WO2005000281A2 - Derives de pyrazolidinedione - Google Patents

Derives de pyrazolidinedione Download PDF

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Publication number
WO2005000281A2
WO2005000281A2 PCT/EP2004/006471 EP2004006471W WO2005000281A2 WO 2005000281 A2 WO2005000281 A2 WO 2005000281A2 EP 2004006471 W EP2004006471 W EP 2004006471W WO 2005000281 A2 WO2005000281 A2 WO 2005000281A2
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Prior art keywords
phenyl
propoxy
dione
pyrazolidine
methyl
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PCT/EP2004/006471
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English (en)
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WO2005000281A3 (fr
Inventor
Olivier Houille
Heinz Fretz
Kurt Hilpert
Markus Riederer
Thomas Giller
Oliver Valdenaire
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Actelion Pharmaceuticals Ltd.
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Priority to US10/562,623 priority Critical patent/US20070037846A1/en
Priority to CA002529436A priority patent/CA2529436A1/fr
Priority to EP04739938A priority patent/EP1638540A2/fr
Priority to JP2006515947A priority patent/JP2007506661A/ja
Publication of WO2005000281A2 publication Critical patent/WO2005000281A2/fr
Publication of WO2005000281A3 publication Critical patent/WO2005000281A3/fr

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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
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    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
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    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton
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    • C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
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    • C07C47/56—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing hydroxy groups
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    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • the present invention relates to alkylidene pyrazolidinedione derivatives which are effective platelet ADP receptor antagonists and can be used for the prevention and/or treatment of peripheral vascular, of visceral-, hepatic- and renal-vascular, of cardiovascular and of cerebrovascular diseases or conditions associated with platelet aggregation, including thrombosis in humans and other mammals.
  • Hemostasis is referred to as the cooperation of complex, interrelated events maintaining the fluidity of the blood in the vascular system while allowing the rapid formation of a solid blood clot to prevent excessive blood loss (hemorrhage) subsequent to blood vessel injury.
  • a cascade of processes is initiated, such as contraction of the vessels, platelet adhesion and aggregation, activation of the coagulation cascade and later also of the fibrinolytic system.
  • Hemostasis is initiated by adhesion of blood platelets or thrombocytes to the exposed, highly thrombogenic, subendothelial connective tissue of the damaged vessels and aggregate to form a platelet plug to stop bleeding.
  • thrombus pathological malfunction of hemostasis can result in developing of an unwanted, in some instances life-threatening, intravascular thrombus .
  • Conditions such as turbulent blood flow in diseased vessels, disruption of underlying vessel wall, for example most commonly due to arteriosclerosis, exposure of damaged endothelial cells and release of mediators from circulating cells, activate platelet adhesion and aggregation resulting in arterial thrombus formation and hence block off arterial blood vessels causing serious disease.
  • Thrombi also form as a consequence of stasis or slow blood flow in veins. Venous thrombi can easily embolize, that means portions of them detach and travel through the circulatory system eventually blocking other vessels.
  • Venous thrombosis, thrombophlebitis, arterial embolism, coronary and cerebral arterial thrombosis, unstable angina, myocardial infarction, stroke, cerebral embolisms, kidney and pulmonary embolisms are serious conditions that are the common cause of death and disability in patients with vascular disease.
  • Initial stimuli such as thrombin, collagen, von WiUebrand factor (vWf) , thromboxane A2 (TxA2) and 7ADP, activate platelets by binding to their respective cell surface receptors. Many of these receptors belong to the family of seven transmembrane helices containing G-protein-coupled receptors, and their importance in platelet activation has been demonstrated
  • platelets Upon activation, platelets change shape from a disc shape to a round form with pseudopodia, which enforces subsequent platelet adhesion and aggregation. The final common event of aggregation culminates in cross-linking the platelets by binding of fibrinogen to its receptor, glycoprotein Ilb-IIIa (GPIIb-IIIa, integrin IIb ⁇ 3 ) receptor.
  • GPIIb-IIIa glycoprotein Ilb-IIIa
  • antiplatelet agents have been developed over the past several years (see review, Dogne et al . , Curr. Med. Chem. 2002, 9(5), 577-589) .
  • One of the first and so far most widely used agents in antiplatelet therapy is aspirin, which irreversibly inhibits the enzyme cyclooxygenase-1 and thereby affecting the TxA2 pathway.
  • aspirin is an agent that irreversibly inhibits the enzyme cyclooxygenase-1 and thereby affecting the TxA2 pathway.
  • treatment with aspirin remains the standard therapy against which new therapeutics are compared and judged.
  • the phosphodiesterase inhibitors dipyridamole and cilostazol have been introduced as antiplatelet agents.
  • GPIIb/lIIa receptor The EPIC investigators, New Engl . J. Med. 1994, 330, 956-961) .
  • GPIIb/lIIa receptor antagonists abciximab, eptifibatide, and tirofiban
  • orally active GPIIb/lIIa antagonists like sibrafiban, xemilofiban, and orbofiban were under clinical evaluation but have not been successful so far.
  • Indirect or direct thrombin inhibitors e . g.
  • Adenosine 5' -diphosphate was identified as a key mediator in platelet activation and aggregation acting on at least two platelet ADP receptors of the G-protein coupled P2 receptor family (Shaver S. R., Curr. Opin. Drug Dicovery & Development 2001, 4 (5) , 665-670) .
  • the P2Y- L receptor initiates aggregation through mobilization of calcium stores and is required for platelet shape change.
  • the more recently identified P2Y 12 receptor also denoted P2Y ADP , P2Y AC , P2Y cyc , P 2T , P2T AC , (see review, Barnard E. A. and Simon J., Trends Pharmacol. Sci.
  • analogues of the endogenous antagonist ATP for example AR-C (formerly FPL or ARL) 67085MX and AR-C69931MX (Cangrelor) , reached phase II clinical studies.
  • AR-C now FPL or ARL
  • AR-C69931MX Cangrelor
  • These inhibitors are selective platelet ADP receptor antagonists, which inhibit ADP-dependent platelet aggregation, and are effective in vivo (see review, Chattaraj S. C, Curr. Opin. Invest. Drugs, 2001, 2(2), 250-255).
  • Bombrun A. et al . disclose the use of alkylidene pyrazolidinedione derivatives for the treatment and /or prevention of diabetes type I and/or II, impaired glucose tolerance, insulin resistance, hyperglycemia, obesity, and polycystic ovary syndrome via inhibition of phosphotyrosine phosphatases (PTPs) , in particular PTP1B, TC-PTP, SHP and GLEPP- 1.
  • PTPs phosphotyrosine phosphatases
  • Hassan S. (Canadian patent application CA 2,012,634, published September 20, 1991) claims alkylidene pyrazolidinedione derivatives blocking platelet activating factor (PAF) and leukotriene D4 (LTD4) .
  • PAF platelet activating factor
  • LTD4 leukotriene D4
  • Krogdal T. G. discloses 3 , 5-pyrazolidinedione derivatives to combat viral infections.
  • the present invention relates to the use of pyrazolidinedione derivatives of the general formula
  • R x is hydrogen, optionally substituted alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl or alkanoyl; and R 2 is aryl or heteroaryl; tautomers thereof ; geometric isomers thereof and tautomers of these geometric isomers, including mixtures of individual compounds of formula (I) , or tautomers thereof, and their geometric isomers, or tautomers thereof ; pharmaceutically acceptable acid addition salts of compounds which are basic; pharmaceutically acceptable salts of compounds containing acidic groups with bases; pharmaceutically acceptable esters of compounds containing hydroxy or carboxy groups; prodrugs of compounds in which a prodrug forming group is present; as well as hydrates or solvates thereof; as platelet adenosine diphosphate receptor antagonists for the prevention and/or treatment of peripheral vascular, of visceral-, hepatic- and renal -vascular, of cardiovascular and of cerebrovascular diseases or conditions associated with platelet aggregat
  • R ⁇ is preferably hydrogen, alkyl, aryl, heteroaryl or alkanoyl, particularly hydrogen, alkyl, phenyl, bromophenyl, chlorophenyl, fluorophenyl, methylphenyl, methoxyphenyl , cyanophenyl , alkoxycarbonylphenyl , pyridinyl or alkanoyl, more particularly hydrogen, methyl, phenyl, 2- pyridinyl, 4-pyridinyl, 2-methylphenyl , 4-methylphenyl, 4- methoxyphenyl , 2-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 4- cyanophenyl, 4-ethoxycarbonylphenyl or acetyl .
