CA2120756A1

CA2120756A1 - Pyridinol derivatives as medicaments

Info

Publication number: CA2120756A1
Application number: CA002120756A
Authority: CA
Inventors: Roderick Alan Porter; Hunter Douglas Prain; Kenneth John Murray; Brian Herbert Warrington
Original assignee: Individual
Current assignee: SmithKline Beecham Ltd
Priority date: 1991-10-11
Filing date: 1992-10-09
Publication date: 1993-04-15
Also published as: MX9205851A; ZA927786B; AU654051B2; WO1993007137A1; EP0607217A1; JPH07500102A; AU2693392A; GB9121651D0; PT100949A

Abstract

Trisubstituted pyridinol derivatives are described as agonists of a cyclic AMP-dependent protein kinase useful as medicaments.

Description

2 1 ~7~6 ` ~V093/07l37 PCT/GB92/01~7 PYRIDINOL DERIYATIVES 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 combating such conditions where such agonism is thought to be beneficial. They are likely to have anti-proliferative, anti-aggregatory, cholesterol-lowering, smooth muscle relaxant, positive lusitropic, anti-allergic or anti-inflammatory activities. They are likely to be useful in the treatment of cardiovascular diseases where there is --component of diastolic failure, cancer, psoriasis, atheroschlerosis, thrombosis, chronic reversible lung disease ---such as asthma and bronchitis, allergic disease such as 20 allergic asthma, allergic rhinitis and urticaria or gut ~-motility disorders such as irritable bowel syndrome.

Accordingly the present invention provides compounds of the formula (1~ :
2s a - -,~"R
R

R

Formula (1) or pharmaceutically acceptable salts thereof, wherein :

W093/07137 2 1 ~ 0 7 5 6 - 2 - PCT/GB92/UIP - ~

RO is OH or a bioprecursor thereof, Rl is AOC02H, P(Z)(OH)(OR2), S02H, S03H or 5-tetrazolyl optionally substituted in the l-position by CH2C02H or a 5 bioprecursor thereof, AO is CH2, CH2CH2, CHF, CF2, CR3~oR4), CO or C(oR5)(oR6), R2 is phenyl, C3_5cycloalkyl, C3_5cycloalkylCl_4alkyl, or Cl_8alkyl optionally substituted by Cl_4alkoxy, R3 is H, methyl or ethyl, -~

R~ is H or Cl_3alkyl, - :
R5 and R6 are each Cl_3alkyl or together form a l,2-ethanediyl group or l,3-propanediyl group, ~,.,.
Z .s O or S, ~
Ra is halo or xlyl/ ~ .

xl is CH2, 0 or S, yl is Cl_6alkyl or Ar, Ar is phenyl optionally substituted by one to three :-groups independently selected from halo, Cl_6alkyl, C2_6~alkenylj Cl_6alkoxy, Cl_6polyfluoroalkyl or Cl_6polyfluoroalkoxy, or Ar is l-naphthyl or 2-naphthyl, R is H, Cl_6alkyl or X2Arl wherein x2 is a bond or ethenyl and Pl:T/6B 9 ~ J u I ~ 4 1 ~:
P~ ~68 21207a6 ~ JANUARY t994 Arl is phenyl optionally substituted by one to three groups independently selected from C1_6alkyl, C~_6alkenyl, Cl_6alkoxy, C3_6alkenyloxy, C2_6cycloalkyl, C2_6cycloalkoxy, C1_6alkylthio, phenyl, phenylthio, benzyloxy, C1_6poly- ~.
5 fluoroalkyl, C1_6polyfluoroalkoxy, halo, N(R7)2 or NHCoR7 .:.
wherein R7 is H or C1_6alkyl, or -X(CH2)nY attached to ~-adjacent carbon atoms of the phenyl ring wherein X and Y are :~
independently CH2 or O and n is 1 to 3, wherein said ~
C1_6alkyl, C2_6alkenyl or C1_6alkoxy groups can be - ~:
0 independently substituted by OH, C1_6alkoxy, C2_6cycloalkyl, -~
N(R7)2, Co2R7 or CoN(R7)2; or -~

Ar1 is 1-naphthyl optionally substituted in the 4-position by hydroxy or Cl_6alkoxy, 2-naphthyl optionally substituted in the 1-position by hydroxy or C1_6alkoxy, 3-phenanthryl, 9- ;.
phenanthryl, 2-quinolinyl, 4-quinolinyl, 3-thianaphthenyl or .
2-benzofuranyl, ~-~

with the proviso that R1 is not an unsubstituted 5-tetrazolyl -group when R0 is OH, Ra is C1_4alkyl, and R is Rbo~ RC
wherein Rb is C1_6alkyl, C3_6alkenyl, or C1_4alkyl substituted by 1 to 3 fluoro groups, and Rc is halo, Cl_4alkyl, Cl_4alkoxy, C1_4alkylthio, -NH2, or 2s -NHCoR7.
. ~, Bioprecursors of the groups R0 and Rl are derivatives thereof which are convertible in vivo into the groups R0 and Rl A suitable bioprecursor of the group R0 is oR8 wherein R8 is C1_4alkyl, aryl Cl_4alkyl (for example phenyl C1_4alkyl such as benzyl), C1_4alkanoyl (for example acetyl), aryl C1_4alkanoyl (for example phenyl Cl_4alkanoyl such as benzoyl), arylsulphonyl (for example optionally substituted lJnited l~in~dom P~t~t Offic~ S~J~STlTUTE S~EET

rC~J6B9 2/ 0184 3E ,168 2 1 2 0 7 5 6 n3 JANUARY lg - 3a -phenylsulphonyl or toluenesulphonyl) or C1_4alkylsulphonyl (for example methylsulphonyl).

When R1 is A0C02H a suitable bioprecursor is A0C02R9 -~
5 wherein R9 is an ester-forming group.

When R1 is P(Z)(OH)(OR2) a suitable bioprecursor is .
P(Z)(OR2)2 wherein Z and R2 are as hereinbefore defined or P(Z)(OR2)(0R10) wherein R10 is an O-protecting group. ~;~

,:, ;','',~:.' I ~Jnit~d t'' ~r,.,~ SU8STlTlJTE SHEET
¦ PCT Ir,~ n~ piicatlon I

W093/07137 2 12 ~ ~ 5 6 PCT/GB92/0l~

"'' ' Suitable O-protecting groups include pivaloyloxymethyl, propionyloxymethyl and pivalolyloxycarbonyloxymethyl.

When R1 is 1-(HO2CCH2)-5-tetrazolyl a suitable bioprecursor is 1-(R9O2CCH2)-5-tetrazolyl wherein R9 is as hereinbefore defined.

When Rl is 5-tetrazolyl, a suitable bioprecursor is a N-protected derivative thereof. Suitable N-protecting groups include pivaloyloxymethyl, propionyloxymethyl and pivalolyloxycarbonyloxymethyl.

Alternatively bioprecursors of the groups R0 and R1 are those formed when R1 and R0 are linked together to form a cyclic structure such that R1-R0 is A1CO2 or A20CH20, in which :

A1 is CH2, CH2CH2, CHF, CF2, CR3(oR4), CO or c(oR5)(oR6)~

20 A~ is p(Z)oR2 or CR3(Co2R9), and -:'.
R2 to R6, R9 and Z are as hereinbefore defined. -~

2s Suitably R0 is hydroxy or oR8, preferably hydroxy.
Suitably R is H or Cl_6alkyl. ;~

Suitably R is X2Ar1 as hereinbefore defined.

Suitably R1 is A0CO2H or A0Co2R9.
-Suitably R1 is P(Z)(OH)(OR2) or P(Z)(OR2)2.
:
Suitably R1 is SO2H, SO3H or 5-tetrazolyl.

Sùitably Rl is l-(HO2CCH2)-5-tetrazo~yl or 1-(R902CCH2)-5-tetrazolyl.
'`''. i` ` ' ~

-vo 93/07137 2 1 2 0 7 ~ 6 Pcr/GBg2/0l847 ; ~

Suitably ~1 and R0 are linked together such that R1-R0 i s Al C2 ~ ~

Suitably R1 and R0 are linked together such that R1-R0 is A2OCH20.

By the term alkyl is meant both straight- and branched-chain alkyl. -' By the term C1_6polyfluoroalkyl is meant a C1_6alkyl group having at least one hydrogen replaced with fluoro, e.g.
CF3 or CF2CF2H. ~

Suitably R2 is methyl, ethyl, propyl, butyl, pentyl, ;
hexyl, 2-methoxyethyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclopropylmethyl.

Suitably R3 is H, methyl or ethyl, preferably H or methyl.
.:; .
Suitably R4 is H, methyl, ethyl or propyl, preferably H or methyl.

Suitably R5 and R6 are independently methyl, ethyl or propyl, preferably together they form a l,2-ethanediyl group.

Preferably Z is O.
.
Suitably R~ is C1_4alkyl optionally substituted by hydroxy, e.g. 2-hydroxyethyl or aryl C1_4alkyl ~for example phenyl C1_4alkyl such as benzyl).

Suitably Ra is halo, for example iodo, bromo, or chloro, preferably bromo.

Suitably Ra is xlyl 21.~07~6 - WO93~07137 PCT/GB92/01&

Suitably yl is C1_6alkyl, for example methyl, ethyl, propyl, butyl, pentyl or hexyl.

Suitably yl is Ar as hereinbefore defined.

Suitably Ar is 1-naphthyl or 2-naphthyl or phenyl optionally mono- or di-substituted by chloro.

0 Suitably Arl is phenyl optionally mon~-substituted by a group as hereinbefore defined, for example in the 2,3, or 4 positions by Cl_6alkyl, C1_6alkoxy, C2_6alkenyloxy, ^
C1_6alkylthio, phenyl, phenylthio, benzyloxy, CF3, halo or NHCOR. --Suitably Ar1 is phenyl di-substituted by any groups as hereinbefore defined, for example in the 3,4-,3,5-,2,3-,2,4-or 2,5-, positions by groups independently selected from C2_6alkenyl, C1 6alkoxy, C2_6cycloalkoxy, halo, -X(CH2)nY- or Cl_6alkoxyCl_6alkoxy.

Suitably Ar1 is phenyl trisubstituted by any groups as hereinbefore defined, for example in the 2,3,4-, 2,3,5-, or ` -3,4,5-positions by groups independently selected from C2_6alkenyl, C1_6alkoxy or halo.

Suitably Arl is 1-naphthyl optionally substituted in the 4-position by hydroxy or C1_6alkoxy. Suitably Ar is 2-naphthyl optionally substituted in the 1-position by hydroxy 30 or Cl_6alkoxy. ;-~
-Suitably Ar1 is 3-phenanthr;l or 9-phenanthryl.

Suitably Arl is 2-quinolinyl or 4-quinolinyl.
Suitably Ar1 is 2-benzofuranyl or 3-thianaphthenyl.

~-VO93/07137 2 12 0 7 3 G PCT/GB92/01~7 Examples of Cl_6alkoxy include methoxy, ethoxy, propoxy, butoxy, or pentyloxy. :

Examples of Cl_6alkyl include methyl, ethyl, propyl, 5 butyl, isobutyl or pentyl. ;

Examples of halo include fluoro, chloro, bromo or iodo.

Particular compounds of this invention include :
'~ '-6-methyl-5-(2-naphthylthio)-3-(5-tetrazolyl)pyridin-2(lH)- -.
one, 3-(1 carboxymethyl~5-tetrazolyl)-6-methyl-5-(2-naphthylthio)-pyridin-2(lH)-one, n-propyl-[5-(2-naphthylthio)-2-oxo-1,2-dihydro-3-pyridyl]-phosphonate, 6-methyl-5-phenylthio-3-(5-tetrazolyl)pyridin-2tlH)-one, 5-(4-chlorophenylthio)-6-methyl-3-~5-tetrazolyl)pyridin-2(lH)-one, 2s E-6-(2-phenylethenyl)-5-phenylthio-3-(5-tetrazolyl)pyri.din-2(lH)-one, 3-carboxymethyl-6-methyl-5-5phenylthio)pyridin-2(1H)-one, 6-phenyl-5-phenylthio-3-(5-tetrazolyl)pyridin-2(lH)-one, 5-(3-chlorophenylthio)-6-methyl-3-(5-tetrazolyl)pyridin-2(lH)-one, 5-~2-chlorophenylthio)-6-methyl-3-~5-tetrazolyl)pyridin-2~lH)-one, W093/07137 2 1~ 0 7 5 6 PCT/GB92/01~ -5-(3,4-dichlorophenylthio)-6-methyl-3-(5-tetrazolyl)pyridin-2~lH)-one, . , .
5 5-n-butylthio-6-methyl-3-~5-tetrazolyl)pyridin-2(lH)-one, .

5-n-butylthio-6-(4-methoxy-3-propoxyphenyl)-3-(5- ~
tetrazolyl)pyridin-2(1H)-one, :~.

