CA2182219A1 - Pharmaceutical product comprising a salicylate of an esterifiable beta-blocker - Google Patents

Abstract

Salicylates of esterifiable .beta.-blockers, especially Atenolol-O-Aspirinate, Metoprolol-O-Aspirinate, Pindolol-O-Aspirinate and processes for their preparation are described.

Description

~w~l9~120~68 2182~1~ r 1l~ 5~
^ 1 -PHARMACEUTICAL PROOUCT COMPRISING A SALrCYLUTE OF AN ESTERIFIA~LE

The invention relates to pharmaceutical products.
The term 1~ Blocker as used in this specification refers to pharmacologically active B Blocker compounds which relieve or act as prophylactic again5t cardiovascular 5 disease including hypertension, angina pectoris ~pain in the heart muscle), cardiac failure, or after a heart attack (post myocardial infarction).
Beta-adrenoceptor bloclcing agents or antagonists are competitive inhibitors of catecholamines at beta-10 adrenergic receptor sites. The principal effect of betablockers is to reduce cardiac activity by diminishing or preventing beta-adrenergic receptor stimulation. Beta blockers inhibit the sscretion of renin and alter the sensitivity of the baL~lLt~ Or reflex, they also block 15 the sympathetic drive to the heart. This reduces the chronotropic and inotro]?ic responses during exercise and stress thus limiting oxygen requirements.
The beta blockers are effective in reducing the severity and frequency of exertion angina (i.e. pain in the heart 20 brought on by exercise) that is for angina pectoris.
Beta blockers are also important in anti hypertensive therapy ( lowering of blood pressure ) . This is thought to be achieved through the reduction of heart output, and in the inhibition of renill secretion and a change in the 25 sensitivity of the baroreceptor refle~c.
Aspirin (acetylsalicyli~: acid) has been widely used for many years ~s an analgesic/anti-pyretic and anti-inflammatory agent. As such, it is a 310st u~eful drug.
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 09~l20~68 2182~1g P~lr~5~r ll ~ "

In more recent years, ho~dever, it has been discovered that aspirill has a powerful anti-platelet effect. Platelets are microscopic particles within the blood that, under certain circumstances, can stick together to form a S thrombus (clot). Aspir~n prevents the sticking together of platelets and thus helps prcvent the occurrQnce of heart .~ttack or its complications.
According to the inYention there is provided a pharmaceutical product comprising a salicylate of an 10 esterif iable 13 Blocker .
The term "salicylate" as used in this specification refers to a salicylate or a salt, ester, deriYative, complex t}lereof, or salts of the ester, derivative or complex having anti-platelet act ivity .
15 Preferably, the 13 Blocker is directly esterifiable. In other words ~ the B Bloc)ter has an hydroxy group which is available for esterification.
In a particularly preferred ~ ' ~ i t of the invention the product is formed by esterificatio~ of an esterifiable 20 1~ Blocker with acetylsal icylic acid.
Preferably the 17 Blocker is Ate~lolol.
The invention further provides Atenolol-0-aspirinate and ellantiomer ( s ) thereof .
In another case the B blocker is Metoprolol.
25 The invention also provide~ Metoprolol-0-Aspirinate. In a further embodirnent the B block-r i8 Pindalol.
The invention f urther pl-ovides Pindalol-0-AspirinAt- .

~ W09.V~0~68 21~22~9 r ~ s.l Il 1;~ , The invention also provides a process for preparing a pharmaceutical product of the invention by esterifying an esterifiable B blocker with acetylsalicylic acid.
In another embodiment, the process involves esterifying an 5 esterifiable ~ blocker with salicylic acid.
In one embodiment of the invention the process comprises the steps of :-protecting the secondary amine group in the ~ blocker;
activating the carboxyl group in salicylic acid or derivative thereof;
direct coupling of the activated carboxyl qroup of thesalicylic acid or derivative thereof; and removing protecting groups from the secondary amine group in the ~ blocker.
15 In this case, the secondary the secondary amine group in the ~ blocker is protected by forming an N-BOC derivative of the ~ blocker secon.dary amine an~, after coupling, the N-80C protecting group is removed.
In an: ` ~ii t of the inveneion the N-BOC derivative of 20 the ~ blocker is formed by reaction between the B blocker secondary amine and di-t-butyl in ~-8uOH~H20 to form the tert-butyloxycarbamide derivative.
Preferably the N-BOC protecting group is removed using trifluoro-acetic acid to form the trifluoroacetate s41t of 25 the Aspirinate. Typically the process includes the step of forming the ~ blocker Aspirinate base by extraction _ _ _ _ _ _ _ _ . _ .

20~C8 21~ 2 219 ~ t r~ l l ~ .
from a weakly alkalin~ medium. Preferably the process includes the steps of acidi~ying an alcoholic solution of the Aspirinate base in an acid to form a pharmaceutically acceptable salt.
S In another embodiment of the invention the carboxyl group in salicylic acid or derivative thereof is activated by one or more of :-acid chloride formation;
penta f luorothioes ter f ormation; or ~.n situ forntation of 2,6 dichlorobenzoyl anhydride .

In one case the 1~ is coupled with acetylsalicylic acidderivative having an activated carboxyl group.
In another case the ,~ t~locker is coupled with a salicylic 15 acid derivative having a protected hydroxy group.
Preferably the hydroxy group is protected by benzyl ether formation. In a preferred ` 'i-- ~, salicylic acid is converted into O-benzyloxy benzoic acid.
The process also includes, removing the salicylic acid 20 hydroxy protection grotlp after coupling. Typically the protected s~licylic acid hydroxy group is removed by Lug~nolysis.
In a preferred embodiment of this aspect of the invention, after removal of the protecting group the salicylic acid 25 derivative is acylated.
In one: ' ~ 'i t of the invention the proce~t~ compri~es the steps of :-W0 95l~0s68 218 2 2 ~ 9 ~ LI r.~ l l ~. ~
_; _ forming a protected salicylic acid hydroxy group;
forming an N-BOC derivative of the ~ blocker secondary amine;
coupling of the protected salicylic acid with the 5 N-BOC ~ blocker;
removing the protecting group from the salicylic acid hydroxy group;
acylating the salicylic acid; and removing the N-BOC protecting group.
10 In another embodiment the process comprises the steps of:--forminy an N-80C derivative of the B blocker second~ry amine;
direct coupling of the N-BOC derivative of the ,~
blocker with acetylsalicylic acid;
removing the N-BOC protecting group.
In a further possible embodiment the process compriseS the s teps - of :--.- 20 forming a pentafluorothiophenol ester of acetylsalicylic acid;
forming an N-BOC derivatiYe of the ~ blocker 8econdar,Y amine;

