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WO2002026718A2 - Inhibiteurs du facteur xa à base de pyrimidine-4-one bicyclique - Google Patents

Inhibiteurs du facteur xa à base de pyrimidine-4-one bicyclique Download PDF

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Publication number
WO2002026718A2
WO2002026718A2 PCT/US2001/030335 US0130335W WO0226718A2 WO 2002026718 A2 WO2002026718 A2 WO 2002026718A2 US 0130335 W US0130335 W US 0130335W WO 0226718 A2 WO0226718 A2 WO 0226718A2
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alkyl
compound
compounds
group
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WO2002026718A3 (fr
Inventor
Penglie Zhang
Wenhao Li
Wenrong Huang
Lingyan Wang
Zhaozhong Jon Jia
Robert M. Scarborough
Bing-Yan Zhu
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COR Therapeutics Inc
Millennium Pharmaceuticals Inc
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COR Therapeutics Inc
Millennium Pharmaceuticals Inc
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Priority to AU2002214546A priority Critical patent/AU2002214546A1/en
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Publication of WO2002026718A3 publication Critical patent/WO2002026718A3/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention relates to novel bicyclic pyrimidin-4-one-containing compounds including their pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, and pharmaceutically acceptable compositions thereof which are potent and highly selective inhibitors of isolated factor Xa or when assembled in the prothrombinase complex.
  • These compounds show selectivity for factor Xa versus other proteases of the coagulation (e.g. thrombin, fNIIa, fLXa) or the fibrinolytic cascades (e.g. plasminogen activators, plasmin).
  • the present invention relates to novel bicyclic pyrimidin-4-one-containing compounds including their pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives factor Xa-inhibiting compounds, and pharmaceutically acceptable compositions thereof which are useful as potent and specific inhibitors of blood coagulation in mammals.
  • the invention relates to methods for using these inhibitors as therapeutic agents for disease states in mammals characterized by undesired thrombosis or coagulation disorders.
  • Hemostasis the control of bleeding, occurs by surgical means, or by the physiological properties of vasoconstriction and coagulation.
  • This invention is particularly concerned with blood coagulation and ways in which it assists in maintaining the integrity of mammalian circulation after injury, inflammation, disease, congenital defect, dysfunction or other disruption.
  • platelets and blood coagulation are both involved in thrombus formation, certain components of the coagulation cascade are primarily responsible for the amplification or acceleration of the processes involved in platelet aggregation and fibrin deposition.
  • Thrombin is a key enzyme in the coagulation cascade as well as in hemostasis.
  • Thrombin plays a central role in thrombosis through its ability to catalyze the conversion of fibrinogen into fibrin and through its potent platelet activation activity.
  • Direct or indirect inhibition of thrombin activity has been the focus of a variety of recent anticoagulant strategies as reviewed by Claeson, G., "Synthetic Peptides and Peptidomimetics as Substrates and Inhibitors of Thrombin and Other Proteases in the Blood Coagulation System", Blood Coag. Fibrinol. 5, 411-436 (1994).
  • Several classes of anticoagulants currently used in the clinic directly or indirectly affect thrombin (i.e. heparins, low-molecular weight heparins, heparin-like compounds and coumarins).
  • a prothrombinase complex including Factor Xa (a serine protease, the activated form of its Factor X precursor and a member of the calcium ion binding, gamma carboxyglutamyl (Gla)-containing, vitamin K dependent, blood coagulation glycoprotein family), converts the zymogen prothrombin into the active procoagulant thrombin.
  • Factor Xa a serine protease, the activated form of its Factor X precursor and a member of the calcium ion binding, gamma carboxyglutamyl (Gla)-containing, vitamin K dependent, blood coagulation glycoprotein family
  • Ga carboxyglutamyl
  • Polypeptides derived from hematophagous organisms have been reported which are highly potent and specific inhibitors of factor Xa.
