WO1997049699A1 - Derives piperidine de l'acide acetique et leur utilisation dans le traitement des troubles thrombotiques - Google Patents

Derives piperidine de l'acide acetique et leur utilisation dans le traitement des troubles thrombotiques Download PDF

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Publication number
WO1997049699A1
WO1997049699A1 PCT/EP1997/003196 EP9703196W WO9749699A1 WO 1997049699 A1 WO1997049699 A1 WO 1997049699A1 EP 9703196 W EP9703196 W EP 9703196W WO 9749699 A1 WO9749699 A1 WO 9749699A1
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WO
WIPO (PCT)
Prior art keywords
piperidin
formula
compound
indazol
acetic acid
Prior art date
Application number
PCT/EP1997/003196
Other languages
English (en)
Inventor
David George Allen
Colin David Eldred
Brian David Judkins
William Leonard Mitchell
Original Assignee
Glaxo Group Limited
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from GBGB9613095.0A external-priority patent/GB9613095D0/en
Priority claimed from GBGB9613017.4A external-priority patent/GB9613017D0/en
Priority claimed from GBGB9613018.2A external-priority patent/GB9613018D0/en
Priority to IL12746497A priority Critical patent/IL127464A0/xx
Priority to PL97330797A priority patent/PL330797A1/xx
Priority to AU32611/97A priority patent/AU3261197A/en
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Priority to BR9709930A priority patent/BR9709930A/pt
Priority to EP97928243A priority patent/EP0912555A1/fr
Priority to JP10502284A priority patent/JP2000512648A/ja
Priority to APAP/P/1998/001417A priority patent/AP9801417A0/en
Priority to EA199801015A priority patent/EA199801015A1/ru
Publication of WO1997049699A1 publication Critical patent/WO1997049699A1/fr
Priority to IS4924A priority patent/IS4924A/is

