GB2219938A - Use of a thromboxane receptor antagonist in pregnancy-induced hypertension - Google Patents
Use of a thromboxane receptor antagonist in pregnancy-induced hypertension Download PDFInfo
- Publication number
- GB2219938A GB2219938A GB8913875A GB8913875A GB2219938A GB 2219938 A GB2219938 A GB 2219938A GB 8913875 A GB8913875 A GB 8913875A GB 8913875 A GB8913875 A GB 8913875A GB 2219938 A GB2219938 A GB 2219938A
- Authority
- GB
- United Kingdom
- Prior art keywords
- group
- zero
- formula
- alkyl
- physiologically acceptable
- 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.)
- Withdrawn
Links
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nanotechnology (AREA)
- Biophysics (AREA)
- Biotechnology (AREA)
- General Engineering & Computer Science (AREA)
- Medical Informatics (AREA)
- Molecular Biology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The use of a compound of formula (1> <IMAGE> wherein R<1> is a H or methyl; X is cis or trans -CH=CH- or -CH2CH2-, m is 2, 3 or 4 and n is 1; or X is trans -CH=CH-, m is zero and n is 3; Y is a saturated heterocyclic amino group (attached to the cyclopentane ring via the nitrogen atom) which a has 5-8 ring members; Alk is a straight or branched C1-5 alkyl; l is zero or 1; p is zero, 1, 2, 3 or 4; R<2> is OH, -OCOR<3>, -CO2R<3>, -CONR<3>R<4>, -SO2NR<3>R <4, -NHCOR<3>, -NH3, -NHSO2R<5>, -SO2R<5>, -SR<5>, -NR<3>R<4>, -COR<5>, NHCONR<3>R<4> or -NHCSNH2; R<3>, and R<3a>and R<4> are each H or a C1-4 alkyl or C7-10 aralkyl group; and R<5> is a C1-4 alkyl group; or a physiologically acceptable salt, solvate or cyciodextrin complex thereof in the manufacture of medicaments for the therapy or prophylaxis of conditions associated with vasoconstriction and/or platelet aggregation in the uteroplacental circulation and/or excessive synthesis of thromboxane A2 in a pregnant female subject.
Description
USE OF A THRONBOXANE RECEPTOR ANTAGONIST IN PREGNANCY-INDUCED HYPERTENSION AND RELATED CONDITIONS
This invention relates to a new medical use for a group of thromboxane receptor blocking agents. In particular, it relates to the use of such agents in the therapy or prophylaxis of conditions associated with vasoconstriction and/or platelet aggregation in the uteroplacental circulation and/or excessive synthesis of thromboxane
A2 in pregnant females.
In EP-A-0296802 we describe compounds having the general formula (1)
wherein R1 is a hydrogen atom or a methyl group;
X is cis or trans -CH=CH- or -CH2CH2-, m is 2, 3 or 4 and n
is 1; or X is trans -CH=CH-, m is zero and n is 3;
Y is a saturated heterocyclic amino group (attached to the
cyclopentane ring via the nitrogen atom) which a has 5-8 ring
members and (a) optionally contains in the ring -0-, -S-, -S02- or -NR3a; and/or (b) is optionally substituted by one
or more alkyl groups;
Alk is a straight or branched C15 alkyl chain; X is zero or 1;
p is zero, 1, 2, 3 or 4;
R2 is a hydroxyl group or a group selected from -OCOR3,
-C02R3, -CONR3R4, -502NR3R4, -NHCOR3, -NHSO2R5, -502R5, -SR5, -NR3R4, -CORS,-NHCONR3R4 and -NHCSNH2;
R3, R3a and R4, which may be the same or different,
represent a hydrogen atom or a C1-4 alkyl or C7-1o aralkyl
group; and
R5 is a C14 alkyl group; and the physiologically acceptable salts, solvates and cyclodextrin complexes thereof.
We have stated therein that such compounds inhibit thromboxane A2 and endoperoxide mediated aggregation of blood platelets and contraction of vascular muscle and are thus of particular interest as anti-thrombotic agents.
We have now found that the compounds of EP-A-O296802 are of use in the therapy or prophylaxis of conditions associated with vasoconstriction and/or platelet aggregation in the uteroplacental circulation and/or excessive synthesis of thromboxane A2 in pregnant females. Conditions which are covered by this pathophysiology include pregnancy-induced hypertension, preeclampsia, eclampsia and intrauterine growth retardation.
Thus, according to one aspect of the present invention, we provide a compound of formula (1) or a physiologically acceptable salt, solvate or cyclodextrin complex thereof for use in the manufacture of a medicament for the therapy or prophylaxis of conditions associated with vasoconstriction and/or platelet aggregation in the uteroplacental circulation and/or excessive synthesis of thromboxane A2 in a pregnant female subject.