10 5-benzyl-6-phenyl-3-(5-tetrazolyl)pyridin-2(lH)-one, :~

5-~2-naphthyloxy)-6-phenyl-3-(5-tetrazolyl)pyridin-2(lH)-one, 6-(2-naphthy].)-5-phenylthio-3-(5-tetrazolyl)pyridin-2(lH)-~s one, :~:

5-(2-naphthylthio)-6-phenyl-3-(5-tetrazolyl)pyridin-2(lH)- ::
one, 5-n-butylthio-6-(3,4-dimethoxyphenyl)-3-(5-tetrazolyl)~
pyridin-2(lH)-one, 3-[6-methyl-5-(2-napthylthio)-2-oxo-1,2-dihydro-3-pyridyl]- ~
propionic acid, .
-~
5-phenylthio-6-(9-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)- -~:
pyridin-2(lH)-one, 5-methylthio-6-(4-methoxy-3-propoxyphenyl)-3-~5-tetrazolyl)-pyridin-2(lH)-one, 5-ethylthio-6-(4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)-pyridin-2(lH)-one, 5-bromo-6-(4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)-pyridin-2(1H)-one, -:

. VO93~07137 2 1 2 0 7 ~ 6 PCT/GB92/01847 6-(3,4-dimethoxyphenyl)-5-pentyl-3-(5-tetrazolyl)pyridin~
2(lH)-one, .

6 (2-naphthyl)-5-phenoxy-3-(5-tetrazolyl)pyridin-2(lH)-one, --~ .
5-n-butylthio-6-[3-(E-l-propenyl)-4-methoxyphenyl]-3-(5-tetrazolyl)pyridin-2(lH)-one, ethyl (5-phenylthio-2-oxo-l,2-dihydro-3-pyridyl)phosphonate, ' 5-n-butylthio-6-(4-methoxy-3-n-propylphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one, or 5-n-butylthio-6-[3-(E-l-propenyl)-4-methoxyphenyl]-3-(5-tetrazolyl)pyridin-2(lH)-one, and pharmaceutically acceptable salts thereof.

This invention covers all tautomeric, geometric and optical isomeric forms of compounds of formula ~l). In particular when R0 is hydroxy the compound can exist in its keto tautomeric form : :

Ra R -.

R O
Compounds of the formula (l) can form pharmaceutically acceptable base addition salts with metal ions, such as alkali metals for example sodium or potassium, or with an ;: ammonium ion.

In order to use a compound of the formula ~l) or a 3Q pharmaceutically acceptable salt thereof for the treatment of humans and other mammals it is normally formulated in 2l2~75~
WO 93/07137 PCIYGB92JOlP

- 10 - '~, accordance with standard pharmaceutical practice as a pharmaceutical composition.

Compounds of formula (l) and their pharmaceutically s 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. -~

o Compounds of formula (1) and their pharmaceutically acceptable salts which are active when given orally or via buccal administration can be formulated appropriately in -dosage forms such as liquids, syrups, tablets, capsules and lozenges. An oral liquid formulation will generally consist S 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 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 2s gela~in shell capsule, any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils and are incorporated in a soft gela~in 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, 2-35 pyrrolidone, cyclodextrin, arachis oil, or sesame oil. ~-V093/07137 21 2 0 7 5 ~ PCT/GB92/01~7 A typical suppository formulation comprises a compound of formula (1) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, S 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 o 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 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 aer~sol dose, so that the patient may administer to himself a single dose. ~-~

Each dosage unit for oral administration contains suitably from 0.001 mg/Kg to 30 mg/Kg, and preferably from 0.005 mg/Kg to 15 mg/Kg, and each dosage unit for parenteral administration contains suitably from 0.001 mg/Kg to 10 mg/Kg, of a compound of formula ~1) or a pharmaceutically acceptable salt thereof calculated as the free acid. ;~

The daily dosage regimen for oral administration is suitably about 0.001 mg/Kg to 120 mg~Kg, of a compound of formula (1) or a pharmaceutically acceptable salt thereof calculated as the free acid. The daily dosage regimen for ;~
parenteral administration is suitably about 0.001 mg/Kg to `-~
3s 40 mg/Kg, for example about 0.005 mg/Kg to lO mg/Kg, of a -~
compousld of the formula (1) or a pharmaceutically acceptable ~-salt thereof calculated as the free acid. The active WO93/07137 ~ PCT/GB92/0l~-.
ingredient may be administered as required for example from 1 - 8 times a day or by infusion. The compositions of the invention are agonists of a cA-PrK and are of use in combating 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 ~alve, are ~-~
administered as required and for an adult are conveniently in o the range 0.1 - 5.0 mg of a compound of the formula ~1) or a ~--pharmaceutically acceptable salt thereof. -~

The compounds of this invention may be co-administered -with other pharmaceutically active compounds, for example in ~-combination, concurrently or sequentially. Conveniently the compounds of this invention and the other active compound or compounds are formulated in a single pharmaceutical composition. Examples of compounds which may be included in pharmaceutical compositions with the compounds of the formula 20 (1) are bronchodilators such as sympathomimetic amines for -example isoprenaline, isoetharine, sulbutamol, phenylephrine and ephedrine or xanthine derivatives for example theophyl~ine and aminophylline, anti-allergic agents for example disodium cromoglycate, histamine Hl-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 sequestrant~, -drugs for the treatment of psoriasis, for example retinoids,anthralin, anti-inflammatories for example cortiscosteroids, non-steroid anti-inflammatories such as aspirin, antithrombotics for example dipyridamole, or fibrinolytic ;
agents.
In another aspect the present invention provides a process for the preparation of compounds of the formula (l) ` VO93J07137 2 1 2 0 7 ~ ~ PCT/GBg2~0l847 or pharma~eutically acceptable salts thereof, which process `
comprises :

a) for compounds wherein Rl is AOC02H or AOC02R9 and :
--i) A0 is CR3(oR4), reacting in the presence of a strong base a compound of the formula ~2) :

~ R

. ` :
0~ .-'~ ' Formula (2) wherein R11 is methyl and R and Ra are as hereinbefore defined, -. .
with a compound of the formula (3) :

R3CoCo2R9 (3) 20 wherein R3 and R9 are as hereinbefore defined to form a ~ .
compound of the formula (4) :

R ~ ~

Rl 2,~N ``' ` '' OR "

Formula (4) W093/07137 2 1 2 0 7 ~ fi PCT/GB92J01&

wherein R12 is CR3 (OH)CO2R9 and R, R3, R9, R11, and Ra are as hereinbefore defined an~ thereafter optionally reacting with a C1_3alkylating agent to form the corresponding compound ~
wherein R12 is CR3 (OCl_3alkyl) C02R9, ~ ::
- ii) AO is CO, reacting in the presence of a strong base a compound of the ~:
formula (2) as hereinbefore defined with a compound of the formula (5) :
1~
R902CC02R9 (5) wherein R9 is as hereinbefore defined to form a compound of :
the formula ~4) wherein R12 is COCO2R9 and R, R9, R11 and Ra S are as hereinbefore defined, -iii) A0 is CH~OH), reacting a compound of the formula (4) wherein R12 is COCO2R9 -and R, R9, Rll, and Ra are as hereinbefore defined with a ;~
reducing agent to form the corresponding compound wherein R12 ~ :
is CH(OH)CO2R9, ~-iv) A0 is CH2, reacting a compound of the formula (4) wherein R12 is COCO2H
or COCO2R9 and R, R9, R11, and Ra are as hereinbefore defined -~:
with a suitable reducing agent to form the corresponding :- :
compound wherein R12 is CH2CO2H, -~;
...
v) A0 is C(oR5)toR6), reacting a compound of the formula (4) wherein R12 is COCO2R9 and R, R9, R11, and Ra are as hereinbefore defined with a Cl_3alcohol, 1,2-ethanediol or 1,3-propanediol to form the corresponding compound wherein R12 is C~oR5)(oR6)Co2R9, vi) A0 is CF2, :~
reacting a compound of the formula (4) wherein Rl2 is COCO2R9 ~ -and R, R9, R11, and Ra are as hereinbefore defined with a VO93/07137 2 ~ 2 Q 7 5 6 PCT/GB92/01~7 fluorinating agent to form the corresponding compound wherein R11 is CF2Co~R9, or vii~ A0 is CHF, reacting a compound of the formula (4) wherein R12 is CH(OH)CO2R9 and R, R9, Rl1, and Ra are as hereinbefore defined with a fluorinating agent to form the corresponding compound wherein R12 is CHFCO2R9, 0 and thereafter optionally :

converting the group OR11 into OH ~ ;

converting the group A0C02R9 into A0C02H; or b) for compounds wherein R1 is CH2CO2H, ~-converting a compound of the formula (6) ~ R ~
3 ~ N -C)H .
''-;
Formula (6) wherein R13 is acetyl and R, and Ra are as hereinbefore defined into the corresponding compound wherein R13 is CH2CO2H; or c~ for compounds wherein R1 is CH2CH2CO2H or CH2CH2CO2R9, hydrogenating a compound of the formula (6) wherein R13 is CH=CHCO2H or CH=CHC02R9 and thereafter optionally converting the group CH2CH2C02R9 into CH2CH2CO2H; or WO93~07137 212 0 7 ~ 6 PCT/GB92/0l~ ~

d) for compounds wherein Rl iS P (O) (OH)(OR2), hydrolysing a compound of the formula (6) wherein R13 is P(O)(OR2)2 and R, R2, and Ra are as hereinbefore defined; or -~

s e) for compounds wherein R1 is P(S)(OH)(OR2), converting a compound of the formula (6) wherein R13 is P(o3(NHR14)(oR2) and R14 is phenyl or C2_61_4alkyl and R, and Ra are as -~
hereinbefore defined into the corresponding compound wherein R13 is P(S)(OH)(OR2)i or 1 0 .:
f) for compounds where R1 is SO3H, reacting in the presence of a strong base a compound of the ~-formula (2) as hereinbefore defined with sulphuryl chloride or a chemical equivalent thereof and optionally converting -~
15 the group OR11 into OH; or ;;

g) for compounds wherein Rl is SO2H, reacting in the presence of a strong base a compound of the formula (2) as hereinbefore defined with sulphur dioxide and -20 optionally converting the group ORl1 into OH; or ~-:

h) for compounds wherein R1 is 5-tetrazolyl, reacting a compound of the formula (4) wherein R12 is cyano or a compound of the formula (6) wherein R13 is cyano with an .
azide salt; or i) for compounds wherein R1 is 1-(HO2CCH2)-5-tetrazolyl or l-(R9O2CCH2)-5-tetrazolyl, reacting a compound of the ~-formula (6) wherein R13 is 5-tetrazolyl with a compound of the formula (7) :

LCH2CO2R9 ~7) wherein L is a leaving group and R9 is as hereinbefore defined and thereafter optionally converting the group CO2R9 to CO2H; or .

V093/07l37 PCT/GB92/0l~7 "~"
- 17 - ~

j) for compounds wherein Ra is halo, reacting a compound ~.
of the formula (8) :

R
1~' ~' 5~N

OH ;
, .
Formula (8) wherein R15 is a group R1 as hereinbefore defined or a precursor thereof, and R is as hereinbefore defined, with a -~-suitable halogenating agent, and thereafter if necessary converting a precursor of R1 to R1;

and optionally thereafter : :~

forming a bioprecursor of R~ and/or R1 ~:
forming a pharmaceutically acceptable s~lt. -~:
.
Suitably a compound of the formula (2) is reacted with ~-a strong base such as lithium diisopropylamide, or a C1_4alkyl lithium or aryl lithium such as mesityl lithium in an organic solvent such as tetrahydrofuran, diethylether or ~ :
dimethoxyethane with cooling (-100 - 0C) to form the anion :~
thereof. The strong base may be formed in situ, for example by the addition of a Cl_4alkyl lithium e.g. methyllithium ~::
25 followed by a cataIytic quantity of diisopropylamine. :`
~' The anion of a compound of the formula (2) is suitably reacted with, a compound of the formula (3) or a compound of -~
the formula ~5) in an organic solvent such as tetrahydro- :
furan, diethylether or dimethoxyethane with cooling (-100 to :
0C) to form a compound of the formula (4) wherein R12 is :
CR3~OH)C02R9 or COCO2R9 respectively. A suitable compound :"-WO93/07137 212 ~ 7 5 6 PCT/GB92/01&' ~

- 18 ~
' ,~ ' ~'.'.
of the formula (3) is ethylpyruvate, or ethyl glyoxylate or a chemical equivalent thereof and a suitable compound of the formula (5) is diethyloxalate.

A compound of the formula (4) wherein R12 is ~-~
CR3(0H)Co2R9 is suitably reacted with a C1_3alkylating agent such as iodomethane, iodopropane or dimethylsulphate in the presence of a ~ase such as s~dium hydride or potassium hydroxide in an organic solvent such as dimethylformamide or dimethylsulphoxide at elevated (e.g. 30 - 80C) or preferably ambient temperature to form the corresponding compound -~
wherein R12 is CR3(0C1_3alkyl)CO2R9. When potassium hydroxide is used as base the CO2R9 group may be directly converted to carboxy.

A compound of the formula ~4) wherein R12 is CoCO2R9 is suitably reacted with a reducing agent such as sodium borohydride, or diisobutylaluminium hydride in an organic solvent such as dichloromethane, a C2_61_4alcohol e.g.
ethanol, or acetic acid or mixtures thereof at ambient or elevated temperature (e.g. 30 - 80C), or with cooling (e.g.
0 - 5C) to form the corresponding compound wherein R12 is CH(OH)CO2R9. -A compound of the formula (4) wherein R12 is COCO2H or COCO2Rg is suitably reacted with a reducing agent such as a zinc amalgam in hydrochloric acid in the absence of a solvent `-or in a solvent such as ethanol, acetic acid or dioxan and hydrogen chloride gas at ambient or elevated temperature (e.g. 40-100C) to form the corresponding compound wherein R12 is CH2CO2H. Under these reaction conditions the CO2R9 group is converted to carboxy.