  • R 2 is preferably naphthalenyl , thienyl or pyridyl, particularly naphthalen-2-yl, pyridin-3-yl or thiophen-3-yl . Particularly preferred is the use of compounds of the general formula
  • R x is as defined hereinabove
  • R 3 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkoxy, alkoxyalkoxy, alkenyloxy, cycloalkoxy, cycloalkylalkoxy or alkylsulfonyloxy;
  • R 4 is hydrogen, halogen, hydroxy, alkyl or alkoxy;
  • R 5 is hydrogen, halogen, hydroxy, alkyl, alkoxy, alkoxyalkoxy, hydroxyalkoxy, dihydroxyalkoxy, alkanoyloxyalkoxy, carboxyalkoxy, carboxy-hydroxyalkoxy, carboxy-dihydroxyalkoxy, alkoxycarbonylalkoxy, alkoxycarbonyl-hydroxyalkoxy, alkoxycarbonyl-dihydroxyalkoxy, carbamoylalkoxy, .Aralkylcarbamoylalkoxy, JV / iV-dialkyaminolalkoxy, morpholin-4- ylalkoxy, piperidin-1-ylalkoxy, morpholin-4-ylcarbonylalkoxy, 2, 2-dialkyl [1, 3] dioxolan-4-ylalkoxy or 2, 2-dialkyl-4- carboxy [1,3] dioxolan-5-ylalkoxy; or R 4 und R 5 , together with the phenyl ring
  • R 3 in formula (III) may be alkyl, alkenyl, alkynyl, alkoxy, cycloalkoxy, cycloalkylalkoxy, hydroxyalkoxy or alkoxyalkoxy and R 4 and R s both may be hydrogen, or R 4 may be halogen, alkyl or alkoxy and R 5 may be hydrogen, or R 4 and R 5 each independently may be alkyl or alkoxy.
  • R 3 is preferably methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl, but-1-enyl, pent-1-enyl, but-1-ynyl, pent-1-ynyl, methoxy, ethoxy, propoxy, butoxy, iso-butoxy, 3- methyl-butoxy, pentyloxy, cyclopentyloxy, hexyloxy, cyclopropylmethoxy, cyclobutylmethoxy, 2-hydroxy-ethoxy, 2- methoxy-ethoxy, and preferably R 4 and R 5 both are hydrogen or R 4 is chloro, bromo, methyl or methoxy and R 5 is hydrogen, or R 4 and R s each independently are methyl or methoxy.
  • R 3 in formula (III) may be hydrogen or alkoxy and R 4 and R 5 together with the phenyl ring to which they are attached, may form an optionally substituted naphthalene, tetrahydronaphthalene, indane, lH-indene, isoquinoline, dihydro- benzo [1,4] dioxine or benzo [1, 3] dioxole moiety.
  • R 3 is preferably propoxy and R 4 and R 5 together with the phenyl ring to which they are attached, preferably form a naphthalene-1-yl, indan-4-yl, isoquinolin-5-yl, isoquinolin-8-yl, 1,2,3,4- tetrahydroisoquinoli-8-yl, 2-alkoxycarbonyl-1, 2,3,4- tetrahydroisoquinolin-8-yl or 5, 6, 7, 8-tetrahydronaphthalen-l-yl moiety.
  • R 3 , R 4 and R 5 in formula (III) each are hydroge ; or
  • R 3 and R 5 each are hydrogen and R 4 is methoxy;
  • R 3 and R 4 each are hydrogen and R s is methoxy; or R 4 and R s each are hydrogen and R 3 is tert-butyl, ethoxy, propoxy or butoxy; or
  • R 3 is hydrogen, R 4 is methoxy, and R s is hydroxy; or R 4 is hydrogen, R 3 is methoxy or propoxy and R 5 is methoxy or propoxy; or R s is hydrogen, R 3 is methoxy, ethoxy, propoxy, butyloxy, iso- butyloxy, pentyloxy, hexyloxy, 3 -methylbutoxy, 2-hydroxyethoxy, 2-methoxyethoxy, cyclopropylmethoxy or cyclobutylmethoxy and R 4 is methyl, methoxy, chloro or bromo; or R 3 is methoxy, propoxy, cyclopentyloxy, pent-1-ynyl or ethanesulfonyloxy;
  • R 4 is methyl
  • R s is hydroxy, methyl, pentyl, methoxy, propoxy, 2-methoxyethoxy, 2-hydroxyethoxy, 3 -hydroxypropoxy, 4-hydroxybutoxy, 2,3- dihydroxypropoxy, 4-acetoxybutoxy, carboxymethoxy, 3- carboxypropoxy, 4-carboxybutoxy, 3 -carboxy-2 -hydroxypropoxy, 3- carboxy-2,3-dihydroxypropoxy, ethoxycarbonylmethoxy, 3 - ethoxycarbonylpropoxy, 4-ethoxycarbonylbutoxy, 3 -ethoxycarbonyl- 2-hydroxypropox , 3 -ethoxycarbonyl-2 , 3-dihydroxypropoxy, carbamoylmethoxy 3-iV-ethylcarbamoylpropoxy, 4-JW- ethylcarbamoylbutoxy, 2-N, ⁇ V-dimethylaminoethoxy, 3 -N, N- dmethylaminopropoxy, 2-
  • the present invention thus relates to these novel compounds per se as well as for use as pharmaceutically active ingredients; to pharmaceutical compositions containing one or several of these novel compounds ,- to the use of these novel compounds as platelet adenosine diphosphate receptor antagonists for the prevention and/or treatment of peripheral vascular, of visceral-, hepatic- and renal-vascular, of cardiovascular and of cerebrovascular diseases and conditions associated with platelet aggregation, including thrombosis, and, respectively, for the manufacture of corresponding medicaments; and to the manufacture of these novel compounds .
  • novel compounds provided by the present invention are compounds of the general formula
  • R- L is as defined hereinabove;
  • R 3 ' is alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkoxy, alkoxyalkoxy, alkenyloxy, cycloalkoxy, cycloalkylalkoxy or alkylsulfonyloxy;
  • R 4 ' is halogen, hydroxy, alkyl or alkoxy;
  • R 5 ' is halogen, hydroxy, alkyl, alkoxy, alkoxyalkoxy, hydroxyalkoxy, dihydroxyalkoxy, alkanoyloxyalkoxy, carboxyalkoxy, carboxy-hydroxyalkoxy, carboxy-dihydroxyalkoxy, alkoxycarbonylalkoxy, alkoxycarbonyl-hydroxyalkoxy, alkoxycarbonyl-dihydroxyalkoxy, carbamoylalkoxy, N- alkylcarbamoylalkoxy, N, iV-dialkyaminolalkoxy, morpholin-4- ylalkoxy, piperidin-1-ylalkoxy, morpholin-4-ylcarbonylalkoxy, 2,2-dialkyl [1,3] dioxolan-4-ylalkoxy or 2, 2-dialkyl-4- carboxy [1,3] dioxolan-5-ylalkoxy; or R 4 ' and R 5 ' , together with the phenyl
  • R 3 ' may be alkyl, alkenyl, alkynyl, alkoxy, cycloalkoxy, cycloalkylalkoxy, hydroxyalkoxy or alkoxyalkoxy
  • R 4 ' may be halogen, alkyl or alkoxy
  • R 5 ' may be alkyl or alkoxy.
  • R 3 ' is methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl, but-1-enyl, pent-1-enyl, but-1-ynyl, pent-1-ynyl, methoxy, ethoxy, propoxy, butoxy, iso-butoxy, 3-methyl-butoxy, pentyloxy, cyclopentyloxy, hexyloxy, cyclopropylmethoxy, cyclobutylmethoxy, 2-hydroxy-ethoxy, 2 -methoxy-ethoxy, R 4 ' is chloro, bromo, methyl or methoxy, and R 5 ' is methyl or methoxy.
  • R 3 ' may be alkoxy and R 4 ' and R s ' together with the phenyl ring to which they are attached, may form an optionally substituted naphthalene, tetrahydronaphthalene, indane, lff-indene, isoquinoline, dihydro- benzo [1, 4] dioxine or benzo [1, 3] dioxole ring system.
