CA2022946A1 - Compound - Google Patents

Abstract

B2814/Abs Abstract The (3S,4R)-isomer of a compound of formula (I):

Description

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05 Thls invention relates to a novel benzopyran having 06 pharmacological activity, to a process for its 07 preparation and to its use as a pharmaceutical.

09 EP-A-250077 (Beecham Group p.l.c.) describes a group of 4-amidobenzopyrans in which the 6-position is 11 substituted by inter alia a Cl_6 alkyl group. Example 12 1 describes the compound wherein the 4-substitutent is 13 2-oxopiperidinyl and the 6-substituent is methyl, (El):

O
18 ~ ~ \CH

22 (El) 24 Example 13 describes the compound wherein the 4-substituent is 2-oxopyrrolidinyl and the 26 6-substituent is ethyl, (E13):

29 , N
31 H5C2 ~ ~ ~ c~3 (E13) 37 In both El and E13 the lactam and O~ moieties are trans ~922~

03 and the compounds are lsolated as racemic mixtures of 04 the ~3S,4R)- and (3R,4S)-isomers.

06 A novel compound not specifically described in 07 EP-A-250077 has now been discovered, this compound 08 having blood pressure lowering activity, useful in the 09 treatment of hypertension, and also bronchodilator activity, useful in the treatment of respiratory tract 11 disorders. In addition, this compound is believed to 12 be a K+ channel activator which indicates that is is of 13 potential use in the treatment of disorders associated 14 with smooth muscle contraction of the gastro-intestinal tract, respiratory system, uterus or urinary tract 16 including the ureter. Such disorders include irritable 17 bowel syndrome and diverticular disease; reversible 18 airways obstruction including asthma; premature labour;
19 and incontinence, renal cholic and disorders associated with kidney stones. It is also indicated as of 21 potential use in the treatment of cardiovascular 22 disorders other than hypertension, such as congestive 23 heart failure, angina, peripheral vascular disease, 24 cerebral vascular disease, pulmonary hypertension and right heart failure. It may also be of potential use 26 in the treatment of epilepsy.

28 The present invention provides the (3S,4R)-isomer of a 29 compound of formula (I):

33 ~ o 36 H5C2 ~ cH~33 38 (I) ~22~

03 wherein the lactam and OH moieties are trans.

05 The compound of formula (I) may exist as solvates such 06 as hydrates and these are included wherever a compound 07 of formula (I) is herein referred to.

09 The compound of formula (I) may be prepared as generally described in EP-A-250077.

12 The invention further provides a process for the 13 preparation of a compound of formula (I), which process 14 comprises the reaction of a compound of formula (II):

18 R ~

21 (II) 23 wherein Ra is ethyl or a group or atom convertible 24 thereto; with either 26 i ) a compound of formula (III):

~N ~ (III) H

32 in the form of the piperidinone anion; or 34 ii ) with ammonia to give a trans aminoalcohol of formula (IV):

2 ~ ?d 2 ~ L~

R L OH
05 a~
07 ~ ~ CH3 08 ~IV

which is subsequently acylated with a compound of 11 formula (v):

13 Ll(CH2)4cOL2 (V) wherein Ll and L2 are leaving groups; and thereafter 16 cyclising the resulting compound where necessary;

18 and thereafter converting Ra (when other than ethyl) to 19 ethyl.
21 The compound of formula (III) is preferably generated 22 in the form of the piperidinone anion using a base, 23 such as sodium hydride or potassium t-butoxide.

Suitable values for Ll and L2 include halo, such as 26 chloro, and (for L2), hydroxy, Cl_4 alkoxy or Cl_4 27 alkanoyloxy (i.e. the compound of formula (v) is a 28 mixed anhydride).

Suitable reagents and conditions for reactions i) and 31 ii) are described in EP-A-250077.

33 Ra when cyano may be converted to ethyl by reduction of 34 the cyano to a formyl group using for example, Raney Nickel, then a Wittig reaction using Ph3P+MeBr~ to give 36 the 6-ethenyl derivative which is converted to ethyl by 37 reduction, preferably using palladium on charcoal.