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems

Definitions

  • This invention relates to acetic acid derivatives, to processes for their preparation, to pharmaceutical compositions containing such compounds and to their use in medicine.
  • glycoprotein complex Gp llb/llla is the fibrinogen binding site on platelets that mediates the adhesive function required for platelet aggregation and thrombus formation.
  • Gp llb/llla the fibrinogen binding site on platelets that mediates the adhesive function required for platelet aggregation and thrombus formation.
  • the current invention thus provides a compound of formula (I)
  • Y represents a group
  • R° represents SO2Me or CONH2; and R represents SO2Me.
  • the present invention provides a compound of formula (lb)
  • the present invention provides a compound of formula (Ic)
  • Suitable compounds of the invention include
  • Still further suitable compounds of the invention include: ⁇ 4-[1 -methanesulfonyl-6-(2-piperidin-4-yl-(E)-vinyl)-1 H-indazol-3-yl]-piperidin-1 - yl ⁇ -acetic acid; ⁇ 4-[1 -methanesulfonyl-6-(2-piperidin-4-yl-ethyl)-1 H-indazol-3-yl]-piperidin-1 -yl ⁇ - acetic acid; and salts, solvates, and physiologically functional derivatives thereof.
  • a preferred compound of the invention is ⁇ 4-[3-methanesulfonyl-5-(2-pipe ⁇ din-4- yl-ethyl)-indazol-1-yl]-piperidin-1-yl ⁇ -acetic acid or a salt, solvate, or physiologically functional derivative thereof.
  • a further preferred compound of the invention is ⁇ 4-[3-carbamoyl-5-(2-piperidin- 4-yl-ethyl)-indazol-1-yl)-piperidin-1-yl ⁇ -acetic acid or a salt, solvate, or physiologically functional derivative thereof.
  • a yet further preferred compound of the invention is ⁇ 4-[1-methanesulfonyl-6-(2- piperidin-4-yl-ethyl)-1 H-indazo!-3-yl]-piperidin-1-yl ⁇ -acetic acid, or a salt, solvate, or physiologically functional derivative thereof.
  • Salts and solvates of compounds of formula (I) which are suitable for use in medicine are those wherein the counterion or associated solvent is pharmaceutically acceptable.
  • salts and solvates having a non- pharmaceutically acceptable counterion or associated solvent are within the scope of the present invention having use as intermediates in the preparation of compounds of formula (I) and their pharmaceutically acceptable salts, solvates, and physiologically acceptable derivatives.
  • Suitable pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts formed with inorganic or organic acids (for example hydrochlorides, hydrobromides, sulphates, phosphates, benzoates, naphthoates, hydroxynaphthoates, p-toluenesulphonates, methanesulphonates, sulphamates, ascorbates, tart rates, salicylates, succinates, lactates, glutarates, glutaconates, acetates, tricarballylates, citrates, fumarates and maleates) and inorganic base salts such as alkali metal salts (for example sodium salts). Hydrochloride salts of the compounds of formula (I) are preferred for certain modes of administration. Other salts of the compounds of formula (I) include salts formed with trifluoro-acetic acid.
  • Suitable pharmaceutically acceptable solvates of the compounds of formula (I) include hydrates.
  • alkyl' as a group or part of a group means a straight or branched chain alkyl group, for example a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl or t-butyl group. It is to be understood that the present invention encompasses all isomers of the compounds of formula (I) and their salts, solvates, and physiologically functional derivatives, including all geometric, tautomeric and optical forms, and mixtures thereof (e.g. racemic mixtures).
  • pharmaceutically acceptable derivative is meant a pharmaceutically acceptable salt, solvate, or physiologically functional derivative of a compound of formula (I) as hereinbefore defined.
  • the compounds of formula (I) and their pharmaceutically acceptable derivatives are of interest for use in human and veterinary medicine, particularly in the treatment of thrombotic disorders.
  • thrombotic disorders include occlusive vascular diseases such as myocardial infarction, cardiac fatalities, angina, transient ischaemic attacks and thrombotic stroke, arteriosclerosis, vessel wall disease, peripheral vascular disease, nephropathy, retinopathy, postoperative thrombosis, pulmonary embolism, deep vein thrombosis and retinal vein thrombosis.
  • occlusive vascular diseases such as myocardial infarction, cardiac fatalities, angina, transient ischaemic attacks and thrombotic stroke
  • arteriosclerosis vessel wall disease
  • peripheral vascular disease nephropathy, retinopathy
  • postoperative thrombosis pulmonary embolism
  • deep vein thrombosis and retinal vein thrombosis.
  • the compounds of formula (I) and their pharmaceutically acceptable derivatives are also of interest for use in the prophylactic treatment of peri- and postoperative complications following organ transplantation (particularly cardiac and renal), coronary artery bypass, peripheral artery bypass
  • the compounds of formula (I) and their pharmaceutically acceptable derivatives may also be useful for the treatment of other conditions in which the glycoprotein complex Gp llb/llla or other integrin receptors are implicated.
  • the compounds of formula (I) and their pharmaceutically acceptable derivatives may potentiate wound healing and be useful in the treatment of bone conditions caused or mediated by increased bone resorption.
  • bone diseases are known in the art and include osteoporosis, hypercalcaemia of malignancy, osteopenia due to bone metastases, pe ⁇ odontal disease, hyperparathyroidism, penarticular erosions in rheumatoid arthritis, Paget's disease, immobilization-induced osteopenia and glucocorticoid treatment
  • the compounds of formula (I) and their pharmaceutically acceptable derivatives may also be useful for the treatment of certain cancerous diseases, for example, to prevent or delay metastasis in cancer