~wo 9~l20~68 2 1 8 2 2 ~ g P~ I r direct coupling of the pentafluorothiophenol ester with N-BOC derivative of the ~ blocker; and removing the N-BOC protecting group.
In another embodiment the process comprises the steps of 5 forming acetylsalicoyl chloride;
forming an N-~30C derivative of the ~ blocker secondary amine;
direct coupling of the N-~30C 1~ blocker with acetylsalicoyl chloride; and , removing the N-130C protecting group.
In these ca~es the process preferably include the step, after removal of the protecting group, of forming t~e blocker aspirinate base; and, optionally, forming pharmaceutically acceptable salts thereof by acidificatiOn 15 of an alcoholic solution of the base using appropriate acids .
The invention further provides a ph~ utical product whenever prepared by a process of the invention.
The invention also provides a ph~ ^eutical composition 20 including a pharmaceutical product of the invention. The composition is prefera]~ly in the form of a tablet or capsule .
The inventiOn will be more clearly understood from the following description thereof givan by way of e%ample 25 only.

Wo gS/ZO~G8 ~ ~ ~ 2 2 1 ~} PCI/IE9~/000 l l n Blockers and their salts, their enantiomers and their salts, derivatives ~eg esters) and their salts are all 2-ethanolamine derivatives. More specifically they are compounds of the formula in which R=ip, ~b ur ~hcr nn-l R' rcprcsems ~rious suos~iluenls The following are some examples thereof.
r- _ ' Form N-R
10 Acebutalol HCl ip Alprenolol HCl ip Amosulalol HCl --Arotinolol HCl tb Atenolol 8ase ip 15 Befunolol HCl ip Betaxolol HCl ip Bevanto l o l HC 1 - -Bisopropolol Hemifumarate ip Bopindolol Hemimaleate tb 20 Bucindolol HC1 --Bufetolol HCl tb Bufuralol HCl tb 8unitrolol HCl tb Bupranolol HCl tb 25 Butofilolol Maleate tb Carazolol HCl ip Carteolol HCl tb Carvedilol Base --Celiprolol HC1 tb 30 Cetamolol HC1 tb Cloranolol HC1 tb Dt~ .o~-~nolol HCl ip Diacetolol HC1 ~ W0 95J20~68 ~18 2 ~19 r~
- E -Dilevalol HC1 --Epanolol 3ase --Esmolol HCl ip Indenolol HCl ip S Labetalol HC1 ip Levobunolol HCL ip Levomoprolol HCl ip Medroxalol HCl Mepindolol Sulphate ip ~etipranolol 8a5e ip Metoprolol Tartrate ip Moprolol HCl ip Nadolol Base tb Nifenalol HCl ip Nipradilol Ba5e ip OxFrenolol HCl ip Penbutolol Sulphate tb Pindolol Ba~e ip Pr2ctolol HCl ip Pronethalol HCl ip Propranolol HCl ip Sotalol HCl ip Sul f inalol HCl --Talinolol Ba5e ip Tertatolol HCl tb Timolol HemiMaleate tb Toliprolol HCl ip ip - iso-Propvl Ib - lert-Butvl other - v~rious ~Vo 9~120~G8 ~ ~ ~3 2 219 r g E:ltAMPLE 1 Synthesis of Atenolol-O-aspirinate "Atenolol ~ is ( RS ~ -4- ( 2-ilydroxy-3-isopropyl-aminopropoxy ) -phenylacetamide-British Pharmacopoeia 1993 Volume I page S 55.
Materials:
Acetylsalicylic acid . Sigma Ltd MW 180.16 Atenolol M~i 266.34 Dicyclohexylcarbodiimide (DCC) Sigma Ltd ~W 206.33 Dimethylaminopyridine (DMAP) Sigma Ltd Mil 122.20 ~h~
To a stirred solution of acetylsalicylic acid (3.6gms, 0.02 mol) in 30ml dry dichloromethane was added D~P (0.5 lS gms ) and Atenolol ( S . 32gms, 0 . 02mol ) .
DCC ( 4 . 2gms ) was added gradually at 0C and the reaction mixture stirred for 15 minutes. The icebath was removed and the mixture stirred for a further 3 hours. The precipitated urea was removed by f iltration and the 20 filtrate evaporated in vacuo. The filtrate was taken up in dichloromethane and then washed with 2 x 25ml portions of 20% citric acid and then by 2 x 25ml portions of saturated sodium bicarbonate solution. The organic layer was dried over anhydrolls sodium sulphate and the solvent 2S removed in vacuo to yield the semisolid product Atenolol-O-aspirinate (Yield 30%). The product w~ characterised as Atenolol-o-aspirina~e using FTIR and NMR as ~hown in Figs. 1 and 2.
FTIR (thin film) vCO: 1747, 1650 cm ~ WOg~/20~68 ~1~2~ 9 F 1~

NMR(CDCl3)300MHz: 1.2~, doublet CH(CH,)2: 2.6-2.9O CHl and CH: 3.48~ singlet ARCH2CO: 2.46 singlet ArOCOCH~: 6.9-8.2~ aromatics. (8H~
This method is illustrated schematically in Arpen~li x 1 and 5 is an adaptation of the method de3cribed by Neises and Steglich, Agnew Chem. Int. Ed. 17 (lg78) No. 7, p522-524.
Other appropriate direct esterification methods are given in Larock, R.C., ~ComprehensiYe Organic Transformations pages 966-972, inclusive, published by VCH 1989 10 The product has the following structure.
OCOCH~ ~}.CH2CON~2 COO~ H
~CB2N~IC~tCH3)2 ,~telwlol-O 1~ le ~nd:
F:~AMPr.F~ 2 The Product of Example 1 may also be prepared by indirect esterif ication .

2~ Esterification via acetyls~licyloyl chloride (~
2A) Materials:
Acetylsalicylic acid Sigma Thionyl chloride Aldrich ~ ;~A1C
Atenolol ewO 9S120568 218 2 2 ~ ~ r~ r 1 l , ~.

