GB2127406A - Piperidinylcyclopentanolheptenoic acid salt - Google Patents
Piperidinylcyclopentanolheptenoic acid salt Download PDFInfo
- Publication number
- GB2127406A GB2127406A GB08324632A GB8324632A GB2127406A GB 2127406 A GB2127406 A GB 2127406A GB 08324632 A GB08324632 A GB 08324632A GB 8324632 A GB8324632 A GB 8324632A GB 2127406 A GB2127406 A GB 2127406A
- Authority
- GB
- United Kingdom
- Prior art keywords
- compound
- composition
- solution
- acid
- hydroxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
Abstract
[1R-[1 alpha (Z),2 beta ,3 beta ,5 alpha ]]-(+)-7- [5[[1,1'-Biphenyl)-4-yl]methoxy]-3- hydroxy-2-(1-piperidinyl)cyclopentyl]- 4-heptenoic acid, hydrochloride and pharmaceutical formulations thereof are described. The compound may be used as an anti- thrombotic or anti-asthmatic agent.
Description
SPECIFICATION
Piperidinylcyclopentanol heptenoic acid salt
The endoperoxides prostaglandins G2 and H2 and thromboxane A2 are naturally occurring reactive metabolites of arachidonic acid in human platelets. They are not only potent aggregatory agents but are also constrictors of vascular and bronchial smooth muscle, and therefore substances which antagonise their effects are of considerable interest in human medicine.
We have now found a new compound which has shown endoperoxide and thromboxane antagonist acitivity, and is therefore of interest in the treatment of asthma and cardiovascular diseases.
This compound is [1 R-[1a(Z),2ff3ff5afl-( + )-7-[5-[k1,1 '-biphenyl)-4-yl]methoxy]-3-hydroxy- 2-(1.piperidinyl)cyclopentyl]-4-heptenoic acid, hydrochloride (referred to below as compound A).
The invention is particularly concerned with pharmaceutical compositions containing compound
A and one or more pharmaceutical carriers.
The parent amino acid of Compound A is described in our copending British Patent
Specification 2097397A, together with other aminocyclopentanol acids and esters. Compound
A is advantageous in a number of respects as compared to these compounds generally and in particular to its parent amino acid and other salts or solvates thereof, both as regards its preparation and its use in medicine. Thus for example compound A is readily isolatable from reaction mixtures in which it is prepared, and it is obtainable in a crystalline form of high purity which has desirable characteristics for pharmaceutical formulation.
Compound A inhibits blood platelet aggregation and bronchoconstriction. To determine inhibition of blood platelet aggregation, starved guinea pigs are dosed orally with the compound in a suitable vehicle. Platelet rich plasma is prepared from each animal and aggregation to a range of collagen concentrations is measured after the method of Born (Nature 194, 927-929, (1962). Collagen concentration effect curves for each sample of plasma are calculated and results are expressed as the shift of the curves following treatment with the compound.
The ability of compound A to inhibit bronchoconstriction is determined in the anaesthetized guinea pig by measuring the effect of the compound on the dose response curve of the bronchoconstrictor [1 R-[ 1 a, 4a, 5(Z), 6a( 1 E, 3 S")]]-7-[6-(3-hydroxy- 1 -octenyl)-2-oxabicyclo [2,2,1 hept-5-yl]-5-heptenoic acid (U-46619)
Compound A is thus of interest in the treatment of asthma, and as an inhibitor of platelet aggregation and thrombosis for use in renal dialysis and the treatment and prevention of occlusive vascular diseases such as arteriosclerosis, atherosclerosis, peripheral vascular disease, cerebral vascular disease including transient ischaemic attacks, stroke, pulmonary embolism, diabetic retinopathy, post operative thrombosis, angina and myocardial infarction.It may be formulated in conventional manner for use, with one or more pharmaceutical carriers.
For oral administration, the pharmaceutical composition may take the form of, for example, tablets, capsules, powders, solutions, or syrups prepared by conventional means with acceptable excipients.