  • a compound of formula (I) or a pharmaceutically acceptable derivative thereof for use in human or veterinary medicine, particularly for use in the treatment of thrombotic disorders
  • a compound of formula (I) or a pharmaceutically acceptable derivative thereof for use in the treatment of a condition which is mediated through the Glycoprotein complex Gpllb/llla or other integrin receptor
  • a method of treating a human or animal subject suffering from a condition which is mediated through the Glycoprotein complex Gpllb/llla or other integrin receptor which comprises administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof
  • a method of treating a human or animal subject suffering from a thrombotic disorder comprises administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof It is to be understood that reference to “treatment” includes both treatment of established symptoms and prophylactic treatment, unless explicitly stated otherwise.
  • the compounds of formula (I) and their pharmaceutically acceptable derivatives may advantageously be used in conjunction with one or more other therapeutic agents.
  • suitable agents for adjunctive therapy include thrombolytic agents or any other compound stimulating thrombolysis or fibrinolysis and cytotoxic drugs. It is to be understood that the present invention covers the use of a compound of formula (I) or a pharmaceutically acceptable derivative thereof in combination with one or more other therapeutic agents.
  • compositions comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof adapted for use in human or veterinary medicine.
  • Such compositions may conveniently be presented for use in conventional manner in admixture with one or more physiologically acceptable carriers or excipients.
  • the compounds of formula (I) and their pharmaceutically acceptable derivatives may be formulated for administration in any suitable manner.
  • the compounds may, for example, be formulated for topical administration or administration by inhalation or, more preferably, for oral, transdermal or parenteral administration.
  • the pharmaceutical composition may take the form of, for example, tablets, capsules, powders, solutions, syrups or suspensions prepared by conventional means with acceptable excipients.
  • the pharmaceutical composition may be given in the form of a transdermal patch, such as a transdermal iontophoretic patch.
  • a transdermal patch such as a transdermal iontophoretic patch.
  • the present invention provides an iontophoretic delivery device (for example, an iontophoretic patch) comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof, suitably a pharmaceutically acceptable salt thereof, for example, a hydrochloride salt.
  • Iontophoretic devices and systems as such are known in the art, for instance from, WO-A 9116946, WO-A 9116944, WO-A 9116943, WO-A 9115261 , WO-A 9115260, WO-A 9115259, WO-A 9115258, WO-A 9115257, WO-A 9115250,
  • WO-A 9109645 WO-A 9108795, WO-A 9004433, WO-A 9004432, WO-A 9003825, EP-A 254965, US 4717378, EP-A 252732 and GB-A 2239803, which are incorporated herein by reference.
  • the pharmaceutical composition may be given as an injection or a continuous infusion (e.g. intravenously, intravascularly or subcutaneously).
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
  • formulatory agents such as suspending, stabilising and/or dispersing agents.
  • For administration by injection these may take the form of a unit dose presentation or as a multidose presentation preferably with an added preservative.
  • the active ingredient may be in powder form for reconstitution with a suitable vehicle.
  • the compounds of formula (I) and their pharmaceutically acceptable derivatives may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • the compounds of formula (I) and their pharmaceutically acceptable derivatives may also be used in combination with other therapeutic agents.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof together with a further therapeutic agent, in particular a thrombolytic agent.
  • a further therapeutic agent in particular a thrombolytic agent.
  • the combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention.
  • the individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
  • a proposed daily dosage of a compound of formula (I) for the treatment of man is 0.01 mg/kg to 30 mg/kg, which may be conveniently administered in 1 to 4 doses.
  • the precise dose employed will depend on the age and condition of the patient and on the route of administration.
  • a daily dose of 0.1 mg/kg to 10mg/kg may be suitable for systemic administration.
  • compounds of formula (I) may be prepared by reacting a compound of formula (II)
  • Y is defined as for formula (I) and R represents a leaving group, for example, chloro, bromo or iodo, or a -OSO 2 CF 3 group, with the compound of formula (III) or a protected derivative thereof, in the presence of a transition metal catalyst and at elevated temperature.
  • Suitable transition metal catalysts include palladium catalysts, such as a palladium triarylphosphine catalyst.
  • Suitable temperatures are from about 20 to about 160°C, such as 80 to 120°C, or the reflux temperature of the solvent.
  • the reaction is effected in the presence of a base, such as a tertiary amine, and in a solvent, such as a polar solvent, for example ⁇ /, ⁇ /-dimethylformamide.
  • compounds of formula (I) may be prepared by interconversion, utilising other compounds of formula (I) as precursors.
  • the hydrogenation may be effected in the presence of a transition metal catalyst, such as Raney Nickel, or a palladium, platinum or rhodium catalyst.
  • a transition metal catalyst such as Raney Nickel
  • a palladium, platinum or rhodium catalyst effected in a solvent, such as an alcohol (e.g ethanol)