Xe t hod In a 50ml round bottom f lask equipped with a ref lux condenser with dryin9 tube attached, is placed 36g acetylsalicylic acid. Thionyl chloride 35 . 2gms is added 5 gradually over S minutes. The mixture was heated under gentle reflux for 75 minutes and then cooled. The flask was then transferred to a rotary evaporator in a fume hood and the excess thiony]. chloride removed under vacuum.
The required acetylsalicyloyl chloride was identified by infra red (vC0 1784cm~ ) andNMR(acetyl methyl 3H: 2.4O and aromatics 4H: 8 . 18 to 7 . 2 ~ ) .
Dissolve Atenolol (o.5gms~ 3.75 mmol) in 25ml chloroform in round bottomed flask fitted with a drying tube. The acetylsalicyloyl chloride ( 5.Smls, 37.S mmol~ was added gradually and the solution refluxed for 2 hours. The chloroform was evaporated in vacuo and the residue then taken up in ether. The ether was decolorised using charcoal, filtered and the solvent removed in vacuo. The residue was then dissolved in ethanol and the product recovered by precipitation using ~-hexane as an oily semisolid. The product (2596 yield~ wa~ characterised as Atenolol-O-aspirinate using FTIR and NMR as per appended spectra .
This method is an adaptation of the method described by Anspach, R. et al., Ann. Chem, 367, 172-180, 1909.
The methods described by 1) Satchell Q, Rev, Chem. Soc., 17. 160-203 and 182-1~4, 1963 and 2) Scheithauer; Mayer Top. Sulfur Chem. 4, 1-373, 1979 ma~ also be employed.

Wogsl20~68 21822~ ~ P~ " ~

Esterification of thiols to form esters may also be achieved by treating carboxylic acids such as acetylsalicylic acids, with agents such as:
Trisalkylthioboranes: Pelter et al J. Chem. Soc., S Perkin Trans . l . 1 6 7 2, 1 9 7 7 Phenyldichlorophosphate or the appropriate polyphosphate ester:
I~nmamoto et al Synthesis 134, Liu and Sabesan, Can J Chem ~, [ 2645, 1980 ]
Dellaria et al Synth, Commun.
~, 1043, 1986 Alkylchloroformate and triethylamine: Kim and Kim, J. Org.
Chem . ~Q, 560, 1985 General: Arrieta et al Synth. Commun. 13, 471, 1983 Haslalm Tetrahedron ~, 2409-2433, 1980 O 951205G8 r~
` ~ ~182219 E:XAE~T-F~ 3 - Atenolol Aspirinate Synthesis strategy empl~yed in the coupling of Atenolol to Aspirin .
An alternative route to directly couple Atenolol to acetyl 5 salicylic acid is described in Scheme 1 below. Salicylic acid 1 was dialkylated ~)y forming the benzyl ester as well as the benzyl ether and then hydrolyse the ester functional group of 2 back to the acid under basic conditions. The formation of the benzyl ester of 1 was 10 rapid (Room temperature, 20 min). More vigorous conditions were required to form the benzyl ether (60C 2 hr, 55%). The hydrolysis of the benzyl e9ter of 2 was then carried out under standard basic conditions which gave the acid 3 in 9S'~; yield.
15 One of the more successful methods for the coupling of alcohol units to organic acids is via the lactonisation method described by Yamaguchi and co-workers: Yamaguchi et al Bull. Chem. Soc. Jap.ln, 1979, ~, 1989, Waanders et al Tetrahedron Letters, 1987, 28, 2409. The highest yield of 20 ester 5 was obtained using the following method. The acid

3 and DMAP ( 4 eq) in toluene were dried by azeotropic distillation and to the dried solution was added a solution of 2, 6-dichlorobenzoyl chloride ( 1 eq) in dry toluene. After refluxing this solution for 5 min, 1.0 25 equivalent of N-}30C-Atenolol 4 was added. After refluxing for 25 min, analysis of the solution by TLC implied that all of the acid was consumed. After work up (see experimental section), the ester 5 was isolated in 95 after chromatography.
30 Hy~lL~J~enolysis of the benzyl ether 5 was carried out u5ing an equivalent by weight of 10% Pd/C to benzyl ether 5 in ethanol/ethyl acetate. After work-up the phenol was .~ ~
w095120.~68 2182219 r~",~

isolated in quantitati~e yield. The acetylation of the phenol proceeded cleanly yielding ~he acetate 6 in 90 yield after work up.
Preparation of ester 5 To a solution of salicylic acid 1 (75 mg, 0.54 mmol) in MeOH-H~O (30 ml, 10:1) was added aqueous Cs2CO~ until the pH of the solution was slightly alkaline (Ph 7.5-8.0).
The solvent was then evaporated on a rotary evaporator to leave an oil, to which toluene (30 ml) was added.
Evaporation of the solvent on the rotary evaporator left a white solid of the caesium salt, which was dissolved in l)NF ( 15 ml) . To this 301ution was added benzyl chloride (0.14 g, l.1 mmol, 2.0 eq). The mixture was left stirring at room temperature for 20 min at which time TLC showed that the formation of the benzyl ester had taken place.
The solution was then heated to 60C and after 2 h, TLC
showed that the form~tion of the benzyl ether 2 had taken pl ace .
After cooling to room temperature, the mixture was partitioned between ether-water (l:l, 120 ml). The organic layer was isolated and the aqueous layer extracted with ether (2 x 50 ml). The combined organic layers were washed with water and dried with MgSO~.
Filtration followed by evaporation of the solvent left an oil, which was passed through a plug of silica, eluting with hexane-ethyl acetate ( 30: l ), which gave the benzyl ether 2 ~95 mg, 559~) as an oil. The benzyl ether 2 (95 mg, O . 3 mmol ) was then dissolved in a solution of 2M NaOH
in THF-Ne-OH-H.O (3 3 2! (16 ml), which w~ then refluxed.
After 2h TLC showed that hydrolysis of the benzyl ester of 2 was complete. Removal of the volatiles on the rotary evaporator left an oil, which wa~ partitioned betwe~n ~llo 9~l~0s6~ r ~ r ,~ ~1 822~(7}

