CA2091989A1 - Phenylpyridinol derivatives as medicaments - Google Patents
Phenylpyridinol derivatives as medicamentsInfo
- Publication number
- CA2091989A1 CA2091989A1 CA002091989A CA2091989A CA2091989A1 CA 2091989 A1 CA2091989 A1 CA 2091989A1 CA 002091989 A CA002091989 A CA 002091989A CA 2091989 A CA2091989 A CA 2091989A CA 2091989 A1 CA2091989 A1 CA 2091989A1
- Authority
- CA
- Canada
- Prior art keywords
- pyridin
- tetrazolyl
- methoxy
- phenyl
- cyano
- 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.)
- Abandoned
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/04—Drugs for genital or sexual disorders; Contraceptives for inducing labour or abortion; Uterotonics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
- C07D213/85—Nitriles in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
Phenylpyridinol derivatives are disclosed as medicaments.
Description
W092/06085 2 0 919 ~ 9 PCT/GB91/~1663 PHENYLPYRIDINOL DERIVATIVES
AS MEDICAMENTS
The present invention relates to pyridinol derivatives, processes for their preparation, intermediates in their preparation, their use as medicaments and to pharmaceutical compositions comprising them.
The compounds of this invention are agonists of a cyclic AMP-dependent protein Xinase (cA-PrK) (see J. Biol.
Chem., 1989, 264, 8443 - 8446) and are of use in combatting such conditions where such agonism is thought to be beneficial. They are likely to have anti-proliferative, anti-aggregatory, cholesterol-lowering, smooth muscle relaxant, lusitropic, anti-allergic or anti-inflammatory activities. They are likely to be useful in the treatment of cardiovascular diseases such as congestive heart-failure, cancer, psoriasis, atherosclerosis, thrombosis, chronic reversible lung disease such as asthma and bronchitis, allergic disease such as allergic asthma, allergic rhinitis and urticaria or gut motility disorders such as irritable bowel syndrome.
Accordingly the present invention provides compounds of the formula (1) :
Ar ~ N (1) or pharmaceutically acceptable salts thereof, wherein :
W092/06085 2 0 91~ 8 9 PCT/GB91/01663 RO is OH or a bioprecursàr thereof, Rl is 5-tetrazolyl or a bioprecursor thereof, and Ar is phenyl substituted by one to three groups independently selected from C1_6alkyl, C2_6alkenyl, C1_6alkoxy, C3_6alkenyloxy, C3_6cycloalkyl, C3_6cycloalkoxy, C1_6alkylthio, phenyl, phenylthio, benzyloxy, C1_6polyfluoroalkyl, C1_6polyfluoroalkoxy, halo, NR2, or NHCOR wherein R is H or Cl_6alkyl, or -X(CH2)nY-attached to adjacent carbon atoms of the phenyl ring wherein X
and Y are independently CH2 or O and n is 1 to 3, wherein said C1_6alkyl, C2_6alkenyl or C1_6alkoxy yroups can be independently substituted by OH, C1_6alkoxy, C3_6cycloalkyl, NR2, CO2R or CONR2; with the proviso that Ar is not phenyl monosubstituted by 2-C1_6alkoxy.
Bioprecursors of the group RO are derivatives thereof which are convertible in vivo into the group RO.
A suitable bioprecursor of the group RO is oR2 wherein R2 is C1_4alkyl, arylCl_4alkyl (for example phenylCl_4-alkyl such as benzyl), Cl_4alkanoyl (for example acetyl), arylC1_4alkanoyl (for example phenyl C1_4alkanoyl such as benzoyl), arylsulphonyl (for example optionally substituted phenylsulphonyl or toluenesulphonyl) or Cl_4alkylsulphonyl (for example methylsulphonyl).
Suitably R0 is hydroxy or o~2, preferably hydroxy.
A suitable bioprecursor of Rl is a N-protected tetrazolyl group. Suitable N-protecting groups include pivalolyoxymethyl, propionyloxymethyl and pivaloyloxycarbonyloxymethyl.
AS MEDICAMENTS
The present invention relates to pyridinol derivatives, processes for their preparation, intermediates in their preparation, their use as medicaments and to pharmaceutical compositions comprising them.
The compounds of this invention are agonists of a cyclic AMP-dependent protein Xinase (cA-PrK) (see J. Biol.
Chem., 1989, 264, 8443 - 8446) and are of use in combatting such conditions where such agonism is thought to be beneficial. They are likely to have anti-proliferative, anti-aggregatory, cholesterol-lowering, smooth muscle relaxant, lusitropic, anti-allergic or anti-inflammatory activities. They are likely to be useful in the treatment of cardiovascular diseases such as congestive heart-failure, cancer, psoriasis, atherosclerosis, thrombosis, chronic reversible lung disease such as asthma and bronchitis, allergic disease such as allergic asthma, allergic rhinitis and urticaria or gut motility disorders such as irritable bowel syndrome.
Accordingly the present invention provides compounds of the formula (1) :
Ar ~ N (1) or pharmaceutically acceptable salts thereof, wherein :
W092/06085 2 0 91~ 8 9 PCT/GB91/01663 RO is OH or a bioprecursàr thereof, Rl is 5-tetrazolyl or a bioprecursor thereof, and Ar is phenyl substituted by one to three groups independently selected from C1_6alkyl, C2_6alkenyl, C1_6alkoxy, C3_6alkenyloxy, C3_6cycloalkyl, C3_6cycloalkoxy, C1_6alkylthio, phenyl, phenylthio, benzyloxy, C1_6polyfluoroalkyl, C1_6polyfluoroalkoxy, halo, NR2, or NHCOR wherein R is H or Cl_6alkyl, or -X(CH2)nY-attached to adjacent carbon atoms of the phenyl ring wherein X
and Y are independently CH2 or O and n is 1 to 3, wherein said C1_6alkyl, C2_6alkenyl or C1_6alkoxy yroups can be independently substituted by OH, C1_6alkoxy, C3_6cycloalkyl, NR2, CO2R or CONR2; with the proviso that Ar is not phenyl monosubstituted by 2-C1_6alkoxy.
Bioprecursors of the group RO are derivatives thereof which are convertible in vivo into the group RO.
A suitable bioprecursor of the group RO is oR2 wherein R2 is C1_4alkyl, arylCl_4alkyl (for example phenylCl_4-alkyl such as benzyl), Cl_4alkanoyl (for example acetyl), arylC1_4alkanoyl (for example phenyl C1_4alkanoyl such as benzoyl), arylsulphonyl (for example optionally substituted phenylsulphonyl or toluenesulphonyl) or Cl_4alkylsulphonyl (for example methylsulphonyl).
Suitably R0 is hydroxy or o~2, preferably hydroxy.
A suitable bioprecursor of Rl is a N-protected tetrazolyl group. Suitable N-protecting groups include pivalolyoxymethyl, propionyloxymethyl and pivaloyloxycarbonyloxymethyl.
By the term alkyl is meant both straight- and branched-chain alkyl.
By the term C1_6 polyfluoroalkyl is meant a C1_6alkyl group having at least one hydrogen replaced with fluoro eg.
CF3, or CF2CF2H.
Suitably Ar is phenyl mono-substituted by a group as hereinbefore defined, for example in the 2,3, or 4 positions by C1_6alkyl, C3_6alkenyloxy, C1_6alkylthio, phenyl, phenylthio, benzyloxy, CF3, halo or NHCOR, or in the 3, or 4-positions with C1_6alkoxy.
Suitably Ar is phenyl di-substituted by any groups as hereinbefore defined, for example in the 3,4-,3,5-,2,3-,2,4- or 2,5-, positions by groups independently selected from C2_6alkenyl, C1_5alkoxy, C3 6cycloalkoxy, halo, -X(CH2)nY- or C1_6alkoxy C1_6 alkoxy.
Suitably Ar is phenyl trisubstituted by any groups as hereinbefore defined, for example in the 2,3,4-, 2,3,5-, or 3,4,5-positions by groups independently selected from C2_6alkenyl, C1_6alkoxy or halo.
Examples of Cl_6alkoxy include methoxy, ethoxy, propoxy, butoxy, or pentyloxy.
Examples of C1_6alkyl include methyl, ethyl, propyl, butyl, isobutyl or pentyl.
Examples of halo include fluoro, chloro, bromo or iodo, preferably chloro or bromo.
Particular compounds of this invention include :
W O 92/06085 2 0 91~ ~ 9 P ~ /GB91/01663 6~ thoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(3-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(3-butoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(3-benzyloxyphenyl)-3-(5-tetrazolyl)pyridin-2tlH)-one, 6-(3-bromophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, lS
6-(3-trifluoromethyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(3-ethylphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(4-butoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(4-isobutylphenyl)pyridin-2(lH)-one, 6-(4-biphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(4-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, W092/06085 2 ~ 91~ 8 ~ PCT/GB91/01663 6-(3,4-methylenedioxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(3,4-dichlorophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, s 6-(3,5-dipropoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(3,5-diethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(3,5-dibromophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(2,4-dipropoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, .
6-(2,5-dipropoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(2,3,4-trichlorophenyl)-3-(S-tetrazolyl)pyridin-2(lH)-one, 6-[6-(1,2,3,4-tetrahydronaphthyl)]-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(3-chlorophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-phenylthiophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 3,4-dimethoxyphenyl-3-(5-tetrazolyl)pyridin-2(lH)-one, W ~ 9~/06085 2 ~ 919 8 9 P ~ /GB91/01663 6-(3-methylthiophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(3-butylthiophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(3,4-di-n-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(2,3-di-n-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(3-cyclopentyloxy-4-methoxyphenyl)-3-(S-tetrazolyl)-pyridin-2(lH)-one 6-(3-ethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3,5-dimethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(2-butylthiophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(3-allyloxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(4-methoxy-2-pentyloxyphenyl)-~-(5-tetrazolyl)pyridin-2(lH)-one 6-(3-iso-butoxy-4-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(2-bromo-3,5-diethoxyphenyl-3-(5-tetrazolyl)pyridin-2(lH)-one, W092/0608~ 2 0 919 ~ 9 PCT/GB91/01663 6-(5-bromo-4-methoxy-2-pentyloxphenyl)-3-(5-tetrazolyl)-pyridin-2( lH) -one, 6-(2-allyl-4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)-pyridin-2(lH)-one, 6-[3-(E-1-propenyl)-4-methoxyphenyl]-3-(5-tetrazolyl)pyridi n-2(lH)-one, 6-(4-methoxy-3-propoxyphenyl)-3-[5-(1-pivaloyloxymethyl)-tetrazolyl)pyridin-2(lH)-one, :
6-(4-methoxy-3-propoxyphenyl)-3-[5-(2-pivaloyloxymethyl)-tetrazolyl]pyridin-2(lH)-one, 6-[3-ethoxy-5-(2-methoxyethoxy)phenyl]-3-(5-tetrazolyl)-pyridin-2(lH)-one, 6-[3-(2,2-dimethylpropyloxy)-4-methoxyphenyl~-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(3-ethoxy-4-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 2S 6-(3-propionamidophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(4-methoxy-3-propylphenyl)-3-(5-tetrazolyl)pyridir.-2(lH)-one, 6-(3-bromo-4-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(3-phenyl-4-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-[4-methoxy-3,5-di(E-1-propenyl)phenyl]-3-(5-tetrazolyl)-pyridin-2(lH)-one, 6-[3-(E-1-propenyl)-4-propoxyphenyl]-3-(5-tetrazolyl)-pyridin-2(lH)-one, 6-(3-bromo-4-methoxy-5-propylphenyl)-3-(5-tetrazolyl)-pyridin-2-(lH)-one, 6-(2-butylthio-3,5-diethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(3-bromo-4-N,N-dimethylaminophenyl)-3-(5-tetrazolyl)-pyridin-2(lH)-one, 6-(3-acetamido-4-methoxy-5-propylphenyl)-3-(5-tetrazolyl)-pyridin-2(lH)-one, 6-[3-methoxymethyl-4-methoxy-5-(E-l-propenyl)phenyl]-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-[3-(E-2-carbamoylethenyl)-4-methoxy-5-(E-1-propenyl)-phenyl]-3-(5-tetrazolyl)pyridin-2-(lH)-one, and 6-(3-cyclopropylmethyloxy-4-methoxyphenyl)pyridin-2(lH)-one and pharmaceutically acceptable salt-; thereof.
This invention covers all tautcmeric, geometric and optical isomeric forms of compounds of formula (1). In WO9~/06085 2 0 919 8 9 PCT/GB91t01663 particular when R0 is hydroxy the compound can exist in its keto tautomeric form :
Rl/$~/Ar = Rl/~Ar OH O
Compounds of the formula (l) can form pharmaceutically acceptable base addition salts with metal ions, such as alkali metals for example sodium or potassium, or with an ammonium ion.
In order to use a compound of the formula (l) or a pharmaceutically acceptable salt thereof for the treatment of humans and other mammals it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
Compounds of formula (l) and their pharmaceutically acceptable salts may be administered in standard manner for the treatment of the indicated diseases, for example orally, sublingually, parenterally, transdermally, rectally, via inhalation or via buccal administration.
Compounds of formula (l) and their pharmaceutically acceptable,salts which are active when given orally or via buccal administration can be formulated appropriately in dosage forms such as liquids, syrups, tablets, capsules and lozenges. An oral liquid formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, glycerine or water with a flavouring or colouring agent. Where the W O 92/06085 2 0 919 8 9 PC~r/GB91/01663 composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include starch, celluloses, lactose, sucrose and magnesium stearate.
Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell.
Where the composition is in the form of a soft gelatin shell capsule, any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils and are incorporated in a soft gelatin capsule shell.
Typical parenteral compositions consist of a solution or suspension of the compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil or solubilising agent, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, 2-pyrrolidone, cyclodextrin, arachis oil, or sesame oil.
A typical suppository formulation comprises a compound of formula (1) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding andtor lubricating agent, $or example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogues.
Typical transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
Typical compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered W092/06085 2 ~ 919 ~ 9 ; PCT/GB91/01663 in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane, or are in the form of a powder for insufflation.
Preferably the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer to himself a single dose.
Each dosage unit for oral administration contains suitably from 0.001 mg/Kg to 30 mg/Kg, and preferably from 0.005 mg/Kg to 15 mg/Kg, and each dosage unit for parenteral administration contains suitably from 0.001 mg/Kg to 10 mg/Kg, of a compound of formula (1) or a pharmaceutically acceptable salt thereof calculated as the free acid.
The daily dosage regimen for oral administration is suitably about 0.001 mg/Kg to 120 mg/Kg, of a compound of formula (1) or a pharmaceutically acceptable salt thereof calculated as the free acid. The daily dosage regimen for parenteral administration is suitably about 0.001 mg/Kg to 40 mg/Kg, for example about 0.005 mg/Kg to 10 mg/Kg, of a compound of the formula (1) or a pharmaceutically accept-able salt thereof calculated as the free acid. The active ingredient may be administered as required for example from 1 - 8 times a day or by infusion. The compositions of the invention are agonists of a cA-PrK and are of use in combatting such conditions where such agonism is thought to be beneficial. Such conditions can be treated by administration orally, sublingually topically, rectally, parenterally or by inhalation. For administration by inhalation dosages are controlled by a valve, are administered as required and for an adult are conveniently in the range 0.1 - 5.0 mg of a compound of the formula (1) or a pharmaceutically acceptable salt thereof.
W O 92/06085 2 0 919 g 9 PC~r/GB91/01663 The compounds of this invention may be co-administered with other pharmaceutically active compounds, for example in combination, concurrently or sequentially. Conveniently the compounds of this invention and the other active compound or compounds are formulated in a single pharmaceutical composition.
Examples of compounds which may be included in pharmaceutical compositions with the compounds of the formula (1) are bronchodilators such as sympathomimetic amines for example isoprenaline, isoetharine, sulbutamol, phenylephrine and ephedrine or xanthine derivatives for example theophylline and aminophylline, anti-allergic agents for example disodium cromoglycate, histamine H1-antagonists, drugs used in the treatment of cancer lS such as those which inhibit the synthesis of or inactivate DNA, for example methotrexate, fluoracil, cisplatin, actinomycin D, anti-atherschlerotic agents for example cholesterol lowering drugs such as HMGCoA reductase inhibitors, bile acid sequestrants, drugs for the treatment of psoriasis, for example retinoids, anthralin, anti-inflammatories for example cortiscosteroids, non-steroid anti-inflammatories such as aspirin, antithrombotics for example dipyridamole, or fibrinolytic agents.
In another aspect the present invention provides a process for the preparation of compounds of the formula (1) or pharmaceutically acceptable salts thereof, which process comprises reacting a compound of the formula (2) :
~ Ar ~2) NC
OH
W092/06085 ~ U Yl ~ ~ PCT/GB9i/01663 wherein Ar is as hereinbefore defined with an azide salt, and optionally thereafter :
forming a bioprecursor of R0 and/or o forming a pharmaceutically acceptable salt.
A compound of the formula (2) is suitably reacted with an azide salt such as ammonium, sodium, potassium or aluminium azide in an organic solvent such as dimethylformamide, dimethylsulphoxide, N-methyl-pyrrolidone or tetrahydrofuran at an elevated temperature e.g. 40 - 200C, preferably at the reflux temperature of - the reaction mixture.
A compound of the formula (1) wherein ~ is OH can be converted to the corresponding compound where R0 is oR2 by reaction with R2L wherein R2 is as hereinbefore defined and L is a leaving group such as halo e.g. bromo, chloro, iodo.
A compound of the formula (1) can be converted to a N-protected tetrazolyl derivative by reaction with a suitable N-protecting agent in standard manner, for example with a pivalolyoxymethyl halide.
A compound of the formula (2) can suitably be prepared by reacting a compound of the formula (3) :
ArCOCH = CHLl (3) wherein Ar is as hereinbefore defined and Ll is a displaceable group, with a compound of the formula (4) :
W092/0608; 2 ~ 9 1~ ~ 9 PCT/GB91/01663 H2NCOCH2CN (4) Suitably Ll in a compound of the formula (3) is hydroxy or a derivative thereof for example Ll is protected hydroxy such as silyloxy, an acid residue (for example Cl_6alkanoyloxy) or an ether residue (for example methoxy or ethoxy). Alternatively Ll is a secondary amino group, for example di-Cl_6alkylamino such as dimethylamino or a cyclic amino group such as lo piperidino, pyrrolidino or morpholino. Preferably is hydroxy or dimethylamino.
Suitably an alkali metal (e.g. sodium) salt of a compound of the formula (3) wherein Ll is hydroxy is treated with a compound of the formula (4) under mildly alkaline aqueous conditions, for example in water in the presence of piperidine and glacial acetic acid, at an elevated temperature e.g. 30 - 200C, preferably at the reflux temperature of the reaction mixture.
Alternatively a compound of the formula (3) wherein Ll is a secondary amino group, for example dimethylamino, is treated with a compound of the formula (4) in a suitable solvent such as dimethylformamide, a Cl_4alkanol or pyridine at an elevated temperature e.g.
30 - 200C, preferably at the reflux temperature of the reaction mixture optionally in the presence of a base such as pyridine or an alkali metal alkoxide, e.g. sodium methoxide.
Compounds of the formula (3) wherein Ll is hydroxy can suitably be prepared by reaction under basic conditions of a compound o~ the formula (S) :
ArCOCH3 (5) W092/0608~ ,5 ' PCT/GB91/01663 wherein Ar is as hereinbefore defined, with a compound of the formula HCOL2 wherein L2 is a leaving group.
Suitably L2 is ethoxy or methoxy. Conveniently a solution of a compound of the formula (5) and a compound of the formula HCOL2 in a suitable organic solvent such as diethyl ether is treated with a suitable base such as an alkali metal alkoxide, e.g. sodium methoxide at ambient temperature. The resulting reaction mixture is preferably extracted with water and the aqueous extract which contains the alkali metal salt of a compound of the formula (3) wherein L1 is hydroxy is then treated with a compound of the formula (4) as hereinbefore described.
Compounds of the formula (5) are known or can be prepared by methods known in the art.
Compounds of the formula (3) wherein L1 is a secondary amino group (e.g. dimethylamino) can suitably be prepared by reacting a compound of the formula (5) with a compound of the formula HC(oR3)2Ll wherein R3 is C1_4alkyl and L1 is a secondary amino group (for example HC(oR3)2Ll is N,N-dimethylformamide dimethyl or diethyl acetal), or with a compound of the formula HCL13 where Ll is a secondary amino group (for example HCL13 is trisdimethylaminomethane).
Alternatively a compound of formula (2) can be prepared by demethylation of a compound of formula (6) :
~ Ar (6) NC
OMe wherein Ar is as hereinbefore defined.
Suitable demethylating agents include sodium iodide and chlorotrimethylsilane in an organic solvent such as acetonitrile, or a halohydrocarbon eg. dichloromethane or chloroform at elevated (eg. 30-80C) or ambient temperature or sodium thiomethoxide in an organic solvent such as dimethylformamide at an elevated temperature, for example 40-120C.
The Ar group in compounds of the formula (2j, (5) or (6), preferably (5) or (6) may be appropriately functionalised by methods of aromatic substitution known in the art. For example, a bromo group may be introduced into a suitably substituted phenyl ring (eg. disubstituted in the 2- and 4-positions by electron-donating groups such as C1_6alkoxy) by reaction with a brominating agent such as N-bromosuccinimide or bromine in a solvent such as dimethylformamide. Alternatively a nitro group can be introduced into a phenyl ring by reaction with a suitable nitrating agent, such as nitroniumtetrafluoroborate. Such a group can be readily hydrogenated to an amino group which if desired can be converted to a NHCOR group by reaction with LCOR wherein L is a leaving group and R is as hereinbefore defined. Suitable examples of the reagent LCOR include acid halides (L is halo eg. chloro or bromo) or acid anhydrides (L is OCOR).
W092/06085 2 0 919 ~ 9 PCT/GB91/01663 Other suitable functionalisations include the introduction of an allyl group ortho to a hydroxy substituent on a phenyl ring by reaction with an allyl halide, eg. bromide, to form an allyloxy derivative which on heating undergoes a Claisen rearrangement to form an ortho allyl hydroxy derivative. The hydroxy group can in turn be functionalised, eg. by reaction with a Cl_6alkyl halide to form a Cl_6alkoxy group. If desired, an allyl group can be converted to an E-l-propenyl group by reaction with a strong base, such as sodium methoxide.
This can occur during the conversion of a compound of formula (5) to a compound of formula (2) as hereinbefore described if such a base is used. An E-l-propenyl group can be cleaved to a formyl group by reaction with an lS oxidising agent such as N-methylmorpholine-N-oxide in the presence of a catalyst such as osmium tetroxide to form a l,2,dihydroxypropyl group which on reaction with an oxidising agent such as sodium periodate forms the formyl group. Alternatively the E-l-propenyl group can be converted directly to a formyl group by reaction with a mixture of osmium tetroxide and sodium periodate or by reaction with ozone. A formyl group can in turn be further functionalised, for example it can be converted to a hydroxymethyl group by reaction with a suitable reducing agent such as sodium borohydride, the hydroxymethyl group then being reacted further, eg. with a Cl_6alkyl halide to form a Cl_6alkoxymethyl group. Alternatively a formyl group can be reacted with a suitable Horner Wittig or Wittig reagent such as (R40)2P(o)CH2Co2R4 or Ph3P=CHCO2R4 wherein R4 is Cl_4alkyl to form a CH=CHCo2R4 group which can be optionally hydrolysed to a -CH=CHCO2H group. A -CH=CHCo2R4 group can be converted to a -CH=CHCONR2 group by reaction with an amine HNR2 or a chemical equivalent thereof wherein R is as hereinbefore defined. Alternatively a -CH=CHCO2H
group can be converted to an acid halide, eg. the acid chloride by reaction with oxalyl chloride, which can then W092/06085 2 0 919 ~ 9 ` PCT/GB9l/01663 be reacted with an amine HNR2 or a chemical equivalent thereof. An example of a chemical equivalent is ammonium hydoxide which will form a CH=CHCONH2 group.
A compound of formula (6) is suitably prepared by reacting a compound of formula (2) wherein Ar is as hereinbefore defined with an O-methylating agent such as dimethylformamide dimethylacetal in dimethylformamide or trimethylphosphite at an elevated temperature (eg.
40-120C).
Pharmaceutically acceptable base addition salts of the compounds of the formula (1) may be prepared by standard methods, for example` by reacting a solution of the compound of the formula (1) with a solution of the base.
The following biological test methods, data and Examples serve to illustrate this invention.
Cvclic-AM~ Protein Kinase (cA-PrK) Aqonist Activitv Type II cA-PrK was prepared from the cardiac muscle of a cow. The supernatant from a muscle homogenate (3 mls of 10 mM potassium phosphate, 1 mM EDTA per g tissue) was applied to a column of DEAE-cellulose equilibrated with the homogenisation buffer and the type II cA-PrK was eluted with homogenisation buffer containing 350 mM sodium chloride (Rannels et al., 1983, Methods Enzymol., 99, 55-62).
Type II cA-PrK was assayed for phosphotransferase activity by incubating the enzyme at 30C for 5 minutes with [ -32P]-adenosine triphosphate and a suitable peptide substrate such as malantide (Malencik et al., 1983, Anal. Biochem., 132, 34-40). The reaction was W092/0608; 2 0 919 ~ ~ PCT/GB91/01663 terminated by the addition of hydrochloric acid and the [32P]-phosphopeptide quantified by spotting the reaction mixture onto phosphocellulose papers, The concentration of compound required to give 10% phosphotrans~erase S activation is given as the EClo (~M). The compounds of Examples 1 to 26 had EC1o values in the range 10 -130 ~M.
Inhibition of Platelet Aqqreqation Human platelet-rich-plasma was separated from freshly drawn blood (in acid/citrate/dextrose) and treated with 100 ~M acetylsalicylic acid for 15 minutes at 37C. A
washed platelet suspension was then prepared in a Hepes-isotonic saline buffer after a single centrifugation step and adjusted to a concentration of 1.5x108 cells/ml. Aliquots of this suspension were pre-incubated with compounds for 5 minutes at 37C, then challenged with 1.0 yM U46619. The extent of aggregation after 2 minutes were expressed as a percentage of control and results obtained are expressed as an IC50 (concentration to cause 50% inhibition of platelet aggregation, ~M).
The compounds of Examples 2, 4, 5, 11-13, 15, 19-23, and 25-26 had IC50 values in the range 0.8-300 ~M.
Anti-proliferative activitY
Compounds under test were dissolved in dimethyl-sulphoxide and diluted 1:10,000 with DMEM (Dulbecco's Modified Eagle's Medium) containing 10% fetal bovine serum to give 12.5, 25, 50 and 100 ~M concentrations used in the assay. Indicator cells consisting of 3 human colorectal cells lines (SW-620, NRK-52 and HT-29) were plated at a cell density of 1000 cells in 0.1 ml of DMEM
media in 96 well plates. Cells were incubated for 4 days at 37C and 10% CO2 atmosphere. On day 5, tetrazolium W 092/0608~ 2 ~ ~19 g 9 PCT/GB91/01663 reagent (50 llg MTT/250 111 total medium volume) was added for 16 - 20 hours. Insoluble formazan was dissolved in 150 ~l of dimethylsulphoxide and absorbance was measured using a microculture plate reader at 560 nm interfaced with an IBM computer. Cell line growth and inhibition were expressed in terms of mean absorbance unit of triplicate samples following subtraction of mean background absorbance. IC50 values (concentration that show 50g~ growth inhibition) were determined from the dose 10 response curves. (Cancer Res., 48, 589-601, 1988). In the cell line SW-620 the compound of Example 23 had an IC50 value in the range 56 - 90 ~IM. In the cell line NRK-52 the compound of Example 23 had an IC50 value in the range 46 - 48 ~M. In the cell line HT-29 the 15 compound of Example 23 had an IC50 value in the range of 55 - 66 ~ .
Inhibition of S~ontaneous Contraction in Guinea-Piq Colon Segments of isolated guinea-pig colon (2 cm) were suspended under 2 g tension in standard organ baths containing Krebs solution. The tissues were connected at the free end to isometric transducers which allow recording and display of developed tension on chart recorders. On-line computer capture and analysis was used to quantify the effects of test compounds on spontaneous contractions. Inhibitory responses were calculated as % maximum inhibition of spontaneous contraction distance over 3 consecutive pre and post dose 2 minute readings. The concentration of compound which caused 50% inhibition of the spontaneous contrac:tion is given as the EC50 (~M). The compounds of Examples 5, 15-17 and 23 had EC50 values in the range 2 - 25 ~5.
W092/0608~ 2 0 919 8 9 PCT/GB91/01663 sronchodilatation - In vitro (Tracheal spiral) Spiral strips of guinea-pig trachea were suspended in standard organ baths containing Krebs solution. The tissues were connected at the free end to isometric transducers which allow recording and display of developed tension on chart recorders. Tension was allowed to develop spontaneousl~ and concentrations of test compounds added in a cumulative fashion. The concentration of compound which caused 50% inhibition of the spontaneously developed tension is given as the IC50(~M)-The compounds of Examples 5 and 23 had IC50 values of ll and 6.5 ~M respectively.
Measurement of cardiac muscle relaxation time in rabbitventricle Papillary muscles from the right ventricle of female Albino New Zealand rabbits were mounted in standard organ baths containing oxygenated Krebs solution. One end of the muscle was connected to an isometric transducer which allowed recording of contractile force and its first derivative on chart recorders. Test compounds were added to the bath in a cumulative manner. Relaxation time was calculated as the time taken from peak tension to the end of the contraction. At concentrations of 30-l00 ~M, compounds of Examples 12 and 23 caused a 10-20% decrease in the relaxation time indicating a lusitropic effect of use in the treatment of cardiovascular diseases such as congestive heart failure.
WO 92/0608~ 19 8 9 PCI`/GB91/01663 ExamPle 1 6-(3-Methoxyphenyl)-3-(5-tetrazolyl)pyridin- 2 ( lH ) -one a) 3'-Methoxyacetophenone (15g) and dimethylformamide dimethylacetal (16ml) were heated together at 120C in dimethylformamide (8Oml) for 6 hours, the deep red solution was diluted with ethyl acetate (400ml), washed with water (5xlOOml), dried (MgS04) and solvent removed at reduced pressure. The oil obtained was dissolved in dimethylformamide (80ml), cyanoacetamide (10.08g) and sodium methoxide (10.8g) added and the mixture heated at 130C for 35 minutes. The deep red solution was poured into 5% aqueous acetic acid (400ml), the precipitated product collected by filtration and washed with water, ethanol and diethyl ether. Recrystallisation from n-butanol gave 3-cyano-6-(3-methoxyphenyl)pyridin-2(lH)-one (15.14g) m.p. 251C as a colourless solid.
b) 3-Cyano-6-(3-methoxyphenyl~pyridin-2(lH)-one (lg) sodium azide (0.39g) and ammonium chloride (0.32g) were heated together in N-methylpyrrolidin-2-one (lOml) at 140C for 2hours. The reaction mixture was poured into 10%
aqueous acetic acid (150ml), the precipitated solid collected by filtration, washed with water and recrystallised from n-butanol to give the title compound (0.93g) m.p. 298C (decomp). lH NMR ~(DMSO-d6) 3.87(s,3H), 6.92(d,1H), 7.13(m,1H), 7.41-7.50(m,3H) and 8.48(d,lH).