  • R 3 ' is propoxy and R 4 ' and R s ' together with the phenyl ring to which they are attached, form a naphthalene-1-yl, indan-4-yl, isoquinolin-5-yl, isoquinolin-8-yl, 1,2,3, 4-tetrahydroisoquinoli- 8-yl, 2 -alkoxycarbonyl-1, 2 , 3 , 4-tetrahydroisoquinoli- 8-yl or 5, 6, 7, 8-tetrahydronaphthalen-l-yl moiety.
  • R 3 ' is methoxy, propoxy, eye1opentyloxy, pent-1-ynyl or ethanesulfonyloxy;
  • R 4 ' is methyl;
  • R 5 ' is hydroxy, methyl, pentyl, methoxy, propoxy, 2- methoxyethoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 4- hydroxybutoxy, 2 , 3-dihydroxypropoxy, 4-acetoxybutoxy, carboxymethoxy, 3 -carboxypropoxy, 4-carboxybutoxy, 3-carboxy-2- hydroxypropoxy, 3 -carboxy-2 , 3 -dihydroxypropoxy, ethoxycarbonylmethoxy, 3-ethoxycarbonylpropoxy, 4- ethoxycarbonylbutoxy, 3-ethoxycarbonyl-2-hydroxypropoxy, 3- ethoxycarbonyl-2 , 3 -dihydroxypropoxy, carbamoylmethoxy 3 -N-
  • R 4 ' and R 5 ' together with the phenyl ring to which they are attached, form a naphthalen-1-yl, 5, 6 , 7, 8-tetrahydronaphthalen-l- yl, indan-4-yl, 1, 2 , 3 , 4, -tetraisoquinolin-8-yl or 2-tert- butoxycarbonyl-1, 2,3,4, -tetraisoquinolin-8-yl moiety.
  • Preferred novel compounds include l-phenyl-4- (4-propoxy-naphthalen-l-ylmethylene) -pyrazolidine-3 , 5- dione;
  • novel compounds include l-phenyl-4- [1- (5-propoxy-isoquinolin-8-yl) -methylidene] - pyrazolidine-3 , 5-dione;
  • any reactive group which may be present in the compounds of formulae IV and V being appropriately protected, and, if necessary, splitting off from the condensation product any protecting group (s) which may be undesired.
  • alkyl refers to a saturated aliphatic group including a straight or branched hydrocarbon chain containing 1-8 carbon atoms.
  • Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, iso- butyl (or 2-methylpropyl) , cyclopropylmethyl , n-pentyl, iso- pentyl, iso-amyl, n-amyl, n-hexyl, n-heptyl, n-octyl and the like.
  • the alkyl group can be optionally substituted with one or more substituents, each independently selected from alkenyl, alkoxy, alkoxycarbonyl, alkylcarbonyl, alkylcarbonyloxy, alkylendioxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, amino, aminocarbonyl , aryl, arylalkenyl, arylalkyloxy, aryloxy, aryloxycarbonyl, arylsulfinyl, arylsulfonyl, arylthio, carboxy, cyano, formyl, halogen, haloalkoxy, heterocyclyl, hydroxy, mercapto, nitro, and the like, appended to any carbon atom of the alkyl moiety.
  • substituents each independently selected from alkenyl, alkoxy, alkoxycarbonyl, alkylcarbonyl, alkylcarbony
  • lower alkyl refers to alkyl groups with 1-4 carbon atoms.
  • Representative examples of lower alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso- butyl, tert-butyl and the like.
  • R a -R d refer to substituents, each individually and independently selected from hydrogen and alkyl, alkoxy, alkoxyalkyl and the like.
  • Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2 -methyl-2- propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl and the like.
  • alkylenedioxy refers to a -0(CH 2 ) n O- group, wherein n is preferably 1 or 2 , and wherein the oxygen atoms are appended to two adjacent carbon atoms of the parent molecular moiety.
  • Representative examples of alkylenedioxy include, but are not limited to, methylenedioxy, ethylenedioxy, and the like.
  • alkynyl refers to a straight or branched hydrocarbon chain containing 2-8 carbon atoms with at least one carbon-carbon triple bond (R a -C ⁇ C- R b , R a and R b referring to substituents, each individually and independently selected from hydrogen and alkyl, alkenyl, alkoxy, alkoxyalkyl, and the like) .
  • Representative examples of alkynyl include, but are not limited to, acetylenyl, 1-propynyl, 2- propynyl, 1-butynyl, 3-butynyl, 2-pentynyl, and the like.
  • alkoxy refers to an alkyl group appended to the parent molecular moiety through an oxygen bridge .
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2- propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like.
  • alkoxyalkyl refers to an alkoxy group appended to the parent molecular moiety through an alkyl group.
  • Representative examples of alkoxyalkyl include, but are not limited to, tert- butoxymethyl , 2-ethoxyethyl, 2-methoxyethyl, methoxymethyl , and the like.
  • alkoxycarbonyl refers to an alkoxy group appended to the parent molecular moiety through a carbonyl group.
  • Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl , ethoxycarbonyl , tert-butoxycarbonyl , and the like.
  • alkoxycarbonylalkyl refers to an alkoxycarbonyl group appended to the parent molecular moiety through an alkyl group.
  • alkoxycarbonylalkyl include, but are not limited to, methoxycarbonylpropyl , ethoxycarbonylbutyl , 2-tert- butoxycarbonylethyl, and the like.
  • alkylcarbonyl or "acyl”, as used herein, alone or in any combination, refers to an alkyl group appended to the parent molecular moiety through a carbonyl group.
  • Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2, 2 -dimethyl-1-oxopropyl, 1-oxobutyl, 1- oxopentyl, and the like.
  • alkylcarbonylalkyl refers to an alkylcarbonyl group appended to the parent molecular moiety through an alkyl group.
  • Representative examples of alkylcarbonylalkyl include, but are not limited to, 2-oxopropyl, 3 , 3-dimethyl-2-oxopropyl, 3-oxobutyl, 3-oxopentyl and the like.
  • alkylcarbonyloxy refers to an alkylcarbonyl group appended to the parent molecular moiety through an oxygen bridge .
  • Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, tert-butylcarbonyloxy and the like.
  • alkylsulfinyl refers to an alkyl group appended to the parent molecular moiety through a sulfinyl group.
  • Representative examples of alkylsulfinyl include, but are not limited to, methylsulfinyl, ethylsulfinyl and the like.
  • alkylsulfinylalkyl refers to an alkylsulfinyl group appended to the parent molecular moiety through an alkyl group.
  • Representative examples of alkylsulfinylalkyl include, but are not limited to, methylsulfinylmethyl, ethylsulfinylmethyl and the like.
  • alkylsulfonyl refers to an alkyl group appended to the parent molecular moiety through a sulfonyl group.
  • Representative examples of alkylsulfonyl include, but are not limited to, methylsulfonyl, ethylsulfonyl, and the like.
  • alkylsulfonylalkyl refers to an alkylsulfonyl group appended to the parent molecular moiety through an alkyl group.
  • Representative examples of alkylsulfonylalkyl include, but are not limited to, methylsulfonylmethyl, ethylsulfonylmethyl and the like.
  • alkylthio refers to an alkyl group appended to the parent molecular moiety through a thio group .
  • Representative examples of alkylthio include, but are not limited to, methylthio, ethylthio, tert-butylthio, hexylthio and the like.
  • alkylthioalkyl refers to an alkylthio group appended to the parent molecular moiety through an alkyl group.
  • Representative examples of alkylthioalkyl include, but are not limited to, methylthiomethyl, 2- (ethylthio) ethyl, and the like.
  • amino refers to a -NR e R f group, wherein R e and R f are substituents, each individually and independently selected from hydrogen, alkyl, aryl, arylalkyl, acyl, alkylcarbonyl, arylcarbonyl, carbamoyl, ureido, formyl, alkylsulfonyl, arylsulfonyl, and the like.
  • Representative examples of amino include, but are not limited to, dimethylamino, ethylamino, benzyl- (methyl) amino, and the like.
  • aminoalkyl refers to an amino group appended to the parent molecular moiety through an alkyl group.
  • Representative examples of aminoalkyl include, but are not limited to, aminomethyl, 2- (amino) ethyl, benzyl- (methyl) aminomethyl, dimethylaminomethyl, and the like.
  • aminocarbonyl or “amido”, as used herein, alone or in any combination, refers to an amino group appended to the parent molecular moiety through a carbonyl group.