~22~ fi 03 The compound of formula (I) may either be prepared as a 04 racemic mixture of (3S,4R)- and (3R,4S)-isomers which 05 is subsequently resolved according to the methods 06 disclosed in EP-A-120428, or stereospecifically using 07 resolved intermediates. The compound of formula ~I) 08 may be prepared from a resolved aminoalcohol of formula og (IV) where Ra is cyano which is subsequently converted to ethyl as described above. Preferably, Ra is ethyl 11 in formula (IV), as described in the Example (Method 2) 12 hereinafter.

14 Compounds of formulae (II) and (IV) are known or prepared by analogous methods to those used for 16 structurally similar known compounds. They may be 17 prepared in the manner described in EP-A-76075 and 18 250077, in the name of Beecham Group p.l.c., or by 19 analogous methods thereto.
21 As mentioned previously, the compound of formula (I) 22 has been found to have blood-pressure lowering 23 activity and bronchodilation a~tivity. It is therefore 24 useful in the treatment of hypertension and/or respiratory tract disorders. It is also believed to be 26 of potential use in the treatmen~ of other disorders 27 hereinbefore referred to.

29 The present invention accordingly provides a pharmaceutical composition which comprises the compound 31 of formula (I) and a pharmaceutically acceptable 32 carrier. In particular, the present invention provides 33 an anti-hypertensive or bronchodilatory pharmaceutical 34 composition which comprises an effective amount of the compound of formula (I) and a pharmaceutically 36 acceptable carrier.

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03 The compositions are preferably adapted for oral 04 administration. However, they may be adapted for other 05 modes of administration, for example parenteral 06 administratlon for patients suffering from heart 07 failure. Other alternative modes of administration 08 include sublingual or transdermal administration. A
09 composition may be in the form of spray, aerosol or other conventional method of inhalation, for treating 11 respiratory tract disorders.

13 The compositions may be in the form of tablets, 14 capsules, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations, such 16 as oral or sterile parenteral solutions or suspensions.

18 In order to obtain consistency of administration it is 19 preferred that a composition of the invention is ~in the form of a unit dose.

22 Unit dose presentation forms for oral administration 23 may be tablets and capsules and may contain 24 conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, 26 or polyvinylpyrrolidone; fillers, for example lactose, 27 sugar, maize-starch, calcium phosphate, sorbitol or 28 glycine; tabletting lubricants, for example magnesium 29 stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or 31 microcrystalline cellulose; or pharmaceutically 32 acceptable wettlng agents such as sodium lauryl 33 sulphate.

The solid oral compositions may be prepared by 36 conventional methods of blending, filling or :

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03 tabletting. Repeated blending operations may be used 04 to distribute the active agent throughout those 05 compositions employing large quantities of fillers.
06 Such operations are of course conventional in the art.
07 The tablets may be coated according to methods well 08 known in normal pharmaceutical practice, in particular 09 with an enterlc coating.

11 Oral liquid preparations may be in the form of, for 12 example, emulsions, syrups, or elixirs, or may be 13 presented as a dry product for reconstitution with 14 water or other suitable vehicle before use. Such liquid preparations may contain conventional additives 16 such as suspending agents, for example sorbitol, syrup, 17 methyl cellulose, gelatin, hydroxyethylcellulose, 18 carboxymethylcellulose, aluminium stearate 19 gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia;
21 non-aqueous vehicles (which may include edible oils), 22 for example almond oil, fractionated coconut oil, oily 23 esters such as esters of glycerine, propylene glycol, 24 or ethyl alcohol; preservatives, for example methyl or propyl p~hydroxybenzoate or sorbic acid; and if desired 26 conventional flavouring or colouring agents.

28 For parenteral administration, fluid unit dosage forms 29 are prepared utilizing the compound and a sterile vehicle, and, depending on the concentration used, can 31 be either suspended or dissolved ln the vehicle. In 32 preparing solutions the compound can be dissolved in 33 water for in~ection and filter sterilized before 34 filling into a suitable vial or ampoule and sealing.
Advantageously, adjuvants such as a local anaesthetic, 36 a preservative and buffering agents can be dissolved in - ,~
,- .
~", , 7,~22~ ~fi 03 the vehicle. To enhance the stability, the composition 04 can be frozen after filllng lnto the vial and the water 05 removed under vacuum. Parenteral suspensions are 06 prepared in substantlally the same manner, except that 07 the compound ls suspended ln the vehicle instead of 08 belng dlssolved, and sterilization cannot be 09 accomplished by flltration. The compound can be sterillzed by exposure to ethylene oxide before 11 suspending ln the sterlle vehlcle. Advantageously, a 12 surfactant or wettlng agent ls lncluded ln the 13 composltlon to facilitate unlform distribution of the 14 compound.
16 For transdemal administration, formulations suitable 17 for topical administratlon may be employed, optionally 18 containing penetration enhancers.