~ ExamPle 2 6-(3-Propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one W O 92/06085 2 ~ 919 8 ~ P ~ /GB91/01663 (a) 3'-Hydroxyacetophenone (13.6g), iodopropane (10.7ml) and potassium carbonate (13.8g) were heated together in dimethylformamide (80ml) at 90C for 20hrs. The reaction mixture was diluted with ethyl acetate (400ml), washed with 2N sodium hydroxide (2xlOOml) and water (4xlOOml), dried (MgS04), filtered and solvent removed at reduced pressure to give 3'-propoxyacetophenone (16.46g) as an oil. 1H NMR ~(DMSO-d6) 0.99(t,3H), 1.66-1.83(m,2H), 2.58((s,3H), 3.98(t,3H), 7.19(dd,1H) and 7.39-7.57(m,3H).
The following compounds were similarly prepared from the appropriate phenol and alkyl iodide.
3'-Butoxyacetophenone:- oil, yield 90%, lH NMR
15 ~(DMSO-d6) 0.94(t,3H), 1.37-1.52(m,2H), 1.66-1.77(m,2H), 2.57(s,3H), 4.02(t,2H), 7.19(dd,1H) and 7.39-7.55(m,3H).
3'-Benzyloxyacetophenone:- oil, yield 89%, lH NMR
20 ~tCDC13) 2-57(s,3H), 5.09(s,2H), 7.17(dd,lH) and 7.29-7.56(m,8H).
4'-Methoxy-3'-propoxyacetophenone from 3'~hydroxy-4'-methoxyacetophenone:- (A. Brossi et al J. Org. Chem., 25 1967, 32, 1269) :- oil, yield 71%, lH NMR ~(CDC13) 1.05(t,3H), 1.87(m,2H), 2.56(s,3H), 3.93(s,1H), 4.04((t,2H), 6.88(d,1H), 7.52(d,1H), and 7.57(dd,1H).
3',5'-Dipropoxyacetophenone:- oil, yield 58%, 1H
30 NMR ~(DMSO-d6) 0.98(t,6H) 1.66-1.80(m,4H), 2.55(s,3H), 3.96(t,4H), 6.73(t,lH) and 7.04(d,2H).
3',5'-Diethoxyacetophenone:- oil, yield 64%, 1H NMR
~(DMSO-d6) 1.42(t,6H), 2.56(s,3H), 4.05(q,4H), 35 6.64(t,1H) and 7.07(d,2H).
W092/06085 2 0 91 9 8 g PCT/GB91/01663 2',5'-Dipropoxyacetophenone:- oil, yield 64%, lH
NMR ~(DMSO-d6) 0.96(t,3H), 1.04(t,3H), 1.62-1.84(m,4H), 2.S5(s,3H), 3.88(t,2H), 3.99(t,2H) and 7.03-7.11(m,3H).
3',4'-Dipropoxyacetophenone:- yield 95%, lH NMR
~(CDCl3) 1.00-l.l9(m,6H), 1.78-2.02(m,4H), 2.55(s,3H), 3.98-4.17(m,4H), 6.87(d,1H), 7.52(s,lH) and 7.54(d,lH).
3'-Allyloxyacetophenone:- oil, yield 71%, lH
NMR~(CDCl3) 2.58(s,3H), 4.57(d,2H), 5.27-5.47(m,2H), 5.96-6.15(m,1H), 7.12(dd,1H), 7.31(t,1H) and 7.49-7.55(m,2H).
4'-Methoxy-2'-pentyloxyacetophone:-From 4'-methoxy-2'hydroxyacetophenone and iodopentane, yield 92%, lH NMR ~(DMS0-d6)0.86(t.3H), 1.20-1.47(m,4H), 1.74-1.85(m,2H), 2.49(s,3H), 3.82(s,3H), 4.09(t,2H), 6.56-6.62(m,2H) and 7.66(d,lH).
3'-iso-Butoxy-4'-methoxyacetophenone:-From 4'-methoxy-3'-hydroxyacetophenone and iso-butyl bromide using acetone as solvent, yield 68~. lH NMR
~(DMSO-d6) O.99(d,6H), 1.96-2.15(m,1H), 2.53(s,3H), 3.78(d,lH), 3.86(s,3H), 7.06(d,lH), 7.42(d,lH) and 7.62(dd,1H).
3'-Allyloxy-4'-methoxyacetophenone:-From 4'-methoxy-3'-hydroxyacetophenone and allyl bromide, yield 67%, lH NMR ~(CDCl3) 2.55(s,3H), 3.95(s,3H), 4.63-4.68(m,2H), 5.29-5.47(m,lH), 6.02-6.18(m,lH), 6.90(d,1H),7.53(d,1H) and 7.60(dd,1H).
3'-(2,2,-dimethylpropyloxy)-4'-methoxyacetophenone:-Fr m 4'-methoxy-3'-hydroxyacetophenone and 1-bromo-2,2-dimethylpropane, yield 76~, lH NMR ~(CDCl3) W O 92/06085 2 O 9 19 ~ ~ PC~r/GB91/01663 1.07(s,9H), 2.56(s,3H), 3.69(s,2H), 6.88(d,1H) and 7.50-7.58(m,2H).
3'-ethoxy-4'-methoxyacetophenone:-from 3'-hydroxy-4'-methoxyacetophenone and iodoethane using acetone as solvent, yield 83%, lH NMR ~(CDC13) 1.49(t,3H),2.57(s,3H),3.94(s,3H),4.17(q,2H),6.8g(d,1H),7.53 -7.60(m,2H).
3'-Allyl-4'-methoxyacetophenone:-from 3'-allyl-4'-hydroxyacetophenone, yield 87% as an oil.
lH NMR ~(CDCl3)2.55(s,3H),3.40(d,2H),3.89(s,3H), 5.02-5.10(m,2H), 5.90-6.04(m,lH),6.88(d,lH),7.77(d,lH) and 7.85(dd,lH).
(b) From 3'-propoxyacetophenone (9g), 3-cyano-6-(3-propoxyphenyl)pyridin-2(1H)-one (3.49g) m.p. 240-241C
after recrystallisation from ethanol, was prepared according to the method of Example l(a).
(c) From 3-cyano-6-(3-propoxyphenyl)pyridin-2(lH)-one (lg), the title compound (0.61g) m.p. 270-271C after recrystallisation from n-butanol, was prepared according to the method of Example l(b).
Exam~le 3 6-(3-Butoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one (a) 3'-Butoxyacetophenone (17.3g) and dimethylformamide dimethylacetal (11.9g) were boiled together in dimethylformamide (9Oml) for 15 hours. The deep red solution was cooled to room temperature, cyanoacetamide (8.3g) and sodium methoxide (10.3g) added and the mixture boiled for a further 3 hours. The reaction mixture was W092/0608~ 2 ~ 9 ~. 9 8 9 PCT/GB91/01663 poured into 10% aqueous acetic acid (300ml) the precipitated product separated by filtration, washed with water and recrystallised from n-butanol to give 3-cyano-6-(3-butoxyphenyl)pyridin-2(lH)-one (10.66g) m.p.
201-202C.
(b) From 3-cyano-6-(3-butoxyphenyl)pyridin-2(1H)-one (2.15g), the title compound (o.55g) m.p. 259-260C after recrystallisation from n-butanol, was prepared according to the method of Example l(b).
Example 4 6-(3-Benzyloxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one (a) From 3'-benzyloxyphenylacetophenone (20.2g), 3-cyano-6-(3-benzyloxyphenyl)pyridin-2(lH)-one (2.6g) m.p.202-203C after recrystallisation from ethanol, was prepared according to the method of Example 3(a).
(b) From 3-cyano-6-(3-benzyloxyphenyl)pyridin-2(lH)-one (lg), the title compound (0.35g) m.p.276C (decomp) after recrystallisation from dimethylformamide was prepared according to the method of Example l(b). lH NMR
~(DMSO-d6) 5.23(s,2H), 6.91(d,1H), 7.16-7.20(m,1H), 7.31-7.54(m,8H), 8.47(d,1H) and 12.67(br s,lH).
Example 5 6-(3-Bromophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one (a) From 3'-bromoacetophenone ~13.2g), 3-cyano-6-(3-35 bromophenyl)pyridin-2(1H)-one (21.8g) m.p. 309C (decomp) after recrystallisation from n-butanol, was prepared W092/06085 2 0 919 ~ 9 PCT/G~91/01663 according to the method of Example l(a). lH NMR
~(DMSO-d6) 6.89(br s,lH), 7.48(t,1H), 7.75(d,1H), 7.83(d,lH), 8.06(s,lH), 8.21(d,lH) and 12.75(br s,lH).
(b) From 3-cyano-6-(3-bromophenyl)pyridin-2(lH)-one (1.37g), the title compound (0.39g) m.p. 285-286C after recrystallisation from dimethylformamide, was prepared according to the method of Example l(b).
ExamPle 6 6-(3-Trifluoromethyl)-3-(5-tetrazolyl)pyridin-2(IH)-one (a) From 3'-trifluoromethylacetophenone (9.4g), 3-cyano-6-(3-trifluoromethylphenyl)pyridin-2~lH)-one (11.38g) m.p.255-256C after recrystallisation from ethanol, was prepared according to the method of Example 3(a).
(b) From 3-cyano-6-(3-trifluoromethylphenyl)pyridin-2(lH)-one (1.06g), the title compound (0.93g) m.p.274-275C after recrystallisation from n-butanol, was prepared according to the method of Example l(b).
ExamPle 7 6-(3-Ethylphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one (a) From 3'-ethylacetophenone (7.4g), 3-cyano-6-(3-ethylphenyl)pyridin-2(lH)-one (3.97g~ m.p.241-242C after recrystallisation from n-butanol, was prepared according to the method of Example 3(a).
(b) From 3-cyano-6-(3-ethylphenyl)pyridin-2(1H)-one (0.89g), the title compound (0.37g) m.p.278-279C after W092/0608~ 2 0 9 i 9 8 9 PCT/GB91/01663 recrystallisation from n-butanol, was prepared according to the method of Example l(b).
Exam~le 8 6-(4-Butoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one ta) From 4'-butoxyacetophenone (5.6g), 3-cyano-6-(4-o butoxyphenyl)pyridin-2(lH)-one (1.12g) m.p. 245C after recrystallisation from ethanol, was prepared according to the method of Example l(a).
(b) A mixture of 3-cyano-6-(4-butoxyphenyl)pyridin-2(lH)-one (0.3g), sodium azide (0.098g), ammonium chloride (0.08g) and lithium chloride (0.064g) were heated in dimethylformamide (15ml) at 120C for 72 hours. Solvent was removed at reduced pressure, the product precipitated by the addition of 10% aqueous acetic acid (40ml) and separated by filtration. The solid was dissolved in 5%
potassium hydrogen carbonate and insoluble material - separated by filtration. The filtrate was acidified with conc. hydrochloric acid, the precipitated product collected by filtration and recrystallised from ethanol to give the title compound (0.05g) m.p.289-292C.
Example 9 6-(4-iso~utylphenyl)pyridin-2(lH)-one (a) From 4'-isobutylacetophenone (8.8g); 3-cyano-6-(4-isobutylphenyl)pyridin-2(lH)-one (6.0g) m.p. 264C after recrystallisation from ethanol, was prepared according to the method of Example 3(a).
W092/0608~ PCT/GB91/01663 (b) From 3-cyano-6-(4-isobutylphenyl)pyridin-2(1H)-one (2.52g), the title compound (1.54g) m.p. 275C (decomp) after recrystallisation from dimethylformamide, was prepared according to the method of Example l(b) but using dimethylformamide instead of N-methylpyrrolidin-2-one as solvent. lH NMR ~(DMSO-d6) 0.89(d,6H), 1.81-1.96 (m,lH), 2.51(m,2H), 6.87(d,lH), 7.33(d,2H), 7.78(d,2H), 8.46(d,1H) and 12.63(br s,lH).
ExamPl 10 6-(4-Biphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one 15 (a) From 4-acetylbiphenyl (19.6g), 6-(4-biphenyl)-3-cyanopyridin-2(lH3-one (14.01g) m.p. 312-316C after recrystallisation from n-butanol, was prepared according to the method of Example l(a).
20 (b) From 6-(4-biphenyl)-3-cyanopyridin-2(1H)-one (1.36g), the title compound (0.84g) m.p. 305C (decomp) after recrystallisation from dimethylformamide, was prepared according to the method of Example l(b). 1H NMR
~(DMSO-d6) 7.00(d,lH), 7.41-7.S4(m,3H), 7.77(d,2H), 25 7.85(d,2H), 7.98(d,2H) and 8.50(d,lH).
ExamPle 11 6-(4-Propoxy,phenyl)-3-(S-tetrazolyl)pyridin-2(1H)-one (a) From 4'-propoxyacetophenone (15.4g) (E. Eckhart and J. Varga, Maqvar. Kem. FolYoirat 1961, 67, 509, Chem Abs. 1962, S6, 15557e), 35 3-cyano-6-(4-propoxyphenyl)pyridin-2(lH)-one (1.8g) m.p.
262-265C after recrystallisation from dimethylformamide, was prepared according to the method of Example 3(a).
(b) From 3-cyano-6-(4-propoxyphenyl)pyridin-2(lH)-one (lg), the title compound (0.85g) m.p. 292C (decomp) after recrystallisation from dimethylformamide, was prepared according to the method of Example l(b). lH NMR
~(DMSO-d6) 0.99(tr3H), 1.63-1.84(m,2H), 4.02(t,2H), 6.81(d,lH), 7.07(d,2H), 7.82(d,2H~ and 8.45(d,lH).
Exam~le 12 6-(4-Methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one (a) From 4'-methoxy-3'-propoxyacetophenone (12g), 3-cyano-6-(4-methoxy-3-propoxyphenyl)pyridin-2(lH)-one (14.03g) m.p. 24~.C after recrystallisation from ethanol, was prepared according to the method of Example 3(a).
(b) From 3-cyano-6-(4-methoxy-3-propoxyphenyl)pyridin-2(lH)-one (3.12g), the title compound (1.69g) m.p.
289-290C after recrystallisation from n-butanol, was prepared according to the method of Example l(b).
ExamPle 13 6-(3,4-Methylenedioxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one (a) From 3',4'-(methylenedioxy)acetophenone (16.4g), 3-cyano-6-(3,4-methylenedioxyphenyl)pyridin-2(lH)-one (10.2g) m.p. ~320C after recrystallisation from dimethyl-formamide, was prepared according to the method of Example 35 3(a). lH NMR ~(DMSO-d6) 6.13(s,2H), 6.72(d,1H), 7.06(d,1H), 7.36-7.42(m,2H), 8.13(d,1H) and 12.58(br s,lH).
W092/0608; 2 0 919 8 9 PCT/GB91/01663 (b) From 3-cyano-6-(3,4-methylenedioxyphenyl)pyridin-2(lH)-one (0.96g), the title compound (O.lg) m.p. >325C
after recrystallisation from ethanol, was prepared according to the method of Example l(b) but using dimethylformamide instead of N-methylpyrrolidinone as solvent. lH-NMR ~(DMSO-d6) 6.14(s,2H), 6.83(d,1H), 7.08(d,lH),7.37-7.46(m,2H), 8.43(d,lH), 12.S5(br s,lH) and 13.28(br s,lH).
Ex,~mPle 14 6-(3,4-Dichlorophenyl)-3-(5-tetrazolyl)pyridi~-2(lH)-one 15 (a) From 3',4'-dichloroacetophenone (18.9g), 3-cyano-6-(3,4-dichlorophenyl~pyridin-2(lH)-one (1.94g) m.p. >330C after recrystallisation from dimethyl-formamide, was prepared according to the method of Example l(a). lH NMR ~(DMSO-d6) 6.97(br d,lH), 7.76-7.87 20 (m,2H), 8.15(s,1H) and 8.23(d,1H).
(b) From 3-cyano-6-(3,4-dichlorophenyl)pyridin-2(lH)-one (1.06g), the title compound (0.54g) m.p.295C (decomp) after recrystallisation from dimethylformamide, was prepared according to the method of Example l(b) but using dimethylformamide instead of N-methylpyrrolidinone as solvent. lH NMR ~(DMSO-d6) 7.02(d,1H) 7.76-7.89 (m,2H), 8.17(s,lH) and 8.48(s,lH).
ExamPle 15 6-(3,5-Dipropoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one (a) From 3',5'-dipropoxyacetophenone (11.82g), 3-cyano-6-(3,5-dipropoxyphenyl)pyridin-2(lH)-one (7.lg) m.p.
W092/0608~ 2 0 9 ~ 9 8 9 PCT/GB91/01663 209-210C after recrystallisation from ethanol, was prepared according to the method of Example 3(a).
(b) From 3-cyano-6-(3,5-dipropoxyphenyl)pyridin-2(lH)-one (1.25g), the title compound (1.31g) m.p.224-225C after recrystallisation from n-butanol, was prepared according to the method of Example l(b).
Example 16 6-(3,5-Diethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one (a) From 3',5'-diethoxyacetophenone (4.16g), 3-cyano-6-(3,5-diethoxyphenyl)pyridin-2(1H)-one (l.Og) m.p.259-261C
after recrystallisation from n-butanol, was prepared according to the method of Example 3(a).
(b) From 3-cyano-6-(3,5-diethoxyphenyl)pyridin-2(lH)-one (0.82g), the title compound (0,57g) m.p. 282-283C after recrystallisation from n-butanol, was prepared according to the method of Example l(b).
Example 17 6-(3,5-Dibromophenyl)-3-(5-tetrazolyl)pyridin-2(IH)-one (a) From 3',5'-dibromoacetophenone (M. Tashiro, S Mataka, H. Nakamura and K Nakayama, J. Chem. Soc. Perkin Trans I., 1988, 179) (l.llg), 3-cyano-6-(3,5-dibromophenyl)pyridin-2(lH)-one (0.73g) m.p. >300C after recrystallisation from n-butanol, was prepared according to the method of Example 3(a). 1H NMR ~(DMSO-d6) 7.00(br d,lH), 8.02(s,1H), 8.09(s,2H) and 8.23(d,lH).
W O 92/0608~ 2 0 g 19 8 9 P ~ /GB91/01663 (b) From 3-cyano-6-(3,5-dibromophenyl)pyridin-2(lH)-one (o.s3g), the title compound (0.15g) m.p. 295-296C
(decomp) after recrystallisation from n-butanol was prepared according to the method of Example l(a). lH NMR
S ~(DMSO-d6) 7.10(br d,lH), 8.02(s,1H), 8.13(s,2H) and 8.47(d,lH).
Example 18 10 6-(2,4-Dipropoxyphenyl)-3-(5-tetrazolyl)pyridin-2(IH)-one (a) From 2',4'-dipropoxyacetophenone (17.9g) (P.
Chabrier, H. Najer, R. Giudicelli and E. Joannie-Voisinet, 15 8ull. Soc. Chim. France, l9S8, 1488.), 3-cyano-6-(2,4-dipropoxyphenyl)pyridin-2(1H)-one (1.69g) m.p. 148C after recrystallisation from ethanol, was prepared according to the method of Example 3(a).
20 (b) From 3-cyano-6-(2,4-dipropoxyphenyl)pyridin-2(1H)-one (lg), the title compound (0.60g) m.p. 205C after recrystallisation twice from ethanol, was prepared according to the method of Example l(b).
Exam~le 19 6-(2,5-Dipropoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one 30 (a) From 2',5'-dipropoxyphenylacetophenone (11.8g), 3-cyano-6-(2,5-dipropoxyphenyl)pyridin-2(lH)-one (14.36g) m.p. 160-162C after recrystallisation from ethanol, was prepared according to the method of Example 3(a). 1H NMR
~(DMS0-d6) 0.92(t,3H), 0.97(t,3H), 1.61-1.76(m,4H), 3S 3.92(t,4H), 6.54(d,lH), 7.01-7.06(m,3H), 8.18(d,1H).
W092/06085 2 0 ~19 ~ 9 PCT/GB9l/01663 (b) From 3-cyano-6-(2,5-dipropoxyphenyl)pyridin-2(lH)-one (2.5g), the title compound (0.81g) m.p.188-189C after recrystallisation from ethanol, was prepared according to the method of Example l(b).
ExamPle 20 6-(2,3,4-Trichlorophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one (a) 2',3',4'-Trichloroacetophenone (22.15g) and dimethylformamide (12.5g3 were boiled in dimethylformamide (lOOml) for 3 hours. The solution was diluted with ethyl acetate (500ml), washed with water (6xlOOml), dried (MgS04), filtered and solvent removed at reduced pressure. The residue was triturated with diethyl ether to give 3-N,N-dimethylamino-1-(2,3,4-trichlorophenyl)prop-2-ene-1-one (17.5g). lH NMR ~(DMSO-d6) 2.8~(s,3H) 3.08(br s,3H), 5.17(d,1H), 7.1(very br,lH), 7.30(br d,lH) and 7.65(d,1H).
(b) A solution of 3-N,N-dimethylamino-1-(2,3,4-trichlorophenyl)prop-2-ene-1-one (9.8g) and cyanoacetamide (3.18g) in dimethylformamide (35ml) was boiled for 48 hours. The reaction mixture was poured into 10% aqueous acetic acid (lOOml), the precipitated product separated by filtration and recrystallised from ethanol to give 3-cyano-6-(2,3,4-trichlorophenyl)pyridin-2(1H)-one (4.4g). 1H NMR ~(DMSO-d6) 6.52(d,lH),7.58(d,lH), 7.79(d,1H), 8.24(d,1H) and 12.95(br s,lH).
(c) From 3-cyano-6-(2,3,4-trichlorophenyl)pyridin-2(1H)-one (1.2g), the title compound (1.21g) m.p.>300C
after recrystallisation from dimethylformamide/water, was prepared according to the method of Example l(a). lH NMR
~(DMSO-d6) 6.63(d,lH), 7.61(d,lH), 7.83(d,lH), W092/0608~ 2 0 919 ~ 9 PCT/GB91/01663 8.51(d,1H) and 12.98(br s,lH).
EXamD1e 2 1 6-[6-(1,2,3,4-Tetrahydronaphthyl)]-3-(5-tetrazolyl)pyridin-2(lH)-one (a) From 6-acetyltetralin (4.23g), 3-cyano-6-[6-(1,2,3,4-tetrahydronaphthyl)]pyridin-2(lH)-one (1.27g) m.p.
245-246OC after recrystallisation from n-butanol, was prepared according to the method of Example 3(a). lH NMR
~(DMSO-d6) 1.75(m,4H), 2.77(m,4H), 6.71(d,lH), 7.19 (d,lH), 7.50(d,1H), 7.53(s,1H) and 8.15(d,1H).
(b) From 3-cyano-6-[6-(1,2,3,4-tetrahydronaphthyl)pyridin-2(lH)-one (lg), the title compound (0.55g) m.p. 284-285C
after recrystallisation from dimethylformamide/water,was prepared according to the method of Example l(b).
Exam~le 22 6-(3-Chlorophenyl)-3-(5-tetrazolyl~pyridin-2(lH)-one (a) From 3'-chloroacetophenone (15.46g), 6-(3-chloro-phenyl)-3-cyanopyridin-2(lH)-one (17.12g) m.p. 304-305C
after recrystallisation from n-butanol, was prepared according to the method of Example 3(a).
(b) From 6-(3-chlorophenyl)pyridin-2(1H)-one (1.2g), the title compound (l.Olg) m.p. 301-302C (decomp) after recrystallisation from n-butanol, was prepared according to the method of Example l(b). lH NMR ~(DMSO-d6) 6.94(d,1H), 7.48-7.62(m,2H), 7.81(d,1~), 7.96(s,1H), 8.48(d,lH) and 12.77(br s,lH) W092/0608; 2 0 9 ~ 9 8 9 PCT/GB91/01663 Example 23 6-(3-Phenylthiophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one (a) 3'-Phenylthioacetophenone (2.05g) (L. Victor, Brit.
Pat. 1,519,354) and dimethylformamide dimethylacetal (1.19g) were heated together in dimethylformamide (lOml) at 100C for 18 hours. The reaction mixture was diluted with ethyl acetate (50ml) washed with water (6x30ml), dried (MgS04) filtered and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, dichloromethane-5% ethanol/dichloromethane eluant) to give 3-N,N-dimethylamino-1-(3-phenylthiophenyl)-prop-2-ene-1-one (1.72g) as a yellow oil.
(b) A mixture of 3-N,N-dimethylamino-1-~3-phenylthio-phenyl)prop-2-ene-1-one (1.72g), sodium methoxide (0.76g) and cyanoacetamide (0.59g) were boiled together in dimethylformamide (lOml) for 1 hour. The reaction mixture was poured into 10% aqueous acetic acid (lOOml), the precipitated product separated by filtration and recrystallised from ethanol to give 3-cyano-6-(3-phenylthiophenyl)pyridin-2(lH)-one (l.Og) m.p. 262-264C.
(c) From 3-cyano-6-(3-phenylthiophenyl)pyridin-2(1H)-one (0.79g), the title compound (0.77g) m.p.265-266C after recrystallisation from n-butanol, was prepared according to the method of Example l(b).
Exam~le 24 3,4-Dimethoxyphenyl-3-(S-tetrazolyl)pyridin-2(lH)-one (a) From 3',4'-Dimethoxyacetophenone (18g), 3-cyano-6-W092/0608~ 2 0 ~ ~ PCT/GB91/01663 (3,4-dimethoxyphenyl)pyridin-2(1H)-one (9.86g) m.p.
269-270C after recrystallisation from ethanol, was prepared according to the method of Example l(a).
(b) From 3-cyano-6-(3,4-dimethoxyphenyl)pyridin-2(lH)-one (1.02g), the title compound (0.02g) m.p. 293-295C after recrystallisation from dimethylformamide, was prepared accordlng to the method of Example l(b).
Example 25 6-(3-Methylthiophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one 15 (a) From 3'-methylthioacetophenone (4.64g), 3-cyano-6-(3-methylthiophenyl)pyridin-2(lH)-one (4.3g) m.p.234-238C
after recrystallisation from ethanol, was prepared according to the method of Example 3(a).
(b) From 3-cyano-6-(3-methylthiophenyl)pyridin-2tlH)-one (lg), the title compound (0.85g) m.p.274-2760C (decomp) after recrystallisation from n-butanol, was prepared according to the method of Example l(b). 1H NMR
~(DMSO-d6) 2.58(s,3H), 6.91(d,1H), 7.39-7.63(m,3H), 25 7.68(s,1H) and 8.47(d,1H).
Example 26 6-(3-Butylthiophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one (a) Copper-(I)-n-butylmercaptide (R. Adams, W. Reijschneider and A. Ferretti, Org, Syn. Coll. Vol., V, plO7) (3.34g) and 3-cyano-6-(3-bromophenyl)pyridin-2(lH)-one (2.61g) were heated together in a mixture of quinoline (lOml) and pyridine (3ml) at 160C for 4 hours.
W O 92/0608~ 2 0 ~ 9 P ~ /GB91/01663 The reaction mixture was poured onto conc. hydrochloric acid (30ml) and ice (lOOg) and the precipitated material collected by filtration. The residue was column chromatographed (silica gel, dichloromethane-dichloromethane/2% ethanol) to give 3-cyano-6-(3-butylthiophenyl)pyridin-2(lH)-one (0.35g) m.p. 191-193C after recrystallisation from ethanol.
(b) From 3-cyano-6-(3-butylthiophenyl)pyridin-2(lH)-one (0.23g), the title compound (O.llg) m.p.237-238C after recrystallisation from n-butanol, was prepared according to the method of Example l(b).
Example 27 6-(3,4-Di-Propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one (a) From 3',4'-di-propoxyacetophenone (3.6g) 3-cyano-6-(3,4-dipropoxyphenyl)pyridin-2(1H)-one (3.21g) m.p. 249C after recrystallisation from ethanol, was prepared according to the method of Example 3(a).
(b) From 3-cyano-6-(3,4-di-propoxyphenyl)-pyridin-2(lH)-one (l.OOg) the title compound m.p. 280C
(decomp) after recrystallisation from n-butanol,was prepared according to the method of Example l(b). lH NMR
~d6-DMSO) 0.97-1.05(m,6H), 1.71-1.81(m,4H), 4.01(t,2H), 4.03(t,2H), 6.88(d,lH), 7.09(d,lH), 7.43(d,1H), 7.46(s,1Hj and 8.44(d,1H) and 12.61(br.s,1H).
Example 28 6-(2,3-di-Propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one W O 92/0608~ 2 0 919 ~ ~ P ~ /GB91/01663 (a) From 2,3-dihydroxybenzaldehyde (20g), 2,3-di-propoxy benzaldehyde (18.6g) isolated as an oil was prepared according to the method of Example 2(a). lH-NMR
~(CDCl3) 1.04(t,3H), l.O9(t,3H), 1.74-1.96(m,4H), 3.97(t,2H), 4.15(t,3H), 7.03-7.16(m,2H), 7.39(dd,lH) and 10.47(s,lH) (~) To a solution of 2,3-di-propoxybenzaldehyde (18.6g) in tetrahydrofuran at -78C methyl lithium (61ml, l.SM in diethyl ether) was added over 10 minutes. The reaction mixture was stirred at -78C for two hours and at room temperature for 16 hours. After quenching with water the organic phase was separated, dried (MgS04) and solvent removed to give 1-(2,3-di-propoxyphenyl)-1-hydroxyethane (20g) as an oil. lH-NMR ~(CDCl3) 1.04(t,3H), 1.06(t,3H), 1.72-1.93(m,4H), 3.89tt,2H), 3.99(t,2H), 5.15(m,lH), 6.80(m,lH) and 6.95-7.04(m,2H).
(c) To an ice cooled solution of 1-(2,3-di-propoxy-phenyl)-1-hydroxyethane (20g) in dichloromethane (250ml) powdered 4A molecular sieves (23g), N-methylmorpholine-N-oxide (14.9g) and tetrapropylammonium perruthenate (lg).
The mixture was stirred for one hour with ice cooling and at room temperature overnight. After filtration through Hyflo solvent was removed at reduced pressure to give 2',3'-di-propoxyacetophenone (18.3g). lH-NMR ~(CDCl3) 1.03(t,3H), 1.08(t,3H), 1.72-1.96(m,4H), 2.63(s,3H), 3.96(t,2H), 4.01(t,2H) and 6.99-7.19(m,3H).