  • United States Patent 4,588,587 describes anticoagulant activity in the saliva of the Mexican leech, Haementeria officinalis. A principal component of this saliva was shown to be the polypeptide factor Xa inhibitor, antistasin (ATS), by Nutt, E. et al, "The Amino Acid Sequence of Antistasin, a Potent Inhibitor of Factor Xa Reveals a Repeated Internal Structure", J. Biol. Chem., 263, 10162-10167 (1988).
  • ATS antistasin
  • tick anticoagulant peptide Another potent and highly specific inhibitor of Factor Xa, called tick anticoagulant peptide (TAP), has been isolated from the whole body extract of the soft tick Ornithidoros moubata, as reported by Waxman, L., et al, "Tick Anticoagulant Peptide (TAP) is a Novel Inhibitor of Blood Coagulation Factor Xa" Science, 248, 593-596 (1990).
  • Factor Xa inhibitory compounds which are not large polypeptide-type inhibitors have also been reported including: Tidwell, R.R. et al, "Strategies for Anticoagulation With Synthetic Protease Inhibitors. Xa Inhibitors Versus Thrombin Inhibitors", Thromb. Res., 19, 339-349 (1980); Turner, A.D. et al, "p-Amidino
  • Factor Xa inhibitors which are small molecule organic compounds, such as nitrogen containing heterocyclic compounds which have amidino substituent groups, wherein two functional groups of the compounds can bind to Factor Xa at two of its active sites.
  • WO 99/10316 describes compounds having a 4-phenyl-N-alkylamidino-piperidine and 4-phenoxy-N-alkylamidino-piperidine group connected to a 3-amidinophenyl group via a carboxamidealkyleneamino
  • EP 798295 describes compounds having a 4-phenoxy-N-alkylamidino- piperidine group connected to an amidinonaphthyl group via a substituted or unsubstituted sulfonamide or carboxamide bridging group.
  • the present invention relates to novel bicyclic pyrimidin-4-one-containing compounds including their pharmaceutically acceptable isomers, salts, hydrates, solvate and prodrug derivatives, which have particular biological properties and are useful as potent and specific inhibitors of blood coagulation in mammals.
  • the compounds can act as potent and highly selective inhibitors of isolated Factor Xa or when assembled in the prothrombinase complex.
  • the invention also provides compositions containing such compounds.
  • the compounds of the invention may be used as diagnostic reagents or as therapeutic reagents for disease states in mammals which have coagulation disorders.
  • the invention further provides methods for preventing or treating a condition in a mammal characterized by undesired thrombosis by administration of a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier.
  • the methods of the invention comprise administering a pharmaceutical composition of the invention in combination with an additional therapeutic agent such as an antithrombotic and/or a thrombolytic agent and/or an anticoagulant.
  • such conditions include, for example, any thrombotically mediated acute coronary or cerebrovascular syndrome, any thrombotic syndrome occurring in the venous system, any coagulopathy, and any thrombotic complications associated with extracorporeal circulation or instrumentation, and for the inhibition of coagulation in biological samples (e.g. stored blood products and samples).
  • biological samples e.g. stored blood products and samples.
  • the invention provides a compound of the general formulae (I) or (II): wherein:
  • A is a member selected from the group consisting of:
  • R lc is H, C 1-6 alkyl or C 3-8 cycloalkyl
  • R a and R b are independently H, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2 - 6 alkynyl; or R a and R b taken together with the nitrogen to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and its oxidized forms, piperazinyl, 4-methyl-l -piperazinyl, morpholinylcarbaldehyde, piperazinylcarbaldehyde or thiomorpholinylcarbaldehyde and its oxidized forms;
  • Q is a member selected from the group consisting of:
  • R 1 is a H, Cl, F, Br, I, -C 1-6 alkyl, -OC ⁇ -6 alkyl, -OhaloC 1-6 alkyl, -SO 2 C 1-6 alkyl, - NRaR , or -SC 1-6 alkyl, where R a and R b are as set forth above;
  • R 2 is a H, Cl, F, I, Br, -OC 1-6 alkyl or -NR a R b , where R a and R b are as set forth above;
  • R 3 , R 4 ' R 5 , R 6 and R 7 are each H, -F, -Cl or -Br, OC 1-6 alkyl, -OhaloC 1-6 alkyl, -NR a R b ;
  • Y is CH or N
  • X is O or S
  • alkenyl refers to a trivalent straight chain or branched chain unsaturated aliphatic radical.
