WO1992004334A1

WO1992004334A1 - Compounds

Info

Publication number: WO1992004334A1
Application number: PCT/GB1991/001545
Authority: WO
Inventors: Deirdre Mary Bernadette Hickey; David Gwynn Cooper
Original assignee: Smith Kline & French Laboratories Limited
Priority date: 1990-09-11
Filing date: 1991-09-10
Publication date: 1992-03-19
Also published as: AU8624791A; JPH06500791A; EP0548227A1; GB9019841D0

Abstract

Substituted 4,5-diaryl heterocycles, processes for preparing them, pharmaceutical compositions containing them and their use in therapy, inter alia, in the treatment of cardiovascular disorders.

Description

COMPOϋNDS

The present invention relates to novel substituted heterocyclic compounds, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.

The present invention therefore provides in a first aspect compounds of structure (I) :

in which each group Ar is the same or different and is optionally substituted phenyl or optionally substituted heteroaryl; X is nitrogen or CR¹

Y is nitrogen, N(CH₂)_nA or C(CH₂)_nA

Z is nitrogen, oxygen or N(CH₂)_nA, and the dotted line indicates the optional presence of a double bond so as to form a fully unsaturated heterocyclic ring;

R¹ is hydrogen, C₁_₄al yl, optionally substituted phenyl or optionally substituted heteroaryl; n is 4 to 12; and

A is C0₂H or a group hydrolysable to C0₂H, 5-tetrazolyl, S0₃H, P(0)(OR)₂, P(0)(OH)₂, or

P(0) (R) (OR) in which R is hydrogen or C₁_ alkyl, or a pharmaceutically acceptable salt thereof, provided that

° X, Y and Z are not all at the same time, nitrogen; ⁰ when X is CR¹, Y and Z are not both nitrogen; ° when Y is N(CH₂)_nA, Z is nitrogen; and ° when Z is oxygen, Y is C(CH )_nA.

5 Suitably, each group Ar is the same and is optionally substituted phenyl or optionally substituted heteroaryl. More suitably, each group Ar is the same and is optionally substituted phenyl. Preferably each group Ar is the same and is unsubstituted phenyl.

10.

Suitably, X is nitrogen or CR¹; preferably X is nitrogen.

Suitably, Y is nitrogen, N(CH₂)_nA or C(CH₂)_nA; 15 preferably, Y is nitrogen or N(CH₂)_nA; most preferably Y is N(CH₂)_nA.

Suitably, Z is nitrogen, N(CH₂)_nA or oxygen; preferably Z is nitrogen or N(CH₂)_nA; most preferably 0 Z is nitrogen.

Suitably, n is 4 to 12, preferably 4 to 8 and most preferably 7 or 8.

5 Suitably, A is C0 H or a group hydrolysable to C0₂H, 5-tetrazolyl, S0₃H, P(0)(0R)₂, P(0) (0H)₂, or P(O) (R) (OR) in which R is hydrogen or C₁_₄alkyl; preferably A is C0 H or a group hydrolysable to C0₂H, for example C0₂C₁_₄alkyl such as C0 CH₃ or 0 C0₂C₂H₅.

Suitably, R¹ is hydrogen, C₁_₄alkyl, optionally substituted phenyl or optionally substituted heteroaryl. Preferably R¹ is hydrogen. 5 Suitable substituents for phenyl groups Ar and R¹ include, for example, 1-3 groups which may be the same or different and are selected from C₁_₄alkyl, haloC₁_₄alkyl such as CF₃, halogen, hydroxy and C₁_₄alkoxy.

5

Suitable heteroaryl groups include, for example, saturated or unsaturated 5- or 6-membered rings comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulphur. Preferred such rings include, for

10. example, thienyl and furyl rings.

Particularly preferred compounds of structure (I) include:

2-(8-carboxyoctyl)-4,5-diphenyltriazole; 15 l-(8-carboxyoctyl)-4,5-diphenyltriazole; and 2-(8-ethoxycarbonyloctyl)-4,5-diphenyltriazole.

