PT101073A - PHENOL DERIVATIVES, ITS USE AND PREPARATION PROCESS AND PHARMACEUTICAL COMPOSITIONS - Google Patents

Description

74 501 CT / mrp / P3 0198 f

The present invention relates to phenol derivatives, processes for their preparation, intermediates in their preparation, their use as medicaments and pharmaceutical compositions comprising them.

The compounds of this invention are agonists of a cyclic AMP-dependent protein kinase (cA-PrK) (see J. Biol. Chem. 1989, 264, 8443-8446) and are useful in combating conditions where the agonism is beneficial. They are likely to exhibit anti-proliferative, anti-aggregating, cholesterol lowering, smooth muscle relaxant, lusitropic positive, anti-allergic or anti-inflammatory activities. They are likely to be useful in the treatment of cardiovascular diseases where there is a component of diastolic insufficiency, cancer, psoriasis, atherosclerosis, thrombosis, re-stenosis, chronic reversible lung disease such as asthma and bronchitis, allergic disease such as allergic asthma, allergic rhinitis, and urticaria, or intestinal motility disorders such as irritable bowel syndrome.

Accordingly, the present invention provides compounds of formula (1):

Or a pharmaceutically acceptable salt thereof, wherein: R 1 is OH or a bioprecursor thereof, R 1 is A 2 CO 2 H, P (Z) (OH) (OR 2), SO 2 H, SO 3 H or a 5-tetrazolyl or a bioprecursor thereof, A is CH2, CHF, CF2, CR3 (OR4), CO or C (OR5) (OR6), R2 is phenyl, C3-5 cycloalkyl, C1-6 cycloalkylC1-4 alkyl, or C1-6 alkyl optionally substituted with C1-4 alkoxy, R3 is H , methyl or ethyl, R 4 is H or C 1-6 alkyl, R 504 CT / mrp / P 30198 and

R5 and R8 are each C1-3 alkyl or together form a 1,2-ethanediyl group or a 1,3-propanediyl group, Z is O or S, and

Ar is phenyl optionally substituted with one to three groups independently selected from C alquilo alquilo alquiloalkyl, C₂ al alalkenyl, C alco alco alcoalkoxy, C al al alalkenyloxy, C_ ciclo ciclocycloalkyl, cycloalkoxy_,, C ^ alquil alquilalkylthio, phenyl, phenylthio, benzyloxy, polyfluoro C _quiloquiloalkyl, polyfluoroalkoxyC _gg , wherein R7 is H or C1-6 alkyl, or -X (CH2) n Y- attached to adjacent carbon atoms of the phenyl ring wherein X and Y are independently CH 2 or O en e la 3, wherein the said C1-6 alkyl, C2-6 alkenyl or C1-6 alkoxy groups may be independently substituted with OH, C1-6 alkoxy, C3-6 cycloalkyl, N (R7) 2, CO2 OR7 or CO (R7) 2.

Bioprecursors of the groups R ° and R1 are derivatives thereof which are convertible in vivo into the groups R ° and R1.

A suitable bioprecursor of the group R 6 is OR 8 wherein R 8 is C 1-4 alkanoyl (for example acetyl), arylC 1-4 alkanoyl (for example phenylC 1-4 alkanoyl such as benzoyl), arylsulfonyl (for example toluenesulfonyl or optionally substituted phenylsulfonyl) or C 1-4 alkylsulfonyl (for example methylsulfonyl) .

When R1 is A0CO2H, a suitable bioprecursor is A0CO2R9 wherein R9 is an ester-forming group.

When R 2 is P (Z) (OH) (OR 2), a suitable bioprecursor is P (Z) (O R 2) 2 wherein Z and R 2 are as defined above or P (Z) (OR 2) 8) wherein R 10 is a protecting group of 0. Suitable protecting groups include pivaloyloxymethyl, propionyloxymethyl and pivalolyloxycarbonyloxymethyl.

When R1 is 5-tetrazolyl, a suitable bioprecursor is an N-protected derivative thereof. Suitable N-protecting groups include pivalolyloxymethyl, propionyloxymethyl and pivalolyloxycarbonyloxymethyl. 74 501 CT / mrp / P30198

-3-

Alternatively, bioprecursors of the groups R 1 and R 1 are those formed when R 1 and R 2 are bonded together to form a cyclic structure so that R 1 -R 8 is AlCO 2 or A20 CH 2 O, wherein: A 1 is CH 2, CH 2, CF 2 , CR 3 (O R 4), CO or C (O R 5) (O R 6) / A 2 is P (Z) O R 2 or CR 3 (CO 2 R 9), and R 2 to R 6, R 9 and Z are as defined above.

Suitably R ° is hydroxy or OR8, preferably hydroxy.

Suitably R3- is A8CO2H or A8CO2R9.

Suitably R 3 'is P (Z) (OH) (OR 2) or P (Z) (OR 2) 2.

Suitably R1 is SO2 H, SO2 -H or 5-tetrazolyl.

Suitably R1 and R3 are bonded together so that R3-R8 is A - * - CO2

Suitably R 4 and R 8 are bonded together so that R 2 -R 8 is A 2 OCH 2 O. The term alkyl represents straight and branched alkyl. The term C1-4 polyfluoroalkyl represents a C1-6 alkyl group having at least one fluorine substituted hydrogen, e.g. CF3 or CF2CF2H.

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

Suitably R 3 is H, methyl or ethyl, preferably H or methyl.

Suitably R4 is H, methyl, ethyl or propyl, preferably H or methyl. 74 501 CT / mrp / P3098 / 1: c -Y., /

-4-

Suitably R e and R são are independently methyl, ethyl or propyl, preferably together forming a 1,2-ethanediyl group.

Preferably Z is O.

Suitably R 9 is C 1-4 alkyl optionally substituted with hydroxy, e.g. 2-hydroxyethyl or arylC1-4 alkyl (for example phenylC1-4alkyl such as benzyl).

Suitably Ar is phenyl optionally monosubstituted with a group as defined hereinbefore, for example at the 2, 3 or 4 positions, with C1-6 alkyl, C1-6 alkoxy, C3-6 alkenyloxy, C1-6 alkylthio, phenyl, phenylthio, benzyloxy, CF3, halo or NHCOR7.

Suitably Ar is phenyl disubstituted with any groups as defined hereinbefore, for example at the 3,4-, 3,5-, 2,3-, 2,4- or 2,5- positions, with groups independently selected from C2-8 alkenyl C1-6 alkoxy, C3-6 cycloalkoxy, halo, -X (CH2) n Y "or C1-6 alkoxyC1-6 alkoxy.

Suitably Ar is phenyl trisubstituted with any groups as defined hereinbefore, for example at the 2,3,4-, 2,3,5-, or 3,4,5- positions, with groups independently selected from C2-6 alkenyl, C1-6 alkoxy or halo.

Examples of C1-6 alkoxy include methoxy, ethoxy, propoxy, butoxy, or pentyloxy.

Examples of C1-4 alkyl include methyl, ethyl, propyl, butyl, isobutyl or pentyl.