A compound of the formula (4) wherein R12 is CoCO2R9 is suitably reacted with a C1_3alcohol, 1,2-ethanediol or 1,3-propanediol in the presence of an acid catalyst such as paratoluenesulphonic acid, concentrated sulphuric acid or ~093/07137 2 1 2 0 7 ~ ~ PCT/GB92/01~7 ~-.
anhydrous hydrogen chloride, at ambient or elevated ~ -temperature to form the corresponding compound wherein R12 is c ( oR5 ) ( oR6 ) Co2R9 . -`~

A compound of the formula (4) wherein R12 is COC02R9 or CHoHC02R9 is suitably reacted with a fluorinating agent such as diethylaminosulphur trifluoride in an organic solvent such as a halohydrocarbon or an ether such as glyme, or THF at ambient or elevated tempera~ure (e.g. 30-60C) to form the 0 corresponding compound where R12 is CF2CO2R9 or CHFC02R9 ~-respectively. ~ -A compound of the formula (4) wherein 0Rll is methoxy can suitably be converted to the corresponding compound wherein 0R11 is hydroxy by reaction with sodium iodide and chlorotrimethylsilane in an organic solvent such as acetonitrile, or a halohydrocarbon e.g. dichloromethane or chloroform at elevated (e.g. 30 - 80C~ or preferably ambient temperature. This method is particularly suitable for preparing compounds of the formula (1) wherein R1 is AOC02R9 since the ester-forming group R9 is not hydrolysed under the reaction conditions. Another method utilises sodium -~
thiomethoxide in an organic solvent such as dimethylformamide at an elevated temperature for example 40 - 12~C. The more forcing conditions of this method are suitable for preparing compounds of formula (1) wherein Rl is AOC02H.

A compound of the formula (4) wherein R12 is AOC02R9 can suitably be converted to the corresponding compound wherein R12 is AOC02H by reaction with an aqueous base such as sodium or potassium hydroxide at ambient or elevated --temperature (e.g. 40 - 120). This method is particularly ~ suitable for preparing compounds of the formula ~1) wherein -~
R0 is methoxy since the OR11 group is not hydrolysed.
Another hydrolysis method utilises aqueous acid such as concentrated hydrochloric acid at an elevated temperature ` WO93/07137 212 ~ 7 5 6 PCT/GB92/OI~f- ~

';
(e.g. 40 - 120C) which provides directly compounds of the formula (1) wherein R0 is hydroxy and R1 is AOCO2H.

Suitably a compound of the formula (6) wherein R13 is 5 acetyl is converted to the corresponding compound where R13 is CH2CO2H by reaction with sulphur and morpholine at elevated temperature (e.g. 50 - 200C), followed by hydrolysis with an aqueous base such as sodium hydroxide at elevated temperature, preferably at the reflux temperature of o the reaction mixture.

Suitably a compound of the formula (6) wherein R13 is CH=CHCO2H or CH=CHCO2R9 is hydrogenated (suitably 1 to 5 atmospheres of hydrogen) in the presence of a suitable catalyst e.g. a rhodium catalyst such as tris(triphenyl-phosphine)rhodium ~I) chloride, in a suitable solvent such as a C~_4alkanol or tetrahydrofuran at ambient or elevated temperature (e.g. 40 - lOO~C), preferably ambient temperature.
A compound of the formula (6) wherein R13 is CH=CHCO2R~
is suitably prepared by reacting a compound of formula (6) wherein R13 is CHO with a suitable Wittig reagent such as (Ph)3P=CHCO2R9 in an organic solvent such as toluene, or tetrahydrofuran at an elevated temperature (e.g. 50 - 150C), conveniently at the reflux temperature of the reaction mixture. If desired the compound of formula (6) wherein R13 is CH=CHCO2R9 can be converted to the corresponding compound where R13 is CH=CHCO2H as hereinbefore described.
A compound of the formula (6) where R13 is CHO is suitably prepared by reacting the corresponding compound wherein R13 is cyano with a suitable reducing agent such as diisobutylaluminium hydride followed by acidic aqueous work-up.

~093/07~37 212 ~ 7 ~ ~ PCT/GB92/01847 Suitably a compound of the formula ~6) wherein R13 is -~
P(O)(OR2)2 is hydrolysed by reaction with an aqueous base such as sodium hydroxide optionally in a cosolvent such as a C1_4alcohol at an elevated temperature (e.g. 40-100C), 5 preferably at the reflux temperature of the reaction mixture.

Suitably a compound of the formula (6) wherein R13 is P(o)(NHR14)(oR2) is converted to the corresponding compound wherein R9 is P(S)(OH)(OR2) by reaction with a strong base -~
10 such as sodium hydride in an organic solvent such as -dimethoxyethane at ambient or elevated temperature, (e.g. 40 - 100C) followed by reaction with carbon disulphide.

Suitably the anion of a compound of the formula (2) ~
prepared as hereinbefore described is reacted with sulphuryl -~-chloride or a chemical equivalent thereof or with sulphur dioxide in an organic solvent such as tetrahydrofuran with -cooling t-100 - 0C) to form after aqueous work-up a compound of the formula (4~ wherein R12 is SO3H or SO2H
respectively and ORll is methoxy which if desired can be converted to the corresponding compound wherein ORl1 is hydroxy as hereinbefore described.

A compound of the formula (4) wherein Rll is cyano or a 2s compound of the formula (6) wherein R13 is cyano 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 - 200C, -preferably at 100-150C to form the corresponding 5-tetrazolyl compound.

Suitably a compound of the formula ~6) wherein R13 is -5-tetrazolyl is reacted with a compound of the formula (7) in -~
an organic solvent such as dimethylformamide or acetonitrile in the presence of a base such as potassium or sodium W093/07137 2 1 2 ~ 7 ~ 6 PCT/GB92tO18~

bicarbonate at ambient or elevated temperature (e.g. 40-l60C) Suitably a compound of the formula ~6) wherein Rl3 is l-(R902CCH2)-5-tetrazolyl is hydrolysed by reaction with an aqueous base such as sodium hydroxide optionally in a ;
cosolvent such as a Cl_4alcohol at an elevated temperature (e.g. 40 - 100C), preferably at the reflux temperature of ~ -the reaction mixture. ~

A compound of the formula (8) is suitably reacted with a halogenating agent, for example a brominating agent such as N-bromosuccinimide in an organic solvent such as dimethylformamide or dimethylsulphoxide, at ambient or elevated temperature, e.g. 40-200C, conveniently at the reflux temperature of the reaction mixture. An example of a bioprecursor of the group Rl is cyano, which can be converted as hereinbefore described to 5-tetrazolyl.

If desired a compound of the formula (l) wherein Rl is AOC02H can be converted to the corresponding compound wherein Rl is AOC02R9 by reaction with a compound R9OH wherein R9 is as hereinbefore defined.

A compound of the formula (l) wherein RO is OH can be converted to the corresponding compound where RO is oR8 by reaction with R8Ll wher~in R8 is as hereinbefore defined and Ll is a leaving group such as halo e.g. bromo, chloro, iodo.

If desired a compound of the formula (l) wherein Rl is P(Z)(OR2)(OH) can be converted to the corresponding compound wherein Rl is P(Z)(OR2)~0RlO) by reaction with a suitable 0-protecting agent in standard manner. For example the compound can be reacted with a pivalolyloxymethyl halide.
A compound of the formula (l) wherein Rl is 5-tetrazole can be reacted with a suitable N-protecting agent in a ~V093/07137 2 1 2 ~ 7 ~ 6 PCT/GB92/01~7 standard manner, for example with a pivalolyloxymethyl halide.
-A compound of the formula (1) wherein R1-RO is AlC02 is s suitably prepared by heating a compound of the formula (1) wherein R1 is AlC02H and RO is OH with a dehydrating agent such as acetic anhydride, at an elevated temperature (e.g. 40 - 200C), preferably at the reflux temperature of the -~
reaction mixture.
: ~:
A compound of the formula (1) wherein R1-RO is A20CH20 is suitably prepared by reacting a compound of the formula (1) wherein R1 is A20H and RO is OH with a dihalomethane such :-~
as diiodo or dibromomethane in the presence of silver carbona;e in an organic solvent such as dimethylformamide at an elevated temperature (e.g. 40 - 120C).

A compound of the formula (2) is suitably prepared by reacting a compound of the formula (6) wherein R13 is hydrogen with an O-methylating agent such as dimethyl-formamide dimethylacetal in dimethylformamide or -trimethylphosphite at an elevated temperature (e.g. 40 -120C) or with iodomethane and silver carbonate in toluene or chloroform.
2s ~--A compound of *he formula (6) wherein R is X2Ar1, x2 is ethenyl and R13 is cyano i~ suitably prepared by reaction of the corresponding compound wherein R is methyl with Ar1CHO in the presence of a base such as tetrabutylammonium fluoride in an organic solvent such as tetrahydrofuran followed by workup and treatment of the resulting compound with a dehydrating agent such as acetic anhydride in acetic acid at ambient or elevated tempexature ~e.g. 40 - 150C), preferably the reflux -~
temperature of the reaction mixture.

2 12 0 7 ~ 6 WO93/07137 PCT/GB92/018~-A compound of the formula (6) wherein Ra is xlYl~ R13 is cyano, acetyl or hydrogen is suitably prepared by reaction of a compound of the formula (9) :
1 1 (9) Y X CCOR
Il 2 CHL

with a compound of the formula ~10) :

R16CH2CONH2 (10) wherein R16 is cyano, acetyl or hydrogen respectively, and L2 0 is a displaceable group and X1, yl and R are as hereinbefore defined.

Suitably L2 in a compound of the formula (9) is hydroxy or a derivative thereof for example L2 is protected hydroxy such as silyloxy, an acid residue ~for example C1_6alkanoyloxy) or an ether residue (for example methoxy or ethoxy). Alternatively L2 is a secondary amino group, for example di-Cl_6alkylamino such as dimethylamino or a cyclic amino group such as piperidino, pyrrolidino or morpholino.
Preferably L2 is hydroxy or dimethylamino.

Suitably an alkali metal (e.g. sodium) salt of a compound of the formula (9) wherein L2 is hydroxy is treated with a compound`of the formula (10) under mildly alkaline 2s aqueous conditions, for example in water in the presence of piperidine and glacial acetic acid, at an elevated temperature (e.g. 30 - 200C), preferably at the reflux temperature of the reaction mixture.

Alternatively a compound of the formula (9) wherein L2 is a secondary amino group, for example dimethylamino, is treated with a compound of the formula ~10) in a suitable 2 1 2 ~ 7 ~ 6 PCT/GB92/01847 ~
- 25 ~

solvent such as dimethylformamide, a C1_4alkanol or pyridine at an elevated temperature e.g. (30 - 200C), preferably at the reflux temperature of the reaction mixture optionally in the presence of a base such as pyridine or an alkali metal s alkoxide, e.~. sodium methoxide.

Compounds of the formula (9) wherein L2 is hydroxy can -suitably be prepared by reaction under basic conditions of a ~-compound of the formula (11) : -1 0 ' ~ " ' Y1X1CH2COR (11) ~
~'.
wherein R, X1 and yl are as hereinbefore defined, with a oompound of the formu~a HCoL3 wherein L3 is a leaving group.

Suitably L3 is ethoxy or methoxy. Conveniently a ~
solution of a compound of the formula (11) and a compound of ~-the formula HCoL3 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 (9) 2s wherein L2 is hydroxy is then treated with a compound of the --formula (10) as hereinbefore described.
.
Compounds of the formula (9) wherein L2 is a secondary amino group (e.g. dimethylamino) can suitably be prepared by reacting a compound of the formula (11) with a compound of the formula HC~oR17)2L2 wherein R17 is C1_4alkyl and L2 is a secondary amino group ~for example HC~oR17)2L2 is N,N-dimethylformamide dimethyl or diethyl acetal). Alternatively a compound of the formula ~11) can be reacted with a compound 3s of the formula HC~L2)3 ~for example tris dimethylamino-methane).

W093/07137 212 0 7 a 6 PCT/GB92/OlB' A compound of the formula ~11) wherPin X1 is O or S is suitably prepared by reaction of a compound of the formula (12) :

ylx3H (12) wherein X3 is O or S and yl is as hereinbefore defined with a compound of the formula (13) :

lo RCoCH2L9 (13) wherein R is as hereinbefore defined and L4 is a leaving group such as halo.

Suitably a compound of the formula (12) and a compound of the formula (13) in a suitable organic solvent such as dimethylformamide are treated with a base such as potassium carbonate at ambient or elevated temperature (e.g. 40-160C) A compound of the formula (11) wherein Xl is S and yl is C1_6alkyl can also be prepared by reacting a compound of the formula (13) with sodium or potassium thioacetate followed by treatment of the intermediate with a base such as sodium methoxide and an alkylating agent such as a Cl_6alkyl 25 halide, e.g. iodomethane or iodoethane in a solvent such as -dimethylformamide or methanol.

A compound of the formula (6) wherein R13 is acetyl can also be;prepared by reacting a compound of the formula (6) -~
30 wherein R13 is cyano with methyl lithium followed by aqueous -work up with for example dilute hydrochloric acid or aqueous ammonium chloride.