The compounds of structure (I) can be prepared using procedures analogous to those known in the art. The 0 present invention therefore provides in a further aspect a process for the preparation of compounds of structure (I) which comprises:

(a) for compounds in which Z is other than oxygen 5 reaction of a compound of structure (II) :

in which

Ar and X are as described in structure (I) and Y_a is N 5 or C(CH )_nA; with a compound of structure:

L(CH₂)_nA (III)

5 in which n and A are as described for structure (I) and L is a leaving group; or

(b) reaction of a compound of structure (IV) :

10.

15 in which Ar and X are as described in structure (I) , Y_b is N, N(CH₂)_nA_b or C(CH₂)_nA_b, Z_b is N, 0 or N(CH₂)_nA_b provided that: ° X, Y_b and Z_b are not all nitrogen, ° when X is CR¹, Y_b and Z_b are not both nitrogen,

20 ° when Y_b is N(CH₂)_nA_b, Z_b is nitrogen, and ° when Z_b is 0, Y_b is -C(CH₂)_nA_b;

A_b is a group convertible to a group A as described in structure (I) , with a reagent suitable to convert the group A_b into a group A and, optionally thereafter,

25 converting one group A into another group A, and optionally forming a salt.

Suitable leaving groups L will be apparent to those skilled in the art and include, for example, halogen, 30 such as bromine.

Suitable groups A_b convertible to a group A include, for example, where A is C0₂H, CN groups, which

35 can be converted into C0₂H groups by reaction with, for example, sulphuric acid. Other groups and suitable reagents will be apparent to those skilled in the art.

The reaction between compounds of structures (II) and (III) can be carried out in a suitable solvent in th presence of a base at a temperature of between ambient and the reflux temperature of the solvent used. For example, compounds of structure (I) in which X and Y are both nitrogen and Z is N(CH )_nC0₂R, can be prepared by reacting a compound of structure (II) in which X and Y_a are both nitrogen with a compound of structure (III) in which L is bromine and A is C0₂H, in aqueous solution in the presence of sodium hydroxide as base. Further reaction of said compound of structure (I) with, for example, p-toluene sulphonic acid in ethanol gives the corresponding compound in which A is C0 CH₃. The compounds of structures (II) and (III) are available commercially, or can be prepared by standard techniques.

The reaction between compounds of structure (IV) and a reagent suitable to convert the group A_b to a group A will, of course, take place under conditions which will depend on the nature of the group A_b. As already described, for example when A_b is CN, reaction with sulphuric acid under aqueous conditions affords the desired compounds of structure (I) in which A is C0₂H. Other suitable groups and conditions will be apparent to those skilled in the art. Compounds of structure (IV) are available commercially or can be prepared by standard procedures. For example, compounds of structure (IV) in which X is nitrogen, Y_b is C(CH₂)_nCN and Z_b is oxygen can be prepared via the following reaction sequence: -6-

n^B

The compounds of structure (I) and their pharmaceutically acceptable salts have been found to be PGI₂ agonists and as such are useful in therapy for the treatment of disease conditions in which such an effect is beneficial.

More specifically, the compounds are expected to have utility as antithrombotic, vasodilatory, anti- atherosclerotic, antiinflammatory and cytoprotective agents. In particular, as antithrombotic and vasodilatory agents, the compounds are expected to be useful in the treatment of cardiovascular occlusive disorders including spasmodic and thrombotic disorders; coronary heart disease (primary and secondary prevention) stroke; post-operative thrombosis utilisation including post-angioplasty; deep vein thrombosis; peripheral vascular disease and Reynaud's disease. As antiathero- sclerotic agents the compounds would be expected to reduce atherosclerotic plaque formation; and as cytoprotective agents the compounds would be expected to protect liver and gastric mucosa, protect against mucosal and ulcerative damage and reduce infarct size in myocardial infarct.

