AU644016B2 - Phenylpyridinol derivatives as medicaments - Google Patents

Phenylpyridinol derivatives as medicaments Download PDF

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Publication number
AU644016B2
AU644016B2 AU85431/91A AU8543191A AU644016B2 AU 644016 B2 AU644016 B2 AU 644016B2 AU 85431/91 A AU85431/91 A AU 85431/91A AU 8543191 A AU8543191 A AU 8543191A AU 644016 B2 AU644016 B2 AU 644016B2
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Australia
Prior art keywords
pyridin
tetrazolyl
methoxy
international
cyano
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AU85431/91A
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AU8543191A (en
Inventor
Kenneth John Murray
Roderick Alan Porter
Hunter Douglas Prain
Brian Herbert Warrington
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Smith Kline and French Laboratories Ltd
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Smith Kline and French Laboratories Ltd
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Priority claimed from GB909021184A external-priority patent/GB9021184D0/en
Priority claimed from GB919117657A external-priority patent/GB9117657D0/en
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    • 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
    • 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

Description

OPI TATE 28/04/92 AOJP DATE 11/06/92 APPLN. ID 85431 91
PCT
PCT NUMBER PCT/GB91/01663 INTERNATIONAL
(PCT)
(51) International Patent Classification 5 (11) International Publication Number: WO 92/06085 C07D 401/04, A61K 31/44 Al (43) International Publication Date: 16 April 1992 (16.04.92) (21) International Application Number: PCT/GB91/01663 (74) Agent: THOMPSON, Clive, Corporate Patents, Smith- Kline Beecham, Mundells, Welwyn Garden City, Hert- (22) International Filing Date: 26 September 1991 (26.09.91) fordshire AL7 IEY (GB).
Priority data: (81) Designated States: AT (European patent), AU, BE (Euro- 9021184.8 28 September 1990 (28.09.90) GB pean patent), CA, CH (European patent), DE (Euro- 9117657.8 15 August 1991 (15.08.91) GB pean patent), DK (European patent), ES (European patent), FR (European patent), GB (European patent), GR (European patent), IT (European patent), JP, KR, LU (71) Applicant (for all designated States except US): SMITH (European patent), NL (European patent), SE (Euro- KLINE FRENCH LABORATORIES LIMITED pean patent), US.
[GB/GB]; Mundells, Welwin Garden City, Hertfordshire AL7 IEY (GB).
Published (72) Inventors; and With international search report.
Inventors/Applicants (for US only): PORTER, Roderick, Al- Before the expiration of the time limit for amending the an [GB/GB]; MURRAY, Kenneth, John [GB/GB]; claims and to be republished in the event of the receipt of WARRINGTON, Brian, Herbert [GB/GB]; PRAIN, amendments.
Hunter, Douglas [GB/GB]; SmithKline Beecham Pharmaceuticals, The Frythe, Welwyn, Hertfordshire 6 6 4 6 AL6 9AR (GB).
(54) Title: PHENYLPYRIDINOL DERIVATIVES AS MEDICAMENTS (57) Abstract Phenylpyridinol derivatives are disclosed as medicaments.
WO 92/06085 PCr/GB9/01663 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 kinase (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, ;:E..-aggregatory, cholesterollowering, 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 0 Ar N (1) 1 R 0 or pharmaceutically acceptable salts thereof, wherein WO 92/06085 WO 9206085PCTF/GB9I /01663 -2 RO is OH or a bioprecursor thereof,
R
1 is 5-tetrazoly'l or a bioprecursor thereof, and Ar is phenyl substituted by one to three groups independently selected from CI-.
6 alkyl, C 2 6 alkenyl, C 1 6 alkoxy,
C
3 6 alkenyloxy, C 3 6 cycloalkyl, C 3 6 cycloalkoxy, Cl- 6 alkylthio, phenyl, phenylthio, benzyloxy,
C
1 6 polyfluoroalkyl, C 1 6 polyfluoroalkoxy, halo, NR 2 or NHCOR wherein R is H or C 1 6 alkyl, or -X(CH 2 )nyattached to adjacent carbon atoms of the phenyl ring wherein X and Y are independently CH 2 or 0 and n is 1 to 3, wherein said C 1 6 alkyl, C 2 6 alkenyl or C 1 6 alkoxy groups can be independently substituted by OH, C 1 6 a1]oxy, C3- 6 cycloalkyl, N~R 2
CO
2 R or CONR 2 with the proviso that Ar is not phenyl monosubstituted by 2-C 1 6 alkoxy.
Bioprecursors of the group R 0 are derivatives thereof which are convertible in vivo into the group R 0 A suitable bioprecursor of the group RO is OR 2 whe: ein
R
2 is C 1 4 alkyl, arylC...
4 alkyl (for example phenylC 1 4 alkyl such as benzyl), C 1 4 alkanoyl (for example acetyl), arylC 1 4 alkanoyl (for example phenyl C 1 4 alkanoyl such as benzoyl), arylsulphonyl (for example optionally substituted phenylsulphonyl or toluenesulphonyl) or Cl 1 4 alkylsulphonyl (f~or example methylsulphonyl).
Suitably RO is hydroxy or OR 2 preferably hydroxy.
A suitable bioprecursor of R 1 is a N-protected tetrazolyl group. Suitable N-protecting groups include pivalolyoxymethyl, propionyloxymethyl and pivaloyloxycarbonyloxymethyl.
WO 92/06085 PCT/GB91/01663 3 By the term alkyl is meant both straight- and branchedchain alkyl.
By the term C 1 -6 polyfluoroalkyl is meant a C 1 -6alkyl group having at least one hydrogen replaced with fluoro eg.
CF
3 or CF 2
CF
2
H.
Suitably Ar is phenyl mono-substituted by a group as hereinbefore defined, for example in the 2,3, or 4 positions by C_-6alkyl, C 3 6 alkenyloxy, Cl_ 6 alkylthio, phenyl, phenylthio, benzyloxy, CF 3 halo or NHCOR, or in the 3, or 4-positions with C 1 _galkoxy.
Suitably Ar is phenyl di-substituted by any groups as hereinbefore defined, for example in the or positions by groups independently selected from C2-6alkenyl, C 1 -6alkoxy,
C
3 _6cycloalkoxy, halo, -X(CH 2 )nY- or C 1 _6alkoxy C1-6 alkoxy.
Suitably Ar is phenyl trisubstituted by any groups as hereinbefore defined, for example in the 2,3,5-, or 3,4,5-positions by groups independently selected from C2_ 6 alkenyl, C 1 -6alkoxy or halo.
Examples of Cl-6alkoxy include methoxy, ethoxy, propoxy, butoxy, or pentyloxy.
Examples of C 1 -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 P C Lf C 91/166 3 2 2 03 '92 22052/ P30 140 -4 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(lH)-one, 6-(3-benzyloxyphenyl) -3-(5-tetrazolyl)pyridin-2 (1H) -one, 6-(3-bromophenyl) -3-(5-tetrazolyl)pyridin-2(FI)-one, 6-(3-trifluoromethyl) -3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(3-ethylphenyl)-3-(5-tetrazolyl)pyridin-2(I-)-one, 6- (4-butoxyphenyl) (5-tetrazolyl) pyridin-2 (1H) -one, 6- (4-isr& I' phenyl) (5-tetrazolyl) pyridin-2 (1H) -one, 6-(4-biphenyl) -3-(5-tetrazolyl)pyridin-2 (1H)-one, 6-(4-propoxyphenyl)-3-(5-tetra;oy)pyridil-2(H)-ofle, 6- (4-methoxy-3-propoxyphenyl) (5-tetrazolyl) pyridin- 2 (1H) -one, WO 92/06085 PrG9/I6 PCT/GP-9j/01663 6-(3,4-methylenedioxypheny~l)-3-(5-tetrazolyl)pyridin-2 (li) one, 6- (3 ,4-dichlorophenyl) -3-(5-tetrazolyl)pyridin-2 (1H) -one, 6- 5-dipropoxyphenyl) -3-(5-tetrazolyl)pyridin-2 (iN)-one, 6-(3,5-diethoxyphenyl)-3-(5-tetrazolyl)pyridin-2 (iN)-one, 6- 5-dibrornophenyl) k5-tetrazolyl)pyridin-2 (IN)-one, 6-(2 ,4-dipropoxyphenyi) -3-(5-tetrazoiyi)pyridin-2 (1H) -one, 6- (2 ,5-dipropoxyphenyl) (5-tetrazolyl) pyridin-2 (iH) -one, 6-(2,3,4-trichioropheny4-3-(5-tetrazoyl)pyridin-2(lH-)one, 6-[6-(1,2,3,4-tetrahydronaphthyi) 2 (iH) -one, 6- (3-chiorophenyl) (5-tetrazolyl) pyridin-2 (iH) -one, 6- (3-phenyithiophenyl) (5-tetrazoiyl)pyridin-2 (lH) -one, 3, 4-dimethoxyphernyl-3-(5-tetrazolyl)pyridin-2 (iH) -one, WO 92/06085 Pf69/16 PCF/GB91/01663 -6 6- (3-methyithiophenyl) (5-tetrazolyl)pyridin-2 (1H) one, 6- (3-butyithiophenyl) (5-tetrazolyl) pyridin-2 (iH) -one, 6- 4-di-n-prcpoxyphenyl) (5-tetrazolyl)pyridin-2 (1H) one, 6-(2 ,3-di-n-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2 (lH) one, 6- (3-cyclopentyloxy-4-methoxyphenyl) (5-tetrazolyl) pyridin-2 (1H) -one 6-(3-ethoxyphenyl)-3-(5-tetrazolyl)pyridin-2 (1H)-one, 6- 5-dimethoxyphenyl) (5-tetrazolyl) pyridin-2 (1H) -one, 6- (2-butyithiophenyl) (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) 2(11-)-one, 6-(2-bromo-3 ,5-diethoxyphenyl-3-(5-tetrazolyl)pyridii- 2(lH)-one, WO 92/06085 WO 926085PT/GB91 /01663 -7 6- (5-broro-4-methoxy-2-pentyloxphenyl) (5-tetrazolyl) pyridin-2 (lH) -one, 6-(2-allyl-4-methoxy-3-propoxyphenyl) -3-(5-tetrazolyl) pyridin-2 (1H) -one, 6-f 3-(E-1-propenyl) -4-methoxyphenyl]-3-(5-tetrazolyl)pyridi n-2 (1H) -one, 6- (4-metho,,;y-3--propoxyphenyl) -3-[5-(1-pival-oyloxynethyl) tetrazolyl) pyridin-2 (lH) -one, 6- (4-methoxy-3-propoxyphenyl) -3-f 5- (2-pivaloyloxynethyl) tetrazolyl]pyridin-2 (1H) -one, 6-[3-ethoxy-5-(2-methoxyethoxy)phenyl]-3-(5-tetrazolyl) pyridin-2 (1H) -one, 6-f 2-dimethyipropyloxy) -4-inethoxyphenylj tetrazolyl)pyridin-2 (1H) -one, 6-(3-ethoxy-4-inethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)one, 6-(3-propionamidophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6- (4-methoxy-3-propylphenyl) -3-(5-tetrazolyl)pyridin-2 (1H) one, 6-(3-bromo-4-Inethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)one, 6- (3-phen'41-4-methoxyphenyl) (5-tetrazolyl)pyridin-2 (1H) one, WO 92/06085 WO 9206085PCF/GB91/01663 8- 6- [4-methoxy-3 ,5-di (E-1-propenyl) phenylj (5-tetrazolyl) pyridin-2 (lH) -one, 6- (E-l-propenyl) -4-propoxyphenyl] -3-(5-tetrazolyl) pyridin-2 (1H) -one, 6- (3-broio-4-methoxy-5-propylphenyl) (5-tetrazolyl) pyridin-2- (lH) -one, 6- (2-butylthio-3 ,5-diethoxyphenyl) 2 (1H) -one, -omno-4-N,N-dimethylaminophenyl) -3-(5-tetrazolyl) pyridin-2 (1H) -one, 6- (3-acetamido-4-methoxy-5-propylphenyl) (5-tetrazolyl) pyridin-2 (1H) -one, 6-[3-methoxymethyl-4-methoxy-5- (E-1-propenyl)phenyl)-3- tetrazolyl)pyridin-2 (1H) -one, 6- (E-2-carbamoylethenyl) -4-nethoxy-5- (E-1-propenyl) phenyl]-3-(5-tetrazolyl)pyridin-2-(lH) -one, and 63-cyclopropylmethyloxy-,4-methoxyphenyl) ryridin-2 (1 -one and ph-armaceutically acceptable salts thereof.
This invention covers all tautcmeric, geometric and optical isomeric forms of compounds of formula In WO 92/06085 PCT/GB91/01663 -9particular when RO is hydroxy the compound can exist in its keto tautomeric form Ar Ar N NH
R
1 N
R
1
OH
Compounds of the formula 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 or a pharmaceutically acceptable salt thereof for the treatment of humans and other mammals it is normally formulw'ed in accordance with standard pharmaceutical practice as a pharmaceutical composition.
Compounds of formula 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 e.nd 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 WO 921608,51 PCr/GB91/01I.63 10 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 tarrier 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 or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for 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 WO 92/06085 PCT/GB91/01663 11 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 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 or a pharmaceutically acceptable salt thereof calculated as the free acid. The daily dosage regimen for parenteral administratio is suitably about 0.001 mg/Kg to mg/Kg, for example about 0.005 mg/Kg to 10 mg/Kg, of a compound of the formula or a pharmaceutically acceptable salt thereof calculated as the free acid. The active ingredient may ba administered as required for example from 1 8 times a day or by infusion. The compositions of the invention are agonist' 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 or a pharmaceutically acceptable salt thereof.
WO 92/06085 PCT/GB91/01663 12 The compounds of this invention ay be co-administered with other pharmaceutically active compounds, for example i7 .mbination, 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 are bronchodilators such as sympathomimetic amines for exarple isoprenaline, isoetharine, sulbutamol, phenylephrine and ephedrine or xanthine derivatives for example theophylline and aminophylline, anti-allergic agents for example disodium cromoglycate, histamine
H
1 -antagonists, drugs used in the treatment of cancer 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 ribrinolytic 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 ON (2)
NC'
OH
WO 92/06085 PCT/GB91/01663 13 wherein Ar is as hereinbefore defined with an azide salt, and optionally thereafter o forming a bioprecursor of RO and/or R 1 o forming a pharmaceutically acceptable salt.