A compound of the formula (6) wherein R13 is hydrogen can also be prepared by heating a compound of formula (11) as hereinbefore defined with a C1_~alkyl propiolate (such as methyl propiolate) and ammonia in a solvent such as a 2 1 2 0 7 5 6 PCT/GB92/01~7 ;;

C1_~alkanol in a pressure vessel at elevated temperature (40-200C) preferably at 100C.
;.
Alternatively a compound of the formula (6) wherein R13 is hydrogen can be prepared by reacting a compound of the formula ~6) wherein R13 is cyano with orthophosphoric acid at an elevated temperature, e.g. 50 - 200C.

Alternatively a compound of the formula (6) whereln xl lo is O or S, R is H or C1_6alkyl and R13 is hydrogen or cyano can be prepared by reaction of a compound of the formula (14) :

L

B
OH

Formula (14) wherein L5 is halo, for example bromo, A is H or Cl_6alkyl and 8 is H or cyano, with a compound of the formula (12) as hereinbefore defined or a chemical equivalent thereof in a ~-~
solvent such as dimethylformamide or N-methylpyrrolidinone or quinoline in the presence of a base such as potassium carbonate or pyridine at ambient or elevated temperature (e.g. 40 - 160C). An example of a chemical equivalent of a compound of the formula (12) is a copper salt such as a bis-2~ (Cl_6alkylthio) copper salt.

A compound of formula (4) wherein R12 is cyano is suitably prepared by reacting the anion of a compound of formula (2) wherein R, Ra and R11 are as hereinbefore defined with dimethylformamide with cooling (e.g. -80 to 10C), 212~756 WO93/07137 PCT/GB92/O1~``

followed by ambient temperature and aqueous work-up. The resulting compound of formula (4) wherein R12 is carbox-aldehyde is treated with hydroxylamine hydrochloride and sodium acetate in a suitable solvent such as ethanol or methanol at elevated temperature, e.g. 40-100C, preferably at the reflux temperature of the reaction mixture followed by dehydrating the product obtained for example by heating with acetic anhydride.

lo A compound of the formula (6) wherein R13 is cyano or acetyl and R, and ~a are as hereinbefore defined can be suitably prepared by reaction of a compound of formula (4) wherein R12 is cyano or acetyl and R, R11, and Ra, X1 and yl are as hereinbefore defined with a demethylating agent such as sodium iodide/chlorotrimethylsilane in the absence of solvent or in an organic solvent such as acetonitrile or ~-chloroform at an elevated temperature (e.g. 40 to 100C) or at ambient temperature.

A compound of the formula (6) wherein R13 is P(O)(OR2) can be prepared by treating a compound of the formula (2) wherein R11 is P(O)(OR2)2 with a strong base such as lithium diisopropylamide in an organic solvent such as tetra-hydrofuran with cooling (e.g. -100-0C).
2s A compound of the formula ~2) wherein R11 is P(O)~OR2) is suitably prepared by treating a compound of the formula (6) wherein R13 is hydrogen with a compound of the formula -~
(15):
L6P(O)(OR2)2 (15) ;

wherein L6 is a leaving group and R2 is as hereinbefore defined with a base such as diisopropylethylamine.
Suitably L6 is halo, for example chloro or bromo.

VO93/07137 212 Q 7 5 6 PCT/GB92/01~7 ~ ~

A compound of formula (2) wherein Rll is P(o)(OR2)~ can also be prepared by treating a compound of the formula ~6) wherein R13 is hydrogen with a compound of the formula (16):

HP(O)~OR2)2 ~16) wherein R2 is as hereinbefore defined in the presence of an amine base such as triethylamine, and carbon tetrachlorlde. ~;;

Alternatively, a compound of the formula (6) wherein R13 is P(O)(OR2)2 is suitably prepared by treating a compound of the formula ~6) wherein R13 is hydrogen with a compound of the formula (15) in the presence of a strong base such as lithium diisopropylamide in an organic solvent such as 5 tetrahydrofuran with cooling (e.g. -100-0C) without ~
isolation of the intermediate compound of the formula (2) -wherein R11 is P(O)~OR2)2 A compound of formula (6) wherein R13 is hydrogen is -suitably prepared by demethylating a compound of formula (2) as hereinbefore defined. Suitably a compound of formula (2) is treated with boron tribromide in an organic solvent such -~-as dichloromethane or toluene with cooling (e.g. -80 to 10C) followed by ambient temperature and aqueous work-up. Or a -`~
compound of formula (2) is treated with sodium iodide and chlorotrimethylsilane at ambient or elevated ~emperature (e.g. 40-80C) conveniently ambient temperature in a solvent such as acetonitrile or dichloromethane.
.-A compound of the formula (6) wherein R13 is -~
P(o)(NHR14)(oR2) can be prepared by reaction of a compound of the formula (6) wherein R13 is P~O)(OH)(OR2) with carbon tetrachloride, triphenylphosphine and aniline or a `
Cl_4alkylamine in an organic solvent such as pyridine at 3s ambient temperature or with cooling (e.~. -10 to 5C).
Alternatively a compound of the formula (6) where R13 is P(O)(OH)(OR2) can be reacted with dimethylformamide and ~ 1 2 ~ 6 WO93/07137 PCT/GB92J018`

oxalyl chloride in an organic solvent such as a halo hydrocarbon e.g. dichloromethane at ambient temperature, followed by reaction with aniline or a C1_4alkylamine preferably with cooling (-10 to 5C).

A compound of the formula ~2) wherein Ra is syl can be prepared by reaction of a compound of the formula ~17) : -R
r(~~
~11 ; ~'.
OR

0 Formula (17) wherein L7 is halo such as bromo or iodo, R11 is methyl and R ;~
is as hereinbefore defined with a compound of the formula (12) or a chemical equivalent thereof wherein X3 is S and yl S is as hereinbefore defined. An example of a suitable chemical equivalent is a tin complex such as ;~
phenyltributyltin sulphide when yl is phenyl which can be reacted with a compound of the formula (17) according to the method of Kosugi et al as noted in Example 27 hereinafter.
-Pharmaceutically acceptable base addition salts of the ;
compounds of the formula (1) may be prepared by standard -~
methods, for example by reacting a solution of the compound of the formula (1) with a solution of the base.
2s The following biological test methods, data and Examples serve to illustrate this invention.

Cyclic-AMP Protein Ki~ase (cA-PrK) Agoni~t Activity . ~093/07l37 212 D 7 .S ~ PCT/GB92/01~7 : :

Type II cA-PrK was prepared from the cardiac muscle of a cow. The supernatant from a muscle homogenate (3 mls of 10 mM po~assium phosphate, 1 mM EDTA per g tissue) was applied to a column of DEAE-cellulose equilibrated with the 5 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 : :
o activity by incubating the enzyme at 30C for 5 minutes with [~-3~P]-adenosine triphosphate and a suitable peptide substrate such as malantide (Malencik et al., 1983, Anal. -~:
Biochem., 132, 34-40). The reacticn was terminated by the addition of hydrochloric acid and the [32P]-phosphopeptide lS quantified by spotting the reaction mixture onto phosphocellulose papers. The concentration of compound required to give 10% phosphotransferase activation is given as the EC1o (~M). The compounds of Examples 1 to 27 had . ;
EClo values in the range 0.09 - 100 ~M. .
`
Inhibitioa of Platelet Aggregation : .
Human platelet-rich-plasma was separated from freshly ~:~
drawn blood (in acid/citrate/dextrose) and treated with 2s 100 ~M acetylsalicylic acid for 15 minutes at 37C. A ~-~
washed platelet suspension was then prepared in a Hepes- .~.
isotonic saline buffer after a single centrifugation step and :~
adjusted to a concentration of l.Sx108 cells/ml. Aliquots of this suspension- were~pre-incubated with compounds for 5 minutes at 37C, then challenged with 1.0 ~M U46619. The `
extent of aggregation after 2 minutes were expressed as a percentage of control and results obtained are expressed as an ICso (concentration to cause 50% inhibition of platelet aggregation, ~M). The compounds of Examples 1 to 6, 9, 13, 3s 15, 16, 18 to 21 and 23 to 26 had ICso values in the range 2 to 300 ~M.

21207~i6 WO93/07137 PCT/GB92/01~-Inhibition of Spontanoou~ Contraction in GuinQa-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.
0 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~o (~M). The compounds of Examples l and 4 had EC50 values of 21 and 60 ~M
respectively.
.- .'' Bronchodilatation - In vitro ~-.:
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 2s 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 ICso~M).

The compounds of Examples l, 4, 5, 13, 18 and 20 to 22 had ICso values in the range 9 to l00 ~N. -~

Measurement of cardiac muicle relaxation time in rahhit ventricle 3s Papillary muscles from the right ventricle of female Albino New Zealand rabbits are mounted in standard organ /07137 2 1 2 ~ 7 a 6 PCT/GB92/01847 baths containing oxygenated Krebs solution. One end of the muscle is connected to an isometric transducer which allows recording of contractile force and its first derivative on ~-chart recorders. Test compounds are added to the bath in a s cumulative manner. Relaxation time is calculated as the time -taken from peak tension to the end of the contraction.
Compounds which cause a decrease in the relaxation time -~
indicate a positive lusitropic effect of use in the treatment~;~
of cardiovascular diseases where there is a component of diastolic failure such as congestive heart failure, angina, hypertension and cardiomyopathy.

''`'.';

~ ~ .

wo 93/07137 2 i 2 ~ 7 5 G PCT/GB92/01~ ~

Example 1 , 6-Methyl-5- (2-naphthylthio)-3-(5-tetrazolyl)pyridin-2(lH)-one '~ .
5 (a) A mixture of chloroacetone (9.3g), 2-naphthalenethiol (16g) and potassium carbonate ~13.8g) was stirred in dimethylformamide (lOOml) at room temperature for 48 hours.
After diluting with ethyl acetate (400ml), the organic phase was washed with water (6x200ml), dried (MgS04) filtered and ~-lo solvent removed at reduced pressure to give 1-(2-naphthyl- ~-thio)propan-2-one (20.2g) as an oil. 1H NMR ~(CDC13) ~-~
2.26(s,3H), 3.74(s,2H), 7.23-7.48( m,3H) and 7.71-7.93(m,4H).

(b) 1-(2-Naphthylthio)propan-2-one (16.2g) was dissolved in dimethylformamide (lOOml) containing dimethylformamide dimethylacetal (9.52g) and boiled for 72 hours. The solution was cooled to room temperature, cyanoacetamide (6.72g) and sodium methoxide (8.64g) added, the solution boiled for a ~ further 1 hour, poured into 10% aqueous acetic acid (3QOml) 20 and the precipitated product collected by filtration. ~-~
Recrystallisation from ethanol gave 3-cyano-6-methyl-5-(2-naphthylthio)pyridin-2(lH)-one (8.24g) m.p. 247-249C.

(c) A mixture of 3-cyano-6-methyl-5-~2-naphthylthio)-pyridin-2(lH)-one (l.Og) ammonium chloride (0.24g) and sodium azide (0.29~) in N-methylpyrrolidinone was heated at 14~C ~-~
for 4 hours. The reaction mixture was poured into 10% aqueous acetic acid (50ml) and the precipitated product collected by filtration. Recrystallisation from dimethylformamide gave the title compound (0.53g) m.p.296-297C.
''."'.

.' ...: .-93/07137 2 1 2 ~ 7 5 6 PCT/GB92/01~7 Example 2 ~;~

3-~1-Carboxymet~yl-5-tQtrazolyl)-6-methyl-5-(2-naphthylthio~-pyridi~-2(lH)-one ~
(a) A mixture of 6-methyl~5-~2-naphthylthio~-3-(S- ~-tetrazolyl)pyridin-2(1~)-one (6.37g), ethyl bromoacetate ~3.16g) and sodium bicarbonate (1.74g) were stirred in dimethylformamide (70ml) at room temperature for 10 hrs and lo at 50C for 2 hours. The mixture was diluted with ethyl acetate (300ml) washed with water (6x200ml), dried (MgSO4) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, ethyl acetate eluant) to give in order of elution i) 3-(1-carboethoxymethyl-5-lS tetrazolyl)-6-methyl-S-(2-naphthylthio)pyridin-2(lH)-one (0.54g) ii) 3-(2-carboethoxymethyl-5-tetrazolyl)-6-methyl-~-(2-naphthylthio)pyridin-2(lH)-one (0.75g).

tb) A solution of 3-(1-carboethoxymethyl-5-tetrazolyl)-6-methyl-5-(2-naphthylthio)pyridin-2(1H)-one (0.54g) in lN
sodium hydroxide/ethanol (40ml,1:1) was stirred at room temperature for 4 hours, poured into 2N hydrochloric acid (50ml) and extracted with ethyl ace~ate (3x50ml). The combined organic extracts were washed with water, dried (MgSO4) and solvent removed. The residue was recrystallised ; from ethanol to give the title compound (0.2g) m.p.
270C(decomp). 1H NMR ~(DMSO-d6) 2.47(s,3H), 5.50(s,2H), 7.33(dd,lH7.41-7.56(m,2H), 7.65~s,lH), 7.80-7.93(m,3H) and -~
7.98~s,lH~.
Example 3 ~-Propyl-t5-(2-naphthylthio)-2-oxo-1,2-dihydro-3-pyridyl3-phosp~onate odium salt 3s (a) A mixture of 5-bromopyridin-2(lH)-one (1.74g), 2-naphthalenethiol (1.6g) and potassium carbonate (1.38g) were 21~07~6 W093/07137 PCT/GB92/01~- ~