(d) From 2',3'-dipropoxyacetophenone (lOg), 3-cyano-6-(2,3-di-propoxyphenyl)pyridin-2(1H)-one (1.87g) m.p. 195-198C was prepared according to the method of Example 3(a), omitting sodium methoxide. 1H-NMR
(d6-DMSO) 0.81(t,3H), l.Ol(t,3H), 1.51(m,2H), 1.76(m,2H), 3.84(t,2H), 3.99(t,2H), 6.43(d,lH), 6.97(d,1H), 7.10- 7.27(m,2H) and 8.17(d,1H).
W092/0608~ 2 0 919 ~ ~ PCT/GB91/01663 (e) From 3-cyano-6-(2,3-di-propoxyphenyl)pyridin-2(1H~-one (lg), the title compound (0.47g) m.p. 186-187C
after recrystallisation from aqueous ethanol was prepared according to the method of Example l(b).
Exam~le 2g 6-(3-Cyclopentyloxy-4-methoxyphenyl)-3-(5-tetrazolyl)-pyridin-2(lH)-one (a) A mixture of 3'-hydroxy-4'-methoxyacetophenone (20.8g), potassium carbonate (24.15g), cyclopentyl bromide (22.35g) and potassium iodide (3.32g) were combined in acetone (250ml) and boiled for 24 hours. Dimethylformamide '5 (25ml) was added and boiling continued for a further 24 hours. The reaction mixture was cooled to room temperature, filtered and solvent removed at reduced pressure. The residue was dissolved in diethyl ether (200ml) washed with 2N sodium hydroxide (3x50ml) and water, dried and solvent removed at reduced pressure to give 3'cyclopentyloxy, 4'-methoxyacetophenone as an oil that solidified on standing m.p. 59-60C.
(b) From 3'-cyclopentyloxy-4'-methoxyacetophenone (11~25g), 3-cyano-6-(3-cyclopentyloxy-4-methoxyphenyl)-pyridin-2(1H~-one (4.07g) m.p.259-260C after digestion with acetonitrile was prepared according to the method of Example 3(a) omitting sodium methoxide.
(c) From 3-cyano-6-(3-cyclopentyloxyphenyl-4-methoxyphenyl)pyridin-2(1H)-one (0.8g), the title compound (0.6g) m.p. 286-287C (decomp) after recrystallisation from dimethylformamide was prepared according to the method of Example l(b). lH-NMR ~(d6-DMSO) W O 92/06085 2 ~ g g PC~r/GB91/01663 1.54-2.02(m,8H), 3.83(s,3H), 5.00(m,lH), 6.87(d,lH), 7.10(d,1H), 7.43(s,1H), 7.46(d,1H) and 8.44(d,1H).
Example 30 6-(3-Ethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one (a) A mixture of 3-hydroxyacetophenone (6.8g) and tris(dimethylamino)methane (14.5g) were heated together in dimethylformamide (30ml) at 80C for 4 hours. The reaction mixture was cooled to room temperature cyanoacetamide (8.4g) added and the mixture boiled for 8 hours. After cooling to room temperature the mixture was poured into 10% aqueous acetic acid (200ml), filtered and the residue washed with water and ethanol to give 3-cyano-6-(3-hydroxyphenyl)pyridin-2(lH)-one. lH-NMR ~(d6-DMSO) 6.64(br.d,1H), 6.95(dd,1H), 7.12(s,1H), 7.20(d,1H), 7.32(t,1H), 8.15(d,1H), 9.87(s,1H) and 12.70(b,.s,1H).
(b) To a suspension of sodium hydride (lg, 50% in oil) in dimethylformamide (15ml) 3-cyano-6-(3-hydroxy-phenyl)pyridin-2(lH)-one (2.12g) was added in portions over 30 minutes. When gas evolution had ceased iodoethane (1.56g) was added and the mixture stirred overnight. The mixture was diluted with ethyl acetate (lOOml), washed with 2N hydrochloric acid (2x30ml) and with water (4x50ml), dried (MgS04) and solvent removed at reduced pressure. The residue was recrystallised from n-butanol to give 3-cyano-6-(3-ethoxyphenyl)pyridin-2(lH)-one (0.68g). 1H-NMR ~(d6-DMSO) 1.35(t,3H), 4.12(q,2H), 6.80(d,1H), 7.08(d,1H), 7.31-7.47(m,3H) and 8.18(d,lH).
(5) From 3-cyano-6-(3-ethoxyphenyl)pyridin-2(1H)-one (0.5g), the title compound (0.44g) m.p.279C (decomp) W092/06085 PCT/GB9t/01663 2091~8~
after recrystallisation from n-butanol, was prepared according to the method of Example l(b). lH-NMR
~(d6-DMSO) 1.36(t,3H), 4.14(q,2H), 6.90(d,lH), 7.10(m,lH), 7.34-7.48(m,3H) and 8.47(d,lH).
Exam~le 31 6-(3,5-Dimethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one (a) From 3',5'-dimethoxyacetophenone (4.1g), 3-cyano-6-(3,5-dimethoxyphenyl)pyridin-2(lH)-one (2.4lg) m.p. 297C after recrystallisation from ethanol, was prepared according to the method of Example 3(a).
(b) From 3-cyano-6-(3,5-dimethoxyphenyl)pyridin-2(lH)-one (1.4g), the title compound (1.36g) m.p. 338C (decomp) after recrystallisation from acetonitrile/dimethyl-formamide was prepared according to the method of Example l(b). lH NMR ~(d6-DMSO) 3.86(s,6H), 6.66(m,1H), 6.95(d,1H), 7.02(m,2H), 8.47(d,1H) and 12.66(br.s,1H).
ExamPle 32 6-(2-Butylthiophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one (a) From 2'-bromoacetophenone (19.9g), 6-(2-bromophenyl)-3-cyanopyridin-2(1H)-one (11.4g) m.p. 245-246C after recrystallisation from ethanol,was prepared according to the method of Example l(a).
(b) From 6-(2-bromophenyl)-3-cyanopyridin-2(lH)-one (2.6lg), 6-(2-butylthiophenyl)-3-cyanopyridin-2(lH)-one (0.83g) m.p.163-165C after recrystallisation from W092/06085 2 ~ 919 8 ~ PCT/GB91/01663 ethanol, was prepared according to the method of Example 26(a).
(c) From 6-(2-butylthiophenyl)-3-cyanopyridin-2(lH)-one (0.71g), the title compound (0.53g) m.p.l81-182C after recrystallisation from ethanol, was prepared according to the method of Example l(b).
Example 33 6-(3-Allyloxyphenyl)-3-(5-tetrazolyl)p~ridin-2(1H)-one ~a) From 3'-allyloxyacetophenone (15.07g), 6-(3-allyloxyphenyl)-3-cyanopyridin-2(lH)-one (14.7g) was prepared according to the method of Example 3(a). lH NMR
o(d6-DMSO) 4.67(d,2H), 5.26-5.46(m,2H), 5.98-6.20(m,1H), 6.80(d,1H), 7.13(m,1H), 7.33(m,3H) and 8.20(d,1H).
(b) From 6-(3-allyloxyphenyl)-3-cyanopyridin-2(1H)-one (lg), the title compound (0.34g) m.p.260C (decomp) after recrystallisation from n-butanol, was prepared according to the method of Example l(b). lH NMR O(d6-DMSO) 4.72(m,2H), 5.28-5.52(m,2H), 6.04-6.20(m,1H), 6.94(d,1H), 7.14(m,lH), 7.48(m,3H) and 8.47(d,lH).
ExamPle 34 6-(4-Methoxy-2-pQntyloxyphenyl)-3-~5-tetrazolyl)pyridin-2(1H)-one (a) From 4'-methoxy-2'-pentyloxyacetophenone (11.8g), 3-cyano-6-(4-methoxy-2-pentyloxyphenyl)pyridin-2(lH)-one (3.4g) m.p. 143-144C after recrystallisation from ethanol, was prepared according to the method of Example 3(a).
W092/0608~ 2 Q 9 ~ PCT/GB91/~1663 ~b) From 3-cyano-6-(4 methoxy-2-pentyloxyphenyl)pyridin-2(lH)-one ~1.25g), the title compound (0.65g) m.p. 193-194C after recrystallisation from ethanol was prepared according to the method of Example l(b).
~xamPle 35 6-~3-i~o-Butoxy-4-metho~yphenyl)-3-(5-tetrazolyl)pyridin-2(1~)-one (a) From 3'-iso-butoxy-4'-methoxyacetophenone (7.6g), 3-cyano-6-(3-iso-butoxy-4-methoxyphenyl)pyridin-2(lH)-one (6.02g) m.p.234-235C after recrystallisation from ethanol, was prepared according to the method of Example 3(a).
(b) From 3-cyano-6-(3-iso-butoxy-4-methoxyphenyl)pyridin-2(lH)-one (1.19g), the title compound (1.2g) m.p. 296-297C
(decomp) after recrystallisation from ethanol, was prepared according to the method of Example l(b). lH NMR ~(DMSO-d6) l.Ol(d,6H), 2.02-2.16(m,lH), 3.85(s,3H3, 3.89(d,2H), 6.89(d,lH), 7.12(d,lH), 7.41-7.50(m,2H) and 8.47(d,lH).
ExamPle 36 6-(2-Bromo-3,5-diethoxyphenyl)-3-(5-tetrazolyl)py~idin-2(1~)-one (a) To an ice cooled solution of 3',5'-diethoxyacetophenone (10.4g) in dimethylformamide (50ml) N-bromosuccinimide (9.79g) was added in portions over 1 hour. The mixture was stirred at 0C for 3 hours and stood at room temperature for 48 hours. After diluting with ethyl acetate (200ml) the mixture was washed with water (5xlOOml), dried (MgS04) and solvent removed at reduced pressure to give 2'-bromo-3',5'-diethoxyacetophenone (12.53g) as an oil.lH NMR ~(CDC13)1.41(t,3H), 1.50(t,3H), 2.60(s,3H), 4.00(q,2H), 4.10(q,2H), 6.45(d,lH) and 6.50(d,lH).
WO 92/0608~ 2 0 919 8 9 . PCr/GBgl/01663 (b) From 2'-bromo-3',5'-diethoxyacetophenone (4.31g), 3-cyano-6- (2-bromo-3,5-diethoxyphenyl)pyridin-2(lH)-one (0.75g) m.p. 234-235C after recrystallisation from 5 ethanol, was prepared according to the method of Example 3(a)-(c) From 3-cyano-6-(2-bromo-3,5-diethoxyphenyl)pyridin-2(lH)-one (0.6g), the title compound m.p. 276C after 10 recrystallisation from ethanol was prepared according to the method of Example l(b).
Example 37 6-(5-Bromo-4-methoxy-2-pentyloxyphenyl)-3-(5-tetrazolyl)-pyridin-2(1EE)-one (a) A mixture of 3-cyano-6-(4-methoxy-2-pentyloxyphenyl)-pyridin-2(lH)-one (1.71g), silver carbonate (1.92g) and 20 iodomethane in chloroform (30ml) were stirred in the dark for 48 hours. After filtration (celite pad) solvent was removed at reduced pressure and the residue column chromatographed (silica gel, 40%hexane/dichloromehane eluant) to give 3-cyano-2-methoxy-6-(4-methoxy-2-25 pentyloxyphenyl)pyridine (1.45g) m.p.76-78C.
(b) To a cooled (ice bath) solution of 3-cyano-2-methoxy-6-(4-methoxy-~-pentyloxyphenyl)pyridine (1.3g) in dimethylformamide (lOml) N-bromosuccinimide (0.71g) was 30 added in portions over 30 minutes. The solution was stirred at room temperature overnight diluted with ethyl acetate (SOml) and washed with water (5x50ml). The organic phase was dried (MgS04) solvent removed at reduced pressure and the residue recrystallised from ethanol to give 3-cyano-2-35 methoxy-6-(5-bromo-4-methoxy-2-pentyloxyphenyl)pyridine (l.lg) m.p. 136-l37C.
W092/06085 2 ~ 91~ ~ 3 PCT/GB91/01663 (c) 3-Cyano-2-methoxy-6-(2-bromo-4-methoxy-2-pentyloxyphenyl)pyridine (lg) and sodium iodide (1.50g) (dried a~ 70C in vacuo for 4 hours) were dissolved in acetonitrile (lOml) and chlorotrimethylsilane (1.08g) added. The reaction mixture was stirred in the dark for 2 hours, diluted with ethyl acetate (SOml) washed with water ~2x50ml), with 5% aqueous sodium metabisulphite (30ml) and water (50ml). The organic phase was dried (MgS04) solvent removed at reduced pressure and the residue recrystallised from ethanol to give 3-cyano-6-(5-bromo-4-methoxy-2-pentyloxyphenyl)pyridin-2(lH)-one (0.55g) m.p.188-190C.
(d) From 3-cyano-6-(5-bromo-4-methoxy-2-pentyloxyphenyl)pyridin-2(lH)-one (0.5g), the title compound (0.38g) m.p.246-248C after recrystallisation from ethanol, was prepared according to the method of Example l(b).
Example 38 6-(2-Allyl 4-m~thoxy-3-propoxyphenyl)-3-(5-tQtrazolyl)-pyridin-2(1~)-one (a) A mixture of 3'-allyloxy-4'-methoxyacetophenone (7.76g) and diethylaniline (5.96g) was degassed with nitrogen for 15 minutes and heated at 215C for 90 minutes. After cooling to room temperature the reaction mixture was dissolved in ethyl acetate (lOOml) and washed with 2N
hydrochloric acid (3xlOOml). The organic phase was dried ~MgS04) and solvent removed at reduced pressure to give after recrystallisation from ethanol/water 2'-allyl-3'-hydroxy-4'-methoxyacetophenone (S.lg) m.p.~1-83C.
(b) 2'-Allyl-3'-hydroxy-4'-methoxyacetophenone (5.0g), potassium carbonate (3.3g) and iodopropane were heated together in a mixture of dimethylformamide (20ml) and butanone (30ml) for 48 hours~ The mixture was filtered and W092/060~5 2 0 919 ~ 9 PCT/GB91/01663 solvent removed from the filtrate at reduced pressure to give a residue which was dissolved in ethyl acetate (lOOml) and washed with water (5x50ml). The organic phase was dried (MgS04) and solvent removed at reduced pressure to give 2'-allyl-4'-methoxy-3'-propoxyacetophenone (5.0g) as an oil.
1H NMR ~5DMSO-d6) 0.98(t,3H), 1.62-1.80(m,2H), 2.48(s,3H), 3.62-3.69(m,2H), 3.79(t,2H), 3.85(s,3H), 4.82-4.91(m,2H), 5.78-5.93(m,lH), 6.99(d,lH and 7.63(d,lH).
10 (c) From 2'-allyl-4'-methoxy-3'-propoxyacetophenone (4.96g) 3-cyano-6-(2-allyl-4-methoxy-3-propoxyphenyl)pyridin-2(lH)-one (1.15g) m.p. 170-171C after recrystallisation from ethanol was prepared according to the method of Example 3(a) with, however, the omission of sodium methoxide.
(d) From 3-cyano-6-(2-allyl-4-methoxy-3-propoxyphenyl)pyridin-2(lH)-one (0.49g), the title compound (0.24g) m.p. 210-211C after recrystallisation from ethanol was prepared according to the method of Example l(b).
ExamPle 39 ~-t3-(E-l-propenyl)-4-methoxyphenyl]-3-(5-tetrazolyl) pyridin-2(1R)-one (a) From 3-allyl-4-methoxyacetophenone (7.6g), 3-cyano-6-[3-(E-1-propenyl)-4-methoxyphenyl]pyridin-2(lH)-one (4g) after recrystallisation from n-butanol, was prepared according to the method of Example 3(a). 1H NMR ~(DMSO-d 30 1.88(d,3H), 3.87(s,3H), 6.40-6.67(m,3H), 6.~8(d,lH), 7.10(d,lH), 7.72(dd,lH), 7.93(d,lH) and 8.14(d,lH).
(b) From 3-cyano-6-[3-(E-1-propenyl)-4-methoxyphenyl]pyridin-2(1H)-one (2.13g), the title compound 35 (0.8g) m.p. 291-29~C (decomp) after recrystallisation from dimethylformamide was prepared according to the method of Example l(b). lH NMR ~(DMSO-d6) 1.89(d,3H), 3.88(s,3H), W092/06085 2 0 919 ~ 3 PCT/GB91/01663 6.42-6.71(m,3H), 6.90(d,lH), 7.12(d,lH), 7.76(dd,lH), 7.97(d,lH) and 8.44(d,lH).
, ExamPle 40 6-(4-~ethoxy-3-propoxyphsnyl)-3-~S-~l-pi~aloyloxymHthyl)-tetrazolyl)pyridin-2(1~)-one and 6-(4-~ethoxy-3-propoxyphenyl)-3-[5-(2-pivaloyloxymethyl)-tetrazolyl~pyridin-2(1~)-one A mixture of 4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one (1.64g), pivaloyloxymethyl chloride (0.75g), sodium hydrogen carbonate (420mg) and sodium iodide (50mg) were heated in dimethylformamide (5ml) at 70C for 24 hours. The mixture was diluted with ethyl acetate (SOml) and washed with water 6 x SOml). The organic phase was dried (MgS04) filtered and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, 70% hexane/ethyl acetate - 30% hexane/ethyl acetate eluant to give:- a) 6-(4-methoxy-3-propoxyphenyl)-3-[5-(1-pivaloyloxymethyl)tetrazolyl]pyridin-2(lH)-one (0.26g) m.p. 169-170C after recrystallisation from ethanol and b) 6-(4-methoxy-3-propoxyphenyl)-3-[5-~2-pivaloyloxymethyl)tetrazolyl]pyridin-2(lH)-one (0.35g) m.p.195-196C after recrystallisation from ethanol.
Example 41 6-~3-Ethoxy-5-(2-methoxyethoxy)phenyl]-3-(S-tetrazolyl)-pyridin-2(1~)-one a) 3',5'-Dihydroxyacetophenone (15.2g), potassium carbonate (7.59g) and iodoethane (17.16g) were combined and heated at reflux for 15 hours. Additional potassium carbonate (2.76g) and iodoethane (6.2g) were added and heating was continued for a further 10 hours. The reaction mixture was filtered, solvent removed at reduced pressure, the residue dissolved W092/0608S 2 ~ 919 ~ 9 ;; PCT/~B91/0166~
_ ~9 _ in ethyl acetate (lOOml) and extracted with 2N sodium hydroxide (3x50ml). The combined basic extracts were washed with ethyl acetate (2xSOml), acidified with 2N hydrochloric acid and extracted with dichloromethane (3xlOOml). The combined dichloromethane extracts were washed with water (2x50ml), dried (MgS04), filtered and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, dichloromethane eluant) to give 3'-ethoxy-5'-hydroxyacetophenone (4.83g) m.p. 96-98C.
b) To a suspension of sodium hydride (0.92g, 60% in oil washed with hexane) in dimethylformamide (lOml), 3'-ethoxy-5'-hydroxyacetophenone (3.24g) was added in portions over 10 minutes. When gas e~olution had ceased chloroethylmethyl ether (1.9g) and sodium iodide (50mg) were added and the mixture heated to 90C for 18 hours and stirred at room temperature for 24 hours. The mixture was diluted with ethyl acetate (lOOml), washed with 2N sodium hydroxide (3x50ml) and water (3x50ml). The organic phase was dried ~MgS04), filtered and solvent removed at reduced pressure to give 3'-ethoxy-S'-(2-methoxyethoxy)acetophenone (4.03g) as an oil. lH NMR ~(CDCl3) 1.42(t,3H), 2.56(s,3H), 3.46(s,3H), 3.74-3.78(m,2H), 4.05(q,2H), 4.13-4.17(m,2H), 6.68(m,lH) and 7.10(m,2H).
^5 c) From 3'-ethoxy-5'-t2-methoxyethoxy)acetophenone, 3-cyano-6-[3-ethoxy-5-~2-methoxyethoxy)phenyl~pyridin-2~lH)-one (l.lg) m.p.199C after recrystallisation from ethanol, was prepared according to the method of Example 3(a).
d) From 3-cyano-6-[3-ethoxy-5-(2-methoxyethoxy)phenyl]pyridin-2(lH)-one (0.94g), the title compound (0.6g) m.p.205-206C after recrystallisation from ethanol, was prepared according to the method of Example l(b).
W092/0608~ 2 0 919 8 ~ PCT/GB91tO1663 xamPle 42 6-t3-(2,2-Dimethylpropyloxy)-4-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1~)-one a) From 3'-(2,2-dimethylpropyloxy)-4'-methoxyacetophenone ~9.Og), 3-cyano-6-[3-(2,2-dimethylpropyloxy)-4-methoxyphenyl]pyridin-2(lH)-one (3.46g) was prepared according to the method of Example 3(a). lH NMR ~(DMSO d6) 1.02(s,9H), 3.74(s,2H), 3.85(s,3H), 6.79(d,lH), 7.09(d,lH~, 7.42(s,lH), 7.43(d,lH) and 8.14(d,lH).
b) From 3-cyano-6-[3-(2,2-dimethylpropyloxy)-4-methoxyphenyl]pyridin-2(lH)-one (1.2Sg), the title compound (1.28g) m.p. >300C after recrystallisation from n-butanol, was prepared according to the method of Example l(b). lH
NMR ~(DMSO-d6) 1.04(s,9H), 3.77(s,2H), 3.86(s,3H), 6.90(d,lH), 7.10(d,lH), 7.45(m,2H) and 8.44(d,lH).
ExamPle 43 6-(3-Ethoxy-4-methoxyphenyl)-3-(S-tetrazolyl)pyridin-2(1~)-one a) From 3'-ethoxy-4'-methoxyacetophenone (2.91g), 3-cyano-6-(3-ethoxy-4-methoxyphenyl)pyridin-2(lH)-one (2.02g) m.p.273C after recrystallisation from ethanol was prepared according to the method of Example l(a).
b) From 3-cyano-6-(3-ethoxy-4-methoxyphenyl)pyridin-2(lH)-one (l.Og), the title compound (l.Q6g) m.p.299C (decomp) after recrystallisation from n-butanol, was prepared according to the method of Example l(b). lH NMR ~(DMSO-d6) 1.37(t,3H), 3.84(s,3H), 4.15(q,2H), 6.92(d,lH), 7.10(d,lH), 7.41-7.50(m,2H) and 8.43(d,lH).
W092/0608~ 2 0 919 8 ~ PCT/GB91/01663 ExamPle 44 6-(3-~ropionamidophenyl)-3-(5-tetrazolyl)pyridin-2(1~-one a) To a stirred suspension of sodium methoxide (4.32g) in diethyl ether (50ml) a mixture of 3'-propionamidoacetophenone (5.73g) and ethyl formate (4.44g) in tetrahydrofuran (lOOml) was added over 30 minutes. After stirring overnight the mixture was filtered and the residue washed with diethyl ether. The residue was dissolved in water (50ml), the pH adjusted to 9.0 with glacial acetic acid and cyanoacetamide (4.2g) added. The solution obtained was boiled overnight cooled to room temperature and adjusted to pH 5 with glacial acetic acid (US Patent 4,278,681). The precipitated material was collected by filtration, washed thoroughly (4x50ml) with ethanol and recrystallised from dimethylformamide/water to give 3-cyano-6-(3-propionamidophenyl)pyridin-2(lH)-one (0.4g) m.p.
b) From 3-cyano-Ç-(3-propionamidophenyl)pyridin-2(lH)-one (0.3g) the title compound (0.2g) m.p.291-293C (decomp) after recrystallisation from dimethylformamide/water, was prepared according to the method of Example l(b). lH NMR
~(DMSO-d6) l.ll(t,3H), 2.37(q,2H), 6.75(d,lH), 7.46(m,2H), 7.69(m,lH), 8.09(m,lH~ and 8.50(d,lH).
Example 45 6-(4-Methoxy-3-propylphenyl)-3-~5-tetrazolyl)pyridin-2(1~)-one (SB 20525)) (a) A solution of 3'-allyl-4'-methoxyacetophenone t20g) in ethanol ~250ml) containing 10% palladium on charcoal (2g) was treated with hydrogen at 50 p.s.i until the calculated volume of hydrogen had been taken up. The mixture was filtered (celite pad) and solvent removed at reduced W092/06085 2 ~ 919 8 ~ PCT/GB91/01663 pressure. The residue was dissolved in dichloromethane (lOOml) and manganese dioxide (60g) added. The mixture was stirred at room temperature for 48 hours, filtered (celite pad) and solvent removed at reduced pressure to give 4'-methoxy-3'-propylacetophenone (15.16g) as an oil. lH NMR
~(CDCl3) 0.95(t,3H), 1.52-1.79(m,2H), 2.55(s,3H), 2.61(t,2H), 3.88(s,3H), 6.86(d,lH), 7.77(d,lH) and 7.82(dd,lH).
10 (b) From 4'-methoxy-3'-propylacetophenone (5.77g), 3-cyano-6-(4-methoxy-3-propylphenyl)pyridin-2(lH)-one (4.43g) m.p.
239C after recrystallisation from butanol, was prepared according to the method of Example 3(a).
15 (c) From 3-cyano-6-(4-methoxy-3-propylphenyl)pyridin-2(lH)-one (4.02g), the title compound (3.64g) m.p.293-294C
(decomp) after recrystallisation from ethanol, was prepared according to the method of Example l(b). lH NMR ~(DMSO-d6) 0.93(t,3H), 1.51-1.71(m,2H), 2.59(t,2H), 3.87(s,3H), 6.83~d,1H), 7.10(d,1H), 7.68-7.74(m,2H) and 8.46(d,1H).
ExamPle 46 6-(3-Bromo-4-methoxyphenyl)-3-(5-tetrazolyl)pyri~in-2(1~)-one (SB 204617~
(a) From 3'-bromo-4'-methoxyacetophenone (K.W.Rosenmund et.
al. Chem. Ber., 1922, 90, 1957) (2.29g), 3-cyano-6-(3-bromo-4-methoxyphenyl)pyridin-2(lH)-one (1.42g) m.p. 284-286C after recrystallisation from ethanol, was preparedaccording to the method of Example 3(a).
(b) From 3-cyano-6-(3-bromo-4-methoxyphenyl)pyridin-2(lH)-one (1.22g), the title compound (1.28g) m.p. 292-293C
(decomp) after recrystallisation from dimethylformamide, was prepared according to the method of Example l(b). 1H
W092/06085 2 0 919 ~ 9 P~T/GB91/01663 NMR ~(DMSO-d6) 3.94(s,3H), 6.90(d,lH), 7.27(d,lH), 7.90(dd,lH), 8.14(d,lH) and 8.45(d,lH).
Example 47 6-(3-phenyl-4-methoxyphQnyl)-3-(5~tetrazolyl)pyridin-2(1R)-one ~S8 204649) (a) To a suspension of tetrakis(triphenylphosphine)palladium (O) (O.Sg) in aoueous sodium hydrogen carbonate (5.04g in 60ml water), solutions of phenylboronic acid (2.65g) in dimethoxyethane (lOOml) and 3'-bromo-4'-methoxyacetophenone (4.58g) in dimethoxyethane (llOml) were added. The mixture was stirred under reflux for 3 hours cooled to room temperature and solvent removed at reduced pressure. The residue was partitioned between chloroform (200ml) and water (200ml), the organic phase separated dried (MgS04) and solvent removed at reduced pressure. The residue was recrystallised from ethanol to give 4'-methoxy-3'-phenylacetophenone (2.87g) m.p. 92-93C.
(b) From 4'-methoxy-3'-phenylacetophenone (3.3g), 3-cyano-6-(3-phenyl-4-methoxyphenyl)pyridin-2(lH)-one (2.37g) m.p.
288-291C after recrystallisation from propan-2-ol, was prepared according to the method of Example 3(a).
(c) From 3-cyano-6-[(3-phenyl)-4-methoxyphenyl]pyridin-2(lH)-one (0.9lg), the title compound (0.70g) m.p. 289-291C after recrystallisation from dimethylformamide/ethanol, was prepared according to the method of Example l(b). lH NMR ~(DMSO-d6) 3.86(s,3H), 6.92(d,lH), 7.28(d,lH), 7.33-7.48(m,3H), 7.62(d,2H), 7.81-7.89(m,2H~, 8.45(d,lH), 11.96(br.s,lH) and 12.71(br.s,lH) W092/06085 2 0 919 ~ 9 PCT/GB91/01663 ! Example 48 6-[4-~ethoxy-3,5-di~E-1-propenyl)phenyl]-3-~-tetrazolyl)-pyridin-2(lE)-one (SB 204788) (~) From 3'-allyl-4'-hydroxyacetophenone (17.6g), 3'-allyl-4'-allyloxyacetophenone (20.7g) isolated as an oil, was prepared according to the method of Example 2~a) using acetone as solvent. lH NMR ~(CDCl3) 2.55(s,3H), 3.44(d,2H), 4.61~m,2H), 5.04-5.46~m,4H), 5.94-6.10(m,2H), 6.86(d,lH), 7.78d,lH) and 7.83(dd,lH).
(b) From 3'-allyl-4'-allyloxyacetophenone (20.5g), 3',5'-diallyl-4'-hydroxyacetophenone (16.3g) m.p. 83-84C was prepared according to the method of Example 38(a).
(c) From 3',5'-diallyl-4'-hydroxyacetophenone (16g), 3',5'-diallyl-4'-methoxyacetophenone (17g) isolated as an oil, was prepared according to the method of Example 2(a). 1H
NMR ~(CDC13) 2.55(s,3H), 3.46(d,4H), 3.77(s,3H), 5.05-5.14(m,4H), 5.91-6.07(m,2H) and 7.69(s,2H).
(d) From 3',5'-diallyl-4'-methoxyacetophenone (8.5g), 3-cyano-6-[4-methoxy-3,5-di(E-1-propenyl)phenyl]pyridin-2(lH)-one (6.1g) m.p. 248-250C after trituration with hot ethanol, was prepared according to the method of Example 3(a).
(e) From 3-cyano-6-[4-methoxy-3,5-di(E-l-propenyl)phenyl]pyridin-2(lH)-one (0.46g), the title compound (0.27g) m.p. 285-287C (decomp) after recrystallisation from dimethylformamide/water, was prepared according to the method of Example l(b). lH NMR
~(DMSO-d6) 1.92(d,6H), 3.68(s,3H), 6.49-6.68(m,4H), 7.00(d,lH), 7.89(s,2H) and 8.45(d,lH).
W O 92/06085 2 0 9 ~ ~ ~ 9 P ~ /GB91/01663 ExamPle 49 6-[3-(E-l-Propenyl)-4-propoxyphenyl]-3-(5-tetrazolyl)-pyridin-2(1H)-o~e. (SB 201433) (a) From 3'-allyl-4'-hydroxyacetophenone ~5.28g), 3'-allyl-4'-propoxyacetophenone (6.06g) isolated as an oil was prepared according to the method of Example 2(a). lH NMR
~(CDCl3) 1.07(t,3H), 1.66-1.92(m,2H), 2.5S(s,3H), 10 3.41(d,2H), 3.99(t,2H), 5.04-5.12(m,2H), 5.90-6.06(m,lH), 6.86(d,lH), 7.77(d,lH) and 7.83(dd,lH).
