EP0569414A1 - Benzamides - Google Patents

Benzamides

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Publication number
EP0569414A1
EP0569414A1 EP92903462A EP92903462A EP0569414A1 EP 0569414 A1 EP0569414 A1 EP 0569414A1 EP 92903462 A EP92903462 A EP 92903462A EP 92903462 A EP92903462 A EP 92903462A EP 0569414 A1 EP0569414 A1 EP 0569414A1
Authority
EP
European Patent Office
Prior art keywords
cyclopentyloxy
methoxybenzamide
general formula
compounds
compound
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.)
Pending
Application number
EP92903462A
Other languages
German (de)
French (fr)
Inventor
Michael John Rhône-Poulenc Rorer Limited ASHTON
David Charles Rhône-Poulenc Rorer Limited COOK
Garry Rhône-Poulenc Rorer Limited FENTON
Susan Jacqueline Hills
Ian Michael Mcfarlane
Malcolm Norman Palfreyman
Andrew James Ratcliffe
Nigel Rhône-Poulenc Rorer Limited VICKER
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.)
Rhone Poulenc Rorer Ltd
Original Assignee
Rhone Poulenc Rorer Ltd
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
Priority claimed from GB919101777A external-priority patent/GB9101777D0/en
Priority claimed from GB919117727A external-priority patent/GB9117727D0/en
Application filed by Rhone Poulenc Rorer Ltd filed Critical Rhone Poulenc Rorer Ltd
Publication of EP0569414A1 publication Critical patent/EP0569414A1/en
Pending legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
    • C07C65/24—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups polycyclic
    • C07C65/26—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups polycyclic containing rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/56—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/57—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/46—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
    • C07C317/38—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atom of at least one amino group being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfones
    • C07C317/40—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
    • C07C323/40—Y being a hydrogen or a carbon atom
    • C07C323/42—Y being a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/38—Amides of thiocarboxylic acids
    • C07C327/48—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
    • C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms

Definitions

  • BENZAMIDES This invention relates to therapeutically useful benzamide derivatives, to processes for their preparation, to pharmaceutical compositions containing them, and to methods for their use.
  • R represents a straight- or branched-chain alkyl group containing up to about 4 carbon atoms
  • R 2 represents a straight- or branched-chain alkyl group containing from about 2 to about 15, preferably 2 to 12, carbon atoms or a mono-, bi- or tricycloalkyl group containing up to
  • R represents an optionally substituted phenyl, naphthyl or heterocyclyl group, preferably a 5-, 6- or 7-membered heterocyclyl group containing one or more hetero atoms selected from oxygen, sulphur and nitrogen atoms, the optional substituents being one or more substituents selected from halogen atoms, alkyl groups which may carry one or more halogen atoms, and from aryl, arylalkyl, alk ⁇ xy, aryloxy, alkylthio, arylthio, alkoxycarbonyl, aryloxycarbonyl, alkanoyl, aroyl, alkylsulphonyl, arylsulphonyl, alkylsulphinyl, arylsulphinyl, hydroxy, hydroxyalkyl, formyl, alkanoyla ino, aroylamino, cyano and nitro groups, and from amino, carbamoyl and
  • Especially important compounds of the invention include those wherein at least one of the symbols has a value selected from the following:-
  • R represents a methyl group
  • R 2 represents a propyl, butyl, nonyl, dodecyl, cyclohexyl, 8,9,10-trinorbornyl or, more especially, cyclopentyl group
  • R 3 represents an optionally substituted pyrazinyl, pyrimidinyl, isoxazolyl, preferably pyridyl group, or an N-oxide thereof, or an optionally substituted phenyl group; the other symbols being as hereinbefore defined.
  • 6-positions are especially useful.
  • R J represents a substituted heterocyclyl group
  • compounds wherein said heterocyclyl group is substituted on one or both of the positions next to the point of attachment to the rest of the molecule are especially useful. Individual compounds of especial importance .
  • the compounds of general formula I and their pharmaceutically acceptable salts exhibit pharmacological activity and accordingly are of use for the preparation of pharmaceutical compositions and in the treatment of humans and other animals. More especially, they are cyclic AMP phosphodiesterase inhibitors, in particular type IV cyclic AMP phosphodiesterase inhibitors, and thus the present invention provides compounds of general formula I and their pharmaceutically acceptable salts, and compositions containing compounds of general formula I and their pharmaceutically acceptable salts, which are of use in a method for the treatment of a human or animal patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of cyclic AMP phosphodiesterase, for example, they are useful as bronchodilators and asthma-prophylactic agents and agents for the inhibition of eosinophil accumulation and of the function of eosinophils, e.g.
  • inflammatory airways disease especially reversible airway obstruction or asthma
  • other diseases and conditions characterised by, or having an aetiology involving, morbid eosinophil accumulation.
  • inflammatory diseases such as atopic dermatitis, urticaria, allergic rhinitis, psoriasis, rheumatic arthritis, ulcerative colitis, Crohn's disease, adult respiratory distress syndrome and diabetes insipidus
  • other proliferative skin diseases such keratosis and various types of dermatitis
  • conditions associated with cerebral metabolic inhibition such as cerebral senility, ulti-infarct dementia, senile dementia (Alzheimer's disease) , and memory impairment associated with Parkinson's disease
  • neuroprote ⁇ tant activity such as cardiac arrest, stroke, and intermittent
  • Compounds within the scope of the present invention exhibit positive pharmacological activities as demonstrated by the following tests which are believed to correlate to pharmacological activity in humans and other mammals.
  • Compounds of the invention at concentrations from about 10 -9M up to about 10-5M produced about 50% inhibition of porcine aorta cyclic AMP phosphodiest ⁇ erase.
  • Compounds of the invention at concentrations of about 10 -7M to about 10-4M produced about 50% relaxation of guinea-pig tracheal strips, which had been contracted by treatment with spasmogens such as hista ine and carbachol.
  • Compounds of the invention at concentrations from about 10 -8M up to about 10-5M produced about 50% inhibition of superoxide generation from eosinophils harvested from the peritoneal cavities of guinea-pigs.
  • Compounds of the invention at oral doses from about 1 to about 50 mg/kg administered 1 hour before challenge inhibited by about 50% ovalbumin- or PAF- induced hyperreactivity in guinea-pigs.
  • Bronchorelaxant activity was measured in in vivo tests in the anaesthetised guinea-pig according to the method of Dixon and Brodie [J. Physiol., £9_, 97-173, (1903)] in which the effects on histamine-induced - 13 - bronchospasm and mean arterial blood pressure were. determined.
  • Nebulised aerosols generated from aqueous solutions of compounds of the invention were each administered for one minute to the anaesthetised guinea-pigs.
  • dry powder formulations made up from compounds of the invention and lactose were blown into the airways of the anaesthetised guinea-pigs.
  • Compounds of the invention produced from about 30% up to about 90% decrease in bronchospasm when administered at effective doses of about 20-80 ⁇ g, without any significant effect on blood pressure.
  • Compounds of the invention as oral doses of about 1 to about 50mg/kg, administered one hour before challenge, inhibited by at least 50% ovalbumin-induced eosinophilia in guinea-pigs, which is measured 24 hours after challenge.
  • compounds of the invention Administered at doses of about 1 to about 50mg/kg orally or parenterally or at doses of about 20 to about 500 ⁇ g intratracheally, compounds of the invention inhibit PAF or ovalbumin-induced microvascular leakage (measured using fluorescein isothiocyanate dextran) by up to 100% in guinea-pigs.
  • compounds of general formula I wherein R ⁇ , ⁇ 3 R * and R are as hereinbefore defined and Z represents an oxygen atom
  • Z represents an oxygen atom
  • compounds of general formula II hereinafter depicted, wherein R 1 and R2 are as hereinbefore defined and X "" * 1" represents a halogen, e.g. bromine or, preferably, chlorine atom, with compounds of the general formula:-
  • R 3 i.s as hereinbefore defined, preferably in the presence of a base, for example an alkali metal hydroxide or carbonate, e.g. sodium hydroxide or carbonate, an alkali metal hydride, e.g. sodium hydride, or an amine, preferably a tertiary amine, e.g. triethylamine or pyridine, optionally in an inert solvent, for example dichloromethane, dimethylfor - amide, or an ether, e.g. diethyl ether or tetrahydro- furan, preferably at a temperature from 0°C to the reflux temperature or at the melting point of the reaction mixture.
  • a base for example an alkali metal hydroxide or carbonate, e.g. sodium hydroxide or carbonate, an alkali metal hydride, e.g. sodium hydride, or an amine, preferably a tertiary amine, e.g. trieth
  • compounds of general formula I are prepared by the reaction of compounds of general formula IV hereinafter depicted, wherein R 1, R3 and Z are as hereinbefore defined, with compounds of the general formula:-
  • X represents a halogen, preferably bromine, atom, preferably in the presence of a base, for example an alkali metal hydride, e.g. sodium hydride, an alkali metal hydroxide or carbonate, e.g. sodium hydroxide or carbonate, or an amine, preferably a tertiary amine, e.g. triethylamine cr pyridine, optionally in an inert solvent, for example dichloromethane, dimethylformamide, or an ether, e.g. diethyl ether or tetrahydrofuran, preferably at a temperature from 0°C to the reflux temperature.
  • a base for example an alkali metal hydride, e.g. sodium hydride, an alkali metal hydroxide or carbonate, e.g. sodium hydroxide or carbonate, or an amine, preferably a tertiary amine, e.g. triethylamine cr pyridine,
  • compounds of general formula I are prepared by interconversion of other compounds of general formula I.
  • compounds of general formula I wnerem R 1, R2 and R3 are as hereinbefore defined and Z represents a sulphur atom are prepared from compounds of general formula I wherein R 1, R2 and R3 are as hereinbefore defined and Z represents an oxygen atom, fcy reaction with phosphorus pentasulphide or 2,4-bis(4- methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4- disulphide, preferably in a solvent such as pyridine or toluene, and preferably at a temperature from 0°C to the reflux temperature.
  • a solvent such as pyridine or toluene
  • R 3 represents an oxygen atom and R contains an alkylsulphonyl, arylsulphonyl alkylsulphinyl or arylsulphinyl group are prepared by the oxidation of compounds of general formula I wherein R 1 and R2 are as hereinbefore defined, Z represents an oxygen atom and
  • R" contains an alkylthio or arylthio group, preferably by means of reaction with a peroxyacid, e.g. 3-chloro- perbenzoic acid, preferably in an inert solvent, e.g. dichloromethane, preferably at or near room temperature.
  • a peroxyacid e.g. 3-chloro- perbenzoic acid
  • an inert solvent e.g. dichloromethane
  • compounds of general formula I wherein R 1, R2 and Z are as hereinbefore defined, Z preferably being an oxygen atom, and R 3 contains a hydroxymethyl group are prepared by the reduction of compounds of general formula I wherein R 1 , R2 and Z are as hereinbefore defined and R 3 contains an aryloxycarbonyl or, preferably, alkoxycarbonyl group, preferably by means of reaction with an alkali metal borohydride, preferably in an inert solvent, e.g. tetrahydrofuran, preferably at or near room temperature.
  • R 3 preferably being an oxygen atom, and R contains a formyl group are prepared by the oxidation of compounds of general formula I wherein R 1, R2 and Z are as hereinbefore defined and R 3 contains a hydroxymethyl group, preferably by means of reaction with manganese dioxide, preferably in an inert solvent, e.g. dichloromethane, preferably at or above room temperature, more especially at the reflux temperature.
  • an inert solvent e.g. dichloromethane
  • R 3 preferably being an oxygen atom, and R contains an amino group are prepared by the reduction of compounds of general formula I wherein R 1, R2 and Z are as
  • R contains a nitro group, preferably by means of reaction with iron in acidic conditions, e.g. in acetic acid, preferably at or above room temperature, more especially at the reflux temperature.
  • compounds of general formula I wherein R 1, R"° and Z are as hereinbefore defined, Z preferably being an oxygen atom, and R 3 contains an alkanoylamino or aroylamino group are prepared from compounds of general formula I wherein R1, R2 and Z are
  • R contains an amino group, preferably by means of reaction with the appropriate acid halide or acid anhydride, optionally in an inert solvent, and preferably at a temperature from 0°C to the reflux temperature.
  • N-oxides of compounds of general formula I wherein R 1, R2 and Z are as hereinbefore defined, Z preferably being an oxygen atom, and R 3 represents a heterocyclyl group contai.ni ⁇ ng one or more nitrogen ring atoms, are prepared by the oxidation of compounds of general formula I wherein R ,
  • R 2 and Z are as herei.nbefore defined and R3 represents a heterocyclyl group containing one or more nitrogen ring atoms, preferably by means of reaction with a mixture of hydrogen peroxide and an organic acid, e.g. acetic acid, preferably at or above room temperature at
  • salts the counter ions of which are relatively innocuous to the animal organism when used in therapeutic doses so that the beneficial pharmaceutical properties of the parent compounds of general formula I are not vitiated by side-effects ascribable to those counter ions.
  • Suitable acid addition salts for use in pharmaceuticals may be selected from salts derived from inorganic acids, for example hydrohalides, e.g.
  • hydrochlorides and hydrobromides phosphates, sulphates and nitrates, and organic acids, for example oxalates, lactates, tartrates, acetates, salicylates, citrates, propionates, succinates, fumarates, maleates, methylene-bis- ⁇ -hydroxynaphthoates, gentisates, esylates, isethionates and di- ⁇ -toluoyltartrates.
  • organic acids for example oxalates, lactates, tartrates, acetates, salicylates, citrates, propionates, succinates, fumarates, maleates, methylene-bis- ⁇ -hydroxynaphthoates, gentisates, esylates, isethionates and di- ⁇ -toluoyltartrates.
  • acid addition salts of compounds of formula I are prepared by reaction of the parent compounds of formula I with the appropriate acid, by the application or adaptation of known methods.
  • Alkali and alkaline earth metal salts are also suitable for use in pharmaceuticals, especially sodium salts.
  • alkali and alkaline earth metal salts are prepared by reaction of the parent compounds of formula I with the appropriate base, by the application or adaptation of known methods.
  • sodium salts can conveniently be prepared by reaction with sodium hydride.
  • salts of compounds of formula I are useful for the purposes of purification of the parent compounds of formula I, for example by exploitation of the solubility differences between the salts and the parent compounds, by techniques well known to those skilled in the art.
  • the parent compounds of formula I can be regenerated from their salts by the application or adaptation of known methods.
  • parent compounds of general formula I can be regenerated from their acid addition salts by treatment with an alkali, e.g. aqueous sodium bicarbonate solution or aqueous ammonia solution.