The compositions may contain from 0.1% to 99% by 21 welght, preferably from 10-60% by weight, of the actlve 22 materlal, dependlng on the method of administration.

24 The compound of formula (I) is believed to show a synergistic effect with ACE lnhlbltor or ~-blocker 26 antihypertenslve agents and such combination products, 27 for concomltant or sequential administration, are 28 withln the present invention.

The present invention further provides a method of 31 prophylaxis or treatment of hypertension or respiratory 32 tract dlsorders in mammals including man, whlch 33 comprises administering to the suffering mammal an 34 anti-hypertensive or bronchodilatory effective amount of the compound of formula (I).

37 An effective amount will depend on the severity of the ,.

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03 disorder being treated and the weight of the sufferer.
04 ~owever, a unit dose form of a composition of the 05 invention may contain from 0.05 to 50 mg of a compound 06 of the invention and more usually from o.l to 5 mg, for 07 example 0.5 to 2.5 mg such as 0.5, 1 or 2 mg. Such 08 compositions may be administered from 1 to 6 times a 09 day, more usually from 1 to 4 times a day, in a manner such that the daily dose is from 0.01 to 5 mg per kg 11 body weight and more particularly from 0.1 to 3 mg/kg.

13 No toxicological effects are indicated at the 14 aforementioned dosage ranges.
16 The present invention further provides the compound of 17 formula (I) for use in the treatment or prophylaxis of 18 hypertension and/or respiratory tract disorders.

The following example relates to the preparation of the 21 compound of formula ~I).

~ ~J 2 03 Description 1 05 a) ~ trans-4-Am ~AO-~-cvano-3~4-dihYd-ro-2t2 06 dimethvl-2H-l-benzo~vran-3-ol 08 Sodium hydride (80% dispersio~ in oil, 13.7g) was added 09 in portions over lh to a stirred solution of (i)-trans-3-bromo-6-cyano-3,4-dihydro-2,2-dimethyl-2H-benzopyran-11 4-ol (124.3g) in tetrahydrofuran (250ml) kept under a 12 dry nitrogen atmosphere. The mixture was stirred for 13 an additional 0.5h after which a solution of the 14 3,4-epoxide resulted. Ethanol (620ml) followed by 0.880 ammonium hydroxide (375ml) were added, and the 16 resulting mixture stirred at 60-65C for 12h before 17 cooling to room temperature. The organic solvents were 18 evaporated off and the aqueous residue acidified with 19 5N hydrochloric acid (125ml). The mixture was then washed well with dichloromethane (total used = l.OL) 21 before basifying with 40% aq. sodium hydroxide (80ml).
22 It was then re-extracted with dichloromethane (4 x 23 250ml) and the combined extracts washed once with brine 24 and then dried (Na2S04). Evaporation afforded the product as a gum which crystallised. This was broken 26 up and triturated with a mixture of isopropyl ether and 27 dichlormethane before filtering off and washing with 28 further isopropyl ether. The product was dried under 29 suction and finally under vacuum.
31 Yield: 83.5g (87%) m.p.ll6-117C.

33 ~(CDC13): 1.21 (s, 3H); 1.51 ~s, 3H); 2.10 (b, 3H);
34 3.30 (d, J = lOHz, lH); 3.65 (d, J - lOHz, lH), 6.82 (d, J = 8Hz, lH); 7.42 (m, lH) 7.74 (m~ lH) .

