PT101072A - PYRIDINOL DERIVATIVES, ITS USE AND PREPARATION PROCESS AND PHARMACEUTICAL COMPOSITIONS - Google Patents

Description

74 500 Ρ817 74

The present invention relates to pyridinol derivatives, processes for their preparation, intermediates in their preparation, their use as medicaments and the pharmaceutical compositions containing 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 have utility to combat states where this agonism is believed to be beneficial. They are likely to have anti-proliferation, anti-aggregation, cholesterol lowering, smooth muscle relaxation, lusitropia positive, anti-allergic and anti-inflammatory activities. They are likely to be useful in the treatment of cardiovascular diseases in which there is a component of dysesthic insufficiency, cancer, psoriasis, atherosclerosis, thrombosis, re-stenosis, chronic reversible pulmonary diseases such as asthma and bronchitis, allergic diseases 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):

1 R f

(D) or a pharmaceutically acceptable salt thereof, wherein: R1 is OH or a bioprecursor thereof, R1 is A0 CO2 H, P (Z) (OH) (OR2), SO2 H, SO3 H or 5-tetrazolyl or a bioprecursor thereof, A R 2 is phenyl, C 3-5 cycloalkyl, C 3 -C 5 cycloalkyl, or C 1-8 alkyl optionally substituted with C 1-4 alkoxy, R 3 is H, methyl or C 1-6 alkyl; ethyl, R 4 is H or C 1-3 alkyl,

W',. 4,

R 5 and R 6 are each C 1-3 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 C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy, C3-6 alkenyloxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, C1-6 alkylthio, phenyl, phenylthio, benzyloxy, polyfluoroC1-6 alkyl, (CH2) nY bonded to the adjacent carbon atoms of the phenyl ring, wherein X and Y are independently CH2 or O3 wherein, R3 is H or C1-4 alkyl, or said C1-6 alkyl, C1-6 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, or

Ar is 1-naphthyl optionally substituted in the 4-position with hydroxy or C1-6 alkoxy, 2-naphthyl optionally substituted in the 1-position with hydroxy or C1-6 alkoxy, 3-phenanthryl, 9-phenanthryl, 2-quinolinyl, 4-quinolinyl , 3-thienaphthenyl or 2-benzofuranyl.

The 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 where R 8 is C 1-4 alkanoyl (for example acetyl), C 1-4 arylalkanoyl (for example phenylalkanoyloctyl, such as benzoyl), arylsulfonyl (for example optionally substituted phenylsulfonyl or toluenesulfonyl), or C 1-4 alkylsulfonyl (for example methylsulfonyl).

When R1 is A0CO2H, an appropriate bioprecursor is A0CO2R9 where it is an ester forming group.

When R1 is P (Z) (OH) (OR2), an appropriate bioprecursor is P (Z) (OR2) 2 where Z and R2 are as previously defined or P (Z) (OR2) OR10) where R10 is a protecting group of 0. Suitable protecting groups include pivaloyloxymethyl, propionyloxymethyl and pivaloyloxycarbonyloxymethyl. 74 500 Ρ817 74

-3-

When R1 is 5-tetrazolyl, an appropriate bioprecursor is a protected N derivative thereof. Suitable N-protecting groups include pivaloyloxymethyl, propionyloxymethyl and pivaloyloxycarbonyloxymethyl.

Alternatively the bioprecursors of the R 1 and R 2 groups are those formed by forming a cyclic structure such that R 1 -R 2 is A-CO 2 or A 2 OCH 2 O wherein A 1 is CH 2 (OR6) / A2 is P (Z) OR2 or CR3 (CO2 R9) and R2 to R6, R9 and Z are as previously defined.

Suitably R ° is hydroxy or OR8, preferably hydroxy.

Suitably R1 is A0CO2H or R0CO2R9.

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

Suitably R1 is SO2 H, SO3 H or 5-tetrazolyl.

Suitably R1 and R2 are linked together so that R1 -R0 is A1C02.

Suitably R1 and R2 are bonded to each other such that R1 is -O-CH2 Cl2.

By the term alkyl is meant straight-chain and branched alkyl.

By the term polyfluoroalkyl is meant a C1-6 alkyl group having at least one hydrogen substituted with fluoro, for example CF3 or CF2 CF2 H.

Suitably R2 is methyl, ethyl, propyl, butyl, pentyl, hexyl, 2-methoxyethyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclopropylmethyl. 74 500 Ρ817ΡΤ 4-

V & A

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

Suitably R4 is H, methyl, ethyl or propyl, preferably H or methyl.

Suitably R 5 and R 6 are independently methyl, ethyl or propyl and preferably together form a 1,2-ethanediyl group.

Preferably Z is O.

Suitably R9 is C1-4 alkyl optionally substituted with hydroxy, for example 2-hydroxyethyl or arylC1-4 alkyl (e.g. phenylC1-4 alkyl, such as benzyl).

Suitably Ar is phenyl optionally mono-substituted with a group as previously defined, 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 above, for example in the -3,4, -3,5, -2,3, -2,4, or -2,5 positions with groups independently selected from C2-6 alkenyl, C1-6 alkoxy C1-6 alkoxy, halo, -X (CH2) n Y- or C1-6 alkoxy, C1-6 alkoxy.

Suitably Ar is phenyl trisubstituted by any groups as previously defined, 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.

Suitably Ar is 1-naphthyl optionally substituted in the 4-position by hydroxy or C1-6 alkoxy. Suitably Ar is 2-naphthyl optionally substituted in the 1-position with hydroxy or C1-6 alkoxy.

Suitably Ar is 3-phenanthryl or 9-phenanthryl.

74 500 Ρ817 74

Suitably Ar is 2-quinolinyl or 4-quinolinyl.

Suitably Ar is 2-benzofuranyl or 3-thienaphenyl.

Examples of C 1-6 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: ethyl 5- [2-naphthyl) -3-hydroxy-2-pyridyl] phosphonate, 5- (2,4-dipropoxyphenyl) -2- (5-tetrazolyl) pyridin-3-ol, or 5- (4-methoxy-3-propoxyphenyl) -3- (5-tetrazolyl) pyridin-3-ol, and pharmaceutically acceptable salts thereof.

This invention encompasses all geometric and optical tautomeric 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 ammonium ion.

To use a compound of formula (1) or a pharmaceutically acceptable salt thereof for the treatment of humans or other mammals, it is formulated according to standard pharmaceutical practice as a pharmaceutical composition.

The compounds of formula (1) and their pharmaceutically acceptable salts may be administered in a normal manner for the treatment of the diseases indicated, for example, orally, sublingually, parenterally, transdermally, rectally or administered by inhalation or by mouth.

The compounds of formula (1) and their pharmaceutically acceptable salts which are active when given orally or by oral administration may be suitably formulated into dosage forms such as liquids, syrups, tablets, capsules and 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 to prepare 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 encapsulation routine is suitable, for example, by using the aforementioned carriers in a hard gelatin capsule shell. When the composition is in the form of a soft gelatin capsule shell, any pharmaceutical carrier routinely used to prepare dispersions or suspensions may be considered, for example, aqueous gums, celluloses, silicates or oils which are incorporated into a soft gelatin capsule shell .

Typical parenteral compositions consist of a solution or suspension of the compound or salt in an aqueous or non-aqueous sterile support optionally containing a parenterally acceptable oil or solubilizing agent, for example polyethyleneglycol, polyvinylpyrrolidone, lecithin, 2-pyrrolidone, -clodextrin, 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 and / or lubricating agent, for example, polymeric glycols, gelatin, cocoa butter or other low melting vegetable waxes or fats or their synthetic analogues.