It is preferable to employ the compound of formula (1) or a physiologically acceptable salt or solvate thereof in the form of a formulation. The present invention therefore also provides a composition for use in combatting conditions associated with vasoconstriction and/or platelet aggregation in the uteroplacental circulation and/or excessive synthesis of thromboxane A2 in pregnant females comprising a compound of formula (1) or a physiologically acceptable salt, solvate or cyclodextrin complex together, where desirable, with one or more carriers or excipients.
In a further aspect of the invention, we provide a method of treatment of a pregnant female subject for combatting conditions associated with vasoconstriction and/or platelet aggregation in the uteroplacental circulation and/or excessive synthesis of thromboxane
A2 by therapy or prophylaxis which method comprises administering to the subject an effective amount of a compound of formula (1) or a physiologically acceptable salt or solvate thereof.
It will, of course, be appreciated that the aforementioned pregnancy-induced hypertension, preeclampsia and eclampsia are conditions which are not only deleterious to the female subject but which may also lead to growth retardation of the unborn foetus and even foetal loss. Contraction of umbilical vessels by thromboxane A2 may also lead to neonatal complications during parturition.
Suitable salts of a compound of formula (1) include acid addition salts derived from inorganic and organic acids such as hydrochlorides, hyrobromides, sulphates, phosphates, maleates, tartrates, citrates, benzoates, 2chlorobenzoates, p-toluenesulphonates, methanesulphonates, salicylates, fumarates, lactates, hydroxynaphthalenecarboxylates (e.g. l-hydroxy- or 5-hydroxy-2-naphthalenecarboxylates) or furoates, or salts with suitable bases such as alkali metal (e.g. sodium and potassium), alkaline earth metal (e.g. calcium or magnesium), ammonium and substituted ammonium (e.g. dimethylammonium, triethylammonium, 2-hydroxyethyl dimethylammonium, piperazinium,
N,N-dimethylpiperazinium, piperidinium, ethylenediamine and choline) salts. A preferred salt of the compounds of formula (1) is the hydrochloride salt.
A preferred group of compounds of formula (1) for use according to the present invention are those of formula (2)
and the physiologically acceptable salts, solvates and cyclodextrin complexes thereof, wherein X is cis or trans -CH=CH- or -CH SH2-, Y is a saturated heterocyclic amino group which has 5, 6 or 7 ring members and optionally contains in the ring -0-, Alk is a straight C1,3alkyl chain, p is zero, 1 or 2 and R2 is as defined in formula (1) above.
Preferred compounds of formula (2) are those in which R2 represents -OH, -CO2H, -CONH2, -NHCOCH3, -NHS02CH3, -S02NHCH3, -NHCONH2 or -S02 CH3 . Compounds of formula (2) in which the group (CH2)pR2 is attached at the ortho position of the phenyl group in the rest of the molecule are particularly preferred.
In general, preferred compounds of formulae (1) and (2) for use according to the present invention are those in which the carbon atom carrying the a-side chain [i.e. the -O(CH2)nX(CH2)mCO2R1 group in formula (1) and the -OCH2XCH2CH2CO2H group in formula (2)] is in the R configuration (including mixtures containing this isomer).
A preferred compound of formula (1) for use according to the present invention is [la(Z),2ss,5ss]-(+)-6-[[2-(hexahydro-lH-azepin-l- yl)-5-[[2'-(hydroxymethyl)[l,l'-biphenyl]-4-yl]methoxy]cyclopentyl] oxy]-4-hexenoic acid and its physiologically acceptable salts, solvates and cyclodextrin (e.g. B-cyclodextrin) complexes.
The compounds of formula (1) and physiologically acceptable salts, solvates and cyclodextrin complexes thereof and pharmaceutical compositions containing them may be prepared according to the methods described in EP-A-0296802.
The precise dose of the compound of formula (1) or a physiologically acceptable salt or solvate thereof to be administered according to the present invention, the time to begin treatment and the length of the course of treatment will, of course, depend on a number of factors including, for example, the condition of the patient, the specific condition requiring treatment and its severity and the route of administration and will ultimately be at the discretion of the attendant physician or vetinarian. An effective dose, however, is likely to be in the range from 0.05 to 10 mg/kg body weight of patient, l to 4 times daily.
The following examples are provided in illustration of the present invention and should not be construed in any way as constituting a limitation thereof.
The term "active ingredient" as used below refers to a compound of formula (I) and may be, for example, [la(Z),2B,5B]-(+)-6-2- (hexahydro-lH-azepin-l-yl)-5-[[2'-(hydroxymethyl)[l,l'-biphenyl]- 4-yl]methoxy]cyclopentyl]oxy]-4-hexenoic acid or a physiologically acceptable salt, solvate or cyclodextrin (e.g. p-cyclodextrin) complex thereof.