  • hydrogenation may be effected chemically, for example, by using diimide.
  • diimide is generated in situ from a suitable salt, such as diazenedicarboxylic acid, dipotassium salt, and the reaction is effected in the presence of an acid, such as acetic acid, and a solvent, such as an alcohol (e.g. methanol).
  • Another process (C) for preparing compounds of formula (I) thus comprises deprotecting a compound of formula (IV) wherein X and Y are as defined for a compound of formula (I), P' is a carboxyl group or a protected carboxyl group and P" is hydrogen or an amino protecting group, provided that when P' is a carboxyl group, P" is not hydrogen and when P' is a hydrogen, P" is not a carboxyl group.
  • Compounds of formula (IV) may be prepared by processes (A) and (B) as described above, or using any appropriate methods, such as those described in the examples.
  • compounds of formula (I) may be prepared from protected carboxyl derivatives of compounds of formula (I), ie. compounds of formula (IV) wherein P' is a protected carboxyl group.
  • compounds of formula (I) may be prepared from protected amino and/or carboxyl derivatives of compounds of formula (I), ie. compounds of formula (IV) wherein P" is an amino protecting group.
  • the protecting groups used in the preparation of compounds of formula (I) may be used in conventional manner. See, for example, those described in 'Protective Groups in Organic Synthesis' by Theodora W. Green, second edition, (John Wiley and Sons, 1991 ), which also describes methods for the removal of such groups.
  • carboxylic acid ester groups such as carboxylic acid alkyl or aralkyl esters, for example where the alkyl or aralkyl portion of the ester function is methyl, ethyl, tert-butyl, methoxymethyl, benzyl, diphenylmethyl, triphenylmethyl or p-nitrobenzyl.
  • ester is an unbranched alkyl (e.g. methyl) ester deprotection may be effected under conditions of either basic hydrolysis, for example using lithium hydroxide, or acidic hydrolysis, for example using hydrochloric acid.
  • Tert-butyl and triphenylmethyl ester groups may be removed under conditions of acid hydrolysis, for example using formic or trifluoroacetic acid at room temperature or using hydrochloric acid in acetic acid.
  • Benzyl, diphenylmethyl and nitrobenzyl ester groups may be removed by hydrogenolysis in the presence of a metal catalyst (e.g. palladium).
  • Particular amino protecting groups include, for example, aralkyl groups such as benzyl, diphenylmethyl or triphenylmethyl groups; and acyl groups such as N- benzyloxycarbonyl, t-butoxycarbonyl or trifluoroacetyl groups. Removal of acyl groups may be effected under standard conditions as referred to above.
  • the required isomer may conveniently be separated using preparative high performance liquid chromatography (h.p.l.c.) applied to the final title compounds of processes (A) to (C) above or applied prior to any final deprotection step in said processes.
  • preparative high performance liquid chromatography h.p.l.c.
  • the compounds of formula (IV) are also an important aspect of the present invention and include 4- ⁇ 2-[1-(1-tert-butoxycarbonylmethyl- piperidin-4-yl)-3-methane-sulfonyl-1H-indazol-5-yl]-(E)-vinyl ⁇ -piperidi ⁇ e-1- carboxylic acid tert-butyl ester, 1-(1-tert-butoxycarbonylmethyl-piperidin-4-yl)-5- [2-(1-tert-butoxycarbonyl-piperidin-4-yl)-(E)-vinyl]-1H-indazole-3-carboxylic acid methyl ester, 4- ⁇ 2-[1-(1-tert-butoxycarbonylmethyl-piperidin-4-yl)-3-carbamoyl- 1 H-indazol-5-yl]-(E)-vinyl ⁇ -piperidine-1 -carboxylic acid tert-butyl ester, and
  • acids of the invention are isolated following work-up as acid addition salts, e.g. trifluoroacetate or hydrochloride salts.
  • Pharmaceutically acceptable acid addition salts of the compounds of the invention may be prepared from the corresponding trifluoroacetate salts by exchange of ion using conventional means, for example by neutralisation of the trifluoroacetate salt using a base such as aqueous sodium hydroxide, followed by addition of a suitable organic or inorganic acid, for example, hydrochloric acid.
  • pharmaceutically acceptable acid addition salts may be prepared directly by effecting deprotection with the appropriate organic or inorganic acid, for example, hydrochloric acid.
  • Inorganic base salts of the compounds of the invention may also be prepared from the corresponding trifluoroacetate salts by addition of a suitable strong base such as sodium hydroxide.
  • Solvates (e.g. hydrates) of a compound of the invention may be formed during the work-up procedure of one of the aforementioned process steps.
  • OxoneTM (182.2 g) was added portionwise to a stirred suspension of 5-bromo- 3-methylsulfanyl-1 H-indazole (36.0 g) in methanol (450 ml) and water(135 ml). The reaction mixture was stirred at ambient temperature for 3h, concentrated in vacuo and the resulting oil partioned between ethyl acetate and water. The biphasic mixture was separated, the aqueous phase extracted with ethyl acetate, the combined organic extracts were washed with 8 %w/w aqueous sodium bicarbonate and water, dried (MgSO4) and evaporated in vacuo to give the title compound as a off-white solid (38.8 g). Mass spectrum m/z 293.9 (MNH4 + )
  • reaction mixture was evaporated in vacuo and the residue purified by preparative HPLC, eluting with water : acetonitrile : trifluoroacetic acid (gradient 90:10:0.1 to 25:75:0, 20 min, detection 260nm, RT 13 min), to give a white solid which was dissolved in 2N hydrochloric acid and evaporated in vacuo to give the a white solid.
  • the hydrochloric acid procedure was repeated twice. The white solid was trituated with acetone (100 ml) and the suspension evaporated in vacuo.
  • silica was applied as a plug to a flash column of silica gel, eluting with cyclohexane: ethyl acetate (gradient 19:1 to 3:1 ) to give firstly an isomer followed by the title product (22.8g).