  • an alkali e.g. aqueous sodium bicarbonate solution or aqueous ammonia solution.
  • parent compounds of general formula I can be regenerated from their alkali and alkaline earth metal salts by treatment with an acid, e.g. hydrochloric acid.
  • Such isomers can be separated from their mixtures, by the application or adaptation of known methods, for example chromatographic techniques, or they may be separately prepared from the appropriate isomers of their intermediates, for example by the application or adaptation of methods described herein.
  • the starting materials and intermediates can be prepared by the application or adaptation of known methods, for example methods as described in the Reference Examples or their obvious chemical equivalents.
  • compounds of formula II can be prepared from compounds of general formula Va, hereinafter depicted, wherein R 1 and R2 are as hereinbefore defined, by the application or adaptation of known methods for the preparation of acid halides from carboxylic acids.
  • R 1 and R2 are as hereinbefore defined
  • the reaction can be carried out by means of thionyl chloride.
  • Co pounds of formula Va can be prepared by the oxidation of compounds of general formula VI, hereinafter depicted, whereinafter depicted, wherein Rl and R2 are as hereinbefore defined, e.g. by means of reaction with potassium permanganate, or with a mixture of sulphamic acid and sodium chlorite in acetic acid.
  • R 2 OH VIII wherein R ⁇ is as hereinbefore defined, preferably in the presence of a compound such as diisopropyl azodicarboxylate.
  • N-(2-acetylphenyl)-3-cyclopentyloxy-4-methoxybenzamide m.p. 126-127°C
  • N-(2-hydroxyphenyl)-3-cyclopentyloxy-4-methoxybenz ⁇ amide m.p. 169-171°C
  • EXAMPLE 8 Compounds AO.AY.BC.BG.BL.BO.BS.BX.AX.AZ.AW.BV and BW
  • a suspension of sodium hydride (60% dispersion in oil; 2.2g) in dry tetrahydrofuran (25ml) at 15-20°C was treated portionwise with a solution of 4-amino-3,5- dichloropyridine (4.5g; prepared as described in Reference Example 5) in dry tetrahydrofuran (40ml) , with cooling.
  • the mixture was stirred for a further 30 minutes, and then it was cooled to 10°C and treated with a solution of 3-cyclopentyloxy-4-methoxybenzoyl chloride (6.4g) in dry tetrahydrofuran (40ml), dropwise, during 45 minutes at 10°C.
  • Acetic anhydride (10ml) was treated with N-(2,6-dichloro-4-aninophenyl)-3-cyclopentyloxy-4- methoxybenzamide (0.8g; prepared as described in Example 11) , and the reaction mixture was stirred for 2 hours and left to stand overnight. It was then poured into water (100ml) , and extracted with ethyl acetate (100ml) and then with dichloromethane (100ml) . The organic extracts were combined, dried over magnesium sulphate, and evaporated, to give N-(4-acetylammo-2,6-dichlorophenyl)-3-cyclopentyloxy- 4-methoxybenzamide (0.4g), m.p. 250-252°C [Elemental analysis:- C,57.6;H,5.05;N,6.3;C1,16.1%; calculated:- C,57.5;H,5.1;N,6.4;C1,16.2%].
  • REFERENCE EXAMPLE 2 A stirred saturated aqueous solution of potassium permanganate (100ml) was treated with 3-cyclopentyloxy- 4-methoxybenzaldehyde (7.4g; prepared as described hereinbefore in Reference Example 1) and sodium carbonate (3.4g) and the mixture was stirred at 50°C for 1 hour, and then cooled to room temperature. The reaction mixture was acidified by treatment with concentrated hydrochloric acid and then it was treated with aqueous sodium bisulphite solution until a colourless solution was obtained. The reaction mixture was extracted with dichloromethane (2x100ml) and the organic extracts were dried over magnesium sulphate and concentrated.
  • REFERENCE EXAMPLE 8 A stirred suspension of 3-hydroxy-4-methoxybenz- aldehyde (50g) in water (200ml) at between 0 and 5°C was treated dropwise with an aqueous solution of sodium hydroxide (200ml;20%w/v) , followed at between 0 and 5°C by benzoyl chloride (38ml) . The reaction mixture was stirred at between 0 and 5°C for 1 hour and then it was allowed to warm to room temperature and was stirred for a further period of 2 hours.
  • sodium hydroxide 200ml;20%w/v
  • benzoyl chloride 38ml
  • REFERENCE EXAMPLE 11 By proceeding in a manner similar to that described in Example 8, but using 3-benzoyloxy-4- methoxybenzoyl chloride (prepared as described in Reference Example 10) and 4-amino-3,5-dichloropyridine (prepared as described in Reference Example 4) as starting materials, there was prepared N-(3,5-dichloro- pyrid-4-yl)-3-benzoyloxy-4-methoxybenzamide, m.p. 191-192°C.
  • REFERENCE EXAMPLE 14 By proceeding in a manner similar to that described in Reference Example 3, but using the appropriate quantities of the corresponding benzoic acid derivatives, prepared as described hereinbefore in Reference Example 13, there were prepared:- 3-(exo)-8,9,10-trinorbornyl-2-oxy-4-methoxybenzoyl chloride;
  • the present invention also includes within its scope pharmaceutical formulations which comprise at least one of the compounds of formula I or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable carrier or coating.
  • compounds of the present invention may be administered parenterally, rectally or orally, but they are preferably administered by inhalation.
  • compositions containing compounds of the invention and pharmaceutically acceptable salts thereof may be prepared by conventional means.
  • compounds of the invention and pharmaceutically acceptable salts thereof may be dissolved or suspended in a suitable carrier for use in a nebuliser or a suspension or solution aerosol, or may be absorbed or adsorbed onto a suitable solid carrier for use in a dry powder inhaler.
  • Solid compositions for oral administration include compressed tablets, pills, powders and granules.
  • one or more of the active compounds is, or are, admixed with at least one inert diluent such as starch, sucrose or lactose.
  • the compositions may also comprise, as is normal practice, additional substances other than inert diluents, e.g. lubricating agents, such as magnesium stearate.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art such as water and liquid paraffin. Besides inert diluents such compositions may comprise adjuvants, such as wetting and suspending agents, and sweetening, flavouring, perfuming and preserving agents.
  • the compositions according to the invention for oral administration also include capsules of absorbable material such as gelatin, containing one or more of the active substances with or without the addition of diluents or excipients.
  • compositions according to the invention for parenteral administration include sterile aqueous, aqueous-organic, and organic solutions, suspensions and emulsions.
  • organic solvents or suspending media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate.
  • the compositions may also contain adjuvants such as stabilising, preserving, wetting, emulsifying and dispersing agents. They may be sterilised, for example, by filtration through a bacteria-retaining filter, by incorporation in the compositions of sterilising agents, by irradiation or by heating. They may also be manufactured in the form of sterile solid compositions, which can be dissolved in sterile water or some other sterile injectable medium immediately before use.
  • Solid compositions for rectal administration include suppositories formulated in accordance with known methods and containing at least one compound of formula I.
  • compositions of the invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained. Obviously, several unit dosage forms may be administered at about the same time.
  • the dose employed will be determined by the physician, and depends upon the desired therapeutic effect, the route of administration and the duration of the treatment, and the condition of the patient. In the adult, the doses are generally from about 0.001 to about 50, preferably about 0.001 to about 5, mg/kg body weight per day by inhalation.
  • Composition Examples illustrate pharmaceutical compositions according to the present invention.
  • N-(2,6-difluorophenyl)-3-cyclopentyloxy-4- methoxybenzamide (l.Og) (mean particle size 3.5 microns) and lactose (mean particle size 72 microns) were blended together for 30 minutes in a mechanical shaker/mixer.
  • the resulting blend was filled, to a fill weight of 25mg, into No.3 hard gelatine capsules, to give a product suitable for use, for example, with a dry powder inhaler.
  • N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4- methoxybenzamide (l.Og) (mean particle size 3.5 microns) and lactose (mean particle size 72 microns) were blended together for 30 minutes in a mechanical shaker/mixer.
  • the resulting blend was filled, to a fill weight of 25mg, into No.3 hard gelatine capsules, to give a product suitable for use, for example, with a dry powder inhaler.

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Abstract

Benzamide derivatives of the formula (I): <CHEM> wherein R<1> represents alkyl, R<2> represents alkyl or mono-, bi- or tricycloalkyl, R<3> represents an optionally substituted phenyl, naphthyl or heterocyclyl group, and Z represents oxygen or sulphur, and when said heterocyclyl groups contain one or more nitrogen ring atoms, N-oxides thereof, and pharmaceutically acceptable salts thereof, possess useful pharmacological properties.

Description

"BENZAMIDES" This invention relates to therapeutically useful benzamide derivatives, to processes for their preparation, to pharmaceutical compositions containing them, and to methods for their use.
The present invention provides compounds of general formula I, hereinafter depicted, wherein R represents a straight- or branched-chain alkyl group containing up to about 4 carbon atoms, R 2 represents a straight- or branched-chain alkyl group containing from about 2 to about 15, preferably 2 to 12, carbon atoms or a mono-, bi- or tricycloalkyl group containing up to
3 about 10 carbon atoms, R represents an optionally substituted phenyl, naphthyl or heterocyclyl group, preferably a 5-, 6- or 7-membered heterocyclyl group containing one or more hetero atoms selected from oxygen, sulphur and nitrogen atoms, the optional substituents being one or more substituents selected from halogen atoms, alkyl groups which may carry one or more halogen atoms, and from aryl, arylalkyl, alkσxy, aryloxy, alkylthio, arylthio, alkoxycarbonyl, aryloxycarbonyl, alkanoyl, aroyl, alkylsulphonyl, arylsulphonyl, alkylsulphinyl, arylsulphinyl, hydroxy, hydroxyalkyl, formyl, alkanoyla ino, aroylamino, cyano and nitro groups, and from amino, carbamoyl and sulphaπioyl groups which themselves may each carry one or two alkyl substituents, and Z represents an oxygen or sulphur atom, and when said heterocyclyl groups contain one or more nitrogen ring atoms, N-oxides thereof, and pharmaceutically acceptable salts thereof, wherein all aryl groups and moieties, unless otherwise indicated, are selected from phenyl and naphthyl groups optionally substituted by one or more substituents selected from halogen atoms and alkyl and alkoxy groups, and wherein all alkyl groups and moieties, unless otherwise indicated, are straight- or branched- chain and contain up to about 4 carbon atoms.
Especially important compounds of the invention include those wherein at least one of the symbols has a value selected from the following:-
(i) R represents a methyl group; (ii) R 2 represents a propyl, butyl, nonyl, dodecyl, cyclohexyl, 8,9,10-trinorbornyl or, more especially, cyclopentyl group; and/or (lii) R 3 represents an optionally substituted pyrazinyl, pyrimidinyl, isoxazolyl, preferably pyridyl group, or an N-oxide thereof, or an optionally substituted phenyl group; the other symbols being as hereinbefore defined.
3 Among compounds wherein R represents a substituted phenyl group, compounds wherein said phenyl group is substituted in the 2-position or in the 2- and
6-positions are especially useful.