Pharmaceutical Examples (i) 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 ss it is dependent upon the dose level and physical characteristics of the active ingredient.
A. Direct Compression mg/tablet
Active Ingredient 100.00
Microcrystalline Cellulose NF 298.00
Magnesium Stearate BP 2.00
Compression Weight 400.00mug The active ingredient is sieved through a 2501un sieve, blended with the excipients and compressed using 10.Omm punches. Tablets of other strengths may be prepared by altering the compression weight and using punches to suit.
B. Wet Granulation mg/tablet
Active Ingredient 100.00
Lactose BP 238.00
Starch BP 40.00
Pregelatinised Maize Starch BP 20.00
Magnesium Stearate BP 2.00
Compressed Weight 400.00mg
The active ingredient is seived through a 250cam sieve and blended with the lactose, starch and pregelatinised starch. The mixed powders are moistened with purified water, granules are made, dried, screened and blended with the magnesium stearate. 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 hydroxypropyl methyl cellulose using standard techniques. Alternatively the tablets may be sugar coated.
(ii) Capsules
mg/capsule
Active Ingredient 100.00 * STA-RX 1500 99.00
Magnesium Stearate BP 1.00
Fill Weight 200.00mg * A form of directly compressible starch supplied by Colorcorn
Ltd., Orpington, Kent.
The active ingredient is sieved through a 250pm 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.
(iii) Inhalation cartridges
mg/cartridge
Active Ingredient (micronised) 3.00
Lactose BP to 25.00
The active ingredient 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.
(iv) Metered Dose Pressurised Aerosol
mg/metered Per Can
dose
Active Ingredient
(micronised) 0.500 120mg Oleic Acid BP 0.050 l2mg Trichlorofluoromethane BP 22.25 5.34g
Dichlorodifluoromethane BP 60.90 14.629
The active ingredient 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 0 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.
(v) Syrup
mg/5ml dose
Active Ingredient 100.00
Buffer
Flavour
Colour as required
Preservative
Thickening Agent
Sweetening Agent
Purified Water to 5.00 ml
The active ingredient, buffer, flavour, colour, preservative, thickening agent and sweetening agent are dissolved in some of the water, the solution is adjusted to volume and mixed. The syrup produced is clarified by filtration.
(vi) Injection for Intravenous Administration
Active Ingredient 50mug Water for injections BP to 5ml
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 an sutoclave 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.
(vi) Suspensions
mg/5ml dose
Active Ingredient 100.00
Aluminium monostearate 75.00
Sweetening agent )
Flavour ) as required
Colour )
Fractionated coconut oil to 5.00ml The aluminium monostearate is dispensed in about 90S of the fractionated coconut oil. The resulting suspension is heated to 1150 while stirring and then cooled. The sweetening agent, flavour and colour are added and the active ingredient is suitably dispersed. The suspension is made up to volume with the remaining fractionated coconut oil and mixed.
Claims (5)
1. The use of a compound of formula (1)
wherein R1 is a hydrogen atom or a methyl group;
X is cis or trans -CH=CH- or -CH2CH2-, m is 2, 3 or 4 and n
is 1; or X is trans -CH=CH-, m is zero and n is 3;
Y is a saturated heterocyclic amino group (attached to the
cyclopentane ring via the nitrogen atom) which a has 5-8 ring
members and (a) optionally contains in the ring -0-, -S-, -S02- or -NR3a; and/or (b) is optionally substituted by one
or more alkyl groups;
Alk is a straight or branched C15 alkyl chain; X is zero or 1;
p is zero, 1, 2, 3 or 4;
R2 is a hydroxyl group or a group selected from -OCOR3, -CO2R3, -CONR3R4, -S02NR3R4, -NHCOR3, -NHSO2R5, -502R -SR5, -NR3R4, -COR5,-NHCONR3R4 and -NHCSNH2;
R3, R3a and R4, which may be the same or different,
represent a hydrogen atom or a C14 alkyl or C7-10 aralkyl
group; and
R5 is a C14 alkyl group; or a physiologically acceptable salt, solvate or cyclodextrin complex thereof in the manufacture of medicaments for the therapy or prophylaxis of conditions associated with vasoconstriction and/or platelet aggregation in the uteroplacental circulation and/or excessive synthesis of thromboxane A2 in a pregnant female subject.
2. Use as claimed in Claim 1 for the therapy or prophylaxis of pregnancy-induced hypertension, preeclampsia, eclampsia or intrauterine growth retardation.