In addition to the foregoing utilities the compoun have antihyperlipidae ic properties and as such are expected to be of use as lipid lowering agents, and in the treatment of atherosclerosis and its sequelae.

In therapeutic use, the compounds of the present invention are usually administered in a standard pharmaceutical composition. The present invention therefore provides in a further aspect pharmaceutical compositions comprising a compound of structure (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The compounds of structure (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.

A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutical acceptable salt in a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent.

A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrie (s) routinely used for preparing solid formulations.

Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose. -8-

A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.

Typical parenteral compositions consist of a soluti or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.

typical suppository formulation comprises a compound of structure (I) or a pharmaceutically acceptable salt thereof which is active when administere in this way, with a binding and/or lubricating agent suc as polymeric glycols, gelatins or cocoa butter or other low melting vegetable or synthetic waxes or fats.

Preferably the composition is in unit dose form suc as a tablet or capsule.

Each dosage unit for oral administration contains preferably from 1 to 250 g (and for parenteral administration contains preferably from 0.1 to 25 mg) of a compound of the structure (I) or a pharmaceutically acceptable salt thereof calculated as the free base. -9-

The present invention also provides a method of mimicking the effects of PGI₂ which comprises administering to a mammal in need thereof an effective amount of a compound of the structure (I) or a pharmaceutically acceptable salt thereof; and a method of treatment of cardiovascular disorders which comprise administering to a mammal in need thereof an effective amount of a compound of the structure (I) or a pharmaceutically acceptable salt thereof.

The pharmaceutically acceptable compounds of the invention will normally be administered to a subject in daily dosage regimen. For an adult patient this may b for example, an oral dose of between 1 mg and 500 mg, preferably between 1 mg and 250 g, or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg a 100 mg, preferably between 0.1 mg and 25 mg, of the compound of the structure (I) or a pharmaceutically acceptable salt thereof calculated as the free base, th compound being administered 1 to 4 times per day.

Suitably the compounds will be administered for a perio of continuous therapy, for example for a week or more.

The following Examples serve to illustrate the invention. Temperatures are recorded in degrees centigrade.

Examples 1 and 2

1— (7— Me t_hoxycctrbonγlheptyl -4.5-diphenyltriazole

2- ( 7-Methoxycarbonylheptyl) -4.5-diphenyltriazole

5

A solution of 8-bromooctanoic acid (8.32g) and sodium hydroxide (1.49g) in water (50ml) was added to solution of 4,5-diphenyltriazole (7.5g) (Che . Ber., 1970, 103, 1908-17) and sodium hydroxide (1.36g) in wate

¹⁰. (75ml) and the mixture was stirred at 80°C for 21 hours. 2N Aqueous hydrochloric acid (50ml) was carefully added to the cooled reaction and then extracted with diethyl ether (3x100ml) . The ether extracts were combined, washed with water (100ml) , dried over anhydrous magnesiu

15 sulphate and evaporated to dryness in vacuo to give a mixture of 1(2)-(7-carboxyheptyl)-4,5-diphenyltriazole (12.2g) as an oil.

The above mixture (12.2g), p-toluene sulphonic acid,

²⁰ monohydrate (1.2g) and methanol (250ml) were heated at reflux through a soxhlet extractor containing 4A molecular sieves for 3.5 hours. The methanol was remove in vacuo and the residue was dissolved in dichloromethan

(250ml) , wa≤hed with saturated sodium hydrogen carbonate

²⁵ solution (200ml) , water (200ml) , dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo.

Column chromatography on silica gel eluted with dichloromethane gave l-(7-methoxycarbonylheptyl)-4,5- diphenyltriazole (Example 1) (2.4g, 19.4%) and

30 2-(7-methoxycarbonylheptyl)-4,5-diphenyltriazole

(Example 2) (3.2g, 25.2%) as oils.