Typical transdermal formulas comprise a conventional aqueous or nonaqueous carrier, for example, a cream, an ointment, a lotion or a paste or in the form of a medicated patch, dressing or membrane. 3 74 500 Ρ817ΡΤ η '- / / /

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 as a powder for insufflation.

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

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. mg / kg of a compound of formula (1) or a pharmaceutically acceptable salt thereof calculated as the free acid. The daily dosage regimen for oral administration is suitably 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 salt thereof pharmaceutically acceptable amount calculated as free acid. The active ingredient may be administered as needed, for example from 1 to 8 times per day or by infusion. The compositions of the invention are agonists of a Î ± -PrK and have utility to combat conditions in which such agonism is believed to be beneficial. Such states may be treated by oral, sublingual, topical, rectal and parenteral administration or by inhalation. For administration by inhalation the dosages are controlled by a valve, are administered as needed and, for an adult, are conveniently in the range of 0.1 to 5.0 mg of a compound of formula (1) or a pharmaceutically acceptable salt thereof acceptable.

The compounds of this invention may be administered in con-

Together with other pharmaceutically active compounds, for example in combination, concurrently or sequentially. Conveniently, the compounds of this invention and the other active compound (s) are formulated into a single pharmaceutical composition. Examples of compounds which may be included in pharmaceutical compositions with the compounds of formula (1) are bronchodilators such as sympathomimetic amines, for example, isoprenaline, isoetharine, salbutamol, phenylephrine and ephedrine or xanthine derivatives, theophylline and aminophylline, antiallergic agents, for example disodium cromoglycate, histamine antagonists, drugs used in the treatment of cancer such as those which inhibit DNA synthesis or inactivate it, for example methotrexate, fluoroacyl, cisplatin, actinomycin D, anti-atherosclerotic agents, for example, cholesterol lowering drugs such as bile acid sequestrant HMGCoA reductase inhibitors, drugs for the treatment of psoriasis, for example, retinoids, anthralin, anti-inflammatories, for example corticosteroids, anti non-steroidal anti-inflammatory drugs such as aspirin, anti-thrombosis, eg dipyridamole, or fibrinolytic agents.

In another 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 where A9 CO2 H or A9 CO2 R9 and: i) A is CR3 (OR4 ), reacting, in the presence of a strong base, a compound of formula (2):

Wherein R 11 is a protecting group of O and Ar is as previously defined, with a compound of formula (3): wherein R 3 and R 9 are as previously defined to form a compound of formula (4) -9-74 500 Ρ817ΡΤ ν '"

12 R (4) 11

OR where R 3 · 2 is CR 3 (OH) CO 2 R 9 and R 3, R 9, R 11 and Ar are as previously defined and then optionally reacting with an alkylating agent to form the corresponding compound wherein R 12 is CR 3 (O-C 1-3 alkyl) , (ii) A is CO, reacting, in the presence of a strong base, a compound of formula (2) as previously defined with a compound of formula (5): wherein R 9 is as previously defined to form a Compound of formula (4) wherein R 12 is COOCO 2 R 9 and R 9, R 11 and Ar are as previously defined, iii) A is CH (OH), reacting a compound of formula (4) wherein R 3-2 is COOCO 2 R 9 and R 9, R 3 And Ar are as previously defined with a reducing agent to form the corresponding compound wherein R 3-2 is CH (OH) CO 2 R 9, iv) A is CH 2, reacting a compound of formula (4) wherein R 12 is COOCH 2 or C0CO2R9 and R9, R3,3- and Ar are as previously defined with a suitable reducing agent to form the corresponding compound where R12 is CH2 CO2 H, v) A is C (OR5) (OR6), reacting a compound of formula (4) wherein R12 is CO2CO2 R9 and R9, R11 and Ar are as previously defined with a 01000102.3, 1,2-ethanediol or 1,3-propanediol to form the corresponding compound where R3-2 is C (O) R (OR2) CO2 R9, vi) A0 is CF2, reacting a compound of formula (4) wherein R3-2 is CO2CO2 R9 and R9, R3,3 and Ar are as previously defined with a fluorinating agent to form the corresponding compound wherein R13- is CF2CO2R9, or (vii) A is CHF, reacting a compound of formula (4) wherein R3-2 is CH (OH) CO2 R2 and 74,500817, // // y_ · ,, /, ..,. and R9, R11 and Ar are as previously defined with a fluorinating agent to form the corresponding compound where R12 is CHFC02 R9 and then optionally: converting the group OR11 to OH and converting the group A C02 R9 in A0 COOH? or

b) for compounds where R 3 'is CH 2 CO 2 H, convert a compound of formula (6): A (6)

R

OH wherein R3-3 is acetyl and Ar is as previously defined in the corresponding compound wherein R13 is CH2 CO2 H; or (c) for compounds in which R 3 - is CH (O R 4) CO 2 H reacting a compound of formula (4) wherein R 12 is -CH (OH) CN with a C 1 -alkylating agent and / or converting the CN group to CO 2 H, optionally converting the OR 11 group to OH; or (d) for compounds wherein R 3 - is P (O) (OH) (OR 2), hydrolyzing a compound of formula (6) wherein R 13 is P (O) (OR 2) 2 and R 2 and Ar are as previously defined; or e) for compounds where R1 is P (S) (OH) (OR2), converting a compound of formula (6) wherein R13 is P (O) (NHR3-4) (OR2) and R3-4 is phenyl or C 14 alkyl and Ar is as previously defined in the corresponding compound wherein R 13 is P (S) (OH) (OR 2); or f) for compounds wherein R1 is SO3 H, reacting, in the presence of a strong base, a compound of formula (2) as defined above with sulfuryl chloride or a chemical equivalent thereof, and optionally converting the OR11 group to OH; or g) for compounds wherein R1 is SO2 H, reacting, in the presence of a strong base, a compound of formula (2) as defined above with sulfur dioxide and optionally converting the OR11 group to OH; or (h) for compounds wherein R1 is 5-tetrazolyl, reacting a compound of formula (4) wherein R12 is cyano or a compound of formula (6) wherein R3 is cyano with an azide salt and then, if necessary, converting the group OR 11 into OH; or i) for compounds where R1 is as previously defined for the compounds of formula (1) reacting, in the presence of a palladium catalyst, a compound of formula (7):

(7) wherein Rb is a group R1 as defined above or a precursor thereof and Ra is an R6 group as defined above or a precursor thereof and L1 is a leaving group with a compound of formula ):

ArB (OH) 2 (8) or a chemical equivalent thereof where Ar is as previously defined and then, if necessary, converting a precursor of R1 to R1 and / or converting a precursor of R6 to R6, optionally: forming a bioprecursor of R ° and / or R 1 "forming a pharmaceutically acceptable salt.

Suitably, a compound of formula (2) is reacted with a strong base such as lithium diisopropylamide or a C 1-4 alkyl lithium or aryl lithium such as mesityl lithium in an organic solvent such as tetrahydrofuran, diethyl ether or dimethoxyethane with cooling 100 ° to 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, for example methyl lithium followed by a catalytic amount of diisopropylamine. 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 (-100 to 0 ° C ) to form a compound of formula (4) wherein R 12 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.