- 36 - ~-.
combined in dimethylformamide and heated to 130C for 3 ~-hours. The green solution was poured into 2N hydrochloric acid (80ml), ethyl acetate (50ml) and hexane (SOml) added and the mixture stirred for 1 hour. The precipitated solid was separated by filtration, and column chromatographed (silica, dichloromethane-15% ethanol/dichloromethane) to give S-(2-naphthylthio)pyridin2(lH)-one (0.95g). lH NMR (DMSO-d6) 6.41(d,lH), 7.33(dd,lH), 7.42-7.53(m,3H), 7.64(s,lH) and - 7.76-7.90(m,4H) (b) To a suspension of 5-(2-naphthylthio)pyridin- ~-2(lH)-one (0.9g) in tetrahydrofuran (5ml) cooled to -78C
lithium diisopropylamide (1.5M in cyclohexane, 2.7ml) was added over 2 minutes. The mix~ure was stirred at -78C for 15 minutes and at 0C for 30 minutes, recooled to -78C and di-n-propylphosphorochloridate (0.8g) added. After stirring for a further 15 minutes at -78C and at 0C for 30 minutes the solution was recooled to -78C and, lithi~m diisopropylamide -~1.5M in cyclohexane, 2.7ml) was again added. The solution was stirred for 30 minutes at -78C and at 0C for 30 minutes, quenched with 2N hydrochloric acid, diluted with ~
ethyl acetate ~SOml) and the organic phase washed with water -~-(2x30ml), dried ~MgS04), filtered and solvent removed at reduced pressure. The residue was column chromatographed -2s (silica, dichloromethane-10% ethanoltdichloromethane) to give -di-n-propyl [5-(2-naphthylthio)-2-oxo-1,2-dihydro-3-pyridyl]phosphonate (0.41g). lH NMR (DMSO-d6) 0.82(t,6H), 1.47-1.62(m,4H), 3.88-3.97 (m,4H), 7.33(dd,lH), 7.44-7.53(m,2H), 7.66(s,~1H), 7.74-7.90(m,4H) and 8.07(s,1H).
(c) A solution of di-n-propyl [5-(2-naphthylthio)-2-oxo-1,2-dihydro-3-pyridyl]phosphonate ~0.37gj in a mixture of n- :
propanol (3ml) and 2N sodium hydroxide (3ml) was boiled for --10 hours. The solution was stood at room temperature 35 overnight, the precipitated product was separated by -filtration and recrystallised from ethanol to give the title compound (0.14g) m.p. >300C. 1H NMR (0.41g) ~DMSO-d6) 212 ~ 7 ~ ~ PCT/GB92/01~7 0.64(t,3H), 1.31-1.42(m,2H), 3.46-3.60~m,2H), 7.19(d,lH), 7.33-7.81~m,6H) and 7.93(s,1H).

~xample 4 Ç-Methyl-5-phenylthio-3-~5-tetrazolyl)pyridin-2(lH)-cne.

(a) A mixture of chloroace~one (19.9ml) thiophenol (25.6ml) and potassium carbonate (34.5g) was stirred in dimethyl-0 formamide (200ml) at room temperature for 48 hours. Afterdiluting with ethyl acetate (800ml) the organic phase was washed with water (6x500ml) dried (MgSO4) and solvent removed at reduced pressure to give 1-phenylthiopropan-2-one (36.6g) -;
as an oil. lH NMR ~(CDC13) 2.26(s,3H), 3.65(s,2H) and 7.17-7.47(m,5H). ~-Prepared in a similar way from the appropriate thiol or phenol and the 2-haloketone were the following:-1-(9-chlorophenyl)propan-2-one: oil, yield 93%, 1H NMR
~(CDC13) 2.27(s,3H), 3.65(s,2H) and 7.17-7.28(m,4H~;

1~(3-chlorophenylthio)propan-2-one:- oil, yield 74%, lH NMR
~d6-DMSO) 2.23(s,3H), 4.12(s,2H) and 7.20-7.36(m,4H);
1-(2-chlorophenylthio)propan-2-one:- oil, yield 85%, lH NMR
S(d~-DMSO) 2.26(s,3H), 4.14(s,2H), 7.15-7.31(m,3H) and 7.45(dd,lH);

1(3,4-dichlorophenylthio)propan-2-one:- oil, yield 85%, 1H
NMR ~(d6-DMSO) 2.30(s,3H), 4.16(s,2H), 7.26(dd,1H) and 7.52-7.S6(m,2H);

2-l2-naphthyloxy)acetophenone:- oil, yield 88%, lH NMR S(d6-DMSO) 5.71(s,2H), 7.23-7.88(m,10H), and 8.06-8.10(m,2H);

21207~i~
W093/07137 PCT/GB92/01~- -2-phenylthioacetophenone:- oil, yield 96%, 1H NMR ~(CDC13) 4.39(s,2H), 7.25-7.63(m,6H), 7.85~8.02(m,SH) and 8.42(s,lH);
and 5 2-(2-naphthylthio)acetophenone:- oil, yield 80%, lH NMR
~(CDC13) 4.32(s,2H), 7.36-7.97(m,12H).

(b) l-Phenylthiopropan-2-one (36.6g) was dissolved in dimethylformamide (200ml) containing dimethylformamide o dimethylacetal (31.9g) and boiled for 36 hours. The solution ~-was cooled, cyanoacetamide (18.5g) and sodium methoxide (23.8) added, the mixture boiled for a further 2 hours, poured into water (800ml) containing acetic acid (80ml) and the precipitated product collected by filtration. The product -S was recrystallised from ethanol to give 3-cyano-6-methyl-5-phenylthiopyridin-2(lH)-one (19~8g) m.p. 252-254C.
:
(c) A mixture of 3-cyano-6-methyl-5-phenylthiopyridin-2(lH)-one (1.21g) ammonium chloride (0.8g) and sodium azide (0.98g) in N-methylpyrrolidinone was heated at 130C for 4 ~
hours. Addition to water (200ml) containing acetic acid (3ml) ;
precipitated the product which was recrystallised from ethanol to give the title compound (0.47g) m.p.
300C(decomp).
2s -~
Example 5 -' ~
5-~4-ohlorophenylthio)-6-~ethyl-3-(5-tetrazolyl)pyridin-2tl~)-one ~ -(a) 5-(4-Chlorophenyl)-3-cyano-6-methylpyridin-2(lH)-one ~21.6g) m.p. 305C~decomp) was prepared from 1-(4-chloro-thiophenyl)propan-2-one according to the method of Example 4(b). lH NMR ~(DMSO-d6) 2.37(s,3H), 7.17(d,2H), 7.36~d,2H) and 8.26(s,lH).

-~093/07137 21 2 ~ 7 S 6 PCT~GB92/01~7 (b) From 5-(4-chlorophenylthio)-3-cyano-6-methylpyridin-2(lH)-one (5.53g) the title compound (2.49g) m.p. 280C
(decomp) was prepared according to the method of Example 4(c). 1H NMR ~tDMSO-d6) 2.44(s,3H), 7.20(d,2H), 7.37(d,2H) -~
and 8.34(s,lH).

Example 6 E-6-(2-Phenylethenyl~-5-phenylthio-3-(5-tetrazolyl)pyridin-0 2(lH)-one (a) A mixture of 3-cyano-6-methyl-5-phenylthio-pyridin-2(lH)-one (0.55g), benzaldehyde (0.23g) and tetrabutyl-ammonium fluoride (5ml, lM in tetrahydrofuran) were boiled 15 together for 6 hours, 4A molecular sieves (lg) were then added and heating continued for a further 50 hours. The reaction mixture was acidified with 2N hydrochloric acid ~20ml) and the precipitated product separated by filtration washed with ethanol(30ml) and with diethyl ether ~20 ml).
The dried product ~0.7g) was added to a mixture of acetic anhydride (8ml) acetic acid (4ml) and sodium acetate (100mg) and boiled for 7 hours. On cooling the yellow product precipitated which was separated by filtration and washed with water (30ml) to give E-3-cyano-6-(2-phenylethenyl)pyridin-2(lH)-one (0.56g). 1H NMR ~(DMSO-d6) 7.16-7.56(m,11~), 7.84(d,1H) and 8.31(s,1H).

(b) From E-3-cyano-6-(2-phenylethenyl)pyridin-2(lH)-one (0.25g), the title compound (0.05 g) m.p. 292C (dec!omp) after recrystallisation from n-butanol, was prepared according to the method of Example 4(c). 1H NMR ~(DMSO-d6) 7.18-7.61(m,11H), 7.88(d,lH) and 8.38(s,lH).

W093/07137 2 1 2 0 7 5 fi PCT/GB92/018~' -- 40 ~
, ' Example 7 ' '~' .
3-Carboxymethyl-6-methyl-5-(phenylthio)pyridin-2(1~)-on~

5 (a) 3-Cyano-6-methyl-5-phenylthiopyridin-2(lH)-one (5g) was ;-suspended in tetrahydrofuran ~20ml) and cooled to -78C under `-~
nitrogen. Methyl lithium (32ml, 1.5M in diethyl ether) was ~
added over 10 minutes, the mixture stirred for a further 10 -~`
minutes at -78C and for 4 hours at 0C. The reaction mixture 0 was quenched by the addition of saturated ammonium chloride solution (lOml) followed by the addition of 2N hydrochloric acid. After stirring overnight at room temperature the precipitated product was collected by filtration, washed with water (50ml~ and recrystallised from ethanol to give 3 acetyl-6-methyl-5-phenylthiopyridin-2(lH)-on~ (1.39g), -~
m.p.203C. -. "'',':
~b~ A mixture of 3-acetyl-6-methyl-5-phenylthiopyridin- -2(lH)-one (1.39g), sulphur ~0.26g) and morpholine (0.7g) was -~-boiled for 2.5 hours. Sodium hydroxide (2N, 50ml) was added and boiling continued for a further 4 hours. After cooling to ~-room temperature, the reaction mixture was filtered, the ~
filtrate adjusted to pH 4 with conc. hydrochloric acid and ~ -;
the product separated by filtration to give the title `~-compound (0.13g) m.p.217C ~decomp) after recrystallisation -~
from ethanol. lH NMR ~(DMSO-d6) 2.31(s,3H), 7.04-7.18(m,3H), --7.30(t,2H) and 7.41(s,lH). - ;

~ ; Example 8 6-Phenyl-5-phenylthio-3-(5-tetrazolyl)pyridin-2(lH)-one `
.: .
(a) From 2-phenylthioacetophenone (11.4g), 3-cyano-6-phenyl-5-phenylthiopyridin-2(lH)-one (7.76g) m.p. 212-213C
after recrystallisation from ethanol, was prepared according to the method of Example 4(b).

-~'093/07137 2 12 ~ 7 ~ 6 PCT/GB92/01847 (b) From 3-cyano-6-phenyl-S-phenylthiopyridin-2(1H)-one (1.22g), the title compound (0.3g) m.p. 276-278C after recrystallisation from ethanol, was prepared according to the method of Example 4(c).

Example 9 5-(3-Chlorophenylthîo)-6-methyl-3-(5-tetrazolyl)pyridin-2tlH)-one (a) From 1-(3-chlorophenylthio~propan-2-one (3.06g), 5-(3-chlorophenylthio)-3-cyano-6-methylpyridin-2(lH)-one (2.6g) m.p. 245C after recrystallisation from ethanol, was prepared according to the method of Example 4(b).
(b) From 5-(3-chlorophenylthio)-3-cyano-6-methylpyridin-2(lH)-one (lg~ the title compound (l.Olg) m.p.277C after recrystallisation from n-butanol, was prepared according to the method of Example 4(c). lH NMR ~(d6-DMSO) 2.44(s,3H), 7.11(d,1H) 7.25(m,2H), 7.33(t,1~) and 8.36(s,1H).

Example 10 5-~2-Chlorophenylthio)-6-methyl-3-(5-tetrazolyl)pyridin-2~lH)-one (a) From 1-(2-chlorophenylthio)propan-2-one (3.06g), 5-(2-chlorophenylthio)-3-cyano-6-methylpyridin-2(1H)-one (2.19g) m.p. 270C after recrystallisation from ethanol was prepared ~-according to the method of Example 4(b).

(b) From 5-(2-chlorophenylthio)-3-cyano-6-methylpyridin-2(lH)-one (lg), the title compound (0.94g) m.p.289C after recrystallisation from n-butanol was prepared according to 3s the method of Example 4~c).

W093~07l37 212 0 7 5 ~ PCT/GB92/01~

Example 11 5-(3,4-Dichlorophenylthio~-6-methyl-3-(5-tetrazolyl)pyridin-2(lH)-one.
(a) From 1-(3,4-Dichlorophenylthio)propan-2-one (3.14g), 3-cyano-5-(3,4-dichlorophenylthio)-6-methylpyridin-2(1H)-one (1.53g) m.p. 255C after recrystallisation from ethanol, was --prepared according to the method of Example 4(b). ~
. ;'~:
(b) From 3-cyano-S-~3,4-dichlorophenylthio)-6-methylpyridin-2(lH)-one, (0.75g), the title compound (0.75g) ~;~
m.p.297C (decomp) after recrystallisation from n-butanol, was prepared according to the method of Example 4(c). lH NMR
~d~-DMSO) 2.43(s,3H), 7.16(dd,lH), 7.51(d,lH), 7.56(d,lH) and 8.36(s,lH).