  • T.l.c. SiO 2 cyclohexane: EtOAc, 7:3
  • Ref 4 G.A. Bistrocchi et_al., Farmaco. Ed. Sci., 1981 , 36, 315.
  • Trifluoroacetic acid 100ml was added to 5-bromo-1-(1-tert-butoxycarbonyl- piperidin-4-yl)-1H-indazole-3-carboxylic acid methyl ester (22.75g) at 23° during 1 min. After 1 h, the mixture was evaporated in vacuo and the co-evaporated with dichloromethane to give the title product (28.05g) as a light yellow solid.
  • a suspension of 5-bromo-3-formyl-1 H-indazole (143g) was heated to 65-70° in a solution of hydroxylamine-O-sulfonic acid (93.4) in water (1.4L) for 16h. The mixture was cooled to 20° over 1h, filtered and the filter cake washed with water and dried at 45°C to give a solid (146g). This solid was heated at reflux in toluene (3.65L) for 1h and filtered at 90°C. The filtrate was re-heated to give a solution, stirred and cooled to 10°. The suspension is filtered, the filter cake washed with toluene and dried to give the title compound as a pale brown solid
  • the mixture was concentrated to 100g weight and purified by preparative HPLC (Kromsil C8, 10 ⁇ m, reverse phase), eluting with water-acetonitrile-trifluoroacetic acid, 90:10:0.1 %v/v (A) and water- acetonitrile, 25:75 (B) to give a white solid (26g).
  • the solid (23.6g) was dissolved in HPLC grade water (60ml) and adjusted to pH10 with 880 ammonia solution (20ml) added at 20-30° over 0.5h.
  • the milky-white suspension was stirred at 20° for 1.5h and filtered.
  • the filter cake was washed with water with sucking under vacuum for 10min between each wash, dried at 40° for 18h and left to equilibrate under ambient conditions for 4h to give the title compound as a white powder (12.05g).
  • the compound of the invention microcrystalline cellulose, lactose and cross- linked polyvinylpyrrolidone are sieved through a 500 micron sieve and blended in a suitable mixer.
  • the magnesium stearate is sieved through a 250 micron sieve and blended with the active blend.
  • the blend is compressed into tablets using suitable punches.
  • Compound of the invention 5.0mg Lactose 165.0mg Pregelatinised Starch 20.0mg
  • the compound of the invention, lactose and pregelatinised starch are blended together and granulated with water.
  • the wet mass is dried and milled.
  • the magnesium stearate and cross-linked polyvinylpyrrolidone are screened through a 250 micron sieve and blended with the granule.
  • the resultant blend is compressed using suitable tablet punches.
  • Example 8 Capsules a) Compound of the invention 5.0mg Pregelatinised Starch 193.0mg Magnesium Stearate 2.0mq Fill weight 200.0mg
  • the compound of the invention and pregelatinised starch are screened through a 500 micron mesh sieve, blended together and lubricated with magnesium stearate, (meshed through a 250 micron sieve). The blend is filled into hard gelatine capsules of a suitable size.
  • Compound of the invention 5.0mg Lactose 177.0mg Polyvinylpyrrolidone 8.0mg Cross-linked polyvinylpyrrolidone 8.0mg Magnesium Stearate 2.0mo
  • the compound of the invention and lactose are blended together and granulated with a solution of polyvinylpyrrolidone.
  • the wet mass is dried and milled.
  • the magnesium stearate and cross-linked polyvinylpyrrolidone are screened through a 250 micron sieve and blended with the granules.
  • the resultant blend is filled into hard gelatine capsules of a suitable size.
  • Example 9 - Syrup a) Compound of the invention 5.0mg Hydroxypropyl Methylcellulose 45.0mg Propyl Hydroxybenzoate 1.5mg
  • the hydroxypropyl methylcellulose is dispersed in a portion of hot purified water together with the hydroxybenzoates and the solution is allowed to cool to ambient temperature.
  • the saccharin sodium flavours and sorbitol solution are added to the bulk solution.
  • the compound of the invention is dissolved in a portion of the remaining water and added to the bulk solution. Suitable buffers may be added to control the pH in the region of maximum stability.
  • the solution is made up to volume, filtered and filled into suitable containers.
  • Water for injections B. P. to 100.00 Sodium chloride may be added to adjust the tonicity of the solution and the pH may be adjusted to that of maximum stability and/or to facilitate solution of the compound of the invention using dilute acid or alkali or by the addition of suitable buffer salts. Antioxidants and metal chelating salts may also be included.
  • the solution is clarified, made up to final volume with water and the pH remeasured and adjusted if necessary, to provide 10mg/ml of the compound of formula (I).
  • the solution may be packaged for injection, for example by filling and sealing in ampoules, vials or syringes.
  • the ampoules, vials or syringes may be aseptically filled (e.g. the solution may be sterilised by filtration and filled into sterile ampoules under aseptic conditions) and/or terminally sterilised (e.g. by- heating in an autoclave using one of the acceptable cycles).
  • the solution may be packed under an inert atmosphere of nitrogen.
  • the solution is filled into ampoules, sealed by fusion of the glass and terminally sterilised.
  • Further sterile formulations are prepared in a similar manner containing 0.5, 2.0 and 5% w/v of the compound of formula (I), so as to provide respectively ⁇ , 20 and ⁇ Omg/ml of the compound of formula (I).
  • Inhibition of platelet aggregation by compounds of the invention was determined according to the following procedure. Citrated whole blood (1 part 3.8% w/v trisodium citrate; 9 parts blood) was obtained from human volunteers, free of medication for at least 10 days prior to donation. The blood was treated with aspirin (0.1 mM) and prostacyclin (0.06 ⁇ M) prior to centrifugation (1400g, 4 minutes, 20°C). The supernatant platelet-rich plasma (PRP) was isolated and further centrifuged (1400g, 10 minutes, 20°C) to sediment the platelets.