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01 ~ B2814 03 b) Resolution of (i)-trans-4-Amino-6-cYano-3,4-04 dihvdro-2,2-dimethYl-2H-l-benzoPvran-3-ol 06 The title compound (lOOg) was dissolved in isopropyl 07 alcohol (500ml) with stirring and heating to 70C.
08 Water (25oml) was added followed by (+)-ammonium 09 3-bromo-camphor-9-sulphonate (150.5g). The mixture was stirred and warmed back to 70C to effect dissolution.
11 5N Hydrochloric acid (80ml) was then added fairly 12 rapidly until the mixture reached pH5. It was then 13 cooled to 55C before seeding with authentic 14 crystalline product. The mixture was cooled to room temperature before filtering off the product and 16 washing with a mixture of isopropyl alcohol (soml) and 17 water (25ml). After drying in air at 50C the yield of 18 3-bromo-camphor-9-sulphonic acid salt of the (+)-isomer 19 of the title compound was 75g (31%).
21 [a]D2o (c=l, MeOH) = + 88.9, m.p. 288-291C.

23 ~(d6-DMSO): 0.81 (s~ 3H); 1.07 (s~ 3H); 1.15 (s~ 3H);
24 1.10-1.25 (m~ lH); 1.45 (s~ 3H); 1.66-1.88 (m, 2H);
2.05-2.20 (m~ lH), 2.36 (d, J = 14Hz, lH); 2.83 (d, J =
26 14Hz, lH); 2.97 (ss, J = 6,6Hz, lH); 3.64 (dd, J =
27 6,10Hz, lH); 4.30 (d, J = lOHz, lH); 5.00 (d, J = 6Hz, 28 lH); 6.42 (d, J = 6Hz, lH); 7.04 (d, J = 8Hz, lH); 7.76 29 (m, lH); 8.07 (bs, lH); 8.53 (bs, 3H).
31 The foregoing salt (75g) was dissolved in a solution of 32 potassium hydroxide (10.3g) in water (50 ml) and the 33 mixture extracted with dichloromethane (4 x 250ml).
34 The combined extracts were washed once with brine and dried (Na2S04). Evaporation afforded the (+)-(3S,4R) 36 isomer of the title compound as a glassy solid (30.5g;
37 99%). Crystallisation from ethyl acetate-petrol .

,.~ .

2Q; ~3 03 afforded prisms of m.p. 85-86C.

05 [~]D20 (c = 1, MeOH) + 82.4.

07 Description 2 09 a) trans-4-Amino-2,2-dimethyl-6-ethvlchroman-3-ol 11 2,2-Dimethyl-3,4-epoxy-6-ethylchroman (1.596 kg) was 12 dissolved in 2-propanol (4 L) and ammonia (3.2 L) was 13 added. The mixture was warmed gently under reflux 14 using a condenser at -78. This reflux was maintained for 5h and then the mixture was warmed slowly to 60 16 overnight. The solvent was then removed under reduced 17 pressure and the residue was recrystallised from 18 cyclohexane giving 1.19 kg (69%) of the required title 19 amine.
21 b) 4S-Ammonium-3,4-dihYdro-2,2-dimethyl-6-ethyl-2H-l-22 benzoPvran-3R-ol t+)-mandelate 24 (+)-Mandelic acid (0.57 kg) and trans-4-amino-2,2-dimethyl-6-ethylchroman-3-ol (0.75 kg) were dissolved 26 in warm 2-propanol (18 L). The solution was 27 concentrated to 12 L and crystallised giving the title 28 product, 0.523 kg (41.3%).

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03 ExamPle (Method 1) 05 a) 6-Cyano-3,4-dih~dro-2,2-dimethvl-4R-(2-oxo-06 Piperidin-l-yl)-2H-l-benzopvran-3 08 ~
09 ~N~o 1 0 NC ~ ~O~i 5-Chlorovaleryl chloride (8.88g) was added portionwise 16 to a stirred solution of 4R-amino-6-cyano-3,4-17 dihydro-2,2-dimethyl-2_-1-benzopyran-3S-ol (8.33g) and 18 triethylamine (5.8g) in 1-methyl-2-pyrrolidinone (30 19 ml) at ice-bath temperature under an atmosphere of dry nitrogen. The reaction mixture was allowed to warm to 21 room temperature and stirred for a further 16h, then 22 was cooled to -30C, and potassium tert-butoxide 23 (15.43g) added portionwise with vigorous stirring. The 24 reaction mixture was allowed to warm to room temperature and was stirred for 30 min, then poured 26 onto crushed ice, the pH was adjusted to 7 (dilute 27 hydrochloric acid) and the resulting solid collected by 28 filtration, washed with water and dried 1n vacuo to 29 give the title product as a white solid (9.28g).
31 A further crop of product (0.75g) was obtained by 32 extraction of the aqueous filtrate with ethyl acetate.

