GB2151228A - Organic compounds and their pharmaceutical use - Google Patents

Description

1 GB 2 151 228 A 1

SPECIFICATION

Organic compounds and their pharmaceutical use This invention relates to novel compounds, pharmaceutical compositions containing them and their use as 5 pharmaceuticals.

The compounds of the invention have the formula R 1 CO.-Q- 0 - CH 2 X -0Y HO R inwhich R' is hydrogen orCl-6 alkyl, R' is hydrogen, Cl-6alkyl orC3-6 alkenyl,X is -CH=CH- or -(CH2),,where n is 1 to 3, and Y is -M or N-N 'N 20 H and salts thereof.

Compounds of the above formula (1), with the exception of those in which Y is -M which are intermediates in the preparation of the remaining compounds, are inhibitors of leukotriene action, and are thus indicated for use in a variety of pharmacological conditions. For example, they may be used in the prophylactic and therapeutic treatment of immediate hypersensitivity diseases including asthma and in the alleviation of status asthmaticus.

In the above formula (1) reference to a "Cl-6 alkyl" group includes, for example, methyl, ethyl, propyl, isopropyl and tert. butyl, and is preferably methyl, ethyl or propyl. A "C3-6 alkenyi" group includes, for example, allyl, isopropeny], butenyl, isobutenyl and 3-methy]-2-butenyi, and is preferably allyl.

Preferred groups of compounds of formula (1) are those in which R' is C14 alkyl, R 2 is C1-4 alkyl and X is -CH=CH- or -(CH2)rl- where n is 2 or 3.

It will be appreciated that compounds in which X is -CH=CH- exist in stereoisomeric (Z and E) forms 35 such as follows R 1 co- 0 \ N-N CH 40 Q 2 HD R 2 H and 45 N N R CD 0\ CH 2 50 H Since the active compounds of formula (1) bear a tetrazoly] group, an opportunity exists of forming base addition salts, and such salts are included as part of the present invention. Examples of such salts are those 55 derived from ammonium hydroxide and alkali and alkaline earth metal hydroxides, carbonates and bicarbonates, as well as salts derived from aliphatic and aromatic amines, aliphatic diamines and hydroxy alkylamines. Bases especially useful in the preparation of such salts include ammonium hydroxide, potassium carbonate, sodium bicarbonate, calcium hydroxide, methylamine, diethylamine, ethylene diamine, cyclohexylamine and ethanolamine. The potassium and sodium salt forms are particularly preferred.

Apart from pharmaceutical ly acceptable addition salts, other salts are also included within the scope of the invention since they may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts, or they may be useful for identification, characterization or purification of the free compound.

2 GB 2 151 228 A 2 The pharmaceutical compounds of the invention may be prepared by reacting the intermediate of the formula R 1 CO--Q, 0 -CH 2 X -0- CN (11) 5 HO \ R2 where R', R 2 and X have the values given above, with an azicle. Compounds of formula (11) are novel and 10 form part of the present invention.

The process is preferably carried out in an organic solvent such as a polar aprotic solvent, for example dimethylformamide, and suitably at a temperature in the range of from 200C to 1500C, for example, from WC to 12WC. The azide employed can be, for example, an alkali metal azide such as sodium azicle, and we have 15 found that a combination of alkali metal azicle and ammonium chloride is especially convenient.

As mentioned above, if it is desired to produce the E-isomer of the compound in which X is -CH=CH- the Z-isomer prepared by reaction of azide with nitrile compound of formula (11) can be irradiated using intense light, optionally with for example diphenyl disulphide as radical source. Alternatively, the Z-isomer is prepared from the appropriate compound of formula (11) with Z configuration.

Compounds of formula(H) maybe prepared by condensing an appropriate phenol reactant of the formula 20 R 1 CD-"Q\ 7 DH (H1) HD R 2 25 with a nitrile intermediate of the formula 30 Z CH 2 X -c _CN (U) 35 where Z is halo, especially bromo, in a suitable organic solvent and in the presence of an alkali metal hydride such as for example sodium hydride. In theirturn, compounds of formula (IV) can be prepared from derivatives of the formula 40 HOCCH A,7 CH - CH CN 45 where n is 1, 2 or 3, which are prepared by reaction of 4- cyanobenzaldehyde with the appropriate triphenylphosphonium bromide derivative, with optional subsequent reduction.