(b) From 3'-allyl-4'-propoxyacetophenone (5.7g), 3-cyano-6-[3-(E-1-propenyl)-4-propoxyphenyl]pyridin-2(lH)-one (2.57g) 15 m.p. 240-244C after recrystallisation from butanol, was prepared according to the method of Example 3(a).
(c) From 3-cyano-6-[3-(E-1-propenyl)-4-propoxyphenyl]pyridin-2(lH)-one (1.18g), the title compound 20 (0.7g) m.p.290-292C (decomp) after recrystallisation from butanol, was prepared according to the method of Example l(b). lH NMR ~(DMSO-d6) 1.02(t,3H), 1.73-1.86(m,2H), l.90(d,3H), 4.04(t,2H), 6.48-6.61(dq,lH), 6.65(d,lH), 6.89(d,lH), 7.11(d,lH), 7.70(dd,1~:), 7.97(d,lH) and 25 8.43(d,lH).
Example 50 6-(3-Bromo-4-methoxy-5-propylphenyl)-3-(5-tetrazolyl)-30 pyridin-2(1H)-one. ~273/2534) (a) From 4'-methoxy-3'-propylacetophenone (7.6g), 3'-bromo-4'-methoxy-5'-propylacetophenone (4.8g) isolated as an oil after column chromatography (silica gel, 50%
hexane/dichloromethane eluant) was prepared according to the method of Example 36(a). lH NMR ~(CDCl3) 0.98(t,3H), W092/06085 2 0 91~ 8 9 PCT/GB91/01663 1.'7-1.73(m,2H), 2.56(s,3H), 2.67(t,2H), 3.87(s,3H), 7.74(d,lH) and 7.98(d,lH).
(b) From 3'-bromo-4'-methoxy-5'-propylacetophenone (3.4g), 6-(3-bromo-4-methoxy-5-propylphenyl)-3-cyanopyridin-2(lH)-one (1.2g) after recrystallisation from ethanol, was prepared according to the method of Example 3~a). lH NMR
~(DMSO-d6) 0.94(t,3H), 1.57-1.67(m,2H), 2.65(t,2H), 3.79(s,3H), 6.38(br.d,lH), 7.74(d,lH), 7.97(d,lH) and 8.18(d,lH).
(c) From 6-(3-bromo-4-methoxy-5-propylphenyl)-3-cyanopyridin-2(lH)-one (0.39g), the title compound (0.17g) m.p. 2~6-287 (decomp) after recrystallisation from ethanol, was prepared according to the method of Example l(a). lH
NMR S(DMSO-d6) 0.96(t,3H), 1.61-1.70(m,2H), 2.67(t,2H), 3.81(s,3H), 6.94(d,lH), 7.76(d,lH), 7.99(d,lH) and 8.45(d,lH).
Example 51 6-(2-Butylthio-3,5-diethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1R)-one 25 (a) From 2'-bromo-3',5'-diethoxyacetophenone (2.53g), 2'-butylthio-3',5'-diethoxyacetophenone ~1.96g) after column chromatography (silica gel, hexane/dichloromethane 4:1 eluant) was prepared according to the method of Example 26(a). lH NMR ~(CDCl3) 0.87(t,3H), 1.25-1.65(m,10H), 30 2.59(s,3H), 2.76(t,2H), 4.02(q,2H), 4.08(q,2H), 6.33(d,1H) and 6.46(d,1H).
(b) From 2'-butylthio-3',5'-diethoxyacetophenone (1.95g), 3-cyano-6-(2-butylthio-3,5-diethoxyphenyl)pyridin-2(1H)-one (0.13g) after recrystallisation from ethanol, was prepared according to the method of Example 3(a). lH NM~ ~(DMSO-d6) 0.71(t,3H), 1.18-1.43(m,10H), 2.66(t,2H), 4.03-4.18(m,4H), 6.27(d,lH), 6.59(d,lH), 6.71(d,lH) and 8.15(d,lH).
(c) From 3-cyano-6-(2-butylthio-3,5-diethoxyphenyl)-3-(5-tetrazolyl~pyridin-2(lH)-one (0.12g), the title compound (0.08g) m.p. 138-140C after recrystallisation ~rom ethanol, was prepared according to the method of Example l(a). lH NMR ~(DMSO-d6) 0.76(t,3H), 1.18-1.43(m,10H), 2.64(t,2H), 4.05-4.19(m,4H), 6.40(d,lH), 6.62(d,lH), 6.70(d,1H), 8.48(d,1H) and 12.67(br.s,1H).
Example 52 6-~3-Bromo-4-~,N-dimethylam;nophQnyl)-3-(5-tetrazolyl1-pyridin-2(1~)-one ~SB 204789) (a) From 4'-N,N-dimethylaminoacetophenone (4.9g), 3'-bromo-4'-N,N-dimethylaminoacetophenone (7.0g) was prepared according to the method of Example 36(a). lH NMR ~(CDCl3) 2.53(s,3H), 2.91(s,6H), 7.03(d,lH), 7.83(dd,lH) and 8.13(d,lH).
(b) From 3'-bromo-4'-N,N-dimethylaminoacetophenone (2.42g), 3-cyano-6-(3-bromo-4-N,N-dimethylaminophenyl)pyridin-2(lH)-one (2.63g) was prepared according to the method of Example3(a). lH NMR ~(DMSO-d6) 2.82(s,6H), 6.82(d,1H), 7.22(d,1H), 7.79(dd,lH), 8.08(d,lH), 8.15(d,lH) and 12.67(br.slH).
; (c) From 3-cyano-6-(3-bromo-4-N,N-dimethylaminophenyl)pyridin-2(lH)-one (0.8g), the title compound (0.57g) m.p.275-277C was prepared according to the method of Example l(b).
W O 92/06085 2 0 919 8 9 PC~r/GB91/01663 Exau~ple 53 6-~3-Acctamido-4-methoxy-5-propylphenyl) -3-(5-tetrazolyl)pyridin-2(1~)-ono (SB 20~790) (a) From 3'-allyl-4'-hydroxyacetophenone (17.6g), 3'-allyl-4'-benzyloxyacetophenone (23~lg) isolated as an oil was prepared according to the method of Example 2(a) using acetone as solvent. lH NMR ~(CDCl3) 2.55(s,3H), 3.47(d,2H), 5.04-5.11(m,4H), 5.16(s,2H), 5.93-6.09(m,lH), 6.93(d,lH), 7.25-7.41(m,5H), 7.81(s,lH) and 7.82(d,lH).
(b) From 3'-allyl-4'-benzyloxyacetophenone (23g), 6-[4-benzyloxy-3-(E-l-propenyl)phenyl]-3-cyanopyridin-2(lH)-one (11.2g) m.p. 255-257C after recrystallisation from dimethylformamide/water, was prepared according to the method of Example 3(a).
(c) A solution of 6-~4-benzyloxy-3-(E-l-propenyl)phenyl~-3-cyanopyridin-2(lH)-one (6.8g) in dimethylformamide ~20ml) containing dimethylformamide dimethyl acetal (4.76g) was heated at 120C for 6 hours. The mixture was diluted with ethyl acetate (200ml), washed with water (6 x lOOml), dried (MgSO4) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, hexane/dichloromethane 1:1 eluant) to give 6-[4-benzyloxy-3-(E-l-propenyl)phenyl]-3-cyano-2-methoxypyridine (6g) m.p.
124-125C after recrystallisation from ethanol.
(d) A suspension of 6-[4-benzyloxy-3-(E-l-propenyl)phenyl]-3-cyano-2-methoxypyridine (1.78g) in ethanol (250ml) containing 10~ palladium/charcoal (0.2g) was hydrogenated at 50 p.s.i until the calculated quantity of hydrogen had been absorbed. The mixture was filtered (celite pad) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, hexaneldichloromethane 1:1 -2% ethanol/dichloromethane eluant) to give 3-cyano-6-(4-W092/06085 2 ~ 919 8 9 PCT/GB91/01663 _ 59 _ hydroxy-3-propylphenyl)-2-methoxypyridine ~l.Og). 1H NMR
~(CDCl3) l.Ol(t,3H), 1.65-1.74(m,2H), 2.66(t,2H), 4.15(s,3H) 5.19(s,1H), 6.86(d,1H), 7.35(d,1H) and 7.81-7.87(m,3H).
(e) To a stirred suspension of 6-(4-hydroxy-3-propylphenyl)-3-cyano-2-methoxypyridine (1.88g) in sulpholane ~3ml) a solution of nitronium tetrafluoroborate in sulpholane (0.5M, 16ml) was added over 5 minutes with ice cooling. The solution obtained was stirred for 5 hours, additional nitronium tetrafluoroborate (0.5M in sulpholane, 2ml) added and stirring continued for a further 3 hours.
The solution was diluted with diethyl ether ~lOOml) washed with water (8 x lOOml), dried (MgS04) and solvent removed at reduced pressure. The residue was recrystallised from ethanol to give 3-cyano-6-(4-hydroxy-3-nitro-5-propylphenyl)-2-methoxypyridine (1.75g) m.p. 160-162C.
(f) From 3-cyano-6-(4-hydroxy-3-nitro-5-propylphenyl)-2-methoxypyridine (1.57g), 3-cyano-6-(4-methoxy-3-nitro-5-propylphenyl)-2-methoxypyridine (1.53g) m.p. 150-152C was prepared according to the method of Example 2(a) using acetone/dimethylformamide (1:1) as reaction solvent. 1H NMR
~(CDCl3) 1.03(t,3H), 1.67-1.81(m,2H), 2.77(t,2H), 3.95(s,3H), 4.17(s,3H), 7.42(d,lH), 7.96(d,lH), 8.07(d,lH) and 8.35(d,lH).
(g) A suspension of 3-cyano-6-(4-methoxy-3-nitro-5-propylphenyl)-2-methoxypyridine (1.4g) in ethanol (lOOml) containing 10% palladium/charcoal (200mg) was treated with hydrogen at 50 p.s.i until hydrogen uptake was complete.
The mixture was filtered (celite pad) and solvent removed from the filtrate at reduced pressure. The residue was dissolved in dichloromethane (lOml) containing triethylamine (l.Olg) added followed by the addition of acetic anhydride (0.61g) over 5 minutes. The reaction mixture was stirred for 15 hours, diluted with W092/06085 2 ~ 919-8 9 PCT/GB91/01663 dichloromethane (lOOml) and washed with 2N hydrochloric acid (2 x 50ml) and with water (50ml). After drying (MgS04), sol~ent was removed at reduced pressure to give after recrystallisation from ethanol 6-(3-acetamido-4-methoxy-5-propylphenyl-3-cyano-2-methoxypyridine (1.04g) m.p.174-175C.
(h) From 6-(3-acetamido-4-methoxy-5-propylphenyl)-3-cyano-2-methoxypyridine (0.7g), 6-(3-acetamido-4-methoxy-5-propylphenyl)-3-cyanopyridin-2(lH)-one (0.48g) m.p.247-249C was prepared according to the method of Example 37(c). 1H NMR ~(CDCl3) 1.02(t,3H), 1.68-1.83(m,2H), 2.27(s,3H), 2.78(t,2H), 3.83(s,3H), 6.65(d,1H), 7.49(d,1H), 7.80(br.s,lH), 7.90(d,lH) and 8.62(d,lH).
~5 (i) From 6-(3-acetamido-4-methoxy-5-propylphenyl)-3-cyanopyridin-2(lH)-one (0.4g), the title compound (0.25g) m.p. 239-241C after recrystallisation from ethanol, was prepared according to the method of Example l(b) ExamPle 54 6-[3-N~thoxymethyl-4-methoxy-5-~E-1-propenyl)phenyl~-3-(5-tetrazolyl)pyridin-2(1~)-on~ (273/2588) (a) From 3-cyano-6-[4-methoxy-3,5-di(E-1-propenyl)phenyl]pyridin-2(lH)-one (4.59g), 3-cyano-6-[4-methoxy-3,5-di(E-1-propenyl)phenyl]-2-methoxypyridine (4.lg) m.p. 145C was prepared according to the method of Example 5~(c). lH NMR ~(DMSO-d6) 1.93(d,6H), 3.67(s,3H), 4.11(s,3H), 6.42-6.56(m,2H), 6.66(d,2H), 7.87(d,lH), 8.15(s,2H) and 8.30(d,lH).
(b) To an ice cooled suspension of 3-cyano-6-[4-methoxy-3,5-di(E-1-propenyl)phenyl~-2-methoxypyridine (1.6g) in acetone/water (9:1, lOOml) N-methylmorpoline-N-oxide (0.63g) and osmium te~roxide (2.5% w/w solution in tert-W O 92/06085 2 0 919 8 9 P ~ /GB91/01663 butanol, 0.4ml) were added. The mixture was stirred with ice cooling for 1 hour and at room temperature for 1 hour.
Additional N-methylmorpholine-N-oxide (O.lg) was added and stirring continued for an additional 1 hour. The solution was quenched with 5% sodium metabisulphite (5ml) and solvent removed at reduced pressure. The residue was dissolved in ethyl acetate (200ml), washed with water (2 x lOOml)), dried (MgS04) and solvent removed at reduced pressure. Column chromatography (silica gel, dichloromethane-5% ethanol/dichloromethane eluant) gave 3-cyano-6-[3-[1-(1,2-dihydroxypropyl)]-4-methoxy-5-(E-1-propenyl)phenyl]-2-methoxypyridine (0.99g). lH NMR ~(CDCl3) 1.171d,3H), 1.97(d,3H), 2.5(br.s,1H), 2.98(br.s,1H), 3.82(s,3H), 3.94-4.05(m,lH), 4.16(s,3H), 4.77(d,lH), 6.30-6.42(m,lH~, 6.66(d,lH), 7.41(d,lH), 7.90(d,lH), 7.93(d,lH)and 8.08(d,lH).
(c) To a solution of 3-cyano-6-[3-[1-(1,2-dihydroxypropyl)]-4-methoxy-5-(E-1-propenyl)phenyl]-2-methoxypyridine (0.99g) in tetrahydrofuran(20ml) a solutionof sodium metaperiodate (0.64g) in water (3ml) was added.
The mixture was stirred for 2 hours, additional sodium metaperiodate (O.lg) in water (2ml) added and stirring continued for a further 2 hours. The mixture was filtered, diluted with ethyl acetate (lOOml), washed with water (2 x 50ml), dried (MgS04) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, dichloromethane- 5% ethanol/dichloromethane eluant) to give 3-cyano-6-[3-formyl-4-methoxy-5-(E-l-propenyl)phenyl]-2-methoxypyridine (0.7g) m.p. 174C. 1H NMR ~(CDCl3) 2.00(d,3H), 3.93(s,3H), 4.18(s,3H), 6.38-6.53(m,lH), 6.69(d,lH), 7.47(d,lH), 7.94(d,lH), 8.33(d,lH), 8.41(d,lH) and 10.44(lH).
35 (d) A solution of 3-cyano-6-[3-formyl-4-methoxy-5-(E-l-propenyl)phenyl]-2-methoxypyridine (0.65g) in ethanol (lOml) was treated with sodium borohydride (lOOmg) in port ons over 30 minutes. The solution was stirred for a further 2 hours, solvent removed at reduced pressure, the residue dissolved in ethyl acetate (lOOml), washed with water (2 x 50ml) , dried (MgS04) and solvent removed at reduced pressure. The residue was dissolved in dimethyl sulphoxide ~5ml), potassium hydroxide (0.56g, crushed pellets) added, followed by iodomethane (0.6g) and the mixture stirred for 30 minutes. After diluting with ethyl acetate (lOOml) the reaction mixture was washed with water 10 (6 x 50ml), dried (MgS04) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, 40% hexane/dichloromethane - dichloromethane) to give 3-cyano-6-~3-methoxymethyl-4-methoxy-5-(E-1-propenyl)phenyl]-2-methoxypyridine (0.54g) m.p. 81-82C. 1H
NMR ~(CDC13) 1.96(d,3H), 3.47(s,3H), 3.79(s,3H), 4.17(s,3H), 4.56(s,2H), 6.306.42(m,lH), 6.70(d,lH), 7.42(d,lH), 7.88(d,lH), 7.92(d,lH) and 8.10(d,lH).
(e) From 3-cyano-6-[3-methoxymethyl-4-methoxy-5-(E-1-propenyl)phenyl]-2-methoxypyridine (0.54g), 3-cyano-6-[3-methoxymethyl-4-methoxy-5-(E-1-propenyl)phenyl]pyridin-2(lH)-one (0.33g) m.p.188-190C after column chromatography (silica gel, dichloromethane - 2~5% ethanolldichloromethane eluant), was prepared according ~o the method of Example 37(c). lH NMR ~(CDCl3) l.99(d,3H~, 3.49(s,3H), 3.81(s,3H), 4.60(s,2H), 6.46-6.70~m,3H), 7.72(d,1H), 7.85(d,1H), 7.91(d,lH) and 12.89(br.s,lH).
(f) From 3-cyano-6-[3-methoxymethyl-4-methoxy-5-(E-1-propenyl)phenyl]pyridin-2(lH)-one (0.3g) the title compound (0.22g) m.p. 245-246~C after recrystallisation from ethanol, was prepared according to the method of Example l(b). 1H NMR ~(DMSO-d6) 1.92(d,3H), 3.61(s,3H), 3.83(s,3H), 4.81(s,2H), 6.26-6.44(m,lH), 6.68(d,lH), 6.88(d,lH) 7.73(d,lH), 8.04(d,lH), 8.75(d,lH) W092/06085 2 0 9 1~ ~ 9 PCT/GB91/01663 Example 55 6-13-(E-2-Carbamoylethenyl)-4-methoxy-5-~E-1-prop~nyl)phenyl]-3-~5-tetrazolyl)pyridin-2-(lH)-ona 5 (273/2602) (a) Triethylphosphonoacetate (0.9g) was added dropwise to a suspension of sodium hydride (0.18g, 50% in oil) in tetrahydrofuran (lOml). When gas evolution had ceased a solution of 3-cyano-6-[3-formyl-4-methoxy-5-(E-1-propenyl)phenyl]-2-methoxypyridine in tetrahydrofuran (lOml)was added and the mixture stirred for 4 hours.
Ethanol (lOml) and 2N sodium hydroxide (lOml) were added and the mixture boiled for 2 hours. Solvent was removed at reduced pressure, the residue dissolved in water and acidified with 2N hydrochloric acid. The precipitate was collected by filtration to give 3-cyano-6-[3-(E-2-carboxylatoethenyl)-4-methoxy-5-(E-1-prope~yl)phenyl]-2-methoxypyridine (0.9g). lH NMR ~(CDCl3) 1.94(d,3H), 3.73(s,3H), 4.14(s,3H), 6.50-6.62(m,lH), 6.69(d,lH), 6.7 8(d,lH), 7.82(lH), 7.99(d,lH) and 8.33-8.42(m,3H).
(b) Oxalyl chloride (0.76g) was added over 5 minutes to an ice cooled suspension of 3-cyano-6-[3-(E-2-carboxylatoethenyl)-4-methoxy-5-(E-l-propenyl)phenyl]-2-methoxypyridine in dichloromethane (20ml) containing dimethylformamide (O.lml). When gas evolution had ceased (4 hours) solvent was removed at reduced pressure and the residue redissolved in dichloromethane (20ml). To the ice cooled solution ammonium hydroxide (lOml, SG 0.88) was added and the solution stirred at 0C for 30 minutes and at room temperature for 30minutes. The precipitated solid was collected by filtration and recrystallised twice from ethanol to give 3-cyano-6-~3-(E-2-carbamoylethenyl~-4-methoxy-5-(E-1-propenyl)phenyl]pyridin-2(lH)-one (0.4g) m.p. 245-246C. lH NMR ~(DMSO-d6) 1.94(d,3H), 3.72(s,3H), 4.14(s,3H), 6.49-6.62(m,lH), 6.66(d,lH), 6.80~d,lH), W O 92/06085 2 ~ ~19 ~ 9 PC~r/GB91/01663 7.19(br.s,lH), 7.62(br.s,lH), 7.62(d,lH), 7.89(d,lH), 8.27(d,lH), 8.29(d,lH) and 8.34(d,lH).
(c) From 3-cyano-6-[3-(E-2-carbamoylethenyl)-4-methoxy-5-(E-l-propenyl)phenyl]-2-methoxypyridine (0.35g), 3-cyano-6-[3-(E-2-carbamoylethenyl)-4-methoxy-5-(E-l-propenyl)phenyl]pyridin-2(lH)-one (0.2g) m.p. >300C after recrystallisation from dimethylformamide/ethanol/water, was prepared according to the method of Example 37(c). lH NMR
~(DMSO-d6) I.93(d,3H), 3.71(s,3H), 6.51-6.71(m,2H), 6.91(br.d,lH), 7.21(br.s,lH), 7.61(d,lH), 7.62(br.s,lH), 7.93(s,lH), 7.99(s,lH), 8.20(d,lH) and 12.78(br.s,lH).
(d) From 3-cyano-6-[3-(E-2-car~amoylethenyl)-4-methoxy-5-(E-l-propenyl)phenyl]pyridin-2(lH)-one (0.16g), the title compound (0.08g) m.p.292-294C (decomp) after recrystallisation from dimethylformamide/ethanol/water, was prepared according to the method of Example ltb) lH NMR
~(DMSO-d6) 1.94(d,3H), 3.73(s,3H), 6.55-6.72(m,2H), 6.83(d,lH), 7.00(d,lH), 7.23(br.s,lH), 7.62(d,lH), 7.66(br.s,lH), 7.99(d,lH) and 8.48(d,lH).
ExamPl~ 56 6-(3-Cyclopropylmethyloxy-4-methoxyphenyl)pyridin-2~1H)-one (a) From 3'-hydroxy-4'-methoxyacetophenone (3.32g), 3'-cyclopropylmethyloxy-4'-methoxyacetophenone (4.34g) was prepared according to the method of Example 2(a). lH NMR
~(CDCl3) 0.34-0.40(m,2H), 0.63-0.70(m,2H), 1.28-1.43m,lH), 2.56(s,3H), 3.91(d,2H), 3.95(s,3H), 6.89(d,1H), 7.50(d,1H) and 7.56(dd,lH).
(b) From 3'-cyclopropylmethyloxy-4'-methoxyacetophenone (3.55g), 3-cyano-6-(3-cyclopropylmethyloxy-4-me~hoxyphenyl)pyridin-2(lH)-one (1.30g) m.p. 241-242C
after recrystallisation from butanol was prepared according to the method of Example 3(a).
(c) From 3~cyano-6-(3-cyclopropylmethyloxy-4-methoxyphenyl)pyridin-2(lH)-one (0.89g), the title compound (0.67g) m.p. 296-297C (decomp) after recrystallisation from butanol, was prepared according to the method of Example l(b). lH NMR ~(DMSO-d6) 0.32-0.38(m,2H), 0.57-0.66(m,2H), 1.22-1.37(m,1H), 3.85(s,1H), 3.94(d,2H), 6.88(d,1H), 7.10(d,1H), 7.39-7.48(m,2H), 8.43(d,1H) and 12.56(br.s,lH).
ExamPle 57 6-~2-methoxy-4-propoxyphenyll-3-(5-tetrazolyl)pyridin-2~1H)-one (a) From 2'-4'-dihydroxyacetophenone (50g), 2'-hydroxy-4'-propoxyacetophenone (6g) was prepared according to the method of Example 2(a), using bromopropane (40g) and acetone as solvent. lH NMR ~(DMSO-d6) 0.93((t,3H), 1.61-1.72(m,2H), 2.38(s,3H), 3.75(t,2H), 5.61(dd,lH), 5.80(d,lH) and 7.40(d,lH).
(b) From 2'-hydroxy-4'-propoxyacetophenone (6g), 2'-methoxy-4'-propyloxyacetophenone (5.18g) was prepared according to the method of Example 2(a). lH NMR ~(CDCl3) 1.05(t,3H), 1.74-l.91(m,2H), 2.57(s,3H), 3.89(s,3H), 3.97(t,2H), 6.46-6.53(m,2H) and 7.80(d,lH).) (c) From 2'-methoxy-4'-propoxyacetcphenone (5g), 3-cyano-6-(2-methoxy-4-propoxyphenyl)pyridin-2(lH)-one (0.38g) m.p.l86-188C after trituration with diethyl ether was prepared according to the method of Example 3(a). lH NMR
~(DMSO-d6) O.99(t,3H), 1.72-1.81(m,2H), 3.82(s,3H), 4.02(s,2H), 6.47(d,lH), 6.61-6.67(m,2H), 7.39(d,lH) and 8.11(d lH).
W092/06085 2 0 91~ ~ 9 PCT/GB9t/01663 (d) From 3-cyano-6-(2-methoxy-4-propoxyphenyl)pyridin-2(lH)-one (0.36g), the title compound (0.04g) m.p. >300~C
after recry~_allisation from ethanol and trituration with diethyl ether, was prepared according to the method of Example l(b). lH NMR ~(DMSO-d6 at 370K) l.OO(t,3H), 1.69-1.82(m,2H), 3.83(s,3H), 4.02~t,2H), 6.61-6.66tm,2H), 6.98(unresolved,lH), 7.55(unresolved,lH) and 8.44(unresolved,lH).
Example X
Pharmaceutical compositions for oral administration are prepared by combining the following :
% w/w 6-(3-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one 0.5 3.0 7.14 2% w/w Soya lecithin in soya bean oil 90.4588.284.41 - Hydrogenated vegetable 25 shortening and beeswax 9.058.8 8.45 The formulations are then filled into individual soft gelatin capsules.
Examvle Y
A pharmaceutical composition for parenteral administration is prepared by dissolving the title compound of Example 23 (0.02 g) in polyethylene glycol 300 (25 ml) with heating. This solution is then diluted with water for injections Ph. Eur. (to lOO ml). The solution is then sterilised by filtration through a 0.22 micron membrane filter and sealed in sterile containers.
By the term C1_6 polyfluoroalkyl is meant a C1_6alkyl group having at least one hydrogen replaced with fluoro eg.
CF3, or CF2CF2H.
Suitably Ar is phenyl mono-substituted by a group as hereinbefore defined, for example in the 2,3, or 4 positions by C1_6alkyl, C3_6alkenyloxy, C1_6alkylthio, phenyl, phenylthio, benzyloxy, CF3, halo or NHCOR, or in the 3, or 4-positions with C1_6alkoxy.
Suitably Ar is phenyl di-substituted by any groups as hereinbefore defined, for example in the 3,4-,3,5-,2,3-,2,4- or 2,5-, positions by groups independently selected from C2_6alkenyl, C1_5alkoxy, C3 6cycloalkoxy, halo, -X(CH2)nY- or C1_6alkoxy C1_6 alkoxy.
Suitably Ar is phenyl trisubstituted by any groups as hereinbefore defined, for example in the 2,3,4-, 2,3,5-, or 3,4,5-positions by groups independently selected from C2_6alkenyl, C1_6alkoxy or halo.
Examples of Cl_6alkoxy include methoxy, ethoxy, propoxy, butoxy, or pentyloxy.
Examples of C1_6alkyl include methyl, ethyl, propyl, butyl, isobutyl or pentyl.
Examples of halo include fluoro, chloro, bromo or iodo, preferably chloro or bromo.
Particular compounds of this invention include :
W O 92/06085 2 0 91~ ~ 9 P ~ /GB91/01663 6~ thoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(3-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(3-butoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(3-benzyloxyphenyl)-3-(5-tetrazolyl)pyridin-2tlH)-one, 6-(3-bromophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, lS
6-(3-trifluoromethyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(3-ethylphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(4-butoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(4-isobutylphenyl)pyridin-2(lH)-one, 6-(4-biphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(4-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, W092/06085 2 ~ 91~ 8 ~ PCT/GB91/01663 6-(3,4-methylenedioxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(3,4-dichlorophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, s 6-(3,5-dipropoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(3,5-diethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(3,5-dibromophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(2,4-dipropoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, .
6-(2,5-dipropoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(2,3,4-trichlorophenyl)-3-(S-tetrazolyl)pyridin-2(lH)-one, 6-[6-(1,2,3,4-tetrahydronaphthyl)]-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(3-chlorophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-phenylthiophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 3,4-dimethoxyphenyl-3-(5-tetrazolyl)pyridin-2(lH)-one, W ~ 9~/06085 2 ~ 919 8 9 P ~ /GB91/01663 6-(3-methylthiophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(3-butylthiophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(3,4-di-n-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(2,3-di-n-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(3-cyclopentyloxy-4-methoxyphenyl)-3-(S-tetrazolyl)-pyridin-2(lH)-one 6-(3-ethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3,5-dimethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(2-butylthiophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(3-allyloxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(4-methoxy-2-pentyloxyphenyl)-~-(5-tetrazolyl)pyridin-2(lH)-one 6-(3-iso-butoxy-4-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(2-bromo-3,5-diethoxyphenyl-3-(5-tetrazolyl)pyridin-2(lH)-one, W092/0608~ 2 0 919 ~ 9 PCT/GB91/01663 6-(5-bromo-4-methoxy-2-pentyloxphenyl)-3-(5-tetrazolyl)-pyridin-2( lH) -one, 6-(2-allyl-4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)-pyridin-2(lH)-one, 6-[3-(E-1-propenyl)-4-methoxyphenyl]-3-(5-tetrazolyl)pyridi n-2(lH)-one, 6-(4-methoxy-3-propoxyphenyl)-3-[5-(1-pivaloyloxymethyl)-tetrazolyl)pyridin-2(lH)-one, :
6-(4-methoxy-3-propoxyphenyl)-3-[5-(2-pivaloyloxymethyl)-tetrazolyl]pyridin-2(lH)-one, 6-[3-ethoxy-5-(2-methoxyethoxy)phenyl]-3-(5-tetrazolyl)-pyridin-2(lH)-one, 6-[3-(2,2-dimethylpropyloxy)-4-methoxyphenyl~-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(3-ethoxy-4-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 2S 6-(3-propionamidophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(4-methoxy-3-propylphenyl)-3-(5-tetrazolyl)pyridir.-2(lH)-one, 6-(3-bromo-4-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(3-phenyl-4-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-[4-methoxy-3,5-di(E-1-propenyl)phenyl]-3-(5-tetrazolyl)-pyridin-2(lH)-one, 6-[3-(E-1-propenyl)-4-propoxyphenyl]-3-(5-tetrazolyl)-pyridin-2(lH)-one, 6-(3-bromo-4-methoxy-5-propylphenyl)-3-(5-tetrazolyl)-pyridin-2-(lH)-one, 6-(2-butylthio-3,5-diethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(3-bromo-4-N,N-dimethylaminophenyl)-3-(5-tetrazolyl)-pyridin-2(lH)-one, 6-(3-acetamido-4-methoxy-5-propylphenyl)-3-(5-tetrazolyl)-pyridin-2(lH)-one, 6-[3-methoxymethyl-4-methoxy-5-(E-l-propenyl)phenyl]-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-[3-(E-2-carbamoylethenyl)-4-methoxy-5-(E-1-propenyl)-phenyl]-3-(5-tetrazolyl)pyridin-2-(lH)-one, and 6-(3-cyclopropylmethyloxy-4-methoxyphenyl)pyridin-2(lH)-one and pharmaceutically acceptable salt-; thereof.