Example 12 20 S-n-Butylthio-6-methy~-3-(5-tetrazolyl)pyridin-2~lH)-one ~:

(a) To a suspension of 3-cyano-6-methylpyridin-2(lH)-one (6.7g) in dimethyIformamide (50ml), N-bromosuccinimide ~-(8.85g) was added in portions over 10 minutes. The resulting 2s mixture was stirred for 48 hours at room temperature, poured into water (lSOml) and the precipitated material collected by -`
filtration. The residue obtained was washed thoroughly with ~-water and dried to give 5-bromo-3-cyano-6-methylpyridin-2~lH)-one (8.88g) m.p. 254-255C (decomp). lH NMR ~(d6 DMSO) -2.3~(s,3H) and B.35(s,lH).

(b~ A mixture of 5-bromo-3-cyano-6-methylpyridin-2(lH)-one (2.13g) and bis(butylthio)copper was heated in quinoline -~
(lOml) and pyridine (3ml) at 190C for 6 hours. The mixture 3s was filtered and poured into 2N hydrochloric acid (lOOml).
The precipitated solid was collected by filtration and column chromatographed (silica gel, dichloromethane - 5%

~~i0 93/07137 2 1 2 0 7 ~ 6 PCI/GB92/01847 ethanol/dichloromethane) to give 5-butylthio-3-cyano-6-methylpyridin-2(1H)-one (0.12g) m.p. 206-208C after recrystallisation from ethanol.

5 (c) From 5-butyl~hio-3-cyano-6-methylpyridin-2(lH)-one (O.llg) the title compound (0.07g) m.p. 258-259C after recrystallisation from ethanol, was prepared according to the method of Example 4(c).

0 Example 13 5-n-Butylthio-6-(4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one (a) A mixture of 3'-hydroxy-4'-methoxyacetophenon~ (A.
Brosei, H. Gurien, A. I. Rachlin and S. Teitel, J. C)rg.
Chem., 1967, 32, 1269) (8.31g), iodopropane (17g) and -~
potassium carbonate (9.9lg) in acetone (50ml) was boiled for 18 hours. The mixture was cooled to room temperature diluted with ethyl acetate (200ml) and washed with water (200ml), 2N
sodium hydroxide (2 x 200ml) and water (2 x 200ml). The organic phase was dried ~MgS04), and solvent removed at reduced pressure to give 4'-methoxy-3'-propoxyacetophenone ~10.3g) as an oil that solidified on standing m.p. 63-64C.
2s -~
~b~ Copper (II) bromide (13.4g) and 4'-methoxy-3'-propoxyacetophenone (6.25g) were combined in ethyl acetate --~
(60ml) and chloroform (30ml) and the mixture boiled for 90 `-~
minutes. The reaction mixture was cooled to room temperature, filtered and the residue washed thoroughly with dichloromethane. The combined organic phase was washed with -`~
10% aqueous ammonia (3xSOml) and water (2x50ml), dried -~MgS04) and solvent removed at reduced pressure to give 2-bromo-4'-methoxy-3'-propoxyacetophenone (4.94g) m.p. 76-77C
after recrystallisation from aqueous ethanol. -`

WO93/07137 2 12 0 7 S 6 PCT/GB92/01~ ' - 44 - ;
~ .
(c) From 2-bromo-4'methoxy-3'-propoxyacetophenone (4.3g), 2-nrbutylthio-4'-methoxy-3'-propoxyacetophenone (2.17g) m.p.
53-54C after recrystallisation from ethanol was prepared according to the method of Example 4(a).
s :
(d) From 2-n-butylthio-4'-methoxy-3'-propoxyacetophenone (2.52g), 5-n-butylthio-3-cyano-6-(4-methoxy-3-propoxyphenyl)-pyridin-2(1H)-one (2.96g) m.p.137-138C after recrystallisation from ethanol, was prepared according to the method of Example 4~b).

(e) From 5-n-butylthio-3-cyano-6-(4-methoxy-3-propoxyphenyl)pyridin-2(lH)-one (1.12g), the title compound (0.93g) m.p.189-190C after recrystallisation from ethanol was prepared according to the method of Example 4(c).

Example 14 :
5-Benzyl-6-phenyl-3-(5-tetrazolyl)pyridin-2(1H)-onQ ~--(a) From 3-phenylpropiophenone (4.21g), 3-cyano-5-methylphenyl-6-phenylpyridin-2(lH)-one (2.`15g) m.p. 305C -(decomp) after recrystallisation from ethanol, was prepared according to the method of Example 4(b). lH NMR ~(CDCl3) 3.80(s,2H), 7.02(dd,2H), 7.20-7.39(m,3H), 7.40-7.60(m,5H) and 7.71(s,lH). ~-(b1 From 3-cyano-5-methylphenyl-6-phenylpyridin-2(lH)-one ~-~0.86g), the title compound (0.64g) m.p. 269C (decomp) after -recrystallisation from ethanol, was prepared according to the method of Example 4(c). 1H NMR ~(d6-DMSO) 3.7e(s,2H), 7.05~d,2H), 7.18-7.30(m,3H), 7.51(m,5H) and 8.28(s,1H) --` ''0 93/07137 2 1 2 0 7 ~ 6 PCl/GB92/01847 Example 15 5- (2-~aphthyloxy) -6-phenyl-3- (5-tetrazolyl)pyridin-2 (1~) -one (a) From 2-(2-naphthyloxy)acetophenone (2.62g), 3-cyano-S-~2-naphthyloxy)-6-phenylpyridin-2(lH)-one (2.23g) m.p. 272C
(decomp) after recrystallisation from ethansl was prepared according to the method of Example 4(b). 1H NMR ~(d6-DMSO) 7.28(dd,lH), 7.39-7.92(m,11H) and 8.31(s,lH).
;~
(b) From 3-cyano-5-(2-naphthyloxy)-6-phenylpyridin-2(1H)-one (lg) the title compound (0.93g) m.p.307C (decomp) after recrystallisation from n-butanol, was prepared according to the method of Example 4(c). 1H NMR ~(d6-DMSO) (7.31(dd,lH), -S 7.37-7.92(m,11H) and 8.28(s,lH). -~
`-`'~ -Example 16 6-(2-~aphthyl)-5-phenylthio-3-(5-tetrazolyl) pyridin-2 ~lH)-one - -~
(a) From 2-(2-phenylthio)acetonaphthone (13g), 3-cyano-6- ~
(2-naphthyl)-5-phenylthiopyridin-2(lH)-one (4.9g) m.p.228C -after recrystallisation from n-butanol, was prepared -according to the method of Example 4(b).
2s - -(b) From 3-cyano-6-(2-naphthyl)-5-phenylthiopyridin-2(lH)-one (1.82g), the title compound (1.73g) m.p. 249-250C after ~~
recrystallisation from n-butanol, was prepared according to the method of Example 4(c).
Example 17 5-(2-Naphthylthio)-6-phenyl-3-(5-tetrazolyl)pyridin-2(lH)-one 3s (a) From 2-(2-naphthylthio)acetophenone (8g), 3-cyano-5-(2-naphthylthio)-6-phenylpyridin-2(lH)-one ~3.4g) m.p.256-258C

WO93J07137 ~12 ~ 7 5 ~ PCT/GB92/01~ - ~

after trituration with water/ethyl acetate, according to the method of Example 4(b).

(b) From 3-cyano-5-(2-naphthylthio~-6-phenylpyridin-2(lH)-one (3.4g), the title compound ~2.7g) m.p.272-274C after recrystallisation from dimethylformamide/ethanol, was prepared according to the method of Example 4(c).

Exampla 18 , -~
~'`~'"
5-n-Butylthio-6-(3,4-dimethoxyphenyl)-3-(5-tetrazolyl~
pyridin-2(lH)-one) ~a) From 2-bromo-3',4~-dimethoxyacetophenone (3.89g) 2-n- m butylthio-3',4'-dimethoxyacetonphenone (3.87g) isolated as an oil was prepared according to the method of Example 4(a) lH
NMR ~CDCl3) 0~90(t,3H), 1.31-1.63(m,4H), 2.58(t,2H), 3.75~s,2H), 3.94(s,3H), 3.95(s,3H), 6.89~d,lH), 7.55(d,lH) and 7.60(dd,lH~.
'`~
(b) From 2-n-butylthio-3',4'-dimethoxyacetophenone (3.87g), S-n-butylthio-3-cyano-6-(3,4-dimethoxyphenyl)pyridin-2(1H)~
one (1.4g) m.p.192-193C after recrystallisation from ethanol -~
was prepared according to the method of Example 4(b).
(c) From 5-n-butylthio-3-cyano-6-(3,4-dimethoxyphenyl)-pyridin-2(lH)-one (1.03g), the title compound ((0.84g) m.p.197-198C after recrystallisation from ethanol was prepared according to the method of Example 9(c).
Example 19 3-t6-Methyl-5-~2-naphthylthio)-2-oxo-1,2-dihydro-3-pyridyl~-propionic acid (a) To a suspension of 3-cyano-6-methyl-S-~2-naphthylthio)-pyridin-2(lH)-one (2.64g) in dichloromethane (50ml) at -78C

-Y093~07137 2 ~ 2 0 7 ~ 6 PCT/CB92/01~7 a solution of diisobutylaluminium hydride (9.lml, lM in dichloromethane) was added over 10 minutes. The reaction mixture was warmed to room temperature and stirred for 24 hours. Additional diisobutylaluminium hydride (14ml, lM in s dichloromethane) was added and stirring continued for 24 ~-hours. After cooling to 0C the mixture was quenched with 2N
hydrochloric acid (50ml)and stirred for 3 hours. The organic phase was separated and the aqueous phase extracted with -~
dichloromethane (3xSOml). The combined organic extracts~were o washed with saturated sodium hydrogen car~onate (50ml), water (3xSOml), dried (Na2S04), filtered and solvent removed at -~
reduced pressure. The residue (1.08g), and carboethoxy-methylene triphenylphosphorane(1.52g) were heated together at reflux in toluene (16ml) for 3 hours. The reaction mixture S was cooled to room temperature, diluted with dichloromethane -~
and washed with water ~2x50ml), dried (Na2S04), filtered and solvent removed at reduced pressure to give after column chromatography ~silica gel, 20% ethyl acetate/hexane eluant) ethyl E-3-[6-methyl-5-(2-naphthylthio)-2-oxo-1,2-dihydro-3-pyridyl]propenoic acid ~1.06g) m.p.206C. lH NMR 8(CDCl3) 1.28(t,3H), 2.60(s,3H), 4.21(q,2H), 7.06(d,1H), 7.24(dd,1H), 7.41-7.51(m,3H), 7.55(d,lH) and 7.68-7.81(m,4H).

(b) Ethyl E-3-[6-methyl-5-(2-naphthylthio)-2-oxo-1,2-dihydro-3-pyridyl]propenoate (0.9g) and tris(triphenyl-phosphine)rhodium (I) chloride (0.23g) were stirred in -ethanol (40ml) under 1 atmosphere of hydrogen for 16 hours.
Solvent was removed at reduced pressure, the residue dissolved in ethyl acetate (lOOml) and washed with 2N
hydrochloric acid (50ml), saturated sodium hydrogen carbonate (SOml) and water (2xSOml~. The organic phase was dried (Na2S04), filtered and solvent removed at reduced pressure to give ethyl 3-l6-methyl-5-(2-naphthylthio)-2-oxo-1,2-dihydro-3 pyridyl]propanoate ~0.82g). 1H NMR ~(CDC13) 1.14(t,3H), 2~58-2.73(m,2H), 2.74-2.89(m,2H), 4.05(q,2H), 7.22(dd,lH), 7.32-7.81(m,7H) and 12.58(br.s).

W093/07137 ~ 7 5 6 PCT/GB92/01 (c) A solution of ethyl 3-[6-methyl-5-~2-naphthylthio)-2-oxo-l~2-dihydro-3-pyridyl]propanoate (0.6g) in 2N sodium --~
hydroxide/ethanol (1:1, 20ml) was stirred at room temperature overnight. Solvent was removed at reduced pressure, the 5 residue dissolved in lN sodium hydroxide (60ml), washed with dichloromethane (2x50ml). The aqueous phase was cooled (ice ~
bath) and acidified with 2N hydrochloric acid. The -~-precipitate was collected by filtration washed thoroughly -;
with water and recrystallised from ethyl acetate to giv~e the lo title compound (0.48g) m.p.182C.

-, . .
Example 20 -~

5-Phenylthio-6-(4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)- ~ -pyridin-2(lH)-on~

a) From 2-bromo-4~-methoxy-3'-propoxyacetophenone (2.87g), 2-phenylthio-4'-methoxy-3'-propoxyacetophenone (3.11g) ~-isolated as an oil, was prepared according to the method of -Example 4(a). lH NMR ~(CDC13) 1.04(t,3H), 1.80-1.94(m,2H), 3.93(s,3H)3.99(t,2H), 4.24ts,2H), 6.87(d,lH) and 7.20-7.57(m,7H). :

b) From 2-phenylthio-4'-methoxy-3'-propoxyaceto-phenone(3.01g), 3-cyano-5-phenylthio-6-(4-methoxy-3-propoxyphenyl)pyridin-2(lH)-one (1.98g) m.p.210-211 after recrystallisàtion from ethanol, was prepared according to the method of Example 4(b).

c) From 3-cyano-5-phenylthio-6-(4-methoxy-3- ~`
propoxyphenyl)pyridin-2(lH)-one (0.71g), the title compound (0.69g) m.p.191-192 after recrystallisation from ethanol, was prepared according to the method of Example 4(c).

