CA2124003A1 - Phenol derivatives as agonists of a cyclic amp dependent protein kinase - Google Patents

Abstract

Phenol derivatives are described as agonists of a cyclic AMP
dependent protein kinase useful as medicaments.

Description

wo 93/1~107 pcr/GBs2/o2lls -` 2112~003 PHENOL DERIVATIVES AS AGONISTS OF A CYCLI~ AMP DEPENDENT PROTEIN KINhSE

The present invention relates to phenol derivatives, s 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-o dependent protein kinase (cA-PrK) (see J. Biol. Chem., 1989, 264, 8443 - 8446) and are of use in combatting such conditions where such agonism is thought to be beneficial.
They are likely to have anti-proliferative, anti-aggregatory, cholesterol-lowering,~smooth muscle relaxant, positive lusitropic, anti-allergic or anti-inflammatory activi_ies.
They are likely to be useful in the treatment of ; cardiovascular diseases where there is a component of diastolic failure, cancer, psoriasis, atheroschlerosis, thrombosis, re-stenosis, chronic reversible lung disease such 0; as asthma and bronchitis, allergic disease such as allergir asthma, allergic rhinltis and urticaria or gut motility dlsorders such~as~lrrltable bowel syndrome.

Accordingly the present invention p~ovides compounds of the 2;5~ fo~rmula ~

R

; or pharmaceutically acceptable salts thereof, wherein :

RO is OH or a bioprecursor thereof, R1 is AOC02H, P(Z)~OH)(OR2], S02H, S03H or 5-tetrazolyl or a bioprecursor thereof, ~::

WO93/10107 PCT/GB92~02119 2 1~0 ~ ~ 2 A0 is CH2, CHF, CF2 CR3(oR4), CO or C~oR5)(oR6), R2 is phenyl, C3_5cycloalkyl, C3_5cycloalkylC1_4alkyl, or s C1_galkyl 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 g.oup or 1,3-propanediyl group, Z is O or S, and ;~ Ar is phenyl optionally substituted by one to three groups independently~selected from C1_6alkyl, C2_6alkenyl, 1_6alkoxy, C3 6alkenyloxy, C3_6cycloalkyl, : C3_6cycloalkoxy,:Cl_6alkylthio, phenyl, phenylthio, ~ benzyloxy, ~1 6polyfluoroalkyl, C1_6polyfluoroalkoxy, halo, N(R7)2 or NHCoR7 wherein R7 is H or Cl_6alkyl, or ~h~ : -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 Cl_6alkyl, C2_6alkenyl or ~ :Cl_6alkoxy groups can be independently substituted by OH, C1_6alkoxy, C3_6cycloalkyl, N(R7)2, Co2R7 or CoN~R7)2.

Bioprecursors of the groups R0 and R1 are derivatives thereof which are convertible in vivo into the groups R0 and Rl.
A suitablT bioprecursor of the group R0 is oR8 wherein R8 is alkanoyl (for example acetyl), arylC1_~alkanoyl (for : example phenyl C1_4alkanoyl such as benzoyl)~ arylsulphonyl `~ ; (for example optionally substituted phenylsulphonyl or toluenesulphonyl) or C1_4alkylsulphonyl (for example methylsulphonyl).

When R1 is A0C02H a suitable bioprecursor is A0CO2R9 wherein R9 is an ester-forming group.
,~
',~

_ 3 -When Rl 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~(OR10) wherein R10 is an O-protecting group.
s Suitable O-protecting groups include pivaloyloxymethyl, propionyloxymethyl and pivalolyloxycarbonyloxymethyl.

When R1 is 5-~etrazolyl, a suitable biopricursor is a N-protected derivati~e thereof. Suitable N-protecting groups 0 include pivalolyloxymethyl, 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 Rl-R0 is A1CO2 or A20CH20, in which :
i ^
A~1~is CH2, CHF, CF2,~CR3(oR4), CO or C(oR5)~oR6), A2 is p~Z)oR2 or~CR3;(CO2R9), and R2 to R6, R9 and Z are as hereinbefore defined.
i i ~
Suitably R0 is hydroxy or oR8, preferably hydroxy.

Z5~ ~Suit~ably Rl is A0CO~H~or A0Co2R9.

Suitably R1 is P(Z)~OH)(OR2) or P(Z)(OR2)2.

Suitably ~1 is~SO2H, SO3H or 5-tetrazolyl.
Suitably R1 and R0 are linked together such that R1-R0 is ~ A1CO2.

h~ Suitably R1 and R0 are linked together such that R1-R0 is is A20CH20.

By the term alkyl is meant both straight- and branched- chain alkyl ;

WO93/10107 PCTfGB92/02119 4 - ~
2i~Q03 By the term C1_6polyfluoroalkyl is meant a C1_6alkyl group having at least one hydrogen replaced with fluoro, e.g. CF3 or CF2CF2H.

s 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 1,2-ethanediyl group.

Preferably Z is 0.

~ Suitably R9 is Cl_4alkyl optionally subs~ituted by hydroxy, ;~i?~ 20~e.g. 2-hydroxyethyl~or arylCl_4alkyl (for example phènylC1_4alkyl such as benzyl).

Suitably Ar is phenyl optionally mono-substituted by a group as~hereinbefore de~fined, for example in the 2,3, or 4 2s ~posltions by C1_6alkyl, Cl_6alkoxy, C3_6alkenyloxy, Cl~_6alkylthio,~ phenyl~, phenylthio, benzyloxy, CF3, halo or NHCoR7.

Suitably Ar is phenyl di-substituted by any groups as hereinbefore defined, for example in the 3,4-,3,5-,2,3-,2,4-or 2,5-, positions by groups independently selected from C2_6alkenyl, C1_6alkoxy, C3_6cycloalkoxy, halo, -X(CH2)nY- or Cl_6alkoxyC1_6 alkoxy.

; 35~ Suitably Ar is phenyl trisubstituted by any ~roups 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, Cl_6alkoxy or halo.

Examples of Cl_6alkoxy include methoxy, ethoxy, propoxy, butoxy, or pentyloxy.

