WO2015193630A1 - Traitement d'un risque cardio-vasculaire chez des patients présentant une maladie cardio-vasculaire et/ou du diabète - Google Patents

Traitement d'un risque cardio-vasculaire chez des patients présentant une maladie cardio-vasculaire et/ou du diabète Download PDF

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WO2015193630A1
WO2015193630A1 PCT/GB2015/000187 GB2015000187W WO2015193630A1 WO 2015193630 A1 WO2015193630 A1 WO 2015193630A1 GB 2015000187 W GB2015000187 W GB 2015000187W WO 2015193630 A1 WO2015193630 A1 WO 2015193630A1
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compound
dioxan
hex
chlorophenyl
hydroxyphenyl
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PCT/GB2015/000187
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English (en)
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Marco Cattaneo
Norbert Bender
Kjell Sakariassen
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Evolva Sa
Golding, Louise, Ann
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Publication of WO2015193630A1 publication Critical patent/WO2015193630A1/fr

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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/558—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing oxygen as the only ring hetero atom, e.g. thromboxanes
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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

Definitions

  • the invention relates to methods of treating cardiovascular risk in a patient with coronary artery disease and/or diabetes.
  • CVDs cardiovascular diseases
  • Diabetic complications which include cardiovascular events, are manifestations of systemic disease which affect 80% or more of all diabetic patients during their lifetime. And the longer a person has diabetes, the higher the chances of experiencing a cardiovascular event.
  • ASA aspirin
  • P2Y12 receptor antagonists because epinephrine is normally present in circulating blood, especially in the morning, when the incidence of myocardial infarction is particularly high.
  • the invention provides methods for reducing risk of cardiovascular event in a patient with coronary artery disease and/or diabetes being treated with aspirin and/or a P2Y12 inhibitor, comprising administering to a patient a therapeutically effective amount of a pharmaceutically acceptable form of a compound which is (Z)-6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-hydroxyphenyl)- 1 ,3-dioxan-5-yl)hex-4-enoic acid at a time when the patient has an elevated epinephrine level.
  • the invention provides a pharmaceutically acceptable form of a compound which is (Z)-6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-hydroxyphenyl)-1 ,3-dioxan-5-yl)hex-4- enoic acid for use in a method of reducing risk of cardiovascular event in a patient with coronary artery disease and/or diabetes being treated with aspirin and/or a P2Y12 inhibitor, said method comprising administering to said patient a therapeutically effective amount of said compound at a time when the patient has an elevated epinephrine level.
  • the invention provides the use of a pharmaceutically acceptable form of a compound which is (Z)-6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-hydroxyphenyl)-1 ,3-dioxan-5- yl)hex-4-enoic acid in the manufacture of a medicament for use in a method of reducing risk of cardiovascular event in a patient with coronary artery disease and/or diabetes being treated with aspirin and/or a P2Y12 inhibitor, said method comprising administering to said patient a therapeutically effective amount of said compound at a time when the patient has an elevated epinephrine level.
  • the compound (Z)-6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-hydroxyphenyl)-1 ,3- dioxan-5-yl)hex-4-enoic acid is a dual thromboxane receptor (TP) antagonist and thromboxane synthase (TS) inhibitor.
  • TP thromboxane receptor
  • TS thromboxane synthase
  • PD means pharmacodynamic(s)
  • TBS means tert-butylamine salt
  • TP means thromboxane receptor
  • TS means thromboxane synthase
  • TxA 2 means Thromboxane A2
  • TxB 2 means Thromboxane B2
  • CVD means cerebral vascular diseases
  • TIA means transient ischemic attack
  • AA arachidonic acid
  • PRP platelet-rich plasma
  • PPP platelet-poor plasma
  • MEA Multiplate Analyzer
  • LTA light transmission aggregometry
  • hs-CRP means C-reactive protein
  • FPA fibrin peptide
  • ADP means adenosine diphosphate
  • Optional and “optionally” mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
  • optional pharmaceutical excipients indicates that a formulation so described may or may not include pharmaceutical excipients other than those specifically stated to be present, and that the formulation so described includes instances in which the optional excipients are present and instances in which they are not.