The compounds of the present invention are pharmacologically active, being inhibitors of leukotriene action as shown bythe following tests: (a) the in vitro test on guinea pig ileum segments at concentrations of from 10 ng to 50 gg, according to the method of Schild, 1947 Brit. J. Pharm. 2 197-206, using LTD4 as the so antagonist (the pharmacological compounds of the following Examples exhibited an 1C50 against LTD4 Of lessthan 10-4 molar); (b) the in vivo Guinea Pig Pulmonary Function Test of Austen and Drazen 1974 J. Clin.

Invest. 53 1679-1685 at intravenous dosage levels of from 0.05 gg to 5.0 mglkg; and (c) a modified "Herxheirner" test, Journal of Physiology London 117 251 (1952), at doses of from 25 to 200 mglkg. The "Herxheimer" test is based on an LTD4-induced bronchospasm in guinea pigs which closely resembles an 55 asthmatic attack in man. The compounds also inhibitthe formation of leukotrienes, as indicated by their action in the test described by Harvey and Osborne, Journal of Pharmacological Methods 9 147-155 (1983).

The compounds are accordingly indicated for therapeutic use in the treatment of diseases in which leukotrienes are implicated. These include immediate hypersensitivity diseases, allergic reactions of the pulmonary system in which leukotrienes are thought to be casual mediators of bronchospasm, for example, 60 in allergic lung disorders such as extrinsic asthma and industrial asthmas such as Farmers lung and Pigeon Fanciers lung, and in other inflammatory disorders, for example, associated with acute or chronic infectious diseases such as allergic skin diseases, acetopic and atopic eczemas, psoriasis, contact hypersensitivity and angioneurotic oedema, bronchitis and cystic fibrosis and rheumatic fever.

The compounds may be administered by various routes, for example, by the oral or rectal route, by 65 3 GB 2 151 228 A 3 inhalation, topically or parenterally, for example by injection, being usually employed in the form of a pharmaceutical composition. Such compositions form part of the present invention and are prepared in a manner well known in the pharmaceutical art and normally comprise at least one active compound in association with a pharmaceutically acceptable diluent or carrier. In making the compositions of the present invention, the active ingredient will usually be mixed with a carrier, or diluted by a carrier, and/or enclosed within a carrier which may, for example, be in the form of a capsule, sachet, paper or other container. Where the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material which acts as a vehicle, excipient or medium for the active ingredient. Thus, the composition may be in the form of tablets, lozenges, sachets, cachets, elixirs, suspensions, aerosols as a solid or in a liquid medium, ointments containing for example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, injection solutions and suspensions and sterile packaged powders. For administration by inhalation, particular forms of presentation include aerosols, atomisers and vaporisers.

Some examples of suitable carriers are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, syrup, methyl cellulose, methyl- and propyl hydroxybenzoate, talc, magnesium stearate and mineral oil. The compositions of the invention may, as is 15 well known in the art, be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient.

Where the compositions are formulated in unit dosage form, it is preferred that each unit dosage form contains from 5 mg to 500 mg, more usually 25 to 200 mg, of the active ingredient. The term "unit dosage form- refers to physically discrete units suitable as unit dosages for human subjects and animals, each unit 20 containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier.

The active compounds are effective over a wide dosage range and for example dosages per daywill normally fall within the range of 0.5 to 300 mg/kg. and in the treatment of adult humans, more usually in the range of from 5 to 100 mg/kg. However, it will be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances including the condition to be treated, the choice of compound to be administered and the chosen route of administration and therefore the above dosage ranges are not intended to limit the scope of the invention in any way.

The following Examples illustrate the invention.

