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WO1998020015A1 - Medicaments donneurs d'oxyde nitrique - Google Patents

Medicaments donneurs d'oxyde nitrique Download PDF

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Publication number
WO1998020015A1
WO1998020015A1 PCT/GB1997/003034 GB9703034W WO9820015A1 WO 1998020015 A1 WO1998020015 A1 WO 1998020015A1 GB 9703034 W GB9703034 W GB 9703034W WO 9820015 A1 WO9820015 A1 WO 9820015A1
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WO
WIPO (PCT)
Prior art keywords
compound
moiety
rig200
endothelium
vessels
Prior art date
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Ceased
Application number
PCT/GB1997/003034
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English (en)
Inventor
Anthony Robert Butler
Iain Robert Greig
Ian Lennox Megson
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University of St Andrews
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University of St Andrews
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Publication date
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Priority to AU48749/97A priority Critical patent/AU4874997A/en
Publication of WO1998020015A1 publication Critical patent/WO1998020015A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
    • C07H3/06—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
    • C07H3/04—Disaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms

Definitions

  • This invention relates to novel nitric oxide donor drugs, methods of making the same, and to compositions comprising the nitric oxide donor drugs.
  • Nitric oxide occurs extensively in the human body. There are at least five separate physiological systems where it has been found to have an important role: as a messenger molecule in the relaxation of vascular smooth muscle; as an agent for the prevention of platelet aggregation; as a cytotoxic agent produced by the nonspecific immune system; as a messenger molecule in the brain; and as a neutrotransmitter in non-adrenergic, non- cholinergic (“NANC”) nerves.
  • NANC non-adrenergic, non- cholinergic
  • GSNO has been investigated for use to inhibit platelet aggregation during coronary angioplasty and also to treat a form of pre-eclampsia, a high blood pressure condition suffered by some pregnant women (Langford et al. , 1994 Lancet 344, 1458; de Belder et al , 1995 Lancet 345, 124).
  • SNAG (1-S-Nitroso- -D-Glucose tetraacetate), the structure of which is illustrated in Figure lc, in which a nitrosothiol group is linked directly to a substituted glucose molecule, with no intervening moiety.
  • Data presented by Butler et al. at a conference in the U.S.A. (Florida, 17-21st September 1995) and at a conference in the U.K. (St Andrew's, Scotland 25th-28th March 1996) showed that SNAG had a dilatory effect on the micro vessels of the skin in human volunteers and caused dilation in the rat tail artery when applied transdermally.
  • SNAG is a poor candidate for development as a therapeutic substance: it has a relatively short shelf-life which has severe practical limitations.
  • Transdermally delivered nitric oxide donor drugs may be of particular use in alleviating a condition known as Raynaud's Syndrome. This afflicts as much as 5 % of the population of the UK (and 80% of sufferers are female). The condition is caused by a paroxysmal or intermittent spasm of the digital arteries. The affected person suffers cold and very painful fingers and toes when exposed to lower temperatures. In more advanced cases, this can lead to cyanosis and the loss of digits through superficial gangrene.
  • PCTA percutaneous transluminal angioplasty
  • the S-nitrosothiol group is conveniently linked to the intervening moiety by one or more covalent bonds and the intervening moiety conveniently similarly linked to the saccharide moiety by one or more covalent bonds.
  • the saccharide moiety preferably comprises a di- or monosaccharide, more preferably a monosaccharide.
  • the saccharide units making up the mono-, di- or trisaccharide moiety are preferably pentoses or, more preferably, hexoses, although trioses, tetroses or heptoses may be employed for example.
  • saccharide moieties include: maltose, lactose, sucrose (disaccharides), ribose, arabinose, xylose (5C monosaccharides), fructose, galactose, mannose, and glucose (6C monosaccharides).
  • maltose lactose
  • sucrose disaccharides
  • ribose arabinose
  • xylose xylose
  • fructose galactose
  • mannose and glucose (6C monosaccharides
  • glucose (6C monosaccharides
  • one of the hydroxyl groups of the saccharide moiety is lost, or substituted, to allow formation of a covalent bond with the intervening moiety.
  • Substitution of the other hydroxyl groups is not thought to have a significant effect on release of nitric oxide from the S-nitrosothiol group.
  • substitution with comparatively inert groups may be preferred: those skilled in the art will appreciate that polyhydroxy compounds can be diffcult to process due to the reactivity of the hydroxyl groups (e.g. condensation reactions often occur).
  • Substitution may be total (i.e. all the hydroxyl groups may be substituted) or may be partial (from 0-100%), but total substitution is preferred, especially where the saccharide moiety is a monosaccharide, as this avoids the difficulty of achieving selective substitution in chemical syntheses.
  • the intervening moiety and/or the saccharide moiety should be substantially non-polar, as it is believed this may facilitate trans-dermal delivery and/or retention of the compound by damaged blood vessels.
