WO2008065445A1 - Dérivés d'aminoquinazolines dotés de propriétés réduisant la production des plaquettes sanguines - Google Patents

Dérivés d'aminoquinazolines dotés de propriétés réduisant la production des plaquettes sanguines Download PDF

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WO2008065445A1
WO2008065445A1 PCT/GB2007/050698 GB2007050698W WO2008065445A1 WO 2008065445 A1 WO2008065445 A1 WO 2008065445A1 GB 2007050698 W GB2007050698 W GB 2007050698W WO 2008065445 A1 WO2008065445 A1 WO 2008065445A1
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compound
group
alkyl
halo
cyano
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PCT/GB2007/050698
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English (en)
Inventor
Richard Franklin
Bernard Golding
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Shire Llc
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Priority to EP07824910A priority Critical patent/EP2097390A1/fr
Priority to BRPI0719568-0A priority patent/BRPI0719568A2/pt
Priority to AU2007327048A priority patent/AU2007327048B2/en
Priority to CN2007800442221A priority patent/CN101558048B/zh
Priority to JP2009538793A priority patent/JP2010511031A/ja
Priority to CA002670168A priority patent/CA2670168A1/fr
Priority to MX2009005578A priority patent/MX2009005578A/es
Priority to EA200900742A priority patent/EA017139B1/ru
Publication of WO2008065445A1 publication Critical patent/WO2008065445A1/fr
Priority to IL198808A priority patent/IL198808A0/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C07D239/84—Nitrogen atoms
    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • 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