A compound of the formula is suitably reacted with an azide salt such as ammonium, sodium, potassium or aluminium azide in an organic solvent such as dimethylformamide, dimethylsulphoxide, N-methylpyrrolidone or tetrahydrofuran at an elevated temperature e.g. 40 200°C, preferably at the reflux temperature of the reaction mixture.
A compound of the formula wherein RO is OH can be converted to the corresponding compound where RO is
OR
2 by reaction with R 2 L wherein R 2 is as hereinbefore defined and L is a leaving group such as halo e.g. bromo, chloro, iodo.
A compound of the formula 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 can suitably be prepared by reacting a compound of the formula (3) ArCOCH CHL 1 (3) wherein Ar is as hereinbefore defined and L 1 is a displaceable group, with a compound of the formula WO 92/06085 PCT/GB91/01663 14
H
2
NCOCH
2 CN (4) Suitably L 1 in a compound of the formula is hydroxy or a derivative thereof for example L 1 is protected hydroxy such as silyloxy, an acid residue (for example C 1 6 alkanoyloxy) or an ether residue (for example methoxy or ethoxy). Alternatively L 1 is a secondary amino group, for example di-Clgalkylamino such as dimethylamino or a cyclic amino group such as piperidino, pyrrolidino or morpholino. Preferably L 1 is hydroxy or dimethylamino.
Suitably an alkali metal sodium) salt of a compound of the formula wherein L 1 is hydroxy is treated with a compound of the formula under mildly alkaline aqueous conditions, for example in water in the presence of piperidine and glacial acetic acid, at an elevated temperature e.g. 30 200 0 C, preferably at the reflux temperature of the reaction mixture.
Alternatively a compound of the formula wherein
L
1 is a secondary amino group, for example dimethylamino, is treated with a compound of the formula in a suitable solvent such as dimethylformamide, a C1- 4 alkanol or pyridine at an elevated temperature e.g.
200 0 C, 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 wherein L 1 is hydroxy can suitably be prepared by reaction under basic conditions of a compound of the formula ArCOCH 3 WO 92/06085 PCr/G B91 /01663 15 wherein Ar is as hereinbefore defined, with a compound of the formula HCOL 2 wherein L 2 is a leaving group.
Suitably L 2 is ethoxy or methoxy. Conveniently a solution of a compound of the formula and a compound of the formula HCOL 2 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 wherein L 1 is hydroxy is then treated with a compound of the formula as hereinbefore described.
Compounds of the formula are known or can be prepared by methods known in the art.
Compounds of the formula wherein L 1 is a secondary amino group dimethylamino) can suitably be prepared by reacting a compound of the formula with a compound of the formula HC(OR 3 2 L wherein R 3 is Cl-4alkyl and L 1 is a secondary amino group (for example HC(OR 3 2
L
1 is N,N-dimethylformamide dimethyl or diethyl acetal), or with a compound of the formula HCL 3 where 1 1 L is a secondary amino group (for example HCL is trisdimethylaminomethane).
Alternatively a compound of formula can be prepared by demethylarion of a compound of formula WO 92/06085 PCT/GB91/01663 16 Ar NCA (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. 30-80 0 C) or ambient temperature or sodium thiomethoxide in an organic solvent such as dimethylformamide at an elevated temperature, for example 40-120 0
C.
The Ar group in compounds of the formula or preferably or 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- 6 alkoxy) 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).
WO 92/06085 PCT/GB91/01663 17 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 C 1 -6alkyl halide to form a C1-6alkoxy 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 to a compound of formula as hereinbefore described if such a base is used. An E-1-propenyl group can be cleaved to a formyl group by reaction with an oxidising agent such as N-methylmorpholine-N-oxide in the presence of a catalyst such as osmium tetroxide to form a 1,2,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 C 1 6_alkyl halide to form a Cl-6alkoxymethyl group. Alternatively a formyl group can be reacted with a suitable Horner Wittig or Wittig reagent such as (R 4 0) 2 P(O)Ch 2 CO2R 4 or Ph 3
P=CHCO
2
R
4 wherein R 4 is Cl-4alkyl to form a
CH=CHCO
2
R
4 group which can be optionally hydrolysed to a -CH=CHCO 2 H group. A -CH=CHCO 2
R
4 group can be converted to a -CH=CHCONR 2 group by reaction with an amine HNR 2 or a chemical equivalent thereof wherein R is as hereinbefore defined. Alternatively a -CH=CHCO 2
H
group can be converted to an acid halide, eg. the acid chloride by reaction with oxalyl chloride, which can then WO 92/06085 PCT/GB91/01663 18 be reacted with an amine HNR 2 or a chemical equivalent thereof. An example of a chemical equivalent is ammonium hydoxide which will form a CH=CHCONH 2 group.
A compound of formula is suitably prepared by reacting a compound of formula wherein Ar is as hereinbefore defined with an O-methylating agent such as dimethylformamide dimethylacetal in dimethylformamide or trimethylphosphite at an elevated temperature (eg.
40-120 0
C).
Pharmaceutically acceptable base addition salts of the compounds of the formula may be prepared by standard methods, for example by reacting a solution of the compound of the formula with a solution of the base.
The following biological test methods, data and Examples serve to illustrate this invention.
Cyclic-AMP Protein Kinase (cA-PrK) Aqonist Activity Type II cA-PrK was prepared from the cardiac muscle of a cow. The supernatant from a muscle homogenate (3 mis 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 30 0 C for 5 minutes with 32 P]-adenosine triphosphate and a suitable peptide substrate such as malantide (Malencik et al., 1983, Anal. Biochem., 132, 34-40). The reaction was WO 92/06085 PCr/GB91/01663 19 terminated by the addition of hydrochloric acid and the 32 P]-phosphopeptide quantified by spotting the reaction mixture onto phosphocellulose papers. The concentration of compound required to give 10% phosphotransferase activation is given as the EC 10 (pfM). The compounds of Examples 1 to 26 had EC 10 values in the range 10 130 pM.
Inhibition of Platelet Aggregation Human platelet-rich-plasma was separated from freshly drawn blood (in acid/citrate/dextrose) and treated with 100 pM acetylsalicylic acid for 15 minutes at 37 0 C. A washed platelet suspension was then prepared in a Hepes-isotonic saline buffer after a single centrifugation step and adjusted to a concentration of 1.5x10 8 cells/ml. Aliquots of this suspension were pre-incubated with compounds for 5 minutes at 37 0 C, then challenged with pM U46619. The extent of aggregation after 2 minutes were expressed as a percentage of control and results obtained are expressed as an IC 50 (concentration to cause 50% inhibition of platelet aggregation, pM).
The compounds of Examples 2, 4, 5, 11-13, 15, 19-23, and 25-26 had IC 50 values in the range 0.8-300 pM.
Anti-proliferative activity Compounds under test were dissolved in dimethylsulphoxide 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 pM 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 37 0 C and 10% CO 2 atmosphere. On day 5, tetrazolium WO 92/06085 PCT/GB91/01663 20 reagent (50 pg MTT/250 pl total medium volume) was added for 16 20 hours. Insoluble formazan was dissolved in 150 pl 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. IC 50 values (concentration that show 50% growth inhibition) were determined from the dose response curves. (Cancer Res., 48, 589-601, 1988). In the cell line SW-620 the compound of Example 23 had an
IC
50 value in the range 56 90 pM. In the cell line NRK-52 the compound of Example 23 had an IC 50 value in the range 46 48 pM. In the cell line HT-29 the compound of Example 23 had an IC 50 value in the range of 66 M.
Inhibition of Spontaneous Contraction in Guinea-Pig 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 contraction is given as the EC 50 The compounds of Examples 15-17 and 23 had EC 5 0 values in the range 2 25 1 iM.
WO 92/06085 PCT/GB91/01663 21 Bronchodilatation 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 spontaneously 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
IC
50 The compounds of Examples 5 and 23 had IC 50 values of 11 and 6.5 VM respectively.
Measurement of cardiac muscle relaxation time in rabbit ventricle 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 30-100 pM, 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 92/06085 WO 9206085PCT/GB91/01663 22 3-Methoxyphenyl) (5-tetrazolyl) pyridin-2 (iR)-one a) 3'-Methoxyacetophenone (l5g) and dimethylformamide dimethylacetal (l6ml) were heated together at 1200C in dimethylformamide (B0ml) for 6 hours, the deep red solution was diluted with ethyl acetate (400m1), washed with water (5xlO~ml), dried (MgSO 4 and solvent removed at reduced pressure. The oil obtained was dissolved in dimethylformamide (80m1), cyanoacetamide (10. 08g) and sodium methoxide (10.8g) added and the mixture heated at 130 0 C for 35 minutes. The deep red solution was poured into 5% aqueous acetic acid (400m1), the precipitated product collected by filtration and washed with water, ethanol and diethyl ether. Recrystallisation from n-butanol gave 3-cyano-6- (3-methioxyphenyl) pyridin- 2(1H)-one (15.14g) 1n.p. 251 0 C as a colourless ulid.
b) 3-Cyano-6-(3-methoxyphenyl)pyridin-2 (1H) -one (1g) sodium azide (0.39g) and ammnoniumn chloride (0.32g) were heated together in N-methylpyrrolidin-2-one (l0mi) at 140 0 C for 2hours. The reaction mixture was poured into aqueous acetic acid (150Ml) the precipitated solid collected by filtr ation, washed with water and recrystallised from n-butanol to give the title compound (0.93g) m.p. 298 0 C (decomp). 1 IH NM'R &(DMSO-d 6 3.87(s,3H), 6.92(d,lH), 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 WO 92/06085 PCT/GB91/01663 23 3 '-Hydroxyacetophenone (13. 6g), iodopropane (10. 7m1) and potassium carbonate (13.8g) were heated together in dimethylformamide (80m1) at 90 0 C for 20hrs. The reaction mixture was diluted with ethyl acetate (400m1), washed with 2N sodium hydroxide (2xlOOml) and water (4xlOOml), dried (MgSO 4 filtered and solvent removed at reduced pressure to give 3'-propoxyacetophenone (16.46g) as an oil. 1 H NNR S(DMSO-d 6 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,3JH).
The following compounds were similarly prepared from the appropriate phenol and alkyl iodide.
3'-Butoxyacetopheno,- oil, yield SSW%, 1H N1'R S(DMSO-d 6 0.94(t,3H), l.37-1.52(m,2H), l.66-1.77(m,2H), 2.57(s,3i), 4.02(t,2i), 7.19(dd,1H) and 7.39-7.55(m,3H).
31-Benzyloxyacetophenone:- oil, yield 89-0, 1H1 N4I S(CDCl 3 2.57(s,3i), 5.09(s,2H), 7.17(dd,1H) and 7. 29-7 .56 8H).
4' -Methoxy-3 '-propoxyacetophenone from 3' -hydroxy-4 iethoxyacetophenone:- Brossi et al U. Org. Chem., 1967, 32, 1269) :-oil, yield 71%, 1Hi NMYR S(CDCl 3 l.05(t,3H), 1.87(in,2H), 2.56(s,3H), 3.93(s,1H), 6.88(d,lH), 7.52(d,1H), and 7.57(dd,lH).
3',51-Dipropcoxyacetophenonie:- oil, yield 58%, 1
H
NMR &(DMSO-d 6 0.98(t,6H) l.66-1.80(in,4H), 2.55(s,311), 3.96(t,4H), r,.73(t,lH) and 7.04(d,2H).
oil, yield 64%, 1 H NMR 8(DMSO-d 6 l.42(t,6H), 2.56(s,3H), 4.05(q,4H), 6.64(t,lH) and 7.07(d,2H).
WO 92/06085 WO 9206085PCr/GB9I /01663 24 oil, yield 64%, 1 Hi NNIR S(DMSQ-d 6 0.96(t,3H), 1.04(t,3H), l.62-1.84(m,4H), 2.55(s,3H), 3,88(t,2H), 3.99(t,2H) and 7.03-7.11(m,3H).
3',4'-Dipropoxyacetophenone:- yield 95%, IH NMR &(CDC1 3 1.00-1.19(m,6H), l.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,1H).
3-1-Allyloxyacetophenone:- oil, yield 71%, IH NMRS(CDC1 3 2.58(s,3H), 4.57(d,2H), 5.27-5.47(m,2H), 5.96-6.15(m,lH), 7.12(dd,1H), 7.31(t,1H) and 7.49-7.55(m,2H).
4' -Methox j-2' -pentyloxyacetophone: -From 4' -methoxy-2' hydroxyacetophenone and iodopentane, yield 92%, IH NNR &(DMSO-d 6 )O.86(t.3H), l.20-1.47 m,4H), 1.74-1.85(m,2H), 2.49(s,3H), 3.82(s,3H), 4.09(t,2i), 6.56-6.62(m,2H) 'and 7.66(d,1H).
3 '-iso-Butoxy-4 '-methoxyacetophenone: -From 4 '-methoxy-3 '-hydroxyacetophenone and iso-butyl bromide using acetone as solvent, yield 68%. 1 H NMR S(DMSO-d 6 0.99(d,6H), 1.96-2.15(m,1H), 2.53(s,3H), 3.78(d,1H), 3.8C(s,3H), 7.06(d,1H), 7.42(d,lH) and 7.62 (dd,1H).
3 '-Allyloxy-4 '-methoxyacetophenone: -From 4'-methoxy-3'-hydroxyacetophenone and allyl bromide, yield 67%, 1 H NNR &(CDCl 3 2.55(s,3H), 3.95(s,3H), 6.90(d,lH),7.53(d,IH) and 7.60(dd,lH).
-dimethylpropyloxy) -methoxyacetophenone: -Fr m 4'-methoxy-3'-hydroxyacetophenone and l-bromo-2,2dimethyipropane, yield 76%, IH NMR S(CDC1 3 WO 92/0608 5 WO 92/608 SPCU/GB9I /01663 25 1.07(s,9H), 2.56(s,3H), 3.69(s,2H), 6.88(d,lH) and 7.50-7.58(m,2H).
3' -ethoxy-4' -methoxyacetophenone: -from 3'-hydroxy-4'-methoxyacetophenone and iodoethane using acetone as solvent, yield 83%, IH NM~R S(CDCl 3 -7.60 (m,2H).
3 '-Allyl-4 '-methoxyacetophenone: -from 3'-allyl-4'-hydroxyacetophenone, yield 87% as an oil.
1H 6 (CDCl 3 )2.55(s,3H) ,3.40(d,*2H) ,3.89(s,3H), 5.02-5.l0(m,2H), 5.90--6.04(m,1H),6.88(d,lH),7.77(d,1H) and 7.85 (dd,1H).