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

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

Parti~ular compounds of this invention include :

2-(5-tetrazolyl)-5-(2,3-dipropoxyphenyl)phenol, or ethyl 2-hydroxy-4-~2,3-dipropoxyphenyl)phenyl phosphonate, lS and pharmaceutically acceptable salts thereof.

;~ This in~ention covers all tautomeri , geometric and optical isomeric forms of compounds of formula ~l).

Compounds of the formula ~l) can form pharmaceutically acceptable base addition salts with me~al ions, such as alkali metals for example sodium or potassium, or with an ammonium ion.
, ~25 In order to use a compound of the formu}a (l) or a pharma~eutlcally acceptable salt thereof for the treatment of humans~and other mammals it is normally formulated in arcordance with standard pharmaceutical practice as a pharmaceutical composition.
Compounds;of formula (l) and their pharmaceutically acceptable salts may be administered in standard manner for the treatment of the indicated diseases, for example srally, sublingually, parenterally, transdermally, rectally, via inhalation or via buccal administration.
~ .
Compounds of formula (l) and their pharmaceutically accep~able salts which are acti~e when given orally or via buccal administration can be formulated appropriately in ~2~03 - 6 -dosage forms such as liquids, syrups, tablets, capsules and -lozenges. An oral liquid formulation will generally consist ;
of a suspension or solution of the compound or salt in a liquid carrier for exampIe, ethanol, glycerine or water with s a flavouring or colouring agent. Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparin~ solid formulations may be used. Examples of such carriers include starch, celluloses, lactose, sucrose and magnesium stearate. Where the composition is in the O form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell. Where the composition is in the form of a soft gelatin shell capsule, any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be lS considered, for example aqueous gums, celluloses, silicates or oiIs an~ are incorporated in a soft gelatin capsule shell.

; Typical parenteral compositions consist of a solution or suspension of the~compound or salt in a sterile aqueous 2~0 ~or non-aqueous carrier optionally containing a parenterally accept~able oil or solubilising agent, for example ; polyethylene glycoL, polyvinylpyrrolidone, lecithin, 2-pyrrolidone, cyclodextrin, arachis oil, or sesame oil.
. ~.
Zs~ ~A typical suppository formulation comprises a compound of formula (l) or a pharmaceutlcally acceptable salt thereof which is acti~e when administered in this way, with a binding and/or lubricat~ing~agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogues.

Typical transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated 35- ~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 WO93/10107 2 12 4 O ~ 3 PCT/GB92/02119 .

as dichlorodifluoromethane or trichlorofluoromethane, or are in the form of a powder for insufflation.

Preferably the composition is in unit dosage form, for s example a tablet, capsule or metered aerosol dose, so that the patient may administer to himself a single dose.

Each dosage unit for oral administration contains suitably from 0.001 mg~Kg to 30 mg/Kg, and preferably from O.OOS mg/Kg 0 to 15 mg/Kg, and each dosage unit for parenteral administration contains suitably from 0.001 mgtKg to 10 mg/Kg, of a compound of formula (1) or a pharmaceutically acceptable salt thereof calculated as the free acid.

S The daily dosage regimen for oral administration is suitably about 0.001 mg/Xg 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 adm~nistration is~suitably about 0.001 mg/Kg to 40 mg/Kg, for example about 0.005 mg/~g to 10 mg/Kg, of 2 compound of the formula ~1) or a pharmaceutically acceptable salt thereof calculated as the free acid. The active ingredient may be administered as required for example from 1 - 8 times ~ day or by infusion. The compositions of the invention are agonists of a cA-PrK and are of use in co~batting 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 ~y inhalation dosages are controlled by a valve, are administered as required and for ~n~adult are conveniently in the range 0.1 - 5.0 mg of a compound of the formula (1) or a pharmaceutically acceptable ~; salt thereof.
`
3s The compounds of this invention may be co-administered with other pharmaceutically active compsunds, 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 W093/tO107 PCT/~B92/02119 ~ ~ ~ e ~ 0 3 8 composition. Examples of compounds which may be included in pharmaceutical compositions with the compounds of the formula (l) are bronchodilators such as sympathomimetic amines for ;
example isoprenaline, isoetharine, sulbutamol, phenylephrine S and ephedrine or xanthine derivatives for example theophylline 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 : lO methotrexate, fluoracil, cisplatin, actinomycin D, anti-: atherschlerotic agents for example cholesterol lowering drugs such as HMGCoA reductase inhibitors, bile acid sequestrants, drugs for the treatment of psoriasis, for example retinoids, : anthralin, anti-inflammatories for example cortiscosteroids, non-steroid anti-inflammatories such as aspirin, :; antithrombotics for example dipyridamole, or fibrinolytic agents. ~ ~

In~anothèr~ aspect~the present invention provides a process 20~:for the preparation~of compounds of the formula (l) or pharmaceutically acceptable salts thereof, which process ':
: comprises : :

a) fo~ compounds~wherein Rl is AOC02H or AOC02R9 and :
25 ` ~ ~
AO is CR3 (oR4) ~ ~:
réactlng in the presence of a strong base a compound of the :: :formula ~2) :

:~; 30 : ' : ~f ~'~:; ~ 11 (2) 3s wherein Rll is methyl and Al is as hereinbe~ore defined, '~ ~
:

_ 9 _ with a compound of the formula (3) :

R3CoCO2R9 l3) wherein R3 and R9 are as hereinbefore defined~to form a compound of the formula (4) :

~Ar ll R'2~. (4) OR

wherein R12 is C:R3 (OH) C02R9 and R3, R9, Rll, and Ar are as hereinbefore defined and 'chereafter optionally reacting with 15 a: Cl_3alkylating agent ~o form the corresponding compound wherein R12 is C~3 ~OCl_3alkyl) CO;~R9, is CO, reacting in the presence of a strong base a compound of ; 20 the formula ~2) as hereinbefore defined with a compound of the ormula (5) :