Example 1 (E,Z)- 1-(Methoxydimethylmethoxy)-3-(4-cyanophenyl)-prop-2-ene To a suspension of 2-(methoxy-dimethyi-methoxy)-ethyi-tri phenyl phosphoniu m bromide (prepared by the method of E.J. Corey et al. J.A.C.S. 102,7986 (1980), from 2- hydroxyethyitriphenylphosphonium bromide and 2-methoxypropene) (178.8 g) in dry tetrahydrofuran (700 mi), under nitrogen, at -70'C, was 35 added n-butyl lithium (266 mi of 1.55 M solution in hexane), by cannula from a measuring cylinder under nitrogen pressure. The generation of the ylid was shown by the development of a deep orange colour. The mixture was allowed to warm to -30'C and then re-cooled. A solution of 4- eyano-benzaidehyde (51.03 g) in dry tetrahydrofuran (200 mi) was added, and the mixture allowed to attain room temperature. The orange colour was quenched to a straw yellow. The reaction mixture was stirred at room temperature for 3 hours 40 then filtered over High-Flo. The filtrates were evaporated in vacuo and the residual oil extracted with ether (8 x 250 mi). Evaporation of the extracts gave the crude product as an oil. This was further purified by column chromatography (silica, eluant: hexane 50% diethyl ether) to give the product as a yellow oil, consisting of Z:E = 3:1 (Fourier Transform PMR analysis).

Example 2 (E,Z)3(4-Cyanophenyl)-prop-2-ene- 1-ol (E0-1 -(M eth oxydi methyl methoxy)-3-(4-cyanophenyl)-prop-2-ene (12.1 g) was dissolved in a mixtu re of glacial acetic acid (1.5 mi), acetonitrile (96 mi) and water (24 mi) and the solution allowed to stand at room temperature under nitrogen for 60 hours.

The reaction mixture was neutralised with triethylamine (8 mi) and evaporated in vacuo to a yellow oil. The oil was partitioned between water (100 m]) and dichloromethane (2 x 100 mi), the combined organic extracts washed with water (2 X 200 mi), dried (M9S04) and evaporated to yield the product as a yellow oil.

Example 3 (E,Z)- 1-Bromo-3-(4-cyanophenyl)-prop-2-ene To a sti rred sol ution of (E,Z)-3-(4-eyanophenyi)-prop-2-ene-1 -of (3.60 g) in dich loromethane (15 mi) at -5'C under nitrogen was added dropwise a solution of phosphorus tribromide (0. 7 mi) in dichloromethane (5 mi).

The reaction mixture was then allowed to stand at room temperature for 24 hours, then washed with brine (2 x 20 mi), dried (M9S04) and evaporated to yield the product as a yellow oil.

Example 4 (E,Z)-4-[3-(4-Acetyl-3-hydroxy2-prop ylphenoxy)1-propenyllbenzo-nitrile A mixtu re of 2,4-dihydroxy-3-propylacetophenone (1.84 g), sodium carbonate (3.01 g) and (E,Z)-1 -bromo3-(4-cyanophenyl)-prop-2-ene (2.10 g) in dry buta none (40 m 1) was refluxed for 24 hou rs. The reaction 65 4 GB 2 151 228 A 4 mixture was filtered, the filtrates evaporated in vacuo, and the residue partitioned between water (50 mi) and dichloromethane (2 x 50 mi). The combined organic extracts were washed with 2 molar sodium hydroxide (2 X 100 mO and then water (2 x 100 mi), dried (M9S04) and evaporated to give an amber oil which was a mixture of the E and Z forms of the composition indicated in Example 1. The oil was then purified by column chromatography (silica, eluent:hexane 40% ethyl acetate) to yield the separated geometrical isomers:- 5 (i) Z isomer, yellow solid, m.p. 104-106'C. (ii) E isomer, yellow solid, m.p. 116-118'C.