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  • Organic Chemistry (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Animal Behavior & Ethology (AREA)
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Abstract

L'invention concerne les composés de la formule (I), ou un sel, un solvate, ou un dérivé physiologiquement fonctionnel de ces derniers, où X représente CH2-CH2 ou CH=CH; Y représente un groupe de la formule (a) ou (b) où R0 représente SO¿2?Me ou CONH2 et R?1¿ représente SO¿2?Me. L'invention traite aussi de procédés pour leur préparation, de compositions pharmaceutiques contenant ces composés et de leur utilisation en médecine, en particulier, pour traiter les troubles thrombotiques.
PCT/EP1997/003196 1996-06-21 1997-06-19 Derives piperidine de l'acide acetique et leur utilisation dans le traitement des troubles thrombotiques WO1997049699A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
EA199801015A EA199801015A1 (ru) 1996-06-21 1997-06-19 Производные пиперидинуксусной кислоты и их применение при лечении тромботических нарушений
APAP/P/1998/001417A AP9801417A0 (en) 1996-06-21 1997-06-19 Piperidine acetic acid derivatives and their use in the treatment of thrombotic disorders.
JP10502284A JP2000512648A (ja) 1996-06-21 1997-06-19 ピペリジン酢酸誘導体および血栓障害の治療におけるそれらの使用
PL97330797A PL330797A1 (en) 1996-06-21 1997-06-19 Derivatives of piperidinacetic acid and their application in treating thrombotic disorders
AU32611/97A AU3261197A (en) 1996-06-21 1997-06-19 Piperidine acetic acid derivatives and their use in the treatment of thromb otic disorders
IL12746497A IL127464A0 (en) 1996-06-21 1997-06-19 Piperidine acetic acid derivatives and their use in the treatment of thrombotic disorders
BR9709930A BR9709930A (pt) 1996-06-21 1997-06-19 Composto composição farmacêutica uso de um composto e processos para tratamento de um indivíduo humano ou animal e para preparação de um composto
EP97928243A EP0912555A1 (fr) 1996-06-21 1997-06-19 Derives piperidine de l'acide acetique et leur utilisation dans le traitement des troubles thrombotiques
IS4924A IS4924A (is) 1996-06-21 1998-12-15 Píperidín ediksýruafleiður og notkun þeirra við meðhöndlun á segamyndunar truflunum