Example 1 found: C, 72.85; H; 7.23; N, 10.93%

Example 2 found: C, 73.08, H; 7.20; N, 11.00%

^C23^H27^N ₃°2 re iiresϊ ^c, 73.18; H, 7.21; N, 11.13% 35 Example 3

1- (7-Carboxyheptyl_-4.5-diphenyltriazole

1-(7-Methoxycarbonylheptyl)-4,5-diphenyltriazole

(lg) was treated with 2N sodium hydroxide in aqueous ethanol at reflux temperature for 2.5 hours. The ethanol was removed in vacuo and the residual mixture acidified with 2N aq HCl. The aqueous solution was extracted with ethyl acetate and the organic extracts combined, dried over magnesium sulphate and evaporated to dryness in vacuo. Recrystallisation from ethanol and water gave l-(7-carboxyheptyl)-4,5-diphenyltriazole (0.61g, 64%) as a white solid, m.p. 103-104°C. Found: C, 72.66; H, 6.92; N, 11.44%

^C22^H25^N3°2 requires: C, 72.70; H, 6.93; N, 11.56%

Example 4

2-(7-Carboxyheptyl)-4.5-diphenyltriazole

2-(7-Methoxycarbonylheptyl)-4,5-diphenyltriazole (lg) was reacted with 2N sodium hydroxide in a method similar to Example 3. Recrystallisation from ethanol and water gave 2-(7-carboxyheptyl)-4,5-diphenyltriazole (0.76g, 79%) as a white solid, m.p. 86-88°C. Found: C, 72.70; H, 6.94; N, 11.47% ^C22^H25^N3°2 requires: C, 72.70; H, 6.93; N, 11.56%

Example 5

2-(8-Carboxγoctyl.-4.5-diphenyltriazole

a) A mixture of 4,5-diphenyltriazole (llg) , 1,8-dibromooctane (67.6g), and potassium carbonate (10.31g) in dry butanone (300 ml) was heated at reflux temperature for 24 hours. The mixture was filtered and the solvent evaporated to give an oily residue.

5 Distillation to remove 1,8-dibromooctane and column chromatography on silica gel eluted with a hexane:ethyl acetate gradient gave 2-(8-bromooctyl)-4,5-diphenyl- triazole (11.13g, 54%) as an oil. NMR 5 (CDC1₃) 1.2-1.5 (8H, m, 4xCH₂) , 1.84 (2H, m,

10. CH₂) , 2.05 (2H, m, CH₂) , 3.37 (2H, t, Br-CH₂) , 4.47 (2H, t, N-CH₂), 7.3-7.6 (10H, m, 2xPh) ppm

And l-(8-bromooctyl)-4,5-diphenyltriazole (2.12g, 10.3%) as a white solid, m.p. 90-91°C after recrystallisation

15 from hexane.

Found: C, 64.01; H, 6.47; N, 10.09; Br, 19.84%; C₂₂H₂₆BrN₃ requires C, 64.08; H, 6.36; N, 10.19; Br, 19.3 NMR 5 (CDC1₃) 1.1-1.5 (8H, m, 4xCH₂) , 1.65-1.9 (4H, m, 2xCH₂) , 3.37 (2H, t, Br-CH₂) , 4.20 (2H, t, NCH₂) ,

20 7.2-7.55 (10H, m, 2xPh) ppm

b) 2-(8-Bromooctyl)-4,5-diphenyltriazole (7g) in dimethylsulphoxide (220ml) was added to a suspension of sodium cyanide (lg) in dimethylsulphoxide (60ml) over 15

25 minutes. The reaction mixture was stirred at 24°C for 1 hour and at 50°C for 2 hours. The cooled reaction mixture was poured into water (600ml) , extracted with diethyl ether (4x200ml) . The extracts were combined, washed with water (100ml) , dried over anhydrous magnesium