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

Particular compounds of this invention include: 2- (5-Tetrazolyl) -5- (2,3-dipropoxyphenyl) phenol, or 2-hydroxy-

(2,3-dipropoxyphenyl) phenyl-phosphonate, and the pharmaceutically acceptable salts thereof.

This invention encompasses all tautomeric, geometric and optical isomeric forms of the compounds of formula (1).

The compounds of formula (1) may form pharmaceutically acceptable base addition salts with metal ions, such as alkali metals, for example sodium or potassium, or with an ammonium ion. In order to use a compound of formula (1) or a pharmaceutically acceptable salt thereof in the treatment of humans or other mammals, it is usually formulated according to standard pharmaceutical practice as a pharmaceutical composition.

The compounds of formula (1) and their pharmaceutically acceptable salts may be administered in the usual manner for the treatment of the diseases indicated, for example, by oral, sublingual, parenteral, transdermal, rectal, inhalation or buccal administration.

The compounds of formula (1) and their pharmaceutically acceptable salts which are active when administered orally or buccally, may be suitably formulated in dosage forms such as liquids, syrups, tablets, capsules or troches. An oral liquid formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier, for example, ethanol, glycerin or water, with a flavoring or coloring agent. When the composition is in the form of a tablet, any pharmaceutical carrier routinely used in the preparation of solid formulations may be used. Examples of such carriers include starch, celluloses, lactose, sucrose and magnesium stearate. When the composition is in the form of a capsule, any routine encapsulation is suitable, for example, the use of the above-mentioned carriers in a hard gelatin capsule shell. When the

The composition is in the form of a soft gelatin capsule, it may be considered any pharmaceutical carrier routinely used in the preparation of dispersions or suspensions, for example, celluloses, silicates, aqueous gums or oils, and are incorporated in a soft gelatin capsule shell. to the parenteral compositions are comprised of a solution or suspension of the compound or salt in a sterile aqueous or non-aqueous carrier, optionally containing a solubilizing agent or parenterally acceptable oil, for example, polyethylene glycol, polyvinylpyrrolidone, lecithin, 2-pyrrolidone, cyclodextrin , peanut oil or sesame oil.

A typical suppository formulation comprises a compound of formula (1) or a pharmaceutically acceptable salt thereof, which is active when administered in this manner, with a binding agent and / or lubricant, for example polymeric glycols, gelatin, cocoa butter or other vegetable fats or waxes or their low melting point synthetic analogues.

Typical transdermal formulations comprise a conventional aqueous or non-aqueous carrier, for example a cream, ointment, lotion or paste, or are in the form of a medicated patch, dressing or membrane.

Typical inhalation compositions are in the form of a solution, suspension or emulsion which may be administered in the form of an aerosol using a conventional propellant, such as dichlorodifluoromethane or trichlorofluoromethane, or are in the form of a powder for insufflation.

Preferably the composition is in unit dosage form, for example a graduated tablet, capsule or dose of aerosol, so that the patient can administer a single dose thereto. -7 .Ψt. / _ 74 501 CT / mrp / P30198 and; /

Each dosage unit for oral administration suitably contains from 0.001 mg / kg to 30 mg / kg, and preferably from 0.005 mg / kg to 15 mg / kg, and each dosage unit for parenteral administration suitably contains from 0.001 mg / kg to 10 mg / kg of a compound of formula (1) or a pharmaceutically acceptable salt thereof calculated as the free acid. The daily dosage schedule for oral administration is suitably from about 0.001 mg / kg to 120 mg / kg of a compound of formula (1) or a pharmaceutically acceptable salt thereof calculated as the free acid. The daily dosage regimen for parenteral administration is suitably from about 0.001 mg / kg to 40 mg / kg, for example from about 0.005 mg / kg to 10 mg / kg, of a compound of formula (1) or a pharmaceutically acceptable salt thereof. A pharmaceutically acceptable salt calculated as the free acid. The active ingredient may be administered as necessary, for example from 1-8 times a day or by infusion. The compositions of the invention are agonists of a α-PrK and are used in combating conditions where it is believed that said agonism is beneficial. Said conditions may be treated by oral, sublingual, topical, rectal, parenteral or inhalation administration. For administration by inhalation, the dosages are controlled by a valve, are administered as necessary and for an adult conveniently lie in the range of 0.1-5.0 mg of a compound of formula (I) or a salt thereof pharmaceutically acceptable.

The compounds of this invention may be co-administered with other pharmaceutically active compounds, for example, in combination, simultaneously or sequentially. Conveniently, the compound of this invention and the other or other active compounds are formulated into a single pharmaceutical composition. Examples of compounds which may be included in pharmaceutical compositions together with the compounds of formula (1) are bronchodilators such as sympathomimetic amines, for example iso-prenalin, isoetharine, salbutamol, phenylephrine and ephedrine, or xanthine derivatives, for example for example, aminophylline and theophylline, anti-allergic agents such as disodium cromoglycate, histamine antagonists, drugs used in the treatment of cancer such as those which inhibit synthesis or inactivation -activate the DNA, for example, methotrexate, fluoracyl, cisplatin, actinomycin D, anti-atherosclerotic agents, for example, cholesterol lowering drugs such as HMGCoA reductase inhibitors, bile acid sequestrants, psoriasis drugs, for example, retinoids, anthralin, anti-inflammatories such as corticosteroids, non-steroidal anti-inflammatory drugs such as aspirin, antithrombotic agents such as, dipyridamole, or fibrinolytic agents.

In a further aspect, the present invention provides a process for the preparation of compounds of formula (1) or pharmaceutically acceptable salts thereof, which process comprises: a) for compounds in which R1 is A0CO2H or A0CO2R9 and: i) A R3 is OR3, the reaction, in the presence of a strong base, of a compound of formula (2):

(3): in which R 3 and R 9 are as defined above, to form a compound of formula (4): ## STR3 ## in which R 11 is methyl and Ar is as defined above, with a compound of formula

OR-9-74501 CT / mrp / P30198. / wherein R 12 is CR 3 (OH) CO 2 R 9 and R 3, R 9, R 11 and Ar are as defined above, and optionally thereafter the reaction with a C 1-3 alkylating agent to form the corresponding compound in which R 12 is CR 3 Ii) A is CO, reacting, in the presence of a strong base, a compound of formula (2), defined as above, with a compound of formula (5): wherein R 1, R 2, R 3, in which R 9 is defined as above, to form a compound of formula (4) wherein R 2 is CO 2 CO 2 R 9 and R 9, R 4 and R 6 are as defined above, , the reaction of a compound of formula (4) wherein R 12 is COOCO 2 R 9 and R 9, R 11 and Ar are as defined above with a reducing agent to form the corresponding compound in which R 12 is CH (OH) CO 2 R 9, iv) A Is CH 2, the reaction of a compound of formula (4), wherein R 12 is COOCO 2 H or COOCO 2 R 9 and R 9, R 11 and Ar are as defined above, with a suitable reducing agent to form the corresponding color compound (4) wherein R 12 is COCH 2 R 9 and R 9, R 11 and Ar are as defined above, with a C 1 -C 5 alcohol, 1,2-ethanediol or 1,3-propanediol to form the corresponding compound in which R 12 is C (O R 5) (O R 6) CO 2 R 9, vi) A is CF 2, the reaction of a compound of formula (4) wherein R12 is CO2CO2 R9 and R9, R11 and Ar are defined as above, with a fluorinating agent to form the corresponding compound in which R11 is -CH2 CH3, R11 is -CO- reacting a compound of formula (4) wherein R 12 is CH (OH) CO 2 R 9 and R 9, R 11 and Ar are as defined above, with a fluorinating agent to form the corresponding compound in which R 2 is CH 3 CH 2 R 9, and then optionally:

conversion of the group OR 11 into OH conversion of the group A ° CO 2 R 9 to A ° CO 2 H; or

b) for compounds in which R 1 is CH 2 COOH, the conversion of a compound of formula (6): wherein R 13 is acetyl and Ar is as defined above, in the corresponding compound in which R 13 is CH 2 COOH; or (c) for compounds in which R3- is CH (OR4) CO2CO, reacting a compound of formula (4) wherein R12 is -CH (OH) CN with a C1-3 alkylating agent and / or converting the CN group in CO 2 H and, optionally, the conversion of the group OR 11 into OH; or (d) for compounds in which R 1 is P (O) (OH) (OR 2), hydrolyzing a compound of formula (6) wherein R 13 is P (O) (O R 2) 2 and R 2 and Ar are as previously defined ; or (e) for compounds in which R 1 is P (S) (OH) (OR 2), the conversion of a compound of formula (6), wherein R 13 is P (O) (NHR 14) (OR 2) and R 14 is phenyl or C 1-4 alkyl and Ar is as defined above, in the corresponding compound in which R 13 is P (S) (OH) (OR 2); or f) for compounds in which R 1 is SO 3 H, the reaction, in the presence of a strong base, of a compound of formula (2), defined as above, with sulfuryl chloride or a chemical equivalent thereof and optionally converting the group OR 11 to OH, or g) for compounds in which R 1 is SO 2 H, reacting, in the presence of a strong base, a compound of formula (2) , defined as above, with sulfur dioxide and, optionally, conversion of the group OR 11 into OH; or h) for compounds in which R 1 is 5-tetrazolyl, the reaction of a compound of formula (4) wherein R 12 is cyano and R 11 is as defined above or benzenesulfonyl, or a compound of formula (6) wherein R 12 is cyano, with an azide salt and then, if necessary, conversion of the group OR 11 into OH; or i) for compounds in which R1 is defined as for the compounds of formula (1), reacting, in the presence of a palladium catalyst, a compound of formula (7):

wherein R 15 is a group R 1 defined as above or a precursor thereof, R a is R ° or OR 11 is as previously defined, and A is a leaving group, with a compound of formula (8);

ArB (OH) 2 (8) or a chemical equivalent thereof, wherein Ar is as defined above, and then, if necessary, conversion of a precursor of R1 into R1 and / or conversion of the group OR11 into OH, and then , optionally: forming a bioprecursor of R ° and / or R1 forming a pharmaceutically acceptable salt. 74 501 CT / mrp / P30198 12

Suitably a compound of formula (2) reacts with a strong base, such as lithium diisopropylamide, or a C1-4 alkyl lithium or aryl lithium such as mesityl lithium, in an organic solvent such as tetrahydrofuran, diethyl ether or dimethoxyethane , with cooling (-100 ° -0 ° C) to form its anion. The strong base can be formed in situ. for example by the addition of a C 1-4 alkyl lithium, e.g. methyl lithium, followed by a catalytic amount of diisopropylamide. The anion of a compound of formula (2) is suitably reacted with a compound of formula (3) or a compound of formula (5) in an organic solvent such as tetrahydrofuran, diethyl ether or dimethoxyethane, with cooling (-100ø at 0 ° C) to form a compound of formula (4) wherein R 2 is CR 3 (OH) CO 2 R 9 or COO 2 R 9, respectively. A suitable compound of formula (3) is ethyl pyruvate, or ethyl glyoxylate or a chemical equivalent thereof, and a suitable compound of formula (5) is diethyl oxalate.

A compound of formula (4) wherein R 12 is CR 3 (OH) CO 2 R 9 is suitably reacted with a 0-3 alkylating agent such as iodomethane, iodopropane or dimethylsulfate in the presence of a base such as sodium hydride or potassium hydroxide , in an organic solvent such as dimethylformamide or dimethylsulfoxide, at an elevated temperature (e.g. 30 ° -80 ° C) or preferably at ambient temperature, to form the corresponding compound in which R12 is CR3 (O-C1-3 alkyl) CO2 R9. When potassium hydroxide is used as the base, the CO 2 R 9 group can be directly converted to carboxy.

A compound of formula (4) wherein R 12 is CO 2 CO 2 R 9 is suitably reacted with a reducing agent such as sodium borohydride or diisobutylaluminium hydride, in an organic solvent such as dichloromethane, C 1 -C 4 alcohol, e.g. ethanol, or acetic acid, or mixtures thereof, at ambient temperature or at an elevated temperature (e.g. 30 ° -80 ° C), or with cooling (e.g., 00-5 ° C), to form the corresponding compound in that R 12 is CH (OH) CO 2 R 9.

74 501 CT / mrp / P30198 -13-

A compound of formula (4) wherein R 2 * 2 is COCO 2 H or COO 2 R 9 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 dioxane , and hydrogen chloride gas, at room temperature or at an elevated temperature (e.g. 40 ° -100 ° C), to form the corresponding compound in which R 12 is CH 2 COOH. Under these reaction conditions the C02 R9 group is converted into carboxy.

A compound of formula (4) wherein R12 is CO2CO2 R9 is suitably reacted with a C1 -C10 -alkyl, 1,2-ethanediol or 1,3-propanediol in the presence of an acid catalyst such as paratoluenesulfonic acid, concentrated sulfuric acid or anhydrous hydrogen chloride, at room temperature or at an elevated temperature to form the corresponding compound in which R 12 is C (OR 5) (OR 6) CO 2 R 9.

A compound of formula (4) wherein R 12 is COOCO 2 R 9 or CHOHCO 2 R 9 is suitably reacted with a fluorinating agent such as diethylaminosulfur trifluoride, in an organic solvent such as a halohydrocarbon or an ether such as glyme or THF, at room temperature or at (e.g., 300-60 ° C) to form the corresponding compound in which R12 is CF2CO2R9 or CHFC02R9.

A compound of formula (4) wherein OR 11 is methoxy can be suitably converted to the corresponding compound in which OR 11 is hydroxy by reaction with sodium iodide and chlorotrimethylsilane, in an organic solvent such as acetonitrile, or a halohydrocarbon, e.g. dichloromethane or chloroform, at an elevated temperature (e.g. 30 ° -80 ° C) or preferably at ambient temperature. This process is particularly suitable for the preparation of compounds of formula (1) wherein R1 is A0CO2R9 since the ester-forming group R9 is not hydrolyzed under these conditions. Another process uses sodium thiomethoxide in an organic solvent such as dimethylformamide at an elevated temperature (e.g. 40e- 120 ° C). The more vigorous conditions of this process are suitable for the preparation of < RTI ID = 0.0 > compounds of formula (1) in which R1 is A0 CO2 H.