Similarly, among compounds wherein RJ represents a substituted heterocyclyl group, compounds wherein said heterocyclyl group is substituted on one or both of the positions next to the point of attachment to the rest of the molecule are especially useful. Individual compounds of especial importance . include the following:- A N-(2,6-difluorophenyl)-3-cyclopentyloxy-4- methoxybenzamide B N-(2-chloro-6-fluorophenyl)-3-cyclopentyloxy-4- methoxybenzamide C N-(2-trifluoromethylphenyl)-3-cyclopentyloxy-4- methoxybenzamide B N-(2,4,6-trichlorophenyl)-3-cyclopentyloxy-4- methoxybenzamide E N-(2,6-dibromophenyl)-3-cyclopentyloxy-4- ethoxybenzamide F N-(2-chloro-6-methylphenyl)-3-cyclopentyloxy-4- methoxybenzamide G N-(2,6-dichlorophenyl)-3-cyclopentyloxy-4- methoxybenzamide H N-(2-fluorophenyl)-3-cyclopentyloxy-4-methoxy- benzamide I N-phenyl-3-cyclopentyloxy-4-methoxybenzamide, J N-(2-methoxyphenyl)-3-cyclopentyloxy-4-methoxy- benzamide K N-(2-chlorophenyl)-3-cyclopentyloxy-4-methoxy- benzamide L N-(3-chlorophenyl)-3-cyclopentyloxy-4-methoxy¬ benzamide N-(4-methoxyphenyl)-3-cyclopentyloxy-4-methpxy- benzamide N N-(2,6-dimethylphenyl)-3-cyclopentyloxy-4- methoxybenzamide 0 N-(2-methylthiophenyl)-3-cyclopentyloxy-4- methoxybenzamide P N-(2-bromophenyl)-3-cyclopentyloxy-4-methoxy- benzamide Q N-(2-methoxycarbonylphenyl)-3-cyclopentyloxy-4- methoxybenzamide R N-(2-aminosulphonylpheny1)-3-cyclopentyloxy-4- methoxybenzamide S N-(2-benzoylphenyl)-3-cyclopentyloxy-4-methoxy- benzamide T N-(2-cyanophenyl)-3-cyclopentyloxy-4-methoxy- benzamide U N-(2,5-dichloropheny1)-3-cyclopentyloxy-4- methoxybenzamide
V N-(3-methylpheny1)-3-cyclopentyloxy-4-methoxy¬ benzamide N-(2-nitrophenyl)-3-cyclopentyloxy-4-methoxy¬ benzamide
X N-(2-di ethylaminopheny1)-3-cyclopentyloxy-4- methoxybenzamide
Y N-(2-acetylphenyl)-3-cyclopentyloxy-4-methoxy- benzamide Z N-(2-hydroxyphenyl)-3-cyclopentyloxy-4-methoxy- benzamide AA N-(2-methylsulphonylphenyl)-3-cyclopentyloxy-4- methoxybenzamide AB N-(2,6-difluorophenyl)-3-cyclohexyloxy-4- methoxybenzamide AC N-(2,6-difluorophenyl)-3-butoxy- -methoxy¬ benzamide AD N-(2,6-difluorophenyl)-3-propoxy-4-methoxy- benzamide AE N-(2-chlorophenyl)-3-cyclopentyloxy-4-methoxy-
(thiobenzamide) AF N-(4-chloropyrid-3-yl)-3-cyclopentyloxy-4- methoxybenzamide AG N-pyrid-2-yl-3-cyclopentyloxy-4-methoxybenzamide AH N-pyrazin-2-yl-3-cyclopentyloxy-4-methoxy- benzamide Al N-pyrimidin-2-y1-3-cyclopent loxy-4-methoxy¬ benzamide AJ N-(3-methylpyrid-2-yl)-3-cyclopentyloxy-4- methoxybenzamide AK N-pyrid-3-yl-3-cyclopentyloxy-4-methoxybenzamide AL N-(3-chloropyrid-2-yl)-3-cyclopentyloxy-4- methoxybenzamide AM N-(3-chloropyrid-4-yl)-3-cyclopentyloxy-4- methoxybenzamide AN N-pyrid-4-yl-3-cyclopentyloxy-4-methoxybenzamide AO N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4- methoxybenzamide
AP N-(3,5-dimethylisoxazol-4-yl)-3-cyclopentyloxy- 4-methoxybenzamide
AQ N-(4,6-dichloropyrimid-5-yl)-3-cyclopentyloxy-4- ethoxybenzamide
AR N-(4-nitrophenyl)-3-cyclopentyloxy-4-methoxy- benzamide
AS N-(2,3,5,6-tetrafluoropyrid-4-yl)-3-cyclo- pentyloxy-4-methoxybenzamide
AT N-(3,5-dichloro-2,6-difluoropyrid-4-yl)-3-cyclo¬ pentyloxy-4-methoxybenza ide
AU N-(2,4,6-trifluorophenyl)-3-cyclopentyloxy-4- methoxybenzamide
AV 3,5-dichloro-4-(3-cyclopentyloxy-4-methoxy- benzamido)pyridine-N-oxide
AW N-(3,5-dichloropyrid-4-yl)-3-(exo-8,9,10- trinorbornyl-2-oxy)-4-methoxybenzamide
AX N-(3,5-dichloropyrid-4-yl)- -cyclohexyloxy-4- methoxybenzamide
AY N-(3,5-dibrσmopyrid-4-yl)-3-cyclopentyloxy-4- methoxybenzamide
AZ N-(3,5-dichloropyrid-4-yl)-3-butoxy-4-methoxy¬ benzamide BA N- (3-methyl-5-bromoisothiazol-4-yl) -3-cyclo- pentyloxy-4-methoxybenzamide BB N-(3,5-dimethylisothiazol-4-yl)-3-cyclo- pentyloxy-4-methoxybenzamide BC N-(3,5-dimethylpyrid-4-yl)-3-cyclopentyloxy-4- methoxybenzamide BD N-(5-cyano-3-methylisothiazol-4-yl)-3-cyclo- pentyloxy-4 methoxybenzamide BE N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4- methoxy(thiobenzamide) BF N-(2,6-dichloro-4-methoxyphenyl)-3-cyclo- pentyloxy-4-methoxybenzamide BG N-(2,6-dichloro-4-cyanophenyl)-3-cyclopentyloxy-
4-methoxybenzamide BH N-(2,6-dichloro-4-carbamoylphenyl)-3-cyclo- pentyloxy-4-methoxybenzamide BI N-(2,6-dichloro-4-aminophenyl)-3-cyclopentyloxy-
4-methoxybenzamide BJ N-(3-chloro-2,5,6-trifluoropyrid-4-yl)-3-cyclo- pentyloxy-4-methoxybenzamide BK N-(3,5-dibromopyrid-4-yl)-3-butoxy-4-methoxy- benzamide BL N-(2 ,6-dichloro-4-methoxycarbonylphenyl)-3- cyclopentyloxy-4-methoxybenzamide BM N-(4-acetylamino-2 ,6-dichlorophenyl)-3-cyclo¬ pentyloxy-4-methoxybenzamide BN N-(3,5-dichloropyrid-4-yl)-3-nonyloxy-4- methoxybenzamide BO N-(2,6-dichloro-4-formylphenyl)-3-cyclo- pentyloxy-4-methoxybenzamide BP N-(2,6-dichlorophenyl)-3-(exo-8,9,10-trinor- bornyl-2-oxy)-4-methoxybenzamide BQ N-(2,3,5-trifluoropyrid-4-yl)-3-cyclopentyloxy-
4-methoxybenzamide BR sodium salt of N-(3,5-dichloropyrid-4-yl)-3- cyclopentyloxy-4-methoxybenzamide BS N-(2,6-dichloro-4-ethoxycarbonylphenyl)-3- cyclopentyloxy-4-methoxybenzamide BT N-(2,6-dichloro-4-hydroxymethylphenyl)-3-cyclo- pentyloxy-4-methoxybenzamide BU N-(3,5-dichloropyrid-4-yl)-3-dodecyloxy-4- methoxybenzamide BV (R)-N-(3,5-dichloropyrid-4-yl)-3-(exo-8,9,10- trinorbornyl-2-oxy)-4-methoxybenzamide BW (S)-N-(3,5-dichloropyrid-4-yl)-3-(exo-8,9,10- trinorbornyl-2-oxy)-4-methoxybenzamide BX N-(2,6-dichloro-4-nitrophenyl)-3-cyclopentyloxy-
4-methoxybenzamide
The letters A to BX are allocated to compounds for easy reference in this specification.
The compounds of general formula I and their pharmaceutically acceptable salts exhibit pharmacological activity and accordingly are of use for the preparation of pharmaceutical compositions and in the treatment of humans and other animals. More especially, they are cyclic AMP phosphodiesterase inhibitors, in particular type IV cyclic AMP phosphodiesterase inhibitors, and thus the present invention provides compounds of general formula I and their pharmaceutically acceptable salts, and compositions containing compounds of general formula I and their pharmaceutically acceptable salts, which are of use in a method for the treatment of a human or animal patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of cyclic AMP phosphodiesterase, for example, they are useful as bronchodilators and asthma-prophylactic agents and agents for the inhibition of eosinophil accumulation and of the function of eosinophils, e.g. for the treatment of inflammatory airways disease, especially reversible airway obstruction or asthma, and for the treatment of other diseases and conditions characterised by, or having an aetiology involving, morbid eosinophil accumulation. As further examples of conditions which can be ameliorated by the administration of inhibitors of cyclic AMP phosphodiesterase such as compounds of general formula I there may be mentioned inflammatory diseases, such as atopic dermatitis, urticaria, allergic rhinitis, psoriasis, rheumatic arthritis, ulcerative colitis, Crohn's disease, adult respiratory distress syndrome and diabetes insipidus, other proliferative skin diseases such keratosis and various types of dermatitis, conditions associated with cerebral metabolic inhibition, such as cerebral senility, ulti-infarct dementia, senile dementia (Alzheimer's disease) , and memory impairment associated with Parkinson's disease, and conditions ameliorated by neuroproteσtant activity, such as cardiac arrest, stroke, and intermittent claudication.
According to a further feature of the invention there is provided a method for the treatment of a human or animal patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of cyclic AMP phosphodiesterase, for example conditions as hereinbefore described.
Compounds within the scope of the present invention exhibit positive pharmacological activities as demonstrated by the following tests which are believed to correlate to pharmacological activity in humans and other mammals. Compounds of the invention at concentrations from about 10 -9M up to about 10-5M produced about 50% inhibition of porcine aorta cyclic AMP phosphodiest¬ erase.
Compounds of the invention at concentrations of about 10 -7M to about 10-4M produced about 50% relaxation of guinea-pig tracheal strips, which had been contracted by treatment with spasmogens such as hista ine and carbachol.
Compounds of the invention at intraperitoneal doses from about 1 to about 25 mg/kg or at oral doses from about 1 to about 50 mg/kg inhibited by about 50% the accumulation of eosinophils in the lungs of guinea-pigs.
Compounds of the invention at concentrations from about 10 -8M up to about 10-5M produced about 50% inhibition of superoxide generation from eosinophils harvested from the peritoneal cavities of guinea-pigs.
Compounds of the invention at oral doses from about 1 to about 50 mg/kg administered 1 hour before challenge inhibited by about 50% ovalbumin- or PAF- induced hyperreactivity in guinea-pigs.
Bronchorelaxant activity was measured in in vivo tests in the anaesthetised guinea-pig according to the method of Dixon and Brodie [J. Physiol., £9_, 97-173, (1903)] in which the effects on histamine-induced - 13 - bronchospasm and mean arterial blood pressure were. determined.
Nebulised aerosols generated from aqueous solutions of compounds of the invention were each administered for one minute to the anaesthetised guinea-pigs.
Alternatively, dry powder formulations made up from compounds of the invention and lactose were blown into the airways of the anaesthetised guinea-pigs.
Compounds of the invention produced from about 30% up to about 90% decrease in bronchospasm when administered at effective doses of about 20-80μg, without any significant effect on blood pressure.
Compounds of the invention as oral doses of about 1 to about 50mg/kg, administered one hour before challenge, inhibited by at least 50% ovalbumin-induced eosinophilia in guinea-pigs, which is measured 24 hours after challenge.
Administered at doses of about 1 to about 50mg/kg orally or parenterally or at doses of about 20 to about 500μg intratracheally, compounds of the invention inhibit PAF or ovalbumin-induced microvascular leakage (measured using fluorescein isothiocyanate dextran) by up to 100% in guinea-pigs.
The value of the compounds of the invention is enhanced by their very low mammalian toxicity levels. Compounds of formula (I) can be prepared by.the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature.
Thus, according to a feature of the present invention, compounds of general formula I, wherein R~, ι 3 R* and R are as hereinbefore defined and Z represents an oxygen atom, are prepared by the reaction of compounds of general formula II hereinafter depicted, wherein R 1 and R2 are as hereinbefore defined and X""*1" represents a halogen, e.g. bromine or, preferably, chlorine atom, with compounds of the general formula:-
NH2R3 III wherein R 3 i.s as hereinbefore defined, preferably in the presence of a base, for example an alkali metal hydroxide or carbonate, e.g. sodium hydroxide or carbonate, an alkali metal hydride, e.g. sodium hydride, or an amine, preferably a tertiary amine, e.g. triethylamine or pyridine, optionally in an inert solvent, for example dichloromethane, dimethylfor - amide, or an ether, e.g. diethyl ether or tetrahydro- furan, preferably at a temperature from 0°C to the reflux temperature or at the melting point of the reaction mixture.
According to a further feature of the present invention, compounds of general formula I are prepared by the reaction of compounds of general formula IV hereinafter depicted, wherein R 1, R3 and Z are as hereinbefore defined, with compounds of the general formula:-
R2X2 v
2 . 2 wnerem R is as hereinbefore defined and X represents a halogen, preferably bromine, atom, preferably in the presence of a base, for example an alkali metal hydride, e.g. sodium hydride, an alkali metal hydroxide or carbonate, e.g. sodium hydroxide or carbonate, or an amine, preferably a tertiary amine, e.g. triethylamine cr pyridine, optionally in an inert solvent, for example dichloromethane, dimethylformamide, or an ether, e.g. diethyl ether or tetrahydrofuran, preferably at a temperature from 0°C to the reflux temperature.
According to a further feature of the present invention, compounds of general formula I are prepared by interconversion of other compounds of general formula I.
For example, compounds of general formula I wnerem R 1, R2 and R3 are as hereinbefore defined and Z represents a sulphur atom are prepared from compounds of general formula I wherein R 1, R2 and R3 are as hereinbefore defined and Z represents an oxygen atom, fcy reaction with phosphorus pentasulphide or 2,4-bis(4- methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4- disulphide, preferably in a solvent such as pyridine or toluene, and preferably at a temperature from 0°C to the reflux temperature.
As another example, compounds of general formula ι 2 Z wherein R"1, and R are as hereinbefore defined, Z
3 represents an oxygen atom and R contains an alkylsulphonyl, arylsulphonyl alkylsulphinyl or arylsulphinyl group are prepared by the oxidation of compounds of general formula I wherein R 1 and R2 are as hereinbefore defined, Z represents an oxygen atom and
R" contains an alkylthio or arylthio group, preferably by means of reaction with a peroxyacid, e.g. 3-chloro- perbenzoic acid, preferably in an inert solvent, e.g. dichloromethane, preferably at or near room temperature.
As another example, compounds of general formula I wherein R 1, R2 and Z are as hereinbefore defined, Z preferably being an oxygen atom, and R 3 contains a hydroxymethyl group are prepared by the reduction of compounds of general formula I wherein R 1 , R2 and Z are as hereinbefore defined and R 3 contains an aryloxycarbonyl or, preferably, alkoxycarbonyl group, preferably by means of reaction with an alkali metal borohydride, preferably in an inert solvent, e.g. tetrahydrofuran, preferably at or near room temperature.
As another example, compounds of general formula I wherein R 1, R2 and Z are as hereinbefore defined, Z
3 preferably being an oxygen atom, and R contains a formyl group are prepared by the oxidation of compounds of general formula I wherein R 1, R2 and Z are as hereinbefore defined and R 3 contains a hydroxymethyl group, preferably by means of reaction with manganese dioxide, preferably in an inert solvent, e.g. dichloromethane, preferably at or above room temperature, more especially at the reflux temperature.
As another example, compounds of general formula I wherein R 1, R2 and Z are as hereinbefore defined, Z
3 preferably being an oxygen atom, and R contains an amino group are prepared by the reduction of compounds of general formula I wherein R 1, R2 and Z are as
3 hereinbefore defined and R contains a nitro group, preferably by means of reaction with iron in acidic conditions, e.g. in acetic acid, preferably at or above room temperature, more especially at the reflux temperature.
As another example, compounds of general formula I wherein R 1, R"° and Z are as hereinbefore defined, Z preferably being an oxygen atom, and R 3 contains an alkanoylamino or aroylamino group are prepared from compounds of general formula I wherein R1, R2 and Z are
3 as hereinbefore defined and R contains an amino group, preferably by means of reaction with the appropriate acid halide or acid anhydride, optionally in an inert solvent, and preferably at a temperature from 0°C to the reflux temperature.
As another example, N-oxides of compounds of general formula I wherein R 1, R2 and Z are as hereinbefore defined, Z preferably being an oxygen atom, and R 3 represents a heterocyclyl group contai.ni■ng one or more nitrogen ring atoms, are prepared by the oxidation of compounds of general formula I wherein R ,
R 2 and Z are as herei.nbefore defined and R3 represents a heterocyclyl group containing one or more nitrogen ring atoms, preferably by means of reaction with a mixture of hydrogen peroxide and an organic acid, e.g. acetic acid, preferably at or above room temperature at
60-90°C.
By the term "pharmaceutically acceptable salts" as used in this specification is meant salts the counter ions of which are relatively innocuous to the animal organism when used in therapeutic doses so that the beneficial pharmaceutical properties of the parent compounds of general formula I are not vitiated by side-effects ascribable to those counter ions. Suitable acid addition salts for use in pharmaceuticals may be selected from salts derived from inorganic acids, for example hydrohalides, e.g. hydrochlorides and hydrobromides, phosphates, sulphates and nitrates, and organic acids, for example oxalates, lactates, tartrates, acetates, salicylates, citrates, propionates, succinates, fumarates, maleates, methylene-bis-β-hydroxynaphthoates, gentisates, esylates, isethionates and di-β-toluoyltartrates.