  • Representative examples of aminocarbonyl include, but are not limited to, dimethylaminocarbonyl , benzyl-aminocarbonyl , ethylaminocarbonyl , and the like.
  • aminocarbonylalkyl refers to an aminocarbonyl group appended to the parent molecular moiety through an alkyl group.
  • Representative examples of aminocarbonylalkyl include, but are not limited to, 2-amino-2-oxoethyl, 2- (benzylamino) -2-oxoethyl, 2- (methylamino) - 2-oxoethyl, -amino-4-oxobutyl, 4- (dimethylamino) -4-oxobutyl, and the like.
  • aryl refers to an carbocyclic group having at least one aromatic ring, e . g. phenyl or biphenyl, or multiple condensed ring systems, in which at least one ring is aromatic, e . g. 1,2,3,4- tetrahydronaphthyl, naphthyl, anthryl, phenanthryl, fluorenyl, and the like.
  • the aryl group may be optionally substituted with one or more functional groups individually and independently selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl , alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylendioxy, alkylsulfinyl, alkylsulfinylalkyl, alkylsulfonyl, alkylsulfonylalkyl, alkylthio, alkylthioalkyl, alkynyl, amino, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, aryl, arylalkenyl, arylalkyloxy, arylalkyl, aryloxy, aryloxycarbonyl, aryloxycarbonylalkyl, arylsulfinylalkyl, arylsulfinylalky
  • arylalkenyl refers to an aryl group appended to the parent molecular moiety through an alkenyl group.
  • the aryl group may be unsubstituted or substituted.
  • Representative examples of arylalkenyl include, but are not limited to, 2-phenylethenyl, 3- phenylpropen-2-yl, 2-naphth-2-ylethenyl, and the like.
  • arylalkoxy refers to an aryl group appended to the parent molecular moiety through an alkoxy group.
  • the aryl group may be unsubstituted or substituted.
  • Representative examples of arylalkoxy include, but are not limited to, 2-phenylethoxy, 5- phenylpentyloxy, 3-naphth-2-ylpropoxy, and the like.
  • arylalkyl refers to an aryl group appended to the parent molecular moiety through an alkyl group.
  • the aryl group may be unsubstituted or substituted.
  • Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, 2-naphth-2-ylethyl, and the like.
  • aryloxy refers to an aryl group appended to the parent molecular moiety through an oxygen bridge.
  • the aryl group can be unsubstituted or substituted.
  • Representative examples of aryloxy include, but are not limited to, phenoxy, naphthyloxy, 3-bromophenoxy, 4- chlorophenoxy, 4-methylphenoxy, 3 , 4-dimethoxyphenoxy, and the like.
  • R e and R £ are substituents, each individually and independently selected from hydrogen, alkyl, arylalkyl, and the like.
  • thiocarbamoyl refers to a -C(S)NR e R £ group.
  • carbonyl as used herein, alone or in any combination, refers to a -C(O) group.
  • carboxyalkyl refers to a carboxy group appended to the parent molecular moiety through an alkyl group.
  • Representative examples of carboxyalkyl include, but are not limited to, carboxymethyl , 2-carboxyethyl, 3-carboxypropyl, and the like.
  • cyano refers to a -C ⁇ N group.
  • cyanoalkyl refers to a cyano group appended to the parent molecular moiety through an alkyl group.
  • Representative examples of cyanoalkyl include, but are not limited to, cyanomethyl, 2- cyanoethyl, 3-cyanopropyl, and the like.
  • cycloalkyl refers to a saturated cyclic hydrocarbon moiety containing 3-15 carbon atoms, optionally substituted with one or more groups, each individually and independently selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylendioxy, alkylsulfinyl, alkylsulfinylalkyl, alkylsulfonyl, alkylsulfonylalkyl, alkylthio, alkylthioalkyl, alkynyl, amino, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, aryl, arylalkenyl, arylalkyloxy, arylalkyl, aryloxy, aryloxycarbonyl,
  • cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • one of the distal rings may be aromatic, e . g. , 1-indanyl, 2-indanyl, tetrahydronaphthalene, and the like.
  • cycloalkenyl and cycloalkynyl refer to unsaturated cyclic hydrocarbon moieties containing at least one carbon-carbon double or carbon-carbon triple bond, respectively. Such moieties may be optionally substituted with one or more groups as discussed hereinabove or the cycloalkyl groups .
  • formyl refers to a -C(0)H group.
  • formylalkyl refers to a formyl group, appended to the parent molecular moiety through an alkyl group.
  • formylalkyl include, but are not limited to, formylmethyl , 2- formylethyl, and the like.
  • halo or halogen, as used herein, alone or in any combination, refers to fluorine, bromine, chlorine, and iodine.
  • haloalkyl refers to an alkyl group having at least one hydrogen atom replaced with a halogen atom.
  • Representative examples of haloalkyl include, but are not limited to, chloromethyl , 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, 2-chloro-3-fluoropentyl, and the like.
  • haloalkoxy refers to an alkoxy group having at least one hydrogen atom replaced with a halogen atom.
  • Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, pentafluoroethoxy, and the like.
  • heterocyclyl refers to a monocyclic, bicyclic or polycyclic ring system containing up to 15 ring atoms, at least one of these being a hetero atom independently selected from nitrogen, oxygen or sulfur.
  • the ring system may be saturated, partially unsaturated, unsaturated or aromatic.
  • heterocyclyl include, but are not limited to, furyl, imidazolyl, imidazolinyl, imidazolidinyl, isothiazolyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrrrolinyl, pyrrolidinyl, tetrahydrofuranyl , tetrahydrofuranyl, tetrahydrothienyl, thiadiazolyl, thiazolyl, thiazolinyl, thiazolidinyl, thienyl, thiomorpholinyl, 1, 1-dioxothiomorpholinyl,
  • heterocyclyl moieties may be optionally substituted with one or more groups, each individually and independently selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylendioxy, alkylsulfinyl, alkylsulfinylalkyl, alkylsulfonyl, alkylsulfonylalkyl, alkylthio, alkylthioalkyl, alkynyl, amino, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, aryl, arylalkenyl, arylalkyloxy, arylalkyl, aryloxy, aryloxycarbonyl, aryloxycarbonylalkyl, arylsulfinylalkyl, arylsulfinyl
  • heteroaryl as used herein, alone or in any combination, is a special case of heterocyclyl and refers to a mono- or bicyclic or polycyclic aromatic ring system, in which at least one heterocyclic ring is aromatic.
  • heterocyclylalkenyl refers to a heterocyclyl group appended to the parent molecular moiety through an alkenyl group.
  • Representative examples of heterocyclylalkenyl include, but are not limited to, 2-pyrid-3-ylethenyl, 3-quinolin-3-ylpropen-2-yl, 5-pyrid-4- ylpenten-4-yl, and the like.
  • heterocyclylalkoxy refers to a heterocyclyl group appended to the parent molecular moiety through an alkoxy group.
  • Representative examples of heterocyclylalkoxy include, but are not limited to, 2-pyrid-3-ylethoxy, 3-quinolin-3-ylpropoxy, 5-pyrid-4- ylpentyloxy, and the like.
  • heterocyclylalkyl refers to a heterocyclyl group appended to the parent molecular moiety through an alkyl group.
  • Representative examples of heterocyclylalkyl include, but are not limited to, 2- pyrid-3 -ylmethyl, 2-pyrimidin-2-ylpropyl, and the like.
  • heterocyclyloxy refers to a heterocyclyl group appended to the parent molecular moiety through an oxy group.
  • Representative examples of heterocyclyloxy include, but are not limited to, pyrid-3-yloxy, quinolin-3-yloxy, and the like.
  • hydroxy or "hydroxyl” as used herein, alone or in any combination, refers to an -OH group
  • hydroxyalkyl refers to an alkyl group having at least one hydrogen atom replaced with a hydroxy group.
  • Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl , 2-hydroxyethyl, 3-hydroxypropyl, 2-ethyl-4- hydroxyheptyl , and the like.
  • nitro refers to a -N0 2 group.
  • oxy refers to a -O- group.
  • mercapto and thiol refer to a -SH group.
  • Other compounds of this invention may contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms, and thus may give rise to optically pure enantiomers, mixtures of enantiomers, racemates, enantiomer-pure diastereomers, mixtures of diastereomers, epimers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R) - , (5) - or ⁇ R, S) ⁇ configured, preferably in the (R) - or (5) -configuration.