  • substituted groups can, in theory, be any groups it is clearly preferred to avoid groups which cause toxicity, either when joined to the drug or when cleaved therefrom.
  • Convenient substituting groups are alkyl or acyl groups (which may in turn be substituted or unsubstituted). Particularly convenient are acetyl groups, which are inert on the compound and may be cleaved from the compound in vivo to give safe, non-toxic acetic acid or acetate.
  • the substituting groups are fairly small comprising, for example, 1-4 carbon atoms, although larger substituting groups may be used if desired.
  • a hydroxyl group of the saccharide moiety is substituted by an amino group, which amino group conveniently forms an amide bond (CONH) with the intervening moiety.
  • preferred saccharides are amino-saccharides, especially amino monosaccharides (e.g. amino-glucose).
  • the amino group may be at any position, but in relation to aminoglucose position 2 is preferred, as 2-aminoglucose is a readily available compound.
  • the intervening moiety located between the saccharide moiety and the nitrosothiol group, is conveniently joined to the saccharide moiety by an amide bond.
  • the intervening moiety is preferably of relatively small size (e.g. comprising two to twenty carbon atoms).
  • R, , R 2 and R 3 may all be the same, or may all be different or wherein any pair thereof may be the same, and wherein R, , R 2 and R 3 may be: H, or substituted or unsubstituted alkyl, acyl or aryl groups.
  • R is preferably N-acyl (especially N-acetyl i.e. NHCOCH 3 );
  • R 2 is preferably alkyl (especially methyl); and
  • R 3 is preferably alkyl (especially methyl).
  • the stabilising effect of the intervening moiety on the S-nitrosothiol group is due in large part to R 2 and R 3 , which are substantially adjacent to the S-nitrosothiol group, and is explained in greater detail by Butler et al. (J. Chem. Soc. Perk. Trans 2, in press).
  • the intervening moiety comprises penicillamine or a derivative thereof.
  • Penicillamine is readily available commercially and has already been licensed for use as a drug (e.g. sold under the trade marks PendramineTM and DistamineTM).
  • the intervening moiety typically comprises N-acetylpenicillamine.
  • Figure 2 shows the structure of one compound in accordance with the invention where the intervening moiety comprises N-acetylpenicillamine.
  • the invention provides a method of making the compound defined above, the method comprising reacting reagents under suitable conditions so as to form a compound comprising a saccharide moiety covalently linked to a nitrosothiol group via an intervening moiety.
  • the method may also comprise the further step of isolating or substantially purifying the desired compound from other products of the reaction and/or unreacted reagents.
  • Conventional isolation or purification techniques will be suitable for this purpose and include, for example, fractional distillation, crystallisation, precipitation, chromatography and the like.
  • the invention provides a pharmaceutical composition comprising the compound defined above and a physiologically acceptable carrier. Suitable carrier substances will be well known to those skilled in the art.
  • the invention also provides a method of making a pharmaceutical composition, comprising mixing the compound defined above with a physiologically acceptable carrier and optionally dividing the composition into unitary doses.
  • Suitable physiologically acceptable carriers include saline or phosphate-buffered saline or inert solids (such as kaolin) and the like, the choice of which will depend, at least in part, on the proposed route of delivery of the composition.
  • Compounds in accordance with the invention may be delivered to a subject by injection (e.g. sub-cutaneous, intra-muscular, intra-venous routes).
  • the compounds are delivered transdermally.
  • the invention provides a skin covering for application to the skin of a mammalian (typically human) subject, the skin covering comprising an effective amount of a compound in accordance with the first aspect of the invention.
  • an effective amount of the compound will vary slightly with the activity of the particular compound in question, but those skilled in the art will readily be able to determine an appropriate amount by routine trial and error.
  • an effective amount will vary between lmg and 10 grams of the compound (more normally between lOmgs and 1 gram).
  • the skin covering conveniently comprises an adhesive for releasable attachment to the skin of a human subject, such as the adhesives used in self-adhesive nicotine patches or sticking plasters.
  • the skin covering takes the form of a patch, plaster, bandage, gauze, wound dressing or the like, impregnated, coated or otherwise treated with a compound in accordance with the first aspect of the invention.
  • the invention provides a method of causing relaxation of smooth muscle (especially including vascular smooth muscle, leading to vasodilation) of a mammalian (desirably human) subject, the method comprising delivering to the subject an effective amount of a compound in accordance with the first aspect of the invention.
  • the compound is preferably delivered transdermally (for example, by use of a patch, plaster, bandage, gauze, wound dressing or the like defined above).
  • the method of causing vasodilation may be especially useful in promoting wound healing and/ or in the treatment of Raynaud's Syndrome.