As will be self-evident to those skilled in the art, some of the compounds of general formula I do not form stable salts. However, acid addition salts are most likely to be formed by compounds of formula I wherein R 3 represents a nitrogen-containing heterocyclyl group and/or wherein R 3 contains an ammo group as a substituent.
According to a further feature of the invention, acid addition salts of compounds of formula I are prepared by reaction of the parent compounds of formula I with the appropriate acid, by the application or adaptation of known methods.
Alkali and alkaline earth metal salts are also suitable for use in pharmaceuticals, especially sodium salts. According to a further feature alkali and alkaline earth metal salts are prepared by reaction of the parent compounds of formula I with the appropriate base, by the application or adaptation of known methods. For example, sodium salts can conveniently be prepared by reaction with sodium hydride.
As well as being useful in themselves as active compounds, salts of compounds of formula I are useful for the purposes of purification of the parent compounds of formula I, for example by exploitation of the solubility differences between the salts and the parent compounds, by techniques well known to those skilled in the art.
The parent compounds of formula I can be regenerated from their salts by the application or adaptation of known methods.
For example, parent compounds of general formula I can be regenerated from their acid addition salts by treatment with an alkali, e.g. aqueous sodium bicarbonate solution or aqueous ammonia solution.
Similarly, parent compounds of general formula I can be regenerated from their alkali and alkaline earth metal salts by treatment with an acid, e.g. hydrochloric acid.
In this specification reference to compounds of formula I is intended to include reference to their pharmaceutically acceptable salts, where the context so permits.
It will be apparent to those skilled in the art that certain compounds of general formula I can exhibit isomerism, for example optical isomerism. All isomers within general formula I, and their mixtures, are within the scope of the invention.
Such isomers can be separated from their mixtures, by the application or adaptation of known methods, for example chromatographic techniques, or they may be separately prepared from the appropriate isomers of their intermediates, for example by the application or adaptation of methods described herein.
The starting materials and intermediates can be prepared by the application or adaptation of known methods, for example methods as described in the Reference Examples or their obvious chemical equivalents.
For example, compounds of formula II can be prepared from compounds of general formula Va, hereinafter depicted, wherein R 1 and R2 are as hereinbefore defined, by the application or adaptation of known methods for the preparation of acid halides from carboxylic acids. For example, when X represents a chlorine atom, the reaction can be carried out by means of thionyl chloride. Co pounds of formula Va can be prepared by the oxidation of compounds of general formula VI, hereinafter depicted, wherein Rl and R2 are as hereinbefore defined, e.g. by means of reaction with potassium permanganate, or with a mixture of sulphamic acid and sodium chlorite in acetic acid.
Compounds of formula VI can be prepared from compounds of general formula VII, hereinafter depicted, wherein R"" is as hereinbefore defined, by reaction with compounds of formula V as hereinbefore defined, or alternatively by reaction with compounds of the general formula:-
R2OH VIII wherein Rώ is as hereinbefore defined, preferably in the presence of a compound such as diisopropyl azodicarboxylate.
The following Examples illustrate the preparation of the compounds according to the invention and the Reference Examples illustrate the preparation of the intermediates.
In the nuclear magnetic resonance spectra (NMR) the chemical shifts are expressed in ppm relative to tetramethylsilane. Abbreviations have the following significances:- s = singlet; d = doublet; t = triplet; q = quartet; m = multiplet; dd = doublet of doublets; b = broad.
EXAMPLE 1
Compounds A.B.C,D,E.F,G.H,I.J K.L.M.N.O.P.O.R.S.T.U.V.W.X.Y and Z
A stirred solution of 2,6-difluoroaniline (1.52g) and triethyla ine (l.lθg) in dichloromethane (50ml) at room temperature was treated with a solution of 3-cyclopentyloxy-4-methoxybenzoyl chloride (3.0g, prepared as described hereinafter in Reference Example 3) in dichloromethane (50ml), dropwise. The solution was stirred and headed at reflux for 4 hours, then it was cooled, washed with water and dried over magnesium sulphate. The solution was concentrated and the resulting residue was recrystallised from ethyl acetate, to give N-(2,6-difluoropheηyl)-3-cyclopentyloxy- 4-methoxybenzamide (1.9g), m.p. 158-160°C [NMR(CDCl-) :- 1.55-1.7(m,3H) ,1.8-2.05(m,5H) ,3.93(s,3H) ,4.85(m,lH) , 6.9(d,lH) ,6.95-7.03(m,2H) ,7.2-7.3(m,1H) ,7.35(bs,lH) , 7.45(q,lH) ,7.53(d,lH) ; Elemental analysis:- C,65.1; H,5.6;F,10.4;N,4.2%; Calculated:- C,65.7;H,5.5;F,10.9; N,4.0%1.
By proceeding in a similar manner, but replacing the 2,6-difluoroaniline by the appropriate quantities of the corresponding aniline derivatives, there were prepared:-
N-(2-chloro-6-fluorophenyl)-3-cyclopentyloxy-4-methoxy¬ benzamide, m.p. 140-142°C [Elemental analysis:-C,62.3; H,5.2;C1,9.7;N,3.6%; Calculated:- C,62.7;H,5.3;C1,9.75; N,3.85%];
N-(2-trifluoromethylphenyl)-3-cyclopentyloxy-4-methoxy¬ benzamide, m.p. 127-129°C [Elemental analysis:- C,63.4; H,5.5;F,13.3;N,3.3%; Calculated:- C,63.3;H,5.3;F,15.0; N,3.7%];
N-(2,4,6-trichlorophenyl)-3-cyclopentyloxy-4-methoxy- benza ide, m.p. 173°C [Elemental analysis:- C,55.2; H,4.4;C1,26.4;N,3.1; Calculated:- C,55.0;H,4.4;C1,25.6; N,3.4%];
N-(2,6-dibromophenyl)-3-cyclopentyloxy-4-methoxy¬ benzamide, m.p. 133°C [Elemental analysis:- C,48.5; H,4.0;Br,33.9;N,2.85%; Calculated:- C,48.6;H,4.1; Br,34.1;N,3.0%]; N-(2-chloro-6-methylphenyl)-3-cyclopentyloxy-4- - 27 - methoxybenzamide, m.p. 138-140°C [Elemental analysis: - C,66.3;H,6.2;C1,10.3;N,3.8%; Calculated:- C, 66.75; H, 6.2; Cl, 9.85 ;N, 3.9%];
N- (2 , 6-dichlorophenyl) -3 -cyclopentyloxy-4 -methoxybenz¬ amide, m.p. 138-140°C [Elemental analysis:- C,59.8; H,5.1;C1,19.1;N,3.3%; Calculated:- C,60.0;H,5.0;C1,18.65; N,3.7%];
N- (2 -fluorophenyl) -3 -cyclopentyloxy-4 -methoxybenzamide, m.p. 137°C [Elemental analysis:- C, 69.3;H, 6.2;F,5.7; N,4.0%; Calculated:- C,69.3;H,6.1;F,5.8;N,4.25%] ; N-phenyl-3-cyclopentyloxy-4 -methoxybenzamide, m.p. 169-173 °C [Elemental analysis:- C,73.2;H, 6.7; N,4.2%; Calculated:- C,73.3;H,6.8;N,4.5%] ; N- (2-methoxyphenyl) -3 -cyclopentyloxy-4 -methoxy¬ benzamide, m.p. 132-134°C [Elemental analysis:- C,70.1; H,6.8;N,4.0%; Calculated:- C,70.4;H,6.8;N,4.1%] ; N- ( 2 -chlorophenyl ) -3 -cyclopentyloxy-4 -methoxybenzamide , m.p. 122-124°C [Elemental analysis:- C,65.8;H,5.8;C1,10.5; N,3.9%; Calculated:- C,66.0;H,5.8;C1,10.25;N,4.05%] ; N- ( 3 -chlorophenyl ) -3 -cyclopentyloxy-4 -methoxybenzamide , m.p. 110-112°C [Elemental analysis:- C, 65.9;H,6.5;C1, 9.8; N,3.7%; Calculated:- C, 66.0;H,5.8;C1, 10.25;N, 4.05%] ; N- (4-methoxyphenyl) -3 -cyclopentyloxy-4 -methoxy¬ benzamide, m.p. 182-184°C [Elemental analysis:- C,68.7; H,6.6;N.3.8%;Calculated for C2QH23N04 :%H20:- C,68.55; H,6.9;N.4.0%]; - 28 - N-(2,6-dimethylphenyl)-3-cyclopentyloxy-4-methoxybenz¬ amide, m.p. 130-131°C [Elemental analysis:- C,74.2; H,7.4;N,4.1%; Calculated:- C,74.3;H,7.4;N,4.13%]; N-(2-methylthiαphenyl)-3-cyclopentyloxy-4-methoxybenz¬ amide, m.p. 128-130°C [Elemental analysis:- C,67.6; H,6.5;N,3.9;S,8.9%; Calculated:- C,67.2;H,6.5;N,3.9; S,9.0%];
N-(2-bromophenyl)-3-cyclopentyloxy-4-methoxybenzamide, m.p. 126-128°C [Elemental analysis:- C,58.2;H,5.1; Br,20.4;N,3.5%; Calculated:- C,58.5;H,5.2;Br,20.5; N,3.6%];
N-(2-methoxycarbonylphenyl)-3-cyclopentyloxy-4-methoxy¬ benzamide, m.p. 105-107°C [Elemental analysis:- 68.4; H,6.35;N,3.7%; Calculated:- 68.3;6.3;N,3.8%]; N-(2-aminosulphonylphenyl)-3-cyclopentyloxy-4-methoxy¬ benzamide, m.p. 248°C [Elemental analysis:- C,58.0; H,5.5;N,6.9%; Calculated:- C,58.45;H,5.7;N,7.2%]; N-(2-benzoylphenyl)-3-cyclopentyloxy-4-methoxybenzamide, m.p. 106-107βC [Elemental analysis:- C,75.5;H,6.3; N,3.3%; Calculated:- C,75.2;H,6.1;N,3.4%]; N-(2-cyanophenyl)-3-eyelopentyloxy-4-methoxybenzamide, m.p. 170-172°C [Elemental analysis:- C,71.0;H,6.0; N,8.1%; Calculated:- C,75.2;H,6.1;N,3.4%]; N-(2,5-dichlorophenyl)-3-cyclopentyloxy-4-methoxybenz¬ amide, m.p. 117-119°C [Elemental analysis:- C,59.7; H,5.0;C1,18.5;N,3.7%; Calculated:- C,60.0;H,5.0; C1,18.65;N,3.7%];
N-(3-methylphenyl)-3-cyclopentyloxy-4-methoxybenz- amide, m.p. 147-149°C [Elemental analysis:- C,73.8; H,7.1;N,4.2%; Calculated:- C,73.8;H,7.1;N,4.3%]; N-(2-nitrophenyl)-3-cyclopentyloxy-4-methoxybenzamide, m.p. 130-132°C [Elemental analysis:- C,64.0;H,5.7; N,7.4%; Calculated:- C,64.0;H,5.7;N,7.9%]; N-(2-dimethylaminophenyl)-3-cyclopentyloxy-4-methoxy¬ benzamide,in the form of a brown oil [Elemental analysis:- C,71.5;H,7.4;N,7.4%; Calculated:- C,71.2; H,7.4;N,7.9%];
N-(2-acetylphenyl)-3-cyclopentyloxy-4-methoxybenzamide, m.p. 126-127°C [Elemental analysis:- C,71.0;H,6.6; N,3.9%; Calculated:- C,71.4;H,6.6;N,4.0%]; and N-(2-hydroxyphenyl)-3-cyclopentyloxy-4-methoxybenz¬ amide, m.p. 169-171°C [Elemental analysis:- C,69.5; H,6.5;N,3.9%; Calculated:- C,69.7;H,6.5;N,4.3%] .
EXAMPLE 2 Compound AA
A stirred solution of N-(2-methylthiophenyl)-3- cyclopentyloxy-4-methoxybenzamide (l.80g; prepared as described hereinbefore in Example 1) was treated with a solution of 3-chloroperbenzoic acid (3.60g; 85% pure) in dichloromethane (72ml) , dropwise, and then it was stirred at room temperature for 5 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution and then with water, and then it was dried over magnesium sulphate. Concen¬ tration gave N-(2-methylsulphonylphenyl)-3-cyclo- pentyloxy-4-methoxybenzamide, (1.12g), in the form of a white solid, m.p. 119-121°C [NMR(CDC1 ) :- 1.52-2.16 (m,8H) ,3.1(s,3H) ,3.94(s,3H) ,4.9(m,lH) ,6.96(d,IH) ,7.46 (m,lH) ,7.6(m,2H) ,7.7(t,lH) ,7.95(d,lH) ,8.68(d,lH) ; Elemental analysis:- C,61.6;H,6.0;N,3.5;S,8.5%; Calculated:- C,61.7;H,5.95;N,3.6;S,8.5%] .
EXAMPLE 3 Compounds AB. AC and AD
By proceeding in a manner similar to that described hereinbefore in Example 1, but using the appropriate quantities of the corresponding acid chlorides, prepared as described hereinafter in Reference Example 3, there were prepared:- N-(2,6-difluorophenyl)-3-cyclohexyloxy-4-methoxy¬ benzamide, m.p. 60°C [Elemental analysis:- C,66.1; H,6.3;N,3.3%; Calculated:- C,66.5;H,5.9;N,3.9%] ; N-(2,6-difluorophenyl)-3-butoxy-4-methoxy¬ benzamide, m.p. 150-152°C. [Elemental analysis:- C,64.6;H,5.8;N,4.2; Calculated:- C,64.5;H,5.7; N,4.2%]; and
N-(2,6-difluorophenyl)-3-propoxy-4-methoxybenzamide, m.p. 170-174°C. [Elemental analysis:- C,63.4;H,5.4; N,4.4%; Calculated:- C,63.5;H,5.3;N,4.4%] . EXAMPLE 4 Compound AE
3-Cyclopentyloxy-4-methoxybenzoyl chloride (13.3g) and 2-chloroaniline (6.6g) were dissolved in pyridine (50ml) and the solution was allowed to stand at room temperature for l hour. Phosphorus pentasulphide (13g) was added and the stirred mixture was heated at 110°C for 1.5 hours. After cooling to room temperature the mixture was poured into an ice-cold solution of concentrated hydrochloric acid (100ml) in water (400ml) . The mixture was stirred for 1 hour and the yellow solid was collected, washed with water and subjected to flash chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (3:lv/v), to give N-(2-chlorophenyl)-3- cyclopentyloxy-4-methoxy(thiobenzamide) (5.4g), m.p. 129-131°C [Elemental analysis:- C,62.6;H,5.5;N,3.9; S,8.9%; Calculated:- C,63.1;H,5.6;N,3.9;S,8.9%] .
EXAMPLE 5 Compounds AF, AG, AH, Al. AJ. AK AL, AM and AN
A stirred solution of 4-chloropyrid-3-ylamine (1.94g) and 3-cyclopentyloxy-4-methoxybenzoyl chloride (3.85g) in pyridine (50ml) was heated at 80°C for 7 hours and then it was allowed to stand overnight. The reaction mixture was evaporated, to give a brown oil, which was subjected to mplc on silica gel, using diethyl ether as eluent, to give N-(4-chloropyrid-3- yl)-3-cyclopentyloxy-4-methoxybenzamide (3.1g), m.p. 130-132°C.
By proceeding in a similar manner, but using the appropriate quantities of the appropriate amines instead of the 4-chloropyrid-3-ylamine used as a starting material, there were prepared:- N-pyrid-2-y1-3-cyclopentyloxy-4-methoxybenzamide, m.p. 92-94°C;
N-pyrazin-2-yl-3-cyclopentyloxy-4-methoxybenzamide, m.p. 80-82°C;
N-pyrimidin-2-yl-3-cyclopentyloxy-4-methoxybenzamide, m.p. 108-110°C;
N-(3-methylpyrid-2-yl)-3-cyclopentyloxy-4-methoxy- benzamide, m.p. 55°C;
N-pyrid-3-yl-3-cyclopentyloxy-4-methoxybenzamide, m.p. 170-172°C;
N-(3-chloropyrid-2-yl)-3-cyclopentyloxy-4-methoxybenza- ide, m.p. 138-140°C;
N-(3-chloropyrid-4-yl)-3-cyclopentyloxy-4-methoxy- benzamide, m.p. 124-126°C
N-pyrid-4-yl-3-cyclopentyloxy-4-methoxybenzamide, m.p. 163-165°C. EXAMPLE 6 Compound AO
4-Amino-3,5-dichloropyridine (4.Og) and 3-cyclopentyloxy-4-methoxybenzoyl chloride (6.26g) were intimately ground together in a mortar with a pestle, and transferred to a round-bottomed flask. The mixture was melted, using a hot air gun external to the flask, stirring with a magnetical stirrer. After 10 minutes, heating was ceased and the melt was allowed to cool. The resulting material was triturated with dichloromethane and the residual solid was filtered off. The filtrate was concentrated to give a fawn solid, which was subjected to flash chromatography on silica gel, eluting with diethyl ether, to give N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4- ethoxybenzamide (l.87g), m.p. 155-157°C. [Elemental analysis: C,56.3;H,4.7;N,7.2;C1,18.4%; calculated: C,56.7;H,4.76;N,7.35;C1,18.6%; IR spectrum:- 1661cm"" , 3244cm"" ^*
- 34 - EXAMPLE 7 Compound AP
By proceeding in a manner similar to that described hereinbefore in Example 1, but replacing the 2,6-difluoroaniline used as a starting material by the appropriate quantity of 4-amino-3,5-dimethylisoxazole, there was prepared N-(3,5-dimethylisoxazol-4-yl)-3- cyclopentyloxy-4-methoxybenzamide, m.p. 150-152°C. [Elemental analysis: C,65.6;H,6.8;N,8.5%; calculated: C,65.4;H,6.7;N,8.5%] .
EXAMPLE 8 Compounds AO.AY.BC.BG.BL.BO.BS.BX.AX.AZ.AW.BV and BW
A suspension of sodium hydride (60% dispersion in oil; 2.2g) in dry tetrahydrofuran (25ml) at 15-20°C was treated portionwise with a solution of 4-amino-3,5- dichloropyridine (4.5g; prepared as described in Reference Example 5) in dry tetrahydrofuran (40ml) , with cooling. The mixture was stirred for a further 30 minutes, and then it was cooled to 10°C and treated with a solution of 3-cyclopentyloxy-4-methoxybenzoyl chloride (6.4g) in dry tetrahydrofuran (40ml), dropwise, during 45 minutes at 10°C. The mixture was stirred at 10°C for 30 minutes and was then treated with dilute hydrochloric acid (50ml;IN), followed by dichloromethane (75ml) . The layers were separated and the aqueous layer was washed with a further quantity of dichloromethane (25ml) . The combined organic layers were washed with water (50ml) , with saturated aqueous sodium bicarbonate solution (100ml) , and with water (50ml) , dried over magnesium sulphate and evaporated to dryness. The resulting residue was recrystallised from isopropanol, to give N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxy¬ benzamide (7.0g).
By proceeding in a similar manner, but replacing the 4-amino-3,5-dichloropyridine used as a starting material by the appropriate quantities of the appropriate 'amines, and optionally using dimethylformamide instead of tetrahydrofuran, there were prepared:-
N-(3,5-dibromopyrid-4-yl)-3-cyclopentyloxy-4-methoxy- benzamide, m.p. 160-162°C [Elemental analysis:- C,46.4;H,3.9;N,6.1%; calculated:- C,46.0;H,3.9;N,6.0%] ; N-(3,5-dimethylpyrid-4-yl)-3-cyclopentyloxy-4-methoxy¬ benzamide, m.p. 77-80°C [Elemental analysis:- C,67.2;H,6.9;N,7.8%; calculated:- C,67.0;H,7.3;N,7.8%] ; N-(2,6-dichloro-4-cyanophenyl)-3-cyclopentyloxy-4- ethoxybenzamide, m.p. 170-172°C [Elemental analysis:- C,59.1;H,4.5;N,7.0;C1,17.5%; calculated:- C,59.3;H,4.5; N,6.9;C1,17.5];
N-(2,6-dichloro-4-methoxycarbonylphenyl)-3-cyclo- pentyloxy-4-methoxybenzamide, m.p. 158-160°C [Elemental analysis:- C,57.4;H,4.9;N,3.2;C1,16.4%; calculated:- C,57.5;H,4.8;N,3.2;C1,16.2%];
N-(2,3,5-trifluoropyrid-4-yl)-3-cyclopentyloxy-4- methoxybenza ide, m.p. 144-146°C [Elemental analysis:- C,59.3;H,4.9;N,7.5%; calculated:- C,59.0;H,4.7; N,7.65%];
N-(2,6-dichloro-4-ethoxycarbonylphenyl)-3-cyclopentyl- oxy-4-methoxybenzamide, m.p. 164-166°C; N-(2,6-dichloro-4-nitrophenyl)-3-cyclopentyloxy-4- methoxybenzamide, m.p. 154-156°C; N-(3,5-dichloropyrid-4-yl)-3-cyclohexyloxy-4-methoxy- benzamide, m.p. 170°C [Elemental analysis:- C,57.8; H,5.1;N,7.0;C1,17.8%; calculated:- C,57.7;H,5.1;N,7.1; Cl,17.9%];
N-(3,5-dichloropyrid-4-yl)-3-butoxy-4-methoxybenzamide, m.p. 165-167βC [Elemental analysis:- C,55.1;H,4.8; N,7.6;C1,19.2%; calculated:- C,55.3;H,4.9;N,7.6; Cl-19.2%] ;
N-(3,5-dichloropyrid-4-yl)-3-(exo-8,9,10-trinorbornyl- 2-oxy)-4-methoxybenzamide, m.p. 149-150°C [Elemental analysis:- C,58.8;H,4.9;N,6.7%; calculated:- C,59.0; H,5.0;N,6.9%];
(R)-N-(3,5-dichloropyrid-4-yl)-3-(exo-8,9,10-trinor- bornyl-2-oxy)-4-methoxybenzamide, m.p. 155-156°C [Elemental analysis:- C,58.8;H,5.0;N,6.8%] ; and (S)-N-(3,5-dichloropyrid-4-yl)-3-(exo-8,9,10-trinor- bornyl-2-oxy)-4-methoxybenzamide, m.p. 156-157°C.
EXAMPLE 9 Compound AV
A stirred suspension of N-(3,5-dichloropyrid-4- y1)-3-cyclopentyloxy-4-methoxybenzamide (2.Og; prepared as described in Example 6) in glacial acetic acid (8ml) was treated with an aqueous solution of hydrogen peroxide (6ml;27.5%). The mixture was stirred for 3 hours at 70-80°C and then it was treated with a further portion of hydrogen peroxide solution (4ml) , and the solution was stirred for a further 12 hours. The solution was then cooled, basified by treatment with concentrated aqueous sodium hydroxide solution, and extracted with dichloromethane (2x3Oml) . The organic extract was washed with brine (30ml) , dried over magnesium sulphate and evaporated. The resulting residue was recrystallised from ethyl acetate, to give 3,5-dichloro-4-(3-cyclopentyloxy-4-methoxybenzamido)- pyridine-N-oxide (0.73g), m.p. 118-120°C [Elemental analysis:-C,53.0;H,4.4;N,6.8%; calculated for
C 18 H18°4N2Cl2:0*5H2O:" C,53.2;H,4.7;N,6.9%] .
EXAMPLE 10
Compound BE
A stirred solution of N-(3,5-dichloropyrid-4- yl)-3-cyclopentyloxy-4-methoxybenzamide (2.0g; prepared as described in Example 6) in toluene (50ml) was treated with 2,4-bis(4-methoxyphenyl)-l,3-dithia-2,4- diphosphetane-2,4-disulphide (3.0g), and the mixture was heated at 100°C for 2 hours. After cooling to room temperature and filtration, the filtrate was concentrated .in vacuo, to give a yellow oil. This oil was subjected to flash chromatography on silica gel, using a mixture of pentane and ethyl acetate (8:2v/v) as eluent, to give N-(3,5-dichloropyrid-4-yl)- 3-cyclopentyloxy-4-methoxy(thiobenzamide) (0.64g) m.p. 118-119°C [Elemental analysis:- C,54.1;H,4.6;C1,17.4; - 39 -
N,6.8%; calculated:- C,54.4;H,4.6;C1,17.85;N,7.05%] .
EXAMPLE 11 Compound BI
A solution of N-(2,6-dichloro-4-nitrophenyl)-3- cyclopentyloxy-4-methoxybenzamide (1.5g; prepared as described in Example 8) in glacial acetic acid (22ml) was treated with iron pin dust (1.3g) and the mixture was heated with stirring at 90 "C for 1 hour. The reaction mixture was cooled, basified to pH8 by treatment with saturated aqueous sodium carbonate solution, and extracted with ethyl acetate (2 x 150ml) . The combined organic extract was dried over magnesium sulphate and concentrated in vacuo, to give a white solid. This solid was subjected to flash chromatography, eluting with a mixture of ethyl acetate and pentane (l:lv/v), to give N-(2,6-dichloro-4-amino- phenyl)-3-cyclopentyloxy-4-methoxybenzamide (0.8g) , m.p. 170-172°C [Elemental analysis:- C,54.8;H,5.04; N,6.5;C1,17.4%; calculated:- C,57.7;H,5.1;N,7.1; Cl,17.9%].
EXAMPLE 12 Compound BM
Acetic anhydride (10ml) was treated with N-(2,6-dichloro-4-aninophenyl)-3-cyclopentyloxy-4- methoxybenzamide (0.8g; prepared as described in Example 11) , and the reaction mixture was stirred for 2 hours and left to stand overnight. It was then poured into water (100ml) , and extracted with ethyl acetate (100ml) and then with dichloromethane (100ml) . The organic extracts were combined, dried over magnesium sulphate, and evaporated, to give N-(4-acetylammo-2,6-dichlorophenyl)-3-cyclopentyloxy- 4-methoxybenzamide (0.4g), m.p. 250-252°C [Elemental analysis:- C,57.6;H,5.05;N,6.3;C1,16.1%; calculated:- C,57.5;H,5.1;N,6.4;C1,16.2%].
EXAMPLE 13 Compounds BN and BU
A stirred solution of N-(3,5-dichloropyrid-4- yl)-3-hydroxy-4-methoxybenzamide (2.0g; prepared as described in Reference Example 12) in dimethylformamide (20ml) at room temperature under nitrogen was treated portionwise with a suspension of sodium hydride (60% dispersion in oil; 0.26g), and then it was stirred for a further hour at room temperature. It was then treated dropwise with 1-bromononane (1.2ml) and stirred at 60°C for 5 hours. The solution was then cooled to room temperature , diluted with water (60ml) , and extracted with ethyl acetate (2x100ml) . The combined organic extracts were dried over magnesium sulphate and evaporated, to give a white solid, which was subjected to flash chromatography on silica gel, eluting with -butyl methyl ether, to give N-(3,5-dichloropyrid-4- yl)-3-nonyloxy-4-methoxybenzamide (0.56g), m.p. . 151-153βC [Elemental analysis:- C,60.3;H,6.45;N,6.3%; calculated:- C,60.1;H,6.4;N,6.4%] .
By proceeding in a similar manner, but using the appropriate quantity of 1-bromododecane, there was prepared N-(3,5-dichloropyrid-4-yl)-3-dodecyloxy-4- ethoxybenzamide, m.p.l43-l45°C.
EXAMPLE 14 Compound BO
A solution of N-(2,6-dichloro-4-hydroxymethyl- phenyl)-3-cyclopentyloxy-4-methoxybenzamide (4.4g) in dichloromethane (30ml) was treated with activated manganese dioxide (6.2g) , and the mixture was stirred at reflux for 24 hours. The mixture was filtered, the filtrate was evaporated, and the resulting residue was subjected to flash chromatography on silica gel, eluting with ethyl acetate, to give N-(2,6-dichloro-4- formylphenyl)-3-cyclopentyloxy-4-methoxybenzamide (2.4g), m.p. 96-98°C [Elemental analysis:- C,59.0; H,5.l;N,3.1%; calculated:- C,58.8;H,4.7;N,3.4%] .
EXAMPLE 15 Compound BT
A stirred solution of N-(2,6-dichloro-4-ethoxy- carbonylpheny1)-3-cyclopentyloxy-4-methoxybenzamide (6.lg;prepared as described in Example 8) in dry tetrahydrofuran (80ml) at room temperature under argon - 42 - was treated dropwise with a solution of lithium . borohydride in tetrahydrofuran (115ml;2M) . The mixture was stirred overnight and then it was treated portionwise with saturated brine (200ml) and stirred for 30 minutes. The organic layer was then washed with water, dried over magnesium sulphate and evaporated. The resulting residue was subjected to flash chromatography on silica gel, to give N-(2,6-dichloro-4-hydroxymethylphenyl)-3-cyclopenty1- oxy-4-methoxybenzamide (4.4g), m.p. 174-176°C [Elemental analysis:- C,57.1;H,5.4;N,2.9%; calculated for C20H21O4NCl2:0.5H2O:- C,57.3;H,5.3;N,3.3%] .
EXAMPLE 16 Compound BR
A solution of N-(3,5-dichloropyrid-4-yl)-3- cyclopentyloxy-4-methoxybenzamide (3.8g; prepared as described in Example 6) in dry tetrahydrofuran (25ml) was treated with a suspension of sodium hydride (60% dispersion in oil; 0.40g), and the mixture was stirred until effervescence had ceased and a solution had formed. This solution was evaporated in vacuo and the resulting residue was triturated with t-butyl methyl ether (20ml) . The resulting off-white solid was filtered off, quickly washed with t-butyl methyl ether (2x20ml) and dried, to give the sodium salt of N-(3,5-dichloropyrid-4-yl)-3-cyclopent loxy-4-methoxy- benzamide (3.5g), m.p. 265-270°C (with decomposition) [NMR(DMSO-Dg) :- 1.52-1.93(m,8H) ,4.77(s,3H) ,4.75-4.80 (m,lH) ,6.98(d,lH) ,7.58(dd,lH) ,7.60(s,lH) ,8.20(s,2H) ; IR spectrum:- strong peak at 1508cm~ , with no peaks at or near 1661cm —1 nor 3244cm—1, which would have been characteristics of the starting material].
EXAMPLE 17
Compounds AU. BF and BP
By proceeding in a manner similar to that described in Example 5, but replacing the 4-chloropyrid-3-ylamine used as a starting material by the appropriate quantities of the corresponding aniline derivatives, there were prepared:-
N-(2,4,6-trifluorophenyl)-3-cyclopentyloxy-4-methoxy- benzamide, m.p. 160-162°C [Elemental analysis:- C,62.5; H,5.0;N,3.6%; calculated:- C,62.5;H,5.0;N,3.8%] ; and N-(2,6-dichloro-4-methoxyphenyl)-3-cyclopentyloxy-4- methoxybenzamide, m.p. 126-128°C [Elemental analysis:- C,57.9;H,4.9;N,3.2%; calculated:- C,58.5;H,5.2;N,3.4%] .
By again proceeding in a similar manner, but replacing the 4-chloropyrid-3-ylamine and the 3-cyclopentyloxy-4-methoxybenzoyl chloride by the appropriate quantities of 2,6-dichloroaniline and 3-(exo-8,9,lO-trinorbornyl-2-oxy)-4-methoxybenzoyl chloride (prepared as described in Reference Example 14), there was prepared N-(2,6-dichlorophenyl)-3-(exo- 8,9,lθ-trinorbornyl-2-oxy)-4-methoxybenzamide, m.p. 106-107°C [Elemental analysis:- C,61.8;H,5.2;N,3.2%; calculated:- C,62.1;H,5.2;N,3.45%] .
EXAMPLE 18 Compounds AO. AS. AT, BP. BH. BJ and BK
By proceeding in a manner similar to that described in Example 6, but replacing the 4-amino-3,5-dichloropyridine used as a starting material by the appropriate quantities of the corresponding amines, there were prepared:- N-(4,6-dichloropyrimid-5-yl)-3-cyclopentyloxy-4- methoxybenzamide, m.p. 191-193°C [Elemental analysis:- C,53.1;H,4.4;C1,18.6;N,10.9%; calculated:- C,53.1; H,4.5;Cl,18.6;N,10.8%];
N-(2,3,5,6-tetrafluoropyrid-4-yl)-3-cyclopentyloxy-4- methoxybenzamide, m.p. 178-180°C [Elemental analysis:- C, 56.0;H,4.l;N,7.2%; calculated:- C,56.25,*H,4.2;N,7.3%];
N-(3,5-dichloro-2,6-difluoropyrid-4-yl)-3-cyclopentyl- oxy-4-methoxybenzamide, m.p. 188-190°C [Elemental analysis:- C,51.5;H,3.8;N,6.8;C1,17.0%; calculated:- C,51.8;H,3.9;N,6.7;C1,17.0%];
N-(5-cyano-3-methylisothiazol-4-yl)-3-cyclopentyloxy- 4-methoxybenzamide, m.p. 163-164°C [Elemental analysis:- C,60.0;H,5.3;N,11.7%; calculated:- C,60.5; H,5.85;N,11.8%]; N-(2,6-dichloro-4-carbamoylphenyl)-3-cyclopentyloxy-4- methoxybenzamide, m.p. 245-247° [Elemental analysis:- C,54.0;H,4.5;N,6.4%; calculated:- C,54.4;H,5.0; N,6.35%]; and
N-(3-chloro-2,5,6-trifluoropyrid-4-yl)-3-cyclopenty1- oxy-4-methoxybenzamide, m.p. 188-190°C [Elemental analysis:- C,53.7;H,3.95;N,6.81;C1,8.9%; calculated:- C,53.94;H,4.0;N,7.0;Cl,8.85%].
By again proceeding in a similar manner, but replacing the 4-amino-3,5-dichloropyridine and the 3-cyclopentyloxy-4-methoxybenzoyl chloride by the appropriate quantities of 4-amino-3,5-dibromopyridine and 3-butoxy-4-methoxybenzoyl chloride (prepared as described in Reference Example 3) , there was prepared N-(3,5-dibromopyrid-4-yl)-3-butoxy-4-methoxybenzamide, m.p. 160-162°C [Elemental analysis:- C,44.6;H,3.9; N,6.1%; calculated:- C,44.6;H,4.0;N,6.1%] .
EXAMPLE 19 Compounds AR. BA and BB
By proceeding in a manner similar to that described in Example 1, but replacing the 2,6-difluoro- aniline used as starting material by the appropriate quantities of the corresponding amines, there were prepared:-
N-(4-nitrophenyl)-3-cyclopentyloxy-4-methoxybenzamide, m.p.l78-180°C [Elemental analysis:- C,64.1;H,5.7; N,7.5%; calculated:- C,64.0;H,5.7;N,7.9%] ; N-(3-methyl-5-bromoisothiazol-4-yl)-3-cyclopentyloxy-4- methoxybenzamide, m.p. 160-162°C [Elemental analysis:- C,50.0;H,4.7;N,6.8%; calculated:- C,49.6;H,4.7;N,6.8%] ; and
N-(3,5-dimethylisothiazol-4-yl)-3-cyclopentyloxy-4- methoxybenzamide, m.p. 140-141°C [Elemental analysis:- C,62.4;H,6.35;N,8.0%; calculated:- C,62.4;H,6.4;N,8.1%] .
REFERENCE EXAMPLE 1 A stirred solution of 3-hydroxy-4-methoxy- benzaldehyde (2.00g) in dry dimethylformamide (20ml) was treated portionwise with sodium hydride (60% in oil; 0.56g) and the mixture was then heated for 1 hour at 50°C. It was then treated dropwise with cyclopentyl bromide (2.36g) and was stirred and heated at 50°C for 22 hours. The solution was diluted with water (100ml) and extracted with diethyl ether (2x100ml) . The ethereal extracts were combined, dried over magnesium sulphate and concentrated, to give 3-cyclopentyloxy-4-methoxybenzaldehyde (1.65g) in the form of a golden oil.
By proceeding in a similar manner, but using the appropriate quantities of cyclohexyl bromide, butyl bromide and propyl bromide, respectively, there were prepared:-
3-cyclohexyloxy-4-methoxybenzaldehyde in the form of a golden oil [Elemental analysis:- C,71.8;H,7.8%; Calculated:- C,71.8;H,7.7%];
3-butoxy-4-methoxybenzaldehyde in the form of a light brown oil [NMR(CDC13) :- 1.0(t,3H) ,1.5(m,2H) ,1.9(m,2H) , 3.96(S,3H) ,4.1(t,2H) ,6.96(d,lH) ,7.4(m,2H) ,9.8(S,1H) ] ; and 3-propoxy-4-methoxybenzaldehyde [NMR(CDCl^) :- 9.85(S,1H) ,7.4(dd,lH) ,7.4(d,lH) ,7.0(d,lH) ,4.05(t,2H) , 4.0(s,3H) ,1.9(m,2H) ,1.06(t,3H) ] . REFERENCE EXAMPLE 2 A stirred saturated aqueous solution of potassium permanganate (100ml) was treated with 3-cyclopentyloxy- 4-methoxybenzaldehyde (7.4g; prepared as described hereinbefore in Reference Example 1) and sodium carbonate (3.4g) and the mixture was stirred at 50°C for 1 hour, and then cooled to room temperature. The reaction mixture was acidified by treatment with concentrated hydrochloric acid and then it was treated with aqueous sodium bisulphite solution until a colourless solution was obtained. The reaction mixture was extracted with dichloromethane (2x100ml) and the organic extracts were dried over magnesium sulphate and concentrated. The resulting residue was recrystallised from diethyl ether, to give 3-cyclo¬ pentyloxy-4-methoxybenzoic acid (4.78g) in the form of white crystals. [NMR(CDC13) :- 1.7(s,2H) ,1.8-2.2 (m,6H) ,3.95(S,3H) ,4.85(S,1H) ,6.9(bs,IH)7.6(bs,IH) , 7.8(s,lH) ,9.8(s,lH) ; Elemental analysis:- C,65.6; H,6.8%; Calculated:- C,66.1;H,6.8%] .
By proceeding in a similar manner, but using the appropriate quantities of the corresponding benzaldehyde derivatives, prepared as described hereinbefore in Reference Example 1, there were prepared:- 3-cyclohexyloxy-4-methoxybenzoic acid in the form of a white solid, m.p. 158-160°C [NMR(CDC13) :- 1.2-2.1 (m,10H) ,3.94(S,3H) ,4.3(m,lH) ,6.9(d,IH) ,7.6(S,IH) ,7.75 (d,lH)];
3-butoxy-4-methoxybenzoic acid in the form of a white solid, m.p. 130-132°C [NMR(CDC13) :- 1.0 (t,3H), 1.5 (m,2H) ,1.85(m,2H) ,3.95(S,3H) ,4.1(t,2H) ,6.92(d,2H) ,7.6 (s,lH) ,7.75(d,lH) ]; and
3-propoxy-4-methoxybenzoic acid [ (NMR(CDC1_,) :- 7.76 (dd,lH) ,7.6(d,lH) ,6.9(d,lH) ,4.04(t,2H) ,3.94(s,3H) ,1.9 (m,2H) ,1.05(t,3H) ].
REFERENCE EXAMPLE 3 Stirred thionyl chloride (20ml) was treated with 3-cyclopentyloxy-4-methoxybenzoic acid (5.0g; prepared as described hereinbefore in Reference Example 2) portionwise and the solution was then heated at 85°C for 3 hours. Toluene (50ml) was added and the mixture was concentrated to give 3-cyclopentyloxy-4- methoxybenzoyl chloride (4.12g) in the form of an oil which slowly crystallised. [NMR(CDC1_) :- 1.6-1.7 (m,2H) ,1.8-1.95(m,4H) ,1.94-2.05(m,2H) ,3.94(s,3H) ,4.85 (m,lH) ,6.9(d,lH) ,7.55(d,lH) ,7.8(q,lH) ; Elemental analysis:- C,61.3;H,5.94;C1,13.9%; Calculated:- C,61.3; H,5.94;C1,13.92%] .
By proceeding in a similar manner, but using the appropriate quantities of the corresponding benzoic acid derivatives, prepared as described hereinbefore in Reference Example 2, there were prepared:- 3-cyclohexyloxy-4-methoxybenzoyl chloride in the form of a colourless solid;
3-butoxy-4-methoxybenzoyl chloride in the form of a light brown oil; and
3-propoxy-4-methoxybenzoyl chloride [ (NMR(CDCl-) :- 7.82 (dd,lH) ,7.53(d,lH) ,6.92(d,lH) ,4.03 (t,2H) ,3.96(s,3H) ,1.89 (m,2H) ,1.06(t,3H)].
REFERENCE EXAMPLE 4 A stirred solution of 4-aminopyridine (40g) in concentrated hydrochloric acid (500ml) at 80°C. was treated dropwise with aqueous hydrogen peroxide solution (200ml;15%w/w) , keeping the temperature between 80°C. and 85βC. The solution was then cooled and basified by dropwise treatment with aqueous sodium hydroxide solution (50%w/w) , keeping the temperature below 15°C The resulting white flocculent precipitate was recrystallised from toluene, to give 4-amino-3,5-dichloropyridine (61.5g) , m.p. 161.5-162.5°C. REFERENCE EXAMPLE 5 A solution of 4-aminopyridine (47g) in concentrated hydrochloric acid (355ml) was treated portionwise at 80°C with an aqueous solution of sodium hypochlorite (550ml,*15%w/v) . The mixture was cooled to 30°C and basified by treatment with aqueous sodium hydroxide solution (300ml;35%w/v) during 20 minutes. The mixture was stirred and cooled for a further 30 minutes and then it was filtered. The solid was washed well with water and dried at 60°C, to give 4-amino-3,5-dichloropyridine (69.5g) .
REFERENCE EXAMPLE 6 A solution of 3-cyclopentyloxy-4-methoxybenz- aldehyde (66g) and sulphamic acid (39.6g) in glacial acetic acid (500ml) was treated dropwise during 1 hour with a solution of sodium chlorite (35g) in water (150ml) . The mixture was stirred at 20°C during 1 hour and then it was treated with water (500ml) dropwise during 30 minutes. The resulting solid was filtered, washed with water and dried, to give 3-cyclopentyloxy-4-methoxybenzoic acid (60.9g) in the form of white crystals [Elemental analysis:- C,65.8; H,6.7%; calculated:- C,66.1;H,6.8%] .
REFERENCE EXAMPLE 7 A solution of triphenylphosphine (17.5g) in dry tetrahydrofuran (50ml) under nitrogen was treated with a solution of diisopropyl azodicarboxylate (13.5g) in dry tetrahydrofuran (50ml) . The solution was stirred was treated with a solution of endo-8,9,10-trinor- borneol (5.0g) in dry tetrahydrofuran (50ml) followed by a solution of 3-hydroxy-4-methoxybenzaldehyde (10.2g) in dry tetrahydrofuran (50ml). The solution was heated at reflux for 15 hours, cooled, poured into water (600ml) , and extracted with diethyl ether (300ml) . The extract was washed with water (100ml) , with aqueous sodium hydroxide solution (2xl00ml;lM) and with water (2xl00ml) , dried over magnesium sulphate and evaporated, to give an oil, which was subjected to flash chromatography on silica gel, eluting with a mixture of pentane and ethyl acetate (95:5v/v) to give 3-(exo-8,9,10-trinorbornyl-2-oxy)-4-methoxybenzaldehyde (3.2g), m.p. 56-61°C.
REFERENCE EXAMPLE 8 A stirred suspension of 3-hydroxy-4-methoxybenz- aldehyde (50g) in water (200ml) at between 0 and 5°C was treated dropwise with an aqueous solution of sodium hydroxide (200ml;20%w/v) , followed at between 0 and 5°C by benzoyl chloride (38ml) . The reaction mixture was stirred at between 0 and 5°C for 1 hour and then it was allowed to warm to room temperature and was stirred for a further period of 2 hours. The resulting solution was extracted with dichloromethane (2x200ml) and the combined extract was washed with water (200ml) , dried over magnesium sulphate and concentrated, to give 2-methoxy-5-formylphenyl benzoate (35.2g) , m.p.70-72°C.
REFERENCE EXAMPLE 9
A stirred solution of potassium permanganate (28g) in acetone (200ml) was treated with 2-methoxy-5- formylphenyl benzoate (35.2g; prepared as described in Reference Example 8) , and the resulting vigorously reacting mixture was cooled in an ice bath. It was then stirred at room temperature for 3 hours. The mixture was then concentrated and the residue was treated with saturated aqueous sodium metabisulphite solution (300ml) . The resulting white solid was filtered off, washed well with water (200ml) , and dried, to give 3-benzoyloxy-4-methoxybenzoic acid (29.3g), m.p. 180-183°C.
REFERENCE EXAMPLE 10
A solution of 3-benzoyloxy-4-methoxybenzoic acid (29.3g; prepared as described in Reference Example 9) in toluene (300ml) was treated with thionyl chloride (30ml) and heated on the steam bath for 6 hours. It was then cooled, filtered and concentrated, to give 3-benzoyloxy-4-methoxybenzoyl chloride (28.7g), m.p. 120-122°C. REFERENCE EXAMPLE 11 By proceeding in a manner similar to that described in Example 8, but using 3-benzoyloxy-4- methoxybenzoyl chloride (prepared as described in Reference Example 10) and 4-amino-3,5-dichloropyridine (prepared as described in Reference Example 4) as starting materials, there was prepared N-(3,5-dichloro- pyrid-4-yl)-3-benzoyloxy-4-methoxybenzamide, m.p. 191-192°C.
REFERENCE EXAMPLE 12 A solution of N-(3,5-dichloropyrid-4-yl)-3- benzoyloxy-4-methoxybenzamide (13.4g; prepared as described in Reference Example 11) in methanol (160ml) and water (60ml) was treated with anhydrous potassium carbonate (18g) , and stirred overnight at room temperature. It was then brought to pH7 by treatment with dilute hydrochloric acid (2N) , and concentrated. The residue was treated with water (100ml) and filtered, and the resulting solid was dried, to give N-(3,5-dichloropyrid-4-yl)-3-hydroxy-4-methoxybenzamide (8.8g), m.p. 227-228°C.
REFERENCE EXAMPLE 13 By proceeding in a manner similar to that described in Reference Example 2, but using the appropriate quantities of 3-(exo-8,9,10-trinorbornyl- 2-oxy)-4-methoxybenzaldehyde (prepared as described in Reference Example 7) and (R)-3-(exo-8,9,10-trinor- bornyl-2-oxy)-4-methoxybenzaldehyde and (S)-3-(exo- 8,9,lO-trinorbornyl-2-oxy)-4-methoxybenzaldehyde [similarly prepared from (R)-endo-8,9,10-trinorborneol and ( S)-endo-8,9.10-trinorborneol or as described in the specification of European Patent Publication No. 0428302A2] there were prepared:-
3-(exo)-8,9,10-trinorbornyl-2-oxy-4-methoxybenzoic acid, m.p. 155-156°C;
(R)-3-(exo -8,9,l0-trinorbornyl-2-oxy-4-methoxybenzoic acid, m.p. 155-156°C; and
(H)-3-(exo)-8,9,10-trinorbornyl-2-oxy-4-methoxybenzoic acid, m.p. 155-156°C.
REFERENCE EXAMPLE 14 By proceeding in a manner similar to that described in Reference Example 3, but using the appropriate quantities of the corresponding benzoic acid derivatives, prepared as described hereinbefore in Reference Example 13, there were prepared:- 3-(exo)-8,9,10-trinorbornyl-2-oxy-4-methoxybenzoyl chloride;
(E)-3-(exo)-8,9,lθ-trinorbornyl-2-oxy-4-methoxybenzoyl chloride; and
(S)-3-(exo)-8,9,10-trinorbornyl-2-oxy-4-methoxybenzoyl chloride; each in the form of oils. The present invention also includes within its scope pharmaceutical formulations which comprise at least one of the compounds of formula I or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable carrier or coating.
In clinical practice compounds of the present invention may be administered parenterally, rectally or orally, but they are preferably administered by inhalation.
Suitable compositions containing compounds of the invention and pharmaceutically acceptable salts thereof may be prepared by conventional means. For example, compounds of the invention and pharmaceutically acceptable salts thereof may be dissolved or suspended in a suitable carrier for use in a nebuliser or a suspension or solution aerosol, or may be absorbed or adsorbed onto a suitable solid carrier for use in a dry powder inhaler.
Solid compositions for oral administration include compressed tablets, pills, powders and granules. In such solid compositions, one or more of the active compounds is, or are, admixed with at least one inert diluent such as starch, sucrose or lactose. The compositions may also comprise, as is normal practice, additional substances other than inert diluents, e.g. lubricating agents, such as magnesium stearate.
Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art such as water and liquid paraffin. Besides inert diluents such compositions may comprise adjuvants, such as wetting and suspending agents, and sweetening, flavouring, perfuming and preserving agents. The compositions according to the invention for oral administration also include capsules of absorbable material such as gelatin, containing one or more of the active substances with or without the addition of diluents or excipients.
Compositions according to the invention for parenteral administration include sterile aqueous, aqueous-organic, and organic solutions, suspensions and emulsions. Examples of organic solvents or suspending media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. The compositions may also contain adjuvants such as stabilising, preserving, wetting, emulsifying and dispersing agents. They may be sterilised, for example, by filtration through a bacteria-retaining filter, by incorporation in the compositions of sterilising agents, by irradiation or by heating. They may also be manufactured in the form of sterile solid compositions, which can be dissolved in sterile water or some other sterile injectable medium immediately before use.
Solid compositions for rectal administration include suppositories formulated in accordance with known methods and containing at least one compound of formula I.
The percentage of active ingredient in the compositions of the invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained. Obviously, several unit dosage forms may be administered at about the same time. The dose employed will be determined by the physician, and depends upon the desired therapeutic effect, the route of administration and the duration of the treatment, and the condition of the patient. In the adult, the doses are generally from about 0.001 to about 50, preferably about 0.001 to about 5, mg/kg body weight per day by inhalation. The following Composition Examples illustrate pharmaceutical compositions according to the present invention.
COMPOSITION EXAMPLE 1
N-(2,6-difluorophenyl)-3-cyclopentyloxy-4- methoxybenzamide (l.Og) (mean particle size 3.5 microns) and lactose (mean particle size 72 microns) were blended together for 30 minutes in a mechanical shaker/mixer. The resulting blend was filled, to a fill weight of 25mg, into No.3 hard gelatine capsules, to give a product suitable for use, for example, with a dry powder inhaler.
COMPOSITION EXAMPLE 2
N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4- methoxybenzamide (l.Og) (mean particle size 3.5 microns) and lactose (mean particle size 72 microns) were blended together for 30 minutes in a mechanical shaker/mixer. The resulting blend was filled, to a fill weight of 25mg, into No.3 hard gelatine capsules, to give a product suitable for use, for example, with a dry powder inhaler.

Claims

CLAIMS l. A benzamide derivative of the general formula
(I):
wherein R1 represents a straight- or branched-chain alkyl group containing up to 4 carbon atoms, R2 represents a straight- or branched-chain alkyl group containing from 2 to 15 carbon atoms or a mono-, bi- or tricycloalkyl group containing up to 10 carbon atoms, R3 represents an optionally substituted phenyl, naphthyl or heterocyclyl group, and Z represents an oxygen or sulphur atom, and when said heterocyclyl groups contain one or more nitrogen ring atoms, N-oxides thereof, and pharmaceutically acceptable salts thereof.
2. A compound according to claim 1 wherein the heterocyclyl group is a 5-, 6- or 7-membered heterocyclyl group containing one or more hetero atoms selected from oxygen, sulphur and nitrogen atoms, and the optional substituents on phenyl, naphthyl or heterocyclyl being one or more substituents selected from halogen atoms, alkyl groups which may carry one or more halogen atoms, and from aryl, arylalkyl, alkoxy, aryloxy, alkylthio, arylthio, alkoxycarbonyl, aryloxycarbonyl, alkanoyl, aroyl, alkylsulphonyl, arylsulphonyl, alkylsulphinyl, arylsulphinyl, hydroxy, hydroxyalkyl, formyl, alkanoylamino, aroylamino, cyano and nitro groups, and from amino, carbamoyl and sulphamoyl groups which themselves may each carry one or two alkyl substituents, wherein all aryl groups and moieties, unless otherwise indicated, are selected from phenyl and naphthyl groups optionally substituted by one or more substituents selected from halogen atoms and alkyl and alkoxy groups, and wherein all alkyl groups and moieties, unless otherwise indicated, are straight- or branched-chain and contain up to 4 carbon atoms.
3. A compound according to claim 1 or 2 wherein R2 represents a straight- or branched-chain alkyl group containing from 2 to 12 carbon atoms.
4. A compound according to claim 1 wherein at least one of the symbols has a value selected from the following:-
(i) R1 represents a methyl group;
(ii) R2 represents a propyl, butyl, nonyl, dodecyl, cyclohexyl, 8,9,10-trinorbornyl or cyclopentyl group; and/or
(iii) R3 represents an optionally substituted pyrazinyl, pyrimidinyl, isoxazolyl, or pyridyl group, or an N-oxide thereof, or an optionally substituted phenyl group; the other symbols being as hereinbefore defined.
5. A compound according to claim 4 wherein R2 represents cyclopentyl and R3 represents optionally substituted pyridyl.
6. A compound according to any one of preceding claims wherein R3 represents a phenyl group which is substituted in the 2-position or in the 2- and 6- positions.
7. A compound according to any one of claims 1 to 5 wherein R3 represents a heterocyclyl group substituted on one or both of the positions next to the point of attachment to the rest of the molecule.
8. A compound according to claim 1 which is hereinbefore identified as any one of A to BX or a pharmaceutically acceptable salt thereof.
9. A process for the preparation of a compound according to claim 1 which comprises
(a) the reaction of a compound of the general formula (II) :
wherein R1 and R2 are as defined in claim 1 and X1 represents a halogen atom with a compound of the general formula (III) :
NH-R5 (III) wherein R3 is as defined in claim 1; or
(b) the reaction of a compound of the general formula
wherein R!, R3 and Z are as defined in claim 1 with a compound of the general formula (V) :
RX2 (V)
wherein R2 is as defined in claim l and X2 represents a halogen atom; optionally followed by the conversion of a compound of general formula (I) thus obtained into another compound of σeneral formula (I) ; and optionally converting the compound of general formula
(I) thus obtained into a salt thereof.
10. A pharmaceutical composition which comprises a benzamide derivative of general formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable carrier or coating.
11. A method for the treatment of a human or animal patient suffering from, or subject to, a condition which can be ameliorated by the administration of an inhibitor of cyclic AMP phosphodiesterase, which method comprises the administration of an effective amount of a benzamide derivative as defined in claim 1 or a pharmaceutically acceptable salt thereof.