Ρ817ΡΤ

A compound of formula (4) wherein R 12 is CR 3 (OH) CO 2 R 9 is suitably reacted with an alkylating agent such as iodomethane, iodopropane or dimethyl sulfate in the presence of a base such as sodium hydride or potassium hydroxide in an organic solvent such as dimethylformamide or dimethyl sulfoxide at elevated temperature (e.g., 30 to 80 ° C) or preferably at room temperature to form the corresponding compound where R 12 is CR 3 (O-C 1-3 alkyl) CO 2 R 9. When potassium hydroxide is used as the base the CO 2 R 9 group can be converted directly into carboxy.

A compound of formula (4) wherein R 2 * 2 and CO 2 CO 2 R 9 is suitably reacted with a reducing agent such as sodium borohydride or diisobutylaluminum hydride in an organic solvent such as dichloromethane, a C álcool álcool álcool alcohol, for example ethanol , or acetic acid or mixtures thereof at room temperature or elevated temperature (e.g. 30 to 80 ° C) or with cooling (e.g. 0 to 5 ° C) to form the corresponding compound where R 12 is CH (OH) CO 2 R 9.

A compound of formula (4) wherein R 12 is COOCO 2 H or COOCO 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 elevated temperature (e.g., 40 to 100 ° C) to form the corresponding compound where R 12 is CH 2 COOH. Under these reaction conditions the CO 2 R 9 group is converted into carboxy.

A compound of formula (4) wherein R 2 is CO 2 CO 2 R 9 is suitably reacted with alcohol 02.3, 1,2-ethanediol or 1,3-propanediol in the presence of an acid catalyst such as paratoluenesulfonic acid, concentrated sulfuric acid or chloride of anhydrous hydrogen, at room temperature or elevated temperature to form the corresponding compound wherein R 2 is C (OR 3) (OR 2 R 3) 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 fluorination agent as trifluoride in diethylaminosulfur trifluoride in an organic solvent such as a halohydrocarbyl or an ether such as glyme or THF at room temperature or elevated (e.g., 30 to 60 ° C) to form the corresponding compound when R 12 is CF 2 CO 2 R 9 or CH 3 CO 2 R 9 respectively.

Examples of O-protecting groups for R1 include methyl or benzyl. A compound of formula (4) wherein OR 11 is methoxy can be suitably converted to the corresponding compound wherein OR 11 is hydroxy by reaction with sodium iodide and chlorotrimethylsilane in an organic solvent such as acetonitrile or a halohydrazide, for example dichloromethane or chloroform at elevated temperature (e.g. 30 to 80 ° C) or, preferably, at room temperature. This process is particularly suitable for preparing compounds of formula (1) wherein R1 is A0CO2R9 provided that the ester forming group R9 is not hydrolyzed under the reaction conditions. Another process uses sodium thiomethoxide in an organic solvent such as dimethylformamide at an elevated temperature, for example 40 to 120 ° C. More vigorous conditions of this process are suitable for preparing compounds of formula (1) wherein R3 is A9 CO2 H. Alternatively, a compound of formula (4) wherein OR 11 is benzyloxy may be converted to the corresponding compound wherein OR 11 is hydroxy in a conventional manner, for example by catalytic hydrogenation over palladium on carbon or by reacting it with sodium in liquid ammonia.

A compound of formula (4) wherein R 12 is A ° CO 2 R 9 may suitably be converted to the corresponding compound wherein R 12 is A0 CO 2 H by reaction with an aqueous base such as sodium or potassium hydroxide at ambient or elevated temperature , 40 to 120 ° C). This process is particularly suitable for preparing 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 to 120 ° C) which directly provides compounds of formula (1) wherein R ° is hydroxy and R1 is A0CO2H. 74 500 Ρ817ΡΤ -S'r

Suitably a compound of formula (6) wherein R 13 is acetyl is converted to the corresponding compound wherein R 3 is CH 2 CO 2 H by reaction with sulfur and morpholine at elevated temperature (for example, 50-200 ° C) followed by hydrolysis with a base aqueous solution as sodium hydroxide at elevated temperature, preferably at the reflux temperature of the reaction mixture.

Suitably, a compound of formula (4) wherein R 12 is -CH (OH) CN is reacted with an alkylating agent as described above followed by reaction with an aqueous inorganic acid such as hydrochloric acid at ambient temperature or at elevated temperature , preferably at the reflux temperature, to prepare the corresponding compound wherein R 12 is CH (O-C 1-3 alkyl) CO 2 H. Alkylation can be omitted if the corresponding compound where R 12 is CH (OH) CO 2 H is as desired. During the hydrolysis of the CN group, the OR 1 - group may be converted to hydroxy. If this does not happen and if necessary, this group can be converted into hydroxy as described above.

A compound of formula (4) wherein R 2 * 2 is -CH (OH) CN may be prepared by reacting the corresponding compound wherein R 12 is CHO with a cyanide source such as potassium cyanide in the presence of an acid such as preferably at room temperature.

A compound of formula (4) or (6) wherein R 12 or R 13 is CHO is suitably prepared by reacting the corresponding compound wherein R 12 or R 13 is cyano with a suitable reducing agent such as diisobutylaluminium hydride followed by aqueous acid treatment.

Suitably a compound of formula (6) wherein R3 is P (O) (OR2) 2 is hydrolyzed by reaction with an aqueous base such as sodium hydroxide optionally in a cosolvent such as a cl-4 alcohol at an elevated temperature (e.g., 40 to 100 ° C), preferably at the reflux temperature of the reaction mixture. 74 500 Ρ817ΡΤ ///

-15-

Suitably a compound of formula (6) wherein R13 is P (o) (NHR14 (OR2) is converted to the corresponding compound wherein R9 is P (S) (OH) (OR2) by reaction with a strong base such as sodium hydride in organic solvent such as dimethoxyethane at room temperature or at elevated temperature (e.g., 40 to 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 to 0 ° C) to form, after aqueous treatment, a compound of formula (4) wherein R 12 is SO 3 H or SO 2 H respectively and OR 11 is as previously defined, which may be converted, if necessary, to the corresponding compound wherein 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 13 is cyano is suitably reacted with an azide salt such as ammonium, sodium or aluminum azide in an organic solvent such as dimethylformamide, dimethyl sulfoxide, N methylpyrrolidone or tetrahydrofuran at an elevated temperature, for example 40 to 200 ° C, preferably 100 to 150 ° C to form the corresponding 5-tetrazolyl compound. Preferably, in a compound of formula (4) is benzyloxy as this group is converted directly to hydroxy under the reaction conditions.

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 carbonate of aqueous sodium and optionally lithium chloride in an organic solvent such as dimethylformamide, dimethoxyethane, acetonitrile, toluene, tetrahydrofuran, ethanol or mixtures thereof, at elevated temperatures (for example 30 to 150 ° C), preferably at the temperature of the mixture. Suitably, L 1 is halo, for example -16- 74 500 Ρ 817 Ρ iodine, bromine or chlorine and preferably L 1 is a trifluoromethanesulfonate. 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 butane] palladium (Pd (dppb) Cl2) dichloride, [1,3-bis (diphenylphosphine) propane] palladium dichloride (Pd (dppp) Cl2), [1,2-bis- (diphenylphosphine) ethane] palladium dichloride (Pd (dppe) Cl2), bis (tri-o-tolylphosphine) palladium diacetate or dichloride (Pd (totp) (OAc) 2 or (Pd (totp) Cl2) or 1,1'-bis diphenylphosphine) ferro-cinopalladium (Pd [dppf] (OAc) 2 or (Pd (dppf) C 12).