ether ( 50 ml ) and water ( 50 ml ~ . The aqueous phase was extracted and to it was added a dilute aqueous HCl ( 1 M, 100 ml ) and ether ( 100 ml ) . The organic layer was isolated and the aqueous layer extracted with ether ( 2 x 50 ml ) . The combined organic extracts were washed wlth water, dried with MgSO~ and filtered.
Evaporation, left an acid 3 as a gum, which was dissolved in toluene ( 50 ml ) and to this solution was added DI~AP
( 146 mg, 1. 2 mmol ) . This solution was then dried thoroughly by azeotropic distillation and to the dried solution was added a solution of 2, 6-dichlorobenzoyl chloride (62.5 mg, 0.3 mmol) in dry toluene (5 ml). The solution was then refluxed for 5 min and then N-BOC-Atenolol (109 mg, 0.3 mmol, leq) was added. After 10 min of refluxing TLC showed that the formation of ester 5 was complete. Evaporation of the solvent on the rotary evaporator left a gum, which was dissolved in DCM and passed through a plug of silica eluting with ethyl acetate to give the ester 5 as an oil ( 160 mg, 9396); ~H [selected peaks only) 1.11 (6H, m, CH(C~)2), 1.45 (9H, s, (CH~)~C-O), 3.46 (2H,s,PhC~zCONH2~, 3.56 and 4.13 (5H, m, OC~2CH-CH2NCH), 5.13 (2H, s, be~zylC~zO), 5.53, 5.60 and 5.99 (3H, br, m, C~-OCO a~d CONH2), 6.82-7.9 (13H, m, aromatic proton resonances ) . C ( selected peaks only) 20 . 7 ( 2 x C, CH(_H~)z, 28.4 (3 x C, (5~H,),C-O), 42-2 (lC, Ph~H2CNH2)~
67.7 and 71.9 (2C,-N~H2CH~H20Ar), 79.8 (lC, (CH~ -O), 113.5-158.1 (Aromatic carbon resonances), 165.5 and 174.1 ( 2 x C, ~OOCH and ~ONH2 ) -H~.~uy.:..olysi~ of the Benzyl ether of 5 and AcetylatLon of 3 0 the resulting Phenol to give acetate 5 .
To a solution of 5 (0.1 g, 0.17 mmol) in ethyl acetate 15 ml ) and ethanol ( 5 ml ) was added 10% Pd/C ~ 0 . lg) .
Hydrogenolysis of the benzyl ether wa~ carried out at 1 WO 9.;120~68 ~ ( ~ I I
2i8~219 atm pressure under an atmosphere of hydrogen at room temperature. After ~4 h TLC indicated that complete removal of the benzyl ester had taken place. The solvent was then removed on the rotary evaporator to leave a black gum. This was then dissolved in DCM, filtered and the f iltrate concentrated and passed through a silica gel plug eluting with ethyl ac-3tate. Evaporation of the eluent left the phenol as an oil (79 mg, 95~ H (selected peak only) 10.69 (lH, s, Plnenolic O_). The phenol was then dissolved in anhydrous DCM (5 ml) and to it was added Et~N
(65 mg, 0.65 mmol) and DM.2~P (79 mg, 0.65 mmol). After stirring for 4 h at RT, analysis by TLC ~howed that all of the phenol had been consumed. Evaporation of the solvent left an oil, which wa6 passed through a plug of silica, eluting with ethyl ac~tate. Evaporation of the eluent gave acetate 6 as an colourless oil (81 mg, 949~), ;H
(selected peak only) 2.32 (3H, s, C~CoO1.
Removal of the N-BOC protecting group of 6 to give amino trifluoLoac~ate salt 7 To a stirred solution of TFA (3 ml) in nnhydrous DCM (3 ml ) at room temperature was added N-~OC carbamate 6 ( 81 mg, 0.15 mmol). After 3 h of stirring at 0C, the volatiles were removed by evaporation under reduced pressure. DCM
( 3 x 20 ml ) was added to the residue and removed by evaporation under reduced pressure to leave the alkylammonium trifluoro-acetate sal~ 7 as a clear colourless oil. H (selected peaks only) 1.33 (6H, m, CH(C~3)2), 2.29 (3H, s, C~COO), 3.44 (2H, s, PhC_2CONH2), 3.49 and 4.23 (SH, m, OC_2CHINC_), 5.53, 5.60 ~md 6.66 (3H, br m, C~-OCO and ~ON~2), 6.85 and 7.08 (4H, 2d, bon70noAretamide proton regonances), 7.09, 7.28, 7.S7 and 7.99 (4H, d, t, t, d, l~spirin aromatic proton L~ Cl -nreS~.
~C (selected pe~k5 only) lg-O (2 x C, CH(IH~)2, 21.4 (1 x C, ~H3CO-O), 42.2 (lC, Ph_H2CONH2), 55.0 ~nd 70.1 (2 x C, ~ Wo 9i/205G8 P~ 5:~ r r l l ~ 2 1 ~
1, _HCHzN~H~_H~), 67.7 and 71.9 12C, -N5~Hz-CH_H20Ar), 115 and 132 (2 x C, benzeneacetamide CH resonances), 124, 128, 134, and 136 14 x C, Aspirin aromatic CH resonances), 122, 130, 152 and 157 (4 x C, Qua~ernary aromatic carbons), 157, 164 and 172 ~3 x C, COO, COO and CONHz).
Legend for spectroscop:ic data Figs. 3 to 14 inclusive.
Fig. 3: ~H nmr Compound 5 Scheme 1 above Fig. 4: DEPT nmr Compound S Scheme 1 above Fig. 5: I~c nmr Compound 5 Scheme 1 above Fig. 6: IH nmr Connpound 5d (phenol) Scheme 1 above Fig. 7: ~lC nmr Conpound 5a (phenol~ Scheme 1 above Fig . 8: DEPT nmr Cornpound 5a ~ phenol ) Scheme 1 above Fig. 9: IH nmr Cornpound 6 Scheme 1 above Fig. 10: DEPT nmr Connpound 6 Scheme 1 above Fig. 11: ~'C nmr Conpound 6 Scheme 1 above Fig. 12: IH nmr At~znolol aspirinate sa]Lt form Scheme 1 above Compound 7 Fig. 13: DEPT nmr Atenolol aspirinate Scheme 1 above sa].t form Conpound 7 Fig. 14 I~C nmr Atenolol aspirinate Scheme 1 above sa].t form Compound 7 25 Preparation of Atenolo:L Aspirinate and conversion to its hydrochloride, f umarate and tartrate salts .
Atenolol Aspirinate Trifluoroacetate (0.29) was dissolved in 5 ml of methanol and treated with 10~ aqueous NaHCO~
( 100 ml ) . The aqueous solution was extracted with 3 x 30 30 ml dichloromerhane. The organic ~olution was dried (Na25O,) and evaporated yielding Atenolol aspirinate.

~ W0 9~20~68 r~
2~8~219 . f~~.

Atenolol aspirinate wa~ dissol~ed in 5~ methanolic HCl and stirred for 30 min. 1'he solvent was evaporated to yield the hydrochloric salt.
Treatment of Atenolol aspirina~e with 0.5 equivalents of 5 fumaric or tartaric acid ln methanol yielded the corresponding fumarate and tartrate salts on evaporation of the solvent.