  • the compounds of the invention may be used to prevent or treat narrowing of blood vessels whose endothelial integrity has been impaired (e.g. due to performance of surgical procedures such as percutaneous transluminal angioplasty ["PCTA”] or coronary artery-bypass grafting ["CABG”]).
  • PCTA percutaneous transluminal angioplasty
  • CABG coronary artery-bypass grafting
  • following PCTA blood vessels may be treated with a compound in accordance with the invention as a preventative or therapeutic measure.
  • the invention provides for use of the compound defined above in the preparation of a medicament to cause relaxation of smooth muscle in a mammalian (typically human) subject.
  • the medicament is used for the relaxation of vascular smooth muscle, such that use of the medicament leads to vasodilation in a subject.
  • the medicament may be used to treat a number of conditions, such as Raynaud's Syndrome, or to prevent restenosis of blood vessels following surgical procedures (e.g. PCTA or CABG), as described above, but other conditions which are ameliorated by smooth muscle relaxation may also be usefully treated by the medicament.
  • Figures la, lb and lc illustrate the structures of prior art S-nitrosothiol compounds
  • Figure 2 shows the structure of a compound in accordance with the invention, having use as a nitric oxide donor drug
  • Figure 3 is a schematic illustration of a route by which the compound shown in Figure 2 may be synthesised
  • Figures 4a-4d are pressure recordings showing vasodilator responses to sequential bolus micro-injections (10 ⁇ l) of SNAP (4a and 4b) or RIG200 (4c and 4d; log M concentrations as indicated) into the perfusate of endothelium- intact and endothelium-denuded vessels.
  • Perfusion with Hb (10 ⁇ M) is indicated by the solid bar.
  • the bar at the lower left of the figures indicates scale (vertically, a 25% response; horizontally, 5 minutes).
  • Figures 7a-c show pressure recordings of vasodilator responses to single bolus micro- injections of 10 "3 M RIG200 in: (7a) an endothelium-intact vessel in the absence of L- NAME; and (7b) an endothelium-denuded vessel in the absence of L-NAME but perfused with Hb (10 ⁇ M) for the period indicated; and (7c) an endothelium-denuded vessel perfused with L-NAME for the period indicated (3 h).
  • the scale marker on the left indicates (vertically) a 25% response and (horizontally) 30 minutes.
  • FIGS. 8-10 illustrate schematically the synthesis of certain compounds in accordance with the invention.
  • Figure 11 shows the general formula of compounds according to a preferred embodiment of the invention.
  • RIG200 One compound in accordance with the present invention has the structure shown in Figure 2, and for convenience has the code name RIG200.
  • the inventors have synthesised and authenticated the compound and conducted biological assays.
  • RIG200 has the formal chemical name N- N-acetyl-5 , -nitrosopenicillaminyl)-2-aminoglucose tetraacetate.
  • RIG200 has been synthesised in the laboratory, via the route illustrated schematically in
  • Glucosamine hydrochloride (20 g) was dissolved in 1 M ⁇ aOH (94 ml). Anisaldehyde was added (11.4 ml) and the mixture shaken until a white precipitate was seen. The flask was cooled in a freezer for 10 mins and filtered. The white solid was washed with ice water and chilled ether. The solid was dried in a vac oven to give a white product (26.2 g, 95.1 %). m.p. 163°C (lit. 166°C).
  • Anisol glucosamine tetra-O-acetate was prepared as follows: The above product (15 g) was cooled with stirring in a mixture of pyridine (81 ml) and acetic anhydride (45 ml). The mixture was left to stand at room temperature overnight and then poured into ice water with stirring. A white precipitate appeared and was filtered, dried and recrystallised from ethanol. m.p. 187°C (lit. 16 188°C).
  • Glucosamine tetra-O-acetate hydrochloride was prepared as follows: The product from above was dissolved in the minimum amount of acetone with heating. A small quantity of water was added and the mixture cooled. Concentrated HC1 was added dropwise until a precipitate was seen. Chilling was continued whilst stirring with ether, to remove the anisaldehyde. The solid was filtered and washed with chilled ether and was found not to melt (as in the literature).
  • Glucosamine tetra-O-acetate was prepared as follows: the above product (4.7 g) was dissolved in water. NaOAc (3.4 g, 2 eq) was added and a white suspension formed. The suspension was extracted with DCM (3 x 50 ml), dried (MgSO 4 ) and evaporated. Recrystallisation from ether gave a white solid.
  • Glycopeptide "GLUPEN” was prepared as follows: Glucosamine acetate (1.3 g) and N- Acetyl penicillamine (0.7 g) were stirred in DCM. The penicillamine remains as a suspension. The coupling agent l-Cyclohexyl-3-(2-morpholino-ethyl) carbodiimide metho- p-toluene sulphonate (1.6 g, 1 eq.) was added and the mixture stirred at room temperature. The suspension briefly went into solution before a white precipitate appeared. Stirring was continued for 24 hrs. The solution was washed with 1 M HCl, saturated KHCO 3 , and water, then dried (MgSO 4 ) and evaporated.
  • RIG200 The precursors (shown in Figure 3) of RIG200 are all known compounds.
  • the immediately preceding thiol compound has been characterised by 13 C NMR spectroscopy and by a satisfactory elemental analysis.
  • the S-nitrosothiol (i.e. RIG200) itself has been characterised by the inventors using 13 C NMR spectroscopy, by the characteristic visible spectrum of an SNO group, and by mass spectroscopy.