R9o2c~o2R

2s: wherein ~9 is as hereinbefore defined to form a compound of ~ _ the formula (4) wherein R12 is COCO2R9 and R9, R11 and Ar are : ~ as hereinbefore defined, A0 is CH (OH~, : 30 reacting a compound of the formula (4) wherein R12 is COC02R9 ~: and R9, R11, and Ar are as hereinbefore defined with a reducing agent to form the corresponding compound wherein R12 ls CH (OH) CO2R9, iv) A0 is CH2, W093/10107 PCT~GB92/02119 2124003 - lO- `

reacting a compound of the formula (4) wherein R12 is COC02H
or COCO~R9 and R9, Rll, and Ar are as hereinbefore defined with a suitable reducing agent to form the corresponding compound wherein R12 is CH2C02H, v) AO is C~oR5t~oR6), --~
reacting a compound of the formula (4) wherein R12 is COC02R9 and R9, Rll, and Ar 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)(aR6)Co2~9, vi) AO is CF2, reacting a compound of the formula (4) wherein R12 is COC02R9 and R9, R11, and Ar are as hereinbefore defined with a S fluorinating agent to form the corresponding compound wherein Rll is CF2C02R9, or :~
~ii) AO is C~F, ; ~ reactlng a compound of the formula (4) wherein R12 is CH(OH)C02R9 and~R9,~Rl1, and Ar are as hereinbefore defined with a fluorinating agent to form the corresponding compound wherein R12 is CHEC02R9, and thereafter optionally :
2s : ~ converting the group OR11 into OH

~ ~ con~erting the group AOC02R9 into AQCO~H; or : ~ bi for compounds wherein Rl is CH2C02H, converting a compound of the formula ~6) :

: il I
R ~ (6) , , ~ 35 C~H

W093/10107 2 12 ~ O 0 3 PCT/GB92~02119 wherein ~13 is acetyl and Ar is as hereinbefore defined into the corresponding compound wherein R13 is CH2C02H; or s c) for compounds wherein Rl is CH(oR4)Co2H reacting a compound of the formula (4~ wherein R12 is -C.~(OH)CN with a Cl_3alkylating agent and/or converting the group CN into C02H, and optionally converting the group ORll into OH; or lo d) for compounds wherein Rl is P(O)~OH)(OR2), hydrolysing a compound of the formula (5) wherein R13 is P(O)(OR2)2 and R2, and Ar are as hereinbefore defined; or : e) for compounds wherein Rl is P(S)(OH)(OR2), converting a compound of the formula (6) wherein R13 is P(o)(N~R14)(oR2) and R14 is phenyl or Cl_4alkyl and Ar is as hereinbefore : defined into the corresponding compound wherein R13 is P~S)(OH)(OR2); or ~ ~ .
f~ for compounds:where Rl is S03H, reacting in the presen~e 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 ORll into OH; or ~- : 2:5 :~ ~ g)~ for compounds wherein Rl is S02H, 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 ORll into OH; or h~ for compounds wherein Rl is 5-tetrazolyl, reacting a compound of the formula (4) wherein R12 is cyano and Rll is as hereinbefore defined or benzenesulphonyl, or a compound of he formula (6) wherein R12 is cyano with an azide salt and thereafter if necessary converting the group ORll into OH; or i) for compounds wherein Rl is as defined for compounds of the formula (1) reacting in the presence of a palladium catalyst a compound of the formula (7):

W~93/10107 PCT/GB92/02119 2 ~ 0 3 Rb~g , Ra wherein Rb is a group Rl as hereinbefore defined or a precursor thereof and Ra is R0 or ORll as hereinbefore defined and Ll is a leaving ~roup with a compound of the formula (8~:
ArBSO~2 ~8) or a chemical equivalent thereof wherein Ar is as hereinbefore defined and then, if necessary, con~erting a ~: : lS precursor of Rl into Rl and/or converting the group ORll into ;~ OH~

and optionally thereafter :

20: forming a ~ioprecursor of R~ and/or Rl forming a pharmaceutically acceptable salt.

Sui~ably a compound of the formula (2) is reacted with ~
2s strong base such as lithium diisopropylamide, or a Cl_~alkyl lithium or aryl lithium such as mesityl lith~um 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 followed by a ca~alytic quantity of diisopropylamine.

The anion of a compound of the formula (2) is suitably reacted wi~h, a compound of the formula (3) or a compound of : 35 the formula (5) in an organic sol~ent such as WO93/10107 ~ 1 2 ~ O 0 3 PCT/~B~2/02119 tetrahydrofuran, diethylether or dimethoxyethane with cooling ~-100 to 0C) to form a compound of the formula (4) wherein ~12 is CR3(0H)C02~9 or COCO2R9 respectively. A suitable compound of the formula (3) is ethylpyruvate, or ethyl s glyoxylate or a chemical equivalent thereof and a suitable compound of the formula (5) is diethyloxalate-.

A compound of the formula (4~ wherein R1~ is CR3~0H)Co2R9 is suitably reacted with a Cl_3alkylating agent such as 0 iodomethane, iodopropane or dimethylsulphate in the presence of a base such as sodium 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(OC1_~alkyl)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 20 ~suitably reacted wlth a reducing agent such as sodium borohydride, or diisobutylaluminium hydride in an organic solvent such as dichloromethane, a C1_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 C~( ~)CO2R9. ; ~ ~

A compound of the formula ~4) wherein R12 is COCO2H or COCO2R9 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 am~ient or elevated temperature (e.g. 40-100C) to form the corresponding compound wherein R12 is CH2CO2H. Under these reaction conditions the CO2R9 group is con~erted 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 ~ ::

2 l2 40 ~3 - 14 - "`"`

paratoluenesulphonic acid, concentrated sulphuric acid or anhydrous hydrogen chloride, at ambient or elevated temperature to form the corresponding compound wherein R12 is c (oR5) (oR6) C02R9.
s A compound of the formula (4) wherein R12 is COCO2R9 or CHOHCO2R9 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 lo am~ient or elevated temperature (e.g. 30-6QC) to orm the corresponding compound where R12 is CF2C02R9 or CHFCO2R9 respectively.

A compound of the formula (4) wherein OR11 is methoxy can 1S suitably be converted to the corresponding compound wherein ORll is hydroxy by reaction with sodium iodide and chlorotrimethylsilane in an organic solvent such as acetonitrile~ or~a~hal~ohydrocarbon e.g. dichloromethane or chloroform at elevated~(e.g. 30 - 80C) or preferably ambient 20 ~temperature. This method ~s particularly suitable for preparing compounds of the formula (1) wherein R1 is AOCO2~9 since the ester-forming~group R9 is not hydrolysed under the reacti~on conditions.~ Another method utilises sodium thiomethoxidè in an ~orqanic sol~ent such as dimethylformamide ~at~an ele*ated temperature for example 40 - 120C. The more forcing; conditions of this method are suitable for preparing compounds~of formula~ ~1) wherein R1 is AOC02H.