The compound my be formulated for parenteral administration by bolus injections or continuous infusion. Formulations for injections may be presented in unit dosage form in ampoules, or in multi-dose containers, with an added preservative.
For administration by inhalation the compound is conveniently delivered in the form of an aerosol spray presentation from pressurised packs or a nebuliser, or as a cartridge from which the powdered composition may be inhaled with the aid of a suitable device. In the case of a pressurised aerosol the dosage unit may be determined by providing a valve to deliver a metered amount.
For use as an antithrombotic agent, compound A is preferably administered orally, for example in amounts of 0.05 to 5 mg/kg body weight, 1 to 4 times daily.
For use in the treatment of asthma, the compound may also be administered orally in amounts of 0.05 to 5 mg/kg body weight, 1 to 4 times daily; preferably however it is administered by inhalation at doses varying from 0.3 to 30 mg, 1 to 4 times daily. The compound may be used in combination with other anti-asthmatic agents.
The unit dose formulations thus usually contain 3.5 to 350 mg of compound A. The precise dose administered will of course depend on the age and condition of the patient.
Suitable methods for preparing compound A are described below.
Compound A may be prepared by treating the parent amino acid or an appropriate ester (e.g.
the trityl ester) with hydrogen chloride or hydrochloric acid. The salt is for example prepared by adding hydrogen chloride to a solution of the parent amino acid in an organic solvent such as ether, ethyl acetate, CH2CI2 or dimethoxyethane, at temperatures of for example 0 C to room temperature.
The following examples illustrate the invention. Temperatures are in 0 C, The following abbreviations are used: T.L.C-Thin layer chromatography, using SiO2 unless otherwise stated.
ER-ether; EA-ethyl acetate;
TH F-tetrahydrofuran; DlBALdiisobutylaluminium hydride;
Chromatography was carried out using silic gel.
'Dried' refers to drying with MgSO4.
'Hyflo' is a filtration aid.
The preparations of Intermediates 1 and 2 are described in British Patent Specification 2097397A.
Intermediate 1 [1R-[1α(Z),2ss,3ss,5α]-( + )-Methyl 7-f5-fT'1, 1 '-Biphenyl-4-yl)methoxy]-3-hydroxy-2-(1-piperdinyl) cyclopentyl)-4-heptenoate Intermediate 2 Ti R-( I a, 2ss, 3α,5α)]-5-[[(1,1'-Biphenyl]-4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl)cyclopentane acetaldehyde
Intermediate 3 Ti R-( 1 a, 2ss, 3a, 5a)j-( + )-5-TT(1,1'-Biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl)cyclopen
tane propanol.
A solution of Intermediate 2 (1 3.0g) in toluene (39ml) was added dropwise to a suspension of potassium tertbutoxide (5.96g) in toluene (52ml). Methoxymethyltriphenylphosphonium chloride (15.939) was added and the mixture stirred overnight (18h). 2N Hydrochloric acid (52ml) was added and the mixture was heated with stirring at 40 for 30 min. Solid K2CO3 (139) was added, the organic phase separated, washed with water (52 ml) and dried azeotropically to give a solution of Intermediate 3 in toluene (115ml).A portion of the solution (8.8ml) was purified by chromatography eluting with 9:1 EA-methanol to give the title compound as a foam (0.53g). T.L.C. 4:1 EA-methanol Rf 0.15
Intermediate 4 yl R-[1α(Z),2ss, 3a, 5all-( + )-7-[5-[[(1, 1 tBiphenyl)-4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl)cyclo- pentylj-4-heptenoic acid, hydrochloride
To a solution of potassium tertbutoxide (21.499) in toluene (198ml) and THF (52ml) under N2 was added 3-(carboxypropyl)triphenylphosphonium bromide (41.149). After 1 1 /2h a solution of Intermediate 3 (24.59) in toluene (220ml) was added and the mixture stirred for 3h. Water (125 ml) was added, the mixture vigorously shaken and the phases separated.The aqueous phase was washed with toluene (2 X 225ml) (discarded), then acidified (to pH 7.5) with 2N hydrochloric acid and extracted with CH2CI2 (2 x 225ml). The combined CH2Cl2 extracts were dried and evaporated to give the title compound, base (24.479) as a gum.