This invention covers all tautcmeric, geometric and optical isomeric forms of compounds of formula (1). In WO9~/06085 2 0 919 8 9 PCT/GB91t01663 particular when R0 is hydroxy the compound can exist in its keto tautomeric form :
Rl/$~/Ar = Rl/~Ar OH O
Compounds of the formula (l) can form pharmaceutically acceptable base addition salts with metal ions, such as alkali metals for example sodium or potassium, or with an ammonium ion.
In order to use a compound of the formula (l) or a pharmaceutically acceptable salt thereof for the treatment of humans and other mammals it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
Compounds of formula (l) and their pharmaceutically acceptable salts may be administered in standard manner for the treatment of the indicated diseases, for example orally, sublingually, parenterally, transdermally, rectally, via inhalation or via buccal administration.
Compounds of formula (l) and their pharmaceutically acceptable,salts which are active when given orally or via buccal administration can be formulated appropriately in dosage forms such as liquids, syrups, tablets, capsules and lozenges. An oral liquid formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, glycerine or water with a flavouring or colouring agent. Where the W O 92/06085 2 0 919 8 9 PC~r/GB91/01663 composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include starch, celluloses, lactose, sucrose and magnesium stearate.
Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell.
Where the composition is in the form of a soft gelatin shell capsule, any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils and are incorporated in a soft gelatin capsule shell.
Typical parenteral compositions consist of a solution or suspension of the compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil or solubilising agent, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, 2-pyrrolidone, cyclodextrin, arachis oil, or sesame oil.
A typical suppository formulation comprises a compound of formula (1) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding andtor lubricating agent, $or example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogues.
Typical transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
Typical compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered W092/06085 2 ~ 919 ~ 9 ; PCT/GB91/01663 in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane, or are in the form of a powder for insufflation.
Preferably the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer to himself a single dose.
Each dosage unit for oral administration contains suitably from 0.001 mg/Kg to 30 mg/Kg, and preferably from 0.005 mg/Kg to 15 mg/Kg, and each dosage unit for parenteral administration contains suitably from 0.001 mg/Kg to 10 mg/Kg, of a compound of formula (1) or a pharmaceutically acceptable salt thereof calculated as the free acid.
The daily dosage regimen for oral administration is suitably about 0.001 mg/Kg to 120 mg/Kg, of a compound of formula (1) or a pharmaceutically acceptable salt thereof calculated as the free acid. The daily dosage regimen for parenteral administration is suitably about 0.001 mg/Kg to 40 mg/Kg, for example about 0.005 mg/Kg to 10 mg/Kg, of a compound of the formula (1) or a pharmaceutically accept-able salt thereof calculated as the free acid. The active ingredient may be administered as required for example from 1 - 8 times a day or by infusion. The compositions of the invention are agonists of a cA-PrK and are of use in combatting such conditions where such agonism is thought to be beneficial. Such conditions can be treated by administration orally, sublingually topically, rectally, parenterally or by inhalation. For administration by inhalation dosages are controlled by a valve, are administered as required and for an adult are conveniently in the range 0.1 - 5.0 mg of a compound of the formula (1) or a pharmaceutically acceptable salt thereof.
W O 92/06085 2 0 919 g 9 PC~r/GB91/01663 The compounds of this invention may be co-administered with other pharmaceutically active compounds, for example in combination, concurrently or sequentially. Conveniently the compounds of this invention and the other active compound or compounds are formulated in a single pharmaceutical composition.
Examples of compounds which may be included in pharmaceutical compositions with the compounds of the formula (1) are bronchodilators such as sympathomimetic amines for example isoprenaline, isoetharine, sulbutamol, phenylephrine and ephedrine or xanthine derivatives for example theophylline and aminophylline, anti-allergic agents for example disodium cromoglycate, histamine H1-antagonists, drugs used in the treatment of cancer lS such as those which inhibit the synthesis of or inactivate DNA, for example methotrexate, fluoracil, cisplatin, actinomycin D, anti-atherschlerotic agents for example cholesterol lowering drugs such as HMGCoA reductase inhibitors, bile acid sequestrants, drugs for the treatment of psoriasis, for example retinoids, anthralin, anti-inflammatories for example cortiscosteroids, non-steroid anti-inflammatories such as aspirin, antithrombotics for example dipyridamole, or fibrinolytic agents.
In another aspect the present invention provides a process for the preparation of compounds of the formula (1) or pharmaceutically acceptable salts thereof, which process comprises reacting a compound of the formula (2) :
~ Ar ~2) NC
OH
W092/06085 ~ U Yl ~ ~ PCT/GB9i/01663 wherein Ar is as hereinbefore defined with an azide salt, and optionally thereafter :
forming a bioprecursor of R0 and/or o forming a pharmaceutically acceptable salt.
A compound of the formula (2) is suitably reacted with an azide salt such as ammonium, sodium, potassium or aluminium azide in an organic solvent such as dimethylformamide, dimethylsulphoxide, N-methyl-pyrrolidone or tetrahydrofuran at an elevated temperature e.g. 40 - 200C, preferably at the reflux temperature of - the reaction mixture.
A compound of the formula (1) wherein ~ is OH can be converted to the corresponding compound where R0 is oR2 by reaction with R2L wherein R2 is as hereinbefore defined and L is a leaving group such as halo e.g. bromo, chloro, iodo.
A compound of the formula (1) can be converted to a N-protected tetrazolyl derivative by reaction with a suitable N-protecting agent in standard manner, for example with a pivalolyoxymethyl halide.
A compound of the formula (2) can suitably be prepared by reacting a compound of the formula (3) :
ArCOCH = CHLl (3) wherein Ar is as hereinbefore defined and Ll is a displaceable group, with a compound of the formula (4) :
W092/0608; 2 ~ 9 1~ ~ 9 PCT/GB91/01663 H2NCOCH2CN (4) Suitably Ll in a compound of the formula (3) is hydroxy or a derivative thereof for example Ll is protected hydroxy such as silyloxy, an acid residue (for example Cl_6alkanoyloxy) or an ether residue (for example methoxy or ethoxy). Alternatively Ll is a secondary amino group, for example di-Cl_6alkylamino such as dimethylamino or a cyclic amino group such as lo piperidino, pyrrolidino or morpholino. Preferably is hydroxy or dimethylamino.
Suitably an alkali metal (e.g. sodium) salt of a compound of the formula (3) wherein Ll is hydroxy is treated with a compound of the formula (4) under mildly alkaline aqueous conditions, for example in water in the presence of piperidine and glacial acetic acid, at an elevated temperature e.g. 30 - 200C, preferably at the reflux temperature of the reaction mixture.
Alternatively a compound of the formula (3) wherein Ll is a secondary amino group, for example dimethylamino, is treated with a compound of the formula (4) in a suitable solvent such as dimethylformamide, a Cl_4alkanol or pyridine at an elevated temperature e.g.
30 - 200C, preferably at the reflux temperature of the reaction mixture optionally in the presence of a base such as pyridine or an alkali metal alkoxide, e.g. sodium methoxide.
Compounds of the formula (3) wherein Ll is hydroxy can suitably be prepared by reaction under basic conditions of a compound o~ the formula (S) :
ArCOCH3 (5) W092/0608~ ,5 ' PCT/GB91/01663 wherein Ar is as hereinbefore defined, with a compound of the formula HCOL2 wherein L2 is a leaving group.
Suitably L2 is ethoxy or methoxy. Conveniently a solution of a compound of the formula (5) and a compound of the formula HCOL2 in a suitable organic solvent such as diethyl ether is treated with a suitable base such as an alkali metal alkoxide, e.g. sodium methoxide at ambient temperature. The resulting reaction mixture is preferably extracted with water and the aqueous extract which contains the alkali metal salt of a compound of the formula (3) wherein L1 is hydroxy is then treated with a compound of the formula (4) as hereinbefore described.
Compounds of the formula (5) are known or can be prepared by methods known in the art.
Compounds of the formula (3) wherein L1 is a secondary amino group (e.g. dimethylamino) can suitably be prepared by reacting a compound of the formula (5) with a compound of the formula HC(oR3)2Ll wherein R3 is C1_4alkyl and L1 is a secondary amino group (for example HC(oR3)2Ll is N,N-dimethylformamide dimethyl or diethyl acetal), or with a compound of the formula HCL13 where Ll is a secondary amino group (for example HCL13 is trisdimethylaminomethane).
Alternatively a compound of formula (2) can be prepared by demethylation of a compound of formula (6) :
~ Ar (6) NC
OMe wherein Ar is as hereinbefore defined.
Suitable demethylating agents include sodium iodide and chlorotrimethylsilane in an organic solvent such as acetonitrile, or a halohydrocarbon eg. dichloromethane or chloroform at elevated (eg. 30-80C) or ambient temperature or sodium thiomethoxide in an organic solvent such as dimethylformamide at an elevated temperature, for example 40-120C.
The Ar group in compounds of the formula (2j, (5) or (6), preferably (5) or (6) may be appropriately functionalised by methods of aromatic substitution known in the art. For example, a bromo group may be introduced into a suitably substituted phenyl ring (eg. disubstituted in the 2- and 4-positions by electron-donating groups such as C1_6alkoxy) by reaction with a brominating agent such as N-bromosuccinimide or bromine in a solvent such as dimethylformamide. Alternatively a nitro group can be introduced into a phenyl ring by reaction with a suitable nitrating agent, such as nitroniumtetrafluoroborate. Such a group can be readily hydrogenated to an amino group which if desired can be converted to a NHCOR group by reaction with LCOR wherein L is a leaving group and R is as hereinbefore defined. Suitable examples of the reagent LCOR include acid halides (L is halo eg. chloro or bromo) or acid anhydrides (L is OCOR).
W092/06085 2 0 919 ~ 9 PCT/GB91/01663 Other suitable functionalisations include the introduction of an allyl group ortho to a hydroxy substituent on a phenyl ring by reaction with an allyl halide, eg. bromide, to form an allyloxy derivative which on heating undergoes a Claisen rearrangement to form an ortho allyl hydroxy derivative. The hydroxy group can in turn be functionalised, eg. by reaction with a Cl_6alkyl halide to form a Cl_6alkoxy group. If desired, an allyl group can be converted to an E-l-propenyl group by reaction with a strong base, such as sodium methoxide.
This can occur during the conversion of a compound of formula (5) to a compound of formula (2) as hereinbefore described if such a base is used. An E-l-propenyl group can be cleaved to a formyl group by reaction with an lS oxidising agent such as N-methylmorpholine-N-oxide in the presence of a catalyst such as osmium tetroxide to form a l,2,dihydroxypropyl group which on reaction with an oxidising agent such as sodium periodate forms the formyl group. Alternatively the E-l-propenyl group can be converted directly to a formyl group by reaction with a mixture of osmium tetroxide and sodium periodate or by reaction with ozone. A formyl group can in turn be further functionalised, for example it can be converted to a hydroxymethyl group by reaction with a suitable reducing agent such as sodium borohydride, the hydroxymethyl group then being reacted further, eg. with a Cl_6alkyl halide to form a Cl_6alkoxymethyl group. Alternatively a formyl group can be reacted with a suitable Horner Wittig or Wittig reagent such as (R40)2P(o)CH2Co2R4 or Ph3P=CHCO2R4 wherein R4 is Cl_4alkyl to form a CH=CHCo2R4 group which can be optionally hydrolysed to a -CH=CHCO2H group. A -CH=CHCo2R4 group can be converted to a -CH=CHCONR2 group by reaction with an amine HNR2 or a chemical equivalent thereof wherein R is as hereinbefore defined. Alternatively a -CH=CHCO2H
group can be converted to an acid halide, eg. the acid chloride by reaction with oxalyl chloride, which can then W092/06085 2 0 919 ~ 9 ` PCT/GB9l/01663 be reacted with an amine HNR2 or a chemical equivalent thereof. An example of a chemical equivalent is ammonium hydoxide which will form a CH=CHCONH2 group.
A compound of formula (6) is suitably prepared by reacting a compound of formula (2) wherein Ar is as hereinbefore defined with an O-methylating agent such as dimethylformamide dimethylacetal in dimethylformamide or trimethylphosphite at an elevated temperature (eg.
40-120C).
Pharmaceutically acceptable base addition salts of the compounds of the formula (1) may be prepared by standard methods, for example` by reacting a solution of the compound of the formula (1) with a solution of the base.
The following biological test methods, data and Examples serve to illustrate this invention.
Cvclic-AM~ Protein Kinase (cA-PrK) Aqonist Activitv Type II cA-PrK was prepared from the cardiac muscle of a cow. The supernatant from a muscle homogenate (3 mls of 10 mM potassium phosphate, 1 mM EDTA per g tissue) was applied to a column of DEAE-cellulose equilibrated with the homogenisation buffer and the type II cA-PrK was eluted with homogenisation buffer containing 350 mM sodium chloride (Rannels et al., 1983, Methods Enzymol., 99, 55-62).
Type II cA-PrK was assayed for phosphotransferase activity by incubating the enzyme at 30C for 5 minutes with [ -32P]-adenosine triphosphate and a suitable peptide substrate such as malantide (Malencik et al., 1983, Anal. Biochem., 132, 34-40). The reaction was W092/0608; 2 0 919 ~ ~ PCT/GB91/01663 terminated by the addition of hydrochloric acid and the [32P]-phosphopeptide quantified by spotting the reaction mixture onto phosphocellulose papers, The concentration of compound required to give 10% phosphotrans~erase S activation is given as the EClo (~M). The compounds of Examples 1 to 26 had EC1o values in the range 10 -130 ~M.
Inhibition of Platelet Aqqreqation Human platelet-rich-plasma was separated from freshly drawn blood (in acid/citrate/dextrose) and treated with 100 ~M acetylsalicylic acid for 15 minutes at 37C. A
washed platelet suspension was then prepared in a Hepes-isotonic saline buffer after a single centrifugation step and adjusted to a concentration of 1.5x108 cells/ml. Aliquots of this suspension were pre-incubated with compounds for 5 minutes at 37C, then challenged with 1.0 yM U46619. The extent of aggregation after 2 minutes were expressed as a percentage of control and results obtained are expressed as an IC50 (concentration to cause 50% inhibition of platelet aggregation, ~M).
The compounds of Examples 2, 4, 5, 11-13, 15, 19-23, and 25-26 had IC50 values in the range 0.8-300 ~M.
Anti-proliferative activitY
Compounds under test were dissolved in dimethyl-sulphoxide and diluted 1:10,000 with DMEM (Dulbecco's Modified Eagle's Medium) containing 10% fetal bovine serum to give 12.5, 25, 50 and 100 ~M concentrations used in the assay. Indicator cells consisting of 3 human colorectal cells lines (SW-620, NRK-52 and HT-29) were plated at a cell density of 1000 cells in 0.1 ml of DMEM
media in 96 well plates. Cells were incubated for 4 days at 37C and 10% CO2 atmosphere. On day 5, tetrazolium W 092/0608~ 2 ~ ~19 g 9 PCT/GB91/01663 reagent (50 llg MTT/250 111 total medium volume) was added for 16 - 20 hours. Insoluble formazan was dissolved in 150 ~l of dimethylsulphoxide and absorbance was measured using a microculture plate reader at 560 nm interfaced with an IBM computer. Cell line growth and inhibition were expressed in terms of mean absorbance unit of triplicate samples following subtraction of mean background absorbance. IC50 values (concentration that show 50g~ growth inhibition) were determined from the dose 10 response curves. (Cancer Res., 48, 589-601, 1988). In the cell line SW-620 the compound of Example 23 had an IC50 value in the range 56 - 90 ~IM. In the cell line NRK-52 the compound of Example 23 had an IC50 value in the range 46 - 48 ~M. In the cell line HT-29 the 15 compound of Example 23 had an IC50 value in the range of 55 - 66 ~ .
Inhibition of S~ontaneous Contraction in Guinea-Piq Colon Segments of isolated guinea-pig colon (2 cm) were suspended under 2 g tension in standard organ baths containing Krebs solution. The tissues were connected at the free end to isometric transducers which allow recording and display of developed tension on chart recorders. On-line computer capture and analysis was used to quantify the effects of test compounds on spontaneous contractions. Inhibitory responses were calculated as % maximum inhibition of spontaneous contraction distance over 3 consecutive pre and post dose 2 minute readings. The concentration of compound which caused 50% inhibition of the spontaneous contrac:tion is given as the EC50 (~M). The compounds of Examples 5, 15-17 and 23 had EC50 values in the range 2 - 25 ~5.
W092/0608~ 2 0 919 8 9 PCT/GB91/01663 sronchodilatation - In vitro (Tracheal spiral) Spiral strips of guinea-pig trachea were suspended in standard organ baths containing Krebs solution. The tissues were connected at the free end to isometric transducers which allow recording and display of developed tension on chart recorders. Tension was allowed to develop spontaneousl~ and concentrations of test compounds added in a cumulative fashion. The concentration of compound which caused 50% inhibition of the spontaneously developed tension is given as the IC50(~M)-The compounds of Examples 5 and 23 had IC50 values of ll and 6.5 ~M respectively.
Measurement of cardiac muscle relaxation time in rabbitventricle Papillary muscles from the right ventricle of female Albino New Zealand rabbits were mounted in standard organ baths containing oxygenated Krebs solution. One end of the muscle was connected to an isometric transducer which allowed recording of contractile force and its first derivative on chart recorders. Test compounds were added to the bath in a cumulative manner. Relaxation time was calculated as the time taken from peak tension to the end of the contraction. At concentrations of 30-l00 ~M, compounds of Examples 12 and 23 caused a 10-20% decrease in the relaxation time indicating a lusitropic effect of use in the treatment of cardiovascular diseases such as congestive heart failure.
WO 92/0608~ 19 8 9 PCI`/GB91/01663 ExamPle 1 6-(3-Methoxyphenyl)-3-(5-tetrazolyl)pyridin- 2 ( lH ) -one a) 3'-Methoxyacetophenone (15g) and dimethylformamide dimethylacetal (16ml) were heated together at 120C in dimethylformamide (8Oml) for 6 hours, the deep red solution was diluted with ethyl acetate (400ml), washed with water (5xlOOml), dried (MgS04) and solvent removed at reduced pressure. The oil obtained was dissolved in dimethylformamide (80ml), cyanoacetamide (10.08g) and sodium methoxide (10.8g) added and the mixture heated at 130C for 35 minutes. The deep red solution was poured into 5% aqueous acetic acid (400ml), the precipitated product collected by filtration and washed with water, ethanol and diethyl ether. Recrystallisation from n-butanol gave 3-cyano-6-(3-methoxyphenyl)pyridin-2(lH)-one (15.14g) m.p. 251C as a colourless solid.
b) 3-Cyano-6-(3-methoxyphenyl~pyridin-2(lH)-one (lg) sodium azide (0.39g) and ammonium chloride (0.32g) were heated together in N-methylpyrrolidin-2-one (lOml) at 140C for 2hours. The reaction mixture was poured into 10%
aqueous acetic acid (150ml), the precipitated solid collected by filtration, washed with water and recrystallised from n-butanol to give the title compound (0.93g) m.p. 298C (decomp). lH NMR ~(DMSO-d6) 3.87(s,3H), 6.92(d,1H), 7.13(m,1H), 7.41-7.50(m,3H) and 8.48(d,lH).
~ ExamPle 2 6-(3-Propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one W O 92/06085 2 ~ 919 8 ~ P ~ /GB91/01663 (a) 3'-Hydroxyacetophenone (13.6g), iodopropane (10.7ml) and potassium carbonate (13.8g) were heated together in dimethylformamide (80ml) at 90C for 20hrs. The reaction mixture was diluted with ethyl acetate (400ml), washed with 2N sodium hydroxide (2xlOOml) and water (4xlOOml), dried (MgS04), filtered and solvent removed at reduced pressure to give 3'-propoxyacetophenone (16.46g) as an oil. 1H NMR ~(DMSO-d6) 0.99(t,3H), 1.66-1.83(m,2H), 2.58((s,3H), 3.98(t,3H), 7.19(dd,1H) and 7.39-7.57(m,3H).
The following compounds were similarly prepared from the appropriate phenol and alkyl iodide.
3'-Butoxyacetophenone:- oil, yield 90%, lH NMR
15 ~(DMSO-d6) 0.94(t,3H), 1.37-1.52(m,2H), 1.66-1.77(m,2H), 2.57(s,3H), 4.02(t,2H), 7.19(dd,1H) and 7.39-7.55(m,3H).
3'-Benzyloxyacetophenone:- oil, yield 89%, lH NMR
20 ~tCDC13) 2-57(s,3H), 5.09(s,2H), 7.17(dd,lH) and 7.29-7.56(m,8H).
4'-Methoxy-3'-propoxyacetophenone from 3'~hydroxy-4'-methoxyacetophenone:- (A. Brossi et al J. Org. Chem., 25 1967, 32, 1269) :- oil, yield 71%, lH NMR ~(CDC13) 1.05(t,3H), 1.87(m,2H), 2.56(s,3H), 3.93(s,1H), 4.04((t,2H), 6.88(d,1H), 7.52(d,1H), and 7.57(dd,1H).
3',5'-Dipropoxyacetophenone:- oil, yield 58%, 1H
30 NMR ~(DMSO-d6) 0.98(t,6H) 1.66-1.80(m,4H), 2.55(s,3H), 3.96(t,4H), 6.73(t,lH) and 7.04(d,2H).
3',5'-Diethoxyacetophenone:- oil, yield 64%, 1H NMR
~(DMSO-d6) 1.42(t,6H), 2.56(s,3H), 4.05(q,4H), 35 6.64(t,1H) and 7.07(d,2H).
W092/06085 2 0 91 9 8 g PCT/GB91/01663 2',5'-Dipropoxyacetophenone:- oil, yield 64%, lH
NMR ~(DMSO-d6) 0.96(t,3H), 1.04(t,3H), 1.62-1.84(m,4H), 2.S5(s,3H), 3.88(t,2H), 3.99(t,2H) and 7.03-7.11(m,3H).
3',4'-Dipropoxyacetophenone:- yield 95%, lH NMR
~(CDCl3) 1.00-l.l9(m,6H), 1.78-2.02(m,4H), 2.55(s,3H), 3.98-4.17(m,4H), 6.87(d,1H), 7.52(s,lH) and 7.54(d,lH).
3'-Allyloxyacetophenone:- oil, yield 71%, lH
NMR~(CDCl3) 2.58(s,3H), 4.57(d,2H), 5.27-5.47(m,2H), 5.96-6.15(m,1H), 7.12(dd,1H), 7.31(t,1H) and 7.49-7.55(m,2H).
4'-Methoxy-2'-pentyloxyacetophone:-From 4'-methoxy-2'hydroxyacetophenone and iodopentane, yield 92%, lH NMR ~(DMS0-d6)0.86(t.3H), 1.20-1.47(m,4H), 1.74-1.85(m,2H), 2.49(s,3H), 3.82(s,3H), 4.09(t,2H), 6.56-6.62(m,2H) and 7.66(d,lH).
3'-iso-Butoxy-4'-methoxyacetophenone:-From 4'-methoxy-3'-hydroxyacetophenone and iso-butyl bromide using acetone as solvent, yield 68~. lH NMR
~(DMSO-d6) O.99(d,6H), 1.96-2.15(m,1H), 2.53(s,3H), 3.78(d,lH), 3.86(s,3H), 7.06(d,lH), 7.42(d,lH) and 7.62(dd,1H).
3'-Allyloxy-4'-methoxyacetophenone:-From 4'-methoxy-3'-hydroxyacetophenone and allyl bromide, yield 67%, lH NMR ~(CDCl3) 2.55(s,3H), 3.95(s,3H), 4.63-4.68(m,2H), 5.29-5.47(m,lH), 6.02-6.18(m,lH), 6.90(d,1H),7.53(d,1H) and 7.60(dd,1H).
3'-(2,2,-dimethylpropyloxy)-4'-methoxyacetophenone:-Fr m 4'-methoxy-3'-hydroxyacetophenone and 1-bromo-2,2-dimethylpropane, yield 76~, lH NMR ~(CDCl3) W O 92/06085 2 O 9 19 ~ ~ PC~r/GB91/01663 1.07(s,9H), 2.56(s,3H), 3.69(s,2H), 6.88(d,1H) and 7.50-7.58(m,2H).
3'-ethoxy-4'-methoxyacetophenone:-from 3'-hydroxy-4'-methoxyacetophenone and iodoethane using acetone as solvent, yield 83%, lH NMR ~(CDC13) 1.49(t,3H),2.57(s,3H),3.94(s,3H),4.17(q,2H),6.8g(d,1H),7.53 -7.60(m,2H).
3'-Allyl-4'-methoxyacetophenone:-from 3'-allyl-4'-hydroxyacetophenone, yield 87% as an oil.
lH NMR ~(CDCl3)2.55(s,3H),3.40(d,2H),3.89(s,3H), 5.02-5.10(m,2H), 5.90-6.04(m,lH),6.88(d,lH),7.77(d,lH) and 7.85(dd,lH).
(b) From 3'-propoxyacetophenone (9g), 3-cyano-6-(3-propoxyphenyl)pyridin-2(1H)-one (3.49g) m.p. 240-241C
after recrystallisation from ethanol, was prepared according to the method of Example l(a).
(c) From 3-cyano-6-(3-propoxyphenyl)pyridin-2(lH)-one (lg), the title compound (0.61g) m.p. 270-271C after recrystallisation from n-butanol, was prepared according to the method of Example l(b).
Exam~le 3 6-(3-Butoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one (a) 3'-Butoxyacetophenone (17.3g) and dimethylformamide dimethylacetal (11.9g) were boiled together in dimethylformamide (9Oml) for 15 hours. The deep red solution was cooled to room temperature, cyanoacetamide (8.3g) and sodium methoxide (10.3g) added and the mixture boiled for a further 3 hours. The reaction mixture was W092/0608~ 2 ~ 9 ~. 9 8 9 PCT/GB91/01663 poured into 10% aqueous acetic acid (300ml) the precipitated product separated by filtration, washed with water and recrystallised from n-butanol to give 3-cyano-6-(3-butoxyphenyl)pyridin-2(lH)-one (10.66g) m.p.
201-202C.
(b) From 3-cyano-6-(3-butoxyphenyl)pyridin-2(1H)-one (2.15g), the title compound (o.55g) m.p. 259-260C after recrystallisation from n-butanol, was prepared according to the method of Example l(b).
Example 4 6-(3-Benzyloxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one (a) From 3'-benzyloxyphenylacetophenone (20.2g), 3-cyano-6-(3-benzyloxyphenyl)pyridin-2(lH)-one (2.6g) m.p.202-203C after recrystallisation from ethanol, was prepared according to the method of Example 3(a).
(b) From 3-cyano-6-(3-benzyloxyphenyl)pyridin-2(lH)-one (lg), the title compound (0.35g) m.p.276C (decomp) after recrystallisation from dimethylformamide was prepared according to the method of Example l(b). lH NMR
~(DMSO-d6) 5.23(s,2H), 6.91(d,1H), 7.16-7.20(m,1H), 7.31-7.54(m,8H), 8.47(d,1H) and 12.67(br s,lH).
Example 5 6-(3-Bromophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one (a) From 3'-bromoacetophenone ~13.2g), 3-cyano-6-(3-35 bromophenyl)pyridin-2(1H)-one (21.8g) m.p. 309C (decomp) after recrystallisation from n-butanol, was prepared W092/06085 2 0 919 ~ 9 PCT/G~91/01663 according to the method of Example l(a). lH NMR
~(DMSO-d6) 6.89(br s,lH), 7.48(t,1H), 7.75(d,1H), 7.83(d,lH), 8.06(s,lH), 8.21(d,lH) and 12.75(br s,lH).
(b) From 3-cyano-6-(3-bromophenyl)pyridin-2(lH)-one (1.37g), the title compound (0.39g) m.p. 285-286C after recrystallisation from dimethylformamide, was prepared according to the method of Example l(b).
ExamPle 6 6-(3-Trifluoromethyl)-3-(5-tetrazolyl)pyridin-2(IH)-one (a) From 3'-trifluoromethylacetophenone (9.4g), 3-cyano-6-(3-trifluoromethylphenyl)pyridin-2~lH)-one (11.38g) m.p.255-256C after recrystallisation from ethanol, was prepared according to the method of Example 3(a).
(b) From 3-cyano-6-(3-trifluoromethylphenyl)pyridin-2(lH)-one (1.06g), the title compound (0.93g) m.p.274-275C after recrystallisation from n-butanol, was prepared according to the method of Example l(b).
ExamPle 7 6-(3-Ethylphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one (a) From 3'-ethylacetophenone (7.4g), 3-cyano-6-(3-ethylphenyl)pyridin-2(lH)-one (3.97g~ m.p.241-242C after recrystallisation from n-butanol, was prepared according to the method of Example 3(a).
(b) From 3-cyano-6-(3-ethylphenyl)pyridin-2(1H)-one (0.89g), the title compound (0.37g) m.p.278-279C after W092/0608~ 2 0 9 i 9 8 9 PCT/GB91/01663 recrystallisation from n-butanol, was prepared according to the method of Example l(b).
Exam~le 8 6-(4-Butoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one ta) From 4'-butoxyacetophenone (5.6g), 3-cyano-6-(4-o butoxyphenyl)pyridin-2(lH)-one (1.12g) m.p. 245C after recrystallisation from ethanol, was prepared according to the method of Example l(a).
(b) A mixture of 3-cyano-6-(4-butoxyphenyl)pyridin-2(lH)-one (0.3g), sodium azide (0.098g), ammonium chloride (0.08g) and lithium chloride (0.064g) were heated in dimethylformamide (15ml) at 120C for 72 hours. Solvent was removed at reduced pressure, the product precipitated by the addition of 10% aqueous acetic acid (40ml) and separated by filtration. The solid was dissolved in 5%
potassium hydrogen carbonate and insoluble material - separated by filtration. The filtrate was acidified with conc. hydrochloric acid, the precipitated product collected by filtration and recrystallised from ethanol to give the title compound (0.05g) m.p.289-292C.
Example 9 6-(4-iso~utylphenyl)pyridin-2(lH)-one (a) From 4'-isobutylacetophenone (8.8g); 3-cyano-6-(4-isobutylphenyl)pyridin-2(lH)-one (6.0g) m.p. 264C after recrystallisation from ethanol, was prepared according to the method of Example 3(a).
W092/0608~ PCT/GB91/01663 (b) From 3-cyano-6-(4-isobutylphenyl)pyridin-2(1H)-one (2.52g), the title compound (1.54g) m.p. 275C (decomp) after recrystallisation from dimethylformamide, was prepared according to the method of Example l(b) but using dimethylformamide instead of N-methylpyrrolidin-2-one as solvent. lH NMR ~(DMSO-d6) 0.89(d,6H), 1.81-1.96 (m,lH), 2.51(m,2H), 6.87(d,lH), 7.33(d,2H), 7.78(d,2H), 8.46(d,1H) and 12.63(br s,lH).