By a chemical equivalent of a compound of formula (8) is meant 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 may be used which may be suitably prepared by reacting a suitable aryl halide (such as ArBr or Ar) with a base such as t-butyl lithium followed by reaction with a trimethyl tin halide ( for example 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 Ra is a group R ° as previously defined and Rb is a group R 2 - as previously defined, the reaction of a compound of formula (7) with a compound of formula (8) directly results in compounds of formula (1) .

An example of a precursor of R * * is when Rb is hydrogen. Examples of an R precurs precursor are when R é is halo, such as chloro, which may be converted to another OR precurs precursor such as methoxy or benzyloxy by reaction with either sodium methoxide or benzyl alcohol and a base such as tert-butoxide of potassium, preferably 74 500 Ρ817ΡΤ

and in the presence of an 18-crown-6 or 15-crown-5 crown ether. Preferably a compound of formula (7), wherein Ra is chlorine, R3 is hydrogen and L1 is trifluoromethane sulfonate, is reacted with a compound of formula (8) or a chemical equivalent thereof, followed by conversion of Ra which is chlorine in Ra which is OR 11 to form a compound of formula (2). This compound can then be converted to a compound of formula (1) as described herein.

Other precursors of R1 include CN, CHO or COMe. The reaction of a compound of formula (7) wherein Rb represents this precursor and Ra is OH or a compound of formula (8) or a chemical equivalent thereof results in a compound of formula (4) or compound of formula (6) wherein R 12 or R 13 is CN, CHO or COMe. These compounds can be converted into compounds of formula (1) as described herein.

If necessary, a compound of formula (1) wherein R1 is A3 CC2 H may be converted to the corresponding compound wherein R3 is A0 CO2 R9 by reaction with a compound R90 H where R9 is as previously defined.

A compound of formula (1) wherein R 6 is OH can be converted to the corresponding compound where R 6 and OR 8 by reaction with R 8 L 2 where R 8 is as previously defined and L 2 is a leaving group as halo, for example bromine , chlorine or iodine.

If a compound of formula (1) where R1 is P (Z) (OR2) (OH) may be converted to the corresponding compound where R1 is P (Z) (OR2) (OR10) by reaction with an O-protecting agent appropriate, in a common way. 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 normal manner, for example with a pivalolyloxymethyl halide.

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

A compound of formula (1) wherein R 1 -R 2 is A 2 CH 2 O is suitably prepared by reacting a compound of formula (1) wherein R 1 is A 2 OH and R 2 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 to 120 ° C).

A compound of formula (2) is suitably prepared by reacting a compound of formula (6) wherein R3 · 3 is hydrogen with a methylating agent such as dimethylformamide dimethyl acetal in dimethylformamide or trimethyl phosphite at an elevated temperature (e.g. , 40 to 120 ° C) or with iodomethane and silver carbonate in toluene or chloroform or with an O benzylating agent such as bromide or benzyl chloride in the presence of a base such as potassium carbonate or sodium hydride . This process can also be used to convert compounds of formula (6) into the corresponding compounds of formula (4) and the compounds of formula (7) where Ra is hydroxy in the corresponding compounds wherein Ra is OR11.

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

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

A compound of formula (6) wherein R 13 is cyano or acetyl and Ar is as previously defined may be suitably prepared by 74 500 Ρ 817 ΡΤ by reacting a compound of formula (4) ) where R 12 is cyano or acetyl and Re Ar are as previously defined with a methylating or debenzylating agent as previously described.

A compound of formula (4) wherein R 12 is cyano is suitably prepared by reacting the anion of a compound of formula (2) wherein Ar and R 11 are as previously defined with dimethylformamide with cooling (for example -80 to 10 ° C), then at room temperature and with aqueous treatment. The resulting compound of formula (4) wherein R 2 is carboxaldehyde is treated with hydroxylamine hydrochloride and sodium acetate in an appropriate solvent such as ethanol or methanol at elevated temperature, for example 40 to 100øC, 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 (4) wherein R 12 is cyano is most suitably prepared by reacting a compound of formula (9):

where Ar and R11 are as previously defined with a dimethylcarbamoyl halide as the chloride, followed by reaction with trimethylsilyl cyanide, suitably at room temperature in a solvent such as dichloromethane.

A compound of formula (9) is suitably prepared by reacting a compound of formula (2) with an oxidizing agent such as metachloroperbenzoic acid in an organic solvent such as dichloromethane.

A compound of formula (6) wherein R 13 is P (O) (OR 2) 2 may be prepared by treating a compound of formula (2) wherein R 11 is P (O) (OR 2) 2 with a strong base such as lithium diisopropylamide

74 500 Ρ 817 ΡΤ in an organic solvent such as tetrahydrofuran, with cooling (e.g., -100 to 0 ° C).

A compound of formula (2) wherein R 11 is P (O) (OR 2) 2 is suitably prepared by treating a compound of formula (6) wherein R 13 is hydrogen with a compound of formula ) where L 3 is a leaving group and R 2 is as previously defined with a base such as diisopropylethylamine.

Suitably L3 is halo, for example chlorine or bromine.

A compound of formula (2) wherein R1 is P (O) (OR2) 2 may also be prepared by treating a compound of formula (6) wherein R13 is hydrogen with a compound of formula (11) (0R2) 2 (11) wherein R2 is as previously defined, 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 treating a compound of formula (6) wherein R 13 is hydrogen with a compound of formula (10) in the presence of a strong base as to lithium diisopropylamide in an organic solvent such as tetrahydrofuran, with cooling (for example -100 to 0 ° C) without isolation of the intermediate compound of formula (2) wherein R 11 is P (O) (O R 2) 2.

A compound of formula (6) wherein R 13 is hydrogen is suitably prepared by demethylating or debenzylating a compound of formula (2) as hereinbefore defined. Suitably a compound of formula (2) wherein R 11 is methoxy is treated with boron tribromide in an organic solvent such as dichloromethane or toluene, with cooling (for example -80 to 10 ° C) followed by warming to room temperature and treatment aqueous. Or a compound of formula (2) is treated with sodium iodide and chlorotrimethylsilane at room temperature or at elevated temperature (e.g., 40 to 80 ° C), conveniently at room temperature, in a solvent such as acetonitrile or dichloromethane. 74 500 Ρ817ΡΤ / > W

-21-

A compound of formula (6) wherein R 13 is P (O) (NHR 14) (OR 2) may be prepared by reacting a compound of formula (6) wherein R 13 is P (O) (OH) (OR 2) 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 (for example -10 to 5 ° C). Alternatively, a compound of formula (6) wherein R 13 is P (O) (OH) (OR 2) may be reacted with dimethylformamide and oxalyl chloride in an organic solvent such as a hydrocarbon halo, for example 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 in a common manner, for example from a compound of formula (12): (12)

Wherein Ra and L - * - are as previously defined, using processes similar to those described for preparing compounds of formula (I).

Thus, a compound of formula (7) wherein Rb is P (O) (OR2) 2 may be prepared by reacting a compound of formula (12) wherein Ra is OH with a compound of formula (10) or (11) in a manner similar to that of the reaction of a compound of formula (6) wherein R3 is hydrogen with a compound of the formulas (10) or (11). If necessary, the Ra group can then be converted to OR 11 as previously described.

Similarly, a compound of formula (12) wherein Ra is OR * * * * can be treated in the presence of a strong base with a compound of formula (3), a compound of formula (5), sulfur sulfur dioxide or 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 that corresponding to the corresponding 74 500 Ρ 817 reaction with a compound of formula (2) as described above. Particularly suitable as the strong base is lithium te-trimethylpiperidine.