3. Use as claimed in Claim 1 or Claim 2 in which the compound of formula (1) is [la(Z),2ss,5g]-(+)-6-[[2-(hexahydro-lH-azepin-l- yl)-5-[ [2 '-(hydroxymethyl) [l,l'-biphenyl)-4-yl]methoxy]cyclopentyl] oxy]-4-hexenoic acid or a physiologically acceptable salt, solvate or cyclodextrin complex thereof.
4. Use as claimed in any preceding claim in which the medicament is in a form suitable for oral or parenteral administration.
5. Use as claimed in Claim 4 wherein said medicament comprises a compound of formula (1) or a physiologically acceptable salt, solvate or cyclodextrin complex thereof in an amount sufficient to administer 0.05 to lOmg/kg body weight per day to said pregnant female subject.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB888814728A GB8814728D0 (en) | 1988-06-21 | 1988-06-21 | Medicaments |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB8913875D0 GB8913875D0 (en) | 1989-08-02 |
| GB2219938A true GB2219938A (en) | 1989-12-28 |
Family
ID=10639068
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB888814728A Pending GB8814728D0 (en) | 1988-06-21 | 1988-06-21 | Medicaments |
| GB8913875A Withdrawn GB2219938A (en) | 1988-06-21 | 1989-06-16 | Use of a thromboxane receptor antagonist in pregnancy-induced hypertension |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB888814728A Pending GB8814728D0 (en) | 1988-06-21 | 1988-06-21 | Medicaments |
Country Status (1)
| Country | Link |
|---|---|
| GB (2) | GB8814728D0 (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0296802A1 (en) * | 1987-06-22 | 1988-12-28 | Glaxo Group Limited | Aminocyclopentyl ethers and their preparation and pharmaceutical formulation |
-
1988
- 1988-06-21 GB GB888814728A patent/GB8814728D0/en active Pending
-
1989
- 1989-06-16 GB GB8913875A patent/GB2219938A/en not_active Withdrawn
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0296802A1 (en) * | 1987-06-22 | 1988-12-28 | Glaxo Group Limited | Aminocyclopentyl ethers and their preparation and pharmaceutical formulation |
Also Published As
| Publication number | Publication date |
|---|---|
| GB8913875D0 (en) | 1989-08-02 |
| GB8814728D0 (en) | 1988-07-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5578632A (en) | Medicaments for the treatment of gastrointestinal dysfunction | |
| CZ282679B6 (en) | The use of 2-amino-6-n-propylamino-4,5,6,7-tetrahydrobenzothiazole for preparing a pharmaceutical preparation | |
| US4489080A (en) | Process for analgesic treatment | |
| AU603895B2 (en) | Improved flunarizine-containing compositions | |
| EP0070714B1 (en) | Use of ibuprofen or flurbiprofen for the manufacture of a medicament for treating respiratory disorders | |
| IL106743A (en) | Tablets with improved bioavailability of the active material clodronic acid | |
| US4439451A (en) | Treatment of the blood-brain barrier with flurbiprofen | |
| US4331687A (en) | Treatment of Parkinson's disease | |
| CA1336686C (en) | Method of inhibiting onset of or treating migraine headache using a thromboxane a- receptor antagonist | |
| US4439450A (en) | Treatment of the blood-brain barrier with ibuprofen | |
| CA1313500C (en) | Pharmaceutical compositions for the treatment of occlusive vascular diseases | |
| GB2219938A (en) | Use of a thromboxane receptor antagonist in pregnancy-induced hypertension | |
| US4447451A (en) | Treatment of adult respiratory distress syndrome | |
| EP0085544A1 (en) | The use of aralkanoic acids and esters for the treatment of myelogenous leukemia | |
| US4443476A (en) | Treatment of adult respiratory distress syndrome | |
| US6372763B1 (en) | Treatment and prevention of cardiac disorders using selective serotonin re-uptake inhibitors (SSRI) | |
| GB2219939A (en) | Use of a thromboxane receptor antagonist in renal diseases and dysfunction | |
| GB2127406A (en) | Piperidinylcyclopentanolheptenoic acid salt | |
| US5081153A (en) | Sterile parenteral composition | |
| US4968703A (en) | Pharmaceutical compositions for the treatment of occlusive vascular diseases | |
| US5015648A (en) | Use of a thromboxane receptor antagonist in pregnancy-induced hypertension and related conditions | |
| WO1997023477A1 (en) | Dibenzothiepin derivatives and pharmaceutical compositions | |
| US4393054A (en) | Method of treating cardiac arrhythmia | |
| IE43955B1 (en) | Pharmaceutical composition and dosage units thereof | |
| CZ200085A3 (en) | Medicament against heart disorders and pharmaceutical preparation containing SSRI |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |