-7°C.
Found: C,58.92; H,3.85; N,14.57. C22H15Cl2N5O, 0.5 H2O, 0.5 EtOAc requires C,58.91; H,4.12; N,14.31%.
PREPARATION
2-Amino-4'-(2-methylimidazo[4.5-c]pyrid-1-yl) acetophenone hydrochloride
(a) 4-(4-Acetylphenyl)amino-3-nitropyridive hydrochloride
A solution of 4-chlaro-3-nitropyridine hydrochloride (9.75 g, 50 nmol) in ethanol (40 ml) was added to a slurry of p-aminoacetophenone (6.76 g, 50 nmol) in ethanol (25 ml), and the mixture was stirred at room temperature overnight. The mixture was chilled in ice, and the yellow solid filtered off and dried (10.1 g, 69%). m.p. 197-200°C.
(b) 4-(4-Acetylphenyl)amino-3-aminopyridine
4-(4-acetylphenyl) nitropyridine hydrochloride (2.0 g,
78.8 nmol) was partitioned between aqueous sodium hydroxide and dichloromethane ( 3 × 20 ml). The combined organic phases were washed with water (20 ml) and concentrated under reduced pressure to give a solid. Ethanol (20 ml) was added, and the solution was hydrogenated over 5% palladitm on carbon (0.2 g) at 50 p.s.i. (3.4 bar) for 3.5 hours. The catalyst was filtered off, and the solvent removed under reduced pressure to give a brown solid, (1.8 g, ca 100%) which was used directly for the next stage without purification.
(c) 4-2-(Methyl_imidazo[4,5-clpyrid-1-yl)acetophenone
A solution of 4-(4-acetylphenyl)amino-3-aminopyridine (68.0 g, 0.3 nmol) in acetic acid (204 ml) and acetic anhydride (204 ml) was heated at 95ºC for 1.5 hours then cooled and concentrated under reduced pressure. The residue was dissolved in water (500 ml) and rendered basic by the addition of saturated aqueous aπmonia. The product was filtered off, washed with water (2 × 100 ml) and dried under vacuum to give the title compound, (61.0 g, 81%) as a brown solid, m.p. 155-156°C (from water).
(d) Ethyl 4'-(2-methylimidazo[4,5-c]pyrid-1-yl)benzoylacetate A solution of 4-(2-methylimidazo[4,5-c]pyrid--1-yl-acetophenone (17.5 g, 69.7 nmol) in dry tetxahydrofuran (175 ml) was added to a slurry of sodium hydride (3.68 g, 153 nmol) in a mixture of dry tetrahydrofuran (35 ml) and diethyl carbonate (24.7 g, 209 nmol) at reflux with stirring over 45 minutes. After a further 1 hour, the mixture was cooled, hexane (200 ml) was added, and the resulting precipitate was filtered off and washed with hexane (2 × 100 ml). The solid was suspended in ethyl acetate (200 ml) and acetic acid (10.2 g) was added. After stirring far 15 minutes, water (200 ml) was added, and the organic layer was separated. The aqueous phase was extracted with ethyl acetate (100 ml) and the combined organic solutions were washed with water (200 ml), dried (MgSO4) and concentrated to give the title product as a gun (17.3 g, 77%). Further purification by flash
chromatography (eluting with ethyl acetate/methanol (7:1) gave the title compound as a white solid. m.p. 111-112ºC.
(e) Ethyl 4'-(2-Methylimidazopyrid-1-yl)-2-oximinobenzoylacetate
A solution of sodiim nitrite (3.3 g, 47 nmol) in water (40 ml) was added in drops to a solution of ethyl 4'-(2-methylimidazo[4,5-c]pyrid-1-yl)benzoylacetate (12.6 g, 39 nmol) in glacial acetic acid (45 ml) at 5°C. After 1.5 hours the mixture was partitioned between dichloromethane and brine. The organic layer was washed again with brine and then with saturated aqueous sodiim bicarbonate, dried (MgSO.) and evaporated to an oil which rapidly crystallised on addition of ether (9.61 g, 70%), (2:1 mixture of syn/anti isomers). M.p. 168-170°C
(f) Ethyl 2-acetamido-4'-(2-methylimidazo[4,5-c]pyrid-c-yl]-benzoylacetate
A solution of the product from e) above (6 g, 17 nmol) in acetic acid (33 ml) and acetic anhydride (9 ml) was hydrogenated over 5% palladium an carbon (1 g) at 50 p.s.i. (3.45 bar) at 30ºC for 5 hours. The mixture was filtered through a filter pad, washing the cake with methanol and the filtrate was evaporated. The residue was chromatographed eluting with methanol and then 10% methanol in ethyl acetate to afford a colourless foam (6.1 g, 94%). M.p. 71-73°C.
(g) 2-Amino-4'-(2-methylimidazo[4,5-c]pyrid-1-yl)acetophenone dihydrochloride
A solution of the product from f) above (1.2 g, 3.2 nmol) in 2M hydrochloric acid (30 ml) was heated at reflux for 3 hours. The solution was evaporated to dryness to yield the amine hydrochloride salt as a colourless foam (1.35 g), which was stored under vacuum.

Claims

A conpound of the formal a:-
or a pharmaceuticalllyy acceptable salt thereof, wherein R1, R2 and
R3 are each H or methyl, R4 is hydrogen, halo, C1-C4 alkyl, or
C1-C4 alkoxy and n is an integer of from 1 to 3.
2. A ccmpound as claimed in claim 1 wherein R1, R2 and R3 are H,
R4 is chlorine and n is 1 or 2.
3. A conpound as claimed in claim 2 wherein said compound is: 7-chloro-3,4-dihydro-2-[4'-(2-methylimidazo[4,5-c]pyrid-1-yl)-phenyl]-5H-1,4-benzodiazepin-5-one,
7,8-dichloro-3,4-dihydro-2-[4'-(2-methylimidazo[4,5-c]pyrid-1-yl)- phenyl]-5H-1,4 -benzodiazepin-5-one or
7,9-dichloro-3,4-dihydro-2-[4,-(2-methylimidazo[4 ,5-c]pyrid-1-yl )-phenyl]-5H-1,4-benzodiazepin-5-one.
4. A process for preparing a compound of the formula (I) as claimed in claim 1 which comprises cyclising a compound of the formula:
5. A pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3, together with a
pharmaceutically acceptable diluent or carrier.
6. A compound of the formula (I) or a pharmaceutically
acceptable salt thereof as claimed in any one of claims 1 to 3 for use in medicine, in particular for use in the treatment of allergic, inflammatory and hypersecretory conditions in humans.
PROCESS CLAIMS
7. A process for preparing a compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein R1, R2 and
R3 are each H or methyl, R4 is hydrogen, halo, C1-C4 alkyl, or
C1-C4 alkoxy and n is an integer of from 1 to 3, which comprises cyclising a compound of the formula:
8. A process as claimed in claim 7 wherein R1, R2 and R3 are H, R4 is chlorine and n is 1 or 2.
9. A process as claimed in claim 8 wherein said compound of formula (I) produced is: 7-chloro-3,4-dihydro-2-[4 '-(2-methylimidazo[4,5-c]pyrid-1-yl)-phenyl]-5H-1,4-benzodiazepin-5-one,
7,8-dichloro-3,4-dihydro-2-[4 ' -(2-methylimidazo[4,5-c]pyrid-1-yl)-phenyl]-5H-1,4-benzodiazepin-5-one or
7,9-dichloro-3,4-dihydro-2-[4'-(2-methylimidazo[4,5-c]pyrid-1-yl)phenyl]-5H-1,4-benzodiazepin-5-one.
EP91912594A 1990-07-13 1991-07-04 Imidazopyridine paf antagonists Ceased EP0539418A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9015524 1990-07-13
GB909015524A GB9015524D0 (en) 1990-07-13 1990-07-13 Therapeutic agents

Publications (1)

Publication Number Publication Date
EP0539418A1 true EP0539418A1 (en) 1993-05-05

Family

ID=10679106

Family Applications (1)

Application Number Title Priority Date Filing Date
EP91912594A Ceased EP0539418A1 (en) 1990-07-13 1991-07-04 Imidazopyridine paf antagonists

Country Status (8)

Country Link
EP (1) EP0539418A1 (en)
JP (1) JPH05507932A (en)
CA (1) CA2083056A1 (en)
FI (1) FI930108A (en)
GB (1) GB9015524D0 (en)
IE (1) IE912432A1 (en)
PT (1) PT98285A (en)
WO (1) WO1992000978A1 (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007034277A1 (en) * 2005-09-19 2007-03-29 Pfizer Products Inc. Aryl substituted imidazo [4,5-c] pyridine compounds as c3a receptor antagonists
WO2010012745A2 (en) * 2008-07-29 2010-02-04 Boehringer Ingelheim International Gmbh Benzimidazoles
TWI812739B (en) * 2018-06-21 2023-08-21 景凱生物科技股份有限公司 Nadph oxidase inhibitors, pharmaceutical composition comprising the same, and application thereof

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MY104933A (en) * 1987-09-30 1994-07-30 Pfizer Ltd Platelet activating factor antagonists
ES2052172T3 (en) * 1989-03-23 1994-07-01 Pfizer DIAZEPINE BASED ANTIALERGIC AGENTS.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9200978A1 *

Also Published As

Publication number Publication date
FI930108A0 (en) 1993-01-12
FI930108A (en) 1993-01-12
PT98285A (en) 1992-05-29
CA2083056A1 (en) 1992-01-14
GB9015524D0 (en) 1990-08-29
IE912432A1 (en) 1992-01-15
WO1992000978A1 (en) 1992-01-23
JPH05507932A (en) 1993-11-11

Similar Documents

Publication Publication Date Title
EP0419210B1 (en) Novel benzimidazole compounds and their use
US4668686A (en) Imidazoquinoline antithrombrogenic cardiotonic agents
JP2506541B2 (en) Imidazopyridine PAF / H ▲ Lower 1 ▼ Antagonist
EP0466711B1 (en) Dihydropyrimidine antiallergy agents
JPH1087631A (en) 2-aminobenzazepine derivative
EP0258033A2 (en) Dihydropyridine anti-allergic and anti-inflammatory agents
EP0299727B1 (en) Therapeutic agents
EP0266989B1 (en) Dihydropyridine anti-allergic and anti-inflammatory agents
EP0530207A1 (en) Imidazopyridine paf antagonists
EP0467895A1 (en) Dihydropyridine antiallergy agents
US4962200A (en) Nitrogen-containing compound
EP0539418A1 (en) Imidazopyridine paf antagonists
EP0329357B1 (en) Dihydropyridine anti-allergic and anti-inflammatory agents
US4801590A (en) Pyrido(1,8)naphthyridinones, and their use as pharmaceuticals
GB2233974A (en) Dihydropyridine antiinflammatory agent
US4963560A (en) 1,4-dihydropyridine derivatives
US4612317A (en) Tetrahydro-β-carboline dithioic acid derivatives and treatment of liver diseases
HU202506B (en) Process for producing benzoxazolone derivatives
EP0462986B1 (en) Imidazopyrimidine antiallergy agents
EP0613470B1 (en) Novel 4-cinnolinone derivatives, their preparation and application in therapy
US4628057A (en) Tetrahydro-β-carboline derivatives and treatment of liver diseases
US4904684A (en) 2-(4,5-dihydro-1H-imidazol-2-yl)-1,2,4,5-tetrahydropyrrolo[3,2,1-hi]indole derivatives useful as antidiabetic agents
US6005105A (en) Process for producing imidazole derivative
IE913102A1 (en) Therapeutic agents
EP0568540A1 (en) 2,4-DIOXO-PYRIDO 2,3-d]PYRIMIDINE-3-ACETIC ACIDS AND ESTERS AND SALTS THEREOF

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19921218

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE

17Q First examination report despatched

Effective date: 19930727

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN REFUSED

18R Application refused

Effective date: 19940121