A compound of formula (12) wherein Ra is chloro and L1 is trifluoromethanesulfonate is suitably prepared by reacting 3-chloro-5-hydroxypyridine with trifluoromethanesulfonic anhydride in the presence of a suitable base, for example 4-N, N- dimethylaminopyridine in an organic solvent such as dichloromethane.

A compound of formula (8) is suitably prepared by reacting the organolithium or Grignard reagent, formed from a compound of formula (13):

Ar-L4 (13) where L4 is bromo or iodo and Ar is as previously defined with a trialkyl borate α1-4 as trimethyl, triisopropyl or tri-n-butyl borate in an organic solvent such as diethyl ether or tetra -hydrofuran with cooling (e.g. -80 to 10 ° C). The Ar group in compounds of formula (2), (4), (6) or (13), preferably (2) or (4) may be suitably functionalized by aromatic substitution processes known in the art. For example, a bromo group may be introduced into a suitably substituted phenyl ring (for example, disubstituted at the 2- and 4-positions with electron donor groups such as C1-6 alkoxy), and reaction with a brominating agent such as N-bromosuccinimide or the bromine in a 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 easily hydrogenated to give an amino group which may, if necessary, is converted to an NHCOR 7 group by reaction with LCOR 7 where L is a leaving group and R 7 is as previously defined Suitable examples of the LCOR reagent include (L is halo, for example chlorine or bromine) or acid anhydrides (L is OCOR7.) / r / r

74 500 Ρ817ΡΤ -23- /

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, for example bromide, to form an allyloxy derivative which, when heated, undergoes a Claisen rearrangement to form a ortho-allyl-hydroxy 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 necessary, 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 with osmium tetroxide to form a 1,2-dihydroxypropyl group which, on reaction with an oxidizing agent such as sodium periodate forms the formyl group. Alternatively, the E-1-propenyl group may be converted directly to a formyl group by reaction with a mixture of osmium tetroxide and sodium periodate or by reaction with ozone. A formyl group may in turn be further functionalized, for example it may be converted to a hydroxymethyl group by reaction with a suitable reducing agent such as sodium borohydride, then reacting the hydroxymethyl group, for example with a Cl-6 alkyl halide To form an alkoxy-G-methyl group. Alternatively, a formyl group may be reacted with a suitable Wittig or Wittig Horner's reagent such as (R-O) 2 P (O) CH 2 CO 2 R 15 or Ph 3 P =: CHCO 2 R -1 1-5 where R 15 is C 1-4 alkyl to form a CH = CHCO 2 R 15 group which may optionally be hydrolyzed to give a -CH = CHCOOH group. A -CH = CHC02R15 group may be converted into a -CH = CHC0N (R7) 2 group by reaction with an amine HN (R7) 2 or a chemical equivalent thereof where R7 is as previously defined. Alternatively, a -CH = CHCH2 H group may be converted to an acid halide, for example the acid chloride, by reaction with oxalyl chloride which may then be reacted with an amine HN (R7) 2 or a chemical equivalent thereof. An example of a chemical equivalent is ammonium hydroxide which will form a CH = CHCONH 2 group.

The pharmaceutically acceptable base addition salts of the 74,500 Ρ 817ΡΤ -24-

compounds of formula (1) may be prepared by standard 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 serve to illustrate this invention.

Amino Acid Activity of AMP Cyclic Protein Kinase (cA-PrK) cA-PrK Type II was prepared from the heart muscle of a cow. Supernatant from a muscle homogenate (3 ml of 10 mM potassium phosphate, 1 mM EDTA per g of tissue) was applied to a DEAE-cellulose column equilibrated with homogenization buffer and the type-A c-PrK was eluted with homogenization buffer containing 350 mM sodium chloride (Rannels et al., 1983, Methods Enzymol, 99, 55-62). Type II cA-PrK was assayed for phospho-transferase activity by incubating the enzyme at 5 ° C for 5 minutes with [T-32 P] -adenosine triphosphate and a suitable peptidic substrate as malantide (Malencik et al., 1983, Anal Biochem., 132, 34-40). The reaction was quenched by the addition of hydrochloric acid and [32p] -phosphopeptide was quantitated by placing the reaction mixture in spots on phosphocellulose papers. The concentration of compound required to give 10% phosphotransferase activation is given as EC10 (MM). The compounds of examples 1 to 3 had EC10 values in the range of 1.8 to 100 μΜ.

Inhibition of platelet aggregation

Platelet rich human plasma was separated from freshly collected blood (acid / citrate / dextrose) and treated with 100 μ ace acetylsalicylic acid for 15 minutes at 37 ° C. A washed platelet suspension was then prepared in a Hepes-isotonic saline buffer after a single centrifugation step and adjusted to a concentration of 1.5 x 108 cells / ml. Aliquots of this suspension were preincubated with compounds for 5 minutes at 37 ° C and then challenged with 1.0 μΜ of U46619. The extent of aggregation after 2 minutes was expressed as a percent control and the results. obtained are expressed as IC50 (concentration causing 50% inhibition of platelet aggregation, μΜ). The compounds of examples 1 to 3 had IC 50 values in the range of 6 to 109 μΜ.

Inhibition of spontaneous contraction in guinea pig colon

Segments of colon isolated from guinea pig (2 cm) were suspended under 2 g of strain in normal organ baths containing Krebs solution. The tissues were connected by the free end to isometric transducers that allow to register and display the voltage developed in graphic registers. On-line computer capture and analysis was used to quantify the effects of test compounds on spontaneous contractions. Inhibitory responses were calculated as the maximal% inhibition of spontaneous contraction distance in 3 consecutive readings 2 minutes before and after dosing. The concentration of the compound causing 50% inhibition of the spontaneous concentration is given as the EC 50 (μΜ).

Bronco-dilatation - in vitro

Spiral strips of guinea pig trachea were suspended in normal organ baths containing Krebs solution. The tissues were connected by the free end to isometric transducers which allowed to register and display the voltage developed in the graphic recorders, the voltage was allowed to develop spontaneously and the concentrations of test compounds were cumulatively added. The concentration of compound causing 50% inhibition of the spontaneously developed stress is given as the IC 50 (μΜ). The compound of Example 1 had an IC 50 value of 100 μΜ.

Measurement of cardiac muscle relaxation time in the rabbit ventricle Papillary muscles of the right ventricle of New Zealand Albino female rabbits were assembled in normal organ baths containing oxygenated Krebs solution. One end of the muscle is attached to an isometric transducer which allows recording of the contraction force and its first derivative in chart registers. Test compounds are added 74 500 Ρ 817 ΡΤ

26 to the bath in a cumulative manner. The relaxation time is calculated as the time from the peak of tension to the end of the contraction. Compounds which cause a relaxation time decrease indicate a positive lusitropic effect of the use in the treatment of cardiovascular diseases where there is a component of diastolic insufficiency such as in congestive heart failure, angina, hypertension and cardiomyopathy.