Example 5 (Z)-1-,f2-Hydroxy-3-propyl-4-[3-(4- 1H-tetrazol-5-yl-phenyl)prop-2-enyloxyl-phenyllethanone A mixture of (Z)-4-[3-(4-acetyi-3-hydroxy-2-propyi-phenoxy)-1-propenyll- benzonitrile (from Example 4) (1.14 g), sodium azide (1.11 g) and ammonium chloride (0.90 g) in dry dimethy[formamide (10 mi) was stirred at 1 OOOC for 4 hours. The reaction mixture was cooled, poured into water (250 mi) and stirred vigorously for 15 minutes. The suspended solid was then collected by filtration and dissolved in 2 molar sodium hydroxide 15 solution (50 mi). The basic solution was washed with diethyl ether (2 X 50 mi), filtered and acidified with concentrated hydrochloric acid. The precipitated solid was collected byfiltration, washed with water on the sinter, and dried in vacuo. Finally recrystallisation from ethanollwater with decolourisation gave the title compound as a fawn solid, m.p. 162166'C.

Example 6 (E)- 1-,2-Hydroxy-3-propyl-4-[3-(4- 1H-tetrazol-5-yl-phenyl)prop-2-enyloxyl-phenyllethanone A mixture of (E)-4-[3-(4-acetyi-3-hydroxy-2-propyi-phenoxy)-1-propyll- benzonitrile (from Example 4) (2.32 g), sodium azide (2.25 g) and ammonium chloride (1.85 g) in dry dimethylformamide (25 mi) was stirred at 1 OOOC for 4 hours. The reaction mixture was allowed to cool, then stirred with water (1 litre) for 10 minutes. The suspended solid was filtered off, and dissolved in a 2 molar solution of sodium hydroxide (200 m]). The basic solution was washed with diethyl ether (2 x 200 mi), filtered, and acidified with concentrated hydrochloric acid. The precipitated solid was collected by filtration, washed with water on the sinter, and dried in vacuo. Recrystallisation from ethanollwater with decolourisation gave the title compound as a fawn solid, m.p. 186-190'C.

Example 7 (E)-1-f2-Hydroxy-3-propyl-4-[3-(4-1H-tetrazol-5-ylphenyl)-prop-2-enyloxylph enyethanone (Alternative procedure to Example 6) A mixture of (Z)-1-1;2-hydroxy-3-propyl-4-[3-(4-1H-tetrazol-5-yi-phenyi)prop-2-enyloxyl-p henyiethanone 35 (100 mg) and diphenyldisulphide (10 mg) in methanol (5 mi) was stirred and irradiated under a quartz lamp for 24 hours. The reaction mixture was evaporated in vacuo and excess diphenyl disulphide removed from the residue by chromatography (silica, eluent: chloroform 5% methanol). Final recrystallisation from ethanoliwater with decolourisation gave the title compound as an off- white solid, m.p. 182-1860C.

Example 8

3-(4-Cyanophenyl)-propan- 1-ol A solution of (E,Z)-3-(4-cyanophenyi)-prop-2-ene-1 -ol (from Example 2) (3.60 9) in absolute ethanol (100 m 1) was hydrogenated at room temperatu re and 60 p.s.i. using 10% palladium on charcoal (100 mg) as catalyst. Hydrogen uptake was complete in a few minutes. The reaction mixture was filtered over High-Flo, 45 and the catalyst cake washed with chloroform. The combined filtrates and washing were evaporated in vacuo to give the product as a light-yellow oil.

Example 9

1-Bromo-3-(4-cyanophenyl)-propane To a stirred solution of 3-(4-cyanophenyi)-propan-l-ol (2.80 g) in dichloromethane (15 mi) at -5'C under nitrogen was added dropwise a solution of phosphorus tribromide (0.55 m]) in dichloromethane (5 mi). The reaction mixture was then allowed to stand at room temperature for 24 hours, washed with brine ( 2 x 20 mi), dried (M9S04) and evaporated in vacuo to give a yellow oil. The oil was distilled in a bulb-to-bulb apparatus to give the product as a clear oil, b.p. 120'C10.35 mmHg.

so Example 10

4-[3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-propyll-benzonitrile To a suspension of washed (toluene 3x) 50% sodium hydride (0.11 g) in dry dimethylformamide (5 m]) under nitrogen was added a solution of 2,4-dihydroxy-3-propyi-actophenone (0.87 9) in dry dimethylforma- 60 mide (5 mi). The mixture was then heated at WC for 15 minutes, and a solution of 1-bromo-3-(4 cyanophenyi)-propane (1.00 g) in dry dimethy[formamide (5 mi) was added dropwise. Stirring was continued at 1OWC for 4 hours, and then the reaction mixture was evaporated in vacuo. The residual oil was stirred with water (50 mi) and extracted with dichloromethane (2 x 50 mi); the combined extracts washed GB 2 151 228 A 5 with 2 M sodium hydroxide (2 x 100 mi) and water (2 x 100 mi), dried (M9S04) and evaporated in vacuo to give the product as a brown oil.