  • Treating and “treatment” refer to any treatment of a disease or the complications arising from a disease in a mammal, particularly a human, and include:
  • treating refers to any treatment of a disease or the complications arising from a disease in a mammal, particularly a human, and include:
  • the phrase "therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician.
  • Modified release formulations as used herein refer to pharmaceutical formulations designed to release the drug or pharmaceutical in a manner that is different than an immediate release formulation.
  • a modified release formulation may be a controlled release, sustained release, extended release, or delayed release formulation.
  • Particular modified release formulations suitable for use in the invention are extended release formulations that release a drug or compound in the body over an extended period of time.
  • Compound 1 is a racemic mixture of (Z)-6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2- hydroxyphenyl)-1 ,3-dioxan-5-yl)hex-4-enoic acid and (Z)-6-((2R,4R,5S)-2-(2-chlorophenyl)-4-(2- hydroxyphenyl)-1 ,3-dioxan-5-yl)hex-4-enoic acid as described in WO 2008/089461.
  • the synthesis of Compound 1 is described in Example 1 of WO 2008/089461 ; see Scheme 2, structure 2-14.
  • Compound 2 is (Z)-6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-hydroxyphenyl)-1 ,3- dioxan-5-yl)hex-4-enoic acid, a single enantiomer of Compound 1.
  • the separation of Compound 2 from its enantiomer is described in Example 30 of WO 2008/089461.
  • Compound 3 is iert-butylammonium (Z)-6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2- hydroxyphenyl)-1 ,3-dioxan-5-yl)hex-4-enoate (the ferf-butylamine salt (TBS) of Compound 2) as described in WO 2008/089461 .
  • Compound 3 is a dual thromboxane receptor (TP) antagonist and thromboxane synthase (TS) inhibitor. The preparation of Compound 3 is described in Example 36 of WO 2008/089461.
  • Compound 2 is a highly active TP antagonist and a thromboxane synthase
  • Compound 3 is a highly soluble and crystalline salt of Compound 2, and is a highly effective vehicle for the delivery of Compound 2.
  • Compound 3 has been shown to antagonize TP receptor activation in vivo at concentrations ranging from 0.125 to 2.5 mg/kg. See, e.g., Richardson A. ef a/. Eur J Clin Pharmacol. 2013 69(3):459-65. DOI:10.1007/s00228-012-1348-9. The disclosure of this article is incorporated herein by reference in its entirety.
  • cardiovascular events such as, for example, thrombotic disorders, vascular inflammation, vascular oxidative stress, arterial thrombotic events, complications of peripheral arterial diseases, cardiovascular diseases including myocardial infarction, acute coronary syndrome, angina, percutaneous coronary intervention, cerebrovascular diseases (CVD) such as stroke and transient ischemic attacks (TIAs) and carotid stenosis.
  • CVD cerebrovascular diseases
  • TIAs stroke and transient ischemic attacks
  • carotid stenosis carotid stenosis.
  • the disclosed invention provides methods for reducing risk of cardiovascular event in a patient with coronary artery disease being treated with aspirin and/or a P2Y12 inhibitor, comprising administering to the patient a therapeutically effective amount of a pharmaceutically acceptable form of a compound which is (Z)-6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-hydroxyphenyl)-1 ,3-dioxan-5- yl)hex-4-enoic acid at a time when the patient has an elevated epinephrine level.
  • the disclosed invention also provides a pharmaceutically acceptable form of a compound which is (Z)-6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-hydroxyphenyl)-1 ,3-dioxan-5-yl)hex-4- enoic acid for use in a method of reducing risk of cardiovascular event in a patient with coronary artery disease being treated with aspirin and/or a P2Y12 inhibitor, said method comprising administering to the patient a therapeutically effective amount of said compound at a time when the patient has an elevated epinephrine level.
  • the disclosed invention also provides methods for reducing risk of cardiovascular event in a diabetic patient being treated with aspirin and/or a P2Y12 inhibitor, comprising administering to the patient a therapeutically effective amount of a pharmaceutically acceptable form of a compound which is (Z)-6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-hydroxyphenyl)-1 ,3-dioxan-5-yl)hex-4-enoic acid at a time when the patient has an elevated epinephrine level.
  • the disclosed invention also provides a pharmaceutically acceptable form of a compound which is (Z)-6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-hydroxyphenyl)-1 ,3-dioxan-5-yl)hex-4- enoic acid for use in a method of reducing risk of cardiovascular event in a diabetic patient being treated with aspirin and/or a P2Y12 inhibitor, said method comprising administering to the patient a therapeutically effective amount of said compound at a time when the patient has an elevated epinephrine level.