From 3'-propoxyacetophenone 3-cyano-6-(3propoxyphenyl)pyridin-2(1H)-one (3.49g) m.p. 240-241 0
C
after recrystallisation from ethanol, was prepared according to the method of Example 1(a).
From 3-cyano-6-(3-propoxyphenyl)pyridin-2 (iN)-one the title compound (0.61g) m.p. 270-271 0 C after recrystallisation from n-butanol, was prepared according to the method of Example 1(b).
Example 3 6- (3-Butoxyphenyl) (5-tetrazolyl) pyridin-2 (IT-i)-one 3'-Butoxyacetophenone (17.3g) and dimethylformamide dimethylacetal (11..9g) were boiled together in dimethylformamide (90m1) 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 WO 92/ 06085 PCT/GB9I /01663 -26 poured into 10% aqueous acetic acid (300m1) 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.
201-202 0
C.
From 3-cyano-6- (3-butoxyphenyl)pyridin-2 (1H) -one (2.15g), the title compound (0.55g) m.p. 259-260 0 C after recrystallisation from n-butanol, was prepared according to the method of Example 1(b).
Example 4 6- (3-Benzyloxyphenyl) (5-tetrazolyl) pyridin-2 (31) -one From 3' -benzyloxyphenylacetophenone (20. 2g), 3-cyano-6- (3-benzyloxyphenyl)pyridin-2 (1H) -one 6g) m.p.202-203 0 C after recrystallisation from ethanol, was prepared according to the method of Example 3(a).
From 3-cyano-6- (3-benzyloxyphenyl)pyridin-2 (1H) -one the title compound (0.35g) m.p.276 0 C (decomp) after recrystallisation from dixethylformamide was prepared according to the method of Example 1 H NMR S(DMSO-d 6 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,1H).
Examrtle 6-(3-Bromophenyl) (5-tetrazolyl)pyridin-2 (1H) -one From 3'-bromoacetophenone (13.2g), 3-cyano--6-(3bromophenyl)pyridin-2(1H)-one (21.8g) m.p. 309 0 C (decornp) after recrystallisation from n-butanol, was prepared WO 92/06085 PCr-/GB91/01663 -27 according to the method of Example 1 H NMR S(DMSO-d 6 6.89(br s,1H), 7.48(t,1H), 7.75(d,lH), 7.83(d,lH), 8.06(s,lH), 8.21(d,1H) and 12.75(br s,lH).
From 3-cyano-6- (3-bromophenyl)pyridin-2 (11)-one (l.37g), the title compound (0.39g) m.p. 285-286 0 C after recrystallisation from dimethylformamide, was prepared according to the method of Example 1(b).
Example 6 6- (3-Trifluoromethyl) (5-tetrazolyl) pyridin-2 (11)-one From 3'-trifluoromethylacetophenone 3-cyano- 6-(3-trifluoromethylphenyl)pyridin-2 (lH)-one (11.38g) m.p.255-256 0 C after recrystallisation from ethanol, was prepared according to the method of Example 3(a).
From 3-cyano-6- (3-trifluoromethylphenyl) pyridin- 2(lH)-one (1.06g), the title compound (0.93g) m.p.274-275 0 C after recrystallisation from n-butanol, was prepared according to the method of Example 1(b).
Example 7 6- (3-Ethylphenyl) -3-(5-tetrazolyl)pyridin-2(111)-one From 3'-ethylacetophenone 3-cyano-6-(3ethylphenyl)pyridin-2(lH)-one (3.97g) m.p.241-242 0 C after recrystallisation from n-butanol, was prepared according to the method of Example 3(a).
From 3-cyano-6-(3-ethylphenyl)pyridin-2(lH)-one (0.89g), the title compound (0.37g) m.p.278-279 0 C after 9 1/0166 3 22052/P30140 2 2 06 92 28recrystallisation from n-butanol, was prepared according to the method of Example 1(b).
Example 8 6- (4-Butoxyphenyl) -3-(5-tetrazolyl)pyridin-2 (1H) -one From 4 '-butoxyacetophenone 6g), 3-cyano-6-(4butoxyphenyl)pyridin-2(1H)-one (1.12g) m.p. 245 0 C after recrystallisation from ethanol, was prepared according to the method of Example 1(a).
A mixture of 3-cyano-6-(4-butoxyphenyl)pyridin- 2(111)-one sodium azide (0.098g), ammon.ium chloride (0.08g) and lithium chloride (C.064g) were heated in dimethylformamide (15m1) at 120 0 C for 72 hours. Solvent was removed at reduced pressure, the product precipitated by the addition of 10% aqueous acetic acid (40m1) and separated by filtration. The solid was dissolved in 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.289-292 0
C.
Example 9 6-(4-isoButylphenyl)-3- (-5-tetrazolyl) pyrid.in-2 (1H) -one From 4'-isobutylacetophenone 3-cyano-6-(4isobutylphenyl)pyridin-2(lH)-one (6.0g) m.p. 264 0 C after recrystallisation from ethanol, was prepared according to the method of Example 3(a).
WO 92/06085 PCT'/GB9I /01663 29 From 3-cyano-6-(4-isobutylphenyl)pyridin-2 (1H) -one (2.52g), the title compound (l.54g) m.p. 275 0 C (decomp) after recrystallisation from dimethylformamide, was prepared according to the metho~d of Example 1(b) but using dimethylformamide instead of N-methylpyrrolidin-2-one as solvent. 1 H NMR1 S(DMSO-d 6 Q.89(d,6H), 1.81-1.96 2.51(rn,2H), 6.87(d,lH), 7.33(d,2H), 7.78(d,2H), 8.46(d,lH) and 12.63(br s,lH).
Exam~le 6- (4-Biphenyl) -3-(5-tetrazolyl) pyridin-2 (1H) -one From 4-acetylbiphenyl (19.6g), 6-(4-biphenyl)-3cyanopyridin-2(lH)-one (14.01g) m.p. 312-316 0 C after recrystallisation from n-butanol, was prepared according to the method of Example 1(a).
From 6-(4-biphenyl)-3-cyanopyridin-2(lH)-one (1.36g), the title compound (0.84g) m.p. 305 0 C (decomp) after recrystallisation from dimethylformamide, was prepared according to the method of Example 1 H NM4R S(DMS0-d 6 7.00(d,lH), 7.41-7.54(m,3H), 7.77(d,2i), 7.85(d,2H), 7.98(d,2H) and 8.50(d,lH).
Example 11 6-(4-Propoxyphenyl) -3-(5-tetrazolyl)pyridin-2 (211)-one From 4'-propoxyacetophenone (15.4g) Eckhart and J. Varga, Magyar. Kern. Folvoirat 1961, 67, 509, Chem Abs. 1962, 56, 15557e), 3-cyano-6-(4-propoxyphenyl)pyridin-2(lH)-one (1.8g) m.p.
262-265 0 C after recrystallisation from dimethylformamide, WO 92/06085PT/BI'16 PCF/GB91/01663 30 was prepared according to the method of Example 3(a).
From 3-cyano-6- (4-propoxyphenyl)pyridin-2(lH) -one the title compound (0.85g) 292 0 C (decomp) after recrystallisation from dimethylformamide, was prepared according to the method of Example 1 H NMR &(DMSO.-d 6 0.99(t,3H), 1.63-1.84(ma,2H), 4.02(t,2H), 6.81(d,lH), 7.07(d,2H), 7.82(d,2H) and 8.45(d,lH).
Example 12 6- (4-Methoxy-3-propoxyphenyl) (5-tetrazolyl) pyridin- 2(111)-one From 4 '-methoxy-3 '-propoxyacetophenone (12g), 3-cyano- 6-(4-rethoxy-3-propoxyphenyl)pyridin-2 (lH) -one (14. 03g) m.p. 241 0 C after recrystallisation from ethanol, was prepared according to the method of Example 3(a).
From 3-cyano-6- (4-methoxy-3-propoxyphenyl) pyridin- 2(l1i)-one (3.12g), the title compound (1.69g) m.p.
289-290 0 C after recrystallisation from n-butanol, was prepared according to the method of Example 1(b).
Example-13 6- (3,4-Methylenedioxyphenyl) -3-(5-tetrazolyl) pyridin- 2(111)-one From 3' ,4'-(methylenedioxy)acetophenone (16.4g), 3-cyano--6-(3, 4-methylenedioxyphenyl)pyridin-2 (lH) -one (10.2g) m.p. >320 0 C after recrystallisation from dimethylformamide, was prepared according to the method of Example -Ii NMRP 6(DMSO-d 6 6.13(s,2H), 6.72(d,lH), 7.06(d,lH), 7.36-7.42(m,2H), 8.13(cl,lH) and 12-58(br s,lH).
WO 92/06085 PCr/GB9I /01663 -31 From 3-cyano-6- 4-methylenedioxyphenyl) pyridin- 2(lH)-one (0.96g), the title compound (0.1g) m.p. >325 0
C
after recrystallisation from ethanol, was prepared according to the method of Example 1(b) but using dimethylformamide instead of N-methylpyrrolidinone as solvent. IH-NMR S(DMSO-d 6 6.14(s,2H), 6.83(d,1H), 7.08(d,lH),7.37-7.46(m,2H), 8.43(d,lH), 12.55(br s,lH) and 13. 28 (br s,l1H) Example 14 6- (3 ,4-Dichiorophenyl) (5-tetrazolyl) pyridin-2 (1H) -one From 3',4'-dichloroacetophenone (18.9g), 3-cyano-6-(3, 4-dichlorophenyl)pyridin-2 (lH) -one 94g) m.p. >330 0 C after recrystallisation from dimethylformamide, was prepared according to the method of Example lIH NM~R S(DMSO-d 6 6.97(br d,lH),.7.76-7.87 8.15(s,lH) and 8.23(d,1H).
From 3-cyano-6-(3,4-dichlorophenyl)pyridin-2 (lH) -one (1.06g), the title compound (0.54g) m.p.295 0 C (decomp) after recrystallisation from dimethylformamide, was prepared~ according to the method of Example 1(b) but using dimethylformamide instead of N-methylpyrrolidinone as solvent. 1 H N14R &(DMSO-d 6 7.02(d,lH) 7.76-7.89 8.17(s,1H) and 8.48(s,1H).
Example 6- 5-Dipropoxyphenyl) -3-(5-tetrazolyl)pyridin-2 -one From 3' ,5'-dipropoxyacetophenone (11.82g), 3-cyano-6- (3,5-dipropoxyphenyl)pyridin--2(lH)-one (7.1g) m.p.
WO 92/06085 WO 9206085PCTF/GB91/01663 32 209-2100C after recrystallisation from ethanol, was prepared according to the method of Example 3(a).
From 3-cyano-6-(3,5-dipropoxyphenyl)pyridin-2 (lH) -one (1.25g), the title compound (1.31g) m.p.224-225 0 C after recrystallisation from n-butanol, was prepared according to the method of Example 1(b).
Example 16 6- (3,5-Diethoxyphenyl) (5-tetrazolyl) pyridin-2 (11) -one From 3' ,5'-diethoxyacetophenone 16g), 3-cyano-6- (3,5-diethoxyphenyl)pyridini-2(1H)-one (1.0g) m.p.259-261 0
C
after recrystallisation from n-butanol, was prepared according to the method of Example 3(a).
From 3-cyano-6-(3,5-diethoxyphenyl)pyridin-2 (lH) -one (0.82g), the title compound (0,57g) m.p. 282-283 0 C after recrystallisation from n-butanol, was prepared according to the method of Example 1(b).
Example 17 6- 5-Dibromophenyl) (5-tetrazolyl) pyridin-2 (1H) -one From 3',5'-dibromoacetophenc-ne Tashiro, S Mataka, H. Nakamura and K Nakayama, J. Chem. Soc. Perkin Trans I., 1988, 179) (1.11g), 3-cyano-6-(3,5-dibromophenyl)pyridin- 2(lH)-one (0.73g) m.p. >300 0 C after recrystallisation from n-butanol, was prepared according to the method of Example 1 H NMIR &(DMSO-d 6 7.00(br d,lH), 8.02(s,1H), 8.09(s,2H) and 8.23(d,lH).
WO 92/06085 PCT/GB9I /01663 -33 From 3-cyano-6-(3 ,5-dibromophenyl) pyridin-2 (11fl -one (0.53g), the title compound (0.15g) m.p. 295-296 0
C
(decomp) after recrystallisation from n-butanol was prepared according to the method of Example 1H NMR S(DMSO-d 6 7.l0(br d,1H), 8.02(s,1H), 8.13(s,2H) and 8.47(d,lH).
Example 18 6- (2,4 -Dipropoxyphenyl) (5-tetrazolyl) pyridin-2 (11) -one From 2',4'-dipropoxyacetophenone (17.9g) (P.
Chabrier, H. Najer, R. Giudicelli and E. Joannie-Voisinet, Bull. Soc. Chim. France, 1958, 1488.), 3-cyano-6-(2,4dipropo.,yphenyl)pyridin-2(lH)-one (1.69g) m.p. 1480C after recrystallisation from ethanol, was prepared according to the method of Example 3(a).
From 3-cyano-6-(2, 4-dipropoxyphenyl~pyridin-2 (lH) -one the title compound (0.60g) m.p. 205 0 C after recrystallisation twice from ethanol, was prepared according to the method of Example 1(b).
Example 19 6- (2,5-Dipropoxyphenyl) (5-tetrazolyl) pyridin-2 (1H) -one From 2' ,5'-dipropoxyphenylacetophenone (11.8g), 3-cyano-6- 5-dipropoxyphenyl'pyridin-2 (lH) -one (14. 36g) m.p. 160-162 0 C after recrystallisation from ethanol, was prepared according to the method of Example 1 H NMR &(DMSO-d 6 0.92(t,3H), 0.97(t,3H), l.61-l.76(m,4H), 3.92(t,4H), 6.54(d,lH), 7.01-7.06(m,3H), 8.18(d,1H).
WO 92/06085 PCr/GB9I /01663 34 From 3-cyano-6-(2, 5-dipropoxyphenyl)pyridin-2 (1H) -one the title compound (0.81g) m.p.,188-189 0 C after recrystallisation from ethanol, was prepared according to the method of Example 1(b).