  • Such isomers can be obtained by methods within the knowledge of one skilled in the art, e. g.
  • the present invention refers to compounds containing centers of any geometric asymmetry, like, for example, unsymmetrically substituted olefinic double bond, including E or Z geometric isomers and mixtures thereof. Generally, pure isomers of compounds of formulae (I) and (III) are preferred over isomeric mixtures.
  • the compounds of formulae (I) and (III) may be used in the form of pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts refers to relatively nontoxic, inorganic or organic acid and base addition salts, which retain the biological effectiveness and properties of the parent compound, and which are not biologically or otherwise undesirable (see, e . g. , Berge et al . , J. Pharm. Sci. 1977, 66, 1- 19) .
  • Certain compounds of the present invention can contain one or more basic functional groups, such as amino, alkylamino, or arylamino, and, thus, be capable of forming pharmaceutically acceptable acid addition salts.
  • These acid addition salts may be prepared by standard procedures in a suitable solvent from the parent compound of formula (I) or (III), with an appropriate amount of an inorganic acid, including, but not limited to, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid; or of an organic acid, including, but not limited to, acetic acid, propionic acid, octanoic acid, decanoic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, ascorbic acid, amino acids, such as glutamic acid or aspartic acid, benzoic acid, cinnamic acid, salicylic acid, mandelic acid, methanesulfonic
  • Certain compounds of the present invention may, on the other hand, contain one or more acidic functional groups and, thus, be capable of forming pharmaceutically acceptable base addition salts.
  • These salts can be prepared by addition of an appropriate amount, usually in stoichiometric ratio, of an alkaline reagent, such as hydroxide, carbonate or alkoxide, containing the appropriate cation, to the free acid in a suitable solvent.
  • an alkaline reagent such as hydroxide, carbonate or alkoxide, containing the appropriate cation
  • Preferred inorganic salts include, but are not limited to, ammonium, sodium, potassium, calcium or magnesium, also zinc salts and the like.
  • Preferred salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, W-ethylpiperidine, piperidine, polyamine resins, and the like.
  • basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, W-ethylpiperidine, piperidine, polyamine resins, and the like.
  • salts for isolation or purification purposes, it is also possible to use pharmaceutically unacceptable salts, for example perchlorates, picolinates, picrates, or the like.
  • pharmaceutically acceptable salts or free compounds are employed, where applicable in the form of pharmaceutical preparations, and these are therefore preferred.
  • Certain compounds of formulae (I) and (III) may exist in solvated as well unsolvated forms, such as, for example, hydrated forms, or their crystals may, for example, include the solvent used for crystallization. Different crystalline forms may be present.
  • the present invention encompasses all such solvated and unsolvated forms.
  • prodrug derivatives of the parent compounds of formulae (I) and (III) .
  • prodrug refers to pharmacologically inactive precursors of a drug that may be converted into its therapeutically active form under physiological conditions in vivo, for example, when they undergo solvolysis, or enzymatic degradation in blood, or in cells, (Bundgard H. , “Design of Prodrugs", pp. 7-9, 21-24, Elsevier, Amsterdam (1985); Silverman R. B., "The Organic Chemistry of Drug Design and Drug Action", pp. 352-401, Academic Press, San Diego, CA (1992); Higuchi T. et al . , "Pro-drug as Novel Delivery Systems", A.C.S.
  • prodrug also includes any covalently bonded carriers, which release the active parent compound in vivo when administered to a mammal .
  • Prodrug modifications of a compound often offer advantages of solubility, bioavailability, absorption, tissue compatibility, tissue distribution, or delayed release in the mammalian organism.
  • Prodrugs are variations or derivatives of the compounds of formulae (I) and (III) , which have groups cleavable under metabolic conditions, for example, pharmaceutically acceptable esters, or amides. Such groups can be cleaved enzymatically or non-enzymatically, or hydrolytically to the free hydroxy, carboxy, or amino group of the active parent compound.
  • the prodrug is a reduced form, which is oxidized in vivo to the therapeutic compound, for example, a thiol, which is oxidized to a sulfonate or sulfate, an alcohol to a carboxylic acid.
  • esters of the compounds of formulae (I) and (III) are pharmaceutically acceptable esters of the compounds of formulae (I) and (III) .
  • pharmaceutically acceptable esters refers to relatively non-toxic, esterified products of the parent compound. These esters can be prepared in si tu during the final isolation and purification of the compounds, or by separately reacting the purified compounds in its free acid or hydroxyl form with a suitable esterifying agent.
  • Carboxylic acids can be converted into esters via treatment with an alcohol in the presence of a catalyst .
  • Hydroxyl containing derivatives can be converted into esters via treatment with an esterifying agent such as alkanoyl halides .
  • the term further includes lower hydrocarbon groups capable of being solvated under physiological conditions, for example, alkyl esters, preferred methyl, ethyl, and propyl ester, methoxymethyl ester, methylthiomethyl ester, pivaloyloxymethyl ester and the like (see, e . g. , Berge et al . , J. Pharm. Sci. 1977, 66, 1-19).
  • the compounds of the present invention have useful, in particular pharmacologically useful, properties. They are able to specifically antagonize the effect of endogenous ADP on its platelet ADP receptor, the P2Y 12 receptor.
  • the platelet ADP receptor P2Y 12 upon activation with ADP is responsible for blood platelet aggregation.
  • the compounds of formulae (I) and (III) are therefore useful in treatment or prevention of vascular diseases that respond to the blockade of the P2Y 12 receptor.
  • a compound or a pharmaceutical composition of the invention may be used as a drug (medicine) or therapeutic agent for prevention and/ or treatment of peripheral vascular, cardiovascular and cerebrovascular diseases or conditions, associated with platelet aggregation, particularly related to thrombosis in humans and other mammals.
  • Such compounds may be useful as inhibitors of platelet activation, aggregation and degranulation, as antithrombotic agents or in the treatment and/or prevention of, for example any thrombosis, particularly platelet-dependent thrombotic indications, including, but not limited to, acute myocardial infarction, unstable angina, coronary angioplasty (PTCA) , perithrombolysis, primary arterial thrombotic complications of atherosclerosis such as thrombotic or embolic stroke, chronic stable angina, transient ischemic attacks, strokes, peripheral vascular disease, myocardial infarction with or without thrombolysis, pre-eclampsia/ eclampsia, venous thrombosis such as deep venous thrombosis, venoocclusive disease, embolism, disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, heparin-induced thrombocytopenia, hemolytic uremic syndrome, thrombo
  • the compounds of the invention may also be used for the prevention of mechanically-induced platelet activation in vivo, for example to prevent microthromboembolism in cardiopulmonary bypass; or in vi tro in the preservation of blood products, for example 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, atheromatous plaque formation/progression, vascular stenosis/restenosis and asthma, in which platelet-derived factors play a role in the disease process.
  • the compounds of formulae (I) and (III) may be used as standard or reference compounds in tests or assays involving the inhibition of the platelet ADP receptor, P2Y 12 .
  • Such compounds could be made commercially available for use as a reference, quality standard or control, for example in pharmaceutical research when developing new assays or protocols related to P2Y 12 activity.
  • compounds of formulae (I) and (III) antagonize the ADP dependent activation of the platelet ADP receptor P2Y 12 .
  • the biological effect of such compounds may be tested in a variety of in vi tro, ex vivo and in vivo assays.
  • the ability of the compounds of formulae (I) and (III) to bind to the P2Y 12 receptor may be measured by methods similar to those described in Gachet C. et al . , Br. J. Hematol . 1995, 91, 434-444 and by the method described below in Example 16.
  • IC 50 values i.e. the concentrations where half-maximal inhibition of the interaction is found
  • test compounds of formulae (I) and (III) Exemplary IC S0 values determined in this test are given below in Example 17.
  • the ability of the compounds of the invention to inhibit ADP- induced aggregation of platelets may be measured by methods similar to those described in Born G.V.R., and Cross M. . , J. Physiol. 1963, 168, 178-195 and the method described below in Example 18.
  • ED 50 i.e. the effective dose where half- maximal inhibition of the aggregation is found
  • test compounds of formulae (I) and (III) are found with test compounds of formulae (I) and (III) .