  • the disclosed invention further provides the use of a pharmaceutically acceptable form of a compound which is (Z)-6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-hydroxyphenyl)-1 ,3-dioxan-5- yl)hex-4-enoic acid in the manufacture of a medicament for use in any of the methods of treatment herein described.
  • the P2Y12 inhibitor is selected from cangrelor, prasugrel, ticagrelor, elinogrel, clopidogrel (Plavix®), or ticlopidine, and combinations thereof.
  • (2-chlorophenyl)-4-(2-hydroxyphenyl)-1 ,3-dioxan-5-yl)hex-4-enoic acid is a dose from about 0.0001 mg to about 20 mg of (Z)-6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-hydroxyphenyl)-1 ,3-dioxan-5-yl)hex-4- enoic acid per kg of the patient body weight per day. [0036] In further embodiments, the therapeutically effective amount of (Z)-6-((2S,4S,5R)-2-
  • (2-chlorophenyl)-4-(2-hydroxyphenyl)-1 ,3-dioxan-5-yl)hex-4-enoic acid is a dose of from about 0.001 mg to about 1 mg of (Z)-6-((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-hydroxyphenyl)-1 ,3-dioxan-5-yl)hex-4- enoic acid per kg of the patient body weight per day.
  • the time when the patient has an elevated epinephrine level is in the morning.
  • elevated epinephrine level is meant a plasma level of epinephrine which exceeds the normal level in a resting adult, in particular a level which is above about twice the normal epinephrine level.
  • the normal plasma level of epinephrine in a resting adult is below about 10 ng/L.
  • an “elevated epinephrine level” may be considered one which is at least 10 ng/L, for example, a plasma level of about 20 ng/L or higher.
  • the "morning" will generally be understood to mean the first few hours following waking, for example, the period of up to about 3 hours from waking.
  • the cardiovascular event is myocardial infarction, thrombosis, a thrombotic disorder, stent triggered thrombus formation, stent induced restenosis, stent- triggered hyperplasia, peripheral arterial disease, pulmonary embolism or thrombus formation.
  • ((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-hydroxyphenyl)-1 ,3-dioxan-5-yl)hex-4-enoic acid is an amorphous form, a crystalline form, a salt, a polymorph, a co-crystal, a solvate, or a prodrug.
  • the pharmaceutically acceptable form useful in the invention comprises Compound 2 (as the acid).
  • the pharmaceutically acceptable form may be a crystalline or amorphous salt of Compound 2 selected from, e.g., tert- butylamine salts, sodium salts, potassium salts, arginine salts, lysine salts, calcium salts, zinc salts, magnesium salts, choline salts, ethylenediamine salts, ethanolamine salts, ammonium salts, hydroxyethylpyrrolidine salts, dimethylaminoethanol salts, hydroxyethylmorpholine salts, N- ethylglucamine salts, N-methylglucamine salts, tromethamine salts, imidazole salts, or wherein the compound is a di-salt on both the carboxylic acid and the phenol moieties, such as, for example a di- sodium and a di-potassium salt.
  • Compound 2 selected from, e.g., tert- butylamine salts, sodium salts, potassium salts, argin
  • ((2S,4S,5R)-2-(2-chlorophenyl)-4-(2-hydroxyphenyl)-1 ,3-dioxan-5-yl)hex-4-enoic acid is a solvate selected from (a) hydrates of (Z)-6-((2S,4S,5R)-2- ⁇ 2-chlorophenyl)-4-(2-hydroxyphenyl)-1 ,3-dioxan-5- yl)hex-4-enoic acid or a salt thereof, (b) ethanol, 1-butanol, isopropanol and dioxane solvates of Compound 3, (c) co-crystals of Compound 3 with glycerol, and (d) methyl fert-butyl ether (MTBE) solvates of Compound 3, or the co-crystal is the tert-butylamine salt of a racemic mixture of (Z)-6- ((2S,4S,5R)-2
  • the pharmaceutically acceptable form may be a prodrug.
  • Prodrug refers to a derivative of an active compound (drug) that undergoes a transformation under the conditions of use, such as within the body, to release an active drug.
  • Prodrugs are frequently, but not necessarily, pharmacologically inactive until converted into the active drug.
  • Prodrugs are typically obtained by masking a functional group in the drug believed to be in part required for activity with a "progroup”.
  • Progroups are typically attached to the functional group of the drug via bonds that are cleavable under specified conditions of use.
  • the cleavage of the progroup may proceed spontaneously, such as by way of a hydrolysis reaction, or it may be catalyzed or induced by another agent, such as by an enzyme, by light, by acid, or by a change of or exposure to a physical or environmental parameter, such as a change of temperature, or combination thereof.