ExamPl 10 6-(4-Biphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one 15 (a) From 4-acetylbiphenyl (19.6g), 6-(4-biphenyl)-3-cyanopyridin-2(lH3-one (14.01g) m.p. 312-316C after recrystallisation from n-butanol, was prepared according to the method of Example l(a).
20 (b) From 6-(4-biphenyl)-3-cyanopyridin-2(1H)-one (1.36g), the title compound (0.84g) m.p. 305C (decomp) after recrystallisation from dimethylformamide, was prepared according to the method of Example l(b). 1H NMR
~(DMSO-d6) 7.00(d,lH), 7.41-7.S4(m,3H), 7.77(d,2H), 25 7.85(d,2H), 7.98(d,2H) and 8.50(d,lH).
ExamPle 11 6-(4-Propoxy,phenyl)-3-(S-tetrazolyl)pyridin-2(1H)-one (a) From 4'-propoxyacetophenone (15.4g) (E. Eckhart and J. Varga, Maqvar. Kem. FolYoirat 1961, 67, 509, Chem Abs. 1962, S6, 15557e), 35 3-cyano-6-(4-propoxyphenyl)pyridin-2(lH)-one (1.8g) m.p.
262-265C after recrystallisation from dimethylformamide, was prepared according to the method of Example 3(a).
(b) From 3-cyano-6-(4-propoxyphenyl)pyridin-2(lH)-one (lg), the title compound (0.85g) m.p. 292C (decomp) after recrystallisation from dimethylformamide, was prepared according to the method of Example l(b). lH NMR
~(DMSO-d6) 0.99(tr3H), 1.63-1.84(m,2H), 4.02(t,2H), 6.81(d,lH), 7.07(d,2H), 7.82(d,2H~ and 8.45(d,lH).
Exam~le 12 6-(4-Methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one (a) From 4'-methoxy-3'-propoxyacetophenone (12g), 3-cyano-6-(4-methoxy-3-propoxyphenyl)pyridin-2(lH)-one (14.03g) m.p. 24~.C after recrystallisation from ethanol, was prepared according to the method of Example 3(a).
(b) From 3-cyano-6-(4-methoxy-3-propoxyphenyl)pyridin-2(lH)-one (3.12g), the title compound (1.69g) m.p.
289-290C after recrystallisation from n-butanol, was prepared according to the method of Example l(b).
ExamPle 13 6-(3,4-Methylenedioxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one (a) From 3',4'-(methylenedioxy)acetophenone (16.4g), 3-cyano-6-(3,4-methylenedioxyphenyl)pyridin-2(lH)-one (10.2g) m.p. ~320C after recrystallisation from dimethyl-formamide, was prepared according to the method of Example 35 3(a). lH NMR ~(DMSO-d6) 6.13(s,2H), 6.72(d,1H), 7.06(d,1H), 7.36-7.42(m,2H), 8.13(d,1H) and 12.58(br s,lH).
W092/0608; 2 0 919 8 9 PCT/GB91/01663 (b) From 3-cyano-6-(3,4-methylenedioxyphenyl)pyridin-2(lH)-one (0.96g), the title compound (O.lg) m.p. >325C
after recrystallisation from ethanol, was prepared according to the method of Example l(b) but using dimethylformamide instead of N-methylpyrrolidinone as solvent. lH-NMR ~(DMSO-d6) 6.14(s,2H), 6.83(d,1H), 7.08(d,lH),7.37-7.46(m,2H), 8.43(d,lH), 12.S5(br s,lH) and 13.28(br s,lH).
Ex,~mPle 14 6-(3,4-Dichlorophenyl)-3-(5-tetrazolyl)pyridi~-2(lH)-one 15 (a) From 3',4'-dichloroacetophenone (18.9g), 3-cyano-6-(3,4-dichlorophenyl~pyridin-2(lH)-one (1.94g) m.p. >330C after recrystallisation from dimethyl-formamide, was prepared according to the method of Example l(a). lH NMR ~(DMSO-d6) 6.97(br d,lH), 7.76-7.87 20 (m,2H), 8.15(s,1H) and 8.23(d,1H).
(b) From 3-cyano-6-(3,4-dichlorophenyl)pyridin-2(lH)-one (1.06g), the title compound (0.54g) m.p.295C (decomp) after recrystallisation from dimethylformamide, was prepared according to the method of Example l(b) but using dimethylformamide instead of N-methylpyrrolidinone as solvent. lH NMR ~(DMSO-d6) 7.02(d,1H) 7.76-7.89 (m,2H), 8.17(s,lH) and 8.48(s,lH).
ExamPle 15 6-(3,5-Dipropoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one (a) From 3',5'-dipropoxyacetophenone (11.82g), 3-cyano-6-(3,5-dipropoxyphenyl)pyridin-2(lH)-one (7.lg) m.p.
W092/0608~ 2 0 9 ~ 9 8 9 PCT/GB91/01663 209-210C after recrystallisation from ethanol, was prepared according to the method of Example 3(a).
(b) From 3-cyano-6-(3,5-dipropoxyphenyl)pyridin-2(lH)-one (1.25g), the title compound (1.31g) m.p.224-225C after recrystallisation from n-butanol, was prepared according to the method of Example l(b).
Example 16 6-(3,5-Diethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one (a) From 3',5'-diethoxyacetophenone (4.16g), 3-cyano-6-(3,5-diethoxyphenyl)pyridin-2(1H)-one (l.Og) m.p.259-261C
after recrystallisation from n-butanol, was prepared according to the method of Example 3(a).
(b) From 3-cyano-6-(3,5-diethoxyphenyl)pyridin-2(lH)-one (0.82g), the title compound (0,57g) m.p. 282-283C after recrystallisation from n-butanol, was prepared according to the method of Example l(b).
Example 17 6-(3,5-Dibromophenyl)-3-(5-tetrazolyl)pyridin-2(IH)-one (a) From 3',5'-dibromoacetophenone (M. Tashiro, S Mataka, H. Nakamura and K Nakayama, J. Chem. Soc. Perkin Trans I., 1988, 179) (l.llg), 3-cyano-6-(3,5-dibromophenyl)pyridin-2(lH)-one (0.73g) m.p. >300C after recrystallisation from n-butanol, was prepared according to the method of Example 3(a). 1H NMR ~(DMSO-d6) 7.00(br d,lH), 8.02(s,1H), 8.09(s,2H) and 8.23(d,lH).
W O 92/0608~ 2 0 g 19 8 9 P ~ /GB91/01663 (b) From 3-cyano-6-(3,5-dibromophenyl)pyridin-2(lH)-one (o.s3g), the title compound (0.15g) m.p. 295-296C
(decomp) after recrystallisation from n-butanol was prepared according to the method of Example l(a). lH NMR
S ~(DMSO-d6) 7.10(br d,lH), 8.02(s,1H), 8.13(s,2H) and 8.47(d,lH).
Example 18 10 6-(2,4-Dipropoxyphenyl)-3-(5-tetrazolyl)pyridin-2(IH)-one (a) From 2',4'-dipropoxyacetophenone (17.9g) (P.
Chabrier, H. Najer, R. Giudicelli and E. Joannie-Voisinet, 15 8ull. Soc. Chim. France, l9S8, 1488.), 3-cyano-6-(2,4-dipropoxyphenyl)pyridin-2(1H)-one (1.69g) m.p. 148C after recrystallisation from ethanol, was prepared according to the method of Example 3(a).
20 (b) From 3-cyano-6-(2,4-dipropoxyphenyl)pyridin-2(1H)-one (lg), the title compound (0.60g) m.p. 205C after recrystallisation twice from ethanol, was prepared according to the method of Example l(b).
Exam~le 19 6-(2,5-Dipropoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one 30 (a) From 2',5'-dipropoxyphenylacetophenone (11.8g), 3-cyano-6-(2,5-dipropoxyphenyl)pyridin-2(lH)-one (14.36g) m.p. 160-162C after recrystallisation from ethanol, was prepared according to the method of Example 3(a). 1H NMR
~(DMS0-d6) 0.92(t,3H), 0.97(t,3H), 1.61-1.76(m,4H), 3S 3.92(t,4H), 6.54(d,lH), 7.01-7.06(m,3H), 8.18(d,1H).
W092/06085 2 0 ~19 ~ 9 PCT/GB9l/01663 (b) From 3-cyano-6-(2,5-dipropoxyphenyl)pyridin-2(lH)-one (2.5g), the title compound (0.81g) m.p.188-189C after recrystallisation from ethanol, was prepared according to the method of Example l(b).
ExamPle 20 6-(2,3,4-Trichlorophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one (a) 2',3',4'-Trichloroacetophenone (22.15g) and dimethylformamide (12.5g3 were boiled in dimethylformamide (lOOml) for 3 hours. The solution was diluted with ethyl acetate (500ml), washed with water (6xlOOml), dried (MgS04), filtered and solvent removed at reduced pressure. The residue was triturated with diethyl ether to give 3-N,N-dimethylamino-1-(2,3,4-trichlorophenyl)prop-2-ene-1-one (17.5g). lH NMR ~(DMSO-d6) 2.8~(s,3H) 3.08(br s,3H), 5.17(d,1H), 7.1(very br,lH), 7.30(br d,lH) and 7.65(d,1H).
(b) A solution of 3-N,N-dimethylamino-1-(2,3,4-trichlorophenyl)prop-2-ene-1-one (9.8g) and cyanoacetamide (3.18g) in dimethylformamide (35ml) was boiled for 48 hours. The reaction mixture was poured into 10% aqueous acetic acid (lOOml), the precipitated product separated by filtration and recrystallised from ethanol to give 3-cyano-6-(2,3,4-trichlorophenyl)pyridin-2(1H)-one (4.4g). 1H NMR ~(DMSO-d6) 6.52(d,lH),7.58(d,lH), 7.79(d,1H), 8.24(d,1H) and 12.95(br s,lH).
(c) From 3-cyano-6-(2,3,4-trichlorophenyl)pyridin-2(1H)-one (1.2g), the title compound (1.21g) m.p.>300C
after recrystallisation from dimethylformamide/water, was prepared according to the method of Example l(a). lH NMR
~(DMSO-d6) 6.63(d,lH), 7.61(d,lH), 7.83(d,lH), W092/0608~ 2 0 919 ~ 9 PCT/GB91/01663 8.51(d,1H) and 12.98(br s,lH).
EXamD1e 2 1 6-[6-(1,2,3,4-Tetrahydronaphthyl)]-3-(5-tetrazolyl)pyridin-2(lH)-one (a) From 6-acetyltetralin (4.23g), 3-cyano-6-[6-(1,2,3,4-tetrahydronaphthyl)]pyridin-2(lH)-one (1.27g) m.p.
245-246OC after recrystallisation from n-butanol, was prepared according to the method of Example 3(a). lH NMR
~(DMSO-d6) 1.75(m,4H), 2.77(m,4H), 6.71(d,lH), 7.19 (d,lH), 7.50(d,1H), 7.53(s,1H) and 8.15(d,1H).
(b) From 3-cyano-6-[6-(1,2,3,4-tetrahydronaphthyl)pyridin-2(lH)-one (lg), the title compound (0.55g) m.p. 284-285C
after recrystallisation from dimethylformamide/water,was prepared according to the method of Example l(b).
Exam~le 22 6-(3-Chlorophenyl)-3-(5-tetrazolyl~pyridin-2(lH)-one (a) From 3'-chloroacetophenone (15.46g), 6-(3-chloro-phenyl)-3-cyanopyridin-2(lH)-one (17.12g) m.p. 304-305C
after recrystallisation from n-butanol, was prepared according to the method of Example 3(a).
(b) From 6-(3-chlorophenyl)pyridin-2(1H)-one (1.2g), the title compound (l.Olg) m.p. 301-302C (decomp) after recrystallisation from n-butanol, was prepared according to the method of Example l(b). lH NMR ~(DMSO-d6) 6.94(d,1H), 7.48-7.62(m,2H), 7.81(d,1~), 7.96(s,1H), 8.48(d,lH) and 12.77(br s,lH) W092/0608; 2 0 9 ~ 9 8 9 PCT/GB91/01663 Example 23 6-(3-Phenylthiophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one (a) 3'-Phenylthioacetophenone (2.05g) (L. Victor, Brit.
Pat. 1,519,354) and dimethylformamide dimethylacetal (1.19g) were heated together in dimethylformamide (lOml) at 100C for 18 hours. The reaction mixture was diluted with ethyl acetate (50ml) washed with water (6x30ml), dried (MgS04) filtered and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, dichloromethane-5% ethanol/dichloromethane eluant) to give 3-N,N-dimethylamino-1-(3-phenylthiophenyl)-prop-2-ene-1-one (1.72g) as a yellow oil.
(b) A mixture of 3-N,N-dimethylamino-1-~3-phenylthio-phenyl)prop-2-ene-1-one (1.72g), sodium methoxide (0.76g) and cyanoacetamide (0.59g) were boiled together in dimethylformamide (lOml) for 1 hour. The reaction mixture was poured into 10% aqueous acetic acid (lOOml), the precipitated product separated by filtration and recrystallised from ethanol to give 3-cyano-6-(3-phenylthiophenyl)pyridin-2(lH)-one (l.Og) m.p. 262-264C.
(c) From 3-cyano-6-(3-phenylthiophenyl)pyridin-2(1H)-one (0.79g), the title compound (0.77g) m.p.265-266C after recrystallisation from n-butanol, was prepared according to the method of Example l(b).
Exam~le 24 3,4-Dimethoxyphenyl-3-(S-tetrazolyl)pyridin-2(lH)-one (a) From 3',4'-Dimethoxyacetophenone (18g), 3-cyano-6-W092/0608~ 2 0 ~ ~ PCT/GB91/01663 (3,4-dimethoxyphenyl)pyridin-2(1H)-one (9.86g) m.p.
269-270C after recrystallisation from ethanol, was prepared according to the method of Example l(a).
(b) From 3-cyano-6-(3,4-dimethoxyphenyl)pyridin-2(lH)-one (1.02g), the title compound (0.02g) m.p. 293-295C after recrystallisation from dimethylformamide, was prepared accordlng to the method of Example l(b).
Example 25 6-(3-Methylthiophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one 15 (a) From 3'-methylthioacetophenone (4.64g), 3-cyano-6-(3-methylthiophenyl)pyridin-2(lH)-one (4.3g) m.p.234-238C
after recrystallisation from ethanol, was prepared according to the method of Example 3(a).
(b) From 3-cyano-6-(3-methylthiophenyl)pyridin-2tlH)-one (lg), the title compound (0.85g) m.p.274-2760C (decomp) after recrystallisation from n-butanol, was prepared according to the method of Example l(b). 1H NMR
~(DMSO-d6) 2.58(s,3H), 6.91(d,1H), 7.39-7.63(m,3H), 25 7.68(s,1H) and 8.47(d,1H).
Example 26 6-(3-Butylthiophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one (a) Copper-(I)-n-butylmercaptide (R. Adams, W. Reijschneider and A. Ferretti, Org, Syn. Coll. Vol., V, plO7) (3.34g) and 3-cyano-6-(3-bromophenyl)pyridin-2(lH)-one (2.61g) were heated together in a mixture of quinoline (lOml) and pyridine (3ml) at 160C for 4 hours.
W O 92/0608~ 2 0 ~ 9 P ~ /GB91/01663 The reaction mixture was poured onto conc. hydrochloric acid (30ml) and ice (lOOg) and the precipitated material collected by filtration. The residue was column chromatographed (silica gel, dichloromethane-dichloromethane/2% ethanol) to give 3-cyano-6-(3-butylthiophenyl)pyridin-2(lH)-one (0.35g) m.p. 191-193C after recrystallisation from ethanol.
(b) From 3-cyano-6-(3-butylthiophenyl)pyridin-2(lH)-one (0.23g), the title compound (O.llg) m.p.237-238C after recrystallisation from n-butanol, was prepared according to the method of Example l(b).
Example 27 6-(3,4-Di-Propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one (a) From 3',4'-di-propoxyacetophenone (3.6g) 3-cyano-6-(3,4-dipropoxyphenyl)pyridin-2(1H)-one (3.21g) m.p. 249C after recrystallisation from ethanol, was prepared according to the method of Example 3(a).
(b) From 3-cyano-6-(3,4-di-propoxyphenyl)-pyridin-2(lH)-one (l.OOg) the title compound m.p. 280C
(decomp) after recrystallisation from n-butanol,was prepared according to the method of Example l(b). lH NMR
~d6-DMSO) 0.97-1.05(m,6H), 1.71-1.81(m,4H), 4.01(t,2H), 4.03(t,2H), 6.88(d,lH), 7.09(d,lH), 7.43(d,1H), 7.46(s,1Hj and 8.44(d,1H) and 12.61(br.s,1H).
Example 28 6-(2,3-di-Propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one W O 92/0608~ 2 0 919 ~ ~ P ~ /GB91/01663 (a) From 2,3-dihydroxybenzaldehyde (20g), 2,3-di-propoxy benzaldehyde (18.6g) isolated as an oil was prepared according to the method of Example 2(a). lH-NMR
~(CDCl3) 1.04(t,3H), l.O9(t,3H), 1.74-1.96(m,4H), 3.97(t,2H), 4.15(t,3H), 7.03-7.16(m,2H), 7.39(dd,lH) and 10.47(s,lH) (~) To a solution of 2,3-di-propoxybenzaldehyde (18.6g) in tetrahydrofuran at -78C methyl lithium (61ml, l.SM in diethyl ether) was added over 10 minutes. The reaction mixture was stirred at -78C for two hours and at room temperature for 16 hours. After quenching with water the organic phase was separated, dried (MgS04) and solvent removed to give 1-(2,3-di-propoxyphenyl)-1-hydroxyethane (20g) as an oil. lH-NMR ~(CDCl3) 1.04(t,3H), 1.06(t,3H), 1.72-1.93(m,4H), 3.89tt,2H), 3.99(t,2H), 5.15(m,lH), 6.80(m,lH) and 6.95-7.04(m,2H).
(c) To an ice cooled solution of 1-(2,3-di-propoxy-phenyl)-1-hydroxyethane (20g) in dichloromethane (250ml) powdered 4A molecular sieves (23g), N-methylmorpholine-N-oxide (14.9g) and tetrapropylammonium perruthenate (lg).
The mixture was stirred for one hour with ice cooling and at room temperature overnight. After filtration through Hyflo solvent was removed at reduced pressure to give 2',3'-di-propoxyacetophenone (18.3g). lH-NMR ~(CDCl3) 1.03(t,3H), 1.08(t,3H), 1.72-1.96(m,4H), 2.63(s,3H), 3.96(t,2H), 4.01(t,2H) and 6.99-7.19(m,3H).
(d) From 2',3'-dipropoxyacetophenone (lOg), 3-cyano-6-(2,3-di-propoxyphenyl)pyridin-2(1H)-one (1.87g) m.p. 195-198C was prepared according to the method of Example 3(a), omitting sodium methoxide. 1H-NMR
(d6-DMSO) 0.81(t,3H), l.Ol(t,3H), 1.51(m,2H), 1.76(m,2H), 3.84(t,2H), 3.99(t,2H), 6.43(d,lH), 6.97(d,1H), 7.10- 7.27(m,2H) and 8.17(d,1H).
W092/0608~ 2 0 919 ~ ~ PCT/GB91/01663 (e) From 3-cyano-6-(2,3-di-propoxyphenyl)pyridin-2(1H~-one (lg), the title compound (0.47g) m.p. 186-187C
after recrystallisation from aqueous ethanol was prepared according to the method of Example l(b).
Exam~le 2g 6-(3-Cyclopentyloxy-4-methoxyphenyl)-3-(5-tetrazolyl)-pyridin-2(lH)-one (a) A mixture of 3'-hydroxy-4'-methoxyacetophenone (20.8g), potassium carbonate (24.15g), cyclopentyl bromide (22.35g) and potassium iodide (3.32g) were combined in acetone (250ml) and boiled for 24 hours. Dimethylformamide '5 (25ml) was added and boiling continued for a further 24 hours. The reaction mixture was cooled to room temperature, filtered and solvent removed at reduced pressure. The residue was dissolved in diethyl ether (200ml) washed with 2N sodium hydroxide (3x50ml) and water, dried and solvent removed at reduced pressure to give 3'cyclopentyloxy, 4'-methoxyacetophenone as an oil that solidified on standing m.p. 59-60C.
(b) From 3'-cyclopentyloxy-4'-methoxyacetophenone (11~25g), 3-cyano-6-(3-cyclopentyloxy-4-methoxyphenyl)-pyridin-2(1H~-one (4.07g) m.p.259-260C after digestion with acetonitrile was prepared according to the method of Example 3(a) omitting sodium methoxide.
(c) From 3-cyano-6-(3-cyclopentyloxyphenyl-4-methoxyphenyl)pyridin-2(1H)-one (0.8g), the title compound (0.6g) m.p. 286-287C (decomp) after recrystallisation from dimethylformamide was prepared according to the method of Example l(b). lH-NMR ~(d6-DMSO) W O 92/06085 2 ~ g g PC~r/GB91/01663 1.54-2.02(m,8H), 3.83(s,3H), 5.00(m,lH), 6.87(d,lH), 7.10(d,1H), 7.43(s,1H), 7.46(d,1H) and 8.44(d,1H).
Example 30 6-(3-Ethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one (a) A mixture of 3-hydroxyacetophenone (6.8g) and tris(dimethylamino)methane (14.5g) were heated together in dimethylformamide (30ml) at 80C for 4 hours. The reaction mixture was cooled to room temperature cyanoacetamide (8.4g) added and the mixture boiled for 8 hours. After cooling to room temperature the mixture was poured into 10% aqueous acetic acid (200ml), filtered and the residue washed with water and ethanol to give 3-cyano-6-(3-hydroxyphenyl)pyridin-2(lH)-one. lH-NMR ~(d6-DMSO) 6.64(br.d,1H), 6.95(dd,1H), 7.12(s,1H), 7.20(d,1H), 7.32(t,1H), 8.15(d,1H), 9.87(s,1H) and 12.70(b,.s,1H).
(b) To a suspension of sodium hydride (lg, 50% in oil) in dimethylformamide (15ml) 3-cyano-6-(3-hydroxy-phenyl)pyridin-2(lH)-one (2.12g) was added in portions over 30 minutes. When gas evolution had ceased iodoethane (1.56g) was added and the mixture stirred overnight. The mixture was diluted with ethyl acetate (lOOml), washed with 2N hydrochloric acid (2x30ml) and with water (4x50ml), dried (MgS04) and solvent removed at reduced pressure. The residue was recrystallised from n-butanol to give 3-cyano-6-(3-ethoxyphenyl)pyridin-2(lH)-one (0.68g). 1H-NMR ~(d6-DMSO) 1.35(t,3H), 4.12(q,2H), 6.80(d,1H), 7.08(d,1H), 7.31-7.47(m,3H) and 8.18(d,lH).
(5) From 3-cyano-6-(3-ethoxyphenyl)pyridin-2(1H)-one (0.5g), the title compound (0.44g) m.p.279C (decomp) W092/06085 PCT/GB9t/01663 2091~8~
after recrystallisation from n-butanol, was prepared according to the method of Example l(b). lH-NMR
~(d6-DMSO) 1.36(t,3H), 4.14(q,2H), 6.90(d,lH), 7.10(m,lH), 7.34-7.48(m,3H) and 8.47(d,lH).
Exam~le 31 6-(3,5-Dimethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one (a) From 3',5'-dimethoxyacetophenone (4.1g), 3-cyano-6-(3,5-dimethoxyphenyl)pyridin-2(lH)-one (2.4lg) m.p. 297C after recrystallisation from ethanol, was prepared according to the method of Example 3(a).
(b) From 3-cyano-6-(3,5-dimethoxyphenyl)pyridin-2(lH)-one (1.4g), the title compound (1.36g) m.p. 338C (decomp) after recrystallisation from acetonitrile/dimethyl-formamide was prepared according to the method of Example l(b). lH NMR ~(d6-DMSO) 3.86(s,6H), 6.66(m,1H), 6.95(d,1H), 7.02(m,2H), 8.47(d,1H) and 12.66(br.s,1H).
ExamPle 32 6-(2-Butylthiophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one (a) From 2'-bromoacetophenone (19.9g), 6-(2-bromophenyl)-3-cyanopyridin-2(1H)-one (11.4g) m.p. 245-246C after recrystallisation from ethanol,was prepared according to the method of Example l(a).
(b) From 6-(2-bromophenyl)-3-cyanopyridin-2(lH)-one (2.6lg), 6-(2-butylthiophenyl)-3-cyanopyridin-2(lH)-one (0.83g) m.p.163-165C after recrystallisation from W092/06085 2 ~ 919 8 ~ PCT/GB91/01663 ethanol, was prepared according to the method of Example 26(a).
(c) From 6-(2-butylthiophenyl)-3-cyanopyridin-2(lH)-one (0.71g), the title compound (0.53g) m.p.l81-182C after recrystallisation from ethanol, was prepared according to the method of Example l(b).
Example 33 6-(3-Allyloxyphenyl)-3-(5-tetrazolyl)p~ridin-2(1H)-one ~a) From 3'-allyloxyacetophenone (15.07g), 6-(3-allyloxyphenyl)-3-cyanopyridin-2(lH)-one (14.7g) was prepared according to the method of Example 3(a). lH NMR
o(d6-DMSO) 4.67(d,2H), 5.26-5.46(m,2H), 5.98-6.20(m,1H), 6.80(d,1H), 7.13(m,1H), 7.33(m,3H) and 8.20(d,1H).
(b) From 6-(3-allyloxyphenyl)-3-cyanopyridin-2(1H)-one (lg), the title compound (0.34g) m.p.260C (decomp) after recrystallisation from n-butanol, was prepared according to the method of Example l(b). lH NMR O(d6-DMSO) 4.72(m,2H), 5.28-5.52(m,2H), 6.04-6.20(m,1H), 6.94(d,1H), 7.14(m,lH), 7.48(m,3H) and 8.47(d,lH).
ExamPle 34 6-(4-Methoxy-2-pQntyloxyphenyl)-3-~5-tetrazolyl)pyridin-2(1H)-one (a) From 4'-methoxy-2'-pentyloxyacetophenone (11.8g), 3-cyano-6-(4-methoxy-2-pentyloxyphenyl)pyridin-2(lH)-one (3.4g) m.p. 143-144C after recrystallisation from ethanol, was prepared according to the method of Example 3(a).
W092/0608~ 2 Q 9 ~ PCT/GB91/~1663 ~b) From 3-cyano-6-(4 methoxy-2-pentyloxyphenyl)pyridin-2(lH)-one ~1.25g), the title compound (0.65g) m.p. 193-194C after recrystallisation from ethanol was prepared according to the method of Example l(b).
~xamPle 35 6-~3-i~o-Butoxy-4-metho~yphenyl)-3-(5-tetrazolyl)pyridin-2(1~)-one (a) From 3'-iso-butoxy-4'-methoxyacetophenone (7.6g), 3-cyano-6-(3-iso-butoxy-4-methoxyphenyl)pyridin-2(lH)-one (6.02g) m.p.234-235C after recrystallisation from ethanol, was prepared according to the method of Example 3(a).
(b) From 3-cyano-6-(3-iso-butoxy-4-methoxyphenyl)pyridin-2(lH)-one (1.19g), the title compound (1.2g) m.p. 296-297C
(decomp) after recrystallisation from ethanol, was prepared according to the method of Example l(b). lH NMR ~(DMSO-d6) l.Ol(d,6H), 2.02-2.16(m,lH), 3.85(s,3H3, 3.89(d,2H), 6.89(d,lH), 7.12(d,lH), 7.41-7.50(m,2H) and 8.47(d,lH).
ExamPle 36 6-(2-Bromo-3,5-diethoxyphenyl)-3-(5-tetrazolyl)py~idin-2(1~)-one (a) To an ice cooled solution of 3',5'-diethoxyacetophenone (10.4g) in dimethylformamide (50ml) N-bromosuccinimide (9.79g) was added in portions over 1 hour. The mixture was stirred at 0C for 3 hours and stood at room temperature for 48 hours. After diluting with ethyl acetate (200ml) the mixture was washed with water (5xlOOml), dried (MgS04) and solvent removed at reduced pressure to give 2'-bromo-3',5'-diethoxyacetophenone (12.53g) as an oil.lH NMR ~(CDC13)1.41(t,3H), 1.50(t,3H), 2.60(s,3H), 4.00(q,2H), 4.10(q,2H), 6.45(d,lH) and 6.50(d,lH).
WO 92/0608~ 2 0 919 8 9 . PCr/GBgl/01663 (b) From 2'-bromo-3',5'-diethoxyacetophenone (4.31g), 3-cyano-6- (2-bromo-3,5-diethoxyphenyl)pyridin-2(lH)-one (0.75g) m.p. 234-235C after recrystallisation from 5 ethanol, was prepared according to the method of Example 3(a)-(c) From 3-cyano-6-(2-bromo-3,5-diethoxyphenyl)pyridin-2(lH)-one (0.6g), the title compound m.p. 276C after 10 recrystallisation from ethanol was prepared according to the method of Example l(b).
Example 37 6-(5-Bromo-4-methoxy-2-pentyloxyphenyl)-3-(5-tetrazolyl)-pyridin-2(1EE)-one (a) A mixture of 3-cyano-6-(4-methoxy-2-pentyloxyphenyl)-pyridin-2(lH)-one (1.71g), silver carbonate (1.92g) and 20 iodomethane in chloroform (30ml) were stirred in the dark for 48 hours. After filtration (celite pad) solvent was removed at reduced pressure and the residue column chromatographed (silica gel, 40%hexane/dichloromehane eluant) to give 3-cyano-2-methoxy-6-(4-methoxy-2-25 pentyloxyphenyl)pyridine (1.45g) m.p.76-78C.
(b) To a cooled (ice bath) solution of 3-cyano-2-methoxy-6-(4-methoxy-~-pentyloxyphenyl)pyridine (1.3g) in dimethylformamide (lOml) N-bromosuccinimide (0.71g) was 30 added in portions over 30 minutes. The solution was stirred at room temperature overnight diluted with ethyl acetate (SOml) and washed with water (5x50ml). The organic phase was dried (MgS04) solvent removed at reduced pressure and the residue recrystallised from ethanol to give 3-cyano-2-35 methoxy-6-(5-bromo-4-methoxy-2-pentyloxyphenyl)pyridine (l.lg) m.p. 136-l37C.
W092/06085 2 ~ 91~ ~ 3 PCT/GB91/01663 (c) 3-Cyano-2-methoxy-6-(2-bromo-4-methoxy-2-pentyloxyphenyl)pyridine (lg) and sodium iodide (1.50g) (dried a~ 70C in vacuo for 4 hours) were dissolved in acetonitrile (lOml) and chlorotrimethylsilane (1.08g) added. The reaction mixture was stirred in the dark for 2 hours, diluted with ethyl acetate (SOml) washed with water ~2x50ml), with 5% aqueous sodium metabisulphite (30ml) and water (50ml). The organic phase was dried (MgS04) solvent removed at reduced pressure and the residue recrystallised from ethanol to give 3-cyano-6-(5-bromo-4-methoxy-2-pentyloxyphenyl)pyridin-2(lH)-one (0.55g) m.p.188-190C.
(d) From 3-cyano-6-(5-bromo-4-methoxy-2-pentyloxyphenyl)pyridin-2(lH)-one (0.5g), the title compound (0.38g) m.p.246-248C after recrystallisation from ethanol, was prepared according to the method of Example l(b).
Example 38 6-(2-Allyl 4-m~thoxy-3-propoxyphenyl)-3-(5-tQtrazolyl)-pyridin-2(1~)-one (a) A mixture of 3'-allyloxy-4'-methoxyacetophenone (7.76g) and diethylaniline (5.96g) was degassed with nitrogen for 15 minutes and heated at 215C for 90 minutes. After cooling to room temperature the reaction mixture was dissolved in ethyl acetate (lOOml) and washed with 2N
hydrochloric acid (3xlOOml). The organic phase was dried ~MgS04) and solvent removed at reduced pressure to give after recrystallisation from ethanol/water 2'-allyl-3'-hydroxy-4'-methoxyacetophenone (S.lg) m.p.~1-83C.
(b) 2'-Allyl-3'-hydroxy-4'-methoxyacetophenone (5.0g), potassium carbonate (3.3g) and iodopropane were heated together in a mixture of dimethylformamide (20ml) and butanone (30ml) for 48 hours~ The mixture was filtered and W092/060~5 2 0 919 ~ 9 PCT/GB91/01663 solvent removed from the filtrate at reduced pressure to give a residue which was dissolved in ethyl acetate (lOOml) and washed with water (5x50ml). The organic phase was dried (MgS04) and solvent removed at reduced pressure to give 2'-allyl-4'-methoxy-3'-propoxyacetophenone (5.0g) as an oil.
1H NMR ~5DMSO-d6) 0.98(t,3H), 1.62-1.80(m,2H), 2.48(s,3H), 3.62-3.69(m,2H), 3.79(t,2H), 3.85(s,3H), 4.82-4.91(m,2H), 5.78-5.93(m,lH), 6.99(d,lH and 7.63(d,lH).
10 (c) From 2'-allyl-4'-methoxy-3'-propoxyacetophenone (4.96g) 3-cyano-6-(2-allyl-4-methoxy-3-propoxyphenyl)pyridin-2(lH)-one (1.15g) m.p. 170-171C after recrystallisation from ethanol was prepared according to the method of Example 3(a) with, however, the omission of sodium methoxide.
(d) From 3-cyano-6-(2-allyl-4-methoxy-3-propoxyphenyl)pyridin-2(lH)-one (0.49g), the title compound (0.24g) m.p. 210-211C after recrystallisation from ethanol was prepared according to the method of Example l(b).
ExamPle 39 ~-t3-(E-l-propenyl)-4-methoxyphenyl]-3-(5-tetrazolyl) pyridin-2(1R)-one (a) From 3-allyl-4-methoxyacetophenone (7.6g), 3-cyano-6-[3-(E-1-propenyl)-4-methoxyphenyl]pyridin-2(lH)-one (4g) after recrystallisation from n-butanol, was prepared according to the method of Example 3(a). 1H NMR ~(DMSO-d 30 1.88(d,3H), 3.87(s,3H), 6.40-6.67(m,3H), 6.~8(d,lH), 7.10(d,lH), 7.72(dd,lH), 7.93(d,lH) and 8.14(d,lH).
(b) From 3-cyano-6-[3-(E-1-propenyl)-4-methoxyphenyl]pyridin-2(1H)-one (2.13g), the title compound 35 (0.8g) m.p. 291-29~C (decomp) after recrystallisation from dimethylformamide was prepared according to the method of Example l(b). lH NMR ~(DMSO-d6) 1.89(d,3H), 3.88(s,3H), W092/06085 2 0 919 ~ 3 PCT/GB91/01663 6.42-6.71(m,3H), 6.90(d,lH), 7.12(d,lH), 7.76(dd,lH), 7.97(d,lH) and 8.44(d,lH).
, ExamPle 40 6-(4-~ethoxy-3-propoxyphsnyl)-3-~S-~l-pi~aloyloxymHthyl)-tetrazolyl)pyridin-2(1~)-one and 6-(4-~ethoxy-3-propoxyphenyl)-3-[5-(2-pivaloyloxymethyl)-tetrazolyl~pyridin-2(1~)-one A mixture of 4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one (1.64g), pivaloyloxymethyl chloride (0.75g), sodium hydrogen carbonate (420mg) and sodium iodide (50mg) were heated in dimethylformamide (5ml) at 70C for 24 hours. The mixture was diluted with ethyl acetate (SOml) and washed with water 6 x SOml). The organic phase was dried (MgS04) filtered and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, 70% hexane/ethyl acetate - 30% hexane/ethyl acetate eluant to give:- a) 6-(4-methoxy-3-propoxyphenyl)-3-[5-(1-pivaloyloxymethyl)tetrazolyl]pyridin-2(lH)-one (0.26g) m.p. 169-170C after recrystallisation from ethanol and b) 6-(4-methoxy-3-propoxyphenyl)-3-[5-~2-pivaloyloxymethyl)tetrazolyl]pyridin-2(lH)-one (0.35g) m.p.195-196C after recrystallisation from ethanol.
Example 41 6-~3-Ethoxy-5-(2-methoxyethoxy)phenyl]-3-(S-tetrazolyl)-pyridin-2(1~)-one a) 3',5'-Dihydroxyacetophenone (15.2g), potassium carbonate (7.59g) and iodoethane (17.16g) were combined and heated at reflux for 15 hours. Additional potassium carbonate (2.76g) and iodoethane (6.2g) were added and heating was continued for a further 10 hours. The reaction mixture was filtered, solvent removed at reduced pressure, the residue dissolved W092/0608S 2 ~ 919 ~ 9 ;; PCT/~B91/0166~
_ ~9 _ in ethyl acetate (lOOml) and extracted with 2N sodium hydroxide (3x50ml). The combined basic extracts were washed with ethyl acetate (2xSOml), acidified with 2N hydrochloric acid and extracted with dichloromethane (3xlOOml). The combined dichloromethane extracts were washed with water (2x50ml), dried (MgS04), filtered and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, dichloromethane eluant) to give 3'-ethoxy-5'-hydroxyacetophenone (4.83g) m.p. 96-98C.
b) To a suspension of sodium hydride (0.92g, 60% in oil washed with hexane) in dimethylformamide (lOml), 3'-ethoxy-5'-hydroxyacetophenone (3.24g) was added in portions over 10 minutes. When gas e~olution had ceased chloroethylmethyl ether (1.9g) and sodium iodide (50mg) were added and the mixture heated to 90C for 18 hours and stirred at room temperature for 24 hours. The mixture was diluted with ethyl acetate (lOOml), washed with 2N sodium hydroxide (3x50ml) and water (3x50ml). The organic phase was dried ~MgS04), filtered and solvent removed at reduced pressure to give 3'-ethoxy-S'-(2-methoxyethoxy)acetophenone (4.03g) as an oil. lH NMR ~(CDCl3) 1.42(t,3H), 2.56(s,3H), 3.46(s,3H), 3.74-3.78(m,2H), 4.05(q,2H), 4.13-4.17(m,2H), 6.68(m,lH) and 7.10(m,2H).
^5 c) From 3'-ethoxy-5'-t2-methoxyethoxy)acetophenone, 3-cyano-6-[3-ethoxy-5-~2-methoxyethoxy)phenyl~pyridin-2~lH)-one (l.lg) m.p.199C after recrystallisation from ethanol, was prepared according to the method of Example 3(a).
d) From 3-cyano-6-[3-ethoxy-5-(2-methoxyethoxy)phenyl]pyridin-2(lH)-one (0.94g), the title compound (0.6g) m.p.205-206C after recrystallisation from ethanol, was prepared according to the method of Example l(b).
W092/0608~ 2 0 919 8 ~ PCT/GB91tO1663 xamPle 42 6-t3-(2,2-Dimethylpropyloxy)-4-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1~)-one a) From 3'-(2,2-dimethylpropyloxy)-4'-methoxyacetophenone ~9.Og), 3-cyano-6-[3-(2,2-dimethylpropyloxy)-4-methoxyphenyl]pyridin-2(lH)-one (3.46g) was prepared according to the method of Example 3(a). lH NMR ~(DMSO d6) 1.02(s,9H), 3.74(s,2H), 3.85(s,3H), 6.79(d,lH), 7.09(d,lH~, 7.42(s,lH), 7.43(d,lH) and 8.14(d,lH).
b) From 3-cyano-6-[3-(2,2-dimethylpropyloxy)-4-methoxyphenyl]pyridin-2(lH)-one (1.2Sg), the title compound (1.28g) m.p. >300C after recrystallisation from n-butanol, was prepared according to the method of Example l(b). lH
NMR ~(DMSO-d6) 1.04(s,9H), 3.77(s,2H), 3.86(s,3H), 6.90(d,lH), 7.10(d,lH), 7.45(m,2H) and 8.44(d,lH).
ExamPle 43 6-(3-Ethoxy-4-methoxyphenyl)-3-(S-tetrazolyl)pyridin-2(1~)-one a) From 3'-ethoxy-4'-methoxyacetophenone (2.91g), 3-cyano-6-(3-ethoxy-4-methoxyphenyl)pyridin-2(lH)-one (2.02g) m.p.273C after recrystallisation from ethanol was prepared according to the method of Example l(a).
b) From 3-cyano-6-(3-ethoxy-4-methoxyphenyl)pyridin-2(lH)-one (l.Og), the title compound (l.Q6g) m.p.299C (decomp) after recrystallisation from n-butanol, was prepared according to the method of Example l(b). lH NMR ~(DMSO-d6) 1.37(t,3H), 3.84(s,3H), 4.15(q,2H), 6.92(d,lH), 7.10(d,lH), 7.41-7.50(m,2H) and 8.43(d,lH).
W092/0608~ 2 0 919 8 ~ PCT/GB91/01663 ExamPle 44 6-(3-~ropionamidophenyl)-3-(5-tetrazolyl)pyridin-2(1~-one a) To a stirred suspension of sodium methoxide (4.32g) in diethyl ether (50ml) a mixture of 3'-propionamidoacetophenone (5.73g) and ethyl formate (4.44g) in tetrahydrofuran (lOOml) was added over 30 minutes. After stirring overnight the mixture was filtered and the residue washed with diethyl ether. The residue was dissolved in water (50ml), the pH adjusted to 9.0 with glacial acetic acid and cyanoacetamide (4.2g) added. The solution obtained was boiled overnight cooled to room temperature and adjusted to pH 5 with glacial acetic acid (US Patent 4,278,681). The precipitated material was collected by filtration, washed thoroughly (4x50ml) with ethanol and recrystallised from dimethylformamide/water to give 3-cyano-6-(3-propionamidophenyl)pyridin-2(lH)-one (0.4g) m.p.
b) From 3-cyano-Ç-(3-propionamidophenyl)pyridin-2(lH)-one (0.3g) the title compound (0.2g) m.p.291-293C (decomp) after recrystallisation from dimethylformamide/water, was prepared according to the method of Example l(b). lH NMR
~(DMSO-d6) l.ll(t,3H), 2.37(q,2H), 6.75(d,lH), 7.46(m,2H), 7.69(m,lH), 8.09(m,lH~ and 8.50(d,lH).
Example 45 6-(4-Methoxy-3-propylphenyl)-3-~5-tetrazolyl)pyridin-2(1~)-one (SB 20525)) (a) A solution of 3'-allyl-4'-methoxyacetophenone t20g) in ethanol ~250ml) containing 10% palladium on charcoal (2g) was treated with hydrogen at 50 p.s.i until the calculated volume of hydrogen had been taken up. The mixture was filtered (celite pad) and solvent removed at reduced W092/06085 2 ~ 919 8 ~ PCT/GB91/01663 pressure. The residue was dissolved in dichloromethane (lOOml) and manganese dioxide (60g) added. The mixture was stirred at room temperature for 48 hours, filtered (celite pad) and solvent removed at reduced pressure to give 4'-methoxy-3'-propylacetophenone (15.16g) as an oil. lH NMR
~(CDCl3) 0.95(t,3H), 1.52-1.79(m,2H), 2.55(s,3H), 2.61(t,2H), 3.88(s,3H), 6.86(d,lH), 7.77(d,lH) and 7.82(dd,lH).
10 (b) From 4'-methoxy-3'-propylacetophenone (5.77g), 3-cyano-6-(4-methoxy-3-propylphenyl)pyridin-2(lH)-one (4.43g) m.p.
239C after recrystallisation from butanol, was prepared according to the method of Example 3(a).
15 (c) From 3-cyano-6-(4-methoxy-3-propylphenyl)pyridin-2(lH)-one (4.02g), the title compound (3.64g) m.p.293-294C
(decomp) after recrystallisation from ethanol, was prepared according to the method of Example l(b). lH NMR ~(DMSO-d6) 0.93(t,3H), 1.51-1.71(m,2H), 2.59(t,2H), 3.87(s,3H), 6.83~d,1H), 7.10(d,1H), 7.68-7.74(m,2H) and 8.46(d,1H).
ExamPle 46 6-(3-Bromo-4-methoxyphenyl)-3-(5-tetrazolyl)pyri~in-2(1~)-one (SB 204617~
(a) From 3'-bromo-4'-methoxyacetophenone (K.W.Rosenmund et.
al. Chem. Ber., 1922, 90, 1957) (2.29g), 3-cyano-6-(3-bromo-4-methoxyphenyl)pyridin-2(lH)-one (1.42g) m.p. 284-286C after recrystallisation from ethanol, was preparedaccording to the method of Example 3(a).
(b) From 3-cyano-6-(3-bromo-4-methoxyphenyl)pyridin-2(lH)-one (1.22g), the title compound (1.28g) m.p. 292-293C
(decomp) after recrystallisation from dimethylformamide, was prepared according to the method of Example l(b). 1H
W092/06085 2 0 919 ~ 9 P~T/GB91/01663 NMR ~(DMSO-d6) 3.94(s,3H), 6.90(d,lH), 7.27(d,lH), 7.90(dd,lH), 8.14(d,lH) and 8.45(d,lH).
Example 47 6-(3-phenyl-4-methoxyphQnyl)-3-(5~tetrazolyl)pyridin-2(1R)-one ~S8 204649) (a) To a suspension of tetrakis(triphenylphosphine)palladium (O) (O.Sg) in aoueous sodium hydrogen carbonate (5.04g in 60ml water), solutions of phenylboronic acid (2.65g) in dimethoxyethane (lOOml) and 3'-bromo-4'-methoxyacetophenone (4.58g) in dimethoxyethane (llOml) were added. The mixture was stirred under reflux for 3 hours cooled to room temperature and solvent removed at reduced pressure. The residue was partitioned between chloroform (200ml) and water (200ml), the organic phase separated dried (MgS04) and solvent removed at reduced pressure. The residue was recrystallised from ethanol to give 4'-methoxy-3'-phenylacetophenone (2.87g) m.p. 92-93C.
(b) From 4'-methoxy-3'-phenylacetophenone (3.3g), 3-cyano-6-(3-phenyl-4-methoxyphenyl)pyridin-2(lH)-one (2.37g) m.p.
288-291C after recrystallisation from propan-2-ol, was prepared according to the method of Example 3(a).
(c) From 3-cyano-6-[(3-phenyl)-4-methoxyphenyl]pyridin-2(lH)-one (0.9lg), the title compound (0.70g) m.p. 289-291C after recrystallisation from dimethylformamide/ethanol, was prepared according to the method of Example l(b). lH NMR ~(DMSO-d6) 3.86(s,3H), 6.92(d,lH), 7.28(d,lH), 7.33-7.48(m,3H), 7.62(d,2H), 7.81-7.89(m,2H~, 8.45(d,lH), 11.96(br.s,lH) and 12.71(br.s,lH) W092/06085 2 0 919 ~ 9 PCT/GB91/01663 ! Example 48 6-[4-~ethoxy-3,5-di~E-1-propenyl)phenyl]-3-~-tetrazolyl)-pyridin-2(lE)-one (SB 204788) (~) From 3'-allyl-4'-hydroxyacetophenone (17.6g), 3'-allyl-4'-allyloxyacetophenone (20.7g) isolated as an oil, was prepared according to the method of Example 2~a) using acetone as solvent. lH NMR ~(CDCl3) 2.55(s,3H), 3.44(d,2H), 4.61~m,2H), 5.04-5.46~m,4H), 5.94-6.10(m,2H), 6.86(d,lH), 7.78d,lH) and 7.83(dd,lH).
(b) From 3'-allyl-4'-allyloxyacetophenone (20.5g), 3',5'-diallyl-4'-hydroxyacetophenone (16.3g) m.p. 83-84C was prepared according to the method of Example 38(a).
(c) From 3',5'-diallyl-4'-hydroxyacetophenone (16g), 3',5'-diallyl-4'-methoxyacetophenone (17g) isolated as an oil, was prepared according to the method of Example 2(a). 1H
NMR ~(CDC13) 2.55(s,3H), 3.46(d,4H), 3.77(s,3H), 5.05-5.14(m,4H), 5.91-6.07(m,2H) and 7.69(s,2H).
(d) From 3',5'-diallyl-4'-methoxyacetophenone (8.5g), 3-cyano-6-[4-methoxy-3,5-di(E-1-propenyl)phenyl]pyridin-2(lH)-one (6.1g) m.p. 248-250C after trituration with hot ethanol, was prepared according to the method of Example 3(a).
(e) From 3-cyano-6-[4-methoxy-3,5-di(E-l-propenyl)phenyl]pyridin-2(lH)-one (0.46g), the title compound (0.27g) m.p. 285-287C (decomp) after recrystallisation from dimethylformamide/water, was prepared according to the method of Example l(b). lH NMR
~(DMSO-d6) 1.92(d,6H), 3.68(s,3H), 6.49-6.68(m,4H), 7.00(d,lH), 7.89(s,2H) and 8.45(d,lH).
W O 92/06085 2 0 9 ~ ~ ~ 9 P ~ /GB91/01663 ExamPle 49 6-[3-(E-l-Propenyl)-4-propoxyphenyl]-3-(5-tetrazolyl)-pyridin-2(1H)-o~e. (SB 201433) (a) From 3'-allyl-4'-hydroxyacetophenone ~5.28g), 3'-allyl-4'-propoxyacetophenone (6.06g) isolated as an oil was prepared according to the method of Example 2(a). lH NMR
~(CDCl3) 1.07(t,3H), 1.66-1.92(m,2H), 2.5S(s,3H), 10 3.41(d,2H), 3.99(t,2H), 5.04-5.12(m,2H), 5.90-6.06(m,lH), 6.86(d,lH), 7.77(d,lH) and 7.83(dd,lH).
(b) From 3'-allyl-4'-propoxyacetophenone (5.7g), 3-cyano-6-[3-(E-1-propenyl)-4-propoxyphenyl]pyridin-2(lH)-one (2.57g) 15 m.p. 240-244C after recrystallisation from butanol, was prepared according to the method of Example 3(a).
(c) From 3-cyano-6-[3-(E-1-propenyl)-4-propoxyphenyl]pyridin-2(lH)-one (1.18g), the title compound 20 (0.7g) m.p.290-292C (decomp) after recrystallisation from butanol, was prepared according to the method of Example l(b). lH NMR ~(DMSO-d6) 1.02(t,3H), 1.73-1.86(m,2H), l.90(d,3H), 4.04(t,2H), 6.48-6.61(dq,lH), 6.65(d,lH), 6.89(d,lH), 7.11(d,lH), 7.70(dd,1~:), 7.97(d,lH) and 25 8.43(d,lH).
Example 50 6-(3-Bromo-4-methoxy-5-propylphenyl)-3-(5-tetrazolyl)-30 pyridin-2(1H)-one. ~273/2534) (a) From 4'-methoxy-3'-propylacetophenone (7.6g), 3'-bromo-4'-methoxy-5'-propylacetophenone (4.8g) isolated as an oil after column chromatography (silica gel, 50%
hexane/dichloromethane eluant) was prepared according to the method of Example 36(a). lH NMR ~(CDCl3) 0.98(t,3H), W092/06085 2 0 91~ 8 9 PCT/GB91/01663 1.'7-1.73(m,2H), 2.56(s,3H), 2.67(t,2H), 3.87(s,3H), 7.74(d,lH) and 7.98(d,lH).
(b) From 3'-bromo-4'-methoxy-5'-propylacetophenone (3.4g), 6-(3-bromo-4-methoxy-5-propylphenyl)-3-cyanopyridin-2(lH)-one (1.2g) after recrystallisation from ethanol, was prepared according to the method of Example 3~a). lH NMR
~(DMSO-d6) 0.94(t,3H), 1.57-1.67(m,2H), 2.65(t,2H), 3.79(s,3H), 6.38(br.d,lH), 7.74(d,lH), 7.97(d,lH) and 8.18(d,lH).
(c) From 6-(3-bromo-4-methoxy-5-propylphenyl)-3-cyanopyridin-2(lH)-one (0.39g), the title compound (0.17g) m.p. 2~6-287 (decomp) after recrystallisation from ethanol, was prepared according to the method of Example l(a). lH
NMR S(DMSO-d6) 0.96(t,3H), 1.61-1.70(m,2H), 2.67(t,2H), 3.81(s,3H), 6.94(d,lH), 7.76(d,lH), 7.99(d,lH) and 8.45(d,lH).
Example 51 6-(2-Butylthio-3,5-diethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1R)-one 25 (a) From 2'-bromo-3',5'-diethoxyacetophenone (2.53g), 2'-butylthio-3',5'-diethoxyacetophenone ~1.96g) after column chromatography (silica gel, hexane/dichloromethane 4:1 eluant) was prepared according to the method of Example 26(a). lH NMR ~(CDCl3) 0.87(t,3H), 1.25-1.65(m,10H), 30 2.59(s,3H), 2.76(t,2H), 4.02(q,2H), 4.08(q,2H), 6.33(d,1H) and 6.46(d,1H).
(b) From 2'-butylthio-3',5'-diethoxyacetophenone (1.95g), 3-cyano-6-(2-butylthio-3,5-diethoxyphenyl)pyridin-2(1H)-one (0.13g) after recrystallisation from ethanol, was prepared according to the method of Example 3(a). lH NM~ ~(DMSO-d6) 0.71(t,3H), 1.18-1.43(m,10H), 2.66(t,2H), 4.03-4.18(m,4H), 6.27(d,lH), 6.59(d,lH), 6.71(d,lH) and 8.15(d,lH).
(c) From 3-cyano-6-(2-butylthio-3,5-diethoxyphenyl)-3-(5-tetrazolyl~pyridin-2(lH)-one (0.12g), the title compound (0.08g) m.p. 138-140C after recrystallisation ~rom ethanol, was prepared according to the method of Example l(a). lH NMR ~(DMSO-d6) 0.76(t,3H), 1.18-1.43(m,10H), 2.64(t,2H), 4.05-4.19(m,4H), 6.40(d,lH), 6.62(d,lH), 6.70(d,1H), 8.48(d,1H) and 12.67(br.s,1H).
Example 52 6-~3-Bromo-4-~,N-dimethylam;nophQnyl)-3-(5-tetrazolyl1-pyridin-2(1~)-one ~SB 204789) (a) From 4'-N,N-dimethylaminoacetophenone (4.9g), 3'-bromo-4'-N,N-dimethylaminoacetophenone (7.0g) was prepared according to the method of Example 36(a). lH NMR ~(CDCl3) 2.53(s,3H), 2.91(s,6H), 7.03(d,lH), 7.83(dd,lH) and 8.13(d,lH).
(b) From 3'-bromo-4'-N,N-dimethylaminoacetophenone (2.42g), 3-cyano-6-(3-bromo-4-N,N-dimethylaminophenyl)pyridin-2(lH)-one (2.63g) was prepared according to the method of Example3(a). lH NMR ~(DMSO-d6) 2.82(s,6H), 6.82(d,1H), 7.22(d,1H), 7.79(dd,lH), 8.08(d,lH), 8.15(d,lH) and 12.67(br.slH).
; (c) From 3-cyano-6-(3-bromo-4-N,N-dimethylaminophenyl)pyridin-2(lH)-one (0.8g), the title compound (0.57g) m.p.275-277C was prepared according to the method of Example l(b).
W O 92/06085 2 0 919 8 9 PC~r/GB91/01663 Exau~ple 53 6-~3-Acctamido-4-methoxy-5-propylphenyl) -3-(5-tetrazolyl)pyridin-2(1~)-ono (SB 20~790) (a) From 3'-allyl-4'-hydroxyacetophenone (17.6g), 3'-allyl-4'-benzyloxyacetophenone (23~lg) isolated as an oil was prepared according to the method of Example 2(a) using acetone as solvent. lH NMR ~(CDCl3) 2.55(s,3H), 3.47(d,2H), 5.04-5.11(m,4H), 5.16(s,2H), 5.93-6.09(m,lH), 6.93(d,lH), 7.25-7.41(m,5H), 7.81(s,lH) and 7.82(d,lH).
(b) From 3'-allyl-4'-benzyloxyacetophenone (23g), 6-[4-benzyloxy-3-(E-l-propenyl)phenyl]-3-cyanopyridin-2(lH)-one (11.2g) m.p. 255-257C after recrystallisation from dimethylformamide/water, was prepared according to the method of Example 3(a).
(c) A solution of 6-~4-benzyloxy-3-(E-l-propenyl)phenyl~-3-cyanopyridin-2(lH)-one (6.8g) in dimethylformamide ~20ml) containing dimethylformamide dimethyl acetal (4.76g) was heated at 120C for 6 hours. The mixture was diluted with ethyl acetate (200ml), washed with water (6 x lOOml), dried (MgSO4) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, hexane/dichloromethane 1:1 eluant) to give 6-[4-benzyloxy-3-(E-l-propenyl)phenyl]-3-cyano-2-methoxypyridine (6g) m.p.
124-125C after recrystallisation from ethanol.
(d) A suspension of 6-[4-benzyloxy-3-(E-l-propenyl)phenyl]-3-cyano-2-methoxypyridine (1.78g) in ethanol (250ml) containing 10~ palladium/charcoal (0.2g) was hydrogenated at 50 p.s.i until the calculated quantity of hydrogen had been absorbed. The mixture was filtered (celite pad) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, hexaneldichloromethane 1:1 -2% ethanol/dichloromethane eluant) to give 3-cyano-6-(4-W092/06085 2 ~ 919 8 9 PCT/GB91/01663 _ 59 _ hydroxy-3-propylphenyl)-2-methoxypyridine ~l.Og). 1H NMR
~(CDCl3) l.Ol(t,3H), 1.65-1.74(m,2H), 2.66(t,2H), 4.15(s,3H) 5.19(s,1H), 6.86(d,1H), 7.35(d,1H) and 7.81-7.87(m,3H).
(e) To a stirred suspension of 6-(4-hydroxy-3-propylphenyl)-3-cyano-2-methoxypyridine (1.88g) in sulpholane ~3ml) a solution of nitronium tetrafluoroborate in sulpholane (0.5M, 16ml) was added over 5 minutes with ice cooling. The solution obtained was stirred for 5 hours, additional nitronium tetrafluoroborate (0.5M in sulpholane, 2ml) added and stirring continued for a further 3 hours.
The solution was diluted with diethyl ether ~lOOml) washed with water (8 x lOOml), dried (MgS04) and solvent removed at reduced pressure. The residue was recrystallised from ethanol to give 3-cyano-6-(4-hydroxy-3-nitro-5-propylphenyl)-2-methoxypyridine (1.75g) m.p. 160-162C.
(f) From 3-cyano-6-(4-hydroxy-3-nitro-5-propylphenyl)-2-methoxypyridine (1.57g), 3-cyano-6-(4-methoxy-3-nitro-5-propylphenyl)-2-methoxypyridine (1.53g) m.p. 150-152C was prepared according to the method of Example 2(a) using acetone/dimethylformamide (1:1) as reaction solvent. 1H NMR
~(CDCl3) 1.03(t,3H), 1.67-1.81(m,2H), 2.77(t,2H), 3.95(s,3H), 4.17(s,3H), 7.42(d,lH), 7.96(d,lH), 8.07(d,lH) and 8.35(d,lH).
(g) A suspension of 3-cyano-6-(4-methoxy-3-nitro-5-propylphenyl)-2-methoxypyridine (1.4g) in ethanol (lOOml) containing 10% palladium/charcoal (200mg) was treated with hydrogen at 50 p.s.i until hydrogen uptake was complete.
The mixture was filtered (celite pad) and solvent removed from the filtrate at reduced pressure. The residue was dissolved in dichloromethane (lOml) containing triethylamine (l.Olg) added followed by the addition of acetic anhydride (0.61g) over 5 minutes. The reaction mixture was stirred for 15 hours, diluted with W092/06085 2 ~ 919-8 9 PCT/GB91/01663 dichloromethane (lOOml) and washed with 2N hydrochloric acid (2 x 50ml) and with water (50ml). After drying (MgS04), sol~ent was removed at reduced pressure to give after recrystallisation from ethanol 6-(3-acetamido-4-methoxy-5-propylphenyl-3-cyano-2-methoxypyridine (1.04g) m.p.174-175C.
(h) From 6-(3-acetamido-4-methoxy-5-propylphenyl)-3-cyano-2-methoxypyridine (0.7g), 6-(3-acetamido-4-methoxy-5-propylphenyl)-3-cyanopyridin-2(lH)-one (0.48g) m.p.247-249C was prepared according to the method of Example 37(c). 1H NMR ~(CDCl3) 1.02(t,3H), 1.68-1.83(m,2H), 2.27(s,3H), 2.78(t,2H), 3.83(s,3H), 6.65(d,1H), 7.49(d,1H), 7.80(br.s,lH), 7.90(d,lH) and 8.62(d,lH).
~5 (i) From 6-(3-acetamido-4-methoxy-5-propylphenyl)-3-cyanopyridin-2(lH)-one (0.4g), the title compound (0.25g) m.p. 239-241C after recrystallisation from ethanol, was prepared according to the method of Example l(b) ExamPle 54 6-[3-N~thoxymethyl-4-methoxy-5-~E-1-propenyl)phenyl~-3-(5-tetrazolyl)pyridin-2(1~)-on~ (273/2588) (a) From 3-cyano-6-[4-methoxy-3,5-di(E-1-propenyl)phenyl]pyridin-2(lH)-one (4.59g), 3-cyano-6-[4-methoxy-3,5-di(E-1-propenyl)phenyl]-2-methoxypyridine (4.lg) m.p. 145C was prepared according to the method of Example 5~(c). lH NMR ~(DMSO-d6) 1.93(d,6H), 3.67(s,3H), 4.11(s,3H), 6.42-6.56(m,2H), 6.66(d,2H), 7.87(d,lH), 8.15(s,2H) and 8.30(d,lH).