To an ice cold solution of 3-chloro-5-hydroxy-pyridine (4.95 g) and ethyl 4- N, N-dimethylaminopyridine (14 g) in dichloromethane (300 ml) was added trifluoromethanesulfonic anhydride (10 g) for 30 minutes. When the addition was complete the mixture was stirred for an additional 2 hours and poured into 1 M hydrochloric acid (300 ml). The organic phase was separated, washed with water (2 x 100 mL), dried (MgSO4) and the solvent removed under reduced pressure to give 3-chloro-5-trifluoromethanesulfonyloxypyridine (8.9 g) as an oil which solidified after resting. Δ NMR δ (CDCl3) 7.69 (m, 1H), 8.52 (m, 1H) and 8.65 (m, 1H). (b) 2-Naphthylboronic acid (2.33 g) and 3-chloro-5-trifluoromethanesulfonyloxypyridine (3.4 g) was prepared 3-chloro-5- (2-naphthyl) 5 g) according to the procedure of A. Huth, I. Beetz and I. Schumann, Tetrahedron, 1989, 45, 6676. 1 H NMR δ (CDCl 3) 7.52-7.57 (m, 2H) 68 (dd, 1H), 7.84-8.04 (m, 5H), 8.58 (m, 1H) and 8.85 (d, 1H). (c) A mixture of 3-chloro-5- (2-naphthyl) pyridine (2.0 g) and sodium methoxide in dimethylformamide (50 ml) was heated at 130 ° C for 3.5 hours. The mixture was poured onto ice, stirred vigorously for one hour and extracted with diethyl ether (200 ml). The ether extract was washed with water (4 x 100 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was column chromatographed (silica gel, dichloromethane as eluent) to give 3-methoxy-5- (2-naphthyl) pyridine (1.2 g). 1 H NMR δ (CDCl 3) 4.12 (s, 3H), 7.51-27-74.500 Ρ817ΡΤ / // __________________________________ -7/62 (m, 3Η), 7.82-8.04 (m, Δ), 8.19 (dd, 1H) and 8.53 (s, 1H). (d) A solution of 3-methoxy-5- (2-naphthyl) pyridine (2.07 g) in a mixture of acetic acid / hydrobromic acid (250 ml, 2: 3) was boiled for sixty-five hours. After cooling to room temperature, the solvent was removed under reduced pressure and the residue triturated with water (100 ml) to give 3-hydroxy-5- (2-naphthyl) pyridine (1.75 g). NMR (DMSO- (d, 1H), 7.95-8.08 (m, 3H), 8.17 (d, 1H) 28 (s, 1H), 8.52 (d, 1H) and 10.15 (broad s, 1H). (e) To a solution of 3-hydroxy-5- (2-naphthyl) pyridine (1/75 g) in tetrahydrofuran (30 ml) was added lithium diisopropylamide (prepared from n-butyllithium 3 , 8 ml of 2.5M solution in hexane and diisopropylamine (0.81 g) at -78 ° C. When the addition was complete the mixture was warmed to ambient temperature and stirred for 90 minutes, again cooled to -78 ° C and treated with diethyl chlorophosphate (1.38g). The mixture was warmed to ambient temperature, stirred for 15 minutes, cooled back to -78 ° C and treated with additional lithium diisopropylamide (from n-butyl lithium 3.8 ml of 2.5 M solution in hexane and 0.1 M diisopropylamine, 81 g). After stirring at -78 ° C for 15 minutes and at room temperature for 20 minutes, the reaction mixture was poured into a mixture of ice (100 g) and concentrated hydrochloric acid (15 ml) and stirred overnight. The tetrahydrofuran was removed under reduced pressure and the aqueous residue was extracted with dichloromethane (2 x 100 ml). The combined organic extracts were washed with water (2 x 100 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residual oil was column chromatographed (silica gel, dichloromethane followed by diethyl ether followed by 4: 1 ethyl acetate / ethanol as eluents) to give [3-hydroxy-5- (2-naphthyl) -2-pyridyl ] -phosphonate (1.86 g). NMR δ (CDCl 3) 1.39 (t, 6H), 4.15-4.37 (m, 4H), 7.53-7.62 (m, 3H), 7.71 (dd, 1H), 7 , 87-7.95 (m, 3H), 8.08 (s, 1H) and 8.69 (d, 1H). (f) A mixture of diethyl (3-hydroxy-5- (2-naphthyl) -2-pyridyl] phospho-74,500 g) and sodium hydroxide (0.5 g) in water / ethanol (11 ml, 10: 1) was boiled for 12 hours. The solvent was removed under reduced pressure and the residue was dissolved in water (3 ml) and acidified with concentrated hydrochloric acid (15 ml). The precipitated material was collected by filtration and recrystallized from ethanol to give the title compound (0.15 g), m.p. 252-254 ° C. Δ NMR (DMSO-d6) 1.15 (t, 3H), 3.83-3.96 (m, 2H), 7.56-7.62 (m, 2H), 7.98-8.11 (m, 3H), 8.19 (m, 1H), 8.50 (s, 1H) and 8.73 (s, 1H).

(A) A mixture of 4-bromo-resorcinol (25 g), potassium carbonate and iodopropane in dimethylformamide was heated in dimethylformamide to give 2- tformamide at 90 ° C for 18 hours. The solvent was removed under reduced pressure, the residue was triturated with diethyl ether and the filtrate was adsorbed onto silica gel and column chromatographed (silica gel, petroleum ether / diethyl ether 9: 1 as eluent) to give 1-bromo-2,4-dipropoxybenzene (11 g). 1 H NMR (CDCl 3) 1.03 (t, 3H), 1.06 (t, 3H), 1.71-1.94 (m, 4H), 3.89 (q, 2H), 3.92 q, 2H), 6.37 (dd, 1H), 6.46 (d, 1H) and 7.37 (d, 1H). (b) From 2,4-dipropoxyphenyl lithium [prepared by adding 1-bromo-2,4-dipropoxy-benzene (11.0 g) to tert-butyl lithium (48 ml of 1.7 M solution in pentane)] (2,4-dipropoxyphenyl) boronic acid (6.1 g) was prepared according to the procedure of WJ Thompson and J. Gaudino, J. Org. Chem., 1984, 49, 5237. 1 H-NMR (Q, 2H), 4.19 (q, 2H), 1.16 (t, 3H), 1.84-2.04 (m, 4H) ), 6.55 (d, 1H), 6.66 (dd, 1H) and 7.85 (d, 1H). (c) Starting from (2,4-dipropoxyphenyl) boronic acid (5.0 g) and 3-chloro-5-trifluoromethanesulfonyloxypyridine (5.5 g) was prepared 3-chloro-5- -dipropoxyphenyl) pyridine (6.47 g) according to the procedure of example 1 (b). NMR (δ, CDCl3) 0.99 (t, 3H), 1.06 (t, 3H), 1.72-1.89 (m, 4H), 3.93 (t, 2H), 3. , 96 (q, 2H), 6.55-6.59 (m, 2H), 7.26 (d, 1H), 7.87 (m, 1H), 8.45 (d, 1H). 500 Ρ 817 ΡΤ / /, Ο and 8.62 (d, 1H). (d) 3-Chloro-5- (2,4-dipropoxyphenyl) pyridine (3.9 g), benzyl alcohol (20.0 g), potassium t-butoxide (4.0 g) and 18-crown- (0.1 g) were combined in N-methylpyrrolidinone (20 ml) and heated at 130 ° C for 48 hours. The mixture was poured into a mixture of ice (100 g) and concentrated hydrochloric acid (10 ml) and extracted with dichloromethane (3 x 100 ml). The combined organic extracts were dried (MgSO4) and the solvent removed under reduced pressure. The residue was column chromatographed (silica gel, petroleum ether / diethyl ether 4: 1 as eluent) to give 3-benzyloxy-5- (2,4-dipropoxyphenyl) pyridine (1.6 g). 1 H NMR (CDCl 3) 0.97 (t, 3H), 1.06 (t, 3H), 1.65-1.91 (m, 4H), 3.91 (t, 2H), 3.95 t, 2H), 5.13 (s, 2H), 6.51-6.57 (m, 2H), 7.26-7.49 (m, 7H), 8.27 (d, 1H), and 8 , 37 (d, 1H). (e) 3-Chloroperbenzoic acid (2.0 g) was added to a solution of 3-benzyloxy-5- (2,4-dipropoxyphenyl) pyridine (1.6 g) and the mixture was stirred for 3 hours. The solvent was removed under reduced pressure and the residue was column chromatographed (silica gel, dichloromethane / petroleum ether 1: 1 as eluent) to give 3-benzyloxy-5- (2,4-dipropoxyphenyl) pyridine (1.6 g). 1 H NMR δ (CDCl 3) 0.99 (t, 3H), 1.06 (t, 3H), 1.74-1.87 (m, 4H), 3.93 (t, 2H), 3.95 t, 2H), 5.09 (s, 2H), 6.52-6.59 (m, 2H), 7.16-7.20 (m, 2H), 7.40 (s, 5H), 7 , 96 (s, 1H) and 8.13 (s, 1H). (f) From 3-benzyloxy-5- (2,4-dipropoxyphenyl) pyridine N-oxide (1.6 g), 3-benzyloxy-2-cyano-5- (2,4-dipropoxy) (0.8 g) was prepared according to the procedure of WK Pife, Heterocycles, 1984, 22, 93.% NMR (CDCl3) 0.97 (t, 3H), 1.06 (t, 3H), 1.68-1.91 (m, 4H), 3.92 (t, 2H), 3.96 (t, 2H), 5.25 (s, 2H), 6.55 (s, 1H ), 6.56 (dd, 1H), 7.20 (d, 1H), 7.33-7.46 (m, 5H), 7.59 (d, 1H) and 8.44 (d, 1H) . (g) A mixture of 3-benzyloxy-2-cyano-5- (2,4-dipropoxyphenyl) pyridine (0.8 g), sodium azide (0.54 g) and ammonium chloride g were heated together at 74 500 Ρ 817 Ρ