  • a functional assay with cells expressing the human P2Y 12 receptor may be used to detect changes in the levels of intracellular calcium concentration following compound treatment. After addition of the compound the cells are challenged with ADP. In a Fluorescent Imaging Plate Reader (FLIPRTM, Molecular Devices, Sunnyvale, California) fluorescence emission is recorded during both additions, emission peak values above base level after ADP addition were exported, normalized to low controls (no ADP) and high controls (no active compound) . The relative values of the remaining activity were used to determine IC S0 values by curve fitting them to a four-parameter logistic sigmoid curve.
  • FLIPRTM Fluorescent Imaging Plate Reader
  • the ability of the compounds to inhibit ADP induced change of intracellular calcium levels via P2Y ⁇ 2 activation may be measured by methods known of one skilled in the art or by the method described below in Example 19.
  • IC S0 values i.e. the concentration of a compound at which the remaining activity is 50%
  • test compounds of formulae (I) and (III) are obtained with test compounds of formulae (I) and (III) .
  • a compound of formula (I) or (III) according to the invention may show therapeutic efficacy against vascular disorders mentioned herein, especially against thrombotic diseases.
  • a compound of formula (I) or (III) can be administered alone in pure form or in combination with one or more other therapeutic agents, possible combination therapy taking the form of fixed combinations or the administration of a compound of the invention and one or more other therapeutic agents being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic agents.
  • a compound of formula (I) or (III) can besides or in addition be administered especially for anti-thrombotic therapy in combination with other vascular diseases. Long- term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are preventive therapies, for example in patients at risk.
  • the invention relates also to pharmaceutical compositions comprising compounds of formula (III) , to their use in therapeutic, in a broader aspect of the invention also prophylactic treatment or a method of treatment of the diseases mentioned above, to the compounds for said use and to the preparation of pharmaceutical formulations (medicines) .
  • the pharmaceutically acceptable compounds of the present invention may be used, for example, for the preparation of pharmaceutical compositions that comprise an effective amount of the active ingredient together or in admixture with a significant amount of one or more inorganic, organic, solid or liquid, pharmaceutically acceptable carriers .
  • the invention relates also to a pharmaceutical composition that is suitable for administration to a warm-blooded animal, especially a human (or to cells or cell lines derived from a warm-blooded animal, especially a human, e . g. blood platelets) , for the treatment or, in a broader aspect of the invention, prevention of (i.e. prophylaxis against) a disease that responds to blockade of the interaction of the platelet adenosine diphosphate (ADP) receptor with ADP, comprising an amount of a compound of formula (I) or (III) or a pharmaceutically acceptable salt or a prodrug thereof, which is effective for said inhibition, together with at least one pharmaceutically acceptable carrier.
  • ADP platelet adenosine diphosphate
  • compositions according to the invention are those for enteral administration, such as nasal, buccal, rectal, dermal or, especially oral administration, and for parenteral administration, such as intramuscular, intravenous or subcutaneous, intrasternal, intravitreal, injection or infusion, to warm-blooded animals, especially humans.
  • Such compositions comprise an effective dose of the pharmaceutically active ingredient, alone or together with a significant amount of a pharmaceutically acceptable carrier.
  • the dosage of the active ingredient depends on the species of warm-blooded animal, the body weight, the age and the individual conditions, individual pharmacokinetic data, the disease to be treated and the mode of administration .
  • the invention relates also to a process or a method for the treatment of a pathological condition mentioned hereinabove, especially a disease, which responds to blockade of the interaction of the platelet adenosine diphosphate (ADP) receptor with ADP, especially thrombosis.
  • ADP platelet adenosine diphosphate
  • the compounds of formulae (I) and (III) or salts or a prodrugs thereof can be administered as such or especially in the form of pharmaceutical compositions.
  • the dose to be administered to warm-blooded animals is preferably from approximatively 3 mg to approximatively 30 g, more preferably from approximatively 10 mg to approximatively 1000 mg per person per day, divided preferably into 1 to 3 single doses which may, for example, be of the same size.
  • the amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, the weight, and response of the individual patient, the severity of the patient's symptoms, and the like, for example, children usually receive half of the adults dose.
  • compositions comprise from approximately 1% to approximately 95%, preferably from approximately 20% to approximately 90%, active ingredient.
  • Pharmaceutical compositions according to the invention may be, for example, in unit dosage forms such as coated and uncoated tablets, pills, ampoules, vials, suppositories, dragees, or capsules. Further dosage forms are, for example, ointments, creams, pastes, emulsions, foams, chewable gums, tinctures, lip-sticks, drops, sprays or aerosols, syrups or elixirs, dispersions, transdermal patches or pads, or via an intravitreal device that releases the compound in a sustained capacity, and the like. Examples are capsules containing from about 0.05 g to about 1.0 g active ingredient.
  • compositions of the present invention are prepared in a manner known, per se, for example by means of conventional mixing, granulating, coating, dissolving, lyophilizing or con ectioning processes.
  • Solutions of the active ingredient, and also suspensions, and especially isotonic aqueous solutions or suspensions are preferably used, it being possible, for example in the case of lyophilized compositions, that comprise the active ingredient alone or together with a carrier, for example mannitol, for such solutions or suspensions to be produced prior to use .
  • the pharmaceutical compositions may be sterilized and/or may comprise excipients, for example preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating osmotic pressure and/or buffers and are prepared in a manner known per se, for example by means of conventional dissolving or lyophilizing processes.
  • the said solutions or suspensions may comprise viscosity-increasing substances, such as sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin.
  • Suspensions in oil comprise as the oil component the vegetable, synthetic or semi-synthetic oils customary for injection purposes.
  • liquid fatty acid esters that contain as the acid component a long-chain fatty acid having from 8 to 22, especially from 12 to 22, carbon atoms, for example lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid or corresponding unsaturated acids, for example oleic acid, elaidic acid, erucic acid, brasidic acid or linoleic acid, if desired with the addition of antioxidants, for example vitamin E, ⁇ -carotene or 3 , 5-di- tert-butyl-4- hydroxytoluene .
  • the alcohol component of those fatty acid esters has a maximum of 6 carbon atoms and is mono- or poly-hydroxy, for example a mono-, di- or trihydroxy, alcohol, for example methanol, ethanol, propanol, butanol, or pentanol or the isomers thereof, but especially glycol and glycerol.
  • fatty acid esters are therefore to be mentioned: ethyl oleate, iso-propyl myristate, iso-propyl palmitate, "Labrafil M2375” (polyoxyethylene glycerol trioleate, Gattefosse, Paris) , "Miglyol 812” (triglyceride of saturated fatty acids with chain length of C8 to C12, H ⁇ ls AG, Germany), but especially vegetable oils, such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and more especially groundnut oil.
  • vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and more especially groundnut oil.
  • the injection or infusion compositions are prepared in customary manner under sterile conditions; the same applies also to introducing the compositions into ampoules or vials and sealing the containers .
  • compositions for oral administration can be obtained by combining the active ingredient with solid carriers, if desired granulating a resulting mixture, and processing the mixture, if desired or necessary, after the addition of appropriate excipients, into tablets, dragee cores or capsules. It is also possible for them to be incorporated into plastics carriers that allow the active ingredients to diffuse or be released in measured amounts .
  • Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and binders, such as starch pastes using for example corn, wheat, rice, or potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the above-mentioned starches, and/or carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate.
  • fillers such as sugars, for example lactose, saccharose, mannitol or sorbitol
  • cellulose preparations and/or calcium phosphates for example tricalcium phosphate or calcium hydrogen phosphate
  • Excipients are especially flow conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol.
  • Dragee cores are provided with suitable, optionally enteric, coatings, there being used, inter alia, concentrated sugar solutions which may comprise gum Arabic, talc, polyvinylpyrrolidone, polyethylene glycol, and/or titanium dioxide, or coating solutions in suitable organic solvents, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as ethylcellulose phthalate or hydroxypropylmethylcellulose phthalate.
  • Capsules are dry-filled capsules made of gelatin and of soft sealed capsules made of gelatine and a plasticiser, such as glycerol or sorbitol.
  • the dry-filled capsules may comprise the active ingredient in the form of granules, for example with fillers, such as lactose, binders, such as starches, and/or glidants, such as talc or magnesium stearate, and if desired with stabilizers.
  • the active ingredient is preferably dissolved or suspended in suitable oil excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols, it being possible also for stabilizers and/or antibacterial agents to be added.