A compound of formula (4) wherein R 12 is A ° CO 2 R 9 may suitably be converted to the corresponding compound in which R 2 * 2 is A ° CO2 H by reaction with an aqueous base such as sodium or potassium hydroxide at room temperature or at an elevated temperature (e.g. 40- 120 ° C). This process is particularly suitable for the preparation of compounds of formula (1) wherein R ° is methoxy since the OR 11 group is not hydrolyzed. Another hydrolysis process uses aqueous acid such as concentrated hydrochloric acid at an elevated temperature (e.g. 40 ° -20 ° C), which directly provides compounds of formula (1) wherein R ° is hydroxy and R1 is ° co2h.

Suitably a compound of formula (6) wherein R3 is acetyl is converted to the corresponding compound in which R13 is CH2 CO2 H by reaction with sulfur and morpholine at an elevated temperature (eg 50 ° - 200 ° C), followed of hydrolysis with an aqueous base such as sodium hydroxide at an elevated temperature, preferably at the reflux temperature of the reaction mixture.

Suitably a compound of formula (4) wherein R12 is -CH (OH) CN is reacted with a C1-3 alkylating agent as described above, followed by reaction with an aqueous inorganic acid such as hydrochloric acid at ambient temperature or at a temperature preferably at reflux, in order to prepare the corresponding compound in which R 12 is CH (O-C 1-3 alkyl) CO 2 H. Alkylation can be omitted if the corresponding compound in which R 12 is CH (OH) CO 2 H is desired. During the hydrolysis of the CN group, the OR 11 group can be converted into hydroxy. Otherwise, and if desired, this group may be converted to hydroxy as previously described.

A compound of formula (4) wherein R 12 is -CH (OH) CN may be prepared by reacting the corresponding compound in which R 12 is -CHO with a cyanide source such as potassium cyanide in the presence of an acid such as hydrochloric acid , preferably at -15 ° C.

A compound of formula (4) or (6) wherein R 2 is CH 2 is suitably prepared by the reaction of the corresponding compound in which R 2 - or R 3 is cyano, with a reduction such as diisobutylaluminium hydride followed by acid workup.

Suitably a compound of formula (6) wherein R13 is P (O) (OR2) 2 is hydrolyzed by reaction with an aqueous base such as sodium hydroxide optionally in a cosolvent such as a C1-4 alcohol at an elevated temperature ( e.g. 40 ° -100 ° C) / preferably at the reflux temperature of the reaction mixture.

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

Suitably the anion of a compound of formula (2), prepared as described above, is reacted with sulfuryl chloride or a chemical equivalent thereof or with sulfur dioxide in an organic solvent such as tetrahydrofuran, with cooling (-100 ° -0 ° C ) to form, after aqueous workup, a compound of formula (4) wherein R 12 is SO 3 H or SO 2 H, respectively, and R 3 is methoxy, which, if desired, can be converted into the corresponding compound in which OR 11 is hydroxy as previously described.

A compound of formula (4) wherein R 12 is cyano or a compound of formula (6) wherein R 33 is cyano is suitably reacted with an azide salt such as ammonium, sodium or aluminum azide in an organic solvent such as such as diethylformamide, dimethylsulfoxide, N-methylpyrrolidone or tetrahydrofuran, at an elevated temperature, e.g. 40 ° -20 ° C, preferably 100 ° -150 ° C, to form the 5-tetrazolyl compound

Accordingly, there is provided a corresponding cross-sectional view. Preferably in a compound of formula (4) OR 11 is benzenesulfonyl which may be introduced in a common manner, for example by reaction of the corresponding hydroxy compound with benzenesulfonyl chloride in the presence of a base such as triethylamine. This group may be removed in a conventional manner, for example by reaction with a base such as sodium hydroxide.

Suitably a compound of formula (7) is reacted with a compound of formula (8) in the presence of 1-50 mol%, preferably 2-10 mol%, of a palladium catalyst and of a base such as triethylamine, sodium bicarbonate or aqueous sodium chloride and optionally lithium chloride in an organic solvent such as dimethylformamide, dimethoxyethane, acetonitrile, toluene, tetrahydrofuran, ethanol or mixtures thereof, at an elevated temperature (eg 30 °-150 ° C), preferably at a temperature of refluxing of the mixture. Suitably L 1 is halo, for example iodo, bromo or chloro, or a trifluoromethane sulfonate. Subsequently the OR 11 group can be converted to hydroxy as described above for the compounds of formula (4). Examples of palladium catalysts which may be used include: tetrakis (triphenylphosphine) palladium (Pd [PPh3] 4), bis (triphenylphosphine) palladium dichloride (Pd [PPh3] 2 Cl2), [1,4- bis (diphenylphosphine) butadiene] palladium (Pd (dppb) Cl 2), [1,3-bis (diphenylphosphine) propane palladium (Pd (dppp) Cl2) dichloride, [1,2-bis (diphenylphosphine) ethane] Cl2), bis (tri-o-tolylphosphine) palladium diacetate or dichloride (Pd (totp) (OAc) 2 or Pd (totp) Cl2), or 1,1'-bis (diphenylphosphine) -ferrocyanopalladium diacetate or dichloride ( Pd (dppf) (OAc) 2 or Pd (dppf) C 12).

A chemical equivalent of a compound of formula (8) designates a reagent which can couple the Ar group to the pyridyl ring of a

Compound of formula (7). For example, aryl stannanes such as ArSnMe 3, which may suitably be prepared by reaction of a suitable aryl halide (such as ArBr or Ar) with a base such as t-butyllithium, followed by reaction with a trimethyltin halide (e.g. Me 3 SnCl). Alternatively the aryl halide may be reacted with Me3SnSnMe3 in the presence of a palladium catalyst as described above to prepare a suitable aryl stannane.

When Rb is a group R1 as previously defined, the reaction of a compound of formula (7) with a compound of formula (8) results directly in compounds of formula (1).

An example of a precursor for R1 consists of Rb being hydrogen. In this situation, the reaction of a compound of formula (7) with a compound of formula (8) or a chemical equivalent thereof gives a compound of formula (2) or a compound of formula (6) in which R 13 is hydrogen. Said compounds may then be converted to a compound of formula (1) as described herein.

Other precursors for R1 include CN, CHO or COMe. The reaction of a compound of formula (7) wherein Rb represents said precursor with a compound of formula (8) or a chemical equivalent thereof yields a compound of formula (4) or a compound of formula (6) wherein R12 or R 13 is CN, CHO or COMe. Said compounds may be converted to compounds of formula (1) as described herein.

If desired, a compound of formula (1) wherein R1 is A ° C (> 2H may be converted to the corresponding compound in which R1 is A0CO2R9 by reaction with a compound R90H in which R9 is as defined above.