/ -30- Γ,

N-methylpyrrolidinone (15 ml) at 190 ° C for 6 hours. The solvent was removed under reduced pressure and the residue was triturated with water. The crude product was collected by filtration and was chromatographed (reverse phase C18 silica, acetonitrile / 0.1% aqueous trifluoroacetic acid, 3: 2 as eluant) to give the title compound (0.13 g), mp NMR (DMSOd 6) 0.95 (t, 3H), 1.00 (t, 3H), 1.67-1.84 (m, 4H), 3.99 (t, 4H) 6.58-6.68 (m, 2H), 7.47 (d, 1H), 7.64 (s, 1H) and 8.44 (s, 1H).

Example 3 5- (4-Methoxy-3-propoxyphenyl) -3- (5-tetrazolyl) pyridin-3-ol (a) From 3-hydroxy-4-methoxy-nitrobenzene (25 g), 4- methoxy-1-nitro-3-propoxybenzene (31 g) was prepared according to the procedure of example 2 (a). 1 H NMR δ (CDCl 3) 1.07 (t, 3H), 1.82-1.97 (m, 2H), 3.97 (s, 3H), 4.05 (t, 2H) 91 (d, 1H), 7.74 (d, 1H) and 7.90 (dd, 1H). (b) A solution of 4-methoxy-1-nitro-3-propoxybenzene (20 g) in acetic acid (150 ml) containing 10% palladium on carbon (2 g) was heated at 80øC under an atmosphere of 413.7 kPa (60Psi) with stirring for 4 hours. The reaction mixture was filtered under nitrogen into 50% sulfuric acid (300 mL) cooled to 0 ° C and treated with an aqueous sodium nitrite solution (6.9 g in 20 mL of water) at a rate such that temperature did not rise above 5 ° C. When the addition was complete, the mixture was stirred for another 2 hours at 0 ° C and then poured into a solution of potassium iodide (200 g) iodine (40 g) and urea (1 g) in water (300 ml). Dichloromethane (300 ml) was added and the mixture was stirred vigorously at room temperature until gas evolution ceased (3 hours). Sodium metabisulfite (20 g) was added, the organic phase separated, washed with water (2 x 100 ml), dried (MgSO4) and the solvent was removed under reduced pressure. The residue was column chromatographed (silica gel, petroleum ether / dichloromethane 1: 1 as eluent) to give 1-iodo-4-methoxy-3-propoxybenzene (17 g). 1 H NMR δ (CDCl 3) 1.03 (t, 3H), 1.77-1.95 (m, 2H), 3.83 (s, 3H), 3.93 (t, 2H), 6.61 ( d, 1H), 7.11 (d, 1H) and 7.19 (dd, 1H).

(C) From 1-iodo-4-methoxy-3-propoxybenzene (16.9 g), (4-methoxy-3-propoxyphenyl) boronic acid (10.0 g) was prepared according to the procedure of Example 2 (b). 1 H NMR (DMSOd 6) 0.98 (t, 3H), 1.65-1.79 (m, 2H), 3.76 (s, 3H), 3.89 (t, 2H) 91 (d, 1H), 7.32-7.37 (m, 2H) and 7.86 (br s, 2H). (d) Starting from 4-methoxy-3-propoxyphenyl) boronic acid (10.0 g) and 3-chloro-5-trifluoromethanesulfonyloxypyridine (12.6 g) was prepared 3-chloro-5- (4-methoxy- 3-propoxyphenyl) pyridine (11.0 g) according to the procedure of example 1 (b). 1 H NMR δ (CDCl 3) 1.07 (t, 3H), 1.83-1.99 (m, 2H), 3.92 (S, 3H), 4.05 (t, 2H) D, 1H), 7.11 (dd, 1H), 7.81 (m, 1H), 8.50 (d, 1H) and 8.67 (d, 1H) ). (e) From 3-chloro-5- (4-methoxy-3-propoxyphenyl) pyridine (10.0 g) was prepared 3-benzyloxy-5- (4-methoxy-3-propoxyphenyl) ) pyridine according to the procedure of example 2 (d). The crude material was treated with 3-chloroperbenzoic acid (10.0 g) according to the procedure of example 2 (e) to give 3-benzyloxy-5- (4-methoxy-3-propoxyphenyl) pyridine (4.0 g). NMR (CDCl3): δ 1.06 (t, 3H), 1.82-1.97 (m, 2H), 3.91 (s, 3H), 4.00 (t, 2H), 5.13 (s, 2H ), 6.88-7.09 (m, 4H), 7.42 (s, 5H), 7.98 (s, 1H) and 8.14 (s, 1H). (f) From 3-benzyloxy-5- (4-methoxy-3-propoxyphenyl) pyridine N-oxide (3.8 g) was prepared 3-benzyloxy-2-cyano-5- (4- methoxy-3-propoxyphenyl) pyridine (2.3 g) according to the procedure of example 2 (f). 1 H NMR δ (CDCl 3) 1.08 (t, 3H), 1.83-1.98 (m, 2H), 3.98 (s, 3H), 4.01 (t, 2H), 6 , 94-6.98 (m, 2H), 7.07 (dd, 1H), 7.38-7.50 (m, 6H) and 8.45 (d, 1H). (g) Starting from 3-benzyloxy-2-cyano-5- (4-methoxy-3-propoxyphenyl) pyridine (1.55 g) was prepared the title compound (0.6 g) mp 229-230 (Water then 1% aqueous trifluoroacetic acid / acetonitrile 2: 3 as eluent) according to the procedure of example 2 (g). 1 H NMR 1.01 (t, 3H), 1.70-1.81 (m, 2H), 3.83 (s, 3H), 4.05 (t, 2H), 7.10 (d, 1H), 7.30-7.38 (m, 2H), 7.77 (s, 1H) and 8.63 (1H). -32- 74 500 Ρ817ΡΤ

Exemolo 4

Pharmaceutical compositions for oral administration are prepared by combining the following: Ethyl [5- (2-naphthyl) -3-hydroxy-2-pyridyl] phosphonate 0.5% (w / w) 3.0 7.14 2% w / p soybean lecithin in soybean oil 90.45 88.2 84.41 hydrogenated vegetable fat and beeswax 9.05 8.8 8.45

The compositions are then filled into individual soft gelatin capsules.