'VO 93/07137 2 1 2 () 7 5 6 PCI`/GB92/01847 ~ ~

-- 4 9 ~
-' ' Example 21 ~ :

5-Methylthio-6-(4-methoxy-3-propoxyphenyl)-3-(5-tQtrazolyl)-pyridin-2(lH~-one ~ -~a) Potassium thioacetate (5.02g) was added to a cooled ~-(ice bath) solution of 2-bromo-9'-methoxy-3'-propoxy- --acetophenone (6.3g) in dimethylformamide (120ml) containing 4A molecular sieves (7g). The mixture was warmed to roo~
o temperature and stirred for 18 hours. ~fter diluting with -diethyl ether (200ml)the organic phase was washed with lN
hydrochloric acid (200ml), water (4xlOOml), dried (MgS04) and solvent removed at reduced pressure to give 2-acetylthio-4'-methoxy-3'~propoxyacetophenone (6.09g). 1H NMR ~(CDC13) S 1.05(t,3H), 1.79-1.94(m,2H), 2.40(s,3~), 3.94(s,3H), 4.06(t,2H), 4.36(s,2H), 6.90(d,lH), 7.52(d,lH) and 7.63(dd,lH~. -~b) To a solution of 2-acetylthio-4'-methoxy-3'-propoxy-acetophenone (1.12g) in methanol (15ml), a solution of sodium methoxide (0.22g) in methanol (7ml) was added. The solution was stirred for one hour and then treated with iodomethane (0.56g) in methanol(lOml). The solution was stirred for a further 18 hours to give after removal of solvent 2-2s methylthio-4'-methoxy-3'-propoxyacetophenone ~0.51g). 1H NMR ;~
~CDC13~ 1.05~t,3H), 1.81-2.08~m,2H), 2.16(s,3H), 3.73lS,2H), - `
3.94 (5, 3H), 4.04(t,2H), 6.89(d,lH) and 7.55-7.61(m,2H). -(c) From 2-methylthio-4'-methoxy-3'-propoxyacetophénone ~ -(O.Slg), 3-cyano-5-methylthio-6-(4-methoxy-3-propoxyphenyl)- ;
pyridin-2(lH)-one (0.19g) m.p.212-213 after ~
recrystallisation from ethanol, was prepared according to the -method of Example 4(b). -~

3s (d) From 3-cyano-S-methylthio-6-(4-methoxy-3-propoxy-phenyl)pyridin-2~lH)-one (0.17g), the title compound (O.lOg) WO93/07137 2 l 2 ~ 7 .5 5 PCT/GB92/Ol~

- 50 - ~

m.p.225-226~ after recrystallisation from ethanol, was ~ ;
prepared according to the method of Example 4(c).

Example 22 s ~., 5-Ethylthio-6-(4-methoxy-3-propoxyphenyl~-3-(5-tetrazolyl)-pyridin-2(lH)-one -~

a) From 2-acetylthio-4-'methoxy-3'-propoxyacetopheno~e o (1.12g), 2-ethylthio-4'-methoxy-3'-propoxyacetophenone (0.5~g) was prepared according to the method of Exam~le -21~b). 1H NMR ~(CDC13) 1.05(t,3H), 1.27(t,3H), 1.87-1.99(m,2H), 2.57-2.69(m,2HI, 3.76(s,2H), 3.93(s,3H), 4.04(t,2H), 6.89(d,lH) and 7.54-7.62(m,2H).

(b) From 2-ethylthio-4'-methoxy-3'-propoxyacetophenone (0.54g), 3-cyano-5-ethylthio-6-(4-methoxy-3-propoxyphenyl)-pyridin-2(lH~-one (0.18g) m.p.186-187 after trituration with ethanol, was prepared accordin~ to the method of Example 4(b).

(c) From 3-cyano-S-ethylthio-6-(4-methoxy-3-propoxyphenyl)-pyridin-2(lH)-one (0.17g), the title compound (O.llg) m.p.223-224 after recrystallisation from ethanol, was prepared according to the method of Example 4(c).

Exampl~ 23 5-Bromo-6-~4-mQthoxy-3-propoxyphenyl)-3-(5-tetrazolyl)-pyridin-2(1~)-one ~a) A solution of 3-cyano-6-(4-methoxy-3-propoxyphenyl-pyridin-2(1H)-one (1.42g) and N-bromosuccinimide (0.89g) in dimethylformamide (20ml) was boiled for one hour and diluted with water (300ml). The precipitated 5-bromo-3-cyano-6-(4-methoxy-3-propoxyphenyl)pyridin-2(lH)-one (1.73g) m.p.236-237 was washed with water and diethyl ether ` 212 0 7 5 6 PCT/GB92/0l~7 (b) From 5-bromo-6-(4-methoxy-3-propoxyphenyl)pyxidin-2(1H)-one (1.45g), the title compound (1.55g) m.p.238-239 after recrystallisation from dimethylformamide/water, was prepared according to the method of Example 4(c).

Example 24 ~ , 6-(3,4-Dimethoxyphenyl)-5-pentyl-3-(5-tetrazolyl)pyridin-o 2(1H)-one.

(a) To a mixture of heptanoyl chloride (5.3g) and 1,2-dimethoxybenzene (5g) in dichloromethane (50ml) aluminium trichloride (5g) was added portionwise. After the addition was complete the mixture was boiled for one hour, cooled to room temperature and poured into water. The dichloromethane was separated and the aqueous phase extracted with ethyl -ace~ate (3x50ml). The combined organic phases were dried (MgSO4) and solvent removed at red~ced pressure to give 3',4'odimethoxyheptanophenone (8.8g) m.p. 35-37C.

(b) From 3',4'-dimethoxyheptanophenone (5g), 3-cyano-6-(3,4-dimethoxyphenyl)-5-pentylpyridin-2(lH)-one (0.71g) m.p.
182-184C after recrystallisation from ethanol, was prepared 25 according to the method of Example 4(b). --(c) From 3-cyano-6-(3,4-dimethoxyphenyl)-5-pentylpyridin- ~;
2(lH)-one (0.71g), the title compound (Q.6g) m.p~ 212-214C
after recrystallisation from ethanol, was prepared according to the method of Example 4(c).

Example 25 ~ ;

6-~2-Naphthyl)-5-Fhenoxy-3-(5-tetrazolyl)pyridin-2(1H)-one.
(a) From 2-bromo-2'-acetonaphthone (2.25g), 2-phenoxy-2'- --acetonaphthone ~2.2g) was prepared according to the method of W093/07137 2 ~ 2 ~ 7 ~ 6 PCT/GB92tOI~ -Example 4(a). 1H NMR ~(CDC13) 5.39(s,2H), 6.85-7.01(m,3H), 7.25-7.33(m,2H), 7.54-7.65(m,2H) 7.87-8.06(m,4H) and 8.54~s,lH).

s ~b) From 2-phenoxy-2'-acetonaphthone ~2.1g), 3-cyano-6-(2-naphthyl)-5-phenoxypyridin-2~1H)-one (0.73g) m.p. 253-254~C
after recrystallisation from n-butanol was prepared according to the method of Example 4~b).

o ~c) From 3-cyano-6-(2-naphthyl)-5-phenoxypyridin-2(lH)-one ~0.6g), the title compound ~0.49g) m.p. 279C ~decomp) after -recrystallisation from ethanol, was prepared according to the -method of Example 4~c). lH NMR ~d6-DMSO) 7.01-7.04~m,3H), 7.27-7.33(m,2H), 7.57-7.60(m,2H), 7.79(d,lH), 7.91-lS 7.98~m,3H), 8.23~s,lH) and 8.32(s,lH).

Example 26 5-n-Butylthio-6-t3-(~-1-propenyl)-4-~thoxyphenyl]-3-~5-tetrazolyl)pyridin-2~1~)-one.

~a) To a suspension of 3-cyano-6-[3-~F-1-propenyl)-4- ~
methoxyphenyl]pyridin-2~1H)-one ~PCT/GB91/016633 ~2g) in ;-dimethylformamide (20ml), N-iodosuccinimide (2g) was added and the mixture stirred in the dark for 24 hours. After diluting with ethyl acetate (lOOml), washing with water ~6x50ml), drying (Mgsoq) and removing solvent at reduced pressure 3-cyano-5-iodo-6-[3-~E-1-propenyl)-4-methoxyphenyl]pyridin-2~lH)-one ~2.6g) m.p. 233-234C
~decomp) after recrystallisation from ethanol was obtained.

~b) From 3-cyano-5-iodo-6-[3-~E-1-propenyl)-4-methoxyphenyl]pyridin-2~lH)-one ~lg), 3-cyano-5-butylthio-6-[3-tE-1-propenyl)-4-methoxyphenyl]pyridin-2(1H)-one (0.065g) 3s was prepared according to the method of Example 12(b). lH NMR
~(CDC13) 0.79(t,3H), 1.19-1.36(m,4H), 1.93(d,3H), 2.54(t,2H), -vog3/07137 212 0 7 ~ G PCT/GB92/01~7 6.276.42(m,1H), 6.71(d,lH), 6.99(m,lH~, 7.49(m,lH), 7.67(s,lH) and 8.05(s,1H).

tc) From 5-butylthio-3-cyano-6-(E-3-prop-1-enyl-4-methoxyphenyl)pyridin-2(lH~-one (0.065g), the title compound (0.015g) m.p.225-226C after recrystallisation from ethanol was prepared according to the method of Example 4(c). -Example 27 Ethyl (5-phenylthio-2-oxo-1,2-dihydro-3-pyridyl)pho~pho~ate ~odium ~alt.
,,~., (a) Using phenyltributyltin sulphide (lOg~ and 2-methoxy-5-lS bromopyridine (4.32g), 2-methoxy-5-phenylthiopyridine (3.8g) was prepared according to the method of Kosugi et al ~Bull.
Chem. Soc. Jpn., 1985, 58, 3657). lH NMR ~(d6-DMSO) 3.89(s,3H), 6.91(d,lH), 7.16-7.35(m,5H), 7.80~dd,lH) and 8.30(d,lH). ;-(b) A mixture of 2-methoxy-5-phenylthiopyridine (1.74g), chlorotrimethylsilane (2.16g) and sodium iodide (3.0g) were stirred together in acetonitrile (lOml) overnight. The mixture was diluted with ethyl acetate (50ml) and washed with --;
water ~3x50ml), dried (MgS04) and solvent removed at reduced - ~-pressure. The residue was suspended in ethyl acetate (20ml) stirred for 20 minutes and filtered to give as the residue 5- -~phenylthiopyridin-2(lH)-one (0.87g) m.p.181-183C.

(c) From 5-phenylthiopyridin-2(lH)-one (0.61g), diethyl (5-phenylthio-2-oxo-1,2-dihydro-3-pyridyl)phosphonate (0.21g) -~`
m.p.208-209C after recrystallisation from ethanol, was prepared according to the method of Example 3(b).

(d) From diethyl (5-phenylthio-2-oxo-1,2-dihydro-3- -pyridyl)phosphonate(0.18g), the title compound (0.025g) m.p.
280C (softens) after recrystallisation from ethanol/water, W093/07137 2 1 2 ~ 7 ~ 6 PCT/GB92/OIP -was prepared according to the method of Example 3(c). lH NMR
~(d6-DMSO) 1.03(t,3H), 3.60(m,2H), 6.98-7.30, 7.68(d,1H) and 7.87(s,lH).

Example 28 5-n-Butylthio-6-(4-methoxy-3-n-propylphenyl)-3-(5-tetrazolyl)pyridin-2(1~)-one (a) From 4'- methoxy-3'-n-propylacetophenone ~5.0g) 2-bromo-4'-methoxy-3'-n-propylacetophenone (5.4g) was prepared according to the method of Example 13(b).1H NMR
~CDC13) 0.95tt,3H), 1.54-1.69(m,2H), 2.61(t,2H), 3.90(s,3H), 4.41(s,2H), 6.89(d,lH), 7.78(d,lH~, 7.86(dd,lH).
~
(b) From 2-bromo-4'-methoxy-3'-n-propylacetophenone (5.4g), 2-n-butylthio-4'-methoxy-3'-n-propylacetophenone (4.6g) was prepared according to the method of Example 4(a). lH NMR
0.89(,3H), 0.95(t,3H), 1.32-1.48(m,2H), 1.54-1.70(m,4H), 3.74(s,2H), 3.88(s,3H), 6.86(d,lH), 7.77(d,lH) and 7.84(dd,lH).

(c) From 2-n-butylthio-4'-methoxy-3'-n-propylacetophenone (4.6g) , 5-n-butylthio-3-cyano-6-(4-methoxy-3-n-2s propylphenyl)pyridin-2(1H)-one (0.73g) was prepared according to the method o- Example 4(b) lH NMR ~(DMSO-d6) 0.73(t,3H), 0.93(t,3H), l.G7-1.31(m,4H), 1.49-1.64(m,2H), 3.84(3,3H), 7.05(d,1H), 7.28(d,lH), 7.38(dd,lH) and 8.36(s,lH).