  • suitable oil excipients such as fatty oils, paraffin oil or liquid polyethylene glycols, it being possible also for stabilizers and/or antibacterial agents to be added.
  • Dyes or pigments may be added to the tablets or dragee coatings or the capsule casings, for example for identification purposes or to indicate different dose
  • aqueous solutions of an active ingredient in water-soluble form for example of a water-soluble salt, or aqueous injection suspensions that contain viscosity- increasing substances and stabilizers, are especially suitable.
  • the active ingredient optionally together with excipients, can also be in the form of a lyophilizate and be made into a solution before parenteral administration by the addition of solvents.
  • Compounds of the invention may be manufactured by the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature, for example those described by Larock R. C. in “Comprehensive organic transformations: a guide to functional group preparations", VCH publishers, 1999.
  • reactive functional groups for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions.
  • Conventional protecting groups may be used in accordance with standard practice, for example see Greene T. W. and Wuts P. G. M. in “Protective groups in organic synthesis” Wiley-Interscience, 1999.
  • alkylidene pyrazolidinediones of formula (I) may be prepared by the condensation of pyrazolidinedione of formula (IV) with an aldehyde of formula (V) , optionally in the presence of a suitable base such as pyridine, piperidine, diisopropylethylamine, triethylamine, in a suitable solvent, such as ethanol, methanol, 1-butanol or acetic acid as shown in Scheme 1, hereinbelow.
  • the preferred conditions are heating the pyrazolidinedione of formula (IV) with an aldehyde of formula (V) in ethanol between 60 to 80 °C.
  • R 2 moieties in a structure of formula (I) obtained in step a, such as moieties containing a reactive substituent which is protected, might allow further synthetic modifications (step b) , such as a deprotection step, to give a compound of formula ( I' ) •
  • the tert-butoxycarbonyl group present in 4- [1- (2- ert-butoxycarbonyl-5-propoxy-l, 2, 3 , 4-tetrahydro-isoquinolin- 8-yl) -methylidene] -l-phenyl-pyrazolidine-3, 5-dione can be removed by means of HCI to give l-phenyl-4- [1- (5-propoxy-l, 2, 3 , 4- tetrahydro-isoquinolin-8-yl) -methylidene] -pyrazolidine-3, 5-dione; or the ketal group present in 4- [1- [2- (2, 2-dimethyl- [1,3] dioxolan-4-ylmethoxy) -3 -methyl-4-propoxy-phenyl] - methylidene] -l-phenyl-pyrazolidine-3 , 5-dione can be removed by means of HCI to give 4- [1- [2- (2, 3-
  • Pyrazolidinediones of formula (IV) can be prepared by a method which is analogous to the method described by Conrad M. and Zart A., Ber. 1906, 2282-2288, and shown in Scheme 2, hereinbelow, in a cyclocondensation of a hydrazine of formula 1 with a malonic acid derivative of formula 2, whereby G 1 and LG 2 each represent an appropriate leaving group such as halogen, preferably chloro; or alkoxy, preferably methoxy or ethoxy; or aryloxy; in a suitable solvent, such as methanol or ethanol; in the presence or absence of a base such as sodium methoxide or sodium ethoxide .
  • G 1 and LG 2 each represent an appropriate leaving group such as halogen, preferably chloro; or alkoxy, preferably methoxy or ethoxy; or aryloxy
  • a suitable solvent such as methanol or ethanol
  • a base such as sodium methoxide or sodium ethoxide
  • a compound of formula (IV) can be prepared by cyclizing a compound of formula 3 by a method, which is analogous to the method described by Michaelis A.
  • compounds of formula 3 are prepared by the condensation of hydrazines of formula 1 with malonic acid derivatives of formula 2, whereby LG X is a leaving group such as OH; and LG 2 represents an alkoxy, preferably methoxy or ethoxy; or an aryloxy group in the presence of a coupling reagent, such as 1,3- dicyclohexylcarbodiimide, O- (7-azabenzotriazol-l-yl) -N, N, N' , N' - tetramethyluronium hexafluorophosphate; or a halogen, preferably chloro; in the presence of a base such as triethylamine, N, N- diisopropylethylamine or pyridine; in a suitable solvent such as tetrahydrofuran, dioxane or N, N-dimethylformamide; at low temperatures, preferably below room temperature.
  • a coupling reagent such as 1,3- dicyclohe
  • Aldehydes of formula (V) are commercially available or may be prepared according to methods known to those skilled in the art or by methods described hereinafter.
  • a preferred embodiment of the present invention provides the preparation of tri-substituted benzaldehydes of formula (V) as shown in Scheme 4, hereinbelow, wherein R 3 represents alkoxy, preferably propoxy; and R 4 and R s are as defined hereinabove.
  • Such tri-substituted benzaldehyde can be obtained as depicted in Scheme 4, starting from the corresponding tri-substituted benzene of formula 4b, which is brominated by means of N-bromosuccinimide in acetonitrile at room temperature to yield the bromobenzene derivative of formula 5 (step a) , by a method which is analogous to the method described by Carreno M. C. et al . , J.
  • step b) the bromobenzene derivative of formula 5 is first transformed into the corresponding aryl-lithium intermediate by using an alkyl lithium reagent, preferably butyllithium, in a solvent like tetrahydrofuran, at a temperature below 0°C, preferably at -78°C, and then quenching with a dialkylformamide, such as N, N- dimethylformamide, or an alkyl formate, such as methyl formate, to yield the aldehyde of formula (V) .
  • an alkyl lithium reagent preferably butyllithium
  • a solvent like tetrahydrofuran at a temperature below 0°C, preferably at -78°C
  • a dialkylformamide such as N, N- dimethylformamide
  • an alkyl formate such as methyl formate
  • Another embodiment of the present invention provides the preparation of tri-substituted benzene derivatives of formula 4b, wherein R 3 is alkoxy, preferably propoxy; and R 4 and R s , together with the phenyl ring to which they are attached, form a bicyclic, optionally substituted carbocyclic or heterocyclic ring system; by alkylating the corresponding phenol of formula 4a, wherein R 3 represents hydroxy; with an alkylhalide, preferably 1- bromopropane; in a solvent such as N, N-dimethylformamide; in the presence of a base, such as potassium carbonate, or sodium hydride; at elevated temperatures between 30°C and 100°C.
  • bicyclic compounds of formula 4b are depicted hereinbelow:
  • a benzyl alcohol of formula 7b, wherein R 6 represents hydrogen,- can be obtained by reducing a ketone of formula 7a by means of a reducing agent, such as sodium borohydride, in a solvent such as an alcohol, preferably methanol.
  • a reducing agent such as sodium borohydride
  • a benzyl alcohol of formula 7b, wherein R s represents hydrogen can be reduced, e . g. by hydrogenation in the presence of a metal catalyst, such as palladium on charcoal, to give a compound of formula 7d, which is a representative member of the aforementioned class of tri-subsubstituted benzenes of formula 4b.
  • a metal catalyst such as palladium on charcoal
  • a benzyl alcohol of formula 7b (R 6 representing hydrogen) may be further modified by treating with an alkylhalide in the presence of a base to give a compound of formula 7c, wherein R 6 represents alkyl, representing an example of the aforementioned tri- subsubstituted benzenes of formula 4b.
  • An isoquinoline derivative of formula 9a which is a representative of the aforementioned tri-subsubstituted benzenes of formula 4b, may be prepared from 2-alkoxy-benzaldehyde by a method which is analogous to the procedure described by Hendrickson J. B. et al . , J. Org. Chem. 1983, 3346-3347.
  • a phenol of formula 10 is converted to a benzaldehyde of formula 11 in a well-known formylation reaction such as the Vilsmeier formylation (step a), according to Nielsen S. F. et al . , J. Med. Chem. 1998, 4819-4832.
  • Subsequent alkylation of the hydroxy group in para-position to the formyl group can be achieved by reacting an aldehyde of formula 11 with an R 8 -transferring reagent, such as an alkylhalide, alkylmesylate or alkyltosylate, preferably 1- bromopropane, in a solvent like acetonitrile, in the presence of a base, such as potassium carbonate, at a temperature ranging between room and reflux temperature, preferably around 50°C (step b) .