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
GB9613017.4 1996-06-21
GBGB9613095.0A GB9613095D0 (en) 1996-06-21 1996-06-21 Therapeutic piperidines
GBGB9613018.2A GB9613018D0 (en) 1996-06-21 1996-06-21 Therapeutic indazoles
GBGB9613017.4A GB9613017D0 (en) 1996-06-21 1996-06-21 Therapeutic compounds
GB9613018.2 1996-06-21
GB9613095.0 1996-06-21

Publications (1)

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EP (1) EP0912555A1 (fr)
JP (1) JP2000512648A (fr)
KR (1) KR20000022041A (fr)
AP (1) AP9801417A0 (fr)
AR (1) AR008245A1 (fr)
AU (1) AU3261197A (fr)
BR (1) BR9709930A (fr)
CA (1) CA2258753A1 (fr)
CZ (1) CZ424698A3 (fr)
EA (1) EA199801015A1 (fr)
ID (1) ID17052A (fr)
IL (1) IL127464A0 (fr)
IS (1) IS4924A (fr)
NO (1) NO985974L (fr)
PL (1) PL330797A1 (fr)
TR (1) TR199802665T2 (fr)
WO (1) WO1997049699A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004009548A1 (fr) * 2002-07-18 2004-01-29 Wyeth Ligands de la 5-hydroxytryptamine-6 a base de derives de 1-heterocyclylalkyl-3-sulfonyl-indole ou -indazole
WO2004074243A2 (fr) * 2003-02-14 2004-09-02 Wyeth Heterocyclyl-3-sulfonylindazoles utilises comme ligands de la 5-hydroxytryptamine-6
US7064215B2 (en) 2001-07-03 2006-06-20 Chiron Corporation Indazole benzimidazole compounds
US7482461B2 (en) 2006-04-05 2009-01-27 Wyeth Sulfonyl-3-heterocyclylindazole derivatives as 5-hydroxytryptamine-6 ligands
US7642278B2 (en) 2001-07-03 2010-01-05 Novartis Vaccines And Diagnostics, Inc. Indazole benzimidazole compounds
US8158655B2 (en) 2007-01-10 2012-04-17 Hoffmann-La Roche Inc. Sulfonamide derivatives
CN113655155A (zh) * 2021-07-28 2021-11-16 任贤金 一种测定sph3127有关物质的方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0525629A2 (fr) * 1991-07-27 1993-02-03 Dr. Karl Thomae GmbH Hétérocycles à 5 chaînons, procédé pour leur préparation et médicaments les contenant
EP0542363A2 (fr) * 1991-11-14 1993-05-19 Glaxo Group Limited Dérivés de l'acide piperidine-acétique comme inhibiteurs de l'agrégation des plaquettes sanguines fibrinogen-dépendants
WO1993022303A1 (fr) * 1992-04-23 1993-11-11 Glaxo Group Limited Derives 1-piperazinacetiques utilises comme antagonistes de recepteur de fibrinogene