WO 9~il2i)1i~8 ~ 19 ~ PCi IIE9~/~111(111 ` ~ 21~22~
...
s~ , 11l C_CO, ~ ~cOH-H O(I~ ~ ~ Fb ~ M r OH 1~ U~OH THF.H~O
~~ ~1 e~ ~- D~F ~
o Ht~C\~ < ~=O
O
H ~
n) ~ ~ r , .
~El~ 1~D~l ' ~ ~O~/~
~d~aDO.I~ ~
'' / ' H.N
~~ '\ / . ' ¦¦ --~H. CF,COO
~0~
~Co H~t~

~ W095/20~68 r~ bll 2'1~22~9 . f'.

PL~ to~rolo~ ~7i rirlAte The title compound was prepared according to the reaction scheme below .
S~n~hc~ni~ of O-Benzyloxy bPn~"ic acid ¢~Co~H
OCHIPh 5 i3~n7,ylation of Sal icylLic acid:
Salicylic acid (1) was dissolved in methanol/water (10:1), treated with 1 molar equivalent of 1;2CO~ and stirred at room temperature for 1 hour. The di-ionic ~alt 2 obtained by evaporation of the solvent, wa~ treated with two molar 10 equivalents of benzyl bromide in DN~ and heated to 60C for four hours. After workup and ~ilica-g~l chromatography th~ desired product, iibenzyl salicylat~ 3, was obtained in 61~ yield in addition to benzyl ~alicylate (30%).
HvArolysi~ of Dil-enzyl s~licylate Dibenzyl salicylate 3 (0.3g) was di3solved ln 10 ml of a THF/methanol/water solution (2:1:1) and an equal volume of 2N NaOH wa~ added. The ~olution wa~ refluxed for 15 min. until the starting material had di~appeared a~
evidenced by TLC. Tlle solution was poured onto 100 ml 20 water and extracted with 3 x 30 ml eth~r. The aqueou~
fraction wa~ acidified to pH 3-4 with 2M HCl. The acidic solution was extracted with 3 x 30 ml ether and the combined organic fraction~ were dried tNa2SO~) and evaporated to yield the title , ', O-benzylo~cy 25 benzoic acid 4 as a solid.

~p0 95/20~68 r~ t : l l 22~g Synthesis of N-BOC Metoprolol 5 CH CHlOCH
l eq)/a OH ~' OJ N ~~F~
o Metoprolol (1.0) was dissolved in 5 ml of t-BUO}I/~20 (10:1) and di-t-butyl dicarbonate (0.82q) in 5 ml of t-BuoH/H2o ~10: l ) was added . The solution was stirred for 20 hours 5 and then poured onto 100 ml water. The solution W1~8 extracted with 3 x 30ml of petroleum-ether ~b.p- 40-60C).
The combined organic fractions were dried (Na2SO,) and concentrated. Flash column chromatography using 3: l petroleum-ether:ether ~ave the title compound as a viscous 10 liquid.
Synthesis of N-BOC MetoDrolol O-Ben2yloxy benzo~te 6 C,H2A CH,CH,OCH, ~ oJ~
~0~
N~ ' 0~0 O-Benzyloxy benzoic ~cid 4 ( O 1 lg ) and 4-dimethyl~mino pyridine (0.24g) 2343 dissolved in 20ml of dry toluene.
The $olution was heated to ref lux and 2, 6-dichl~r~ o~ l 15 chloride (o.log) wa~ added. After 10 min- under reflux N-BOC Metoprolol ( O .189 ) in 5 ml dry tolu~ne was added and reflux w~ continued for a further 30 2~in- The mixture WO 9~120568 21~ 2 2 ~ ~ r~"~, ~ r l l . ~,~.

was filtered through silica and the filtrate was evaporated yielding the title compound in quantitative yield .
Debenzylation of N-BOC Meto~rolol O-benzyloxy 6 5 The above compound was dissolved in 20ml of ethanol/dichloromethalle (1:1) and 1 equivalent of Pd-C was added. The mixture was stirred under an atmosphere of hydrogen for 5 hours. The suspension was filtered through silica and the filtrate was evaporated to yield N-BOC
10 Metoprolol Salicylat~ (7) in quantitative yield as a viscous liquid.
Acetylation of N-BOC l~etoprolol Salicylate:
The above compound was dissolved in 20 ml of dry dichloromethane. Tllree molar equivalents of acetic 15 anhydride were added with stirriny. Two molar equivalents of dry tri~thylaminQ and four molar eguivalents of DMAP
were then added and the solution was stirred for 2 hours at room temperature. The solvent was evapor~ted and the residue was sub~ected to slow column chromatography u~ing 20 petroleum-ether:ether 11:1) as eluent. N-BOC Metoprolol Aspirinate ~8~ was obtained as a viscous liquid.
( Yield 80~ ) -Oq~ ~,CHICH20CH, ~JN J~
0~0 ~ ' .
The p,.~ of both a~pirin and l~etoprolol moieties in the product was conf irmed by ;H and ~C ~r.

~O s~/20~G8 2 t8 2 % ~ g ~ J~ "
~, In the ;H nmr the aceta~e methyl group appeared as a 3H
single~ at 2.32 ppm. Th~ aryl hydrogens of aspirin moiety qave rise to 4 multiplets between 6 . 8 and 8 .1 ppm. The latter multiplet was assigned to the aryl hydrogen beta to the ester carbonyl group.
The L~ -ining signals, with the exception of the 9H
singlet at 1. 47 ppm due to the t-butyl group, are similar to those displayed by metoprolol. The exception is the ester hydrogen which is shifted downfield to 5.6 ppm and 10 appears as a broad multiplet. This in itself is strong evidence that the desired coupling has taken place. The corresponding hydrogen of metoprolol is seen at 4 ppm.
The aromatic protons of the metoprolol moiety give rise to two multiplets at 7.~8 ppm and 7.54 ppm. The methine 15 proton of the isopropylamine group and the ArOCHi methylene are present as a broacl multiplet between 3.8 and

4 . 3 ppm. The -Ca1OCH, methyll ne proton~ and the amino methylene protons give a multiplet at 3.4-3.65 ppm. The methoxy group gives a sinqlet at 3 . 34 ppm. The triplet 20 at 2.81 ppm is assigned to the ArCHI methylene protons.
The acetate protons produce a singlet at 2 . 32 ppm. The t-butyl group shows up ~s a singlet at 1. 47 ppm. The L~ -inin~ doublet at 1.14 ppm is due to the isopropylamine methyl protons.
25 "C nmr (ppm) 20.94, 28.37, 29.6, 35.2, 58.54, 67.63, 72.12, 73.73, 79.87, 114.48, 123.1, 123.69, 125.86, 129.72, 131.47, 131.,4, 133.8, 150.66, 156.95, 163.77, 16 9 . 4 8 .