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Families Citing this family (110)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9311281D0 (en) * 1993-06-01 1993-07-21 Rhone Poulenc Rorer Ltd Novel composition of matter
US5698711A (en) 1991-01-28 1997-12-16 Rhone-Poulenc Rorer Limited Compounds containing phenyl linked to aryl or heteroaryl by an aliphatic- or heteroatom-containing linking group
GB9204808D0 (en) * 1992-03-04 1992-04-15 Rhone Poulenc Rorer Ltd Novel compositions of matter
GB9212673D0 (en) * 1992-06-15 1992-07-29 Celltech Ltd Chemical compounds
GB9212693D0 (en) * 1992-06-15 1992-07-29 Celltech Ltd Chemical compounds
WO1993025517A1 (en) * 1992-06-15 1993-12-23 Celltech Limited Trisubstituted phenyl derivatives as selective phosphodiesterase iv inhibitors
JP3775684B2 (en) * 1992-07-28 2006-05-17 ローン−プーラン・ロレ・リミテツド Phenyl-containing compounds linked to an aryl or heteroaryl by an aliphatic- or heteroatom-containing linking group
US5679696A (en) * 1992-07-28 1997-10-21 Rhone-Poulenc Rorer Limited Compounds containing phenyl linked to aryl or heteroaryl by an aliphatic-or heteroatom-containing linking group
GB2269992A (en) * 1992-08-14 1994-03-02 Rh Ne Poulenc Rorer Limited Powder inhalation formulations
GB9222253D0 (en) * 1992-10-23 1992-12-09 Celltech Ltd Chemical compounds
GB9304919D0 (en) * 1993-03-10 1993-04-28 Celltech Ltd Chemical compounds
GB9304920D0 (en) * 1993-03-10 1993-04-28 Celltech Ltd Chemical compounds
GB9311282D0 (en) * 1993-06-01 1993-07-21 Rhone Poulenc Rorer Ltd New compositions of matter
GB9312853D0 (en) 1993-06-22 1993-08-04 Euro Celtique Sa Chemical compounds
SI0706513T1 (en) * 1993-07-02 2002-10-31 Altana Pharma Ag Fluoroalkoxy-substituted benzamides and their use as cyclic nucleotide phosphodiesterase inhibitors
GB9315595D0 (en) * 1993-07-28 1993-09-08 Res Inst Medicine Chem New compounds
EP0711282B1 (en) 1993-07-28 2002-06-05 Aventis Pharma Limited Compounds as pde iv and tnf inhibitors
US5665754A (en) * 1993-09-20 1997-09-09 Glaxo Wellcome Inc. Substituted pyrrolidines
US5502072A (en) * 1993-11-26 1996-03-26 Pfizer Inc. Substituted oxindoles
GB9326173D0 (en) * 1993-12-22 1994-02-23 Celltech Ltd Chemical compounds and process
DE69433594T2 (en) * 1993-12-22 2004-08-05 Celltech R&D Ltd., Slough TRISUBSTITUTED PHENYL DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THE USE THEREOF AS PHOSPHODIESTERASE (TYPE IV) INHIBITORS
GB9401460D0 (en) * 1994-01-26 1994-03-23 Rhone Poulenc Rorer Ltd Compositions of matter
US5786354A (en) * 1994-06-21 1998-07-28 Celltech Therapeutics, Limited Tri-substituted phenyl derivatives and processes for their preparation
US6245774B1 (en) 1994-06-21 2001-06-12 Celltech Therapeutics Limited Tri-substituted phenyl or pyridine derivatives
GB9412571D0 (en) 1994-06-22 1994-08-10 Celltech Ltd Chemical compounds
GB9412573D0 (en) * 1994-06-22 1994-08-10 Celltech Ltd Chemical compounds
GB9412672D0 (en) * 1994-06-23 1994-08-10 Celltech Ltd Chemical compounds
US5591776A (en) * 1994-06-24 1997-01-07 Euro-Celtique, S.A. Pheynl or benzyl-substituted rolipram-based compounds for and method of inhibiting phosphodiesterase IV
US5922751A (en) * 1994-06-24 1999-07-13 Euro-Celtique, S.A. Aryl pyrazole compound for inhibiting phosphodiesterase IV and methods of using same
ATE196765T1 (en) * 1994-07-22 2000-10-15 Byk Gulden Lomberg Chem Fab DIHYDROBENZOFURANES
US5665737B1 (en) * 1994-10-12 1999-02-16 Euro Celtique Sa Substituted benzoxazoles
TW334337B (en) * 1994-11-07 1998-06-21 Novartis Ag Preparation and composition for a compound of controlling and preventing phytopathogenic fungi
WO1996018399A1 (en) 1994-12-13 1996-06-20 Euro-Celtique, S.A. Aryl thioxanthines
US6025361A (en) * 1994-12-13 2000-02-15 Euro-Celtique, S.A. Trisubstituted thioxanthines
GB9507297D0 (en) * 1995-04-07 1995-05-31 Rh Ne Poulenc Rorer Limited New composition of matter
WO1996036595A1 (en) * 1995-05-19 1996-11-21 Chiroscience Limited 3,4-disubstituted-phenylsulphonamides and their therapeutic use
AU5772396A (en) * 1995-05-19 1996-11-29 Chiroscience Limited 3,4-disubstituted-phenylsulphonamides and their therapeutic use
US6268373B1 (en) 1995-06-07 2001-07-31 Euro-Celtique S.A. Trisubstituted thioxanthines
ATE237589T1 (en) * 1995-06-07 2003-05-15 Pfizer CATECHOL DIETHER DERIVATIVES USABLE AS PHARMACEUTICAL AGENTS
WO1997003967A1 (en) * 1995-07-22 1997-02-06 Rhone-Poulenc Rorer Limited Substituted aromatic compounds and their pharmaceutical use
GB9523675D0 (en) 1995-11-20 1996-01-24 Celltech Therapeutics Ltd Chemical compounds
GB9526245D0 (en) * 1995-12-21 1996-02-21 Celltech Therapeutics Ltd Chemical compounds
GB9526246D0 (en) * 1995-12-21 1996-02-21 Celltech Therapeutics Ltd Chemical compounds
US6075016A (en) 1996-04-10 2000-06-13 Euro-Celtique S.A. 6,5-fused aromatic ring systems having enhanced phosphodiesterase IV inhibitory activity
GB9608435D0 (en) * 1996-04-24 1996-06-26 Celltech Therapeutics Ltd Chemical compounds
US5864037A (en) 1996-06-06 1999-01-26 Euro-Celtique, S.A. Methods for the synthesis of chemical compounds having PDE-IV inhibitory activity
EP2223920A3 (en) 1996-06-19 2011-09-28 Aventis Pharma Limited Substituted azabicyclic compounds
US5744473A (en) * 1996-09-16 1998-04-28 Euro-Celtique, S.A. PDE IV inhibitors: "bis-compounds"
GB9619284D0 (en) * 1996-09-16 1996-10-30 Celltech Therapeutics Ltd Chemical compounds
GB9622363D0 (en) * 1996-10-28 1997-01-08 Celltech Therapeutics Ltd Chemical compounds
US5958926A (en) * 1996-11-01 1999-09-28 Nitromed, Inc. Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses
WO1998023620A1 (en) * 1996-11-28 1998-06-04 Cheil Jedang Corporation Cathecol derivatives and a method for the preparation thereof and a pharmaceutical composition containing the same
GB9625184D0 (en) * 1996-12-04 1997-01-22 Celltech Therapeutics Ltd Chemical compounds
WO1998028281A1 (en) 1996-12-23 1998-07-02 Celltech Therapeutics Limited Fused polycyclic 2-aminopyrimidine derivatives, their preparation and their use as protein tyrosine kinase inhibitors
AU5337498A (en) 1997-01-22 1998-08-18 Rhone-Poulenc Rorer Pharmaceuticals Inc. Substituted beta-thiocarboxylic acids
GB9705361D0 (en) 1997-03-14 1997-04-30 Celltech Therapeutics Ltd Chemical compounds
GB9713087D0 (en) * 1997-06-20 1997-08-27 Celltech Therapeutics Ltd Chemical compounds
ES2222614T3 (en) 1997-11-12 2005-02-01 Mitsubishi Chemical Corporation DERIVATIVES OF PURINE AND MEDICINE THAT CONTAINS THEM AS ACTIVE INGREDIENT.
CZ20004350A3 (en) * 1998-05-22 2002-02-13 Avanir Pharmaceuticals Benzimidazole derivatives functioning as IgE modulators
US6369091B1 (en) 1998-05-22 2002-04-09 Avanir Pharmaceuticals Benzimidazole analogs as down-regulators of IgE
US6919366B2 (en) 1998-05-22 2005-07-19 Avanir Pharmaceuticals Benzimidazole derivatives as modulators of IgE
US6911462B2 (en) 1998-05-22 2005-06-28 Avanir Pharmaceuticals Benzimidazole compounds for regulating IgE
US6303645B1 (en) 1998-05-22 2001-10-16 Avanir Pharmaceuticals Benzimidazole derivatives as modulators of IgE
NZ510719A (en) 1998-10-06 2003-02-28 Dainippon Pharmaceutical Co 2,3-disubstituted pyridine derivatives exhibiting phosphodiesterase IV inhibitory activity
JP4336913B2 (en) * 1999-02-12 2009-09-30 大塚製薬株式会社 Method for producing amide derivative
DE60006663T2 (en) 1999-05-11 2004-10-07 Mitsubishi Chem Corp DIHYDRATE OF A PURINE DERIVATIVE, MEDICINES THAT CONTAIN THIS AS AN ACTIVE ACTIVE SUBSTANCE AND INTERMEDIATE PRODUCTS FOR THEIR PRODUCTION
KR100473967B1 (en) * 1999-05-25 2005-03-07 씨제이 주식회사 Cathecol Carboxylamide Derivatives and Pharmaceutical Composition Containing Said Compounds
GB9914258D0 (en) 1999-06-18 1999-08-18 Celltech Therapeutics Ltd Chemical compounds
DE60043318D1 (en) 1999-08-21 2010-01-14 Nycomed Gmbh Synergistic combination of pumafentrine and salmeterol
GB9924862D0 (en) 1999-10-20 1999-12-22 Celltech Therapeutics Ltd Chemical compounds
US6759425B2 (en) 1999-10-21 2004-07-06 Avanir Pharmaceuticals Benzimidazole compounds for modulating IgE and inhibiting cellular proliferation
US7217722B2 (en) 2000-02-01 2007-05-15 Kirin Beer Kabushiki Kaisha Nitrogen-containing compounds having kinase inhibitory activity and drugs containing the same
EP2258689A1 (en) 2000-03-16 2010-12-08 Biolipox AB Benzylated PDE4 inhibitors
CA2407780A1 (en) * 2000-05-25 2001-11-29 Merck Frosst Canada & Co./Merck Frosst Canada & Cie Fluoroalkoxy-substituted benzamide dichloropyridinyl n-oxide pde4 inhibitor
ATE369853T1 (en) 2001-03-12 2007-09-15 Avanir Pharmaceuticals BENZIMIDAZOLE DERIVATIVES FOR IGE MODULATION AND CELL PROLIFERATION INHIBITION
CN1537018A (en) 2001-05-23 2004-10-13 田边制药株式会社 Therapeutic compositions for repairing chondropathy
US20040146561A1 (en) 2001-05-23 2004-07-29 Naoki Sakurai Compositions for promoting healing of bone fracture
WO2002096888A1 (en) 2001-05-29 2002-12-05 Schering Aktiengesellschaft Cdk inhibiting pyrimidines, production thereof and their use as medicaments
MY140561A (en) 2002-02-20 2009-12-31 Nycomed Gmbh Dosage form containing pde 4 inhibitor as active ingredient
AU2003263393A1 (en) * 2002-09-04 2004-03-29 Glenmark Pharmaceuticals Limited New heterocyclic amide compounds useful for the treatment of inflammatory and allergic disorders: process for their preparation and pharmaceutical compositions containing them
AU2003270426A1 (en) 2002-09-12 2004-04-30 Avanir Pharmaceuticals PHENYL-INDOLE COMPOUNDS FOR MODULATING IgE AND INHIBITING CELLULAR PROLIFERATION
TWI276631B (en) 2002-09-12 2007-03-21 Avanir Pharmaceuticals Phenyl-aza-benzimidazole compounds for modulating IgE and inhibiting cellular proliferation
US6822114B1 (en) * 2002-10-08 2004-11-23 Albemarle Corporation Process for production of fluoroalkoxy-substituted benzamides and their intermediates
JP2006506379A (en) 2002-10-23 2006-02-23 グレンマーク・ファーマシューティカルズ・リミテッド Novel tricyclic compounds useful for the treatment of inflammatory and allergic diseases: methods for their preparation and pharmaceutical compositions containing them
US7772188B2 (en) 2003-01-28 2010-08-10 Ironwood Pharmaceuticals, Inc. Methods and compositions for the treatment of gastrointestinal disorders
KR20050115331A (en) 2003-04-01 2005-12-07 어플라이드 리서치 시스템스 에이알에스 홀딩 엔.브이. Inhibitors of phosphodiesterases in infertility
BRPI0409747A (en) 2003-04-11 2006-05-09 Glenmark Pharmaceuticals Sa novel heterocyclic compounds useful for treating inflammatory and allergic disorders, processes for their preparation and pharmaceutical compositions containing these
CA2561047C (en) * 2004-04-08 2013-07-16 Wyeth Method for preparing 3-cyclopentyloxy-4-methoxybenzaldehyde
CA2583497A1 (en) 2004-10-13 2006-04-20 Glenmark Pharmaceuticals S.A. Process for the preparation of n-(3,5-dichloropyrid-4-yl)-4difluoromethoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamide
SI1831227T1 (en) 2004-12-17 2013-09-30 Glenmark Pharmaceuticals S.A. Novel heterocyclic compounds useful for the treatment of inflammatory and allergic disorders
KR101317119B1 (en) 2004-12-17 2013-10-11 그렌마크 파머수티칼스 에스. 아. Novel heterocyclic compounds useful for the treatment of inflammatory and allergic disorders
ES2351161T3 (en) * 2005-05-03 2011-02-01 Ranbaxy Laboratories Limited AZOL-BASED PHOSPHODIESTERASE INHIBITORS.
MY154498A (en) 2007-05-16 2015-06-30 Takeda Gmbh Pyrazolone derivatives as pde4 inhibitors
MX354786B (en) 2007-06-04 2018-03-21 Synergy Pharmaceuticals Inc AGONISTS OF GUANYLATE CYCLASE USEFUL FOR THE TREATMENT OF GASTROINTESTINAL DISORDERS, INFLAMMATION, CANCER and OTHER DISORDERS.
US8969514B2 (en) 2007-06-04 2015-03-03 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
CA2726917C (en) 2008-06-04 2018-06-26 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
WO2010009319A2 (en) 2008-07-16 2010-01-21 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders
US10640457B2 (en) 2009-12-10 2020-05-05 The Trustees Of Columbia University In The City Of New York Histone acetyltransferase activators and uses thereof
US9616097B2 (en) 2010-09-15 2017-04-11 Synergy Pharmaceuticals, Inc. Formulations of guanylate cyclase C agonists and methods of use
WO2012088420A1 (en) * 2010-12-22 2012-06-28 The Trustees Of Columbia University In The City Of New York Histone acetyltransferase modulators and usese thereof
US9580471B2 (en) 2011-03-01 2017-02-28 Synergy Pharmaceuticals, Inc. Process of preparing guanylate cyclase C agonists
WO2013084182A1 (en) 2011-12-08 2013-06-13 Glenmark Pharmaceuticals S.A. Pharmaceutical composition that includes a pde4 enzyme inhibitor and an analgesic agent
US9545446B2 (en) 2013-02-25 2017-01-17 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase and their uses
WO2014151200A2 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions useful for the treatment of gastrointestinal disorders
EP2970384A1 (en) 2013-03-15 2016-01-20 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase and their uses
JP6606491B2 (en) 2013-06-05 2019-11-13 シナジー ファーマシューティカルズ インコーポレイテッド Ultra high purity agonist of guanylate cyclase C, method for producing and using the same
JP6694385B2 (en) 2013-08-09 2020-05-13 アーデリクス，インコーポレーテッド Compounds and methods for inhibiting phosphate transport
EP3165224A1 (en) 2015-11-09 2017-05-10 Albert-Ludwigs-Universität Freiburg Use of pde4 inhibitors for the prophylaxis and/or therapy of dyslipoproteinaemia and related disorders
WO2017089347A1 (en) 2015-11-25 2017-06-01 Inserm (Institut National De La Sante Et De La Recherche Medicale) Methods and pharmaceutical compositions for the treatment of braf inhibitor resistant melanomas
WO2020237096A1 (en) 2019-05-21 2020-11-26 Ardelyx, Inc. Combination for lowering serum phosphate in a patient

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5869812A (en) 1981-10-22 1983-04-26 Chugai Pharmaceut Co Ltd Blood sugar level depressing agent
JPS62158252A (en) * 1985-12-28 1987-07-14 Kirin Brewery Co Ltd 4-aminopyridinebenzamide derivative
WO1991007501A1 (en) 1989-11-13 1991-05-30 Pfizer Inc. Enzymatic resolution of endo-bicyclo[2.2.1]heptan-2-ol and derived pharmaceutical agents

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9212961A1 *

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