Exainle 6- (2,3 ,4-Trichlorophenyl) -3-(5-tetrazolyl)pyridin-2 (11)-one 2' ,4'-Trichloroacetophenoiie (22.15g) and dimethylformamide (12.5g) were boiled in diinethylformamide (lO0ml) for 3 hours. The solution was diluted with ethyl acetate (500m1), washed with water (6x100m1), dried (MgSO 4 filtered and solvent removed at reduced pressure. The residue was triturated with diethyl ether to give 3--N,N-dimethylamino-l- 4-trichlorophenyl) prop- 2-ene-I-one (17.5g). 1H NMR &(DMSO-d 6 2.84(s,3H), 3.08(br s,3H), 5.17(d,1H), 7.1(very br,1H), 7.30(br d,1H) and 7.65(d,1H).
A solution of 3-N,N-dimethylamino-l-(2,3,4trichlorophenyl) prop-2-ene-l--one 8g) and cyanoacetamide (3.18g) in dimethylformamide (35m1) was boiled for 48 hours. The reaction mixture was poured into 10% aqueous acetic acid (lQ0ml), the precipitated product separated by filtration and recrystallised from ethanol to give 3-cyano-6- 4-trichlorophenyl)pyridin-2 (lH) -one 1 H NMR &(DMSO-d 6 6.52(d,lH),7.58(d,lH), 7.79(d,lH), 8.24(d,1H) and 12.95(br s,1H).
From 3-cyano-6-(2 ,3 ,4-trichlorophenyl)pyridin- 2(1H)-one the title compound (1.21g) m.p.>300 0
C
after reczrystallisation from dimethylformamide/water, was prepared according to the method of Example 1 H NMR~ S(DMSO-d 6 6.63(d,1H-), 7.61(d,1H), 7.83(d,lH), WO 92/06085 WO 9206085PCT/GB91/01663 35 8.51(d,lH) and 12.98(br s,1H).
Example 21 6-[6-(1,2,3,4-Tetrahydronaphthyl) 2(11U)-one From 6-acetyltetralin (4.23g), 3-cyano-6-[6-(1,2,3,4tetrahydronaphthyl) ]pyridin-2 (1H) -one 27g) m.p.
245-246 0 C after recrystallisation from n-butanol, was prepared according to the method of Example 3 1H NMR &(DMSQ-d 6 1.75(m,4H), 2.77(m,4H), 6.71(d,1H), 7.19 7.50(d,1H), 7.53(s,1H) and 8.15(d,lH).
From 3-cyano-6-[6-(1,2,3,4-tetrahydronaphthy.)pyridin- 2(11-)-one the title compound (0.55g) m.p. 284-285 0
C
after recrystallisation from dimethylformamide/water ,was prepared according to the method of Example 1(b).
Example 22 6- (3-Chiorophenyl) (5-tetrazolyl) pyridin-2 (1H) -one From 3'-chloroacetophenone (15.46g), 6-(3-chlorophenyl)-3-cyanopyridin-2(lH)-one (17.12g) m.p. 304-305 0
C
after recrystallisation from n-butanol was prepared according to the method of Example 3(a).
From 6-(3-chlorophenyl)pyridin-2(lH)-one the title compound (1.O1g) m.p. 301-302 0 C (decomp) after recrystallisation from n-butanol, was prepared according to the method of Example 1 H NM? &(DMSO-d 6 6.94(d,1H), 7.48-7.62(m,2H), 7.81(d,lH), 7.96(s,lH), 8.48(d,li) and 12.77(br s,1H) WO 92/06085 WO 9206085PCr/GB9I /01663 36 Example 23 6-(3 -Phenyithiophenyl) (5-tetrazolyl) pyridin-2 (lH) -one 3'-Phenylthioacetophenone (2.05g) Victor, Brit.
Pat. 1,519,354) and dimethylformamide dinethylacetal (1.19g) were heated together in dimethylformamide at 1000C for 18 hours. The reaction mixture was diluted with ethyl acetate (50m1) washed with water (6x30m1), dried (MgSO 4 filtered and solvent removed at reduced pressure. The residue was column ciromatographed (silica gel, dichloromethane-5% ethanol/dichioromethane eluant) to give 3-N,N-dimethylamino-l-(3-phenylthiophenyl) prop-2-ene-1-one (1.72g) as a yellow oil.
A mixture of 3-N,N-dimethylamino-1-(3-phenylthiophenyl)prop-2-ene-1-one (1.72g), sodium methoxide (0.76g) and cyanoacetamide (0.59g) were boiled together in dimethylformanide (l0ml) for 1 hour. The reaction mixture was poured into 10% aqueous acetic acid (lO0ml), the precipitated product separated by filtration and recrystallised from ethanol to give 3-cyano-6-(3phenylthiophenyl)pyridin-2(lH)-one (1.0g) P-p. 262-264 0
C.
From 3-cyano-6- (3-phenylthiophenyl)pyridin-2 (1H) -one (0.79g), the title compound (0.77g) m.p.265-266 0 C after recrystallisation from n-butanol, was prepared according to the method of Example 1(b).
Example 24 3, 4-Dimethoxyphenyl-3-(5-tetrazolyl)pyridin-2 (1H) -one From 3',4'-Dimethoxyacetophenone (18g), 3-cvano-6- WO 92/06085 PTG9/16 37 (3,4-dimethoxyphenyl)pyridin-2(1H)-one (9.86g) m-p.
269-270 0 C after recrystallisation from ethanol, was prepared according to the method of Example 1(a).
From 3-cyano-6- (3 ,4-dimethoxyphenyl)pyridin-2 (lH) -one (1.02g), the title compound (0.02g) m.p. 293-295 0 C after recrystallisation from dimethylformamide, was prepared according to the method of Example 1(b).
Example 6-(3-Methylthiophenyl) -3-(5-tetrazolyl)pyridin-2 (11)-one From 3'-methylthioacetophenone (4.64g), 3-cyano-6- (3-methylthiophenyl)pyridin-2(1H)-one (4.3g) m.p.234-238 0
C
after recrystallisation from ethanol, was prepared according to the method of Example 3(a).
From 3-cyano-6- (3-methylthiophenyl) pyridin-2 (1H) -one the title compound (0.85g) m.p.274-276 0 C (decomp) after recrystallisation from n-butanol, was prepared according to the method of Example IH NI4R &(DMSO-d 6 2.58(s,3H), 6.91(d,lH), 7.39-7.63(m,3H), 7.69(s,lH) and 8.47(d,lH).
Exatmple 26 6- (3-Butylthio, .henyl) (5-tetrazolyl) pyridin-2(111)-one Copper-(I) -n-butylmercaptide Adams, W. Reijschneider and A. Ferretti, Org, Syn. Coil. Vol., V, p1O7) (3.34g) and 3-cyano-6-(3-bromophenyl)pyridin- 2(lH)-one (2.61g) were heated together in a mixture of quinoline (l0ml) and pyridine (3m1) at 160 0 C for 4 hours.
WO 92/06085 WO 9206085PCr/GB9]/01663 38 The reaction mixture was poured onto conc. hydrochloric acid (30m1) and ice (1b0g) 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 (11)-one m.p. 191-1930C after recrystallisation from ethanol.
From 3-cyano-6- (3-butylthiophenyl)pyridi4n-2 (1H) -one (0.23g), the title compound (Q.1lg) m.p.237-238 0 C after recrystallisation from n-butanol, was prepared according to the method of Example 1(b).
Example 27 6- (3 ,4-Di-Propoxyphenyl) -3-(5-tetrazolyl)pyridin-2 (1H) one From 31,4 '-di-propoxyacetophenone (3.6Eg) 3-cyano-6-(3 ,4-d-"prcpoxyphenyl)pyridin-2 (1H) -one (3 .21g) m.p. 249 0 C after recrystallisation from ethanol, was prepared according to the method of Example 3(a).
From 3-cyano-6-(3 ,4-di-propoxyphenyl) pyridin-2(1H)-one (1.00g) the title compound 280 0
C
(decomp) af'..er recrystallisation from n-butanol,was prepared according to the method of Example 1 H NMR &d 6 -DMSO) 0.97-l.05(m,6H), l.71-1.81(m,4H), 4.01(t,2H): 4.03(t,2H) 6.88(d,1H) 7.09(d,lH), 7.43(d,1H), 7.46(s,1H) and 8.44(d,1H) and 12.61(br.s,lH).
Example 28 6- (2 ,3-di-Propoxyphenyl) (5-tetrazolyl) pyridin-2 (lii) one WO 92/06035 PTG9/16 PCT/GB91/01663 39 From 2, 3-dihydroxybenzaldehyde (20g), 2, 3-di-propoxybenzaldehyde (18.6g) isolated as an oil was prepared according to the method of Example IH-NI4R S(CDCl 3 l.04(t,3H), 1.09(t,3H), l.74-l.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) .tetrahydrofuran at -780C methyl lithium (61m1, 1.5M in ichlether) was added over 10 minutes. The reaction mixture was stirred at -78 0 C for two hours and at room temperature for 16 hours. After quenching with water the organic phase was separated, dried (MgSO 4 and solvent removed to give 1- 3-di-propoxyphenyl) -l-hydroxyethane (20g) as an oil. 1 H 14R &(CDCl 3 1.04(t,3H), 5.15(m,1H), 6.80(m,lH) and 6.95-7.04(m,2H).
To an ice cooled solution of l-(2,3-di-propoxypheny'L)-l-hydroxyethane (20g) in dichloromethane (250m1) powdered 4A molecular sieves (23g), N-metfhylmorpholine- N-oxide (14.9g) and tetrapropylammonium p- rruthenate (1g).
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' ,3'1-di-propoxyacetophenone (18. 3g) 1 H-NNR 6 (CDCl 3 l.03(t,3H), l.08(t,3H), l.72-l.96(m,4H), 2.63(s,3H), 3.96(t,2H), 4.0l(t,2H) and 6.99-7.19(m,3H).
From 2',3'-diprcpoxyacetophenone 3-cyano-6-(2,3-di-propoxyphenyl)pyridin-2(lH)-one (1.87g) m.p. 195-198 0 C was prepared according to the method of Example omitting sodium methoxide. 1
H-NMR
(d 6 -DMSO) 0.81(t,3H), l.01(t,3H), 1.51(m,2H), l.76(m,2H), 3.84(t,2H), 3.99(t,2H), 6.43(d,1H), 6.97(d,1H), 7.10- 7.27(m,2H) and 8.17(d,lH).
WO 92/06085 WO 9206085PCT/GB91/01663 40 From 3-cyano-6- 3-di-propoxyphenyl)pyridin- 2(lH)-one the title compound (0.47g) m.p. 186-187-C after recrystallisation from aqueous ethanol was prepared according to the method of Example 1(b).
Mr&anple 29 6- (3-Cyclopentylo~k.y-4-methoxyphenyl) (5-tetrazolyl) pyridin-2 (JJ) -one A mixture of 31-hydroxy--41-methoxyacetophenone (20.8g), potassium carbonate (24.15g), cyclopentyl bromide (22.35g) and potassium iodide (3.32g) were combined in acetone (250m1) and boiled for, 24 hours. Dimethylformamide (25m1) 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 (200m1) washed with 2N sodium hydroxide (3x50m1) and water, dried and solvent removed at reduced pressure to give 31cyclopentyloxy, 41-methoxyacetophenone as an oil that solidified on standing m.p. 59-60 0
C.
From 3' -cyclopentyloxy-4 '-methoxyacetophenone (11. 25g), 3-cyano-6-(3-cyclopentyloxy--4-methoxyphenyl) pyridin-2(lH)-one (4.07g) m.p.259-260 0 C after digestion with acetonitrile was prepared according to the method of Example 3(a) omitting sodium methoxide.
From 3-cyano-6- (3-cyclopentyloxyphenyl-4methoxyphenyl)pyridin-2(lH)-one the title compound (0.6g) m.p. 286-287 0 C (decomp) after recrystallisation from dimethylformamide was prepared according to the method of Example 1 H-NMR &(d 6
-DMSO)
WO 92/06085 PCr/GB9 1/01663 41 l.54-2.02(m,8H), 3.83(s,3H), 5.00(m,1H), 6.87(d,lH), 7.lO(d,1H), 7.43(s,11), 7.46(d,1H) and S.44(d,1H).
Example 6- (3-Ethoxyphenyl) (5-tetrazolyl) pyridin-2(111)-one A mixture of 3-hydroxyacetophenone (6.8g) and tris(dimethylamino)methane (14.5g) were heated together in dimethylformamide (30ml) at 80 0 C 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 (200m1), filtered and the residue washed with water and ethanol to give 3-cyano-6-(3hydroxyphenyl) pyridin-2 (1H) -one. 1 H-NMR S (d 6
-DMSO)
6.64(br.d,1H), 6.95(dd,1H), 7.12(s,1H), 7.20(d,lH), 7.32(t,lH), 8.15(d,1H), 9.87(s,1H) and 12.70(br.s,lH).
To a suspension of sodium hydride (1g, 50% in oil) in dimethylformamide (15ml) 3-cyano-6- (3-hydroxyphenyl)pyridin-2(lH)-one (2.12g) was added in portions over 30 minutes. When gas evolution had ceased iodoetbane (1.56g) was added and the mixture stirred overnight. The mixture was diluted with ethyl acetate (lO0ml), washed with 2N hydrochloric acid (2x30ml) and with water (4x50ml), dried (MgSO 4 and solvent removed at reduced pressure. The residue was recrystallised from n-butanol to give 3-cyano-6-(3-ethoxyphenyl)pyridin- 2 (1H) -one 68g) 1 H-NMR (d 6 -DMSO) 1. 35 3H) 4.12(q,2H), 6.80(d,lH), 7.08(d,lH), 7.31-7.47(m,3H) and 8.18 (d,1H).
From 3-cyano-6-(3-ethoxyphenyl)pyridin-2(lH)-one the title compound (0.44g) m.p.279 0 C (decomp) WO 92/06085 PCT/GB91/01663 42 after recrystallisation from n-butanol, was prepared according to the method of Example IHNMRJ &(d 6 -DMSO) 1.36(t,3H), 4.14(q,2H), 6.90(d,1H), 7.10(m,1H), 7.34-7.48(m,3H) and 8.47(d,1H).
Examl1e 31 6- (3,5-Dimethoxyphenyl) (5-tetrazolyl) pyridin-2 (1H) -one From 5'-dimethoxyacetophenone (4.1ig), 3-cyano-6- 5-dimethoxyphenyl)pyridin-2 (3H) -one 41g) m.p. 297 0 C after recrystallisation from ethanol, was prepared according to the method of Example 3 From 3-cyano-6-(3 ,5-dimethoxyphenyl) pyridin-2 (li) -one the title compound (1.36g) m.p. 338 0 C (decomp) after recrystallisation from acetonitrile/dimethylformamide was prepared according to the method of Example 1 H NMR &(d 6 -DMSO) 3.86(s,6H), 6.66(m,1H), 6.95(d,lH), 7.02(m,2H), 8.47(d,1H) and 12.66(br.s,lH).