  • an aldehyde of formula 11 with an R 8 -transferring reagent, such as an alkylhalide, alkylmesylate or alkyltosylate, preferably 1- bromopropane, in a solvent like acetonitrile, in the presence of a base, such as potassium carbonate, at a temperature ranging between room and reflux temperature, preferably around 50°C (step b) .
  • R 8 -transferring reagent such as an al
  • the hydroxy group ortho-positioned to the formyl group in an aldehyde of formula 12 can be alkylated (step c) by treating said aldehyde of formula 12 with an R 9 -transferring reagent, such as an alkylhalide, alkylmesylate or alkyltosylate, in solvents like N, T ⁇ T-dimethylformamide, acetone or butan-2-one, in the presence of a weak base like cesium or potassium carbonate, optionally in the presence of sodium or potassium iodide, at a temperature ranging from room temperature to 140°C, yielding a tri-substituted benzaldehyde of formula (VI) , which after further chemical modifications at R s , e . g. removal of any protecting group (s) (step d) , gives a benzaldehyde of formula (VI') .
  • an R 9 -transferring reagent such as an alkylhalide, alkylmesylate or
  • Example 4 (R is 2-Pyridyl) 4a)
  • the following products 4al and 4a2 were prepared by proceeding in a similar manner to the method described in Example 1, but using l-pyridin-2-yl-pyrazolidine-3 , 5-dione (Example 4b2) in place of l-phenyl-pyrazolidine-3 , 5-dione, and the respective aldehydes :
  • aqueous phase was then acidified to pH 1 by addition of IN aqueous HCI and extracted with EtOAc (3 x 100 ml) .
  • EtOAc 3 x 100 ml
  • the combined organic phases were washed with H 2 0 (50 ml) , brine (50 ml) , dried over MgS0 4 , filtered and concentrated.
  • CHO cells with recombinant expression of the human P2Y 12 receptor were cultured in 24 well cell-culture plates. Cells were washed three times with binding buffer (50 mM Tris pH 7.4, 100 mM NaCI, 1 mM EDTA, 0.5 %BSA) . The cells were then incubated with 0.5 ml per well binding buffer containing tritium-labeled 2-methyl-thio-adenosine 5' -diphosphate (2 -methyl- S-ADP) (between 100 '000 and 300' 000 dpm per well) and various concentrations of test compounds. After incubation at room temperature for 2 hours, cells were washed three times with binding buffer.
  • binding buffer 50 mM Tris pH 7.4, 100 mM NaCI, 1 mM EDTA, 0.5 %BSA
  • the cells were then incubated with 0.5 ml per well binding buffer containing tritium-labeled 2-methyl-thio-adenosine 5' -di
  • Example 17 Test for antagonist binding to the platelet ADP receptor P2Y 19 .
  • IC S0 values ranging between about 0.001 and about 10 ⁇ M.
  • Preferred compounds showed IC S0 values below 1 ⁇ M, particularly preferred compounds showed IC S0 values below 0.1 ⁇ M and still more preferred compounds showed IC S0 values below 0.01 ⁇ M.
  • Exemplary IC S0 values are given below.
  • Example 18 ADP induced Platelet Aggregation
  • Platelet aggregation was measured in a Chronolog lumiaggregometer with stirring (900 rpm) at 37°C. PRP was placed into the cuvette and allowed to equilibrate at 37°C for two min. In a first phase, the ADP concentration to give optimal extent of aggregation was determined for the PRP of each donor. In a second phase, PRP was incubated with inhibitors for 2 min at 37°C prior to the addition of the agonist ADP at 1-5 ⁇ M final concentration.
  • Chinese Hamster Ovary (CHO) cells stably expressing the human P2Y 12 receptor under the control of the cytomegalovirus promoter in the expression vector pcDNA3 (Invitrogen) were grown to near confluency in Ham's F-12 medium supplemented with 10% fetal calf serum (both Bioconcept, Switzerland) under standard mammalian cell culture conditions (37°C and 5% carbon dioxide) .
  • Cells were treated with 0.02% EDTA in phosphate buffer saline (PBS, Gibco) for 10 min, detached by tapping, and collected by centrifugation for five minutes at 200 g, all at room temperature.
  • PBS phosphate buffer saline
  • a FLIPR384 instrument (Molecular Devices) was operated following the manufacturer's standard instructions, adding 10 ⁇ l of compound dissolved at 10 mM in DMSO and diluted prior to the experiment in assay buffer to obtain the desired final concentration. 10 ⁇ l of ADP (Sigma) solution in assay buffer supplemented with bovine serum albumin (fatty acid content ⁇ 0.02%, Sigma) was then added to obtain a final concentration of 3 ⁇ M and 0.1%, respectively. Fluorescence emission was recorded during both additions.
  • a sterile-filtered aqueous solution, with 2% cyclodextrins as solubilisers, of one of the compounds of formula (III) mentioned in the preceding Examples ( e . g. Example 8a) as active ingredient, is so mixed under aseptic conditions, with heating, with a sterile gelatin solution containing phenol as preservative, that 1.0 ml of solution has the following composition:
  • the dry granulates are pressed through a sieve having a mesh size of 1 mm, mixed with a pre-sieved mixture (1 mm sieve) of 330 g of corn starch, the magnesium stearate, the stearic acid and the sodium carboxymethyl starch, and compressed to form slightly biconvex tablets.
  • Example 23 Soft capsules
  • the pulverized active ingredient is suspenden in Lauroglykol ® (propylene glycol laureate, Glattefosse S. A., Saint Priest, France) and ground in a wet pulverizer to produce a particle size of about 1 to 3 ⁇ m. 0.42 g portions of the mixture are then introduced into soft gelatin capsules using a capsule-filling machine .
  • Lauroglykol ® propylene glycol laureate, Glattefosse S. A., Saint Priest, France

Abstract

L'invention concerne des dérivés de pyrazolidinédione de formule générale (I), dans laquelle R1 désigne un hydrogène, un alkyle éventuellement substitué, un cycloalkyle, un aryle, un arylalkyle, un hétéroaryle, un hétéroarylalkyle ou un alkanoyle; et R2 représente un aryle ou un hétéroaryle; des tautomères de ceux-ci; des isomères géométriques de ceux-ci et des tautomères de ces isomères géométriques, notamment des mélanges de composés individuels de formule (I), ou des tautomères de ceux-ci, et des isomères géométriques de ceux-ci ou des tautomères de ceux-ci, des sels d'ajout acides acceptables sur le plan pharmaceutique des composés qui sont basiques; des sels acceptables sur le plan pharmaceutique de composés renfermant des groupes acides avec des bases; des esters acceptables sur le plan pharmaceutique des composés renfermant des groupes hydroxy ou carboxy; des promédicaments de composés dans lesquels un groupe formant un promédicament est présent; ainsi que des hydrates ou solvates de ceux-ci; lesdits dérivés sont actifs comme antagonistes du récepteur de l'adénosine diphosphate des plaquettes et peuvent être utilisés pour la prévention et/ou le traitement de maladies vasculaires périphériques, vasculaires viscérales, hépatiques et rénales, cardio-vasculaires et cérébro-vasculaires ou d'états associés à l'agrégation plaquettaire, notamment la thrombose et, respectivement, pour la fabrication des médicaments correspondants. Quelques composés, mais pas tous, de la formule (I) susmentionnée sont nouveaux.
PCT/EP2004/006471 2003-06-24 2004-06-16 Derives de pyrazolidinedione WO2005000281A2 (fr)

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EP04739938A EP1638540A2 (fr) 2003-06-24 2004-06-16 Dérivés de pyrazolidinedione et leur utilisation comme inhibiteurs d'agrégation plaquettaire
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US8426420B2 (en) 2007-12-26 2013-04-23 Sanofi Heterocyclic pyrazole-carboxamidesas P2Y12 antagonists
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US11179390B2 (en) * 2017-03-15 2021-11-23 Idorsia Pharmaceuticals Ltd Subcutaneous administration of a P2Y12 receptor antagonist
US11584710B2 (en) 2017-07-31 2023-02-21 Horitzonts Tecnologics Hungary Korlátolt Felelosségu Társaság Compounds for treating infections

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CA2529436A1 (fr) 2005-01-16
EP1638540A2 (fr) 2006-03-29
JP2007506661A (ja) 2007-03-22
WO2005002574A1 (fr) 2005-01-13
CN1812782A (zh) 2006-08-02
WO2005000281A3 (fr) 2005-04-14

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