  • mice were killed by cervical dislocation and both femoral arteries were exposed and cannulated immediately distal to the epigastric arterial branch.
  • Cannulated arterial segments (7-8 mm long) were dissected free and transferred to perspex organ bath chambers (1 ml volume) at 37 °C where they were perfused (0.6 ml min- 1 ; Gilson minipuls 3, Anachem, Luton, UK) and superfused (1 ml min "1 , Watson Marlow 3025; Watson Marlow, Falmouth, UK) with fresh oxygenated Krebs buffer solution.
  • Twin vessels were precontracted with phenylephrine (PE) and perfusion pressure was monitored by a differential pressure transducer (T; Sensym SCX 15ANC, Farnell Electronic Components, Leeds, UK) located upstream.
  • PE phenylephrine
  • Vasodilator response amplitude was expressed as a % of PE- induced pressure existing before the first in a series of drug applications (% pressure change; negative values represent relaxation, positive represent constriction). Data are given as % pressure change both at the peak of responses and following response recovery as defined earlier. Mean values are given +_s.e. mean.
  • the apparatus permits exclusive drug delivery to the luminal surface of the vessel by bolus injection (10 ⁇ l) through a resealable rubber septum into the perfusate immediately upstream of the vessel (transit time to artery ⁇ 3 s, through lumen ⁇ 300 ms). Injections of vehicle (Krebs buffer) had no effect on perfusion pressure. Vasodilator responses in control vessels could be compared to those perfused with supramaximal concentrations of either the recognised NO scavenger, ferrohaemoglobin (Martin et al, 1985 J. Pharmacol. Exp. Ther.
  • N ⁇ -nitro-L- arginine methyl ester abbreviated as L-NAME (Rees et al; 1990 Br. J. Pharmacol. 101, 746-752), at 200 ⁇ M.
  • L-NAME N ⁇ -nitro-L- arginine methyl ester
  • endothelial function was assessed by use of the endothelium-dependent vasodilator, carbachol (CCh).
  • CCh carbachol
  • Bolus injections of supra-maximal concentrations of CCh (10 ⁇ l; lOmM) into the perfusate of endothelium-intact vesels caused transient vasodilatations similar to those described in rat tail arteries (Flitney et al, 1992 cited above).
  • air was passed through the lumen until such time as the vessel was unresponsive to CCh (5-10 min).
  • Vasodilator responses to bolus injections of SNAP and RIG200 were made sequentially into the perfusate of precontracted, endothelium-intact or denuded vessels. Responses were deemed to have recovered once pressure was maintained for more than 2.5 min, at which time the next concentration was injected. Time intervals between injections of SNAP and RIG200 were matched for each individual experiment. Responses to 10 ⁇ 3 M concentrations were then allowed to recover for periods of between 15 min and 4 h, after which vessels were perfused with Hb (10 ⁇ M).
  • Vasodilator responses to bolus injections of SNAP and RIG200 were bolus injections of SNAP and RIG200.
  • Responses to the highest concentration of SNAP (10 3M M) caused relaxations of -75.2+_4.7% and generally recovered fully in ⁇ 20 min.
  • RIG200 decomposes spontaneously in solution to release NO in vitro and is capable of causing NO-mediated vasodilatation in rat isolated femoral arteries. Decomposition was found to be slower than that of the parent compound, SNAP, but was not susceptible to trace Cu(I) catalysis in vitro.
  • Bolus injections of both SNAP and RIG200 produced transient responses in endothelium-intact, rat isolated femoral arteries.
  • SNAP-induced vasodilatations in endothelium-denuded vessels were transient whilst those induced by RIG200 were sustained for up to 4 h.
  • Spectrophotometric analysis showed RIG200 to be 5 fold more stable than SNAP in Krebs buffer solution.
  • the rate of SNAP decomposition in vitro is notoriously variable, a feature which is now understood to be due to differences in the amounts of trace Cu(I) present in solutions (Dicks et al, 1996). It has been suggested that a small proportion of Cu(II) is reduced to Cu(I) by thiols present as impurities in solutions of S-nitrosothiols and that it is Cu(I) which catalyzes S-nitrosothiol decomposition (Dicks et al, 1996).
  • the slow rate of recovery observed in RIG200-treated vessels may indicate that NO generated by RIG200 is less accessible to Hb than that derived either from the endothelium or from SNAP.
  • the inhibitory effect of Hb on sustained vasodilatation was reversible on washout ( Figure 7b), indicating continuing NO generation after Hb treatment.
  • RIG200 The stability of RIG200 in vitro is a distinct advantage over existing S-nitrosothiols with regard to its handling, and may be a factor in increasing the duration of vasodilator responses in vivo.
  • the ability of RIG200 to cause selectively sustained vasodilatation in vessels where the endothelium has been removed could have important implications in cardiovascular diseases, where endothelial damage is a contributory factor, and may be useful in preventing restenosis of vessels following surgical procedures like PCTA and CABG (coronary artery-bypass grafting).
  • RIG200 vasodilator drug
  • the inventors have devised synthetic routes for analogous compounds from aminoglucoses where the amino group is at positions 1 , 3 and 6. These analogues may be equally useful as therapeutic compounds, being structurally similar to RIG200.
  • the synthetic routes are described in the following examples.
  • Steps (i)-(vii) involve the following reactions.
  • Steps (i)-(iv) involve the following reactions:

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Abstract

L'invention concerne un composé pouvant libérer de l'oxyde nitrique d'un groupe S-nitrosothiol (-S-N=O). Le composé comprend un groupe S-nitrosothiol lié, par l'intermédiaire d'une fraction interposée, à une fraction mono-, di- ou trisaccharide, ladite fraction mono-, di- ou trisaccharide pouvant être complètement substituée, partiellement substituée, ou insubstituée, ladite fraction interposée servant à stabiliser le groupe S-nitrosothiol pour prévenir une dégradation rapide dudit groupe. L'invention concerne aussi un procédé de fabrication du composé, une composition comprenant le composé et un procédé pouvant favoriser la décontraction des muscles lisses.
PCT/GB1997/003034 1996-11-05 1997-11-04 Medicaments donneurs d'oxyde nitrique Ceased WO1998020015A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU48749/97A AU4874997A (en) 1996-11-05 1997-11-04 Nitric oxide donor drugs

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9622997.6A GB9622997D0 (en) 1996-11-05 1996-11-05 Nitric oxide donor drugs
GB9622997.6 1996-11-05

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WO1998020015A1 true WO1998020015A1 (fr) 1998-05-14

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PCT/GB1997/003034 Ceased WO1998020015A1 (fr) 1996-11-05 1997-11-04 Medicaments donneurs d'oxyde nitrique

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AU (1) AU4874997A (fr)
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WO (1) WO1998020015A1 (fr)

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Cited By (20)

* Cited by examiner, † Cited by third party
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US7731954B2 (en) 2002-04-24 2010-06-08 Insense Limited Wound dressings comprising hydrated hydrogels and enzymes
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