Example 32 6- (2-Butyithiophenyl) (5-tetrazolyl) pyridin-2 (.!J5H -one From 2' -bromoacetophenone (19. 9g), 6- (2-bromophenyl) 3-cyanopyridin-2(1H)-one (11.4g) 245-246 0 C after recrystallisation from ethanol,was prepared according to the method of Example 1(a).
From 6-(2-bromophenyl) -3-cyanopyridin-2 (1H) -one (2.61g), 6-(2-butylthiophenyl)-3-cyanopyridin-2(lH)-one (0.83g) m.p.163-165 0 C after recrystallisation from WO 92/06085 WO 9206085PCT/GB9I /01663 43 ethanol, was prepared according to the method of Example 26(a).
From 6-(2-butylthiophenyl) -3-cyanopyridin-2 (lH) -one (0.7lg), the title compound (0.53g) m.p.181-182 0 C after recrystallisation from ethanol, was prepared according to the method of Example 1(b).
Example 33 6- (3-Allyloxyphenyl) (5-tetrazolyl) pyridin-2 (lH) -one From 3'-allyloxyacetophenoie (15.07g), 6-(3-allyloxyphenyl)-3-cyanopyridin-2 (lH) -one (14 .7g) was prepared according to the method of Example 3 1H HMR &(d 6 -DMSO) 4.67(d,2H), 5.26-5.46(m,2H), 5.98-6.20(m,lH), 6.80(d,lH), 7.13(m,1H), 7.33(m,3H) and 8.20(d,lH).
From 6- (3-allyloxyphenyl) -3-cyanopyridin-2 (lH) -one the title compound (0.34g) m.p.260 0 C (decomp) after recrystallisation from n-butanol, was prepared according to the method of Example 1 H NNR 8(d 6
-DMSO)
4.72(m,2H), 5.28-5.52(m,2H), 6.04-6.20(m,lH), 6.94(d,lH), 7.14(rn,lH), 7.48(m,3H) and 8.47(d,lH).
Example 34 6- (4-Methoxy-2-pentyloxyphenyl) (5-tetrazolyl) pyridin- 2 (1H) -one From 41 -methoxy-2'-pentyloxyacetophenone (11.8g), 3cyano-6- (4-methoxy-2--pentyloxyphenyl)pyridin-2 (lH) -one (3.4g) m.p. 143-144'C after recrystallisation from ethanol, was prepared according to the method of Example 3(a).
WO 92/06085 PCr/GB91/01663 44 From 3-cyano-6- (4-methoxy-2-pentyloxyphenyl) pyridin- 2(1H)-one (l.25g), the title compound (0.65g) m.p. 193- 194C after recrystallisation from ethanol was prepared according to the method of Example 1(b).
Example 6-(3-iso-Butoxy-4-methoxyphenyl)-3-(5-tetrazolyl)pyridin- 2(1)-one From 3'-iso-butoxy-4'-methoxyacetophenone 3cyano-6-(3-iso-butoxy-4-methoxyphenyl)pyridin-2(1H)-one (6.02g) m.p.234-235 0 C after recrystallisation from ethanol, was prepared according to the method of Example 3(a).
From 3-cyano-6- (3-iso-butoxy-4-methoxyphenyl) pyridin- 2(lH)-one (1.19g), the title compound (1.2g) m.p. 296-297 0
C
(decomp) after recrystallisation from ethanol, was prepared according to the method of Example 1H NMR 8(DMSO-d 6 l.01(d,6H), 2.02-2.16(m,lH), 3.85(s,3H), 3.89(d,2H), 6.89(d,1H), 7.12(d,1H), 7.41-7.50(m,2H) and 8.47(d,lH).
Example 36 6- (2-Bromo-3, 5-diethoxyphenyl) 2(1H)-one To an ice cooled solution of (10.4g) in dimethylformamide (50m1) N-bromosuccinimide (9.79g) was added in portions over 1 hour. The mixture was stirred at OOC for 3 hours and stood at room temperature for 48 hours. After diluting with ethyl acetate (200m1) the mixture was washed with water (5xlOOml), dried (MgSO 4 and solvent removed at reduced pressure to give 2'-bromo-3',5'diethoxyacetophenone (12.53g) as an oil.
1 H NMR 8(CDCl 3 l.41(t,3H), 1.50(t,3R), 2.60(s,3H), 4.0O(q,2H), 4.10(q,2H), 6.45(d,1H) and 6.50(d,lH).
WO 92/06085 WO 9206085PCT/GB91/01663 45 From 2' -bromo-3 5'-diethoxyacetophenone (4 .31g), 3cyano-6- (2-bromo-3, 5-diethoxyphenyl) pyridin-2 (IN) -one (0.75g) m.p. 234-235'C after recrystallisation from ethanol, was prepared according to the method of Example 3(a).
From 3-cyano-6- (2-bromo-3, 5-diethoxyphenyl) pyridin- 2(lH)-one (0.6gj), the title compound m.p. 276 0 C after recrystallisation from ethanol was prepared according to the method of Example 1 Examuple 37 6- (5-Bromo-4-methoxy-2-pentyloxyphenyl) (5-tetrazolyl) pyridin-2 (lE)-one A mixture of 3-cyano-6-(4-methoxy-2-pentyloxyphenyl)pyridin-2(lH)-one (1.71g), silver carbonate (1.92g) and iodomethane in chloroform (30m1) 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, eluant) to give 3-cyano-2-methoxy-6-(4-methoxy-2pentyloxyphenyl)pyridine (1.45g) m.p.76-78 0
C.
To a cooled (ice bath) solution of 3-cyano-2-methoxy-6- (4-methoxy-2-pentyloxyphenyl) pyridine (1 .3g) in dimethylformamide (l0ml) N-bromosuccinimide (0.71g) was added in portions over 30 minutes. The' solution was stirred at room temperature overnight diluted with ethyl acetate (50m1) and washed with water (5x50m1) The organic phase was dried (MgS0 4 solvent removed at reduced pressure and the residue recrystallised from ethanol to give 3-cyano-2methoxy-E- (5-bromo-4-methoxy-2-pentyloxyphenyl) pyridine (1.1g) m.p. 136-137"C.
WO 92/06085 PCT/GB91/01663 46 3-Cyano-2-methoxy-6-(2-bromo-4-methoxy-2pentyloxyphenyl)pyridine (Ig) and sodium iodide (1.50g) (dried at 70 0 C in vacuo for 4 hours) were dissolved in acetonitrile (10ml) and chlorotrimethylsilane (1.08g) added. The reaction mixture was stirred in the dark for 2 hours, diluted with ethyl acetate (50ml) washed with water (2x50ml), with 5% aqueous sodium metabisulphite (30ml) and water (50ml). The organic phase was dried (MgSO 4 solvent removed at reduced pressure and the residue recrystallised from ethanol to give 3-cyano-6-(5-bromo-4-methoxy-2pentyloxyphenyl)pyridin-2(1H)-one (0.55g) m.p.188-190 0
C.
From 3-cyano-6-(5-bromo-4-methoxy-2pentyloxyphenyl)pyridin-2(1H)-one the title compound (0.38g) m.p.246-248 0 C after recrystallisation from ethanol, was prepared according to the method of Example S(b).
Example 38 6-(2-Allyl-4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one A mixture of 3'-allyloxy-4'-methoxyacetophenone (7.76g) and diethylaniline (5.96g) was degassed with nitrogen for minutes and heated at 215 0 C for 90 minutes. After cooling to room temperature the reaction mixture was dissolved in ethyl acetate (100ml) and washed with 2N hydrochloric acid (3xl00ml). 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 (5.1g) m.p.81-83 0
C.
2'-Allyl-3'-hydroxy-4'-methoxyacetophenone 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 WO 92/06085 WO 206085PCTr/GB9I /01663 47 solvent removed from the filtrate at reduced pressure to give a residue which was dissolved in ethyl acetate (lO0ml) and washed with water (5x50m1). The organic phase was dried (I.'gSO 4 and solvent removed at reduced pressure to give 2'a].lyl-4'-methoxy-3'-propoxyacetophenone (5.0g) as an oil.
1 H NMR (DMSO-d 6 0.98(t,3H), 1.62-l.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,1H), 6.99(d,1H and 7.63(d,1H).
From 2' -allyl-4' -methoxy-3'-propoxyacetophenone 96g) 3-cyar-io-6- (2-allyl-4-methoxy-3-propoxyphenyl) pyridin-2 (IH) one (1.15g) m.p. 170-171 0 C after recrystallisation from ethanol was prepared according to the method of Example 3(a) with, however, the omission of sodium methoxide.
From 3-cyano-6- (2-allyl-4-methoxy-3propoxyphenyl)pyridin-2(lH)-one (0.49g), the title compound (0.24g) m.p. 210-211 0 C after recrystallisation from ethanol was prepared according to the method of Example 1 Example 39 6- (E-1-propenyl) -4-methoxyphenyl] (5-tetrazolyl) pyridin-2 (1H) -one From 3-allyl-4-methoxyacetophenone 3-cyano-6- (E-l-propenyl) -4-methoxyphenyllpyridin-2 (lH) -one (4g) after recrystallisation from n-butanol, was prepared according to the method of Example 1H NMR 5(DMSO-d 6 l.88(d,3H), 3.87(s,3H), 6.40-6.67(m,3H), 6.78(d,lH), 7.2.0(d,lH), 7.72(dd,lH), 7.93(d,lH) and 8.14(d,lH).
From 3-cyano-6- (E-1-propenyl) -4methoxypheriyllpyridin-2 (lH) -one 13g), the title compound (0.8g) m.p. 291-295 0 C (decomp) after recrystallisation from dimethylformamide was prepared according to the method of Example 1 H NNR 8(DMSO-d 6 1.89(d,3H), 3.88(s,3H), WO 92/06085 PCT/GB9I/01663 48 6.42-6.71(m,3H) 6.90(d,1H) 7.12(d,1H) 7.76(dd,1H), 7. 97 1H) and 8. 44 1H) Example 6- (4-Metboxy-3 -propoxyphenyl) (-pivi loyloxymethyl) tetrazolyl) pyridin-2 (1H) -one and 6- (4-methoxy-3propoxyphenyl) [5-(2-pivaloyloxymethyl) tetrazoly1]pyridin-2 (iN)-one A mixture of 4-methoxy-3-propoxyphenyl) tetrazolyl)pyridin-2 (iN)-one 64g), pivaloyloxymethyl chloride (0.75g), sodium hydrogen carbonate (420mg) and sodium iodide (50mg) were heated in dimethylformamide at 70 0 C for 24 hours. The mixture was diluted with ethyl acetate (50m1) and washed with water 6 x 50m1). The organic phase was dried (MgSO 4 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- (1-pivaloyloxymethyl) tetrazolyl~pyridin-2 (iN)-one (0.26g) m.p. 169-170*C after recrystallisation from ethanol and b) 6- (4-methoxy-3-propox yphenyl) (2pivaloyloxymethyl)tetrazolyllpyridin-2 (iN)-one (0.35g) m.p.195-196 0 C after recrystallisation from ethanol.
Example 41 6- [3-Ethoxy-5- (2-methoxyethoxy) phenyl] (5-tetrazolyl) pyridin-2 (iH)-one a) 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 WO 92/06085 PCT/GB91/01663 49 in ethyl acetate (100ml) and extracted with 2N sodium hydroxide (3x50ml). The combined basic extracts were washed with ethyl acetate (2x50ml), acidified with 2N hydrochloric acid and extracted with dichloromethane (3xl00ml). 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 hydroxyacetophenone (4.83g) m.p. 96-98 0
C.
b) To a suspension of sodium hydride (0.92g, 60% in oil washed with hexane) in dimethylformamide (10ml), 3'-ethoxy- (3.24g) was added in portions over minutes. When gas evolution had ceased chloroethylmethyl ether (1.9g) and sodium iodide (50mg) were added and the mixture heated to 90 0 C for 18 hours and stirred at room temperature for 24 hours. The mixture was diluted with ethyl acetate (100ml), washed with 2N sodium hydroxide (3x50ml) and water (3x50ml). The organic phase was dried (MgSO 4 filtered and solvent removed at reduced pressure to give 3'-ethoxy-5'-(2-methoxyethoxy)acetophenone (4.03g) as an oil. 1 H NMR (CDC13) 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, H) and 7.10(m,2H).
c) From 3'-ethoxy-5'-(2-methoxyethoxy)acetophenone, 3cyano-6-[3-ethoxy-5-(2-methoxyethoxy)phenyl]pyridin-2(1H)one (l.lg) m.p.199 0 C after recrystallisation from ethanol, was prepared according to the method of Example 3(a).
d) From 3-cyano-6-[3-ethoxy-5-(2methoxyethoxy)phenyl]pyridin-2(1H)-one (0.94g), the title compound (0.6g) m.p.205-206 0 C after recrystallisation from ethanol, was prepared according to the method of Example 1 WO 92/06085 WO 9206085PCI'/GB91/01663 50 Example 42 6- 2-Dimethyipropyloxy) -4-methoxyphenyl) tetrazolyi"pyridin-2 (1H) -one a) From 2-dimethyipropyloxy) -~iethoxyacetophenione 3-cyano-6-113-(2,2-dimethylpropyloxy)-4methoxyphenyl~pyridin-2 (iB)-one 46g) was prepared according to the method of Example 1 NM (DMSO d 6 1.02(s,9H), 3.74(s,2H), 3.85(s,3H), 6.79(d,lH), 7.09(d,lH), 7.42(s,1H), 7.43(d,lH) and 8.14(d,1H).
b) From 3-cyano-6- 2-dimethyipropyloxy) -4methoxyphenyllpyridin-2(lH)-one (1.25g), the title compound (1.28g) m.p. >300 0 C after recrystallisation from n-butanol, was prepared according to the method of Example 1 1H NMR B(DMSO-d 6 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-melthoxyphenyl) (5-tetrazolyl)pyridin-2 (lE) one a) From 3' -ethoxy-4' -methoxyacetophenone 91g), 3-cyano- 6- (3-ethoxy-4-methoxyphenyl)pyridin-2 (lH) -one (2 .02g) m.p.273 0 C after recrystallisation from ethanol was prepared according to the method of Example 1 b) From 3-cyano-6- (3-ethoxy-4-methoxyphenyl) pyridin-2 (18)one the title compound (1.06g) m.p.299 0 C (decomp) after recrystallisation from n-butanol, was prepared according to the method of Example 1H NMR 8(DMSO-d 6 7.41-7.50(m,2H) and 8.43(d,lH).