A;compound of the~formula ~4) wherein R12 is AOCO2R9 can suitably be converted to the corresponding compound wherein R12 is AOCO2H by reaction w~th 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 (e.g. 40 -120C) which provides directly compounds of 'he formula ~1) wherein R0 is hydroxy and R1 is AOCO2H.

Suitably a compound of the formula (6) wherein Rl3 is acetyl is converted to the corresponding compound where Rl3 is CH2CO2H by reaction with sulphur and morpholine s at ele~ated 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 the reaction mixture.
:
0 Suitably a compound of formula ~4) where Rl2 is -CH(OH)CN is reacted with a Cl 3alkylating agent as hereinbefore descrlbed followed by reaction with aqueous mineral acid such as hydrochloric acid at ambient or elevated temperature preferably at reflux in order to prepare the corresponding compound where Rl2 is CH(OCl_3alkyl) CO2H. The alkylation can be omitted if the corresponding compound where Rl2 is CH(OH)CO2H is desired. During the hydroly~is of the CN group the OR11 group may~be~converted to hydroxy. If not and if deslred thl~ group~can be converted to hydroxy as hereinbefore described.

A compound of the formula (4) wherein Rl2 is -CH(OH)CN can be prepared by reacting the corresponding compound wherein Rl2 is -CHO with a source of cyanide such as potassium cyanide in 25~ the presence of an~acid such as hydrochloric acid preferably at~ambient temperature.

A compound of the formula (4) or (6) where Rl2 or Rl3 is CHO
is suitably prepared by reacting the corresponding compound wherein Rl2 or R13 is cyano with a suitable reducing agent such as diisobuty}aluminium hydride followed by aqueous acidic work-up.
, ~ ~
Suitably a compound of the formula (6) wherein Rl3 is P(O)(OR2)2 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), ~;; préferably at the reflux temperature of the reaction mixture.

:::
:- ~

21240-03 - 16 - " ~
Suitably a compound of the formula (6) wherein R13 is P~o)(MHR14)(oR2) is con~erted to the corresponding compound wherein R9 is P(S)~OH)(OR2) by reaction with a strong base such as sodium hydride in an organic solvent such as dimethoxyethane at ambient or elevated ~emperature, ~ç.g~ 40 - 100C) followed by reaction with car~sn dis~lphide.

Suitably the anion of a compound of the formula (2) prepared as hereinbefore described is reacted with sulphuryl chloride :
0 or a chemical equivalent thereof or with sulphur dioxide in an organic solvent such as tetrahydrofuran with cooling (-' 100 - 0C) ~o form after aqueous work-up a compound of the formula ~4) wherein R12 is ~03H or SO2H respectively and OR
is methoxy which if desired can be converted to the corresponding compound wherein OR11 is hydroxy as hereinbefore described.

A~compound of the formula ~4) wherein R12 is cyano or a compound of the formula (6) wherein R13 is cyano is suitably ~ 20 reacted with an azide salt such as ammonium, sodium or :~ ~ aluminium azide in an organic solvent such as diethylformamide, dimethylsulphoxide, N-methylpyrrolidone or tetrahydrofuran at an ele~ated temperature e~g. 40-200C, :: ~ preferably at 100-150C to form the corresponding ; 2s 5-tetrazolyl compound. Preferably in a compound of the f~ormula ~4) OR11 is benzenesulphonyl which can be introduced : : in standard manner, for example by reacting the corresponding hydroxy compound with benzenesulphonyl chloride in the presence of a base such as triethylamine. This group can be ; 30 remo~ed in standard manner, for example by reaction with a base such as sodium hydroxide.

Suitably a compound of the formula ~7) is reacted with a ompound of the formula (8) in the pre~ence of 1-50 mole %, ~ 35 preferably 2-10 mole %, of a palladium catalyst and a base : such as triethylamine, sodium bicarbonat~, or aqueous sodium carbonate and optionally lithium chloride ~n an organic ;~ ~ sol~ent such as dimethylformamide, dimethoxyethane acetonitrile, toluene, tetrahydrofuran, ethanol, or mixtures WO93/l0107 2 1 2 4 0 0 ~ PCT/GB92/02119 thereof, at elevated temperature, ~e.g. 30-150C), preferably at the reflux temperature of the mixture. Suitably kl is halo for e~ample iodo, bromo or chloro or a trifluoromethanesulphonate. Subsequently the OR11 group can s be converted to hydroxy as hereinbefore described for compounds of formula (4). Examples of palladium catalysts that can be used include:

tetrakis(triphenylphosphine)palladium (Pd[PPh314), 0 bis(triphenylphosphine)palladium dichloride (Pd~PPh3~2C12), [1,4-bis-(diphenylphosphine)~utane~palladium dichloride (Pd(dppb)C12), [1,3-bis-(diphenylphosphine)propanelpalladium dichloride (Pd(dppp)Cl2)~
~1,2-bis-(diphenylphosphine)ethanelpalladium dichloride (Pd(dppe)C12), bis~tri-o-tolylphosphine)palladium diacetate or dichloride Pd(totp);(OAc)2~or Pd~totp)C12), or bis(d phenylphosphine)ferrocinopalladium diacetate or dichl~oride (Pd[dppf](OAc)2 or Pd~dppflC12).

By a chemical equivalent of a compound of the formula (8) is meant a~reagent that~can couple the Ar group onto the pyridyl ring of a compound of the formula (7). For example aryl 25~stannanes can be used, such as ArSnMe3 which can suitably be prepared by reacting a suitab}e aryl halide (such as ArBr or ArI)~ with a~base~such~as t-butyl lithium followed by reaction with~a trimethyl tin halide (e.g. Me3SnCl). Alternatively the~aryl halide can be reacted with Me3SnSnMe3 in the presence of a palladi~m catalyst as hereinbefore described to prepare a suitable aryl stannane.

When Rb is a group Rl as hereinbefore defined reaction of a compound of the formula (7) with a compound of the formula (8) results directly in compounds of the formula (1).
,, An example of a precursor for R1 is when Rb is hydrogen. In this situation reaction of a compound of the formula (7) with a compound of the formula (8) or a chemical equivalent WO93f10107 PCT/GB92/02119 ~ 1 2 ~ 0 03 - 18 ~
thereof results in a compound of the formula (2) or a compound of the formula (6) wherein Rl3 is hydrogen. Such compounds can then be converted into a compound of the formula (l) as herein described.
Other precursors for R~ include CN, CHO or COMe. Reaction of a compound of the formula (7) wherein Rb represents such a precursor with a ~ompound of the formula (8) or a chemical equivalent thereof results in a compound of the formula (4) 0 or a compound of the formula (6) wherein Rl2 or Rl3 is CN, CHO or COMe. Such compounds can be con~erted to compounds of the formula (l) as herein described.

If desired a compound of the formula (l) wherein Rl is A0CO2H
lS can be converted to the corresponding compound wherein Rl is A0C02R9 by reaction with a compound R9OH wherein R9 is as hereinbefore defined.

' A compound of the formula (lj wherein R0 is OH can be convert,ed to the corresponding compound where R0 is oR8 by reactlon with R8L2~wherein R8 is as hereinbefore defined and ; L2 is a leaving~group such as halo e.g. bromo, chloro, iodo.

If~desired a compound~of the formula (l) wherein Rl is 25~;P~Z~ (OR2)(0H) can~be converted to the corresponding compound wherein~Rl is P(Zj~(OR2)(ORl0)~by reaction with a suitable O-protecting agent in stsndard manner. For example the compound can be reacted with a pivalolyloxymethyl halide.

30~ A compound of the formula (l) wherein Rl is 5-tetrazole can be ~reacted with a suitable N-protecting agent in standard manner, for example with à pivalolyloxymethyl halide.
. ~
A compound of the formula (l) wherein Rl-R0 is AlCO2 is 35 suitably prepared by heating a compound of the formula (l) wherein Rl is AlCO2H and R0 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.

WO 93~10107 2 1 2 4 0 0 3 PCT/GB92/02119 A compound of the formula (1) wherein R1-R0 is A20CH20 is suitably prepared by reacting a compound of the formula (1) wherein R1 is A2OH and R0 is OH with a dihalomethane such as diiodo- or dibromomethane in the presence of silver carbonate 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 dimethylformamide dimethylacetal in dimethylformamide or trimethylphosphite at an elevated temperature (e.g. 40 -120C) or with iodomethane and silver carbonate in toluene or chloroform. This method can also be used for converting compounds of the formula (6) into corresponding compounds of the formula (4) and compounds of formula (7) wherein Ra is hydroxy into corresponding compounds wherein Ra is OR11.
:
A ~compound of the formula (6) wherein R13 is acetyl can also be prepared by reacting a compound of the formula ~6) wherein R13 is cyano with methyl lithium followed by aqueous acidic work up with for example hydrochloric acid.

A compound of the form~la (6) wherein R13 is hydrogen can be prepared by reacting a compound of the formula ~6) wherein R13 is cyano wi~h orthophosphoric acid at an elevated temperature, e.g. 50 - 200C.

A compound of ~ormula (4) wherein R12 is cyano is suitably prepared by reactlng the anion of a compound of formula ~2) wherein Ar and Rll are as hereinbefore defined with dimethylformamide with cooling (e.g. -80 to 10C), followed by ambient temperature and aqueous work-up. The resulting compound of formula (4) wherein R12 is carboxaldehyde is treated with hydroxylamine hydrochloride and sodium acetate in a suitable solvent such as ethanol or methanol at ele~ated temperature, e.g. 40-100~C, preferably at the reflux temperature of the reaction mixture followed by dehydrating , WOg3/10107 PCT/GB92/02119 212~00~

the product o~tained for example by heating with acetic anhydride.

A compound of the formula (6) wherein R13 is cyano or acetyl and Ar is as hereinbefore defined can be suitably prepared by reaction of a compound of formula (4) wherein ~12 is cyano or acetyl and R11 and Ar are as hereinbefore defined with a demethylating agent such as sodium iodide/chlorotrimethylsilane in the absence of solvent or in o 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)~OR2~2 can lS be prepared by treating a compound of the formula 12) wherein R11 is P~O)~OR2)2 with a strong base such as lithium diisopropylamide~in a~ organic solvent such as tetrahydrofuran with cooling (e.g. -100-0C).

20~ ~ A~compound of the~formula ~2) wherein R11 is P~O)~OR2)2 is sui~ably prepared~by treating a compound of the formula ~6) wherein R~3 is hydrogen with a compound of the formula (9):

3P~(o)(oRz)2 (9) 2s ' ~ ~
' wherein~L3 is a lea~ing group and R2 is as hereinbefore defined with a base such as diisopropylethylamine.

Suitably L3 is halo, for example chloro or bromo.
30~
A compound of form~ula, (2), wherein R11 is P(O?~OR2)2 can a~lso be prepared by treating a compound of the formula (6) wherein R13 is hydrogen with a compound of the formula (10):

~P(O)(OR2~2 (10) wherein R2 i5 as hereinbefore defined in the presence of an amine base such as triethylamine, and carbon tetrachloride.

: ~

WO93/10107 PCT/~92/02119 ....

Alternatively, a compound of the formula t6~ 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 (9) in the presence of a strong base such as lithium s diisopropylamide in an organic sol~ent such as 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 temperature e.g. 40-80-C) canveniently 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 ~13 is P(O)~tOH)(OR2) with carbon tetrachloride, triphenylpAosphine and aniline or a Cl_4alkylamine in an ,25~ organi~c solvent such ~as~pyridine at ambient temperature or 'with cooling (e.g~ 10 to 5C). Alternatively a compound of the~formula 16)~where R13 is P(O)~OH)(OR2) can be reacted with~dimethylformamide,~and 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).

Compounds of the formula (7) are known or can be prepared from a compound of the formula (11):

~ , , :~ ~

: ~ :::

2~124003 ~ ~11) s wherein Ra and Ll are as hereinbefore defined using similar methods to those described for preparing compounds of the formula (l).

Thus, a compound of the formula (7) wherein Rb is P(o)~OR2)~
0 can be prepared by reacting a compound of the formula ~ll) wherein Ra is OH with a compound of the formula (9) or ~l0) :~ in similar manner to the reaction of a compound of the f~rmula (6~ wherein Rl~ is hydrogen with a compound of the formula (9) or (l0). If desired th~ group Ra can then be ; IS con~erted to OMe.

Similarly, a compound~ of the formula (ll) where R~ is OMe can be treated in the presence of a stxong base with a compound :: of~the formula (3), a compound of the formula ~5), sulphuryl 20 : chloride, sulphur dioxide or dimethylformamide to prepare a compou~d of:the formula (7).wherein Rb is CR3~oR4)Co2R9, GOCO2R9, SO3H, SO2H,~or C~O respectively in simllar manner to the corresponding reaction with a compound of the formula (2) ; ; as hereinbefore described. Particularly suitable as a strong 2S base is li~hium tetramethyl piperidide.

A.compound of the formula (8) is suita~ly prepared by ~; reacting the organolithium or Grignard reagent, formed from a ~ ~ compound of the formula (12):
:~: 30 Ar-L~ ~12) :~ wherein ~4 is bromo or iodo and Ar is as hereinbefore defined with a tri-Cl_4alkylborate such as trimethyl, tri-isopropyl WO93/10107 2 1 2 4 O 0 3 PCT/GBg2/02llg . - 23 -or tri-n-butyl borate in an organic solvent such as diethyl ether or tetrahydrofuran with cooling ~e.g. - 80-l0C).

The Ar group in compounds of the formula (2), (4), (6) or (12) preferably (2) or (4) may be appropriately functionalised by methods of aromatic substi~ution known in the art. For example, a bromo group may be introduced into a suitably substituted phenyl ring ~eg. disubstituted in the 2-and 4-positions by electron-donating groups such as 0 Cl_6alkoxy) by reaction wi~h a brominating agent such as N-bromosuccinimide or bromine in a solvent such as dimethylformamide. Alternatively a nitro group can be introduced into a phenyl ring by reaction with a suitable nitrating agent, such as nitronium tetrafluoroborate. Such a s group can be readily hydrogenated to an amino group whicn if desired can be converted to a NHCoR7 group by reaction with LCoR7 wherein 1 is a lea~ing gro~lp and R7 is as hereinbefore :~ deflned. Suitable examples of the reagent LCOR include acid hàlides (L is halo eg. c~loro or bromo) or acid anhydrides ~L
is oCoR7).

Other suitable functionalisations include the introduction of ~ an allyl group ortho to a hydroxy substituent on a phenyl :~ ring by reaction:with an allyl halide, eg. bromide, to form 2s :an allyloxy derivative which on heating undergoes a Claisen . rearrangement to form an ortho allyl hydroxy deriYative. The ; hydroxy group can-in turn be functionalised, eg. by reaction.
with a Cl_6alkyl halide to form a Cl_6alkoxy group. If desired, an allyl group can be converted to a~ E-l-propenyl group by reaction with a strong base, such as sodium methoxide. An E-l!-propenyl group can be cleaved to a formyl group by reaction with an oxidising agent such as N-me~hylmorpholine-N-oxide in the presence of a catalyst such : as osmium tetroxide to form a 1, 2,dihydroxypropyl group which on reaction with an oxidising agent such as sodium periodate forms the formyl group. Alternatively the E-l-propenyl group : can be converted directly to a formyl group by reaction with a mixture of osmium tetroxide and sodium periodate or by reaction with ozone. A formyl group can in turn be further ,~ ~ .
2121~3 - 24 -functionalised, for example it can ~e converted to a hydroxymethyl group by reaction with a suitable reducing agent such as sodium borohydride, the hydroxymethyl group then being reacted further, eg. with a Cl_6alkyl halide to form a Cl_6alkoxymethyl group. Alternatively a formyl group can be reacted with a suitable Horner Wittig or Wittig ;
rea~ent such as ~Rl50)2P(Q)CH2C02Rl5 or Ph3P=CHCO2Rl5 wherein Rl5 is Cl_4alkyl to form a CH=CHCO2RlS group which can be optionally hydrolysed to a -CH=CHCO2H group. A -CH=CHCo2Rl5 group can be converted to a -CH=CHCONtR7)2 group by reaction with an amine HNtR7)2 or a chemical equivalent thereof wherein R7 is as hereinbefore defined. Alternatively a -CH=CHCO2H group can be converted to an acid halide, eg. the acid chloride by reaction with oxalyl chloride, which can lS then be reacted with an amine HN(R7)2 or a chemical equivalent thereof. An example of a chemical equivalent is ammonium hydroxide which will form a CH=CHCONH2 group.

Pharmaceutically~acceptable base addition salts of the ;~
compounds of the formula~(l) may be prepared by standard methods, for example~by~reacting a solution of the compound of the formula ~l) with a solution of the base.

The following biological test methods, data and Exampies ;serve~to illustrate this invention.

Cycl~c~AMP Pro~n ~18~sc (ca-Pr~) A4Oniat Acti~ty Type II cA-PrK was prepared from the cardiac muscle of a cow.
The~supernatant from a muscle homogenate ~3 mls of l0 mM
potassium phosphate, 1 mM EDTA per g tissue) was applied to a column of DEAE-cellulose equilibrated with the homogenisation buffer and the type II cA-PrK was eluted with homogenisation buffer containing 350 mM sodium chloride (Rannels et al., 1983, Methods Enzymol., 99, 55-62).

Type II cA-PrK was assayed for phosphotransferase acti~ity by incu~ating the enzyme at 30C for 5 minutes with 32P]-adenosine triphospha~e and a suitable peptide ;

, . . .

substrate such as malantide (Malencik et al., 1983, Anal.
Biochem., 132, 34-4~). The reaction was terminated by the addition of hydrochloric acid and the [32P]-phosphopeptide quantified by spotting the reaction mixture onto s phosphocellulose papers. The concentration of compound required to give 10% phosphotransferase activ-ation is given as the EClo (~M). The compounds of Examples l and 2 had EClo values of 2.6 and l.0 ~M respectively.

Iahibition of ~lat~let A4gregation ~;~ Human platelet-rich-plasma was separated from freshly drawn ~; blood (in acid/citrateidextrose) and treated with l00 ~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.5xl08 cells/ml. Aliquots of this suspension were pre-incubated with compounds for 5 minutes at 37C, then challenged with l.0 ~M U46619. The extent of 20~aggregation after 2 minutes were expressed as a percentage of control and results~obtained are expressed as an IC50 concentration to cause 50% inhibition of platelet aggregation, ~M). The compounds of Examples 1 and 2 had ICso values~of 20 and 38 ~M respectively.
~ ~
IDhibition of Spontan~ou~ CQntraction i~ 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. Inhi~itory responses 3s were calculated as %;maximum inhi~ition 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 EC50 ~1~1 2124003 26 - `"`' Bro~chodilatation - In ~itro Spiral strips of guinea-pig trachea were suspended in standard organ baths containing Krebs solution. The tissues were connected at the free end to isometric transducers which allow recording and display of developed tension on chart recorders. Tension was allowed to develop spontaneously and concentrations of test compounds added in a cumulative fashion. The concentrat~ion of compound which caused 50%
inhibition of the spontaneously developed tension is given as ;~ the IC50(~M).

Measurement o~ cardiac mu~cl~ r~laxation time in rabbit ventricl~

Papillary muscles from the right ventricle of female Albino New~Zealand rabbits~are~mounted in standard organ baths containing oxygenated Krebs solution. One end of the muscle ;20~ ~Ls c~onnected to an isometr1c transducer which allowed recording of contractile force and its first derivative on chart recorders.;;Test compounds are added to the bath in a cumulative manner. ReIaxation time is calculated as the time taken from peak;tension to the end of the contraction.
2s~ 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 fai~ure~such as congestive heart failure, angina, hypertension and cardiomyopathy.

,.. ~ ~- :~ :

:. ~

WO93/10107 2 1 2 4 ~ 0 3 PCT/GB92/02119 Exa~ple 1 2-~5-Tetrazolyl)-5-~2,3-di-n-propo~ypha~yl)ph~ol (a) From l,2-di-n-propoxybenzene ~13.8g~, 2,3-di-n-propoxyphenylboronic acid (13g~ was prepared according to the method of W. J. Thompson and J. Gaudino J. OrgO Chem. 1984, 4g, ~237.

(b) To methyl 2,4-dihydroxybenzoate (5.95g) and 4-N,N-dimethylaminopyridine ~8.65g) in dichloromethane at -50C, trifluoromethanesulphonic anhydride (lO.Og) was added over 5mins. The mixture was warmed to room temperature stirred ~or l hour, treated with 2N hydrochloric acid and the organic phase separated, dried ~MgS04) and solvent removed at reduced pressure. The residue was column chromatographed silica gel, diethyl ether/petroleum ether eluant) to give methyl 2-hydroxy-4-trifluoromethanesulphonyloxy benzoate (S.Og) lH NMR~ (CDCl3) 3.99(s,3H), 7.25~d<lH1, 7.44(dd,lH) and 8.23(d,1H).

(c3 From methyl 2-hydroxy-4-trifluoromethanesulphonyloxy benzoate ~8.7g) and 2,3-di-n-propoxyphenylboronic acid (7.4g) an;d using the method of A. Huth, I. Beetz and I. Schumann, ;Te~trahedron, 1989, 45, 667~, methyl 2-hydroxy-4-(2~3-di-n-p~ropoxyphenyl)benzoate (4.6g) was prepared. lH NMR (CDCl3) ; 0O82(t,3H), l.08(t,3H3, l.48-l.59(m,2H), l.8l-l.95(m,2H), 3.70(t,2H), 3.96(s,3H), 3.98(t,2H), 6.93(d,2H), 7.07-7.17(m,3H), 7.83(d,1H) and 10.76(s,1H).
3~
. . .
(d~ Methyl 2-hydroxy-4-(2,3-di-n-propoxyphenyl)benzoate (2.2g) in ethanol (15ml) and dioxane (30ml) was treated with sodium borohydride llg) and stirred at room temperature for 48 hours. Sol~ent was removed at reduced pressure and the residue column chromatographed Isilica gel, dichloromethane eluant) to gi~e 2-hydroxy-4-12,3-di-n-propoxyphenyl)benzyl alcohol (1.7g). The benzyl alcohol was oxidised according to ~; the method of S. V. Ley et al J. C. S. Chem. Comm., l987, 162~ to give 2-hydroxy-4-(2,3-di-n-propoxyphenyl)-:

W093/10107 PCT/GB9~/021l9 212~003 - 28 -benzaldehyde (0.7~g). lH NMR (CDCl3~ 0.82~t,3H), 1.08(t,3H), 1.41-1.62(m,2H), 1.84-1.95(m,2H), 3.72(t,2H), 3.99~t,2H), 6.91-6.96(m,2H), 7.09(t,lH), 7.18(s,lH), 7.26(dd,lH~, 9.92(s~1H) and 11.06(s,1H)~
..
(e) A solution of 2-hydroxy-4-(2,3-di-n-propoxyphenyl)-benzaldehyde ~0.78g) in ethanol (15ml) and saturated aqueous sodium acetate (8ml) containing hydroxylamine hydrochloride ~0.23g) was stirred for 16 hours. Solvent was removed at reduced pressure acetic anhydride added and the mixture : boiled for 4 hours. Solvent was removed at reduced pressure, the residue dissolved in diethyl ether (50ml) and washed with water ~2 x 50ml~. The organic layer was dried (MgS04) and solvent removed at reduced pressure to give 2-hydroxy-4-(2,3-di-n-propoxyphenyl)benzonitrile (0.8g). IR ~nujol mull) 2,230cm-1.