Example 5

A pharmaceutical composition for parenteral administration is prepared by dissolving the title compound in Example 2 (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 filter membrane and enclosed in sterile containers.

Lisbon, NOV. 1992

By SMITHKLINE BEECHAM plc = 0 0FICIAL AGENT =

Claims (10)

74 500 Ρ817 74 A compound of formula (1) R R 2 is H or a pharmaceutically acceptable salt thereof, characterized in that R 2 is OH or a bioprecursor R 1 is A 2 CO 2 H, P (Z) (OH) (OR 1), SO 2 H, SO 3 H or 5-tetrazolyl or a bioprecursor thereof, A is CH2, CHF, CF2, CR3 (OR4), CO or C (OR5) (OR6), R1 is phenyl, C3-5 cycloalkyl, or optionally substituted C1 -C4 alkyl, R4 is H or C1-4 alkyl, R5 and R6 are each C1-4 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 alkyl, alkyl, C2-6 alkoxy, C1-6 alkoxy, C3-6 alkenyloxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, alkylthioC1-6, phenyl, phenylthio, benzyloxy, polyfluoroC1-6 alkyl. g, polyfluoroalkoxyC1-4, halo, N (R7) 2 or NHCOR7 wherein R7 is H or C1 -C4 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 wherein said C1-6 alkyl, C2-20 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; or Ar is 1-naphthyl optionally substituted at the 4-position by hydroxy or C1-4 alkoxy. 2-naphthyl optionally substituted at the 1-position by hydroxy or C1-4 alkoxy, 3-phenanthryl, 9-phenanthryl, 2-quinolinyl, 4-quinolinyl, 3-thienaphthenyl or 2-benzofuranyl. A compound according to claim 1, characterized in that In which R 9 is an ester-forming group. A compound according to claim 1 wherein R 9 is an ester-forming group. A compound according to claim 1, wherein R 1 is P (Z) (OH) (OR 2) or P (Z) (OR 2) 2. A compound according to claim 1, wherein R 1 is SO 2 H 2 SO 3 H or 5-tetrazolyl. A compound according to claim 1, wherein R 1 and R 2 are bonded together so that R 1 --R 2 is A 2 -CO 2 wherein A 1 is CH 2, CH 2, CF 2, CR 3 (OR 4) CO or C (OR5) (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) (OR 2) or CR 3 (CO 2 R 9) and R 9 is ester forming group. A compound according to claim 1, characterized in that ethyl 5- (2,4-dipropoxyphenyl) -2- (5-hydroxy-2-naphthyl) -3-hydroxy-2-pyridyl] tetrazolyl) pyridin-3-ol or 5- (4-methoxy-3-propoxyphenyl) -3- (5-tetrazolyl) pyridin-3-ol, 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 : â € ƒâ € ƒâ € ƒ (i) A ° is CR3 (OR4), reacting, in the presence of a strong base, a compound of Formula 74 (2) in which R 11 is a protecting group of O 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 (4): in which R 12 is CR 3 (OH) CO 2 R 9 and R 3, R 9, R 11 and Ar are as previously defined, and then optionally , reaction with an alkylating agent to form the corresponding compound in which R 12 is CR 3 (O-C 1-3 alkyl) CO 2 R 9, ii) A is CO, reacting, in the presence of a strong base, a compound of formula (2), as defined above, with a compound of formula (5): wherein R 9 is as defined above, to form a compound of formula (4) wherein R 12 is COOCO 2 R 9 and R 9, R 11, and Ar are as previously defined , iii) A0 is CH (OH), the reaction of a compound of formula (4) in which R12 is CO2CO2 R9 and R9, R11 and Ar are as previously defined, with a reducing agent to form the corresponding compound in which R 12 is CH (OH) CO 2 R 9, iv) A is the reaction of a compound of formula (4) in which R 12 is COOC 2 H or COO 2 R 9 and R 9, R 11 and Ar are as defined above, with a suitable reducing agent to form the corresponding compound in which R 12 is CH 2 COOH, v) A is C (OR 5) (OR 6), or reacting a compound of formula (4) in which R12 is CO2CO2 R9 and R9, R3-3- and Ar are as defined above, with a 01000102.3, 1,2-ethanediol or 1,3-propanediol to form the corresponding compound in which R1 - is C (OR 5) (O R 6) CO 2 R 9, vi) A0 is CP 2, 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 fluorinating agent to form the corresponding compound in which R 11 is CF 2 CO 2 R 9, or vii) A is CHF, the reaction 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 previously defined, m is a fluorinating agent to form the corresponding compound in which R 12 is CHCO 2 R 9, and then optionally: and conversion of the group OR 11 into OH and conversion of the group A ° CO 2 R 9 to A ° CO2 H; or (b) for compounds in which R 3 'is CH 2 COO 2 H, conversion of a compound of formula (6): in which R 13 is acetyl and Ar is as previously defined, in the corresponding compound in which R 13 is CH2CO2H; or c) for compounds in which R 1 is CH (O R 4) CO 2 H, the reaction of a compound of formula (4) in which R 2 is -CH (OH) CN with a C 1-3 alkylation agent and / or conversion of the group CN in CO 2 H and, optionally, conversion of the group OR 13 - in OH - or (d) for compounds in which R1 is P (O) (OH) (OR2), the hydrolysis of a compound of formula (6) wherein R13 is P (O) (OR2) 2, R2 is as defined in claim 1 and Ar is 74,500 Ρ 817 c c c c ..... ..... ..... ...... ----- -: r4 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 C1-4 alkyl and Ar is as defined above, in the corresponding compound in which R13 is P (S) (OH) (OR2); or f) for compounds in which R1 is SO2, the reaction in the presence of a strong base of a compound of formula (2) as defined above with sulfuryl chloride or a chemical equivalent thereof, optionally converting the group OR 11 to OH; or g) for compounds in which R1 is SO2 H, the reaction in the presence of a strong base of a compound of formula (2), defined as above, with sulfur dioxide and, optionally, conversion of the group OR11 to OH ? or h) for compounds in which R1 is 5-tetrazolyl, the reaction of a compound of formula (4) in which R12 is cyano or a compound of formula (6) in which R13 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 as defined for the compounds of formula (1), reacting, in the presence of a palladium catalyst, a compound of formula (7): R (7) in which Rb is a group R1 defined as in claim 1 or a precursor thereof and Ra is a group R ou or as defined in claim 1 or a precursor thereof and L 'is a leaving group, with a compound of (8): ArB (OH) 2 (8) or a chemical equivalent thereof, in which Ar is as defined above, and then, if necessary, conversion of a precursor of R1 into R1 and / or conversion of a precursor of R6 at -6-817 ° C, and then optionally: formation of a bioprecursor of R ° and / or R1 formation of a pharmaceutically acceptable salt. 18. NOV. 1992 Lisbon, By SMITHKLINE BEECHAM plc = 0 0FICIAL AGENT =