WO 92/06085 PCT/GB91/01663 51 Example 44 6-(3-Propionamidophenyl)-3-(5-tetrazolyl)pyridin-2(1E)-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 (100ml) 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 recrystaliised from dimethylformamide/water to give 3cyano-6-(3-propionamidophenyl)pyridin-2 (1H)-one (0.4g) m.p.
328-330 0
C
b) From 3-cyano-6-(3-propionamidophenyl)pyridin-2(1H)-one (0.3g) the title compound (0.2g) m.p.291-293 0 C (decomp) after recrystallisation from dimethylformamide/water, was prepared according to the method of Example 1 H NMR 8(DMSO-d 6 1.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,H).
Example 6-(4-Methoxy-3-propylphenyl)-3-(5-tetrazolyl)pyridin-2(1H)one (SB 20525)) A solution of 3'-allyl-4'-methoxyacetophenone (20g) 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 WO 92/06085 WO 92/6085 C/GB9I/01663 52 pressure. The residue was dissolved in dichloromethan.r, (lO0mi) and manganesa dioxide (60g) added. The mixtu:e 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. IHNMR S(CDC1 3 0.95(t,3H), 1.52-l.79(m,2H), 2.55(s,3H), 2.61(t,2H), 3.88(s,3H), 6.86(d,1H), 7.77(d,1H) and 7.82 (dd, 1H).
From 4'-methoxy-3'-propylacetophenone 1%5.77g), 3-cyano- 6- (4-methoxy-3-propylphenyl)pyridin-2 (1H) -one (4.43g) m.p.
2390C after recrystallisation from butanol, was prepared according to the method of Example 3 From 3-cyano-6- (4-methoxy-3:-propylphenyl) pyridin-2 (1H) one (4.02g), the title compound (3.64g) m.p.293-294*C (decomp) after recrystallisation from ethanol, was prepared according to the method of Example 1HNMR 8(DMSO-d 6 0.93(t,3H), 1.51-l.71(m,2H), 2.59(t,2H), 3.87(s,31f), 6.83(d,1H), 7.10(d,lH), 7.68-7.74(m,2H) and 8.46(d,lH).
Expgple 46, 6- (3-Bromo-4-methoxyphaenyl) (5-tetrazolya~ pyridin-2 (lH) one (SB 204617) From 3' -bromo-4' -methoxyacetophenone (K.W.Rosenmund et.
al. Chem. Ber., 1922, 90, 1957) (2.29g), 3-cyano-6-(3bromo-4-methoxyphenyl)pyridin-2(lH)-one (1.42g) m.p. 284- 28600 after recrystallisation from ethanol, was prepared according to the method of Example 3 From 3-cyano-6- (3-bromo-4-methoxyphenyl)pyridin-2 (lH) one (1.22g), the title compound (1.28g) m.p. 292-293*C (decomp) after recrystallisation from dimetihylformamide, was prepared according to the method of Example 1(b).I WO 92/06085 WO 9206085PCT/GB9I/01663 53 NMR B(DMSO-d 6 3.94(s,3H), 6.90(d,lH), 7.27(d,1H), 7.90(dd,1H), 8.14(d,lH) and 8.45(d,lH).
Example 47 6- (3-phenyl-4-methoxy~phenyl) (5-tetrazolyl)pyridin-2 (lE) one (SB 204649) To a suspension of tetrakis(triphenylphosphine)palladium (0.5g) in aqueous sodium hydrogen carbonate (5.04'g in 60ml water), solutions of phenylbrnronic acid (2.65g) .n dimethoxyethane (lO0mi) and 3' -bromo-4' -methoxyacetophenone (4 .58g) in dimethoxyethane (il0mi) were added. The mixture was stirred under reflux for 3 hours cooled to room temperature and solvent remove-c at reduced pressure. The residue was partitioned between chloroform (200m1) and water (200m1)', the organic phase separated dried (MgjSO 4 and solvent removed at reduced pressure. The residue was recrystallised from ethanol to give 4'-methoxy-3'-phenylacetophenone (2.87g) m.p. 92-93'C.
From 4'-methoxy-3'-phenylacetophenone 3-cyano- 6-(3-phenyl-4-methoxyphenyl)pyridin-2(1H)-one (2.37g) m.p.
288-291'C after recrysta llisation from propan-2-ol, was prepared according to the method of Example 3 From 3-cyano-6- II(3-phenyl) -4-methoxyphenylilpyridin- 2(mH)-one (0.91g), the title compound (0.70g) m.p. 289- 29100 after recrystallisation from dimethylformamide/ethanol, was prepared according to the method of Example 1 H NMR 8(DMS0-d 6 3.86(s,3H), 6.92(d,1H), 7.28(d,1H), 7.33-7.48(m,3H), 7.62(d,2H), 7.81- 7.89(m,2H), 8.45(d,l1i), ll.96(br.s,1H) and 12.71(br.s,lH) WO 92/06085 WO 9206085PCT/GB91/01663 54 Example 48 6- E4-Methoxy-3, 5-di (E-1-propenyl)phenylj (5-tetrazolyl) pyridin-2(1E)-one (SB 204788) From 3'-allyl-4'-hydroxyacetophenone (17.6g), 3'-alJlyl- 4'-allyloxyacetophenone (20.7g) isulated as an oil, was prep.,ared according to the method of Example 2(a) using acetone as solvent. 1HNM S(CDCl 3 2.55(s,3H), 3.44(d,2H), 4.61(m,2H), 5.0/-5.46(m,4H), 5.94-6.10(m,2H), 6.86(d,1H), 7.78d,1H) and 7.83(dd,1H).
From 3'-allyl-4'-allyloxyacetophenone (20.5g), diallyl-4'-hydroxyacetophenone (16.3g) m.p. 83-84'C was prepared according to the method of Example 38 From 3' ,5'-diallyl-4'-hydroxyacetophenone (16g), 31,51diallyl-4'-methoxyacetophenone (17g) isolated as an oil, was prepared according to the method of Example 1 NMR 8(CDC1 3 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).
From 5'-diallyl-4' -inethoxyacetophenone 3cyano-6- [4-methoxy-3, 5-di (E-l-propenyl) phenyl]pyridin- 2(lH)-one (6.1g) m.p. 248-250 0 C after trituration with hot ethanol, was prepared according to the method of Example 3(a).
From 3-cyano-6- [4-methoxy-3, 5-di (E-lpropenyl)phenyllpyridin-2 (lH) -one (0.46g), the title compound (0.27g) m.p. 285-287 0 C (decomp) after recrystallisation from dimethylformamide/water, was prepared according to the method of Example 1 1 H NMR 8(DMSO-d.) l.92(d,66H), 3.68(s,3H), 6.49-6.68(m,4H), 7.00(d,lH), 7.89(s,2H) and 8.45(d,1H).
WO 92/06085 PCT/6B91 /01 Z63 55 Example 49 6- (E-1-Propenyl) -4-propoxyphenylJ (5-tetrazolyl) pyridin-2(1H)-one. (SB 201433) 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 1 H NMR 3.41(d,2H), 3.99(t,2H), 5.04-5.12(m,2H), 5.90-6.06(m,lH), 6.86(d,lH), 7.717(d,lH) and 7.83(dd,lH).
From 3'-allyl-4'-propoxyacetophenone 3-cyano-6- (E-1-propenyl) -4-propoxyphenyllpyridin-2 (1H) -one (2.57g) m.p. 240-244 0 C after recrystallisation from butanol, was prepared according to the method of Example 3 From 3-cyano-6- (E-1-propenyl) -4propoxyphenyl~pyridin-2 (lH) -one (1.18g), the title compound (0.7g) m.p.290-292 0 C (decomp) after recrystallisation from butanol, was prepared according to the method of Example l.90(d,3H) 4.04 (t,2H) 6.48-6.61(dq,lH), 6.65(d,lH), 6.89(d,lHi), 7.11(d,1H), 7.70(dd,lE.), 7.97(d,1H) and 8.43(d,lH).
Example 6- (3-Bromo-4-methoxy-5-propylphenyl) (5-tetrazolyl) pyridin-2(1H)-one. (273/2534) From 4'-methoxy-3' -propylacetophenone 6g), 3' -bromo- (4.8g) isolated as an oil after column chromatography (silica gel, hexane/dichloromethane eluant) was prepared according to the method of Example 3 6(a) 1H NMR 8 (CDCi 3 0. 98 3H) WO 92/06085 PCTr/GB91/01663 56 l.57-l.73(m,2H), 2.56(s,3H), 2.67(t,2H), 3.87(s,3H), 7.74(d,lH) and 7.98(d,lH).
From 3' -bromo-4' -methoxy-5' -propylacetophenone 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 1 H NMR~ 3.79(s,3H), 6.38(br.d,1H), 7.74(d,lH), 7.97(d,1H) and 8.18(d,1H).
From 6- (3-bromo-4-methoxy-5-propylphenyl) -3cyanopyridin-2(lH)--one (0.39g), the title compound (0.17g) m.p. 286-287 (decomp) after recrystallisation from ethanol, was prepared according to the method of Example l 1 3.81(s,3H), 6.94(d,lH), 7.76(d,1H), 7.99(d,1H) and 8.45(d,1H).
Example 51 6- (2-Butylthio-3, 5-diethoxyphenyl) (5-tetrazolyl) pyridin- 2 (lE)-one From 2'-bromo-'3',5'-diethoxyacetophenone (2.53g), 2'butylthio-3'1,5'-diethoxyacetophenone 96g) after column chromatography (silica gel, hexane/dichloromethane 4:1 eluant) was prepared according to the method of Example 2.59(s,3H), 2.76(t,2H), 4.02(q,2H), 4.08(q,2H), 6.33(d,lH) and 6. 4 6(d,1H) From 2' -butylthio-3 5' -diethoxyacetophenone 3-cyano-6- (2-butylthio-3, 5-diethoxyphenyl)pyridin-2 (lH) -one (0.13g) after recrystallisation from ethanol, was prepared according to the method of Example 1 H N1M. 8(DMSO-d 6 WO 92/06085 WO 9206085PCr/GB9I /01663 57 0.77 1.18-1.43(m,10H), 2.66(t,2H), 4.03-4.18 (m,4H), 6.27(d,1H), 6.59(d,1H), 6.71(d,1H) and 8.15(d,1H).
From 3-cyano-6- (2-butylthio-3, 5-diethoxyphenyl) tetrazolyl)pyridin-2(lH)-one (0.12g), the title compound (0.08g) m.p. 138-140 0 C after recrystallisation from ethanol, was prepared according to the method of Example 2.64(t,2H), 4.05-4.19(m,4H), 6.40(d,lH), 6.62(d,1H), 6.70(d,1H), 8.48(d,1H) and 12.67(br.s,1H).
Example 52 6- (3-Bromo-4-N,N-dimethylaminophenyl) (5-tetrazolyl) pyridin-2(lH)-one (SB 204789) From 4' -N,N-dimethylaminoacetophenone 9g), 3' -bromo- 4"NN-dimethylamqinoacetophenone (7.0g) was prepared according to the method of Example 36(a). 1 H NMR B(CDC1 3 2.53(s,31), 2.91(s,61), 7.03(d,1H), 7.83(dd,lH) and 8.13(d,lH).
From 3'-bromo-4'-N,N-dimethylaminoacetophenone (2.42g), 3-cyano-6- (3-bromo-4-N,N-dimethylaminophenyl) pyridin-2 (1H) one (2.63g) was prepared according to the method of Example 1HNMR B(DMSO-d 6 2.82(srE;H), 6.82(d,lH), 7.22(d,1H), 7.79(dd,lH), 8.08(d,lH), 8.15(d,1N) and 12.67(br.slH).
From 3-cyano-6- (3-bromo-4-N,Ndimethylaminophenyl)pyridin-2(lH)-one the title compound (0.57g) in.p.275-277 0 C was prepared according to the method of Example 1 WO 92/06085 WO 9206085PCY/GB91 /01663 58 Example 53 6- (3-Acetamido-4-methoxy-5-propylphenyl) tetrazolyl) pyridin-2 (iN)-one (SB 204790) From 3'-allyl-4'-hydroxyacetophenone (17.6g), 3'-allyl- 4'-benzyloxyacetophenone (23.1g) isolated as an oil was prepared according to the method of Example 2(a) using acetone as solvent. 1 H NMR 8 (CDCl 3 2.55 3H) 3.47 2H), 5.04-5.l1(m,4H), 5.16(s,2H), 5.93-6.09(m,lH), 6.93(d,1H), 7.25-7.41(m,5H), 7.81(s,1H) and 7.82(d,1H).
From 3'-allyl-4'-benzyloxyacetophenone (23g), 6-IAbenzyloxy-3- (E-l-propenyl) phenyl] -3-cyanopyridin-2 (lH) -one (11.2g) m.p. 255-257 0 C after recrystallisation from dimethylformamide/water, was prepared according to the method of Example 3(a).
A solution of 6-[4-benzyloxy-3-(E-l-propenyl)phenyl]-3cyanopyridin-2(lH)-one (6.8g) in dimethylformamide (2Oml) containing dimethylformamide dimethyl acetal (4.76g) was heated at 120 0 C for 6 hours. The mixture was diluted with ethyl acetate (200m1), washed with water (6 x lO0ml), dried (MgSO 4 and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, hexane/dichioromethane 1:1 eluant) to give 6-[4-benzyloxy- 3- (E-l-propenyl)phenyll-3-cyano-2-methoxypyridine (6g) m.p.
124-125 0 C after recrystallisation from ethanol.
A suspension of 6-[4-benzyloxy-3-(E-l-propenyl)phenylll- 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, hexane/dichloromethane 1:1 2% ethanol/dichloromethane eluant) to give 3-cyano-6- (4- WO 92/060W~ PCT/GB9I /01663 59 hydroxy-3-propylphenyl)-2-methoxypyridine 1 H NMR 4.15(s,3H) 6.86(d,1H), 7.35(d,1H) and 7.81- 7 .87 (in,3H).
To a stirred suspension of 6-(4-hydroxy-3propyiphenyl) -3-cyano-2-methoxypyridine 88g) in suipholane (3m1) a solution of nitronium tetrafluoroborate in suipholane (0.5M, 16m1) was added over 5 minutes with ice cooling. The solution obtained was stirred for 5 hours, additional nitronium tetrafluoroborate (0.5M in suipholane, 2ml) added and stirring continued for a further 3 hours.