A compound of formula (1) wherein R 0 is OH may be converted to the corresponding compound in which R 6 is OR 8 by reaction with R 8 L 2 in which R 8 is as defined above and L 2 is a leaving group such as halo, eg . bromo, chloro, 74 501 CT / mrp / P30198 / 7

Iodine.

If desired, a compound of formula (1) wherein R1 is P (Z) (OR2) (OH) may be converted to the corresponding compound in which R1 is P (Z) (OR2) (OR10) by reaction with a protective agent of the suitable O, in conventional manner. For example, the compound may be reacted with a pivalolyloxymethyl halide.

A compound of formula (1) wherein R1 is 5-tetrazole may be reacted with a suitable N-protecting agent in a conventional manner, for example with a pivalolyloxymethyl halide.

A compound of formula (1) wherein R 1 -R 6 is AlOC 2 2 is suitably prepared by heating a compound of formula (1) wherein R 1 is C 1 -C 12 H and R 6 is OH with a dehydrating agent such as acetic anhydride, at an elevated temperature (e.g. 40 ° -200 ° C), preferably at the reflux temperature of the reaction mixture.

A compound of formula (1) wherein R 1 -R 6 is A 2 OCH 2 O is suitably prepared by reaction of a compound of formula (1) wherein R 1 is A 2 OH and R 6 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 ° -120 ° C).

A compound of formula (2) is suitably prepared by reaction of a compound of formula (6) wherein R 13 is hydrogen, with an O-methylating agent such as dimethylformamide dimethyl acetal in dimethylformamide or trimethylphosphite, at an elevated temperature (e.g. 40ø-120øC), or with iodomethane and silver carbonate in toluene or chloroform. This process can also be used for the conversion of compounds of formula (6) into the corresponding compounds of formula (4) and compounds of formula (7) wherein Ra is hydroxy in the corresponding compounds in which Ra is OR11. / 5, pp. 50-501 and / or CT / mrp / P30198 and pp.

A compound of formula (6) wherein R 13 is acetyl may also be prepared by reaction of a compound of formula (6) wherein R 13 is cyano with methyl lithium followed by acid work up with, for example, hydrochloric acid.

A compound of formula (6) wherein R 13 is hydrogen may be prepared by reaction of a compound of formula (6) wherein R 33 is cyano with orthophosphoric acid at an elevated temperature (e.g., 50 ° -200 ° C ).

A compound of formula (4) wherein R 12 is cyano may be suitably prepared by reacting the anion of a compound of formula (2) wherein Ar and R 11 are as defined above with dimethylformamide, with cooling (eg -80ø at 10 ° C), followed by room temperature and aqueous workup. The resulting compound of formula (4) wherein R2 is carboxaldehyde is treated with hydroxylamine hydrochloride and sodium acetate in a suitable solvent such as ethanol or methanol at elevated temperature (e.g. 40 ° -100 ° C), preferably at reflux temperature of the reaction mixture, followed by dehydration of the product obtained, for example by heating with acetic anhydride.

A compound of formula (6) wherein R 13 is cyano or acetyl and Ar is defined as above may suitably be prepared by reacting a compound of formula (4) wherein R 12 is cyano or acetyl and R 11 and Ar are as defined above, with a demethylating agent such as sodium iodide / chlorotrimethylsilane, in the absence of solvent or in an organic solvent such as acetonitrile or chloroform, at an elevated temperature (e.g. 40 ° to 100 ° C) or at room temperature.

A compound of formula (6) wherein R 13 is P (O) (OR 2) 2 may be prepared by treatment of a compound of formula (2) wherein R 11 is P (O) (OR 2) 2 with a strong base such as as lithium diisopropylamide in an organic solvent such as tetrahydrofuran, with cooling (e.g. -100 ° to 0 ° C). Δ 74 501 CT / mrp / P30198 -20-

(I.e.

A compound of formula (2) wherein R 11 is P (O) (OR 2) 2 is suitably prepared by treatment of a compound of formula (6) wherein R 33 is hydrogen with a compound of formula (9): 0) (OR 2) 2 (9) wherein L 3 is a leaving group and R 2 is as defined above, with a base such as diisopropylethylamine.

Suitably L3 is halo, for example chlorine or bromine.

A compound of formula (2) wherein R 3 '3' is P (O) (OR 2) 2 may also suitably be prepared by treatment of a compound of formula (6) wherein R 31-3 is hydrogen with a compound of formula 10): HP (O) (OR2) 2 (10) wherein R2 is as defined above in the presence of an amine base such as triethylamine and carbon tetrachloride.

Alternatively, a compound of formula (6) wherein R 13 is P (O) (OR 2) 2 is suitably prepared by treatment of a compound of formula (6) wherein R 31-3 is hydrogen with a compound of formula ) in the presence of a strong base such as lithium diisopropylamide, in an organic solvent such as tetrahydrofuran, with cooling (e.g. -100 ° to 0 ° C), without isolation of the intermediate compound of formula (2) wherein R3 Is OR (O) (OR2) 2.

A compound of formula (6) wherein R 3 · 3 is hydrogen is suitably prepared by demethylation of a compound of formula (2) as defined above. 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 10 ° C), followed by room temperature and aqueous workup. Or a compound of formula (2) is treated with sodium iodide and chlorotrimethylsilane at the ambient temperature or at an elevated temperature (e.g. 40-80 ° C) conveniently at room temperature , in a solvent such as acetonitrile or dichloromethane.

A compound of formula (6) wherein R13 is P (O) (NHR14) (OR2) may be prepared by reacting a compound of formula (6) wherein R13 is P (O) (OH) (OR2), with carbon tetrachloride, triphenylphosphine and aniline, or a C 1-4 alkylamine, in an organic solvent such as pyridine, at ambient temperature or with cooling (e.g. -10 ° to 5 ° C). Alternatively, a compound of formula (6) in which R 13 is P (O) (OH) (OR 2) may be reacted with dimethylformamide and oxalyl chloride in an organic solvent such as a halohydrocarbon, e.g. dichloromethane at room temperature, followed by reaction with aniline or a C 1-4 alkylamine, preferably with cooling (-10 ° to 5 ° C).

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

wherein Ra and L1 are as defined above, using processes similar to those described for the preparation of compounds of formula (1).

Thus, a compound of formula (7) wherein R1 is P (O) (OR2) 2 may be prepared by reacting a compound of formula (11) wherein Ra is OH with a compound of formula (9) or 10) in a manner similar to the reaction of a compound of formula (6) wherein R 13 is hydrogen with a compound of formula (9) or (10). If desired, the Ra group can then be converted to OMe.

Similarly, a compound of formula (11) wherein Ra is OMe can be treated, in the presence of a strong base, with a compound of formula (3), a compound of formula (5),

Sulfuryl chloride, dimethylformamide, to prepare a compound of formula (7) wherein R b is CR 3 (OR 4) CO 2 R 9, CO 2 CO 2 R 9, SO 3 H, SO 2 H or CHO, respectively, in a manner similar to the corresponding with a compound of formula (2) as previously described. Particularly suitable as a strong base is lithium tetramethylpiperidide.