(b) To an ice cooled suspension of 3-cyano-6-[4-methoxy-3,5-di(E-1-propenyl)phenyl~-2-methoxypyridine (1.6g) in acetone/water (9:1, lOOml) N-methylmorpoline-N-oxide (0.63g) and osmium te~roxide (2.5% w/w solution in tert-W O 92/06085 2 0 919 8 9 P ~ /GB91/01663 butanol, 0.4ml) were added. The mixture was stirred with ice cooling for 1 hour and at room temperature for 1 hour.
Additional N-methylmorpholine-N-oxide (O.lg) was added and stirring continued for an additional 1 hour. The solution was quenched with 5% sodium metabisulphite (5ml) and solvent removed at reduced pressure. The residue was dissolved in ethyl acetate (200ml), washed with water (2 x lOOml)), dried (MgS04) and solvent removed at reduced pressure. Column chromatography (silica gel, dichloromethane-5% ethanol/dichloromethane eluant) gave 3-cyano-6-[3-[1-(1,2-dihydroxypropyl)]-4-methoxy-5-(E-1-propenyl)phenyl]-2-methoxypyridine (0.99g). lH NMR ~(CDCl3) 1.171d,3H), 1.97(d,3H), 2.5(br.s,1H), 2.98(br.s,1H), 3.82(s,3H), 3.94-4.05(m,lH), 4.16(s,3H), 4.77(d,lH), 6.30-6.42(m,lH~, 6.66(d,lH), 7.41(d,lH), 7.90(d,lH), 7.93(d,lH)and 8.08(d,lH).
(c) To a solution of 3-cyano-6-[3-[1-(1,2-dihydroxypropyl)]-4-methoxy-5-(E-1-propenyl)phenyl]-2-methoxypyridine (0.99g) in tetrahydrofuran(20ml) a solutionof sodium metaperiodate (0.64g) in water (3ml) was added.
The mixture was stirred for 2 hours, additional sodium metaperiodate (O.lg) in water (2ml) added and stirring continued for a further 2 hours. The mixture was filtered, diluted with ethyl acetate (lOOml), washed with water (2 x 50ml), dried (MgS04) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, dichloromethane- 5% ethanol/dichloromethane eluant) to give 3-cyano-6-[3-formyl-4-methoxy-5-(E-l-propenyl)phenyl]-2-methoxypyridine (0.7g) m.p. 174C. 1H NMR ~(CDCl3) 2.00(d,3H), 3.93(s,3H), 4.18(s,3H), 6.38-6.53(m,lH), 6.69(d,lH), 7.47(d,lH), 7.94(d,lH), 8.33(d,lH), 8.41(d,lH) and 10.44(lH).
35 (d) A solution of 3-cyano-6-[3-formyl-4-methoxy-5-(E-l-propenyl)phenyl]-2-methoxypyridine (0.65g) in ethanol (lOml) was treated with sodium borohydride (lOOmg) in port ons over 30 minutes. The solution was stirred for a further 2 hours, solvent removed at reduced pressure, the residue dissolved in ethyl acetate (lOOml), washed with water (2 x 50ml) , dried (MgS04) and solvent removed at reduced pressure. The residue was dissolved in dimethyl sulphoxide ~5ml), potassium hydroxide (0.56g, crushed pellets) added, followed by iodomethane (0.6g) and the mixture stirred for 30 minutes. After diluting with ethyl acetate (lOOml) the reaction mixture was washed with water 10 (6 x 50ml), dried (MgS04) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, 40% hexane/dichloromethane - dichloromethane) to give 3-cyano-6-~3-methoxymethyl-4-methoxy-5-(E-1-propenyl)phenyl]-2-methoxypyridine (0.54g) m.p. 81-82C. 1H
NMR ~(CDC13) 1.96(d,3H), 3.47(s,3H), 3.79(s,3H), 4.17(s,3H), 4.56(s,2H), 6.306.42(m,lH), 6.70(d,lH), 7.42(d,lH), 7.88(d,lH), 7.92(d,lH) and 8.10(d,lH).
(e) From 3-cyano-6-[3-methoxymethyl-4-methoxy-5-(E-1-propenyl)phenyl]-2-methoxypyridine (0.54g), 3-cyano-6-[3-methoxymethyl-4-methoxy-5-(E-1-propenyl)phenyl]pyridin-2(lH)-one (0.33g) m.p.188-190C after column chromatography (silica gel, dichloromethane - 2~5% ethanolldichloromethane eluant), was prepared according ~o the method of Example 37(c). lH NMR ~(CDCl3) l.99(d,3H~, 3.49(s,3H), 3.81(s,3H), 4.60(s,2H), 6.46-6.70~m,3H), 7.72(d,1H), 7.85(d,1H), 7.91(d,lH) and 12.89(br.s,lH).
(f) From 3-cyano-6-[3-methoxymethyl-4-methoxy-5-(E-1-propenyl)phenyl]pyridin-2(lH)-one (0.3g) the title compound (0.22g) m.p. 245-246~C after recrystallisation from ethanol, was prepared according to the method of Example l(b). 1H NMR ~(DMSO-d6) 1.92(d,3H), 3.61(s,3H), 3.83(s,3H), 4.81(s,2H), 6.26-6.44(m,lH), 6.68(d,lH), 6.88(d,lH) 7.73(d,lH), 8.04(d,lH), 8.75(d,lH) W092/06085 2 0 9 1~ ~ 9 PCT/GB91/01663 Example 55 6-13-(E-2-Carbamoylethenyl)-4-methoxy-5-~E-1-prop~nyl)phenyl]-3-~5-tetrazolyl)pyridin-2-(lH)-ona 5 (273/2602) (a) Triethylphosphonoacetate (0.9g) was added dropwise to a suspension of sodium hydride (0.18g, 50% in oil) in tetrahydrofuran (lOml). When gas evolution had ceased a solution of 3-cyano-6-[3-formyl-4-methoxy-5-(E-1-propenyl)phenyl]-2-methoxypyridine in tetrahydrofuran (lOml)was added and the mixture stirred for 4 hours.
Ethanol (lOml) and 2N sodium hydroxide (lOml) were added and the mixture boiled for 2 hours. Solvent was removed at reduced pressure, the residue dissolved in water and acidified with 2N hydrochloric acid. The precipitate was collected by filtration to give 3-cyano-6-[3-(E-2-carboxylatoethenyl)-4-methoxy-5-(E-1-prope~yl)phenyl]-2-methoxypyridine (0.9g). lH NMR ~(CDCl3) 1.94(d,3H), 3.73(s,3H), 4.14(s,3H), 6.50-6.62(m,lH), 6.69(d,lH), 6.7 8(d,lH), 7.82(lH), 7.99(d,lH) and 8.33-8.42(m,3H).
(b) Oxalyl chloride (0.76g) was added over 5 minutes to an ice cooled suspension of 3-cyano-6-[3-(E-2-carboxylatoethenyl)-4-methoxy-5-(E-l-propenyl)phenyl]-2-methoxypyridine in dichloromethane (20ml) containing dimethylformamide (O.lml). When gas evolution had ceased (4 hours) solvent was removed at reduced pressure and the residue redissolved in dichloromethane (20ml). To the ice cooled solution ammonium hydroxide (lOml, SG 0.88) was added and the solution stirred at 0C for 30 minutes and at room temperature for 30minutes. The precipitated solid was collected by filtration and recrystallised twice from ethanol to give 3-cyano-6-~3-(E-2-carbamoylethenyl~-4-methoxy-5-(E-1-propenyl)phenyl]pyridin-2(lH)-one (0.4g) m.p. 245-246C. lH NMR ~(DMSO-d6) 1.94(d,3H), 3.72(s,3H), 4.14(s,3H), 6.49-6.62(m,lH), 6.66(d,lH), 6.80~d,lH), W O 92/06085 2 ~ ~19 ~ 9 PC~r/GB91/01663 7.19(br.s,lH), 7.62(br.s,lH), 7.62(d,lH), 7.89(d,lH), 8.27(d,lH), 8.29(d,lH) and 8.34(d,lH).
(c) From 3-cyano-6-[3-(E-2-carbamoylethenyl)-4-methoxy-5-(E-l-propenyl)phenyl]-2-methoxypyridine (0.35g), 3-cyano-6-[3-(E-2-carbamoylethenyl)-4-methoxy-5-(E-l-propenyl)phenyl]pyridin-2(lH)-one (0.2g) m.p. >300C after recrystallisation from dimethylformamide/ethanol/water, was prepared according to the method of Example 37(c). lH NMR
~(DMSO-d6) I.93(d,3H), 3.71(s,3H), 6.51-6.71(m,2H), 6.91(br.d,lH), 7.21(br.s,lH), 7.61(d,lH), 7.62(br.s,lH), 7.93(s,lH), 7.99(s,lH), 8.20(d,lH) and 12.78(br.s,lH).
(d) From 3-cyano-6-[3-(E-2-car~amoylethenyl)-4-methoxy-5-(E-l-propenyl)phenyl]pyridin-2(lH)-one (0.16g), the title compound (0.08g) m.p.292-294C (decomp) after recrystallisation from dimethylformamide/ethanol/water, was prepared according to the method of Example ltb) lH NMR
~(DMSO-d6) 1.94(d,3H), 3.73(s,3H), 6.55-6.72(m,2H), 6.83(d,lH), 7.00(d,lH), 7.23(br.s,lH), 7.62(d,lH), 7.66(br.s,lH), 7.99(d,lH) and 8.48(d,lH).
ExamPl~ 56 6-(3-Cyclopropylmethyloxy-4-methoxyphenyl)pyridin-2~1H)-one (a) From 3'-hydroxy-4'-methoxyacetophenone (3.32g), 3'-cyclopropylmethyloxy-4'-methoxyacetophenone (4.34g) was prepared according to the method of Example 2(a). lH NMR
~(CDCl3) 0.34-0.40(m,2H), 0.63-0.70(m,2H), 1.28-1.43m,lH), 2.56(s,3H), 3.91(d,2H), 3.95(s,3H), 6.89(d,1H), 7.50(d,1H) and 7.56(dd,lH).
(b) From 3'-cyclopropylmethyloxy-4'-methoxyacetophenone (3.55g), 3-cyano-6-(3-cyclopropylmethyloxy-4-me~hoxyphenyl)pyridin-2(lH)-one (1.30g) m.p. 241-242C
after recrystallisation from butanol was prepared according to the method of Example 3(a).
(c) From 3~cyano-6-(3-cyclopropylmethyloxy-4-methoxyphenyl)pyridin-2(lH)-one (0.89g), the title compound (0.67g) m.p. 296-297C (decomp) after recrystallisation from butanol, was prepared according to the method of Example l(b). lH NMR ~(DMSO-d6) 0.32-0.38(m,2H), 0.57-0.66(m,2H), 1.22-1.37(m,1H), 3.85(s,1H), 3.94(d,2H), 6.88(d,1H), 7.10(d,1H), 7.39-7.48(m,2H), 8.43(d,1H) and 12.56(br.s,lH).
ExamPle 57 6-~2-methoxy-4-propoxyphenyll-3-(5-tetrazolyl)pyridin-2~1H)-one (a) From 2'-4'-dihydroxyacetophenone (50g), 2'-hydroxy-4'-propoxyacetophenone (6g) was prepared according to the method of Example 2(a), using bromopropane (40g) and acetone as solvent. lH NMR ~(DMSO-d6) 0.93((t,3H), 1.61-1.72(m,2H), 2.38(s,3H), 3.75(t,2H), 5.61(dd,lH), 5.80(d,lH) and 7.40(d,lH).
(b) From 2'-hydroxy-4'-propoxyacetophenone (6g), 2'-methoxy-4'-propyloxyacetophenone (5.18g) was prepared according to the method of Example 2(a). lH NMR ~(CDCl3) 1.05(t,3H), 1.74-l.91(m,2H), 2.57(s,3H), 3.89(s,3H), 3.97(t,2H), 6.46-6.53(m,2H) and 7.80(d,lH).) (c) From 2'-methoxy-4'-propoxyacetcphenone (5g), 3-cyano-6-(2-methoxy-4-propoxyphenyl)pyridin-2(lH)-one (0.38g) m.p.l86-188C after trituration with diethyl ether was prepared according to the method of Example 3(a). lH NMR
~(DMSO-d6) O.99(t,3H), 1.72-1.81(m,2H), 3.82(s,3H), 4.02(s,2H), 6.47(d,lH), 6.61-6.67(m,2H), 7.39(d,lH) and 8.11(d lH).
W092/06085 2 0 91~ ~ 9 PCT/GB9t/01663 (d) From 3-cyano-6-(2-methoxy-4-propoxyphenyl)pyridin-2(lH)-one (0.36g), the title compound (0.04g) m.p. >300~C
after recry~_allisation from ethanol and trituration with diethyl ether, was prepared according to the method of Example l(b). lH NMR ~(DMSO-d6 at 370K) l.OO(t,3H), 1.69-1.82(m,2H), 3.83(s,3H), 4.02~t,2H), 6.61-6.66tm,2H), 6.98(unresolved,lH), 7.55(unresolved,lH) and 8.44(unresolved,lH).
Example X
Pharmaceutical compositions for oral administration are prepared by combining the following :
% w/w 6-(3-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one 0.5 3.0 7.14 2% w/w Soya lecithin in soya bean oil 90.4588.284.41 - Hydrogenated vegetable 25 shortening and beeswax 9.058.8 8.45 The formulations are then filled into individual soft gelatin capsules.
Examvle Y
A pharmaceutical composition for parenteral administration is prepared by dissolving the title compound of Example 23 (0.02 g) in polyethylene glycol 300 (25 ml) with heating. This solution is then diluted with water for injections Ph. Eur. (to lOO ml). The solution is then sterilised by filtration through a 0.22 micron membrane filter and sealed in sterile containers.
Claims (9)
1. A compound of the formula (1) :
(1) or a pharmaceutically acceptable salt thereof, wherein :
R0 is OH or a bioprecursor thereof, R1 is 5-tetrazolyl, or a bioprecursor thereof and Ar is phenyl substituted by one to three groups independently selected from C1-6alkyl, C2-6alkenyl, C1-6alkoxy, C3-6alkenyloxy, C3-6cycloalkyl, C3-6cycloalkoxy, C1-6alkylthio, phenyl, phenylthio, benzyloxy, C1-6polyfluoroalkyl, C1-6polyfluoroalkoxy, halo, NR2, or NHCOR wherein R is H
or C1-6alkyl, or -X(CH2)nY- attached to adjacent carbon atoms of the phenyl ring wherein X and Y are independently CH2 or O and n is 1 to 3, wherein said C1-6alkyl, C2-6alkenyl or C1-6alkoxy groups can be independently substituted by OH, C1-6alkoxy, C3-6cycloalkyl, NR2, CO2R or CONR2; with the proviso that Ar is not phenyl monosubstituted by 2-C1-6alkoxy.
(1) or a pharmaceutically acceptable salt thereof, wherein :
R0 is OH or a bioprecursor thereof, R1 is 5-tetrazolyl, or a bioprecursor thereof and Ar is phenyl substituted by one to three groups independently selected from C1-6alkyl, C2-6alkenyl, C1-6alkoxy, C3-6alkenyloxy, C3-6cycloalkyl, C3-6cycloalkoxy, C1-6alkylthio, phenyl, phenylthio, benzyloxy, C1-6polyfluoroalkyl, C1-6polyfluoroalkoxy, halo, NR2, or NHCOR wherein R is H
or C1-6alkyl, or -X(CH2)nY- attached to adjacent carbon atoms of the phenyl ring wherein X and Y are independently CH2 or O and n is 1 to 3, wherein said C1-6alkyl, C2-6alkenyl or C1-6alkoxy groups can be independently substituted by OH, C1-6alkoxy, C3-6cycloalkyl, NR2, CO2R or CONR2; with the proviso that Ar is not phenyl monosubstituted by 2-C1-6alkoxy.
2. A compound according to claim 1 wherein R0 is OH or OR2 in which R2 is C1-4alkyl, arylC1-4alkyl, C1-4alkanoyl, arylsulphonyl or C1-4alkylsulphonyl.
3. A compound according to claim 1 or 2 wherein Ar is phenyl mono-substituted by a group as defined in claim 1.
4. A compound according to claim 1 or 2 wherein Ar is phenyl di-substituted by any two groups as defined in claim 1.
5. A compound according to claim 1 or 2 wherein Ar is phenyl trisubstituted by any three groups as defined in claim 1.
6. A compound according to claim 1 which is :
6-(3-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-butoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-benzyloxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-bromophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-trifluoromethyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-ethylphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(4-butoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(4-isobutylphenyl)pyridin-2(1H)-one, 6-(4-biphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(4-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3,4-methylenedioxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3,4-dichlorophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3,5-dipropoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3,5-diethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3,5-dibromophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(2,4-dipropoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(2,5-dipropoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(2,3,4-trichlorophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-[6-(1,2,3,4-tetrahydronaphthyl)]-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-chlorophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-phenylthiophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 3,4-dimethoxyphenyl-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-methylthiophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-butylthiophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3,4-di-n-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(2,3-di-n-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-cyclopentyloxy-4-methoxyphenyl)-3-(5-tetrazolyl)-pyridin-2(1H)-one, 6-(3-ethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3,5-dimethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(2-butylthiophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-allyloxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(4-methoxy-2-pentyloxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-iso-butoxy-4-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(2-bromo-3,5-diethoxyphenyl-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(5-bromo-4-methoxy-2-pentyloxyphenyl)-3-(5-tetrazolyl)-pyridin-2(1H)-one, 6-(2-allyl-4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)-pyridin-2(1H)-one, 6-[3-(E-1-propenyl)-4-methoxyphenyl]-3-(5-tetrazolyl)pyridin -2(1H)-one, 6-(4-methoxy-3-propoxyphenyl)-3-[5-(1-pivaloyloxymethyl)-tetrazolyl]pyridin-2(1H)-one, 6-(4-methoxy-3-propoxyphenyl)-3-[5-(2-pivaloyloxymethyl)-tetrazolyl]pyridin-2(1H)-one, 6-[3-ethoxy-5-(2-methoxyethoxy)phenyl]-3-(5-tetrazolyl)-pyridin-2(1H)-one, 6-[3-(2,2-dimethylpropyloxy)-4-methoxyphenyl]-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-ethoxy-4-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-propionamidophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(4-methoxy-3-propylphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-bromo-4-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-phenyl-4-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-[4-methoxy-3,5-di(E-1-propenyl)phenyl]-3-(5-tetrazolyl)-pyridin-2(1H)-one, 6-[3-(E-1-propenyl)-4-propoxyphenyl]-3-(5-tetrazolyl)-pyridin-2(1H)-one, 6-(3-bromo-4-methoxy-5-propylphenyl)-3-(5-tetrazolyl)-pyridin-2-(1H)-one, 6-(2-butylthio-3,5-diethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-bromo-4-N,N-dimethylaminophenyl)-3-(5-tetrazolyl)-pyridin-2(1H)-one, 6-(3-acetamido-4-methoxy-5-propylphenyl)-3-(5-tetrazolyl)-pyridin-2(1H)-one, 6-[3-methoxymethyl-4-methoxy-5-(E-1-propenyl)phenyl]-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-[3-(E-2-carbamoylethenyl)-4-methoxy-5-(E-1-propenyl)-phenyl]-3-(5-tetrazolyl)pyridin-2-(1H)-one, or 6-(3-cyclopropylmethyloxy-4-methoxyphenyl)pyridin-2(1H)-one or a pharmaceutically acceptable salt thereof.
6-(3-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-butoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-benzyloxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-bromophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-trifluoromethyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-ethylphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(4-butoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(4-isobutylphenyl)pyridin-2(1H)-one, 6-(4-biphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(4-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3,4-methylenedioxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3,4-dichlorophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3,5-dipropoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3,5-diethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3,5-dibromophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(2,4-dipropoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(2,5-dipropoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(2,3,4-trichlorophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-[6-(1,2,3,4-tetrahydronaphthyl)]-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-chlorophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-phenylthiophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 3,4-dimethoxyphenyl-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-methylthiophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-butylthiophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3,4-di-n-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(2,3-di-n-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-cyclopentyloxy-4-methoxyphenyl)-3-(5-tetrazolyl)-pyridin-2(1H)-one, 6-(3-ethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3,5-dimethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(2-butylthiophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-allyloxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(4-methoxy-2-pentyloxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-iso-butoxy-4-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(2-bromo-3,5-diethoxyphenyl-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(5-bromo-4-methoxy-2-pentyloxyphenyl)-3-(5-tetrazolyl)-pyridin-2(1H)-one, 6-(2-allyl-4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)-pyridin-2(1H)-one, 6-[3-(E-1-propenyl)-4-methoxyphenyl]-3-(5-tetrazolyl)pyridin -2(1H)-one, 6-(4-methoxy-3-propoxyphenyl)-3-[5-(1-pivaloyloxymethyl)-tetrazolyl]pyridin-2(1H)-one, 6-(4-methoxy-3-propoxyphenyl)-3-[5-(2-pivaloyloxymethyl)-tetrazolyl]pyridin-2(1H)-one, 6-[3-ethoxy-5-(2-methoxyethoxy)phenyl]-3-(5-tetrazolyl)-pyridin-2(1H)-one, 6-[3-(2,2-dimethylpropyloxy)-4-methoxyphenyl]-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-ethoxy-4-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-propionamidophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(4-methoxy-3-propylphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-bromo-4-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-phenyl-4-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-[4-methoxy-3,5-di(E-1-propenyl)phenyl]-3-(5-tetrazolyl)-pyridin-2(1H)-one, 6-[3-(E-1-propenyl)-4-propoxyphenyl]-3-(5-tetrazolyl)-pyridin-2(1H)-one, 6-(3-bromo-4-methoxy-5-propylphenyl)-3-(5-tetrazolyl)-pyridin-2-(1H)-one, 6-(2-butylthio-3,5-diethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-bromo-4-N,N-dimethylaminophenyl)-3-(5-tetrazolyl)-pyridin-2(1H)-one, 6-(3-acetamido-4-methoxy-5-propylphenyl)-3-(5-tetrazolyl)-pyridin-2(1H)-one, 6-[3-methoxymethyl-4-methoxy-5-(E-1-propenyl)phenyl]-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-[3-(E-2-carbamoylethenyl)-4-methoxy-5-(E-1-propenyl)-phenyl]-3-(5-tetrazolyl)pyridin-2-(1H)-one, or 6-(3-cyclopropylmethyloxy-4-methoxyphenyl)pyridin-2(1H)-one or a pharmaceutically acceptable salt thereof.
7. A compound according to any one of claims 1 to 6 for use as a medicament.
8. A pharmaceutical composition which comprises a compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier.
9. A process for preparing a compound of the formula (1) as defined in claim 1 or a pharmaceutically acceptable salt thereof which process comprises reacting a compound of the formula (2) :
(2) wherein Ar is as hereinbefore defined with an azide salt, and optionally thereafter :
° forming a bioprecursor of R0 and/or R1 ° forming a pharmaceutically acceptable salt.
10. A compound of the formula (2) as defined in
9. A process for preparing a compound of the formula (1) as defined in claim 1 or a pharmaceutically acceptable salt thereof which process comprises reacting a compound of the formula (2) :
(2) wherein Ar is as hereinbefore defined with an azide salt, and optionally thereafter :
° forming a bioprecursor of R0 and/or R1 ° forming a pharmaceutically acceptable salt.
10. A compound of the formula (2) as defined in
claim 9.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB909021184A GB9021184D0 (en) | 1990-09-28 | 1990-09-28 | Chemical compounds |
| GB9021184.8 | 1990-09-28 | ||
| GB919117657A GB9117657D0 (en) | 1991-08-15 | 1991-08-15 | Chemical compounds |
| GB9117657.8 | 1991-08-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2091989A1 true CA2091989A1 (en) | 1992-03-29 |
Family
ID=26297727
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002091989A Abandoned CA2091989A1 (en) | 1990-09-28 | 1991-09-26 | Phenylpyridinol derivatives as medicaments |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP0550576A1 (en) |
| JP (1) | JPH06501254A (en) |
| AU (1) | AU644016B2 (en) |
| CA (1) | CA2091989A1 (en) |
| IE (1) | IE913400A1 (en) |
| MX (1) | MX9101375A (en) |
| NZ (1) | NZ239946A (en) |
| PT (1) | PT99081A (en) |
| WO (1) | WO1992006085A1 (en) |
Families Citing this family (38)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9124577D0 (en) * | 1991-11-20 | 1992-01-08 | Smithkline Beecham Plc | Chemical compounds |
| GB9124578D0 (en) * | 1991-11-20 | 1992-01-08 | Smithkline Beecham Plc | Chemical compounds |
| FR2689012A1 (en) * | 1992-03-27 | 1993-10-01 | Beecham Laboratoires | Use of aryl compounds in the treatment of cardiovascular conditions. |
| GB9212673D0 (en) * | 1992-06-15 | 1992-07-29 | Celltech Ltd | Chemical compounds |
| GB9222253D0 (en) * | 1992-10-23 | 1992-12-09 | Celltech Ltd | Chemical compounds |
| US5814651A (en) * | 1992-12-02 | 1998-09-29 | Pfizer Inc. | Catechol diethers as selective PDEIV inhibitors |
| NZ257955A (en) * | 1992-12-02 | 1996-05-28 | Pfizer | Catechol diethers pharmaceutical compositions |
| US5622977A (en) * | 1992-12-23 | 1997-04-22 | Celltech Therapeutics Limited | Tri-substituted (aryl or heteroaryl) derivatives and pharmaceutical compositions containing the same |
| GB9226830D0 (en) * | 1992-12-23 | 1993-02-17 | 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 |
| 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 |
| US6245774B1 (en) | 1994-06-21 | 2001-06-12 | Celltech Therapeutics Limited | Tri-substituted phenyl or pyridine derivatives |
| US5786354A (en) * | 1994-06-21 | 1998-07-28 | Celltech Therapeutics, Limited | Tri-substituted phenyl derivatives and processes for their preparation |
| GB9412573D0 (en) | 1994-06-22 | 1994-08-10 | Celltech Ltd | Chemical compounds |
| GB9412571D0 (en) | 1994-06-22 | 1994-08-10 | Celltech Ltd | Chemical compounds |
| GB9412672D0 (en) * | 1994-06-23 | 1994-08-10 | Celltech Ltd | Chemical compounds |
| DE19500760A1 (en) * | 1995-01-13 | 1996-07-18 | Basf Ag | Substituted 2-phenylpyridines |
| GB9523675D0 (en) * | 1995-11-20 | 1996-01-24 | Celltech Therapeutics Ltd | Chemical compounds |
| GB9526246D0 (en) * | 1995-12-21 | 1996-02-21 | Celltech Therapeutics Ltd | Chemical compounds |
| GB9526245D0 (en) * | 1995-12-21 | 1996-02-21 | Celltech Therapeutics Ltd | Chemical compounds |
| GB9604926D0 (en) | 1996-03-08 | 1996-05-08 | Sandoz Ltd | Organic compounds |
| GB9608435D0 (en) * | 1996-04-24 | 1996-06-26 | Celltech Therapeutics Ltd | Chemical 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 |
| GB9625184D0 (en) * | 1996-12-04 | 1997-01-22 | Celltech Therapeutics Ltd | Chemical compounds |
| US6057329A (en) * | 1996-12-23 | 2000-05-02 | Celltech Therapeutics Limited | Fused polycyclic 2-aminopyrimidine derivatives |
| 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 |
| GB9914258D0 (en) | 1999-06-18 | 1999-08-18 | Celltech Therapeutics Ltd | Chemical compounds |
| GB9924862D0 (en) | 1999-10-20 | 1999-12-22 | Celltech Therapeutics Ltd | Chemical compounds |
| AR029489A1 (en) | 2000-03-10 | 2003-07-02 | Euro Celtique Sa | PIRIDINES, PYRIMIDINES, PIRAZINAS, TRIAZINES REPLACED BY ARILO, PHARMACEUTICAL COMPOSITIONS AND THE USE OF THE SAME FOR THE MANUFACTURE OF A MEDICINAL PRODUCT |
| PL367130A1 (en) | 2001-05-29 | 2005-02-21 | Schering Aktiengesellschaft | Cdk inhibiting pyrimidines, production thereof and their use as medicaments |
| AR036873A1 (en) | 2001-09-07 | 2004-10-13 | Euro Celtique Sa | PIRIDINAS ARIL REPLACED A, PHARMACEUTICAL COMPOSITIONS AND THE USE OF THE SAME FOR THE PREPARATION OF A MEDICINAL PRODUCT |
| AR037233A1 (en) | 2001-09-07 | 2004-11-03 | Euro Celtique Sa | PIRIDINAS ARIL REPLACED, PHARMACEUTICAL COMPOSITIONS AND THE USE OF SUCH COMPOUNDS FOR THE PREPARATION OF A MEDICINAL PRODUCT |
| US7482366B2 (en) * | 2001-12-21 | 2009-01-27 | X-Ceptor Therapeutics, Inc. | Modulators of LXR |
| JP6816763B2 (en) * | 2016-03-31 | 2021-01-20 | 住友化学株式会社 | Heterocyclic compound |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5651488A (en) * | 1979-10-02 | 1981-05-09 | Meiji Seika Kaisha Ltd | Penicillin derivative and its preparation |
| GB8809481D0 (en) * | 1988-04-21 | 1988-05-25 | Smith Kline French Lab | Chemical compounds |
| GB8923131D0 (en) * | 1989-10-13 | 1989-11-29 | Smith Kline French Lab | Chemical compounds |
-
1991
- 1991-09-26 CA CA002091989A patent/CA2091989A1/en not_active Abandoned
- 1991-09-26 AU AU85431/91A patent/AU644016B2/en not_active Ceased
- 1991-09-26 NZ NZ239946A patent/NZ239946A/en unknown
- 1991-09-26 WO PCT/GB1991/001663 patent/WO1992006085A1/en not_active Application Discontinuation
- 1991-09-26 PT PT99081A patent/PT99081A/en not_active Application Discontinuation
- 1991-09-26 EP EP91917244A patent/EP0550576A1/en not_active Withdrawn
- 1991-09-26 JP JP3515556A patent/JPH06501254A/en active Pending
- 1991-09-27 IE IE340091A patent/IE913400A1/en unknown
- 1991-09-30 MX MX9101375A patent/MX9101375A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU8543191A (en) | 1992-04-28 |
| NZ239946A (en) | 1994-09-27 |
| EP0550576A1 (en) | 1993-07-14 |
| PT99081A (en) | 1992-08-31 |
| AU644016B2 (en) | 1993-12-02 |
| MX9101375A (en) | 1992-05-04 |
| JPH06501254A (en) | 1994-02-10 |
| WO1992006085A1 (en) | 1992-04-16 |
| IE913400A1 (en) | 1992-04-08 |
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