The solution was diluted with diethyl ether (100m1) washed with water (8 x lO0ml), dried (MgSO 4 and solvent removed at reduced pressure. The residue was recrysta-ilised from ethanol to give 3-cyano-6-(4-hydroxy-3-ni,tro-5propylphenyl) -2-methoxypyridine (1.75g) m.p. 160-162 0
C.
From 3-cyano-6- (4-hydroxy-3-nitro-5-propylphenyl) -2methoxypyridine (1.57g), 3-cyano-6-( 4-methoxy-3--nitro-5p ropy lphenyl1) 2-methoxypyri dine (1.53g) m.p. 150-152 0 C was prepared according to the method of Example 2(a) using acetone/diinethylformamide as reaction solvent. IH NMR 8(CDCl 3 l.03(t,3H), l.67-1.81(m,2H), 2.77(t,2H), 3.95(s,3H-), 4.17(s,3H), 7.42(d,1H), 7.96(d,lH), 8.07(d,lH) and 8. 35 1H) A suspension of 3-cyano-6-(4-methoxy-3-nitro-5propyiphenyl) -2-methoxypyridine (1 .4g) in ethanol (100m1) 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 (l0ml) containing triethylamine (1.O1g) added followed by the addition of acetic anhydride (0.61g) over 5 minutes. The reaction mixture was stirred for 15 hours, diluted with WO 92/06085 WO 9206085PCT/GB91/01663 60 dichloromethane (lO0mi) and washed with 2N hydrochloric acid (2 x 5Oml) and with water (50m1). After drying (MgSO 4 solvent was removed at reduced pressure to give after recrystallisation from ethanol 6-(3-acetamido-4methoxy-5-propylphenyl-3-cyano-2-methoxypyridine 04g) m.p.174-175*C.
From 6- (3-acetamido-4-methoxy-.5-propylphenyl) -3-cyano- 2-methoxypyridine 7g), 6- (3-acetamido-4-methoxy-5propylphenyl)-3-cyanopyridin-2(lH)-one (0.48g) m.p.247- 249 0 C was prepared according to the method of Example 2.27(s,3H), 2.78(t,2H), 3.83(s,3H), 6.65(d,lH), 7.49(d,1H), 7.80(br.s,lH), 7.90(d,lH) and 8.62(d,lH).
From 6- (3-acetamido-4-methoxy-5-propylphenyl) -3cyanopyridin-2(1H)-one the title compound (0.25g) m.p. 239-241'C after recrystallisation from ethanol, was prepared according to the method of Example 1(b) Example 54 6- [3-Methoxymethyl-4-methoxy-5- (E-1-propenyl) phenylJ tetrazolyl) pyridin-2 (1H) -one (273/2588) From 3-cyano-6-[I4-methoxy-3, 5-di propenyl)phenyllpyridin-2(I-)-one (4.59g), 3-cyano-6-14methoxy-3, 5-di (E-1-propenyl) phenyll -2-methoxypyridine (4.1g) m.p. 145*C was prepared according to the method of Example 5 1HNMR 8 (DMSO-d 6 1. 93 6H) 3. 67 3H), 4.11 (s,3H) 6.42-6.56(m,2H), 6.66(d,2H) 7.87(d,lH), 8.15 2H) and 8.30 1H) To an ice cooled suspension of 3-cyano-6-[4-methoxy- 3, 5-di (E-1-propenyl)phenyl]-2-methoxypyridine 6g) in acetone/water 1O0ml) N-methylmorpoline-N-oxide (0.63g) and osmium tetroxide w/w solution in tert- WO 92/06085 WO 926085P/GB91/01663 61 butanol, O.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 (0.1g) was added and stirring continued for an additional 1 hour. The solution was quenched with 5% sodium metabisulphite (5m1) and solvent removed at reduced pressure. The residue 'was (jissolved in ethyl acetate (200m1), washed with water (2 x lO0mi)), dried (MgSO 4 and solvent removed at reduced pressure. Column chromatography (silica gel, dichloromethane-5% ethanol/dichioromethane eluant) gave 3cyano-6- 2-dihydroxypropyl) ]-4-methoxy-5- (E-1propenyl) phenyll -2-methoxypyridine 99g) 1 H NMR 8 (CDCl 3 1.17(d,3H), l.97(d,3H), 2.5(br.s,1H), 2.98(br.s,1H), 3.82(s,3H), 3.94-4.05(m,lHi), 4.16(s,3H), 4.77(d,1H), 6.30- 6.42(m,H) 6.66(d,1H), 7.41(d,H) 7.90(d,1H), 7.93(d,I) and 8. 0 8(d,1H) To a solution of 3-cyano-6-[3-II1-(1,2dihydroxypropyl) ]-4-methoxy-5- (E-l-propenyl) phenyl] -2methoxypyridine (0.99g) in tetrahydrofurarn(20ml) a solution of sodium metaperiodate (0.64g) in water (3m1) was added.
The mixture was stirred for 2 hours, additional sodium metaperiodate (0.1g) in water (2m1) added and stirring continued for a further 2 hours. The mixture was filtered, diluted with ethyl acetate (lO0ml), washed with water (2 x 50m1), dried (MgSO 4 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 -rethoxypyri dine (0.7g) m.p. 1-74"C. NI4R (CDCl 3 and 10. 44(1H) A solution of 3-cyano-6-[3-formyl-4-methoxy-5-(E-lpropenyl)phenyll -2-methoxypyridine 65g) in ethanol (l0ml) was treated with sodium borohydride (100mg) in WO 92/06085PC/B1063 PCT/GB91/01663 62 portions over 30 minutes. The solution was stirred for a further 2 hours, solvent removed at reduced pressure, the residue dissolved in ethyl acetate (lO0mi), washed with water (2 x 50m1) dried (MgSO 4 and solvent removed at reduced pressure. The residue w.as dissolved in dimethyl sulphoxide (5m1), potassium hydroxide (0.56g, crushed pellets) added, followed by iodomethane (0.6g) and the mixture stirred for 30 minutes. After diluting with ethyl acetate (lO0ml) the reaction mixture was washed with water (6 x 50m1), dried (MgSO 4 and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, 40% hexane/dichaloromethane dichloromethane) to give 3-cyano-6- (3-methoxymethyl-4-methoxy-5- (E-1propenyl)phenylj-2-methoxypyridine (0.54g) m.p. 81-82*C. IH NMR B(CDC1 3 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,1H), 7.42(d,1H), 7.88(d,1H), 7.92(d,1H) and 8.10(d,1H).
From 3-cyano-6- t3-methoxymethyl-4-fnethoxy-5- propenyl)phenyl]-2-methoxypyridine (0.54g), 3-cyano-6- [3- (E-l-propenyl) phenyllpyridin- 2(lH-)-one (0.33g) m.p.188-190 0 C after column chromatography (silica gel, dichloromethane 2.5% ethanol/dichloromethane eluant), was prepared according to the method of Example 37(c). IH NMR 8(CDC1 3 l.99(d,3Hi, 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,lIH) and 12. 89 (br.s,l1H) (if) From 3-cyano-6- [3-methoxymetL-hyl-4-methoxy-5- (E-1propenyl)phenyl]pyridin-2(1H)-one (0.3g) the title compound (0.22g) m.p. 245-246 0 C after recrystallisation from ethanol, was prepared according to the method of Example 1 H NMR (DMSO-d 6 1.92(d,3H), 3.6l(s,3H), 3.83(s,3H), 4.81(s,2H), 6.26-6.44(m,lH), 6.68(d,lH), 6.88(d,lHi) 7.73 (d,lH) 8.04 (d,lH) 8.75(d,lH) WO 92/06085 PCT/GB91/01663 -63 ExAmple 6- (E-2-Carbamoylethenyl) -4-methoxy-5- (E-1propenyl) phenyl] (5-tetrazolyl) pyridin-2- (iN)-one (273/2602) Triethyiphosphonoacetate (0.9g) was added dropwise to a suspension of sodium hydride (0.18g, 50% in oil) in tetrahydrofuran (l0mmi). When gas evolution had ceased a solution of 3-cyano-6- [3-formyl-4-methoxy-5- (E-1propenyl) phenyl 1-2-methoxypyridine in tetrahydrofuran (l0ml)was added and the mixture stirred for 4 hours.
Ethanol (l0mI) and 2N sodium hydroxide (l0ml) 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-2carboxylatoethenyl) -4-methoxy-5- (E-1-propenyl)phenyl] -2methoxypyridine 1 H NIAR B(CDCl 3 l.94(d,3H), 3.73(s,3H), 4.14(s,3H), 6.50-6.62(m,1H), 6.69(d,1H), 6.7 8(d,lH), 7.82(1H), 7.99(d,lH) and 8.33-8.42(m,3H).
Oxalyl chloride (0.76g) was added over 5 minutes to an ice cooled suspension of 3-cyano-6-t3-(E-2carboxylatoethenyl) -4-methoxy-5- (E-l-propenyl) phe nyll -2methoxypyridine in dichloromethane (20m1) containing dimethylformamide (0.lml). When gas evolution had ceased (4 hours) solvent was removed at reduced pressure arid the residue redissolved in dichloromethane (20m1) To the ice cooled solution ammnonium hydroxide (l0mi, SG 0.88) was added and the solution stirred at 0 0 C 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- (E-2-carbamoylethenyl) -4methoxy-5- (E-1-propenyl)phenyllpyridin-2 (lH) -one (0 .4g) m.p. 245-246'C. 1H- NMR 5 (DMSO-d 6 1.94 3H) 3.72 3H) 4.14(s,3H), 6.49-6.62(m,lH), 6.66(d,1H), WO 92/06085 WO 9206085PCTr/GB91/01663 -64 7.19 (br.s, 1H) 7.62 (br.s, 1H), 7.62 1H), 7.89 1H), 8.27(d,1H), 8.29(d,1H) and 8.34(d,1H).
From 3-cyano-6- (E-2-carbamoylethenyl) (E-1-propenyl)phenyl]-2-methoxypyridine (0.35g), 3-cyano-6- (E-2-c--rbamoylethenyl) -4-methoxy-5- (E-1propenyl)phenyilpyridin-2 (1H) -one (0.2g) m.p. >300 0 C after recrystallisation from dimethylformamide/ethanol/water, was prepared according to the method of Example 37 IHNMR 5(DMSO-d 6 1.93(d,3H), 3.71(s,3H), 6.51-6.71(m,2H), 6.91(br.d,1H), 7.21(br.s,1H), 7.61(d,1H), 7.62(br.s,1H), 7.93(s,1H), 7.99(s,1H), 8.20(d,1H) and 12.78(br.s,1H).
From 3-cyano-6-[3-(E-2-carbamoylethenyl)--4-methoxy-5- (E-1-propenyl)phenyllpyridin-2 (1H) -one (0.16g), the title comp'und (0.08g) m.p.292-294 0 C (decomp) after recrystallisation. from dimethylformamide/ethanol/water, was prepared according to the method of Example 1(b) 1H NMR 8(DMSO-d 6 1.94(d,3H), 3.73(s,3jI), 6.55-6.72(m,2H), 6.83(d,1H), 7.00(d,1H), 7.62(d,1H), 7.66(br.s,1H), 7.99(d,1H) and 8.48(d,1H).
ExamPle 56 6-(3Ccorpymtyoy4-ehx iny)yi -one From 3' -hydroxy-4'-methoxyacetophenone (3.32g) 3'cyclopropylmethyloxy-4' -methoxyacetophenone 34g) was prepared according to the method of Example 2 1HNMR 8(CDCl 3 0.34-0.40(m,2H), 0.63-0.70(m,2H), l.28-l.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,1H).
From 3' -cyclopropylmethyloxy-4' -methoxyacetophenone (3.55g), 3-cyano-6- (3-cyclopropylmethyloxy-4methoxyphenyl)pyridin-2(lH)-one (1.30g) m.p. 241-242 0
C
WO 92/06085 WO 9206085PCr/GB9 1/01663 65 after recrystallisation from butanol was prepared according to the method of Example 3 From 3-cyano-6- (3-cyclopropylmethyloxy-4methoxyphenyl)pyridin-2(1H)-one (0.89g), the title compound (0.67g) m.p. 296-297 0 C (decomp) after recrystallisation from butanol, was prepared according to the method of Example IH NMR 5(DMSO-d 6 0.32-0.38(m,2H), 0.57- 0.66 (in,2H), 1.22-1.37 (in, 3.85(s, 3.94 2H), 6.88(d,1H), 7.10(d,lIi), 7.39-7.48(m,2H), 8.43(d,1H) and 12. 56 (br. s, 1H).
Exa-ie 57 6- (2-methoxy-4-propoxy,,xenyl) (5-tetrazolyl) pyridin- 2 (lE)-one From 2'-4'-dihydroxyacetophenone (50g), 2'-hydroxy-4' propoxyacetophenone (6g) was prepared according to the method of Example using bromopropane (40g) and acetone as solvent. 1 NMR 8(DMSO-d 6 1.61- 1.72(m,2H), 2.38(s,3H), 3.75(t,2H), 5.61(dd,1H), 5.80(d,1H) and 7. 40 (d,1H) From 2'-hydroxy-4'-propoxyacetop,',ienone 2'methoxy-4' -propyloxyacetophenone 18g) was prepared according to the method of Example 1.H NMR 8(CDCl 3 1.05 3H) 1.74-1.91 2.57 3H) 3.89 3i), 3.97(t,2H-), 6.46-6.53(m,2H) and 7/.80(d,lHj.) From 2' -iethoxy-4' -propoxyacetophenone 3-cyano-6- (2-iethoxy-4-propoxyphenyl)pyridin-2 (lH) -one 38g) m.p.186-188*C after trituration with diethyl ether was prepared according to the method of Example 3 H NMR 5(DMSO-d 6 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(in,2H), 7.39(d,1H) and 8.2.l(d,1H).
WO 92/060$5 PCT/GB91/01663 66 From 3-cyano-6-(2-methoxy-4-propoxyphenyl)pyridin- 2(1H)-one (0.36g), the title compound (0.04g) m.p. >300 0
C
after recrystallisation from ethanol and trituration with diethyl ether, was prepared according to the method of Example 1H NMR 8(DMSO-d 6 at 370K) 1.00(t,3H), 1.69-- 1.82(m,2H), 3.83(s,3H), 4.02(t,2H), 6.61-6.66(m,2H), 6.93(unresolved,1H), 7.55(unresolved, H) and 8.44(unresolved,1H).