A compound of formula (8) is suitably prepared by reacting an organolithium or Grignard reagent, formed from a compound of formula (12):

Ar-L4 (12) wherein L4 is bromine or iodine and Ar is defined as above with trialkyl C1-4 -alkyl borate such as trimethyl, triisopropyl or tri-n-butyl borate in an organic solvent such as diethyl ether or tetra -hydrofuran with cooling (e.g. -80 ° -10 ° C). The Ar group in the compounds of formula (2), (4), (6) or (12), preferably (2) or (4), may be suitably functionalized by aromatic substitution processes known in the art. For example, a bromo group on a suitably substituted phenyl ring (eg disubstituted at the 2- and 4-positions by electron donating groups such as C1-6 alkoxy) may be introduced by reaction with a brominating agent such as N-bromosuccinimide or bromine in solvent such as dimethylformamide. Alternatively, a nitro group may be introduced into a phenyl ring by reaction with a suitable nitrating agent, such as nitronium tetrafluoroborate. Such a group may be readily hydrogenated to an amino group which, if desired, may be converted to an NHCOR 7 group by reaction with LCOR 7 in which L is a leaving group and R 7 is as defined above. Suitable examples of the LCOR reagent include acid halides (L is halo, eg chlorine or bromine) 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 an allyloxy derivative which upon heating undergoes a Claisen rearrangement to form an allyl-hydroxy ortho derivative. The hydroxy group may, in turn, be functionalized, for example, by reaction with a C1-6 alkyl halide to form a C1-6 alkoxy group. If desired, an allyl group may be converted to an E-1-propenyl group by reaction with a strong base such as sodium methoxide. An El-propenyl group may be cleaved to formyl group by reaction with an oxidizing agent such as N-methylmorpholine N-oxide in the presence of a catalyst such as osmium tetroxide to form a 1,2-dihydroxypropyl group, which, upon reacting with an oxidizing agent such as sodium periodate, forms the formyl group. Alternatively, the E-1-propenyl group may be directly converted to a formyl group by reaction with a mixture of osmium tetroxide and sodium periodate or by reaction with ozone. A formyl group may in turn be further functionalized, for example, may be converted to a hydroxymethyl group by reaction with a suitable reducing agent such as sodium borohydride, the hydroxymethyl group then reacting additionally, e.g. with a C1-6 alkyl halide to form a C1-6 alkoxymethyl group. Alternatively, a formyl group may be reacted with a suitable Horner wittig or wittig reagent such as (R 1 50) 2 P (O) CH 2 CO 2 R 15 or Ph 3 P = CHCO 2 R 15 wherein R 15 is C 1-4 alkyl to form a CH = CHCO 2 R 15 group, which may optionally be hydrolyzed in a group -CH = CHCOOH. A -CH = CHC02R · * 'group may be converted into a -CH = CHCN (R7) 2 group by reaction with an amine HN (R7) 2 or a chemical equivalent thereof in which R7 is as defined above. Alternatively, a -CH = CHCOOH group may be converted to an acid halide, e.g. the acid chloride, by reaction with oxalyl chloride, which may then be reacted with an amine HN (R 7) 2 or a chemical equivalent thereof. An example of a chemical equivalent is ammonium hydroxide which will form a CH = CHCONH 2 group.

Base addition salts 74 501

> & (1) by conventional procedures, for example by reacting a solution of the compound of formula (1) with a solution of the base.

The following biological test procedures, data and Examples are intended to illustrate this invention.

Amino Acid Activity of AMP-Cyclic Protein Ouinase (cA-PrK) cA-PrK type II was prepared from the heart muscle of a cow. The supernatant from a muscle homogenate (3 ml of 10 mM potassium phosphate, 1 mM EDTA per gram of tissue) was loaded onto a DEAE-cellulose column equilibrated with the homogenization buffer and the type-A c-PrK was eluted with homogenization containing 350 mM sodium chloride (Rannels et al., 1983, Methods Enzol. 99, 55-62). Type II cA-PrK was assayed for phosphotransferase activity by incubating the enzyme at 30 ° C for 5 minutes with [Y -32P] -adenosine triphosphate and a suitable peptidic substrate such as malantido (Malencik et al., 1983, Anal. Biochem., 132, 34-40). The reaction was quenched by addition of hydrochloric acid and the spot quantified [Y -32P] -phosphopeptide of the reaction mixture on phosphocellulose paper. The concentration of the compound required to give 10% phosphorytransferase activation is given as EC q ((μΜ). The compounds of Examples 1 and 2 show EC10 values of 2.6 and 1.0 μ, respectively.

Inhibition of Placental Acrease

Platelet rich human plasma was separated from freshly harvested blood (acid / citrate / dextrose) and treated with 100 μ ace acetylsalicylic acid for 15 minutes at 37 ° C. A platelet suspension washed in a Hepes buffer-isotonic saline solution was then prepared after a single centrifugation step, and adjusted to a concentration of 1.5 x 10 8 cells / ml. Aliquots of this suspension were preincubated with the compounds for 5 minutes at 37 ° C, and then challenged with 1.0 μg 4 / -25 74 501 CT / mrp / P30198 U46619. The extent of aggregation after 2 minutes was expressed as a percent control and the results obtained were expressed as an IC50 (concentration which causes 50% inhibition of the putative aggregation, μΜ). The compounds of Examples 1 and 2 show IC 50 values of 20 and 38 μ, respectively.

Inhibition of Spontaneous Contraction in Colon of Guinea

Guinea pig colon segments (2 cm) were suspended under a tension of 2 g in standard organ baths containing Krebs solution. The tissues were connected to the free end of isometric transducers which allow to record and expose the voltage developed in graphic registers. In-line computer capture and analysis was used to quantify the effects of test compounds on spontaneous contractions. Inhibitory responses were calculated as the% maximum inhibition of the spontaneous contraction distance over 3 consecutive 2 minute pre and post dose readings. The concentration of the compound that caused 50% inhibition of spontaneous contraction is designated as the EC 50 (μΜ).

Bronchodilatation In Vitro

Spiral strips of guinea pig trachea were suspended in standard organ baths containing Krebs solution. The tissues were connected to the free end of isometric transducers which allow to record and expose the voltage developed in graphic registers. Spontaneous development of tension was allowed and concentrations of the test compounds were added cumulatively. The concentration of compound that caused 50% inhibition of spontaneously developed stress is designated as the IC50 (μΜ). 74 501 M, // CT / mrp / P30198

Rabbit Ventricle Heart Muscle Relaxation Time Measurement Papillary Muscles of the Right Ventricle of Rabbits Female New Zealand Albins were mounted in standard organ baths containing oxygenated Krebs solution. One end of the muscle was attached to an isometric transducer which allowed recording of the contractile force and its first derivative for chart recorders. Test compounds were added to the bath in a cumulative manner. The relaxation time is calculated as the time obtained from the peak of tension to the end of the contraction. Compounds which cause a reduction in relaxation time indicate a positive lusitropic effect of interest in the treatment of cardiovascular diseases where there is a component of diastolic insufficiency, such as congestive heart failure / angina, hypertension and cardiomyopathy.

