Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D473/00—Heterocyclic compounds containing purine ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/28—Phosphorus compounds with one or more P—C bonds
  • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
  • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
  • C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
  • C07F9/3821—Acyclic saturated acids which can have further substituents on alkyl substituted by B, Si, P or a metal
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
  • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
  • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
  • C07H19/16—Purine radicals
  • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids

Definitions

• This invention relates to pharmaceutically useful compounds, and processes for their production.
• Adenine triphosphate has potent pharmacological effects on a variety of tissues, the activity of ATP and the other extracellular adenine nucleotides, adenosine diphosphate (ADP) and adenosine monophosphate (AMP), are mediated by P 2 -purinoceptors.
• ADP adenosine diphosphate
• AMP adenosine monophosphate
• the potency of ATP in some tissues, e.g. the bladder may be reduced due to rapid dephosphorylation, to AMP and adenosine, by ectonucleotidases present in these tissues.
• R represents O or CR 3 R 4 ,
• W represents O or CH 2 .
• R 1 , R 2 , R 3 and R 4 independently represent
• X represents S(O) n R 5 , alkyl C 1-6 , alkoxy C 1-6 , acylamino C 1-6 , CONR 6 R 7 , NR 8 R 9 , halogen, a 5- or
• 6-membered S containing heterocycle or phenyl optionally substituted by alkyl C 1-6 ,
• n 0, 1 or 2
• R- represents aryl or alkyl C 1-6 optionally
• R 6 , R 7 , R 8 and R 9 independently represent
• Y represents NH 2 or alkoxy C 1-6 .
• Z represents an acidic moiety
• -Q-Z may also represent hydroxy or -OP(O)(OH) 2 ,
• L 3 is a leaving group
• dialkylamines or saturated or unsaturated cyclicamines include morpholinyl, imidazolyl and triazolyl.
• leaving groups which L 2 may represent include alkyl or arylsulphonyloxy groups such as methane- sulphonyloxy, trifluoromethanesulphonoxy or p-toluene- sulphonyloxy; or trifluoroacetoxy.
• a dipolar aprotic solvent for example,
• reaction may be carried out at a temperature of from -20 to 100°C, e.g. from 10 to 30°C.
• morpholine in the presence of a condensing agent such as dicyclohexylcarbodiimide, preferably in the presence of a protic solvent or mixture of solvents such as t butanol and water.
• a condensing agent such as dicyclohexylcarbodiimide
• a protic solvent or mixture of solvents such as t butanol and water.
• 5'-monophosphates and nucleosides used in the preparation of the compounds of formulae II and IV respectively are either known or may be prepared from known compounds using known techniques, see, for example, "Chemistry of
• process d) may involve the removal of one or more protecting groups.
• Suitable protecting groups and methods for their removal are, for example, those described in "Protective Groups in Organic Chemistry” by Theodora Greene, John Wiley and Sons Inc., 1981. Hydroxy groups may, for example, be protected by arylmethyl groups such as phenylmethyl, diphenylmethyl or triphenylmethyl, or as tetrahydropyranyl derivatives.
• Suitable amino protecting groups include arylmethyl groups such as benzyl, (R,S)- ⁇ -phenylethyl, diphenylmethyl or triphenylmethyl, and acyl groups such as acetyl, trichloroacetyl or trifluoroacetyl. Conventional methods of deprotection may be used including
• Arylmethyl groups may, for example, be removed by
• Tetrahydropyranyl groups may be cleaved by hydrolysis under acidic conditions.
• Acyl groups may be removed by hydrolysis with a base such as sodium hydroxide or potassium carbonate, or a group such as trichloroacetyl may be removed by reduction with, for example, zinc and acetic acid.
• Salts of the compounds of formula I may be formed by reacting the free acid, or a salt thereof, or the free base, or a salt or derivative thereof, with one or more equivalents of the appropriate base or acid.
• the reaction may be carried out in a solvent or medium in which the salt is insoluble or in a solvent in which the salt is soluble, e.g. ethanol, tetrahydrofuran or diethyl ether, which may be removed in vacuo, or by freeze drying.
• the reaction may also be a metathetical process or it may be carried out on an ion exchange resin.
• Pharmaceutically acceptable salts of the compounds of formula I include alkali metal salts, e.g. sodium and potassium salts; alkaline earth metal salts, e.g.
• salts of the Group III elements e.g aluminium salts
• ammonium salts salts with suitable organic bases, for example, salts with hydroxylamine; lower alkylamines, e.g. methylamine or ethylamine; with
• substituted lower alkylamines e.g. hydroxysubstituted alkylamines; or with monocyclic nitrogen heterocyclic compounds, e.g. piperidine or morpholine; and salts with amino acids, e.g. with arginine, lysine etc, or an N-alky derivative thereof; or with an aminosugar, e.g.
• physiologically acceptable salts are preferred, although other salts are also useful, e.g. in isolating or purifying the product.
• Alkyl groups include straight, branched or cyclic, saturated or unsaturated alkyl groups.
• Aryl groups include both carbocyclic and heterocycli groups.
• the groups may contain rings of various numbers C-atoms and may be fused ring structures.
• Particular carbocyclic aryl groups which may be mentioned are phenyl and naphthyl.
• Heteroaryl groups include nitrogen, oxygen or sulphur heterocycles and may contain one or more
• heterocycles containing only one heteroatom include pyrrole, furan, thiophen and pyridine.
• Groups containing more than one heteroatom include
• R 3 and R 4 are the same, we particularly prefer compounds in which R 3 and R 4 both represent hydrogen or Cl.
• S containing heterocycles which X may represent included both saturated and unsaturated heterocycles containing 1 or 2 S atoms.
• a particular heterocyclic group which may be mentioned is thienyl, particularly 2-thienyl.
• R 5 represents alkyl C 1-6
• alkyl groups which may be mentioned include ethyl, butyl and propyl
• Acidic moieties which Z may represent include
• Bronsted-Lowry acids i.e. moieties which act as proton donors.
• the acidic moiety may be mono- or poly-acidic.
• the compounds of formula I are useful because they exhibit pharmacological activity in mammals.
• inhibitors of platelet aggregation may be determined from their ability to act as P 2T receptor antagonists, see
• the compounds may be used in any condition where platelet aggregation or disaggregation is involved.
• the compounds may thus act as anti-thrombotic agents and are indicated in the treatment or prophylaxis of unstable angina, thromboembolic stroke and peripheral vascular disease. They are also indicated in the treatment or prophylaxis of the sequelae of thrombotic complications from angioplasty, thrombolysis, endarterctomy, coronary and vascular graft surgery, renal dialysis and cardio-pulmonary bypass.
• Further indications include the treatment or prophylaxis of disseminated intravascular coagulation, deep vein thrombosis, pre-eclampsia/eclampsia, tissue salvage following surgical or accidental trauma, vasculitis, arteritis, thrombocythaemia, ischemia and migraine.
• the dosage to be administered will vary widely, depending on, amongst other factors, the particular
• a total daily dose of 1g may be suitable, which may be administered in divided doses up to 6 times per day.
• the compounds will generally be administered in the form of a pharmaceutical composition.
• a pharmaceutical composition comprising preferably less than 80% w/w, more preferably less than 50% w/w, e.g. 0.1 to 20%, of a compound of formula I, or a pharmaceutically acceptable salt thereof, as defined above , but without provisos i), ii) (b) and ii) (c), in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
• Examples of pharmaceutical formulations which may be used, and suitable adjuvants, diluents or carriers, are as follows : for intravenous injection or infusion - purified water or saline solution;
• chelating or sequestering agents antioxidants, tonicity adjusting agents, pH-modifying agents and buffering agents.
• Solutions containing a compound of formula I may, if desired, be evaporated, e.g. by freeze drying or spray drying, to give a solid composition, which may be
• the compound of formula I preferably is in a form having a mass median diameter of from 0.01 to 10 ⁇ m.
• the compositions may also contain suitable preserving, stabilising and wetting agents, solubilisers, e.g. a water-soluble cellulose polymer such as hydroxypropyl methylcellulose, or a water-soluble glycol such as propylene glycol, sweetening and colouring agents and flavourings. Where appropriate, the compositions may be formulated in sustained release form.
• a method of treating a condition where platelet aggregation or disaggregation is involved which comprises administering a therapeutically effective amount of a compound of formula I, as defined above but without provisos i), ii) (b) and ii) (c), to a patient suffering from such a condition.
• the compounds of the invention are advantageous in that they are less toxic, more efficacious, are longer acting, have a broader range of activity, are more potent, are more stable, produce fewer side effects, are more easily absorbed, are more readily cleared from the body or have other useful pharmacological properties, than
• step i) The product of step i) (1.0 g) was added to a stirred mixture of phosphorus oxychloride (1.06 ml) and triethyl phosphate (25 ml) at -10oC. After 3 hours the reaction mixture was poured onto ice and the pH adjusted to 7 with solid sodium bicarbonate. The solution was washed with ether (3 ⁇ 150 ml) and then lyophilised. The resulting solid was taken in deionised water and applied to a column of Dowex 50Wx8 (H + form), which was washed with water until the eluate was at pH 6, then eluted with 1M ammonium hydroxide. Lyophilisation afforded the sub-title compound (0.4 g).
• step ii) The product of step ii) (0.4 g) and tri-n-butylamine (0.175 g) were combined in a small volume of water and the solution evaporated to dryness. Azeotropic drying with pyridine (3 ⁇ 15 ml) followed by anhydrous dimethylformamide (2 ⁇ 15 ml) left a residue which was taken into anhydrous dimethylformamide (10 ml). Carbonyldiimidazole (0.77 g) was added, and the reaction left at room temperature for 4 hours before adding methanol (0.24 g). After 30 min the mono tri-n-butylammonium salt of dibromomethylenebisphosphonic acid (6.5 mmol) in anhydrous
• Example 2p)i) The product of Example 2p)i) (1.4 g) was heated with activated Raney nickel (1.5 g) in water (50 ml) at 70°C for 2 hours. After filtration and washing of the solid with water, evaporation of the filtrate afforded the sub-title compound as a colourless solid (0.56 g).
• step i) The product of step i) (3.6 g) in ethanol (400 ml) was cooled to 0° and saturated with ammonia. The solution was allowed to warm to approx. 15°, then heated to 70° in an autoclave for 24 hours, the volatiles were removed in vacuo and the residue chromatographed to afford the sub-title compound (1.95 g).
• the sub-title compound was prepared according to the method of Example 1.
• step i) Bis[(dichlorodihydroxyphosphinyl)methyl]phosphinic acid
• step i) 0.532 g in dry methylene chloride (10 ml) was treated with trimethylsilyl bromide (0.912 g) at ambient temperature for 18 hours .
• the volatiles were removed in vacuo, and the residue taken up in methanol (5 ml) which was evaporated after 2 hours, the resulting oil was taken up in deionised water (10 ml) and extracted well with ether. Cyclohexylamine was added until the pH was approx. 10, then methanol was added until a turbidity persisted.
• the sub-title compound was prepared by the method of Example 6iii).
• step i) methylenebisphosphonic acid.
• step i) was eluted through a column of Dowex 50W ⁇ 8 (n-Bu 4 N + form) with deionised water and the effluent was lyophilised to afford the tetra-n- butylammonium salt of the bisphosphonate material.
• This salt (0.73 mmol) and 1-(2-nitophenyl)ethyl phosphoromorpholidate, N,N'-dicyclohexyl morpholine-1- carboxamidinium salt (1.09 mmol) were stirred in dry pyridine (5 ml) for 48 hours at ambient temperature. The solvent was evaporated and the residue taken up in water (100 ml) and washed with chloroform (2 ⁇ 50 ml). The volume of the aqueous phase was reduced to 10 ml at 30° and applied to a column of DEAE-Sepharose which was eluted with 0-0.4M triethylammonium bicarbonate solution.
• the solvent was evaporated and the residue taken up in water (100 ml) and washed with chloroform (2 ⁇ 50 ml). The volume of the aqueous phase was reduced to 10 ml at 30° and applied to a column of DEAE-Sepharose which was eluted with 0-0.4M trie
• step ii) (0.3 g) in 0.4M
• step i) The product of step i) (2 g) was added to ice-cooled fuming nitric acid (10 ml) over 1 hour and stirred at 0° for a further 1 hour. Pouring into ice followed by drying afforded the sub-title compound as a beige solid (1.7 g).
• step ii) phosphoryl chloride (10 ml) and N,N-diethylaniline (3 ml) were heated to reflux for 1 hour, then concentrated to half volume and poured onto ice to yield a black tar. Extraction of the tar with ether afforded a solution which was dried (MgSO 4 ) then evaporated. The residue was chromatographed (SiO 2 , light petrol) to afford the sub-title compound (0.8 g).
• step iii) To a solution of the product of step iii) (1 g) in glacial acetic acid (10 ml) was added reduced iron powder (1.1 g). The temperature was reduced to 60° by cooling and then heated at 60° for 15 min. The reaction was evaporated to dryness and the residue extracted into ether (100 ml), washed with dilute sodium hydroxide solution and dried.
• step iv) The product of step iv) (4.6 g) was added to a
• step v) The product of step v) (0.2 g) and diethoxymethyl acetate (10 ml) were stirred at ambient temperature under nitrogen for 1 hour, then at 80° for 24 hours. Evaporation afforded a residue which was treated with liquid ammonia (15 ml) in an autoclave at 60° for 16 hours. The ammonia was allowed to evaporate and the residue taken up in 0.5M hydrochloric acid (10 ml) at 60° for 45 min. The volatiles were removed in vacuo and the remaining material dissolved in water (10 ml). Upon neutralisation with concentrated ammonia the sub-title compound crystallised and was
• step vi) was converted to the sub-title compound by the method of Example 1.
• step i) The compound from step i) (5.2 g) was dissolved in 1M sodium methoxide in methanol solution (53 ml) and heated to reflux for 1 hour under nitrogen. Dilution with water (100 ml), neutralisation with dilute hydrochloric acid and evaporation of the methanol gave an oil. Trituration with water and then dichloromethane afforded the sub-title compound as a colourless solid (1.35 g).
• the sub-title compound was prepared according to the method of Example 1.
• platelets were used in aggregation studies no sooner than 2 hours after final resuspension. In all studies 430 ⁇ l aliquots of platelet suspension were
• a concentration of ADP producing a just submaximal response was selected by constructing a concentration/ response curve over the range 10-300 ⁇ M.
• the appropriate solution of ADP was added to the aggregation cuvette in a volume of 10 ⁇ l, 20 min after starting the aggregation trace. Aggregation responses were measured using the maximum rate of change in light transmission, an index given by the PAP4 slope-reader. The submaximal
• concentration of ADP selected at this stage of the protocol was used in the subsequent assessment of antagonist potency of the compounds. All measurements were made in duplicate in platelets from each donor,
• saline or the appropriate solution of test compound was added to an aggregation cuvette in a volume of 30 ⁇ l to give a final concentration of 0, 10, 100 or 1000 ⁇ M. Aggregation at this point was indicative of agonist activity and, if it occurred, agonist potency was estimated by comparison with control ADP responses obtained in a). If aggregation did not occur the previously selected submaximal concentration of ADP was added in a volume of 10 ⁇ l, 15 min after the test compound. Antagonist potency was estimated as a % inhibition of the control ADP response to obtain an
• Results are reported as the negative logarithm of the antagonist potency (pIC 50 ) obtained in duplicate form from each of 4 donors. For compounds with pIC 50 >8 a comment "clean” is made if there is no evidence of P 1 agonist activity. An IC 50 ⁇ 3 is defined as "inactive”.

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• 1992
  • 1992-04-02 EP EP92907588A patent/EP0579643A1/de active Pending
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