~Vo ssl20~68 ~ 1 8 2 2 1~ r~
-- 2~ _ Metoprolol Aspirinate Tri~luoroacetate 9:
O ~¢~CH CH~OCH, NH . CF,COIH
J~
N-BOC Metoprolol Aspirinate 8 (O.OSg) was dissolved in 10 ml dry dichloromethane and tri~luoroacetic acid (3ml) was added. The solution was stirred for 1 hour. The solvent was eYaporated yielding the compound as a viscous liquid.
IH nmr:
The major difference between this spectrum and that of its precursor i8 the absence of 9H sin~let at -1.4 ppm indicating the t-butoxycarbonyl group has been success~ully removed. A broad peak appear~ at -8.1 ppm which is probably due to the protons on the quaternary nitrogen. otherwi5e there is little difference in the spectra as a visual i nspection readily confirms . The isopropylamine methyl groups appear as a doublet at 1. 36 ppm. The acetate metllyl qroup appears as a singlet at 2 . 31 ppm. The ArCH2- m~thylene yroup is seen a~ a triplet as 2 . 83 ppm. The methoxy group appears at 3 . 36 ppm as a singlet. The methine proton of the isopropylamine group and the -CHzOCH~ metllylene give rise to overlapping multiplets at 3.42 to 3-7 ppm- The doublet at 4.24 ppm is as~igned to the ArOCH~- methylene ~.J.ILU~. . The broad multiplet at S . 6 ppm is assigned to the ester methine proton. The metoprolol aromatic protons are present as two multiplet~ at 6.83 ppm and 7-12 ppm- The multiplet at 7.12 ppm al~o contains xignals for one of the a~pirinate ~Wo s~/20~68 ~ . C ~ l l _ 2~82~19 protons. The three remaining multiplets 7.3 ppm, 7.59 ppm and 7 . 95 ppm are due to aspirinate protons .
3C nmr (ppm) 18.SS, 18.81, 20.9, 29.6, 34.93, 45.74, 51.77, 58.4, 67.11, 69.24, S 73.61, 114.44, 121.9, 123.48, 126.22, 12g 94, 131.62, 132.13, 134.74, lS0 35, 156 . 16, 159 . 86, 160 . 37, 160 89, 161.4, 164.16, 170.53.
Legend for s~ .u~.u~ic data Fig~. 15 to 23 inclu~ive.
10 Fig. lS: ~H nmr C~, iund S Scheme 2 Fig. 16: DEPT nmr Compound S Scheme 2 Fig. 17A: ~C nmr C~, und 5 Scheme 2 Fig. 17B: DEPT nmr Coml?ound 5 (comparison)Scheme 2 Fig. 18: IH nmr Compound 8 Scheme 2 15 Fig. 19: ~C nmr C ,,ound 8 Scheme 2 Fig. 20: DEPT nmr C ~ ,, ' 8 Scheme 2 Fig. 21: IH nmr Compound 9 Scheme 2 Fig. 22: ~C nmr C~ nd 9 Scheme 2 Fig. 23: DEPT nmr Compound 9 Scheme 2 20 Preparation of l~etoprol~l Aspirinate ~nd conversion to its hydrochloride, fumarate and tartrate 5~111t5.
Metoprolol Aspirinate Trifluoroacetate (0.2g) was dissolved in 5 ml of met:hanol and treated with 103 aqueous NaHCO~ ( 100 ml ) . The aqueous ~olution was extracted with 25 3 x 30 ml dichloromethalle. The organic solution was dried ( Na25O~ ) and evaporated yielding Metoprolol aspirinate .
Metoprolol a~pirinate wa~ dissolved in 5~ methanolic HCl and stirred for 30 misl. The solveslt was evaporated to yield the hydrorhl-~rir ~alt.
_ _ _ ~IO 95120~68 ~ 1 8 2 2 1 9 Treatment of Metoprolol aspirinate with 0 . 5 equivalents of fumaric or tartaric acid in methanol yielded the corresponding fumarace and tartrate salts on evaporation of the solvent.

~w09~n0~68 ~ t 8 2 2 ~ ~ `
_' SC~3EnE 2 CO~H K2C03 COz K- PhCHIBr (2 cq.) ¢~OH McOH / H20 ~0- K- DMF. 60 C
(1) ~) ~,CO,CH,Ph I NaOH/THF/McOI~ /H20 ~CO~H
~OCH Ph 2. HCI ~H Ph 1. 4-D ',: pyrldin~ (4 cq.) / TolucD~ l a 2. 2 .6- D ' ' ' , I chlorid~ ( I cq) J
CH CH20CH, 3 ~ (I cq.)/a ~J OH
o l~,N~O~

(5) ~, oJ3' H2 Pd-C ~, 0~0 0~0 ~6! ~ ~
q~ ~l3,CHICH~OCH, Ac20 (3 cq.) ~, J CF3COOH. CHzCIz DMAP(~cql o l J ~8) El3N.CHlCl2 ~ ~
o~o Oq~ 3,CH!CH OCH, 1~,o~l (qJ
NH . CF~C()~H

~ WO 95120~i68 P~ C ~ I ~
2 2 1 ~

Alternative Synthesi~3 of Hetoprolol A~3pirinate To a stirred solution ~f acetylsalicylic acid (2) (0.05 g, 0.27 mmol) in 20 ml of dry dichloromethane was added DMAP
(0 005 q) and N-BOC Metoprolol ~1) (0.lg, 0.27 mmol).
S The solution was cooled to 0 C and DCC (0.06 g, 0. 27 mmol) was added. The reacti~n was stirred at 0C for 5 min. and at room temperature overnight.
The precipitated dicyclohexylurea was removed by f iltration and the f i~.tration was washed with 3x30 ml lM
HCl. The organic layer was washed with 3x30 ml water and the combined organic layers were dried (Na25O~) and evaporated. The residue was purified by slow column chromatography to yield N-BOC Metoprolol Aspirin~te ~ 3 ) as ~I viscou~ liquid. This product wa~3 converted to Metoprolol Aspirinate Trif luoroacetate ( ~ ) in the manner alre~dy de~cribed.
rq~ru~u ,CO,H DCC. DMAP (c~
OH~ ~OA~ CN2C~
O l~N~O~l~
o 2 ~,CH~CH,OCH, CF3COOH. CH2a2 o~O

CH2rH~
~OAc o~
~0~
NH . CF,C02H

~Wo 95.120568 2 1 ~ 2 2 1 ~ p.l~ s~

Sl~H~M~ 3 Alternative Synt~esis of Metoprolol Aspirinate ~ru~, ~,~CO2H DCC DMAP (C~
'~pJ OH~ ~O~C CH2C12 ~ 'b'`l<
O. 2 ~N J` CF3COOH, CH2CI2 olo 0~ 0~
H . CF,CO,H
CH~CH,OCH, ~,,0~ O~r ~~ .
J~
Meu~bl ~spwule ~0 95/20~68 2 1 ~ 2 2 1 9 - ` "

S ~ olol ~piri--t~
~_tie for ~t~-i- of ~ olol -piri--t- -H
' H20 ~H ~ oJ ~ 0 Il~ a~
1~ o ~ Td~t-U~' ' ' ~ o3)t-~ a~.
O~l_N~
(V
H~
0~ ~
~`NH
O~
oPq~
o ~ 1 o-~
~trH
~$ ~ o ~
J~ ~ ~
~7~

~0 9~l20568 ~ 1 8 2 2 1 ~
.D

Synthesis of N-BOC Pindolol (2):
~ o~
O ~_N ~o~
Pindolol (1) (0.93g, 3.74mmol) was dissolved in 5ml of t-BuOH/H2O (10:1) and di-t-butyl dicarbonate (0.82g, 3.~4mmol) in 5ml of t-BuOH~H~O (10:1~ was added. The S solution wa~ stirred for 20 hours ænd then poured onto 100ml water. The solution wa~ extracted with 3x30ml of petroleum-ether (b.p. 40-60C). The combined organic fraction~ were dried (Na~SO~) and concentrated. Flash column chromatography using 3sl petroleum-ether~ether gave 10 the title _ , ound as a vi~cous liquid.
The synthesis of O-Benzyloxy benzoic acid (3) has been alre~dy described (see report on the synthesis of Metoprolol Aspirinate Tri~luoroacetate).
~ynthesis of N-~OC PLndolol O-~enzYloxy benzoate (4):
~NH
CH,Ph ~
~0.~
o~O
15 O-Benzyloxy benzoic al:id ~3) (0.llg) and 4-dimethy}amino pyridine (0.24g) were dis~olved in 20ml of dry toluene.
The ~olution w~ he~t~d to reflux and 2,6-dichlo~o~a.~Lvrl _ _ e W0 9sl20s68 ~ 1 ~ 2 2 1 9 r~ "
chloride (0.lOg) was added. After 10 minutes under re~lux N-BOC Pindolol (0.18g, 0.4Bmmol) in Sml dry tQluene was added and reflux was continued for a further 30 minutes.
The mixture was filt~red through silica and the filtrate S was evaporated yielding the title compound in quantitative yield, Debenzylation of N-BOC Pindolol O-ben2yloxy benzoate l~):
~he above ~, i was dissolved in 20ml of ethanol/dichloromethane (1:1) and 1 equivalent of Pd-C was 10 added. The mixture was stirred under an atmosphere of hydrogen for 5 hours. The suspension was flltered through silica and the filtrate wa~ evaporated to yield N-~OC
Pindolol Salicylate ~5) in quantitative yield as viscous liquid .
lS ,Acetylation of N-BOC Pin~nlol Salicylate (5):
llhe above compound was dissolved in 20ml of dry dichloromethane. Three molar equivalents of acetic anhydrLde were added with stirring. Two molar equivalents of dry triethylamine and four molar equivalents of DI~P
20 were then added and the solution wa~ stirred for 2 hours at room temperature. The solvent was evaporated and the residue was subjected to slow column chromatography using petroleum-ether:ether (1,:1) a5 eluent. N-BOC Pindolol Aspirinate (6) was ol~tained as a viscous liquid. (Yield 86~1.
Pin-lolol ~7irin-te llrifluoroacetate (7) s l~,o~l ,~H.a,~,H
~J~

~vo 9s~20568 ~ ~ 8 2 ~ ~ ~ r~ c r r 1, N-BOC Pindolol Aspirinate (6) (0.069) was dissolved in 10ml dry dichloromethane and trifluoroacetic acid (3ml) was added. The solu~:ion was stirred for I hour. The solvent was evaporated yielding the title compound as a 5 viscous liquid.
Pindolol Asvirir~te (r):
~ N~
o~
~o~
I-H
,l~
Pindolol Aspirinate Trlfluoroacetate (0. lg~ was dlssolved in 5ml of methanol and treated with 10) aqueous NaHCO3 ( 100ml) . The aqueou~ solution w~s extracted with 3x30ml 10 dichloromethane. The organic solution wa5 dried (Na2SO~
and evaporated furnishing Pindolol aspirinate.
CQnver~ion of Pindolo:L A~9irinate to it5 hydrochloride, f -r~te and tArtrate sAlts:
Pindolol aspirinate wa3 dissolved in 5~ methanolic HCl and 15 stirred for 30 minutes. The solvent was evaporated to yield the hydrochloride salt.
Treatment of Pindolol aspirinate with 0 . 5 equivalents of fumaric or tartaric acld in methanol yielded the corresponding fumarate and tartrate salts on evaporation 20 of the solvent.

~Wo 9s/~0s68 ~ ~ 8 2 2 ~ ~} r~
, The products of the invention are useful a5 in a single chemical entity a product which acts both as a B blocker and also has anti-platelet activity as described above is provided .
5 The products m~y ]~e formul~ted ln any suitable pharmaceutical compositions using conventional excipients or vehicle~. Usually the pharmaceutical composition will be provided in a form for oral administration, preferably in a capsule or tablet form.
lO It will be appreciated that the composition may include a diuretic and potassium salts in a single tablet or capsule. The diuretic may be frusemide, amiloride, hydrochloroth ~ or a pota3~ium sparing diuretic such as spironolactone or trimterene.
15 It will also be appreciated Shat some of the 1~ blocker asp1rinates especially timilol a~pirinate may be formulated as an eye drop, i.e. for topical application in the treatment of ocular hypertens10n and glaucoma.
It will be appreciated that while the invention has been 20 specifically described with reference to an aspirinates of some B blockers it may also be applied to aspirinates of other esterifiable ~ blockers.
The invention is not limited to the : 'i - ts hereinbefore described which may be varied in detail.