34 lH-n.m.r. ~CDC13) 6 = 1.25 ~s,3H); 1.52 (s,3H);
1.62-2.07 ~m,4H); 2.47-2.66 (m~2H); 2.78-2.96 (m~lH);
36 3.05-3.24 (m,lH); 3.50 (br.s.,lH); 3.77 (d,J=llHz,lH);
37 5.92 (d,J=llHz,lH); 6.88 (d,J=9Hz,lH); 7.26 38 (d,J=2Hz,lH); 7.45 (d.d.,J=2,9Hz,lH).

. ~, ,, : . . .

~2æ~g 03 b) 3,4-Dihydro-2~2-dimethvl-6-formvl-4R-~2-oxo-04 ~iPeridin-l-vl)-2H-l-benzoPyran-3 06 ~

o ~ OHC ~OU

13 6-Cyano-3,4-dihydro-2,2-dimethyl-4R-(2-oxopiperidin-14 1-yl)-2H-l-benzopyran-3~-ol (9.23g), Raney Nickel (6.5g) and formic acid (75% v/v, 100 ml) were heated 16 under reflux, with vigorous stirring, for lh. The hot 17 reaction mixture was filtered, the residue washed with 18 hot ethanol and the combined filtrates were evaporated 19 in vacuo. The residue was treated with dil~te sodium hydrogen carbonate solution until alkaline (pH 9) and 21 then extracted twice with ethyl acetate. The combined 22 ethyl acetate extractions were washed with dilute 23 hydrochloric acid, dilute sodium hydrogen carbonate, 24 then brine, and dried (anhydrous sodium sulphate).
Filtration and evaporation of the solvent gave a solid 26 (8.94g). Recrystallization from ethyl acetate-methanol 27 gave the title product as pale lemon-coloured crystals 28 (6.96g); m.p. 226-229C.

Column chromatography of the mother liquors (silica 31 gel, gradient elutlon chloroform-methanol) gave a 32 second crop of the tltle compound ~lg).

34 lH n.m.r. ~CDC13) 6 , 1.30 (s,3H); 1.56 (s,3H);
1.66-2.01 (m,4H); 2.49-2.74 (m,2H); 2.84-3.01 (m,lH);
36 3.03-3.21 (m,lH); 3.52 (brs,lH); 3.81 (d,J=llHz,1H);
37 5.98 (d,J=llHz,lH); 6.95 (d,J=9HZ,lH); 7.52 38 (d,J=2Hz,lH); 7.72 (dd,J=2,9Hz,lH); 9.86 (s,lH).

.

. :

~2?~L-~3 03 c) 3,4-DihYdro-2,2-dimethvl-6-ethenyl-4R-(2-oxo-04 PiPeridin-l-vl)-2H-l-benzopyran-3S-ol 06 ( ~
07 N~o O~CH3 13 Potassium tert-butoxide (4.14g) was added portionwise 14 to a stirred suspension of methyl triphenylphosphonium - bromide (l2.llg) in dry diethyl ether (100 ml). The 16 mixture was ultrasonicated for 18h. 1-Methyl-2-pyrro-17 lidinone (30 ml) was added and the mixture was 18 ultrasonicated for a further 4h. 3,4-Dihydro-2,2-19 dimethyl-6-formyl-4R-(2-oxopiperidin-1-yl)-2H-l-benzopyran-3S-ol (7.84g) was then added and 21 ultrasonication maintained for lh. The solvent was 22 evaporated in vacuo, and the residue partitioned 23 between ethyl acetate and water. The aqueous phase was 24 further extracted with ethyl acetate and the combined organic extracts washed with water, then brine and 26 dried (anhydrous sodium sulphate). Filtration and 27 evaporation of the solvent gave a gum. Column 28 chromatography (silica gel - Kieselgel 60 - eluting 29 with ethyl acetate) gave a white solid.
Recrystallizations from ethyl acetate then lsopropanol 31 gave the title compound as a white crystalline solid 32 (3g); m.p. 205-8C.