Example 1 2- (5-Tetrazolyl) -5- (2,3-di-n-propoxyphenyl) phenol (a) From 1,2-di-n-propoxybenzene (13.8 g) di-n-propoxyphenylboronic acid (13 g) according to the procedure of WJ Thompson and J. Gaudino, J. Chem., 1984, 49, 5237. (b) Methyl 2,4-dihydroxybenzoate 5.95 g) and 4-N, N-dimethylaminopyridine (8.65 g) in dichloromethane at -50 ° C was added trifluoromethanesulfonic anhydride (10.0 g) over 5 min. The mixture was warmed to the temperature The organic phase was separated, dried (MgSO4), and the solvent removed under reduced pressure. The residue was subjected to column chromatography (silica gel, eluent diethyl ether / petroleum ether) to give methyl 2-hydroxy-4-trifluoromethanesulfonyloxybenzoate (5.0 g) .1H NMR (CDCl3) 3.99 (S, 3H), 7.25 (d, 1H), 7 , 44 (dd, 1H), and 8.23 (d, 1H). 2-hydroxy-4-trifluoro methanesulfonyloxybenzoate (8.7 g) and 2,3-di-n-propoxyphenylboronic acid (7.4 g), and using the procedure of A. Huth, I. Beetz and I. Schumann, Tetrahedron. 1989, 45, 6679, methyl 2-hydroxy-4- (2,3-di-n-propoxyphenyl) benzoate (4.6 g) was prepared. 1 H NMR (CDCl 3) 0.8 2 (t, 3H), 1.08 (t, 3H), 1.48-1.59 (m, 2H), 1.81-1.95 (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). (d) Methyl 2-hydroxy-4- (2,3-di-n-propoxyphenyl) benzoate (2.2 g) in ethanol (15 ml) and dioxane (30 ml) was treated with borohydride (1 g), and stirred at room temperature for 48 hours. The solvent was removed under reduced pressure and the residue subjected to column chromatography (silica gel, eluent dichloromethane) to give the 2-hydroxy-4- (2,3-di-n-propoxyphenyl) benzyl alcohol (1.7 g ). The benzyl alcohol was oxidized according to the procedure of S. V. Ley et al., J. C. S. Chem. Comm. 1987, 1625, to give 2-hydroxy-4- (2,3-di-n-propoxyphenyl) benzaldehyde (0.78 g) .1 H 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 , 7.19 (s, 1H), 7.26 (dd, 1H), 9.92 (s, 1H), 11.9 (s, 1H) A solution of 2-hydroxy-4- (2,3-di-n-propoxy-phenyl) benzaldehyde (0.78 g) in ethanol (15 ml) and aqueous sodium acetate The solvent was removed under reduced pressure, acetic anhydride was added and the mixture was boiled for 4 hours.The solvent was removed under reduced pressure The organic layer was dried (MgSO 4) and the solvent removed under reduced pressure to give 2-hydroxy-4- (2-hydroxy- , 3-di-n-propoxy-phenyl) -benzonitrile (0.8 g) IR (nujol slurry) 2230 cm-1 A mixture of 2-hydroxy-4- (2,3- -propoxy-phenyl) -benzonitril (0.8 g), sodium azide (0.38 g) and ammonium chloride (0.35 g) in N-methylpyrrolidinone (20 ml) was heated at 74 501 T m / pr / P 30198

130 ° C for 3 hours. The reaction mixture was absorbed on silica gel and subjected to column chromatography (silica gel, eluent diethyl ether followed by diethyl ether / methanol 85/15). The appropriate fractions were combined, the solvent was removed under reduced pressure, and the residue was triturated with water to give the title compound (0.26 g), m.p. 187-189 ° C.

Ethyl 2-hydroxy-4- (2,3-di-n-propoxyphenyl) phenyl phosphonate (a) From 3-bromophenol (1.73 g) and 2,3-di-n-propoxyphenylboronic acid , 38 g), 3- (2,3-di-n-propoxyphenyl) phenol was prepared, after 78-80øC, after column chromatography (silica gel, eluent 1: 9 petroleum ether / diethyl ether) , according to the procedure of Example 1 (c). (b) From 3- (2,3-di-n-propoxyphenyl) phenol (1.0 g) was prepared diethyl 3- (2,3-di-n-propoxyphenyl) phenyl phosphate g) according to the procedure of GW Kenner and NR Williams, J. Chem. Soc., 1955, 522. (c) Diethyl 3- (2,3-di-n-propoxyphenyl) phenylphosphate (1.2 g) was rearranged in 2-hydroxy-4- (2,3-di -n-propoxy-phenyl) -phenylphosphonate according to the procedure of LS Melvin, Tet. Letters. 1981, 22, 3375, and subsequently hydrolyzed to the title compound, isolated as an oil, by boiling with 5N aqueous sodium hydroxide (10 ml). 1 H NMR (DMSOd 6) 0.75 (t, 3H), 1.05 (t, 3H), 1.20 (6H), 1.43-1.53 (m, 2H), 1.54-1 (M, 2H), 3.82 (t, 2H), 3.86-3.92 (m, 4H), 4.03 (t, 2H), 6.88-7.66 (m, 5H ) and 7.46 (dd, 1H).

Example 3

Pharmaceutical compositions for oral administration are prepared by the combination of the following: TMP / mrp / P30198 2- (5-Tetrazolyl) -5- (2,3-dipropoxyphenyl) phenol 0.5% P / P 3.0 7.14 Soya lecithin in 2% w / w soybean oil 90.45 88.2 84.41 Hydrogenated vegetable fats and beeswax 9.05 8.8 8.45 The formulations are then placed in individual soft gelatin capsules.

Example 4

A pharmaceutical preparation for parenteral administration is prepared by dissolving ethyl 2-hydroxy-4- (2,3-dipropoxyphenyl) phenylphosphonate (0.02 g) in polyethylene glycol 300 (25 ml) with heating. This solution is then diluted with water for Ph. Eur injections (up to 100 ml). The solution is then sterilized by filtration through a 0.22 micron membrane filter, and sealed in sterile containers.