Example X Pharmaceutical compositions for oral administration are prepared by combining the following w/w 6-(3-methoxyphenyl)-3- (5-tetrazolyl)pyridin-2(lH)-one 0.5 3.0 7.14 2% w/w Soya lecithin in soya bean oil 90.45 88.2 84.41 Hydrogenated vegetable shortening and beeswax 9.05 8.8 8.45 The formulations are tihen filled into individual soft gelatin capsules.
Example Y A pharmaceutical composition for parenteral administration is prepared by dissolving the title compound of Example 23 (0.02 g) in polyethylene glycol 300 ml) with heating. This solution is then diluted with water for injections Ph. Eur. (to 100 ml). The solution is then sterilised by filtration through a 0.22 mricron membrane filter and sealed in sterile containers.

Claims (8)

1. A compound of the formula (1) Ar ON(1 or a pharmaceutically acceptable salt thereof, wherein R0 is OH or a bioprecursor thereof, R 1 is 5-tetrazolyl, or a bioprecursor thereof and Ar is phenyl substituted by one to three groups independently selected from CI- 6 alkyl, C 2 6 alkenyl, C 1 6 alkoxy, C3- 6 alkenyloxy, C 3 6 cycloalkyl, C 3 6 cycloalkoxy, C 1 6 alkylthio, phenyl, phenylthio, benzyloxy, C 1 6 polyfluoroalkyl, CI-. 6 POlyfluoroalkoxy, halo, NR 2 or INICOR wherein R is H or C 1 6 alkyl, or -X(CH 2 )ny- atta--ched to adjacent carbon atoms of the phenyl ring wherein X and Y are independently CH 2 or 0 and n is 1 to 3, wherein said C 1 6 alkyl, C 2 6 alkenyl or C 1 6 alkoxy groups can be independently substituted by OH, Cl 6 alkoxy, C3> 6 cycloalkyl, NR 2 CO 2 R or CONR 2 with the proviso that Ar is not phenyl monosubstituted by
2-Cl 1 6 alkoxy. 2. A compound according to claim 1 wherein R 0 is OH or OR 2 in which R 2 is C 1 4 alkyl, arylC 1 4 alkyl, C1- 4 alkanoyl, arylsuiphonyl or Cl 1 4 alkylsulphonyl. PCT/GB 9 1/016 63 22052/P30140 ~22 Juano 22 06 9 2
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. A compound according to claim I 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-benzyloxcyphenyl) -3-(5-tetrazolyl)pyridin-2 (11)-one, 6-(3-bromophenyl) -3-(5-tetrazolyl)pyridin-2 (lH) -one, 6-(3-trifluoromethyl)-3-(5-tetrazolyl)pyridin-2 (lH) -one, 6-(3-ethylphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6- (4-butoxyphenyl) (5-tetrazolyl) pyridin-2 (lH) -one, 6-(4-isobutylphenyl). (5-tetrazolyl)pyridin-2 -one, 6- (4-biphenyl) -3'-(5-tetrazolyl) pyridin-2 (1H) -one, 6-(4-propoxyphenyl) -3-(5-tetrazolyl)pyridin-2 (lH) -one, WO 92/06085 WO 9206085PCTr/GB91/01663 69 6- (4-methoxy-3-propoxyphenyl) (5-tetrazolyl) pyridin- 2 (iN)-one, 6-(3 ,4-methylenedioxyphenyl) -3-(5-tetrazolyl)pyridin-2 (1H) one, 6- 4-dichlorophenyl) (5-tetrazolyl) pyridin-2 (iN)-one, 6- (3 ,5-dipropoxyphenyl) (5-tetrazolyl) pyridin-2 (iN)-one, 6- 5-diethoxyphenyl) (5-tetrazolyl) pyridin-2 (iN)-one, 6- 5-dibromophenyl) (5-tetrazolyl) pyridin-2 (1H) -one, 6- 4-dipropoxyphenyl) -3-(5-tetrazolyi)pyridin-2 (iN)-one, 6-(2,5-dipropoxyphenyl)-3-(5-tetrazolyl)pyridin-2(l)-one, 6- 3 ,4-trichiorophenyl) (5-tetrazolyl) pyridin-2 (1H) -one, 6-[6-(1,2,3,4-tetrahydronaphthyl) 2 (iH) -one, 6-(3-chiorophenyi)-3-(5-tetrazolyl)pyridin-2 (iN)-one, 6- (3-phenyithiophenyl) (5-tetrazolyi)pyridin-2 (iN)-one, 4-diinethoxyphenyit3-(5-tetrazolyl)pyridin-2 (1H) -one, 6-(3-methyithiophenyi)-3-(5-tetrazolyl)pyridin-2(IH)-one, 6- (3-butyithiophenyL) (5-tetrazolyl) pyridin-2 (iN)-one, WO 92/06085 WO 9206085PCT/GB91/01663 70 6-(3 ,4-di-n-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2 (1H) one, 6- 3-di-n-propoxyphenyl) (5-tetrazolyl) pyridin-2 (1H) one, 6- (3-cyclopentyloxy-4-methoxyphenyl) (5-tetrazolyl) pyridin-2 (1H) -one, 6-(3-ethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, 6- (3 ,5-diiethoxyphenyl)-3-(5-tetrazolyl)pyridin-2 (1H) -one, 6- (2-butyithiophenyl) (5-tetrazolyl) pyridin-2 (1H) -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-inethoxyphenyl) 2 (lH) -one, 6- (2-bromo-3, 5-diethoxypheny (5-tetrazolyl) pyridin- 2 (lH)--one, 6- (5-brolo-4-methoxy-2-pentyloxyphenyl) (5-tetrazolyl) pyridein-2 (1H) -one, 6- (2-allyl-4-methoxy-3-propoxyphenyl) (5-tetrazolyl) pyridin-2 (lH) -one, WO 92/06085 WO 9206085PCr/GB9 1/01663 71 6-[3-(E-1-propenyl) -4-methoxyphenyl)-3-(5-tetrazolyl)pyridin -one, 6- (4-methoxy-3-propoxyphenyl) (1-pivaloyloxymnethyl) tetrazolyljpyridin-2 (1H) -one, 6- (4-nethoxy-3-propoxyphenyl) (2-pivaloyloxymethyl) tetrazolyl]pyridin-2 (lH) -one, 6-[3-ethoxy-5-(2-Inethoxyethoxy)phenyl]-3-(5-tetrazolyl)- pyridin-2 (lH) -one, ,2-diinethylpropyloxy) -4-methoxyphenyl]-3-(5- tetrazolyl) pyridin-2 (1H) -one, 6- (3-ethoxy-4-methoxyphenyl) (5-tetrazolyl) pyridin-2 (1H) one, 6- (3-propionamidophenyl) -3-(5-tetrazolyl)pyridin-2 (lH) -one, 6- (4-methoxy-3-propylphenyl) (5-tetrazolyl) pyridin-2 (1H) one, 6- (3-bromo-4-methoxyphenyl) -3-(5-tetrazolyl ,pyridin-2 one, 6-(3-phenyl-4-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)- one, 6-[4-Inethoxy-3,5-&i(E-1-propenyl)phenyl]-3-(5-tetrazolyl)- pyridin-2 (1H) -one, 6-f 3-(E-1-propenyl)-4-propoxyphenyl]-3-(5-tetrazolyl)- pyridin-2(1H)-one, WO 92/06085 WO 9206085PCT/GB9I /01663 72 6- (3-bromo-4-methoxy-5-propylphenyl) (5-tetrazolyl) pyridin-2- (1H) -one, 6- (2-butylthio-3 ,5-diethoxyphenyl) (5-tetrazolyl) pyridin- 2(lH)-one, 6- (3-bromo-4-N,N-dimethylaminophenyl) (5-tetrazolyl) pyridin-2 (lH) -one, 6- (3-acetamiido-4-methoxy-5-propylphenyl) (5-tetrazolyl) pyridin-2 (1H) -one, 6- [3-methoxymethyl-4-methoxy-5- (E-1-propenyl) phenyl] tetrazolyl) pyridin-2 (1H) -one, (E-2-carbamoylethenyl) -4-methoxy-5- (E-1-propenyl) phenyl]-3-(5-tetrazolyl)pyridin-2-(lH)-one, or (3-cyclopropyllnethyloxy-4-Inethoxyphenyl)pyridin-2()- one or a pharmaceutically acceptable salt thereof. A r-nnmpnilndc rngi t- Any clams1 o uT pc mirAmnrnt-I 7 A pharmaceutical composition which comprises a compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier. -73-
8. A process for preparing a compound of the formula as defined in claim 1 or a pharmaceutically acceptable salt thereof which process comprises reacting a compound of the formula Ar ONj (2) NC OH wherein Ar is as hereinbefore defined with an azide salt, and optionally thereafter: o forming a bioprecursor of RO and/or R 1 o forming a pharmaceutically acceptable salt. Compounds of the formula or processes for their preparation, substantially as hereinbefore described with reference to the Examples. DATED this 22nd day of September, 1993 Smith Kline French Laboratories Limited By Its Patent Attorneys DAVIES COLLISON CAVE i S** ee 930922,p:\oper\dab,85431.spe,73 INTERNATIONAL SEARCH REPORT Internilonal Application No pT/IR ql/nl PC/B 1016 I. CLASSIFICATION OF SUBJECT MATTER (if several classification symbols apply, indicate all) 6 .II 1 According to International Patent Classification (IPC) or to both National Classification and IPC C 07 D 401/04 A 61 K 31/44 FIELDS SEARCHED Minimum Documentation Searched' Classification System Classification Symbols C 07 D 401/00 A 61 K 31/00 Documentation Searched other than Minimum Documentation to the Extent that such Documents are Included in the Fields Searched' m. DOCUMENTS CONSIDERED TO BE RELEVANT 9 Category O Citation of Document, 11 with indication, where appropriate, of the relevant passages 12 Relevant to Claim No. 1 X EP,A,0347027 (SMITH KLINE FRENCH 1,7,8 LABORATORIES LTD) 20 December 1989, see example A Chemical Pharmacological Bulletin, volume 30, no. 1,7,8 12, 1982 (Tokyo, JP) Y. Honma et al.: "Studies on antiallergic agents. I. Phenyl-substituted heterocycles with a 5-tetrazolyl or group", pages
4314-4324, see page 4318, compound 57 X Registry Handbook, number section, 1987, supplement, registry numbers 107982-26-3 through
110170-82-6, Chemical Abstracts Service, (Columbus, Ohio, US) see page 1208, registry numbers 107487-93-4; 107487-94-5, 107487-95-6; 107488-00-6; 107488-01-7; 107488-02-8 o Special categories of cited documents: 10 "T later document published after the International filing date or priority date and not in conflict with the application but document defining the general state of the art which Is not cited to understand the principle or theory underlying the considered to be of particular relevance invention earlier document but published on or after the international -X document of particular relevance; the claimed invention filing date cannot be considered novel or cannot be considered to document which may throw doubts on priority clalm(s) or Involve an inventive step which is cited to establish the publication date of nlother 'Y document of particular relevance; the claimed invention citation or other special reason (as specified) cannot be considered to involve an inventive step when the document referring to an oral disclosure, use, exhibition or document is combined with one or more other such docu- other means ments, such combination being obvious to a person skilled 'P document published prior to the International filing date but in the art. later than the priority date claimed document member of the same patent family IV. CERTIFICATION Date of the Actual Completion of the International Search Date of Mailing of this leaational Search Report 27-12-1991 International Searching Authority Signature e fdifce EUROPEAN PATENT OFFICE F PCI co Jat Weinberg Som PCTIIlSAl21O it(vcot sert) (Jumary 19) International Appliction No Page 2 Il. DOCUMENTS CONSIDERED TO BE RELEVANT (CONTIUEDM FROM TBE SECOND SHEEXT) Category Citation of Document, with Inication, where appropriate, of the relevant passages Relevant to Claim No. x Chemical Abstracts, volume 95, no. 9, 1981, (Columbus, Ohio, US) see page 788, abstract 80943j, BE, A, 885484 (MEIJI SEIKA KAISHA, LTD) 2 February 1981 X Chemical Abstracts, volu'me 86, no. 17, 1977 (Columbus, Ohio, US) J. Liebscher et al.: "Chemistry of activated vinyl halides. Synthesis and reaction behavior of 3-(beta-chlorovinyl)acrylonitriles", see page 513, abstract 120947m, J. Prakt. Chem., 1976, 318(5), 705-30 6- Perm PCTIISA2IO (eau eed) (jamiyIns 9) Fr International FURTHER INFORMATION CONTINUED FROM THE SECOND SHEET Sillcatlon No. PCTI GB91101663 rI I. V. OBSERVATION WHERE CERTAIN CLAIMS WERE FOUND UNSEARCHABLE 1 This International search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons: 1. O Claim numbers because they relate to subject matter not required to be searched by this Authority, namely 2. l Claim numbers 10 because they reat to parts of the International application that do not comply with the prescnbed requirements to such an extent that no meaningful International search can be carried out, specifically. Claim numbers 10: Claim 10 is so broad that a complete search was not possible for economical reasons 3. O Claim numbers the second and third sentences of PCT Rule 6.4(a). because they are dependent claims and are not drafted in accordance with VI.L] OBSERVATIONS WHERE UNITY OF INVENTION IS LACKING 2 This International Searching Authorty found multiple Inventions In this international application as follows' 1. O As all required additional search fees were timely paid by the applicant, this International search report covers all searchable claims of the international application 2. O As only some of the required additional search fees were timely paid by the applicant, this international search report covers only those claims of the International application for which fees were paid, specifically claims: 3 El No required additional search fees ware timely paid by the applicant. Consequently, this international search report is restricted to the invention first mentioned in the claims; it is covered by claim numbers: 4. As all searchable claims could be searched without effort justifying an additional fee, the International Searching Authority did not invite payment of any additional fee Remark on Protest SThe additional search fees were accompanied by applicant's ptest. [D No protest accompanied the payment of additional search fees. Form PCTIISA/210 (supplemental sheet P9412B 05/91 I I ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION NO. GB 9101663 SA 51749 This annex lists the patent family members relating to the patent documents cited in the above-mentioned international search report. The members are as contained in the European Patent Office EDP file on 21/01/92 The European Patent Office is in no way liable for these particulars which are merely given for the purpose of information. Patent document Publication Patent family Publication cited in search report date member(s) date EP-A- 0347027 20-12-89 AU-B- AU-A- JP-A- 616001 3309689 1311067 17-10-91 26-10-89 15-12-89 o For more details about this annex see Official Journal of the European Patent Office, No. 12/82
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