34 A further crop of the title compound (2.2g) was obtained from the recrystallization mother liqueurs 36 after removal of the residual starting material by 37 treatment with excess hydroxylamine and separation by 38 column chromatography.

fi 03 lH n.m.r. (CDC13) 6 = 1.25 (s,3H); 1.50 (s,3H);
04 1.64-1.95 (m,4H); 2.48-2.73 (m,2H); 2.91-3.13 (m,2H);
05 3.19 (brs,lH); 3.79 (d,J=llHz,lH); 5.13 (d,J=llHz);
06 5.58 (d,J=18Hz,lH); 5.91 (d~J=9Hz~lH); 6.62 07 (dd,J=11,18Hz); 6.80 (d,J=9Hz,lH); 6.97 (d,J=2Hz,lH);
08 7.28 (dd,J=2Hz,lH).

d) 3,4-DihYdro-2,2-dimethYl-6-ethvl 4R-(2-oxo-11 Pi-peridin-l-ylL-2H-l-benzopvran-3 13 ~ 1 14 N - - - o H5C2 ~ OH

A mixture of 3,4-dihydro-2,2-dimethyl-6-ethenyl-4R-(2-21 oxopiperidin-1-yl)-2H-l-benzopyran-3S-ol (5.l5g)~ 10%
22 palladium on carbon (0.4g) in ethanol (200 ml) and 23 ethyl acetate (50 ml) were stirred for lh under a 24 hydrogen atmosphere. The catalyst was removed by filtration and the solvent evaporated in vacuo. The 26 residue was dissolved in ethyl acetate and dried 27 (anhydrous sodium sulphate). The solution was filtered 28 and then further filtered through a small pad of 29 Kieselgel 60. Evaporation of the solvent gave a white solid which was recrystallised from diisopropyl ether 31 to give the title compound as a white crystalllne solid 32 (4.5g); m.p. 140-1C.

34 lH n.m.r. (CDC13) ~ = 1.18 (t,J=8Hz,3H); 1.25 (s,3H);
1.50 (S,3H); 1.62-1.96 (m,4H); 2.43-2.73 (m~
36 containingquartet at 2.56, J=8Hz,4H); 2.89-3.14 (m,2H);
37 3.38 (brs,lH); 3.78 (d,J=llHz,lH); 5.88 (d,J=llHz,lH);
38 6.68-6.84 (m,2H); 7.00 (dd,J=2,9Hz,lH).

.

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03 Exam~le (Method 2) 05 3,4-Dihydro-2,2-dimethyl-6-ethYl-4R-(2-oxopiperidin-1-06 yl)-2H-l-benzopYran-3S-ol 08 ~
09 ~ 1 N~--o 11 H5C2 ~ OH
12 ~ ~ C~3 The (+) mandelate of Description 2d) (0.4 kg) was 16 partitioned between toluene (1 L) and 2.5% sodium 17 hydroxide solution (1.92 L). The aqueous layer was 18 separated and washed with toluene (1 L). The combined 19 organic layers were washed with water (2x0.5 L) and the solvent was removed under reduced pressure. The 21 residue was dissolved in toluene (1 L) and 22 triethylamine (0.164 L) and 5-chlorovaleroyl chloride 23 (0.152 L) were added. A solution of potassium 24 tert-butoxide (0.6 kg) in toluene (1.2 L) and 2-propanol (0.5 L) was added and the mixture was 26 stirred overnight. Water (1.0 L) was added and the 27 organic layer was separated. The aqueous layer was 28 extracted with toluene (1.0 L) and the combined organic 29 layers were washed with lN hydrochloric acid (3x0.5 L) and water (4x0.5 L). The solvent was removed under 31 reduced pressure and the solid obtained was triturated 32 wlth hot dl-lsopropyl ether to glve the tltle compound 33 0.275 kg (85~); m.p. 138-140C. [~]D20 (c=l, MeOH) 34 -97.
...

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-ol ~ 18 - B2814 05 The compound of the invention was tested for activity 06 in the following test methods.