(d) From 5-n-butylthio-3-cyano-6-(4-methoxy-3-n-propylphenyl)pyridin-2(lH)-one (0.7g), the title compound (0.43g) m.p. 210-212C, after recrystallisation from ethanol, was prepared according to the method of Example 4(c).
, '~093/07137 ~ 1 2 0 7 5 ~ PCT/GB92/01~7 ~xample 29 5-n-Butylthio-6-~3-(~-1-propenyl)-4-methoxyphenyll-3-(5 tetrazolyl)pyridin-2(1~-one (a) From 3-cyano-6-[3-(E-l-propenyl)-4-methoxyphenyl]- -pyridin-2(lH)-one (WO ~2/06085) (2g), 3-cyano-5-iodo-6-~3-~E-1-propenyl)-4-methoxyphenyl]pyridin-2(lH)-one (2.6g) m.p.
233-234C (decomp), after recrystallisation from ethanol, was 0 prepared according to the method of Example 23(a) replacing N-bromosuccinimide with N-iodosuccinimide.

~b) From 3-cyano-5-iodo-6-[3-~E-l-propenyl)-4- ~
methoxyphenyl]pyridin-2(lH)-one (lg), 5-n-butylthio-3-cyano- -6-[3-(E-l-propenyl)-4-methoxyphenyl]pyridin-2(1H)-one (0.065g) was prepared according to the method of 12(b).

(c) From 5-n-butylthio-3-cyano-6-[3-(E-1-propenyl)-4- `~
methoxyphenyl]pyridin-2(lH)-one (0.065g), the title compound (0.66g) m.p. 225-226C after recrystallis~tion from ethanol, was prepared according to the method of Example 4(c).

' ` WO93/07137 212 0 7 5 ~ PCT/GB92/Ol~ ~

Example 30 Pharmaceutical compositions for oral administration are prepared by combining the following : -._ _ . . _ % w/w 6-methyl-5-~2-naphthylthio)-3-(5-tetrazolyl)pyridin-2~1H)-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 formulatiors are then filled into individual soft gelatin capsules.

0 Example 31 A pharmaceutical composition for parenteral administration is prepared by dissolving the title compound of Example 2 (0.02 g) in polyethylene glycol 300 (25 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 micron membrane filter and sealed in sterile containers.

Claims

1. A compound of the formula (1) :

Formula (1) or a pharmaceutically acceptable salt thereof, wherein :

R0 is OH or a bioprecursor thereof, R1 is A0CO2H, P(Z)(OH)(OR2), SO2H, SO3H or 5-tetrazolyl optionally substituted in the 1-position by CH2CO2H or a bioprecursor thereof, A0 is CH2, CH2CH2, CHF, CF2, CR3(OR4), CO or C(OR5)(OR6), R2 is phenyl, C3-5cycloalkyl, C3-5cycloalkyl C1-4alkyl, or C1-8alkyl optionally substituted by C1-4alkoxy, R3 is H, methyl or ethyl, R4 is H or C1-3alkyl, R5 and R6 are each C1-3alkyl or together form a 1,2-ethanediyl group or 1,3-propanediyl group, Z is O or S, Ra is halo or X1Y1, X1 is CH2, O or S, Y1 is C1-6alkyl or Ar, Ar is phenyl optionally substituted by one to three groups independently selected from halo, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, C1-6polyfluoroalkyl or C1-6polyfluoroalkoxy, or Ar is 1-naphthyl or 2-naphthyl, R is H, C1-6alkyl or X2Ar1 wherein X2 is a bond or ethenyl and Ar1 is phenyl optionally substituted by one to three groups independently selected from C1-6alkyl, C2-6alkenyl, C1-6alkoxy, C3-6alkenyloxy, C2-6cycloalkyl, C2-6cycloalkoxy, C1-6alkylthio, phenyl, phenylthio, benzyloxy, C1-6polyfluoroalkyl, C1-6polyfluoroalkoxy, halo, N(R7)2 or NHCOR7 wherein R7 is H or C1-6alkyl, or -X(CH2)nY attached to adjacent carbon atoms of the phenyl ring wherein X and Y are independently CH2 or O and n is 1 to 3, wherein said C1-6alkyl, C2-6alkenyl or C1-6alkoxy groups can be independently substituted by OH, C1-6alkoxy, C2-6cycloalkyl, N(R7)2, CO2R7, or CON(R7)2; or Ar1 is 1-naphthyl optionally substituted in the 4-position by hydroxy or C1-6alkoxy, 2-naphthyl optionally substituted in the 1-position by hydroxy or C1-6alkoxy, 3-phenanthryl, 9-phenanthryl, 2-quinolinyl, 4-quinolinyl, 3-thianaphthenyl or 2-benzofuranyl, with the proviso that R1 is not an unsubstituted 5-tetrazolyl group when R0 is OH, Ra is C1-4alkyl, and R is - 58a -wherein Rb is C1-6alkyl, C3-6alkenyl, or C1-4alkyl substituted by 1 to 3 fluoro groups, and Rc is halo, C1-4alkyl, C1-4alkoxy, C1-4alkylthio, -NH2, or -NHCOR7.

2. A compound according to claim 1 wherein R is X2Ar1.

3. A compound according claim 1 or 2 wherein R1 is A0CO2H or A0CO2R9 in which R9 is an ester-forming group.

4. A compound according to claim 1 or 2 wherein is P(Z)(OH)(OR2) or P(Z)(OR2)2.

5. A compound according to claim 1 or 2 wherein is SO2H, SO3H or 5-tetrazolyl .

6. A compound according to any one of claims 1 to 5 wherein Ra is X1Y1.

7. A compound according to claim 1 which is :

6-methyl-5-(2-naphthylthio)-3-(5-tetrazolyl)pyridin-2(1H)-one, 3-(1-carboxymethyl-5-tetrazolyl)-6-methyl-5-(2-naphthylthio)-pyridin-2(1H)-one, n-propyl-[5-(2-naphthylthio)-2-oxo-1,2-dihydro-3-pyridyl]-phosphonate, 6-methyl-5-phenylthio-3-(5-tetrazolyl)pyridin-2(1H)-one, 5-(4-chlorophenylthio)-6-methyl-3-(5-tetrazolyl)pyridin-2(1H)-one, E-6-(2-phenylethenyl)-5-phenylthio-3-(5-tetrazolyl)pyridin-2(1H)-one, 3-carboxymethyl-6-methyl-5-(phenylthio)pyridin-2(1H)-one, 6-phenyl-5-phenylthio-3-(5-tetrazolyl)pyridin-2(1H)-one, 5-(3-chlorophenylthio)-6-methyl-3-(5-tetrazolyl)pyridin-2(1H)-one, 5-(2-chlorophenylthio)-6-methyl-3-(5-tetrazolyl)pyridin-2(1H)-one, 5-(3,4-dichlorophenylthio)-6-methyl-3-(5-tetrazolyl)pyridin-2(1H)-one, 5-n-butylthio-6-methyl-3-(5-tetrazolyl)pyridin-2(lH)-one, 5-n-butylthio-6-(4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)-pyridin-2(1H)-one, 5-benzyl-6-phenyl-3-(5-tetrazolyl)pyridin-2(1H)-one, 5-(2-naphthyloxy)-6-phenyl-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(2-naphthyl)-5-phenylthio-3-(5-tetrazolyl)pyridin-2(1H)-one, 5-(2-naphthylthio)-6-phenyl-3-(5-tetrazolyl)pyridin-2(1H)-one, 5-n-butylthio-6-(3,4-dimethoxyphenyl)-3-(5-tetrazolyl)-pyridin-2(1H)-one, 3-[6-methyl-5-(2-napthylthio)-2-oxo-1,2-dihydro-3-pyridyl]-propionic acid, 5-phenylthio-6-(4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)-pyridin-2(1H)-one, 5-methylthio-6-(4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)-pyridin-2(1H)-one, 5-ethylthio-6-(4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)-pyridin-2(1H)-one, 5-bromo-6-(9-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)-pyridin-2(1H)-one, 6-(3,4-dimethoxyphenyl)-5-pentyl-3-(5-tetrazolyl)pyridin-2(1H)-one, 6-(2-naphthyl)-5-phenoxy-3-(5-tetrazolyl)pyridin-2(1H)-one, 5-n-butylthio-6-[3-(E-1-propenyl)-4-methoxyphenyl]-3-(5-tetrazolyl)pyridin-2(1H)-one, ethyl (5-phenylthio-2-oxo-1,2-dihydro-3-pyridyl)phosphonate, 5-n-butylthio-6-(4-methoxy-3-n-propylphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one, or 5-n-butylthio-6-[3-(E-1-propenyl)-4-methoxyphenyl]-3-(5-tetrazolyl)pyridin-2(1H)-one, or a pharmaceutically acceptable salt thereof.

8. A compound according to any one of claims 1 to 7 for use as a medicament.

9. A pharmaceutical composition which comprises a compound according to any one of claims 1 to 7 and a pharmaceutically acceptable carrier.

10. A process for preparing a compound of the formula (1) as defined in claim 1 or a pharmaceutically acceptable salt thereof which process comprises :

a) for compounds wherein R1 is A0CO2H or A0CO2R9 and :

i) A0 is CR3(OR4), reacting in the presence of a strong base a compound of the formula (2) :

Formula (2) wherein R11 is methyl and R, and Ra are as defined in claim 1, with a compound of the formula (3) :

R3COCO2R9 (3) wherein R3 is as defined in claim 1 and R9 is an ester-forming group to form a compound of the formula (4) :

Formula (4) wherein R12 is CR3(OH)CO2R9 and R, R3, R9, R11, and Ra are as hereinbefore defined and thereafter optionally reacting with a C1-3alkylating agent to form the corresponding compound wherein R12 is CR3(OC1-3alkyl)CO2R9, ii) A0 is CO, reacting in the presence of a strong base a compound of the formula (2) as hereinbefore defined with a compound of the formula (5) :

R9O2CCO2R9 (5) wherein R9 is as hereinbefore defined to form a compound of the formula (4) wherein R12 is COCO2R9 and R, R9, R11 and Ra are as hereinbefore defined, iii) A0 is CH(OH), reacting a compound of the formula (4) wherein R12 is COCO2R9 and R, R9, R11, and Ra are as hereinbefore defined with a reducing agent to form the corresponding compound wherein R12 is CH(OH)CO2R9, iv) A0 is CH2, reacting a compound of the formula (4) wherein R12 is COCO2H
or COCO2R9 and R, R9, R11, and Ra are as hereinbefore defined with a suitable reducing agent to form the corresponding compound wherein R12 is CH2CO2H, v) A0 is C(OR5)(OR6), reacting a compound of the formula (4) wherein R12 is COCO2R9 and R, R9, R11, and Ra are as hereinbefore defined with a C1-3alcohol, 1,2-ethanediol or 1,3-propanediol to form the corresponding compound wherein R12 is C(OR5)(OR6)CO2R9, vi) A0 is CF2, reacting a compound of the formula (4) wherein R12 is COCO2R9 and R, R9, R11, and Ra are as hereinbefore defined with a fluorinating agent to form the corresponding compound wherein R11 is CF2CO2R9, or vii) A0 is CHF, reacting a compound of the formula (4) wherein R12 is CH(OH)CO2R9 and R, R9, R11, and Ra are as hereinbefore defined with a fluorinating agent to form the corresponding compound wherein R12 is CHFCO2R9, and thereafter optionally :

° converting the group OR11 into OH

° converting the group A0CO2R9 into A0CO2H; or b) for compounds wherein R1 is CH2CO2H, converting a compound of the formula (6) :

Formula (6) wherein R13 is acetyl and R, and Ra are as hereinbefore defined into the corresponding compound wherein R13 is CH2CO2H; or c) for compounds wherein R1 is CH2CH2CO2H or CH2CH2CO2R9, hydrogenating a compound of the formula (6) wherein R13 is CH=CHCO2H or CH=CHCO2R9 and thereafter optionally converting the group CH2CH2CO2R9 into CH2CH2CO2H; or d) for compounds wherein R1 is P(O)(OH)(OR2), hydrolysing a compound of the formula (6) wherein R13 is P(O)(OR2)2, R2 is as defined in claim 1 and R, and Ra are as hereinbefore defined; or e) for compounds wherein R1 is P(S)(OH)(OR2), converting a compound of the formula (6) wherein R13 is P(O)(NHR14)(OR2) and R14 is phenyl or C2-61-4alkyl and R, and Ra are as hereinbefore defined into the corresponding compound wherein R13 is P(S)(OH)(OR2); or f) for compounds where R1 is SO3H, reacting in the presence of a strong base a compound of the formula (2) as hereinbefore defined with sulphuryl chloride or a chemical equivalent thereof and optionally converting the group OR11 into OH; or g) for compounds wherein R1 is SO2H, reacting in the presence of a strong base a compound of the formula (2) as hereinbefore defined with sulphur dioxide and optionally converting the group OR11 into OH; or h) for compounds wherein R1 is 5-tetrazolyl, reacting a compound of the formula (4) wherein R12 is cyano or a compound of the formula (6) wherein R13 is cyano with an azide salt; or i) for compounds wherein R1 is 1-(HO2CCH2)-5-tetrazolyl or 1-(R9O2CCH2)-5-tetrazolyl, reacting a compound of the formula (6) wherein R13 is 5-tetrazolyl with a compound of the formula (7) :

LCH2CO2R9 (7) wherein L is a leaving group and R9 is as hereinbefore defined and thereafter optionally converting the group CO2R9 to CO2H; or j) for compounds wherein Ra is halo, reacting a compound of the formula (8) :

Formula (8) wherein R15 is a group R1 as hereinbefore defined or a precursor thereof, and R is as hereinbefore defined, with a suitable halogenating agent, and thereafter if necessary converting a precursor of R1 to R1;

and optionally thereafter :

° forming a bioprecursor of R0 and/or R1 ° forming a pharmaceutically acceptable salt.