Lisboa, 18. κοκ 1992

By SMITHKLINE BEECHAM pic = 0 0FICIAL AGENT =

Claims (9)

r A compound of formula (1): wherein R 1, R 2, R 2, R 2, R 3, or a pharmaceutically acceptable salt thereof, characterized in that: R 1 is OH or a bioprecursor thereof, R 1 is A ° CO2 H, P (Z) (OH) (SO 2), SO 2 H, SO 3 H or 5-tetrazolyl or a bioprecursor thereof, R 2 is phenyl, C 3-5 cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, or C 1-8 -alkyl optionally substituted with C 1-4 alkoxy, R 1 is H, methyl or ethyl, R 4 is H (CH 2) or C1-4 alkyl, R5 and R6 are each C1-3 alkyl or together form a 1,2-ethanediyl or 1,3-propanediyl group, Z is O or s and Ar is phenyl optionally substituted with one to three groups independently selected from C1-6 alkyl, C2-6 alkenyl, C1-6 alkoxy, C3-6 alkenyloxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, phenylthio, phenylthio, benzyloxy, polyfluoroC1-6 alkyl, polyfluoroalkoxyC1-6, halo, N (R7) ) 2 or NHCOR 7 wherein R 7 is H or C 1-6 alkyl, or -X (CH 2) n Y- attached to adjacent carbon atoms of the phenyl ring wherein X and Y are independently CH 2 or O en la 3, where said C1-6 alkyl, C2-6 alkenyl or C1-6 alkoxy groups may be independently substituted with OH, C1-6 alkoxy, C3-6 cycloalkyl, N (R7) 2, CO2 OR7 or CON (R7) 2. A compound according to claim 1, wherein R 1 is A 2 CO 2 H or A CO 2 R 9 wherein R 9 is an ester-forming group. A compound according to claim 1, characterized in that it comprises a compound of the formula: ## STR1 ## wherein R 1, R 2, R 2, (I.e. Ο for R1 is Ρ (Ζ) (OH) (OR2) or P (Z) (OR2) 2. A compound according to claim 1, wherein R 1 is SO 2 H, SO 3 H or 5-tetrazolyl. A compound according to claim 1, wherein R 1 and R 2 are connected to each other such that R 1 -R 0 is AlCO 2 wherein A 1 is CH 2, CH 2, CF 2, CR 3 (OR 4), CO or C (O R 5) (OR6). A compound according to claim 1, wherein R 1 and R 2 are bonded together so that R 1 -R 2 is A 2 OCH 2 wherein A 2 is P (Z) (O R 2) or CR 3 (CO 2 R 9) and R 9 is ester forming group. A compound according to claim 1, characterized in that it is: 2- (5-Tetrazolyl) -5- (2,3-dipropoxyphenyl) phenol, or ethyl 2-hydroxy-4- (2,3-dipropoxyphenyl) phenylphosphonate , or a pharmaceutically acceptable salt thereof. A compound according to any one of claims 1 to 7, characterized in that it is used as a medicament. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 and a pharmaceutically acceptable carrier. A process for the preparation of a compound of formula (1) as defined in claim 1, or a pharmaceutically acceptable salt thereof, which comprises: a) for compounds in which R1 is A0CO2H or A0CO2R9 and: i) A is CR3 (OR4), the reaction, in the presence of a strong base, of a compound of formula (2) 74 501 CT / mrp / P30198 -3 in which R 11 is methyl and Ar is as defined in claim 1, with a compound of formula (3): wherein R 3 is as defined in claim 1 and R 9 is an ester-forming group, to form a formula (4): Wherein R 12 is CR 3 (OH) CO 2 R 9 and R 3, R 9, R 11 and Ar are as defined above, and optionally thereafter the reaction with a C 13 alkylation agent to form the corresponding compound in which R 12 is CR 3 ( (Ii) A is CO, reacting, in the presence of a strong base, a compound of formula (2), defined as above, with a compound of formula (5): wherein R 1, R 2, R 3, ) in which R9 is as defined above, to form a compound of formula (4) wherein R12 is CO2CO2 R9 and R9, R11, and Ar are as defined above, iii) A is CH (OH), the reaction of a compound of formula (4) in which R 12 is COOCO 2 R 9 and R 9, R 11 and Ar are as defined above, with a reducing agent to form the corresponding compound in which R 12 is CH (OH) CO 2 R 9, 74 501 CT / mrp / P 30198 f The reaction of a compound of formula (4) in which R 12 is COOCO 2 H or COOCO 2 R 9 and R 9, R 4 and Ar are as previously defined, with an agent (OR 5) (OR 6), the reaction of a compound of formula (4), in which R 12 is COOCO 2 R 9 and R 9, R 11 and Ar are defined as above, with a C ^ álcool álcool, 1,2-ethanediol or 1,3-propanediol alcohol to form the corresponding compound in which R 12 is C (O R 5) (O R 6) CO 2 R 9, vi) A is CF 2, the reaction of a compound of formula (4) in which R 12 is COOC 2 R 9 and R 9, R 11 and Ar are as defined above, with a fluorinating agent to form the corresponding compound in which R 11 is CF 2 CO 2 R 9, or vii) A is CHF, of a compound of formula (4) in which R 12 is CH (OH) CO 2 R 9 and R 9, R 11 and Ar are as defined above, with a fluorinating agent to form the corresponding compound in which R 12 is CHCO 2 R 9, optionally: converting the OR 1 group into OH converting the α 2 CO 2 group into A 2 CO 2 H; or b) for compounds in which R 1 is CH 2 COOH, the conversion of a compound of formula (6): (6) wherein R13 is acetyl and Ar is as defined above, the corresponding compound in which R13 is αΗ2002Η; or c) for compounds in which R1 is CH (OH) CH2 CO2, the reaction of a compound of formula (4) in which R12 is -CH (OH) CN with a C1-3 alkylating agent and / or conversion of the group CN in CO 2 H and, optionally, conversion of the group OR 11 into OH; or (d) for compounds in which R1 is P (O) (OH) (OR2), or hydrolysis of a compound of formula (6) in which R13 is P (O) ( R2 is defined as in claim 1 and Ar is defined as above; or (e) for compounds in which R1 is P (S) (OH) (OR2), the conversion of a compound of formula (6) wherein R13 is P (O) (NHR14) (OR2) and R14 is phenyl or C 1-4 alkyl and Ar is as defined above, in the corresponding compound in which R 13 is P (S) (OH) (OR 2); or f) for compounds in which R 2 is SO 3 H, reacting, in the presence of a strong base, a compound of formula (2), defined as above, with sulfuryl chloride or a chemical equivalent thereof, and optionally, converting the group OR 11 into OH; or g) for compounds in which R 1 is SO 2 H, reacting, in the presence of a strong base, a compound of formula (2) as defined above with sulfur dioxide and optionally converting the group OR 11 into OH; or h) for compounds in which R1 is 5-tetrazolyl, the reaction of a compound of formula (4) in which R12 is cyano and R3-6 is as defined above or benzenesulfonyl, or a compound of formula (6) in which R 12 is cyano, with an azide salt and then, if necessary, conversion of the group OR 11 into OH; or i) for compounds in which R1 is defined as for the compounds of formula (1), reacting, in the presence of a palladium catalyst, a compound of formula (7): in which R3 is a group R1 defined as in claim 1 or a precursor thereof, Ra is R6 or OR11 as previously defined, and L1 is a leaving group, with a compound of formula (8); ArB (OH) 2 (8) or a chemical equivalent thereof, in which Ar is defined as previously, and then, if necessary, conversion of a precursor of R - * into R1 and / or conversion of the group 0R11 to OH, and then optionally: formation of a bioprecursor of R ° and / or R1 formation of a pharmaceutically acceptable salt. Lisbon, 18. hov. m By SMITHKLINE BEECHAM plc = 0 0FICIAL AGENT =