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0525629A2 (fr) * 1991-07-27 1993-02-03 Dr. Karl Thomae GmbH Hétérocycles à 5 chaînons, procédé pour leur préparation et médicaments les contenant
EP0542363A2 (fr) * 1991-11-14 1993-05-19 Glaxo Group Limited Dérivés de l'acide piperidine-acétique comme inhibiteurs de l'agrégation des plaquettes sanguines fibrinogen-dépendants
WO1993022303A1 (fr) * 1992-04-23 1993-11-11 Glaxo Group Limited Derives 1-piperazinacetiques utilises comme antagonistes de recepteur de fibrinogene

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7064215B2 (en) 2001-07-03 2006-06-20 Chiron Corporation Indazole benzimidazole compounds
US7642278B2 (en) 2001-07-03 2010-01-05 Novartis Vaccines And Diagnostics, Inc. Indazole benzimidazole compounds
CN100351236C (zh) * 2002-07-18 2007-11-28 惠氏公司 用作5－羟色胺－6配体的1－杂环基烷基－3－磺酰基－吲哚衍生物，其制备方法和用途
US6995176B2 (en) 2002-07-18 2006-02-07 Wyeth 1-heterocyclylalkyl-3-sulfonyl-indole or -indazole derivatives as 5-hydroxytryptamine-6 ligands
WO2004009548A1 (fr) * 2002-07-18 2004-01-29 Wyeth Ligands de la 5-hydroxytryptamine-6 a base de derives de 1-heterocyclylalkyl-3-sulfonyl-indole ou -indazole
US7589108B2 (en) 2002-07-18 2009-09-15 Wyeth 1-Heterocyclylalkyl-3-sulfonylindole or -indazole derivatives as 5-hydroxytryptamine-6 ligands
WO2004074243A3 (fr) * 2003-02-14 2004-12-02 Wyeth Corp Heterocyclyl-3-sulfonylindazoles utilises comme ligands de la 5-hydroxytryptamine-6
US7238696B2 (en) 2003-02-14 2007-07-03 Wyeth Heterocyclyl-3-sulfonylindazoles as 5-hydroxytryptamine-6 ligands
CN100422171C (zh) * 2003-02-14 2008-10-01 惠氏公司 作为5-羟色胺-6配体的杂环-3-磺酰基吲唑
US7560470B2 (en) 2003-02-14 2009-07-14 Wyeth Heterocyclyl-3-sulfonylindazoles as 5-hydroxytryptamine-6 ligands
WO2004074243A2 (fr) * 2003-02-14 2004-09-02 Wyeth Heterocyclyl-3-sulfonylindazoles utilises comme ligands de la 5-hydroxytryptamine-6
US7482461B2 (en) 2006-04-05 2009-01-27 Wyeth Sulfonyl-3-heterocyclylindazole derivatives as 5-hydroxytryptamine-6 ligands
US8158655B2 (en) 2007-01-10 2012-04-17 Hoffmann-La Roche Inc. Sulfonamide derivatives
CN113655155A (zh) * 2021-07-28 2021-11-16 任贤金 一种测定sph3127有关物质的方法

Also Published As

Publication number Publication date
CA2258753A1 (fr) 1997-12-31
TR199802665T2 (xx) 1999-03-22
AU3261197A (en) 1998-01-14
EA199801015A1 (ru) 1999-08-26
BR9709930A (pt) 1999-08-10
IS4924A (is) 1998-12-15
ID17052A (id) 1997-12-04
EP0912555A1 (fr) 1999-05-06
NO985974L (no) 1999-02-17
IL127464A0 (en) 1999-10-28
PL330797A1 (en) 1999-06-07
JP2000512648A (ja) 2000-09-26
AR008245A1 (es) 1999-12-29
AP9801417A0 (en) 1998-12-31
KR20000022041A (ko) 2000-04-25
NO985974D0 (no) 1998-12-18
CZ424698A3 (cs) 1999-05-12

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