A solution of the base (93mg) in CH2CI2 (1.5ml) was treated with an excess of ethereal hydrogen chloride. The solvents were removed and the residual oil triturated with ER (5ml). The resulting solid was filtered, washed with ER and dried to give the title compound (82mg) m.p
132.5-136 (softens at 128 ) Intermediate 5 [1R-[1α(Z),2ss,3α, 5a1J-( + )-Triphenylmethyl 7-T5-LF(i, 1 '-Biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1- piperidinyl)cyclopentyl]-4-heptenoate
Triethylamine (2.49ml) was added to a cold (5 ) solution of Intermediate 4, base (5.889) and trityl chloride (4.49) in CH2CI2 (24ml). The mixture was stirred for 30min then water (60ml) and further CH2CI2 (30ml) added.The organic phase was separated then evaporated in vacuo. The residue was azeotroped with CH2CI2 (60ml) to give an oil (10.13g) which was chromatographed on alumina (5009), eluting with EA to give the title compound as an oil (5.149). T.L.C. (Al2O2) 49::1 EA- methanol Rf 0.52
Intermediate 6 Ti R-T 1 (Z), 2ss, 5aJJ-( - )-Triphenylmethyl 7-T5-TT(i, 1 '-Biphen yl)-4-yl]methoxy]-3-oxo-2-( l-piperidi- nyl)cyclopentyl]-4-heptenoate Triethylamine (9.17ml) was added at 2 to a stirred solution of Intermediate 5 (6.479) in CH2CI2 (65ml), followed by a solution of pyridine/SO3 complex (5.75g) in dimethylsulphoxide (65ml).
The resulting solution was stirred at 3-5 for 2h and quenched by the dropwise addition of icewater (65ml). The reaction mixture was extracted with diethyl ether (2 x 65ml) and the extract washed with water (65ml), 1 M citric acid (4 x 1 Oml) and water (1 0ml). Evaporation of the dried (NaSO4) solvents gave the title compound as a foam (5.9g). IR (CHBr3) 1740 cm-'
Example 1 Ti R-[1 oe(Z), 2ss, 3ss, 5aJJ-( + )- 7-[5-g 1, 1 'Biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl)cyclo pentyl]-4-heptenoic acid, hydrochloride
Intermediate 1 (10.389) was stirred with ethanol (60 ml) and 5N NaOH (30 ml) at 20 for 16h.
The solution was diluted with water (400 ml) and then extracted with ER (2 X 150ml). The aqueous phase was adjusted to pH 6 with 2N HCI and extracted with CH2CI2 (3 X 200ml).
Evaporation of the combined extracts gave a foam (9.549), the majority (9.3g) of which was taken up into CH2CI2 (50ml) and treated with excess of an ethereal solution of hydrogen chloride. Evaporation in vacuo and trituration of the residue with ER (4 X 75ml) gave the title compound as a powder (9.289). Crystallisation of a sample from EA-methanol gave material of m.p. 124-126 .
1aTh5= +63.1' (CHC13) Example 2 Ti fl-Fl a(Z), 2ss, 3ss, 5aJl-( + )- 7-[5-g 1, 1 '-Biphen yl)-4-yl]methoxy-3-hydroxy-2-( 1 -piperidinyl)cyclopentyl]-4-heptenoic acid, hydrochloride
DIBAL (1 M in hexane, 5.5 ml) was added dropwise at 0-2 to a stirred solution of 2.6-di-tbutyl-4-methylphenol (2.9g) in CH2CI2 (13ml). The solution was stirred at - S to 0 for 1 h and then cooled to - 20". A solution of Intermediate 6 (1.39) in CH2CI2 (13ml) was added at - 18 to - 20". The mixture was stirred at this temperature for 2 1/2 h, 1 N hydrochloric acid (20ml) was then added dropwise, and the mixture was stirred at room temperature for 1 /2h. The phases were separated and the aqueous layer was extracted with CH2CI2 (1 Oml). The organic extracts were combined, washed with brine, dried (Na2SO4) and evaporated to give a yellow gum. The product was triturated with diethyl ether to give a pale yellow powder (0.689).
Recrystallisation from EA-methanol gave m.p. 128-130"; [tx]2D3= + 66.5 (CHCl3) Pharmaceutical Examples
Tablets
These may be prepared by direct compression or wet granulation. The direct compression method is preferred but may not be suitable in all cases as it is dependent upon the dose level and physical characteristics of the active ingredient.
A. Direct Compression mg/tablet
Compound A 100.00
Microcrystalline Cellulose B.P.C. 298.00
Magnesium Stereate 2.00
Compression weight 400.00 mg
Compound A is sieved through a 250 m-6 sieve, blended with the excipients and compressed using 10.0mm punches. Tablets of other strengths may be prepared by altering the compression weight and using punches to suit.
B. Wet Granulation mg/tablet
Compound A 100.00
Lactose B.P. 238.00
Starch B.P. 40.00
Pregelatinised Maize Starch B.P. 20.00
Magnesium Stereate B.P. 2.00
Compressed Weight 400.00 mg
Compound A is sieved through a 250 m-6 sieve and blended with the lactose, starch and pre-gelatinised starch. The mixed powders are moistened with purified water, granules are made, dried, screened and blended with the magnesium stereate. The lubricated granules are compressed into tablets as described for the direct compression formula.
The tablets may be film coated with suitable film forming materials, e.g. methyl cellulose or hydroxylpropyl methyl cellulose using standard techniques. Alternatively the tablets may be sugar coated.
Capsules mg/capsule
Compound A 100.00 *STA-RX 1500 99.00
Magnesium Stearate B.P. 1.00 Fill Weight 200.00 mg * a form of directly compressible starch supplied by Colorcorn Ltd., Orpington, Kent.
Compound A is sieved through a 250 m-6 sieve and blended with the other materials. The mix is filled into No. 2 hard gelatin capsules using a suitable filling machine. Other doses may be prepared by altering the fill weight and if necessary changing the capsule size to suit.
Inhalation cartridges mg/cartridge
Compound A (micronised) 3.00
Lactose B.P. to 25.00
Compound A is micronised in a fluid energy mill to a fine particle size range prior to blending with normal tabletting grade lactose in a high energy mixer. The powder blend is filled into No.
3 hard gelatin capsules on a suitable encapsulating machine.
The contents of the cartridge are administered using a powder inhaler.
Metered Dose Pressurised Aerosol
Mg/metered dose Per can
Compound A (micronised) 0.500 1 20 mg Oleic Acid B.P. 0.050 12 mg
Trichlorofluoromethane B.P. 22.25 5.34 g
Dichlorodifluoromethane B.P. 60.90 14.62 g
Compound A is micronised in a fluid energy mill to a fine particle size range. The oleic acid is mixed with the trichlorofluoromethane at a temperature of 10-15"C and the micronised drug is mixed into this solution with a high shear mixer. The suspension is metered into aluminium aerosol cans and suitable metering valves, delivering a metered dose of 85 mg of suspension, are crimped onto the cans and the dichlorodifluoromethane is pressure filled into the cans through the valves.
Syrup mg/5ml dose
Compound A 100.00
Sucrose B.P. 2750.00 Glvcerine B.P. 500.00
Buffer Flavour t as required Colour Preservative J Distilled Water to 5.00 ml The active ingredient, buffer, flavour, colour and preservative are dissolved in some of the water, and the glycerine is added. The remainder of the water is heated to 80"C and the sucrose is dissolved in this and cooled. The two solutions are combined, adjusted to volume and mixed.
The syrup produced is clarified by filtration.
Injection for Intravenous Administration
Compound A 50 mg
Water for injections BP to 5 ml
Sodium chloride or any other suitable material may be added to adjust the tonicity of the solution and the pH may be adjusted to that of maximum stability of the active ingredient using dilute acid or alkali or by the addition of suitable buffer salts. The solution is prepared, clarified and filled into appropriate sized ampoules sealed by fusion of the glass. The injection is sterilised by heating in a autoclave using one of the acceptable cycles. Alternatively the solution may be sterilised by filtration and filled into sterile ampoules under aseptic conditions. The solution may be packed under an inert atmosphere of nitrogen.
Claims (8)
1. [1 R-[1 (r(Z),2ss,3ss,5a]]-( + )-7-[5-[[(1 , 1 '-Biphenyl)-4-yl]methoxy3-3-hydroxy-2-(1 -piperidi nyl)cyclopentyl]-4-heptenoic acid, hydrochloride.
2. A pharmaceutical composition containing the compound of claim 1 and one or more pharmaceutical carriers.
3. A composition as claimed in claim 2 in the form of a tablet, a capsule, a powder, a solution, a syrup, an ampoule or an aerosol spray formulation.
4. A composition as claimed in claim 2 or claim 3 in a unit dose form containing 3.5 to 350 mg of the compound of claim 1.
5. A composition as claimed in claim 4 in the form of a tablet, capsule or syrup containing about 100 mg of the compound of claim 1, or in the form of a solution for injection containing about 50 mg of the compound of claim 1, or in the form of an inhalation cartridge containing about 3 mg of the compound of claim 1, or in the form of an aerosol spray presentation adapted to deliver about 0.5 mg of the compound of claim 1.
6. A composition as claimed in any of claims 2 to 5 which includes a further anti-asthmatic agent.
7. The use of the compound of claim 1 or a composition as claimed in any one of claims 2 to 6 as an anti-thrombotic or anti-asthmatic agent.
8. A process for the preparation of the compound as claimed in claim 1 which comprises treating the parent amino acid with hydrogen chloride or hydrochloric acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB08324632A GB2127406B (en) | 1982-09-16 | 1983-09-14 | Piperidinlycyclopentanolheptenoic acid salt |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB08226378A GB2108116B (en) | 1981-09-16 | 1982-09-16 | Aminocyclopentane esters and their preparation and pharmaceutical formulation |
| GB8230771 | 1982-10-28 | ||
| GB08324632A GB2127406B (en) | 1982-09-16 | 1983-09-14 | Piperidinlycyclopentanolheptenoic acid salt |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8324632D0 GB8324632D0 (en) | 1983-10-19 |
| GB2127406A true GB2127406A (en) | 1984-04-11 |
| GB2127406B GB2127406B (en) | 1986-03-05 |
Family
ID=27261738
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08324632A Expired GB2127406B (en) | 1982-09-16 | 1983-09-14 | Piperidinlycyclopentanolheptenoic acid salt |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2127406B (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0256805A2 (en) * | 1986-08-08 | 1988-02-24 | Glaxo Group Limited | Pharmaceutical compositions for the treatment of occlusive vascular diseases |
| EP0297853A1 (en) * | 1987-06-30 | 1989-01-04 | Glaxo Group Limited | Preparation of 5-biphenylmethoxy-3-hydroxy-2- piperdinylcyclopentyl-4-heptenoic acid |
| US4835278A (en) * | 1986-01-28 | 1989-05-30 | Glaxo Group Limited | Preparation of piperidinylcyclopentylheptenoic acid derivatives |
| FR2624731A1 (en) * | 1987-12-22 | 1989-06-23 | Glaxo Group Ltd | AQUEOUS COMPOSITIONS CONTAINING A PIPERIDINYLCYCLOPENTYLHEPTENOIC ACID DERIVATIVE |
| EP0337739A2 (en) * | 1988-04-12 | 1989-10-18 | Glaxo Group Limited | Use of TP-receptor antagonists to modify the action of myofibroblasts |
| US5015648A (en) * | 1988-06-21 | 1991-05-14 | Glaxo Group Limited | Use of a thromboxane receptor antagonist in pregnancy-induced hypertension and related conditions |
| US5221695A (en) * | 1987-12-22 | 1993-06-22 | Glaxo Group Limited | Aqueous formulation containing a piperidinylcyclopentylheptenoic acid derivative and beta-cyclodextrin |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2075503A (en) * | 1980-04-30 | 1981-11-18 | Glaxo Group Ltd | Prostanoid aminocyclopentane alkenoic acids and esters and their preparation and pharmaceutical formulation |
| GB2097397A (en) * | 1981-04-29 | 1982-11-03 | Glaxo Group Ltd | Aminocyclopentanol acids and esters as prostaglandin analogues and their preparation and pharmaceutical formulation |
| GB2108116A (en) * | 1981-09-16 | 1983-05-11 | Glaxo Group Ltd | Aminocyclopentane esters and their preparation and pharmaceutical formulation |
-
1983
- 1983-09-14 GB GB08324632A patent/GB2127406B/en not_active Expired
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2075503A (en) * | 1980-04-30 | 1981-11-18 | Glaxo Group Ltd | Prostanoid aminocyclopentane alkenoic acids and esters and their preparation and pharmaceutical formulation |
| GB2097397A (en) * | 1981-04-29 | 1982-11-03 | Glaxo Group Ltd | Aminocyclopentanol acids and esters as prostaglandin analogues and their preparation and pharmaceutical formulation |
| GB2108116A (en) * | 1981-09-16 | 1983-05-11 | Glaxo Group Ltd | Aminocyclopentane esters and their preparation and pharmaceutical formulation |
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4835278A (en) * | 1986-01-28 | 1989-05-30 | Glaxo Group Limited | Preparation of piperidinylcyclopentylheptenoic acid derivatives |
| EP0256805A3 (en) * | 1986-08-08 | 1990-01-10 | Glaxo Group Limited | Pharmaceutical compositions for the treatment of occlusive vascular diseases |
| EP0256805A2 (en) * | 1986-08-08 | 1988-02-24 | Glaxo Group Limited | Pharmaceutical compositions for the treatment of occlusive vascular diseases |
| EP0297853A1 (en) * | 1987-06-30 | 1989-01-04 | Glaxo Group Limited | Preparation of 5-biphenylmethoxy-3-hydroxy-2- piperdinylcyclopentyl-4-heptenoic acid |
| US4933461A (en) * | 1987-06-30 | 1990-06-12 | Glaxo Group Limited | Preparation of a piperidinylcyclopentylheptenoic acid derivative |
| FR2624731A1 (en) * | 1987-12-22 | 1989-06-23 | Glaxo Group Ltd | AQUEOUS COMPOSITIONS CONTAINING A PIPERIDINYLCYCLOPENTYLHEPTENOIC ACID DERIVATIVE |
| BE1001704A3 (en) * | 1987-12-22 | 1990-02-13 | Glaxo Group Ltd | Aqueous compositions containing acid derivative piperidinylcyclopentylheptenoique. |
| GB2211737A (en) * | 1987-12-22 | 1989-07-12 | Glaxo Group Ltd | Aqueous formulations of piperidinylcyclopentylheptenoic acid derivatives |
| GB2211737B (en) * | 1987-12-22 | 1991-12-11 | Glaxo Group Ltd | Aqueous formulations containing a piperidinylcyclopentylheptenoic acid derivative |
| AT395943B (en) * | 1987-12-22 | 1993-04-26 | Glaxo Group Ltd | PHARMACEUTICAL AQUEOUS FORMULATIONS CONTAINING A PIPERIDINYLCYCLOPENTYLHEPTENIC ACID DERIVATIVE |
| US5221695A (en) * | 1987-12-22 | 1993-06-22 | Glaxo Group Limited | Aqueous formulation containing a piperidinylcyclopentylheptenoic acid derivative and beta-cyclodextrin |
| GR880100854A (en) * | 1987-12-22 | 1994-03-31 | Glaxo Group Ltd | Aqueous formulations containing a piperidinylcyclopenthylheptenoic acid derivative |
| EP0337739A2 (en) * | 1988-04-12 | 1989-10-18 | Glaxo Group Limited | Use of TP-receptor antagonists to modify the action of myofibroblasts |
| EP0337739A3 (en) * | 1988-04-12 | 1990-10-10 | Glaxo Group Limited | Use of tp-receptor antagonists to modify the action of myofibroblasts |
| US5015648A (en) * | 1988-06-21 | 1991-05-14 | Glaxo Group Limited | Use of a thromboxane receptor antagonist in pregnancy-induced hypertension and related conditions |
Also Published As
| Publication number | Publication date |
|---|---|
| GB8324632D0 (en) | 1983-10-19 |
| GB2127406B (en) | 1986-03-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4327092A (en) | Aminocyclopentane alkenoic acids and esters and pharmaceutical formulations | |
| NL8802059A (en) | ESTERS AND AMIDS OF CYCLIC CARBONIC ACIDS AND CYCLIC ALCOHOLS AND AMINES. | |
| GB2127406A (en) | Piperidinylcyclopentanolheptenoic acid salt | |
| CH667646A5 (en) | AMINOCYCLOPENTYL ETHER, THEIR PRODUCTION AND PHARMACEUTICAL FORMULATION. | |
| US4166859A (en) | 2-Bromo-6-fluoro-N-(2-imidazolidinylidene)-benzamine and salts thereof and the use to treat hypertension | |
| CA1313500C (en) | Pharmaceutical compositions for the treatment of occlusive vascular diseases | |
| CA1191142A (en) | ¬1R-¬1.alpha.(Z), 2.beta., 3.beta., 5.alpha.||-( )-7-¬5- ¬¬1,1'-BIPHENYL)-4-YL|METHOXY|-3-HYDROXY- 2(1-PIPERIDINYL)CYCLOPENTYL|-4-HEPTENOIC ACID HYDROCHLORIDE | |
| DK154136B (en) | METHOD OF ANALOGUE FOR THE PREPARATION OF 2-AMINO-3-BENZOYLPHENYLACETAMIDES | |
| EP0111608B1 (en) | Pseudotropyl halogeno-benzoates and their use in migraine treatment | |
| US4361575A (en) | Substituted 2-phenylamino-2-imidazolines and salts thereof | |
| JPH0425267B2 (en) | ||
| WO2012119550A1 (en) | C-glucosidase derivative having cyclopropane structure, preparing method therefor, pharmaceutical composition, and use thereof | |
| EP0037187B1 (en) | Salts and aqueous solutions of 6-methylamino-4-oxo-10-propyl-4h-pyrano(3,2-g)-quinoline-2,8-di-carboxylic acid and pharmaceutical compositions containing such salts and solutions | |
| EP0058079B1 (en) | 4-(1-imidazolylmethyl)cinnamic acid hydrochloride monohydrate, method of preparation thereof, and pharmaceutical composition containing same | |
| US4215133A (en) | 2-[N-(2'-Chloro-4'-methyl-thienyl-3')-N-(cyclopropyl-methyl)-amino]-2-imidazoline and salts thereof | |
| EP0127930A2 (en) | Aminocyclopentane esters and their preparation and pharmaceutical formulation | |
| US4977163A (en) | Aminocyclopentanol acids and esters and their preparation and pharmaceutical formulation | |
| US3900478A (en) | 2-methyl-2-piperidino-3'-(trifluoromethyl) propiophenone | |
| US3037981A (en) | Phenyltetrahydropyranylpiperazines | |
| US5039673A (en) | Aminocyclopentyl ethers and their preparation and pharmaceutical formulation | |
| US6242466B1 (en) | Substituted phenylamidines | |
| PL190098B1 (en) | Micromolecular form of derivatives of tetrahydropyridine | |
| GB2167404A (en) | Prostanoid aminocyclopentane alkenoic acids and esters, their preparation and pharmaceutical formulation | |
| GB2167402A (en) | Prostanoid aminocyclopentane alkenamides, their preparation and pharmaceutical formulation | |
| JPS6113445B2 (en) |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19960914 |