Example 11 1-12-Hydroxy-3-propYI-4-13-(4- IH-tetrazol-5-yl-phenyl)propoxyl-phenyPethanone A mixture of 443-(4-acetyl -3-hyd roxy-2-p ro pyl p hen oxy)-p ro pyll- benzo n itri 1 e (1.18 g) sodium azide (0.91 9) and ammonium chloride (0. 75 g) in dry dimethylformamide (20 mi) was stirred at 1 OWC for 4 hours. The reaction mixture was allowed to cool, poured into water (600 mi) and stirred for 10 minutes. The suspended solid was collected by filtration, dried in vacuo and recrystallised from ethanol/water with decolourisation to 10 give the title compound as a fawn solid, m.p. 190-192'C.

Similarly prepared, utilizing the procedures of Examples 1, 2,8,9, 10 and 11 was:

1-2-Hydroxy-3-propyl-4-[4-1H-tetrazol-5-yl-phenyi)-butoxyl-phenyI jetha none, m.p. 150-154'C.

The following Examples illustrate the preparation of typical formulations comprising a pharmacologically active compound of the invention Example 12

Aerosol Active ingredient Ethanol Propellent 121114 mg 30 mi q.s.

The active ingredient is dissolved in ethanol, filled into glass bottles, sealed with a valve (metered to 0.05 mi) and charged with the mixed propellants.

Example 13

Tablet

Active ingredient Dried starch Polyvinyl pyrrolidone Sodium carboxymethyl starch Stearic acid 100M9 400 mg 50 mg 50 mg 20 mg The active ingredient and starch are mixed together and massed with a solution of polyvinyl pyrrolidone in 35 alcohol. The mass is extruded through a screen, dried, sized and mixed with sodium carboxymethyi starch and stearic acid prior to compression on a tablet machine. Tablets weighing 620 mg are obtained.

Example 14 40 Capsules Active ingredient Starch flowable Silicone fluid mg 300 mg 5mg A portion of the starch is mixed with the silicone fluid. To the powder is added the active ingredient and the 45 remainder of the starch. This blended mixture is filled into hard gelatin capsules.

Claims (9)

1. A compound of the formula 72 HO R (I) in which R' is hydrogen or C1.6 alkyl, R 2 is hydrogen, C1.6 alkyl or C3. 6 alkenyl, and X is -CH=CH - or -(CH2),,- where n is 1 to 3, and Y is -CN or N-N IN H 6 GB 2 151 228 A 6 and salts thereof.

2. A compound according to claim 1 in which Y is N-N

3. A compound according to claim 2 in which R' is C1-

4 alkyi, R' is C1-4 alkyl and Xis -CH=CH- or -(CH2)n- where n is2 or3. 2 4. A compound according to claim 3 in which R' is methyl and R ispropyl.

5. A compound according to any of claims 2 to 4 in which Xis -CH=CH-.

6. A pharmaceutical formulation comprising a compound as defined in any of claims 2to 5 or a pharmaceutical ly-acceptable salt thereof, and a diluent or carrier therefor.

7. A process for preparing a compound according to claim 1 of the formula R 1 CO-- 72 D-CH X H 2 HO R which comprises reacting a compound of the formula R 1 CO-Q\ 92 O-CH 2 X -(:y- M FID R (11) where R', R 2 and X have the values defined in claim 1, with an azide.

8. A compound of formulaffi as defined in claim 2, for use as a pharmaceutical.

9. A compound according to claim 1 substantially as disclosed in any of Examples 1 to 11.

Printed in the UK for HMSO, D8818935, 5185, 7102. Published by The Patent Office. 25 Southampton Buildings, London, WC2A lAY, from which copies may be obtained.