  • the agent may be endogenous to the conditions of use, such as an enzyme present in the cells to which the prodrug is administered or the acidic conditions of the stomach, or it may be supplied exogenously. See U.S. Patent No. 8,486,994.
  • the compound may be a dual thromboxane receptor (TP) antagonist and thromboxane synthase (TS) inhibitor selected from compounds of Formula I:
  • X is selected from the group consisting of fluoro, chloro, bromo, trifluoromethyl, substituted phenyl, cyano, methoxy, nitro, hydroxyl and -H
  • Y is selected from the group consisting of fluoro, chloro, bromo, trifluoromethyl, substituted phenyl, cyano, methoxy, nitro, hydroxyl, -C(O)- saccharide and -H
  • Rd is -NH-C 1-6 -alkyl (branched or linear, preferably linear),-0-Ci_ 6 -alkyl (branched or linear, preferably linear), a saccharide or -OH.
  • TP thromboxane receptor
  • TS thromboxane synthase
  • X is selected from the group consisting of fluoro, chloro, bromo, trifluoromethyl, substituted phenyl, cyano, methoxy, nitro, hydroxyl and -H
  • Y is selected from the group consisting of fluoro, chloro, bromo, trifluoromethyl, substituted phenyl, cyano, methoxy, nitro, hydroxyl, -C(O)- saccharide and -H
  • Rd is -NH-C 1-6 -alkyl (branched or linear, preferably linear),-0-C 1-6 -alkyl (branched or linear, preferably linear), a saccharide or -OH.
  • TP thromboxane receptor
  • TS thromboxane synthase
  • X is selected from fluoro, chloro, bromo, trifluoromethyl, optionally substituted phenyl, cyano, methoxy and nitro;
  • Rc is C 1-6 -alkyl (branched or linear, preferably linear), -C(0)-CL 6 - alkyl (branched or linear, preferably linear), -CH(O), a saccharide or -H; and
  • Rd is -NH-C 1-6 -alkyl (branched or linear, preferably linear),-0-C 1-6 -alkyl (branched or linear, preferably linear), glycosyl or -OH.
  • TP thromboxane receptor
  • TS thromboxane synthase
  • X, Z and Y are as specified herein above for compounds of Formula I, preferably X is halogen, more preferably X is chloro, wherein X may be in the ortho, meta and/or para position, preferably the ortho position, and preferably Z and Y are both -H;
  • Rc is C-i_ 6 -alkyl (branched or linear, preferably linear), -C(0)-C 1-6 -alkyl (branched or linear, preferably linear), -CH(O), a saccharide (preferably a mono- or disaccharide, more preferably, a monosaccharide, even more preferably glycosyl) or -H, preferably Rc is methoxy, -C(0)-CH 3 or -H; and Rd is -NH-C ⁇ -alkyl (branched or linear, preferably linea .-O-C ⁇ - alkyl (branched or linear, preferably linear), a saccharide (preferably a mono- or disaccharide, more
  • TP thromboxane receptor
  • TS thromboxane synthase
  • Ri can be hydrogen, halogen, cyano, hydroxyl, or alkyl
  • R 2 can be hydrogen, alkyl, alkenyl, aryl, heteroaryl, or a C 3-30 cyclic or heterocyclic ring optionally substituted with one or more substituent
  • X can be CH, or N
  • n can be 0, 1 , 2, 3, 4, or 5
  • R 5 can be H, OH, alkoxy, alkyl, or halogen.
  • the C 3-30 cyclic or heterocyclic ring can be unsubstituted, singly substituted or multiply substituted acenaphthene, benzothiophene, chromanone, indole, julolidine, naphthalene, quinoline, and the like.
  • the compounds described herein may include functional groups that can be masked with progroups to create prodrugs.
  • Such prodrugs are usually, but need not be, pharmacologically inactive until converted into their active drug form.
  • any available functional moiety may be masked with a progroup to yield a prodrug.
  • Progroups that are cleavable under the desired conditions of use are known in the art.
  • the dual thromboxane receptor (TP) antagonist and thromboxane synthase (TS) inhibitor may be a prodrug of one or the other, or a mixture, of the enantiomers of Formula VI:
  • X can be hydrogen, halogen, cyano, nitro, hydroxyl, haloalkyl, alkyl, or O-R
  • R is a lower alkyl group; n can be 0, 1 , 2, 3, 4, or 5; and Z 2 can be independently selected to be O, N, or S, and R p is independently selected from H, lower alkyl, or a progroup.
  • the prodrugs can thus be compounds where both and Z 2 can be O, and at least one R p is a progroup such as lower alkyl, ester, amide, and the like. The progroup R p metabolizes in vivo to yield the active diaryl 1 ,3-dioxane moiety containing drug.
  • prodrugs can be derivatized with progroups for the synthesis of prodrugs.
  • a wide variety of progroups suitable for masking functional groups in active compounds to yield prodrugs are well- known in the art.
  • a hydroxyl functional group may be masked as a sulfonate, ester or carbonate progroup, which may be hydrolyzed, typically in vivo to provide the hydroxyl group.
  • An amino functional group may be masked as an amide, imine, phosphinyl, phosphonyl, phosphoryl or sulfonyl progroup, which may be hydrolyzed in vivo to provide the amino group.
  • a carboxyl group may be masked as an ester (including silyl esters and thioesters), amide or hydrazide progroup, which may be hydrolyzed in vivo to provide the carboxyl group.
  • ester including silyl esters and thioesters
  • amide or hydrazide progroup which may be hydrolyzed in vivo to provide the carboxyl group.
  • a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group including, but not limited to, groups such as for example (C C 8 )alkyl, (C 2 -C 12 )alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1- (alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1 -(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1- (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(aikoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N (alkoxycarbonyl)amino)ethy
  • groups such as for example (C C 8 )alkyl, (C 2 -C 12
  • the prodrug may also be a compound wherein an -COOH group has reacted with a saccharide to form an ester, the saccharide preferably being a mono- or disaccharide, more preferably, a monosaccharide, even more preferably glucose.
  • the phenol group can be converted to a phosphate ester or an alkyl ester, or derivatized using polyethylene glycol (PEG), alkyloxycarbonykloxymethyl (AOCOM), or as a sterically hindered alkoxycarbonyloxymethyl, as illustrated below.
  • PEG polyethylene glycol
  • AOCOM alkyloxycarbonykloxymethyl
  • Progroups can be selected to provide a prodrug with the intended water solubility, mode of administration and/or intended mechanism or site of metabolism to the active 2,4-diaryl-1 ,3- dioxane compound.
  • the progroup can be lipophilic or hydrophilic, where the lipophilic groups can be used to decrease water solubility and hydrophilic groups can be used to increase water solubility. In this way, prodrugs specifically tailored for selected modes of administration can be obtained.
  • the progroup can also be designed to impart the prodrug with other properties, such as, for example, improved passive intestinal absorption, improved transport-mediated intestinal absorption, protection against fast metabolism (slow-release prodrugs), tissue-selective delivery, passive enrichment in target tissues, targeting-specific transporters, etc.
  • Representative prodrugs useful in the methods of the invention include:
  • Example 1 Effects of Compound 3 on Platelet Aggregation Induced in the Presence of Epinephrine.
  • a total of 50 patients with stable coronary artery disease (CAD) were recruited from the outpatient service of the Cardiology Unit, at Ospedale San Paolo, Milan (Italy) between May 2012 and January 2013. Patients were excluded if they had had any ischemic event or revascularization procedure within the previous 3 months, if their platelet count was ⁇ 120 x 10 9 /L or if they took warfarin or drugs known to affect platelet function (e.g. non-steroidal anti-inflammatory drugs, ticlopidine, dipyridamol) 2 weeks before blood sampling.
  • CAD stable coronary artery disease
  • ASA enteric coated aspirin
  • Patients were males and females of at least 18 years of age, on chronic treatment with ASA or ASA+clopidogrel. Patients did not require the chronic use of any drug affecting haemostasis, other than ASA and clopidogrel; did not partake in drug or alcohol abuse; and did not have any condition that, in the opinion of the investigator, might interfere with the patient's participation in the study, poses an added risk for the patient, or compound the assessment of the patient. Study design
  • U46619 (Z)-7-[(1S,4R,5R,6S)-5-[(E,3S)-3-hydroxyoct-1-enyl]-3-oxabicyclo[2.2.1]heptan-6-yl]hept-5- enoic acid) were from Sigma Aldrich (Milano, IT). Collagen Horm was from Mascia Brunelli (Milano, IT). All concentrations of reagents reported in the text are expressed as final concentrations.
  • Compound 3 was manufactured under GMP conditions and dissolved directly in bi- distilled water, kept, and stored at room temperature for 15 days.
  • platelet rich plasma PRP
  • PPP platelet-poor plasma
  • VASP vasodilator stimulated phosphoprotein
  • BMI pharmacological treatment
  • Group A 24 (4F/20M, aged: 51-83, BMI: 26) were on chronic treatment with ASA and Group B: 26 (2F/24M, aged: 45-82, BMI: 27) with ASA and Clopidogrel.
  • AA (1 mM) by itself did not induce platelet aggregation in any patient, but did cause platelet shape change in all patients both 24h and 3h after drug intake.
  • Compound 3 did not affect AA- induced platelet shape change.
  • Table 1 Effects of Compound 3 (100 nM) on platelet aggregation of patients on treatment with ASA or ASA+clopidogrel, measured by LTA in hirudin PRP.
  • AA arachidonic acid. Differences were not statistically significant Platelet aggregation studied by Multiplate in hirudin whole blood.
  • AA arachidonic acid. Internal contrasts (vehicle vs Compound 3) were evaluated by repeated way ANO VA and Bonferroni post test. *p ⁇ 0.05, ** p ⁇ 0.001

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Abstract

L'invention concerne des procédés de réduction du risque de survenue d'un événement cardio-vasculaire chez des patients présentant une maladie des artères coronaires et/ou du diabète et étant traités avec de l'aspirine et/ou un inhibiteur de P2Y12, par administration à un patient d'une quantité thérapeutiquement efficace d'une forme pharmaceutiquement acceptable d'un composé qui est l'acide (Z)-6-((2S,4S,5R)-2-(2-chlorophényl)-4-(2-hydroxyphényl)-1,3-dioxan-5-yl)hex-4-énoïque, à un moment où le patient présente un niveau élevé d'épinéphrine.
PCT/GB2015/000187 2014-06-18 2015-06-18 Traitement d'un risque cardio-vasculaire chez des patients présentant une maladie cardio-vasculaire et/ou du diabète WO2015193630A1 (fr)

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Cited By (2)

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WO2017192535A1 (fr) * 2016-05-03 2017-11-09 OliVentures, Inc. Procédé permettant de traiter une maladie cardiovasculaire et une fibrose kystique avec un produit combiné contenant de l'hydroxytyrosol
US12083097B2 (en) * 2020-11-13 2024-09-10 Serodus As Dual TNFR1 antagonists and TNER2 agonists for use in renal diseases

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CATTANEO M; CERLETTI C; HARRISON P; HAYWARD CP; KENNY D; NUGENT D; NURDEN P; RAO AK; SCHMAIER AH; WATSON SP: "Recommendations for the Standardization of Light Transmission Aggregometry: A Consensus of the Working Party from the Platelet Physiology Subcommittee of SSC/ISTH.", J THROMB HAEMOST., 10 April 2013 (2013-04-10)
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017192535A1 (fr) * 2016-05-03 2017-11-09 OliVentures, Inc. Procédé permettant de traiter une maladie cardiovasculaire et une fibrose kystique avec un produit combiné contenant de l'hydroxytyrosol
US12083097B2 (en) * 2020-11-13 2024-09-10 Serodus As Dual TNFR1 antagonists and TNER2 agonists for use in renal diseases

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