Definitions

  • This invention relates to the discovery of prodrugs of 3-or 5-substituted analogues of the selective platelet lowering agent anagrelide which have reduced potential for cardiovascular side-effects and which should therefore lead to improved patient compliance and safety in the treatment of myeloproliferative diseases. More specifically, the present invention relates to prodrugs of certain imidazoquinazoline derivatives which have utility as platelet lowering agents in humans. The compounds of the present invention function by inhibiting the formation of blood platelets.
  • Anagrelide hydrochloride (Agrylin®, Xagrid®) is a novel orally administered imidazoquinazoline which selectively reduces platelet count in humans and is used for such purposes in the treatment of myeloproliferative diseases (MPDs), such as essential thrombocythemia (ET), where an elevated platelet count may put the patient at increased thrombotic risk.
  • MPDs myeloproliferative diseases
  • ET essential thrombocythemia
  • the chemical structure of anagrelide, 6,7-dichloro-l,5-dihydroimidazo[2,l-b]- quinazolin-2(3H)-one (hydrochloride monohydrate) is shown in the following formula:
  • anagrelide cardiovascular in nature, tachycardia, palpitations etc and limit the utility of the drug. These are largely attributed to its metabolism to 3- hydroxyanagrelide. This compound was surprisingly found to be some 40-fold more potent as an inhibitor of PDEIII, and therefore potential inotropic agent, than anagrelide itself. Furthermore plasma exposure to this metabolite after treatment with anagrelide is typically three times greater than to the drug itself confirming its pivotal role. Consequently a series of 3-substituted anagrelide analogues has been investigated which has shown that it is possible to introduce metabolism blocking groups at that position and yet still retain the anti-megakaryocytic actions of the drug.
  • 3-substituted compounds typified, by the dimethyl or spirocyclopropyl analogues, are notably less soluble at physiological pH ( ⁇ 7) than the parent compound which presents a significant challenge to their efficient absorption.
  • Anagrelide HCl itself is a poorly soluble drug substance. In the pH range of 4 - 8, the solubility is less thanlO ⁇ g/mL. The solubility increases at pH values above and below this range; for example in 0.1M HCl the solubility is -170 ⁇ g /mL and at pH 11.4 approaches lmg/mL.
  • the dissociation constants (pKal and pKa2) of 2.9 and 9.8 were estimated from the solubility/pH profile of anagrelide HCl. Thus over much of the physiological pH range the drug has very poor aqueous solubility. Even material dissolving in the stomach at pH 1-2 may precipitate in the duodenum at pH 5-6.
  • WO2004/063172 relates to the use of 2-amino-2H-quinazoline derivatives for producing therapeutic agents for the treatment of myeloproliferative diseases, high blood pressure and bronchodilation.
  • This invention provides for prodrugs of anagrelide derivatives substituted at either the 3- or 5- position.
  • metabolism to an analogue of the cardioactive 3- hydroxyanagrelide is blocked either directly (3-substitution) or indirectly (5-substitution).
  • the prodrugs are notably more soluble in vitro (and under anticipated in vivo conditions) than their ring closed analogues offering the potential for better absorption from the GI tract.
  • Such compounds would spontaneously and completely ring close at pH 7 or above thus offering a convenient means of delivering these ring closed anti-megakaryocytic (platelet lowering) agents to the systemic circulation.
  • anagrelide Since the preferred site of metabolism of anagrelide is the 3-position, such compounds are likely to present improved pharmacokinetic profile and hence improve patient compliance and convenience enabling a broader spectrum of patients to be effectively treated.
  • a bulky group In the case of the 5-substituted compounds it is expected that a bulky group is more effective than a smaller group when cyclised to the 'closed ring' anagrelide analogue. Groups such as t-butyl and other bulky blocking groups are thus expected to be of most utility when substituted at the 5-position.
  • a substituent comprising a large group at the 5-position is expected to sterically hinder access to the 3-position by the metabolising cytochrome's active site. This should inhibit formation of the cardioactive metabolite, 3-hydroxyanagrelide.
  • the ring closed compounds of the present invention are especially beneficial because surprisingly they have dramatically lower PDE III inhibitory activity (and hence lower cardioactive potential) than the active metabolite of anagrelide, 3 -hydroxy anagrelide and yet also surprisingly retain their anti-megakaryocytic activity. Indeed these compounds have therapeutic indices which are much more favourable than that for anagrelide itself.
  • the present invention comprises a prodrug of an anagrelide analogue comprising a 3-, 5-, 3, 3- or 5,5-substituted anagrelide compound.
  • first pass metabolism of the rapidly ring closed analogue
  • the invention relates to prodrugs of an anagrelide analogue wherein first pass metabolism to the corresponding analogue of 3- hydroxyanagrelide is effectively blocked.
  • R 1 , R 2 , R 3 and R 4 independently represent hydrogen or a blocking group which functions to prevent metabolic reaction either directly or indirectly at the 3- position;
  • R 1 and R 2 , and/or R 3 and R 4 together with the carbon to which they are attached form a blocking group which functions to prevent metabolic reaction either directly or indirectly at the 3- or 5-position of substitution, the remainder of groups R 1 to R 4 being hydrogen;
  • R is selected from the group comprising: fluoro, chloro, bromo and iodo
  • R 6 is selected from the group comprising: fluoro, chloro, bromo and iodo
  • R 7 and R 8 are independently selected from the group comprising: H; halo; cyano; C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy; and
  • R 9 is H or Ci_ 6 alkyl
  • R 10 is selected from the group comprising: hydrogen; C 1-6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl and C 3 _ 8 cycloalkyl wherein each of the foregoing groups may be optionally substituted by 1 to 5 groups chosen independently from the group comprising: halo, hydroxyl, cyano, nitro, C 1-4 alkylsulphonyl and COOH; or R 10 is a pharmaceutically acceptable cation, and
  • X is O or S
  • R 1 , R 2 , R 3 and R 4 are not all hydrogen.
  • R 1 and R 2 are methyl and R 3 and R 4 are hydrogen then other of R 1 and R 2 is not hydrogen.
  • R 1 and R 2 are independently selected from the group comprising: H; halo; cyano; C 1-6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3 _ 8 cycloalkyl wherein said alkyl, alkenyl, alkynyl or cycloalkyl groups may be optionally substituted by 1 to 5 groups chosen independently from the group comprising: halo, hydroxyl, cyano, nitro, C 1-4 alkylsulphonyl and COOH; C 1-6 hydroxyalkyl; C 1-6 carboxyalkyl; and sulphide;
  • R 1 and R 2 together with the carbon to which they are attached form a C 3 _s carbocyclic ring may be optionally substituted by 1 to 5 groups chosen independently from the group comprising: halo, hydroxyl, cyano, nitro, C 1-4 haloalkyl, C 1-4 alkylsulphonyl and COOH; or R 1 and R 2 together with the carbon to which they are attached represent a C2-6 alkenyl or C2-6 alkynyl group bound through a double bond to the ring to which it is attached and being optionally substituted by one to three groups independently selected from the group comprising: halo, hydroxyl, cyano, C 1-4 haloalkyl and COOH, provided always that one of R 1 and R 2 is not hydroxyl when the other is methyl.
  • R 1 is an optionally substituted C 1-4 alkyl or C 3 _s cycloalkyl group.
  • R 2 is an optionally substituted C 1-4 alkyl or C 3 _ 8 cycloalkyl group.
  • R 1 and R 2 is CF 3 or CHF 2 . More preferably, at least one of R 1 and R 2 is CF 3 .
  • R 1 is preferably methyl, cyclopropyl, CF 3 or CHF 2 . Most preferably, R 1 is methyl.
  • R 2 is preferably methyl, cyclopropyl, CF 3 or CHF 2 . Most preferably R 2 is methyl.
  • R 1 and R 2 together form an optionally substituted C 3 _ 8 cycloalkyl group. Most preferably this is a cyclopropyl group.
  • R 3 and R 4 are independently selected from the group comprising: H; halo; cyano; C 1-6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 3 _ 8 cycloalkyl wherein said alkyl, alkenyl, alkynyl or cycloalkyl roups may be optionally substituted by 1 to 5 groups chosen independently from the group comprising: halo, hydroxyl, cyano, nitro, C 1-4 alkylsulphonyl and COOH; C 1-6 hydroxyalkyl; C 1-6 carboxyalkyl; and sulphide;
  • R 3 and R 4 together with the carbon to which they are attached form a C 3 - S carbocyclic ring may be optionally substituted by 1 to 5 groups chosen independently from the group comprising: halo, hydroxyl, cyano, nitro, C 1-4 haloalkyl, C 1-4 alkylsulphonyl and COOH;
  • R 3 and R 4 together represent a C2-6 alkenyl or C2-6 alkynyl group bound through a double bond to the ring to which it is attached and being optionally substituted by one to three groups independently selected from the group comprising: halo, hydroxyl, cyano, C 1-4 haloalkyl and COOH.
  • R 3 is H or C 1-6 alkyl. Preferably, R 3 is H.
  • R 4 is H or C 1-6 alkyl. Preferably, R 4 is H.
  • R 5 is chloro
  • R 6 is chloro
  • R 7 is H.
  • R is H.
  • R 9 is H or Me. In one embodiment, R 9 is H and compounds in which R 9 is H enjoy good solubility. When R 9 is a C 1-6 alkyl group, such as Me, the PDE III inhibiting activity is effectively eliminated. Me represents a particularly preferred alkyl substituent.
  • R 10 is H or optionally substituted C 1-6 alkyl. Most preferably, R 10 is C 1-6 alkyl. In an alternative embodiment, R 10 is Na or K, with Na being preferred. In an embodiment, X is O.
  • R 1 and R 2 are independently selected from the group comprising: H; cyano; C 1-6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 3 _ 8 cycloalkyl wherein said alkyl, alkenyl, alkynyl or cycloalkyl groups may be optionally substituted by 1 to 5 groups chosen independently from the group comprising: halo, hydroxyl, cyano, nitro, C 1-4 alkylsulphonyl and COOH; C 1-6 hydroxyalkyl; C 1-6 carboxyalkyl; and sulphide;
  • R 1 and R 2 together with the carbon to which they are attached form a C 3 _ 8 carbocyclic ring may be optionally substituted by 1 to 5 groups chosen independently from the group comprising: halo, hydroxyl, cyano, nitro, C 1-4 haloalkyl, C 1-4 alkylsulphonyl and COOH;
  • R 1 and R 2 together represent a C 2 - 6 alkenyl or C 2 - 6 alkynyl group bound through a double bond to the ring to which it is attached and being optionally substituted by one to three groups independently selected from the group comprising: halo, hydroxyl, cyano, C 1-4 haloalkyl and COOH;
  • R 3 and R 4 are hydrogen
  • R 5 is selected from the group comprising: fluoro, chloro, bromo and iodo;
  • R 6 is selected from the group comprising: fluoro, chloro, bromo and iodo;
  • R 7 , R 8 , R 9 and R 10 are hydrogen.
  • R 1 and R 2 are both independently selected from the group comprising: cyano, C 1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, in which the alkyl, alkenyl, and alkynyl groups may be optionally substituted;
  • R 1 and R 2 together represent an optionally substituted C 2 - 6 alkenyl or C 2 - 6 alkynyl group.
  • Particularly preferred individual compounds of the invention include:
  • composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable diluent or carrier, which may be adapted for oral, parenteral or topical administration;
  • a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of a disease selected from: myeloprolific diseases and generalised thrombotic diseases.
  • a method of treating a disease selected from: myeloprolific diseases and generalised thrombotic diseases in a human which comprises treating said human with an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or with a pharmaceutical composition containing any of the foregoing.
  • the present invention also encompasses a method of treating a patient having essential thrombocythemia or other myelproliferative disesase or thrombotic cardiovascular disease or high blood platelet count, which method comprises administering to the patient a therapeutically effective amount of a compound of the present invention.
  • Another embodiment of the present invention includes a method of reducing blood platelet count within a patient, which method comprises administering to the patient a therapeutically effective amount of a compound of the present invention.
  • the present invention encompasses providing the compounds of the present invention for the methods listed above, among others, wherein cardiotoxicity is reduced compared to using anagrelide.
  • the present invention also encompasses pharmaceutical compositions comprising a compound or pharmaceutically acceptable salt of a compound of the present invention and a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable salts of the compounds of Formula (I) include acid addition salts. Examples include hydrochloric and hydrobromide salts.
  • the present invention is directed to new prodrugs of 3-or 5-substituted analogues of the established platelet lowering agent anagrelide. These compounds spontaneously ring close at pH's 7 and above to yield 3-or 5-substituted anagrelides that retain the anti-megakaryocytic properties (hence platelet lowering activity) of anagrelide but have reduced PDEIII inhibitory properties and hence lower potential for unwanted cardiovascular and anti-aggregatory side- effects.
  • anagrelide molecule effectively blocks the principal site of metabolism and thus precludes the formation of the highly potent PDEIII inhibitor 3-OH anagrelide.
  • the 5-substituted analogues have the potential to indirectly sterically hinder metabolism at the preferred 3-position.
  • These 3-or 5-substituted analogues of anagrelide also have the potential for improved pharmacokinetic characteristics since the 3-position in the anagrelide molecule is known to be the major site of metabolism which is the principal mechanism of drug clearance.
  • aqueous solubility of anagrelide at pH 7 is ⁇ 10ug/ml.
  • ethyl- 5,6-dichloro-3,4-dihydro-2-(lH)-iminoquinazoline-3-acetate HBr - an unsubstituted but representative example of these ring open prodrugs - the solubility is ⁇ 5.5mg/ml in distilled water.
  • prodrugs are likely to be extremely rapidly and completely cyclised in plasma to the closed ring 3-alkylanagrelide analogues.
  • rapid and quantitative conversion of ethyl- 5,6-dichloro-3,4-dihydro-2-(lH)-iminoquinazoline-3-acetate HBr - an unsubstituted but representative example of these ring open prodrugs - to anagrelide was demonstrated in human plasma using LC/MS-MS analytical techniques.
  • Human plasma was spiked with anagrelide prodrug (final concentration 100 ng/mL).
  • anagrelide prodrug final concentration 100 ng/mL
  • Figure 1 shows the levels of anagrelide prodrug, ethyl-5,6- dichloro-3,4-dihydro-2-(lH)-iminoquinazoline-3 acetate and anagrelide observed in samples of human plasma, incubated at room temperature over one hour.
  • C max for anagrelide after the prodrug ranged from 170 - 418 ngmL 1 (relative standard deviation, RSD, 26%) compared to 9.5 to 44.3 ngmL 1 after anagrelide itself (RSD 62.5%).
  • RSD relative standard deviation
  • AUC for anagrelide after the prodrug ranged from 367 to 1470 ng.hmL "1 (RSD 34%) compared to 21.6 to mng.hmL ⁇ RSD 71%) after anagrelide itself.
  • the lesser variability was consistent with more efficient absorption. This study illustrated the potential benefits of the open-ring prodrugs to improve absorption.
  • Halo means a group selected from: fluoro, chloro, bromo or iodo.
  • alkyl as used herein as a group or a part of a group refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms.
  • C 1 10 alkyl means a straight or branched alkyl containing at least 1 and at most 10 carbon atoms.
  • alkyl as used herein include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n- pentyl, isobutyl, isopropyl, t-butyl, hexyl, heptyl, octyl, nonyl and decyl.
  • a C 1 4 alkyl group is one embodiment, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or t-butyl.
  • cycloalkyl refers to a non-aromatic monocyclic hydrocarbon ring of 3 to 8 carbon atoms such as, for example, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • spirocyclic refers to a ring system joined to a second ring system at one carbon atom.
  • alkoxy refers to a straight or branched hydrocarbon chain group containing oxygen and the specified number of carbon atoms.
  • C 1 6 alkoxy means a straight or branched alkoxy containing at least 1 and at most 6 carbon atoms.
  • alkoxy as used herein include, but are not limited to, methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy, 2-methylprop-l-oxy, 2-methylprop-2-oxy, pentoxy and hexyloxy.
  • a C 1 4 alkoxy group is one embodiment, for example methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy or 2-methylprop-2-oxy.
  • hydroxyalkyl refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms, which is substituted by 1-3 hydroxyl groups.
  • C 1 4 hydroxyalkyl means a straight or branched alkyl chain containing from 1 to 4 carbon atoms and at least one hydroxyl group; examples of such group include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, hydroxybutyl and the like.
  • alkenyl as used herein as a group or a part of a group refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms and containing at least one double bond.
  • C 2 6 alkenyl means a straight or branched alkenyl containing at least 2 and at most 6 carbon atoms and containing at least one double bond.
  • alkenyl examples include, but are not limited to, ethenyl, 2-propenyl, 3- butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, 3-methylbut-2-enyl, 3-hexenyl and l,l-dimethylbut-2-enyl. It will be appreciated that in groups of the form -0-C 2 6 alkenyl, the double bond is preferably not adjacent to the oxygen.
  • alkynyl as used herein as a group or a part of a group refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms and containing at least one triple bond.
  • C 2 6 alkynyl means a straight or branched alkynyl containing at least 2 and at most 6 carbon atoms and containing at least one triple bond.
  • alkynyl examples include, but are not limited to, ethynyl, 2-propynyl, 3- butynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 3-methyl-2-butynyl, 3-methylbut-2-ynyl, 3- hexynyl and l,l-dimethylbut-2-ynyl. It will be appreciated that in groups of the form -0-C 2 6 alkynyl, the triple bond is preferably not adjacent to the oxygen.
  • halo refers to halogens such as fluorine, chlorine, bromine or iodine atoms.
  • sulfuride refers to a radical of R a -S-R b , wherein a sulfur atom is covalently attached to two hydrocarbon chains, R a and R b , wherein the two hydrocarbon chains may be, for example, but not limited to, any discussed above.
  • the compounds of the invention when cyclised may possess antimegakaryocytic activity in humans. Such activity may be assessed using a well established model. Assessment of the in vitro anti-megakaryocytic activity - and potentially therefore the platelet lowering capability - of the anagrelide prodrugs can be determined using the model of megakaryocytopoiesis (Cohen-Solal et al., Thromb. Haemost. 1997, 78:37-41 and Cramer et al., Blood, 1997, 89:2336-46). This involves examining the differentiation of human CD34 + stem cells into megakaryocytes which ultimately give rise to blood platelets.
  • the compounds of the invention may be particularly useful in the treatment of myeloproliferative diseases.
  • the compounds may also find utility in the treatment of generalised thrombotic diseases.
  • references to treatment include prophylaxis as well as the alleviation and/or cure of established symptoms of a condition.
  • Treating" or “treatment” of a state, disorder or condition includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
  • Myeloproliferative diseases which may be treatable with the compounds of the present invention include: essential thrombocythemia, polycythema vera, chronic idiopathic myelofibrosis, chronic myeloid leukaemia with residual thrombocytosis, reactive thrombocytosis immediately preceding a surgical procedures, as an immediate or post operative preventative measures to minimise the risk of thrombus formation during or post surgery.
  • Thrombotic cardiovascular diseases i.e. patients at increased generalised thrombotic risk
  • TCVD Thrombotic cardiovascular diseases
  • myocardial infarct heart attack
  • coronary stent placement patients having undergone coronary stent placement.
  • the compounds of the present invention may also find utility in indicated for the reduction of atherothrombotic events as follows: recent MI, recent stroke or established peripheral arterial disease, acute coronary syndrome (unstable angina/non-Qwave MI), cardiovascular death, MI, stroke, and refractory ischemia.
  • the spirocyclopropylanagrelide derivative can be prepared using established chemistry as described previously according to the following reaction scheme. Other derivatives can be made in a likewise manner.
  • the final product is obtained by cyclisation of the cyclopropyl precursor in the presence of cyanogen bromide and ethanol.
  • the figures show that the compounds of the invention have substantially improved solubilityover their corresponding closed ring counterparts. This means that the compounds can be formulated and administered to patients in higher dosages than is possible for the closed ring versions. This represents a major clinical advantage.

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Abstract

La présente invention concerne la découverte de promédicaments constitués d'analogues substitués en position 3 ou 5 d'anagrélide, un agent réduisant sélectivement la production des plaquettes. Ces promédicaments présentent un risque réduit d'effets secondaires cardiovasculaires et devraient par conséquent contribuer à une meilleure observance du patient à la thérapie et à une meilleure innocuité dans le traitement de maladies liées à une myéloprolifération. Plus spécifiquement, la présente invention concerne des promédicaments constitués de certains dérivés d'imidazoquinazoline qui peuvent servir d'agents réduisant la production des plaquettes chez les êtres humains. Les composés de la présente invention agissent en inhibant la formation des plaquettes sanguines.
PCT/GB2007/050698 2006-11-28 2007-11-19 Dérivés d'aminoquinazolines dotés de propriétés réduisant la production des plaquettes sanguines WO2008065445A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
EP07824910A EP2097390A1 (fr) 2006-11-28 2007-11-19 Dérivés d'aminoquinazolines dotés de propriétés réduisant la production des plaquettes sanguines
BRPI0719568-0A BRPI0719568A2 (pt) 2006-11-28 2007-11-19 Derivados de amino quinazolinas com propriedades de redução de plaquetas sanguíneas
AU2007327048A AU2007327048B2 (en) 2006-11-28 2007-11-19 Amino quinazolines derivatives with blood platelet reducing properties
CN2007800442221A CN101558048B (zh) 2006-11-28 2007-11-19 具有血小板降低性质的氨基喹唑啉衍生物
JP2009538793A JP2010511031A (ja) 2006-11-28 2007-11-19 血小板減少性を有するアミノキナゾリン誘導体
CA002670168A CA2670168A1 (fr) 2006-11-28 2007-11-19 Derives d'aminoquinazolines dotes de proprietes reduisant la production des plaquettes sanguines
MX2009005578A MX2009005578A (es) 2006-11-28 2007-11-19 Derivados de aminoquinazolinas con propiedades reductoras de plaquetas de la sangre.
EA200900742A EA017139B1 (ru) 2006-11-28 2007-11-19 Производные аминохиназолина с понижающими тромбоциты свойствами
IL198808A IL198808A0 (en) 2006-11-28 2009-05-19 Amino quinazolines derivatives with blood platelet reducing properties

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GBGB0623749.9A GB0623749D0 (en) 2006-11-28 2006-11-28 Substituted quinazolines

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WO2011114163A1 (fr) 2010-03-18 2011-09-22 Shire Llc Quinazolines substituées (cycle ouvert)
US20110263850A1 (en) * 2008-12-17 2011-10-27 Shire Llc Process for the preparation of anagrelide and analogues
US11324746B2 (en) 2014-12-22 2022-05-10 Arovella Therapeutics Limited Use of anagrelide for treating cancer

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CN103254197A (zh) * 2013-05-29 2013-08-21 黑龙江大学 一种盐酸阿那格雷的制备方法

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WO2001040196A1 (fr) * 1999-11-30 2001-06-07 Roberts Laboratories Inc. 2-amino-5,6-dihalo-3,4-dihydroquinazolines dotees de proprietes de reduction de la numeration des thrombocytes
WO2006017822A2 (fr) * 2004-08-04 2006-02-16 Shire Holdings Ag Derives de quinazoline, utilisation de ces derniers dans le traitement de la thrombocythemie
US20060148832A1 (en) * 2003-01-09 2006-07-06 Rolf Sachse Use of 2-amino-2h-quinazoline derivatives for producing therapeutic agents

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WO2001040196A1 (fr) * 1999-11-30 2001-06-07 Roberts Laboratories Inc. 2-amino-5,6-dihalo-3,4-dihydroquinazolines dotees de proprietes de reduction de la numeration des thrombocytes
US20060148832A1 (en) * 2003-01-09 2006-07-06 Rolf Sachse Use of 2-amino-2h-quinazoline derivatives for producing therapeutic agents
WO2006017822A2 (fr) * 2004-08-04 2006-02-16 Shire Holdings Ag Derives de quinazoline, utilisation de ces derniers dans le traitement de la thrombocythemie

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Publication number Priority date Publication date Assignee Title
US20110263850A1 (en) * 2008-12-17 2011-10-27 Shire Llc Process for the preparation of anagrelide and analogues
JP2012512237A (ja) * 2008-12-17 2012-05-31 シャイア エルエルシー アナグレリドの製造法
US8530651B2 (en) * 2008-12-17 2013-09-10 Shire Llc Process for the preparation of anagrelide and analogues
WO2011114163A1 (fr) 2010-03-18 2011-09-22 Shire Llc Quinazolines substituées (cycle ouvert)
US11324746B2 (en) 2014-12-22 2022-05-10 Arovella Therapeutics Limited Use of anagrelide for treating cancer

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TW200829252A (en) 2008-07-16
GB0623749D0 (en) 2007-01-10
CA2670168A1 (fr) 2008-06-05
MY149620A (en) 2013-09-13
EP2097390A1 (fr) 2009-09-09
CN101558048A (zh) 2009-10-14
BRPI0719568A2 (pt) 2013-12-10
AU2007327048B2 (en) 2012-01-12
AU2007327048A1 (en) 2008-06-05
AR064003A1 (es) 2009-03-04
EA017139B1 (ru) 2012-10-30
MX2009005578A (es) 2009-07-29
JP2010511031A (ja) 2010-04-08
EA200900742A1 (ru) 2010-08-30
IL198808A0 (en) 2010-02-17
KR20090089865A (ko) 2009-08-24

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