30 sulphate and evaporated to dryness in vacuo. Column chromatography on silica gel eluted with a hexane:ethyl acetate gradient gave 2-(8-cyanooctyl)-4,5-diphenyl- triazole (5.6g, 92%) as an oil. Found: C, 75.13; H, 7.16; N, 15.24%;

35 ^C23^H26^N4 °-^5H2° requires: C, 75.18; H, 7.41; N, 15.25. c) 2-(8-Cyanooctyl)-4,5-diphenyltriazole (3.0g) was treated with sulphuric acid (50ml) and water (50ml) and the mixture heated at reflux temperature for 4 hours. Water (200ml) was added and the cooled mixture was extracted with ethyl acetate (3 x 75ml) , and the organic extracts combined and evaporated to give a solid. Recrystallisation from ethanol and water gave 2-(8-carboxyoctyl)-4,5-diphenyltriazole (2.37g, 75%) as a white solid m.p. 84-85°C. Found: C, 72.92; H, 7.20; N, 11.07%;

^C2₃ ^H27^N ₃°₂ requires: C, 73.18; H, 7.21; N, 11.13%.

Example 6

1-f8-Carboxyoctyl)-4.5-diphenyltriazole

a) l-(8-Bromooctyl)-4,5-diphenyltriazole (ex. example 5a) (1.8g) was reacted with sodium cyanide in a method similar to Example 5b) . Work-up and recrystallisation from dichloromethane and hexane gave l-(8-cyanooctyl)-4,5 diphenyltriazole (1.16g, 74.4%) as a white solid, m.p. 77-8°C

Found: C, 77.03; H, 7.25; N, 15.35%; C ₃H₂₆N requires: C, 77.06; H, 7.31; N, 15.63%.

b) l-(8-Cyanooctyl)-4,5-diph€inyltriazole (0.9g) was treated with sulphuric acid in a method similar to Example 5a. Work-up and recrystallisation from ethanol and water gave l-(8-carboxyoctyl)-4,5-diphenyltriazole (0.58g, 64%) as a cream solid, m.p. 86-87°C. Found: C, 73.10; H, 7.23; N, 10.82%; ^C2₃ ^H27^N ₃°2 requires: C, 73.18, H, 7.21, N, 11.13%. Example 7

2-f8-Ethoxycarbonyloctyl.-4.5-diphenyltriazole

⁵ A mixture of 2-(8-carboxyoctyl)-4,5-diphenyltriazo (lg) , absolute alcohol (100ml) and concentrated sulphur acid (1ml) was heated at reflux temperature for 3 hours. The solvent was removed in vacuo, the residue dissolved in diethyl ether (100ml) , washed with water (50ml) , dri

10. and evaporated. The residue was chromatographed on silica gel eluted with a hexane:ethyl acetate to give 2-(8-ethoxycarbonyloctyl)-4,5-diphenyltriazole (0.81g, 76%) as an oil. Found: C, 73.84; H, 7.78; N, 10.22%;

15 C₂₅N₃₁N₃0₂ requires: C, 74.04; H, 7.71; N, 10.36%.

Example 8

2-f6-Ethoxycarbonγlhexyl)-4.5-diphenyltriazole

20

4,5-Diphenyltriazole (2.0g) and ethyl 7-bromo- heptanoate (1.5g) were reacted in a method similar to Example 5. Column chromatography on silica gel eluted with a hexane:ethyl acetate gradient gave 2-(6-ethoxy- 25 carbonylhexyl)-4,5-diphenyltriazole (l.lg, 46%) as an oi

Found: C, 73.10; H, 7.45; N, 11.11% ^C2₃ ^H27^N ₃°2 requires C, 73.18; H, 7.21; N, 11.13 !%;.

Example 9

30

2- (6-Carboxγhexγl)4.5-triphenyltriazole

2-(6-Ethoxycarbonylhexyl)-4,5-diphenyltriazole

35 -15-

(0.7g) was reacted with sodium hydroxide in a method similar to Example 3. Recrystallisation from ethano water gave 2-(6-carboxyhexyl)4,5-triphenyltriazole (0.41g, 63%) as white needles, m.p. 88-89°C. Found: C, 71.30; H, 6.54; N, 11.73%;

C₂₁H₂₃N₃0₃ 0.2H₂0 requires: C, 71.44; H, 6.68; N, 11

Example 10

2-(7-Carboxyheptyl_-4.5-diphenyloxazole

a) A mixture of benzoin (26.15g), 8-bromooctanoic (25.0g), 4-dimethylaminopyridine (1.35g), 1,3-dicycl hexylcarbodiimide (25.4g) and dry tetrahydrofuran (3 was stirred under nitrogen at room temperature for 2 hours. The reaction mixture was filtered and the filtrate was evaporated to dryness in vacuo. The re was dissolved in dichloromethane (350ml) , washed wit aqueous hydrochloric acid (3 x 175ml) , saturated sod hydrogen carbonate solution (2 x 200ml) , saturated so chloride solution (220ml) , dried over anhydrous magne sulphate and evaporated to dryness in vacuo. Column chromatography on silica gel eluted with a hexane: dichloromethane gradient gave a yellow oil. This oil stirred in hexane to give 2-oxo-l,2-diphenylethyl

8-bromooctanoate (27.lg, 52.7%) as a pale yellow soli m.p. 60-61°C.

NMR 8 (CDC1₃) 1.2-1.9 (10H, m, 5X CH₂) , 2.46 (2H, m, CH₂C=0) , 3.4 (2H,t, BrCH₂), 6.86 (1H, S, PhCH) , 7.35-7.95 (10H, m, 2xPh) ppm.

b) A mixture of the above ester (26.8g), ammonium acetate (19.4g) and glacial acetic acid (500ml) was stirred at 80°C, under nitrogen, for 2 hours. The -16- glacial acetic acid was removed in vacuo and water (100Oml) was added. The aqueous was extracted with dichloromethane (3 x 250ml) . The organic extracts wer combined, washed with water (200ml) , saturated sodium chloride solution (200ml) , dried over anhydrous magnes sulphate and evaporated to dryness in vacuo. Column chromatography on silica gel eluted with dichlorometha gave l-(7-bromoheptyl)-4,5-diphenyloxazole (14.09g, 55 as an oil. NMR δ (CDC1₃) 1.4 (6H, m, 3x CH₂) , 1.87 (4H, m,

2XCH₂), 2.85 (2H, t, N=CCH₂) , 3.41 (2H, t, BrCH₂) , 7.3-7.7 (10H, m, 2xPh) ppm.

c) 2-(7-Bromoheptyl)-4,5-diphenyloxazole (13.8g) in dimethylsulphoxide (80ml) was added over 45 minutes to mixture of sodium cyanide (1.87g) in dimethylsulphoxid (80ml) . The reaction was stirred at 50°C for 2h, cool and poured into water (500ml) . The aqueous was extrac with diethyl ether (4 x 250ml) . The ether extracts we combined, washed with water (250ml) , dried over anhydr magnesium sulphate and evaporated to dryness in vacuo. Column chromatography on silica gel eluted with a hexa dichloromethane gradient gave 2-(7-cyanoheptyl)-4,5- diphenyloxazole (4.89g, 41%) as an oil. Found: C, 80.20; H, 7.02; N, 8.13%

C₂₃H₂ N₂0 requires: C, 80.31; H, 7.18; n, 8.16%;

d) 2-(7-Cyanoheptyl)-4,5-diphenyloxazole (2.5g) was reacted with sulphuric acid in a method similar to Example 5c. Recrystallisation from ethanol and water gave 2-(7-carboxyheptyl)-4,5-diphenyloxazole (l.lg, 41.7%) as a cream solid, m.p. 82-83°C.

Found: C, 76.07; H, 6.99; N, 3.79%;

^C23^H25^N03 requires: C, 76.00; H, 6.93; N, 3.85%. Examples 11 & 12

8-(3.4-Diphenγlpyrazol-1-yl)octanoic acid 8-( .5-Diphenylpyrazol-l-yl)octanoic acid

5 a) Formyldeoxybenzoin (lOg) was suspended in ethanol (50ml) and hydrazine hydrate (5ml) added giving an orange solution which warmed to 40°C. This solution was stirred at room temperature for 3 hours and the solvent

10. evaporated. The resulting oil was taken up in dichloromethane and washed with dilute hydrochloric acid (pH2) and water, dried over potassium carbonate and evaporated to an orange solid. This was boiled in ether, cooled and filtered giving 3,4-diphenylpyrazole (5.64g, 5 57%) as pale yellow crystals, m.p. 155-6°C.

NMR (CDC1₃) 7.2-7.5 (10 H, m, 2 X Ph) , 7.6 (1H, s, pyraz 5-H) ppm

b) A mixture of 3,4-diphenylpyrazole (2.2g), ethyl 0 8-bromooctanoate (5.5g) and potassium carbonate (3.7g) in dry butanone (50ml) was heated at reflux temperature for 44 hours. The mixture was filtered and the filtrate evaporated to an oil which was chromatographed on silica gel (hexane/ethyl acetate) . The oil obtained was heated 5 at reflux temperature in a mixture of ethanol and 2N sodium hydroxide (1:1) for 1 hour. The ethanol was evaporated and the aqueous residue was acidified with dilute hydrochloric acid to pH 3, extracted with dichloromethane, dried over magnesium sulphate and evaporated to a solid. This was recrystallised from dichloromethane/ether to give 8-(3,4-diphenylpyrazol- 1-yl)octanoic acid (0.48g, 13%) as colourless crystals, m.p. 114-5°C. Found: C, 76.02; H, 7.25; N, 7.63% C₂₃H₂₆N₂0₂ requires: C, 76.21; H, 7.23; N. 7.73% c) The mother liquor from above was evaporated to an oil which was chromatographed on silica gel

(dichloromethane/methanol) giving a solid which was recrystallised from ether/petroleum ether to give

8-(4,5-diphenylpyrazol-l-yl)octanoic acid (0.15g, 5%) as colourless crystals, m.p. 94-5°C.

Found: C, 76.53; H, 7.26; N, 7.82%

^C23__26^N2°2 requires: C, 76.21; H, 7.23 ; N, 7.73%

-19- BIOLOGICAL DATA

METHOD FOR MEASUREMENT OF AGGREGATION OF WASHED HUMAN PLATELETS

Platelets were prepared from freshly drawn human blood. Blood was collected into acid citrate anticoagulant, centrifuged (5 in at 500g) , and the up layer of platelet-rich plasma was removed. This platelet-rich plasma was incubated with aspirin (lOOμM) for 10 min at 37°C and then centrifuged (15 min at 200 The platelet pellet was resuspended (at approx. 1.5 x 1 cells/ml) in medium containing NaCl (145mM) , KC1 (5mM) , MgCl₂ (ImM) , CaCl₂ (0.2mM), Hepes (lOmM, pH 7.4 at 37°C), glucose (lOmM) , apyrase (lOμg/ l) . Aggregation was monitored (as a change in optical density) at 37°C a 4 channel aggregometer (PAP-4 from Biodata Corp.). Fibrinogen (lmg/ml) and CaCl₂ (ImM) were added to aliquots of platelets that were continuously stirred. The test compound (or 0.1% DMSO vehicle) was added 2 mi before the aggregatory stimulus (lμM U46619) . The extent of aggregation was assessed 4 min after addition of the stimulus, and was calculated as % of the control response in the absence of test compound. Dose-respon curves were constructed for measurement of IC₅₀ values for each compound.

METHOD FOR MEASUREMENT OF K_j FOR INHIBITION OF [³H]ILOPROST BINDING TO HUMAN PLATELET MEMBRANES

Membranes were prepared from outdated platelet-ric plasma concentrates obtained from the Blood Transfusion Service. The platelets were homogenised in buffer containing Tris-Cl (5mM, pH 7.4 at 20°C) and EDTA (0.25mM), and then centrifuged (10 min at 26,000g). T membrane pellet was washed twice by homogenisation in buffer containing Tris-Cl (50mM, pH 7.4 at 20°C) and ED (0.25 mM) , followed by centrifugation. For measuremen of [³H]iloprost binding, membranes (0.4-0.8mg) were incubated in the presence of Tris-Cl (50mM, pH 7.4 at 20°C) , MgCl₂ (4mM) , EDTA (40μM) , [³H]iloprost (lOnM) , DMSO (1.85%) , and varying concentrations of the test compounds. For determination of non-specific binding, 20μM iloprost was included. The tubes (triplicates fo each condition) were set up on ice, and then incubated for 30 min at 37°C. The incubations were terminated b rapid filtration on Whatman GF/B filters using a Brande Harvester. The filters were washed and then counted f radioactivity. The K_j^ of the test compounds for inhibition of binding of [³H]iloprost to human platelet membranes was calculated from the IC₅₀ for displacement of [³H]iloprost binding.

RESULTS

The compounds of the Examples in general had IC₅₀ (aggregation) values in the range of from 0.01 - 2.3μM; and i(μM) values in the range of from 0.8 - 10μM.

Claims

Claims :

1. A compound of structure (I) :

in which each group Ar is the same or different and is optionally substituted phenyl or optionally substituted heteroaryl; X is nitrogen or CR¹ Y is nitrogen, N(CH₂)_nA or C(CH₂)_nA

Z is nitrogen, oxygen or N(CH₂)_nA, and the dotted line indicates the optional presence of a double bond so as to form a fully unsaturated heterocyclic ring; R¹ is hydrogen, C₁_₄alkyl, optionally substituted phenyl or optionally substituted heteroaryl; n is 4 to 12; and A is C0₂H or a group hydrolysable to C0₂H,

5-tetrazolyl, S0₃H, P(0)(0R)₂, P(0)(0H)₂, or P(0) (R) (OR) in which R is hydrogen or C₁_₄alkyl, or a pharmaceutically acceptable salt thereof, provided that

° X, Y and Z are not all at the same time, nitrogen; ° when X is CR¹, Y and Z are not both nitrogen; ° when Y is N(CH₂)_nA, Z is nitrogen; and ° when Z is oxygen, Y is C(CH₂)_nA. -22-

2. A compound according to claim 1 in which each group Ar is phenyl, X and Z are both nitrogen and Y is N(CH₂)_nX in which n is 8 and X is C0₂R in which R is C^^alkyl.

3. A process for preparing a compound according claim 1 which comprises:

(a) for compounds in which Z is other than oxygen reaction of a compound of structure (II) :

H

in which

Ar and X are as described in structure (I) and Y_a is N or C(CH )_nA; with a compound of structure:

L(CH₂)_nA (III)

in which n and A are as described for structure (I) and is a leaving group; or

(b) reaction of a compound of structure (IV) :

in which Ar and X are as described in structure (I) , Y_] is N, N(CH₂)_nA_b or C(CH₂)_nA_b, Z_b is N, 0 or

N(CH₂)_nA_b provided that:

° X, Y and Z_b are not all nitrogen, ° when X is CR¹, Y_b and Z_b are not both nitrogen,

⁰ when Y_b is N(CH )_nA_b, Z_b is nitrogen, and

⁰ when Z_b is O, Y_b is -C(CH )_nA_b;

A_b is a group convertible to a group A as described in structure (I) , with a reagent suitable to convert the group A_b into a group A and, optionally thereafter, converting one group A into another group A, and optionally forming a salt.

5. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier.

6. A compound according to claim 1 for use in therapy.