~ ~W0 95120568 ~ ~ ~ 2 2 1 9 P ~ s ~ c D 1 1 _ 35 _ APPENDIX. 1 Sro~b~ 0~ ~tc~o~ot lO-~piri OCOCB3 ~CH20 ~ C~2COh~
H~_C ~ H
COOH \~CE~ CH(C83)2 DMAP OCC
~, OCOC~
C~C~2CON~2 COO~
~C~IlNllC~ 3~1 APPENDI~ 2 ~-- r ~ c~lorEt~
c~OCOCH~ SOC12 C~COC}I.
COO~ OCI
Cll2~cH2coNE~2 CEIC13 / HO_ C~
~ CEI(C~3)~
GO~oCOC~3 ~C~tCON82 COO_ C~ ~
~ r(~-r-3)t O~

Claims (38)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:-

1. A pharmaceutical product comprising a salicylate of an esterifiable .beta. Blocker.

2. A pharmaceutical product as claimed in claim wherein the .beta. Blocker is indirectly esterifiable,

3. A pharmaceutical product as claimed in claim wherein the .beta. Blocker is directly esterifiable,

4. A pharmaceutical product as claimed in claim 1 wherein the .beta. Blocker is atenolol.

5. Atenolol-O-aspirinate.

6. A pharmaceutical product as claimed in claim 3 wherein the .beta. blocker is Metoprolol.

7. Metoprolol-O-Aspirinate.

8. A pharmaceutical product as claimed in claim 3 wherein the .beta. blocker is Pindalol.

9. Pindalol-O-Aspirinate.

10.A pharmaceutical product substantially as hereinbefore described with reference to the examples.

11. A process for preparing a pharmaceutical product as claimed in any preceding claim which comprises esterifying an esterifiable .beta. blocker with acetylsalicylic acid.

12. A process for preparing a pharmaceutical product as claimed in any of claims 1 to 10 which comprises esterifying an esterifiable .beta. blocker with salicylic acid.

13. A process for preparing a pharmaceutical product as claimed in any of claims 1 to 11 comprising the steps of: -protecting the secondary amine group in the .beta.
blocker;
activating the carboxyl group in salicylic acid or derivative thereof;
direct coupling of the activated carboxyl group of the salicylic acid or derivative thereof with the protected .beta. blocker; and removing protecting groups from the secondary amine group in the .beta. blocker.

14. A process as claimed in claim 13 wherein the secondary amine group in the .beta. blocker is protected by forming an N-BOC derivative of the .beta. blocker secondary amine and, after coupling, the N-BOC
protecting group is removed.

15. A process as claimed in claim 14 wherein the N-BOC
derivative of the .beta. blocker is formed by reaction between the .beta. blocker secondary amine and di-t-butyl in t-BuOH/H2O to form the tert-butyloxycarbamide derivative.

16. A process as claimed in claim 14 or 15 wherein the N-BOC protecting group is removed using trifluoro-acetic acid to form the trifluoroacetate salt of the Aspirinate.

17. A process as claimed in claim 16 wherein the process includes the step of forming the .beta. blocker Aspirinate base by extraction from a weakly alkaline medium.

18. A process as claimed in claim 17 wherein the process includes the steps of acidifying an alcoholic solution of the Aspirinate base in an acid to form a pharmaceutically acceptable salt.

l9. A process as claimed in any of claims 13 to 18 wherein the carboxyl group in salicylic acid or derivative thereof is activated by one or more of :-acid chloride formation;
pentafluorothioester formation; or in situ formation of 2, 6 dichlorobenzoyl anhydride.

20. A process as claimed in any of claims 13 to 19 wherein the .beta. blocker is coupled with acetylsalicylic acid derivative having an activated carboxyl group.

21. A process as claimed in any of claims 13 to 19 wherein the .beta. blocker is coupled with a salicylic acid derivative having a protected hydroxy group.

22. A process as claimed in claim 21 wherein the hydroxy group is protected by benzyl ether formation.

23. A process as claimed in claim 21 or 22 wherein salicylic acid is converted into O-benzyloxy benzoic acid.

24. A process as claimed in any of claims 21 to 23 including the step of removing the salicylic acid hydroxy protection group after coupling.

25. A process as claimed in claim 24 wherein the protected salicylic acid hydroxy group is removed by hydrogenolysis.

26. A process as claimed in claim 24 or 25 wherein, after removal of the protecting group the salicylic acid derivative is acylated.

27. A process for preparing a pharmaceutical product as claimed in any of claims 1 to 10 comprising the steps of :-forming a protected salicylic acid hydroxy group;
forming an N-BOC derivative of the .beta. blocker secondary amine;
coupling of the protected salicylic acid with the N-BOC .beta. blocker removing the protecting yroup from the salicylic acid hydroxy group;
acylating the salicylic acid; and removing the N-BOC protecting group.

28. A process for preparing a pharmaceutical product as claimed in any of claims 1 to 10 comprising the steps of :-forming an N-BOC derivative of the .beta. blocker secondary amine;
direct coupling of the N-BOC derivative of the .beta. blocker with acetylsalicylic acid; and removing the N-BOC protecting group.

29. A process for preparing a pharmaceutical product as claimed in any of claims 1 to 10 comprising the steps of :-forming a pentafluorothiophenol ester of acetylsalicylic acid;
forming an N-BOC derivative of the .beta. blocker secondary amine;
direct coupling of the pentafluorothiophenol ester with N-BOC derivative of the .beta. blocker;
and removing the N-BOC protecting group.

30. A process for preparing a pharmaceutical product as claimed in any of claims 1 to 10 comprising the steps :-forming acetylsalicoyl chloride;
forming an N-BOC derivative of the .beta. blocker secondary amine;

direct coupling of the N-BOC .beta. blocker with acetylsalicoyl chloride; and removing the N-BOC protecting group.

31. A process as claimed in any of claims 27 to 30 including the step, after removal of the protecting group, of forming the .beta. blocker aspirinate base and;
optionally, forming pharmaceutically acceptable salts thereof by acidification of an alcoholic solution of the base using appropriate acids.

32. A process substantially as hereinbefore described with reference to the examples.

33. A pharmaceutical product whenever prepared by a process as claimed in any of claims 11 to 31.

34. A pharmaceutical composition including a pharmaceutical product as claimed in any of claims 1 to 10 or 32.

35. A pharmaceutical composition as claimed in claim 34 in the form of a tablet or capsule.

36. A pharmaceutical composition as claimed in claim 34 or 35 wherein the composition includes a diuretic and potassium salts.

37. Timolol aspirinate for topical application in the treatment of ocular hypertension and glaucoma.

38. A pharmaceutical composition substantially as hereinbefore described with reference to the examples.