(f) A mixture of 2-hydroxy-4-~2,3-di-n-propoxyphenyl~-benzonitrile (0.8g), sodium azide (0.38g) and ammonium chloride (0.35g) in N-methylpyrrolidinone (20ml) was heated at 130C for 3 hours. The reaction mixture was absorbed onto silica gel and column chromatographed (silica gel, diethyl :ether then diethyl ether/methanol 85/lS eluant). Appropriate fractions were combined, solvent removed at reduced pressure ~and the~residue triturated with water to give the title compound ~0.26g) m.p. 187-189C.

xampl~ 2 ~: .
~ 30 Ethyl 2-hydroxy-4-~2,3-di-~-propo~yp~Q~yl)phæ~yl phosph4nate , .
~a~ From 3-bromsphenol (1.73g) and 2,3-di-n-propoxyphenyl-~;: boronic acid (2.38g), 3-(2,3-di-n-propoxyphenyl)phenol m.p.
78-80C after column chromatography (silica gel, diethyl ether/petroleum ether 1:9 eluant) was prepared according to the method of Example l(c).

(b) From 3-(2,3-di-n-propoxyphenyl)phenol (l.Og), di2thyl 3-(2,3-di-n-propoxyphenyl) phenyl phosphate ~1.2g) was prepared according to the method of G. W. Kenner and N. R.
Williams J. Chem. Soc. 1955, 522.

(c) Diethyl 3-(2,3-di-n-propoxyphenyl)phenyl phosphate s (1.2g) was rearranged to diethyl 2-hydroxy-4-(2,3-di-n-propoxyphenyl)phenyl phosphonate according to the method of L. S. Melvin Tet. Letters, 1981, 22, 3375 and subsequently hydrolysed to the title compound, isolated as an oil, by boiling with SN aqueous sodium hydroxide (lOml). lH NMR
lo ~DMSO-d6) 0.75(t,3H), 1.05(t,3H), 1.20~6H), 1.43-1.53(m,2H), 1.54-1.83(m,2H), 3.72(t,2H, 3.86-3.92(m,4H), 4.03(t,2H), 6.88-7.66(m,5H) and 7.46~dd,1~).

~ampl~ 3 Pharmaceutical compositions for oral administration are prepared by comhining the following :

2-~(5-tetrazolyl)-5-(2~,~3-dipropoxyphenyl)phenol 0.5 3.0 7.14 2% w/w Soya lecithin in~soya 25~ bean oi1 90.4588.2 84.41 Hydrogenated vegetable shortening and beeswax 9.05 8.B 8.45 30 ~The formulations~are then filled into individual soft gelatin capsules.

mple 4 3s A pharmaceutical composition for parenteral administration is prepared by dissolving ethyl 2-hydroxy-4-(2,3-dipropox~phenyl~phenyl phosphonate ~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 ~ .~

WO 93~10107 PCI~/GB92~02119 ~.
2~2~ 003 - `
solution is ~hen sterilised by filtration through a ~ . 22 micron membrane filter and sealed in sterile containers~

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Claims (10)

Claims

1. A compound of the formula (1) :
(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 or a bioprecursor thereof, A0 is CH2, CHF, CF2l CR3(oR4), CO or C(OR5)(OR6), R2 is phenyl, C3-scycloalkyl, C3-scycloalkylC1-4alkyl, or C1-galkyl optionally substituted by Cl-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, and Ar is phenyl optionally substituted by one to three groups independently selected from C1-6alkyl, C2-6alkenyl, C1-6alkoxy, C3-6alkenyloxy, C3-6cycloalkyl, C3-6cycloalkoxy, C1-6alkylthio, phenyl, phenylthio, benzyloxy, C1-6polyfluoroalkyl, C1-6polyfluoroalkoxy, halo, 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, C3-6cycloalkyl, N(R7)2, CO2R7 or CON(R7)2.

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

3. A compound according to claim 1 wherein R1 is P(Z)(OH)(OR2) or P(Z)(OR2)2.

4. A compound according to claim 1 wherein R1 is SO2H, SO3H or 5-tetrazolyl.

5. A compound according to claim 1 wherein R1 and R0 are linked together such that R1-R0 is A1CO2 in which A1 is CH2, CHF, CF2, CR3(OR4), CO or C(OR5)(OR6).

6. A compound according to claim 1 wherein R1 and R0 are linked together such that R1-R0 is A2OCH2O in which A2 is P(Z)(OR2) or CR3(CO2R9) and R9 is an ester-forming group.

7. A compound according to claim 1 which is :

2-(5-tetrazolyl)-5-(2,3-dipropoxyphenyl)phenol, or ethyl 2-hydroxy-4-(2,3-dipropoxyphenyl)phenyl phosphonate, 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 l 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) (2) wherein R11 is methyl and Ar is 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) :
(4) wherein R12 is CR3(OH)CO2R9 and R3, R9, R11, and Ar 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) :
R9O2CCO2R (5) wherein R9 is as hereinbefore defined to form a compound of the formula (4) wherein R12 is COCO2R9 and R9, R11 and Ax are as hereinbefore defined, iii) A0 is CH(OH), reacting a compound of the formula (4) wherein R12 is COCO2R9 and R9, R11, and Ar 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 R9, R11, and Ar 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 R9, R11, and Ax 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 R9, R11, and Ar 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 R9, R11, and Ar 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) :
(6) wherein R13 is acetyl and Ar is as hereinbefore defined into the corresponding compound wherein R13 is CH2CO2H; or c) for compounds wherein R1 is CH(OR4)CO2H reacting a compound of the formula (4) wherein R12 is -CH(OH)CN with a C1-3alkylating agent and/or converting the group CN into CO2H, and optionally converting the group OR11 into OH; 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 Ar is 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 C1-4alkyl and Ar is 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 and R11 is as hereinbefore defined or benzenesulphonyl, or a compound of the formula (6) wherein R12 is cyano with an azide salt and thereafter if necessary converting the group OR11. into OH; or i) for compounds wherein R1 is as defined for compounds of the formula (1) reacting in the presence of a palladium catalyst a compound of the formula (7):
(7) wherein Rb is a group R1 as defined in claim 1 or a precursor thereof and Ra is R0 or OR11 as hereinbefore defined and L1 is a leaving group with a compound of the formula (8):
ArB(OH)2 (8) or a chemical equivalent thereof wherein Ar is as hereinbefore defined and then, if necessary, converting a precursor of R1 into R1 and/or converting the group OR11 into OH, and optionally thereafter:

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