USRE46276E1 - Triazolo(4,5-D)pyrimidine compounds - Google Patents

Triazolo(4,5-D)pyrimidine compounds Download PDF

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USRE46276E1
USRE46276E1 US14/976,977 US199914976977A USRE46276E US RE46276 E1 USRE46276 E1 US RE46276E1 US 199914976977 A US199914976977 A US 199914976977A US RE46276 E USRE46276 E US RE46276E
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triazolo
pyrimidin
amino
cyclopropyl
difluorophenyl
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David Hardem
Anthony Ingall
Brian Springthorpe
Paul Willis
Simon Guile
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AstraZeneca UK Ltd
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AstraZeneca UK Ltd
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Priority claimed from SE9804211A external-priority patent/SE9804211D0/xx
Priority claimed from SE9901271A external-priority patent/SE9901271D0/xx
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/39—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton
    • C07C211/40—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing only non-condensed rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms

Definitions

  • the present invention provides new triazolo[4,5-d]pyrimidine compounds, their use as medicaments, compositions containing them and processes for their preparation.
  • Platelet adhesion and aggregation are initiating events in arterial thrombosis. Although the process of platelet adhesion to the sub-endothelial surface may have an important role to play in the repair of damaged vessel walls, the platelet aggregation that this initiates can precipitate acute thrombotic occlusion of vital vascular beds, leading to events with high morbidity such as myocardial infarction and unstable angina. The success of interventions used to prevent or alleviate these conditions, such as thrombolysis and angioplasty is also compromised by platelet mediated occlusion or re-occlusion.
  • GPIIb/IIIa glycoprotein IIb/IIIa
  • Thrombin inhibitors such as hirudin are highly effective anti-thrombotic agents, but again may produce excessive bleeding because they function as both anti-platelet and anti-coagulant agents (The TIMI 9a Investigators (1994), Circulation 90, pp. 1624-1630; The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIIa Investigators (1994) Circulation 90, pp. 1631-1637; Neuhaus K. L. et. al. (1994) Circulation 90, pp. 1638-1642).
  • ADP adenosine 5′-diphosphate
  • a pivotal role for ADP is supported by the fact that other agents, such as adrenaline and 5-hydroxytryptamine (5HT, serotonin) will only produce aggregation in the presence of ADP.
  • the limited anti-thrombotic efficacy of aspirin may reflect the fact that it blocks only one source of ADP which is that released in a thromboxane-dependent manner following platelet adhesion (see e.g. Antiplatelet Trialists' Collaboration (1994), Br. Med. J. 308, pp. 81-106 and Antiplatelet Trialists' Collaboration (1994), Br. Med. J. 308, pp. 159-168).
  • Aspirin has no effect on aggregation produced by other sources of ADP, such as damaged cells or ADP released under conditions of turbulent blood flow.
  • ADP-induced platelet aggregation is mediated by the P 2T receptor subtype located on the platelet membrane.
  • the P 2T receptor also known as P2Y ADP or P2T AC
  • P2Y ADP or P2T AC is primarily involved in mediating platelet aggregation/activation and is a G-protein coupled receptor which is as yet uncloned.
  • the pharmacological characteristics of this receptor have been described, for example, in the references by Humphries et al., Br. J. Pharmacology (1994), 113, 1057-1063, and Fagura et al., Br. J. Pharmacology (1998) 124, 157-164.
  • antagonists at this receptor offer significant improvements over other anti-thrombotic agents (see J. Med. Chem. (1999) 42, 213). Accordingly there is a need to find further P 2T (P2Y ADP or P2T AC ) antagonists as anti-thrombotic agents.
  • International Patent Application WO 9905143 discloses generically a series of triazolo[4,5-d]pyrimidine compounds having activity as P 2T (P2Y ADP or P2T AC ) antagonists. It has now been found that certain compounds within the scope of International Patent Application WO 9905143 but not specifically disclosed therein exhibit high potency combined with surprisingly high metabolic stability and bioavailibility, such that the predicted therapeutic dose for prolonged inhibition of aggregation in man shows advantage.
  • Alkyl groups whether alone or as part of another group are straight chained and fully saturated.
  • R 1 is a C 3-5 alkyl optionally substituted by one or more fluorine atoms.
  • R 1 is C 3-5 alkyl optionally substituted on the terminal carbon by three fluorine atoms. More preferably R 1 is 3,3,3,-trifluoropropyl, butyl or propyl.
  • R 2 is phenyl or phenyl substituted by one or more fluorine atoms.
  • R 2 is phenyl, 4-fluorophenyl or 3,4-difluorophenyl.
  • R is XOH where X is CH 2 , OCH 2 CH 2 or a bond.
  • R is CH 2 OH or OCH 2 CH 2 OH.
  • Particularly preferred compounds include:
  • R, R 1 , R 3 and R 4 are as defined in formula (I), or are protected derivatives thereof, or R 3 and R 4 together form a bond in the 5-membered ring, or R is CH 2 CH 2 OR′, where R is C 1-6 alkyl or benzyl, and L is a leaving group such as halogen or SR, with a compound of formula (III):
  • R 2 is as defined in formula (I), or is a protected derivative thereof, or where X is a bond:
  • R 1 is defined in formula (I) and R 8 is H or CH 2 CH 2 OP 3 where P 3 is H or a protecting group or R 8 is CH 2 COOR′ where R′ is C 1-6 alkyl or benzyl, and Z is NH 2 or
  • R 2 is defined in formula (I). and for both (a) and (b) optionally thereafter and in any order:
  • amines of formula (III) can be reacted with amines of formula (III) in the presence of a base, such as a tertiary organic amine, in an inert solvent, such as dichloromethane, at ambient or elevated temperature.
  • a base such as a tertiary organic amine
  • an inert solvent such as dichloromethane
  • suitable bases include inorganic bases such as potassium carbonate.
  • the hydroxy groups R 3 and R 4 can be protected as groups OP 1 and OP 2 where P 1 and P 2 are protecting groups.
  • suitable protecting groups in compounds of formula (II) are C 1-6 alkyl (preferably methyl), benzyl, (C 1-6 alkyl) 3 Si (preferably t-butyldimethylsilyl), and a C(O)C 1-6 alkyl group such as acetyl.
  • the two groups P 1 and P 2 together with the atoms to which they are attached form an alkylidene ring such as a methylidene or isopropylidene ring.
  • P 1 and P 2 can form an alkoxymethylidene ring such as ethoxymethylidene.
  • Protecting groups can be added and removed using known reaction conditions. The use of protecting groups is fully described in ‘Protective Groups in Organic Chemistry’, edited by J W F McOmie, Plenum Press (1973), and ‘Protective Groups in Organic Synthesis’, 2nd edition, T W Greene & P G M Wutz, Wiley-Interscience (1991).
  • Ester protecting groups can be removed by basic hydrolysis, for example by using a metal hydroxide, preferably an alkali metal hydroxide, such as sodium hydroxide or lithium hydroxide, or quaternary ammonium hydroxide in a solvent, such as aqueous ethanol or aqueous tetrahydrofuran, at a temperature of from 10° to 100° C., preferably the temperature is around room temperature; or by acidic hydrolysis using a mineral acid such as HCl or a strong organic acid such as trichloroacetic acid in a solvent such as aqueous 1,4-dioxane.
  • a metal hydroxide preferably an alkali metal hydroxide, such as sodium hydroxide or lithium hydroxide, or quaternary ammonium hydroxide in a solvent, such as aqueous ethanol or aqueous tetrahydrofuran, at a temperature of from 10° to 100° C., preferably the temperature is around room temperature
  • Trialkylsilyl protecting groups can be removed by the use of, for example, a fluoride ion source, for example tetra-n-butylammonium fluoride or hydrogen fluoride.
  • a fluoride ion source for example tetra-n-butylammonium fluoride or hydrogen fluoride.
  • P 1 and are C 1-6 alkyl
  • deprotection can be achieved using boron tribromide.
  • Benzyl groups can be removed by hydrogenolysis using a transition metal catalyst, for example palladium on charcoal, under an atmosphere of hydrogen, at a pressure of from 1 to 5 bar, in a solvent, such as acetic acid.
  • a compound of formula (II) can be prepared by diazotising a compound of formula (V):
  • R 1 is as defined in formula (I), and R is as defined in formula (I), or is a protected derivative thereof, or is OCH 2 CO 2 R′, where R′ is C 1-6 alkyl or benzyl, and L is as defined above and R 3 and R 4 are as defined in formula (I) or are protected derivatives thereof or R 3 and R 4 together form a bond in the 5-membered ring, with a metal nitrite, for example an alkali metal nitrite, especially sodium nitrite in dilute aqueous acid, for example 2M HCl, or with a C 1-6 -alkyl nitrite, in an inert solvent, at a temperature of from about ⁇ 20 to about 100° C.
  • Preferred conditions are isoamyl nitrite in acetonitrile at about 80° C.
  • a compound of formula (V) wherein R is CH 2 OH, R 3 and R 4 are hydroxyl or protected derivatives thereof and L is as defined above, can be prepared by reducing a compound of formula (VI):
  • R 1 , L, P 1 and P 2 are as defined above.
  • the reduction of the nitro group can be carried out for example by using hydrogenation with a transition metal catalyst at a temperature around room temperature, for example palladium on charcoal under an atmosphere of hydrogen, preferably at a pressure from 1 to 5 atmospheres, in a solvent, for example ethanol, or by using iron in an acidic solvent such as acetic acid at a temperature of about 100° C.
  • a transition metal catalyst at a temperature around room temperature, for example palladium on charcoal under an atmosphere of hydrogen, preferably at a pressure from 1 to 5 atmospheres, in a solvent, for example ethanol, or by using iron in an acidic solvent such as acetic acid at a temperature of about 100° C.
  • Reduction of the lactam can be carried out using complex metal hydrides such as lithium aluminium hydride in a solvent such as ether or preferably, by using sodium borohydride in a suitable solvent such as methanol.
  • complex metal hydrides such as lithium aluminium hydride in a solvent such as ether or preferably, by using sodium borohydride in a suitable solvent such as methanol.
  • a compound of formula (VI) can be prepared by reacting a compound of formula (VII):
  • L and R 1 are as defined above and L 1 is a leaving group, for example a halogen atom, wherein L and L 1 are preferably the same, with a compound of formula (VIII):
  • P 1 and P 2 are as defined above, in the presence of a base such as C 1-6 -alkyl-M or MH wherein M is a metal ion, for example n-butyl lithium, in an inert solvent, such as tetrahydrofuran, at a temperature of from about ⁇ 10 to about 100° C.
  • a base such as C 1-6 -alkyl-M or MH wherein M is a metal ion, for example n-butyl lithium
  • an inert solvent such as tetrahydrofuran
  • sodium hydride is used in tetrahydrofuran at room temperature.
  • One or more functional groups can be converted into further functional groups using standard chemistry.
  • a compound where X is a bond can be converted to a compound where X is O(CH 2 ) 2 by treatment with base followed by LY where L is a leaving group and Y is (CH 2 ) 2 OH or a protected version thereof or Y is CH 2 COOR′ where R′ is C 1-6 alkyl or benzyl.
  • a compound where R is CH 2 CH 2 OR may be converted into a compound where R is O(CH 2 ) 2 OH by reduction, for example using DIBAL-H®.
  • the group SR 1 can be interconverted by oxidation of the sulfur, for example using oxoneTM or mCBPA, followed by treatment with a compound R 1′ -SM where R 1′ is a different R 1 group and M is a metal such as sodium.
  • R 1′ -SM where R 1′ is a different R 1 group and M is a metal such as sodium.
  • the product of the sulfur oxidation may be treated with MSH where M is a metal such as sodium, followed by treatment with a base and R 1′ X where R 1′ is a different R 1 group and X is a leaving group.
  • Suitable bases include N,N-diisopropylethylamine.
  • a halogenating agent preferably isoamyl-nitrite and carbon tetrabromide.
  • a compound of formula (II) where R, R 1 , R 3 , and R 4 are defined above and L is NH 2 may be prepared by treating a compound of formula (II) where R, R 1 , R 3 , and R 4 are as defined above and L is a leaving group such as halogen, with ammonia in a solvent such as methanol.
  • R, R 3 and R 4 are as defined in formula (I) or are protected derivatives thereof or R is OCH 2 CO 2 R ′ where R ′ is c 1-6 alkyl or benzyl, or R 3 and R 4 together form a bond in the 5-membered ring, with a compound of formula (VII) as defined above, followed by reduction of the nitro group.
  • the reaction is carried out in an inert solvent such as dichloromethane or 1,4-dioxane, in the presence of a non-nucleophilic base, such as N,N-diisopropylamine, at a tempeature of about ⁇ 20° C. to about 150° C., preferably at ambient temperature.
  • reaction in which R 7 is H or a protected derivative thereof.
  • the reaction can be carried out in the presence of a suitable transition metal complex, preferably tetrakistriphenylphosphine palladium(0).
  • Compounds of formula (XI), where R is OCH 2 CO 2 R′ where R′ is C 1-6 alkyl and R 3 and R 4 together form a bond in the 5-membered ring may be formed from compounds of formula (XIII), where R 7 is H or a protecting group, by treatment with an azide in the presence of a palladium catalyst, followed by reduction of the azide and alkylation of the alcohol as described previously.
  • the amines of formula (III) can be prepared using procedures described in H Nishiyama et al, Bull. Chem. Soc., Jpn., 1995, 68, 1247, P. Newman, Optical Resolution Procedures for Chemical Compounds, Vol. 1, Amines and Related Compounds; Optical Resolution and Information Centre: Manhattan College, Riverdale, N.Y., 1978, p120, J. Vallgarda et al, J. Chem. Soc. Perkin 1, 1994, 461 or in International Patent Application WO 9905143.
  • 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 a derivative thereof, with one or more equivalents of the appropriate base (for example ammonium hydroxide optionally substituted by C 1-6 -alkyl or an alkali metal or alkaline earth metal hydroxide) or acid (for example a hydrohalic (especially HCl), sulphuric, oxalic or phosphoric 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.
  • reaction may also be a metathetical process or it may be carried out on an ion exchange resin.
  • the non-toxic physiologically acceptable salts are preferred, although other salts may be useful, e.g. in isolating or purifying the product.
  • the compounds of the invention act as P 2T (P2Y ADP or P2T AC ) receptor antagonists. Accordingly, the compounds are useful in therapy, including combination therapy, particularly they are indicated for use as: inhibitors of platelet activation, aggregation and degranulation, promoters of platelet disaggregation, anti-thrombotic agents or in the treatment or prophylaxis of unstable angina, primary arterial thrombotic complications of atherosclerosis such as thrombotic or embolic stroke, transient ischaemic attacks, peripheral vascular disease, myocardial infarction with or without thrombolysis, arterial complications due to interventions in atherosclerotic disease such as angioplasty, including coronary angioplasty (PTCA), endarterectomy, stent placement, coronary and other vascular graft surgery, thrombotic complications of surgical or mechanical damage such as tissue salvage following accidental or surgical trauma, reconstructive surgery including skin and muscle flaps, conditions with a diffuse thrombotic/platelet consumption component such as disseminated intra
  • platelet concentrates, or shunt occlusion such as in renal dialysis and plasmapheresis, thrombosis secondary to vascular damage/inflammation such as vasculitis, arteritis, glomerulonephritis, inflammatory bowel disease and organ graft rejection, conditions such as migraine, Raynaud's phenomenon, conditions in which platelets can contribute to the underlying inflammatory disease process in the vascular wall such as atheromatous plaque formation/progression, stenosis/restenosis and in other inflammatory conditions such as asthma, in which platelets and platelet-derived factors are implicated in the immunological disease process. Further indications include treatment of CNS disorders and prevention of the growth and spread of tumours.
  • a compound according to the invention as an active ingredient in the manufacture of a medicament for use in the treatment or prevention of the above disorders.
  • the compounds of the invention are useful for treating myocardial infarction, thrombotic stroke, transient ischaemic attacks, peripheral vascular disease and stable and unstable angina, especially unstable angina.
  • the invention also provides a method of treatment or prevention of the above disorders which comprises administering to a person suffering from or susceptible to such a disorder a therapeutically effective amount of a compound according to the invention.
  • the compounds may be administered topically, e.g. to the lung and/or the airways, in the form of solutions, suspensions, HFA aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, pills, capsules, syrups, powders or granules, or by parenteral administration in the form of sterile parenteral solutions or suspensions, by subcutaneous administration, or by rectal administration in the form of suppositories or transdermally.
  • the compounds of the invention may be administered on their own or as a pharmaceutical composition comprising the compound of the invention in combination with a pharmaceutically acceptable diluent, adjuvant and/or carrier.
  • a pharmaceutically acceptable diluent, adjuvant and/or carrier particularly preferred are compositions not containing material capable of causing an adverse, e.g. an allergic, reaction.
  • Dry powder formulations and pressurised HFA aerosols of the compounds of the invention may be administered by oral or nasal inhalation.
  • the compound is desirably finely divided.
  • the compounds of the invention may also be administered by means of a dry powder inhaler.
  • the inhaler may be a single or a multi dose inhaler, and may be a breath actuated dry powder inhaler.
  • a carrier substance e.g. a mono-, di- or polysaccharide, a sugar alcohol or another polyol.
  • Suitable carriers include sugars and starch.
  • the finely divided compound may be coated by another substance.
  • the powder mixture may also be dispensed into hard gelatine capsules, each containing the desired dose of the active compound.
  • This spheronized powder may be filled into the drug reservoir of a multidose inhaler, e.g. that known as the Turbuhaler® in which a dosing unit meters the desired dose which is then inhaled by the patient.
  • a multidose inhaler e.g. that known as the Turbuhaler®
  • a dosing unit meters the desired dose which is then inhaled by the patient.
  • the pharmaceutical composition comprising the compound of the invention may conveniently be tablets, pills, capsules, syrups, powders or granules for oral administration; sterile parenteral or subcutaneous solutions, suspensions for parenteral administration or suppositories for rectal administration.
  • the active compound may be admixed with an adjuvant or a carrier, e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatine or polyvinylpyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, and the like, and then compressed into tablets.
  • a carrier e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatine or polyvinylpyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, and the like, and then compressed into tablets.
  • the compound may be admixed with e.g. a vegetable oil or polyethylene glycol.
  • Hard gelatine capsules may contain granules of the compound using either the above mentioned excipients for tablets, e.g. lactose, saccharose, sorbitol, mannitol, starches, cellulose derivatives or gelatine. Also liquid or semisolid formulations of the drug may be filled into hard gelatine capsules.
  • Liquid preparations for oral application may be in the form of syrups or suspensions, for example solutions containing the compound, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol.
  • Such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.
  • NMR spectra were measured on a Varian Unity Inova 300 or 400 spectrometer and the MS spectra were measured as follows: EI spectra were obtained on a VG 70-250S or Finnigan Mat Incos-XL spectrometer, FAB spectra were obtained on a VG70-250SEQ spectrometer, ESI and APCI spectra were obtained on Finnigan Mat SSQ7000 or a Micromass Platform spectrometer. Preparative HPLC separations were generally performed using a Novapak®, Bondapak® or Hypersil® column packed with BDSC-18 reverse phase silica.
  • N,N-Diisopropylethylamine (1.29 g) was added to a solution of [3aR-(3a ⁇ ,4 ⁇ ,6 ⁇ ,6a ⁇ )]-6-[7-chloro-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol (prepared as described in International Patent Application WO 9703084) (1.0 g) and the product of step d) (0.75 g) in dichloromethane (25 ml).
  • the subtitle compound was prepared according to the method of Example 1, step a) using 3-(3,4-difluorophenyl)-2-propenoic acid.
  • the subtitle compound was prepared according to the method of Example 1, step b) using the product of step a).
  • the subtitle compound was prepared according to the method of Example 1, step c) using the product of step b).
  • the subtitle compound was prepared according to the method of Example 1, step d) using the product of step c).
  • Isoamyl nitrite (5.1 ml) was added to a solution of [3aR-(3a ⁇ ,4 ⁇ ,6 ⁇ ,6a ⁇ )]-6-[[5-amino-6-Chloro-2-[(3,3,3-trifluoropropyl)thio]-4-pyrimidinyl]-amino]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol (prepared as described in International Patent Application WO 9703084) (8.1 g) in acetonitrile (1000 ml) and the solution heated at 70° C. for 1 hour.
  • step h Prepared according to the method of example 1, step h) using the product of step e).
  • step a) To a solution of the product of step a) (17.1 g) in tetrahydrofuran (500 ml)/water (50 ml) was added N-methylmorpholine-N-oxide (9.4 g) followed by osmium tetroxide (10 ml, 2.5% solution in t-butanol). The mixture was stirred at room temperature for 4 days then treated with sodium hydrosulphite (6.0 g). The suspension was filtered through celite and the product purified (SiO 2 , ethyl acetate:hexane 1:1 as eluant) to afford the subtitle compound (19.1 g).
  • step b) The product from step b) (17.4 g) in 6M HCl (100 ml)/methanol (500 ml) was stirred for 18 hours. The mixture was evaporated and then azeotroped with toluene (4 ⁇ 200 ml) to give a colourless powder (8.7 g). This solid was suspended in acetone (250 ml) containing 2,2-dimethoxypropane (25 ml) and cHCl (0.2 ml) then heated under reflux for 2 hours. The mixture was cooled, evaporated and azeotroped with toluene (3 ⁇ 200 ml). The residue was dissolved in 20% aqueous acetic acid and stirred for 2 hours. The mixture was evaporated and azeotroped with toluene (4 ⁇ 200 ml) to afford the subtitle compound (10.1 g).
  • step f) The product of step f) (13.2 g) in tetrahydrofuran (200 ml) containing 0.88 ammonia (5 ml) was stirred for 2 hours then concentrated to dryness and the residue partitioned between water and ethyl acetate. The organics were dried and then concentrated to afford the subtitle compound (12.5 g).
  • step g) To a solution of the product of step g) (0.50 g) in tetrahydrofuran (25 ml) at 0° C., was added butyllithium (0.62 ml of 2.5N in hexanes). After 20 minutes, the suspension was treated with a solution of trifluoromethanesulfonyloxy-acetic acid methyl ester (0.34 g) (prepared according to the method of Biton, Tetrahedron, 1995, 51, 10513) in tetrahydrofuran (10 ml). The resulting solution was allowed to warm to room temperature then concentrated and purified (SiO 2 , ethyl acetate: hexane 4:6 as eluant) to afford the subtitle compound (0.25 g).
  • step h The product from step h) (1.1 g) and isoamylnitrite (2.4 ml) in bromoform (30 ml) was heated at 80° C. for 30 minutes. The cooled reaction mixture was purified (SiO 2 , ethyl acetate:isohexane 1:4 as eluant) to afford the subtitle compound (0.44 g).
  • step d) (0.61 g) in dichloromethane (25 ml) was added N,N-diisopropylethylamine (0.85 ml). The resulting solution was stirred at room temperature for 16 hours then concentrated in vacuo. Purification (SiO 2 , isohexane:ethylacetate 3:1 as eluant) gave the subtitle compound as a colourless foam (0.77 g).
  • step h Prepared according to the method of example 1, step h) using the product of step k).
  • step f) using the product of step a).
  • step c) To a solution of the product from step c) (3.3 g) in dichloromethane (50 ml), was added pyridine (2.7 ml), 4-dimethylaminopyridine (0.4 g) and acetic anhydride (2.0 ml). The mixture was stirred at room temperature overnight, concentrated in-vacuo and purified (SiO 2 , diethyl ether:isohexane 3:2 as eluent) to give the subtitle compound (2.7 g).
  • step i) using the product of step d).
  • step j) using the product of example 2, step d) and the product of step e).
  • step f) (0.64 g) in 80% aqueous acetic acid (30 ml) was heated at 80° C. for 1 hour. The cooled mixture was poured into saturated sodium bicarbonate solution and extracted into ethyl acetate. The organic phase was dried and concentrated in vacuo to give a gum which was dissolved in methanol (50 ml)/10% aqueous potassium carbonate solution (3 ml). The solution was stirred for 30 minutes, neutralised with acetic acid, and concentrated in vacuo. Purification (SiO 2 , methanol:dichloromethane 1:19 as eluent) gave a solid which was recrystallised (acetonitrile) to give the title compound (0.25 g).
  • step e) Prepared according to the method of example 1, step e) using the product of example 1, step d) and the product of example 3 step f).
  • step f) using the product of step a).
  • the subtitle compound was prepared according to the method of Example 1, step f) using the product of Example 3, step 1.
  • step g) using the product of step b).
  • step k Prepared according to the method of example 3, step k) using the product of step c).
  • step j) using the product of step f) and (1R-trans)-2-phenylcyclopropanamine, [R-(R*,R*)]-2,3-dihydroxybutanedioate (1:1) (prepared as described by L. A. Mitscher et al., J. Med. Chem. 1986, 29, 2044).
  • the subtitle compound was prepared according to the method of Example 1, step e) using the product of Example 3, step f) and the product of example 2, step d).
  • the subtitle compound was prepared according to the method of Example 1, step f) using the product of step a).
  • the subtitle compound was prepared according to the method of Example 4, step c) using the product of step b).
  • the subtitle compound was prepared according to the method of example 3, step e) using 2-(butylthio)-4,6-dichloro-5-nitro-pyrimidine (prepared as described in DE 2223644).
  • the subtitle compound was prepared according to the method of example 3, step d) using the products of steps c) and d).
  • the subtitle compound was prepared according to the method of Example 3, step f) using the product of step e).
  • the subtitle compound was prepared according to the method of Example 3, step j) using the product of step f).
  • Human venous blood (100 ml) was divided equally between 3 tubes, each containing 3.2% trisodium citrate (4 ml) as anti-coagulant.
  • the tubes were centrifuged for 15 minutes at 240 G to obtain a platelet-rich plasma (PRP) to which 300 ng/ml prostacyclin was added to stabilize the platelets during the washing procedure.
  • PRP platelet-rich plasma
  • Red cell free PRP was obtained by centrifugation for 10 minutes at 125G followed by further centrifugation for 15 minutes at 640 G.
  • CFT Calcium Free Tyrode solution (10 ml) (CFT), composition: NaCl 137 mM, NaHCO 3 11.9 mM, NaH 2 PO 4 0.4 mM, KCl 2.7 mM, MgCl 2 1.1 mM, dextrose 5.6 mM, gassed with 95% O 2 /5% CO 2 and maintained at 37° C. Following addition of a further 300 ng/ml PGI 2 , the pooled suspension was centrifuged once more for 15 minutes at 640 G.
  • CFT Calcium Free Tyrode solution
  • the agonist/antagonist potency was assessed as follows.
  • the absorbance of each well in the plate was read at 660 nm to establish a baseline figure.
  • Saline or the appropriate solution of test compound was added to each well in a volume of 10 ⁇ l to give a final concentration of 0, 0.01, 0.1, 1, 10 or 100 mM.
  • the plate was then shaken for 5 min on an orbital shaker on setting 10 and the absorbance read at 660 nm. Aggregation at this point was indicative of agonist activity of the test compound.
  • Saline or ADP (30 mM; 10 ⁇ l of 450 mM) was then added to each well and the plate shaken for a further 5 min before reading the absorbance again at 660 nm.
  • Antagonist potency was estimated as a % inhibition of the control ADP response to obtain an IC 50 .
  • Compounds exemplified have pIC 50 values of more than 5.0.

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US10/323,655 Expired - Lifetime US6974868B2 (en) 1998-12-04 2002-12-20 Compounds
US11/230,493 Expired - Lifetime US7250419B2 (en) 1998-12-04 2005-09-21 Trisubstituted triazolopyrimidines for use in platelet aggregation inhibition
US11/711,838 Abandoned US20070265282A1 (en) 1998-12-04 2007-02-28 Novel compounds
US12/149,771 Abandoned US20080214812A1 (en) 1998-12-04 2008-05-08 Trisubstituted triazolopyrimidines for use in platelet aggregation inhibition
US12/591,395 Abandoned US20100069408A1 (en) 1998-12-04 2009-11-18 Trisubstituted triazolopyrimidines for use in platelet aggregation inhibition
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US13/423,848 Abandoned US20130072503A1 (en) 1998-12-04 2012-03-19 Trisubstituted triazolopyrimidines for use in platelet aggregation inhibition
US13/665,241 Abandoned US20130109702A1 (en) 1998-12-04 2012-10-31 Trisubstituted triazolopyrimidines for use in platelet aggregation inhibition
US14/068,942 Abandoned US20140296258A1 (en) 1998-12-04 2013-10-31 Trisubstituted triazolopyrimidines for use in platelet aggregation inhibiton
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US11/711,838 Abandoned US20070265282A1 (en) 1998-12-04 2007-02-28 Novel compounds
US12/149,771 Abandoned US20080214812A1 (en) 1998-12-04 2008-05-08 Trisubstituted triazolopyrimidines for use in platelet aggregation inhibition
US12/591,395 Abandoned US20100069408A1 (en) 1998-12-04 2009-11-18 Trisubstituted triazolopyrimidines for use in platelet aggregation inhibition
US13/137,125 Abandoned US20120165348A1 (en) 1998-12-04 2011-07-21 Novel compounds
US13/423,848 Abandoned US20130072503A1 (en) 1998-12-04 2012-03-19 Trisubstituted triazolopyrimidines for use in platelet aggregation inhibition
US13/665,241 Abandoned US20130109702A1 (en) 1998-12-04 2012-10-31 Trisubstituted triazolopyrimidines for use in platelet aggregation inhibition
US14/068,942 Abandoned US20140296258A1 (en) 1998-12-04 2013-10-31 Trisubstituted triazolopyrimidines for use in platelet aggregation inhibiton
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