08 1. AntihYPertensive ActivitY

Systolic blood pressures were recorded by a ll modification of the tail cuff method described by I.M.
12 Claxton, M.G. Palfreyman, R.H. Poyser, R.L. Whiting, 13 European Journal of Pharmacology, 37, 179 (1976). A
14 W+W sP recorder, model 8005 was used to display pulses. Prior to all measurements rats were placed in 16 a heated environment (33.5 ~ 0.5C) before transfer to 17 a restraining cage. The determination of blood 18 pressure was the mean of 5 readings. Spontaneously 19 hypertensive rats (ages 12-18 weeks) with systolic blood pressures >180 mmHg were considered hypertensive.

22 The compound of formula (I) of the Example showed a 23 maximum fall in blood pressure of 19% at a dose of 0.05 24 mg/kg p.o.
26 2. Bronchodilator Activitv 28 Male guinea pigs (300-600g) were stunned by a blow to 29 the head and bled from the carotid artery. The trachea was exposed, dissected free of connective tissue, and 31 transferred to oxygenated Krebs solution at 37C.
32 Next, spirals ( 2 per trachea) were prepared by cutting 33 the whole trachea spirally along its longltudinal axis 34 and then divldlng thls splral lengthwise. Each preparation was mounted, using silk thread, in a 10ml 36 organ bath filled with Krebs solution at 37C and 37 bubbled with 5% CO2 with 2 The resting tension of 38 the preparations was set at 2g and changes in ~uscle ..' ~ 3~

03 tension were monitored isometrically by means of a UFI
04 (2OZ) force and displacement transducer (Ormed Ltd) 05 connected to a Linseis pen recorder. All preparations 06 were allowed to equilibrate for 60 minutes. During 07 this equilibration period the preparations were washed 08 by upward displacement at 15 minute intervals and, if 09 necessary, the resting tension was readjusted to 2g using a mechanical micromanipulator system.

12 Once a steady resting tension had been obtained, the 13 preparations were dosed simultaneously with the test 14 compound (1o-8-2xlo-5M), and finally a maximum relaxation achieved by addition of 10-3M isoprenaline.
16 The fall in tension evoked by the test compound was 17 expressed as a percentage of the total relaxation 18 evoked in the presence of 10-3 isoprenaline.
19 Appropriate concentration-relaxation curves were then constructed and values for potency (IC50) were 21 obtained.

23 The compound of formula (I) of the example gave an ICso 24 value of 0.23 ~mol.
26 [The composition of Krebs solution is: sodium chloride 27 118.07mM, sodium hydrogen carbonate 26.19mM, potassium 28 chloride 4.68mM, potassium orthophosphate 1.18mM, 29 magnesium sulphate septahydrate 1.8mM and calcium chloride 2.52mM;pH ca. 7.45.]

Claims (10)

1. The (3S, 4R)-isomer of a compound of formula (I):

(I) wherein the lactam and OH moieties are trans.

2. A process for the preparation of a compound according to claim 1, which process comprises the reaction of a compound of formula (II):

(II) wherein Ra is ethyl or a group or atom convertible thereto; with either i) a compound of formula (III):

(III) in the form of the piperidinone anion; or ii) with ammonia to give a trans aminoalcohol of formula (IV):

(IV) which is subsequently acylated with a compound of formula (V):

L1(CH2)4COL2 (V) wherein L1 and L2 are leaving groups; and thereafter cyclising the resulting compound where necessary;

and thereafter converting Ra (when other than ethyl) to ethyl.

3. 3,4-Dihydro-2,2-dimethyl-6-ethenyl-4R-(2-oxo-piperidin-1-yl)-2H-1-benzopyran-3S-ol.

4. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

5. A method of treatment of hypertension and/or respiratory tract disorders in mammals which comprises the administration to the mammal in need of such treatment, an effective amount of a compound according to claim 1.

6. A compound according to claim 1 for use as an active therapeutic substance.

7. A compound according to claim 1 for use as a potassium channel activator in the treatment of disorders asociated with smooth muscle contraction.

8. A compound according to claim 1 for use in the treatment of hypertension and/or respiratory tract disorders.

9. Use of a compound according to claim 1 in the manufacture of a medicament for use as a potassium channel activator in the treatment of disorders associated with smooth muscle contraction.

10. Use of a compound according to claim 1 in the manufacture of a medicament for use in the treatment of hypertension and/or respiratory tract disorders.