  • alkinyl (or “alkynyl”) refers to a straight or branched chain aliphatic radical that includes at least two carbons joined by a triple bond. If no number of carbons is specified alkenyl and alkinyl each refer to radicals having from 2-12 carbon atoms.
  • alkyl refers to saturated aliphatic groups including straight-chain, branched-chain and cyclic groups having the number of carbon atoms specified, or if no number is specified, having up to 12 carbon atoms.
  • cycloalkyl refers to a mono-, bi-, or tri cyclic aliphatic ring having 3 to 14 carbon atoms and preferably 3 to 7 carbon atoms.
  • the terms "carbocyclic ring structure " and " C 3-16 carbocyclic mono, bicyclic or tricyclic ring structure” or the like are each intended to mean stable ring structures having only carbon atoms as ring atoms wherein the ring structure is a substituted or unsubstituted member selected from the group consisting of: a stable monocyclic ring which is aromatic ring ("aryl") having six ring atoms; a stable monocyclic non-aromatic ring having from 3 to 7 ring atoms in the ring; a stable bicyclic ring structure having a total of from 7 to 12 ring atoms in the two rings wherein the bicyclic ring structure is selected from the group consisting of ring structures in which both of the rings are aromatic, ring structures in which one of the rings is aromatic and ring structures in which both of the rings are non-aromatic; and a stable tricyclic ring structure having a total of from 10 to 16 atoms in the three rings wherein
  • non-aromatic rings when present in the monocyclic, bicyclic or tricyclic ring structure may independently be saturated, partially saturated or fully saturated.
  • carbocyclic ring structures include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), 2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
  • the ring structures described herein may be attached to one or more indicated pendant groups via any carbon atom which results in a stable structure.
  • substituted as used in conjunction with carbocyclic ring structures means that hydrogen atoms attached to the ring carbon atoms of ring structures described herein may be substituted by one or more of the substituents indicated for that structure if such substitution(s) would result in a stable compound.
  • aryl which is included with the term “carbocyclic ring structure” refers to an unsubstituted or substituted aromatic ring, substituted with one, two or three substituents selected from loweralkoxy, loweralkyl, loweralkylamino, hydroxy, halogen, cyano, hydroxyl, mercapto, nitro, thioalkoxy, carboxaldehyde, carboxyl, carboalkoxy and carboxamide, including but not limited to carbocyclic aryl, heterocyclic aryl, and biaryl groups and the like, all of which may be optionally substituted.
  • Preferred aiyl groups include phenyl, halophenyl, loweralkylphenyl, napthyl, biphenyl, phenanthrenyl and naphthacenyl.
  • arylalkyl which is included with the term “carbocyclic aryl” refers to one, two, or three aryl groups having the number of carbon atoms designated, appended to an alkyl group having the number of carbon atoms designated. Suitable arylalkyl groups include, but are not limited to, benzyl, picolyl, naphthylmethyl, phenethyl, benzyhydryl, trityl, and the like, all of which may be optionally substituted.
  • heterocyclic ring or “heterocyclic ring system” is intended to mean a substituted or unsubstituted member selected from the group consisting of stable monocyclic ring having from 5-7 members in the ring itself and having from 1 to 4 hetero ring atoms selected from the group consisting of N, O and S; a stable bicyclic ring structure having a total of from 7 to 12 atoms in the two rings wherein at least one of the two rings has from 1 to 4 hetero atoms selected from N, O and S, including bicyclic ring structures wherein any of the described stable monocyclic heterocyclic rings is fused to a hexane or benzene ring; and a stable tricyclic heterocyclic ring structure having a total of from 10 to 16 atoms in the three rings wherein at least one of the three rings has from 1 to 4 hetero atoms selected from the group consisting of N, O and S.
  • heterocyclic ring or “heterocyclic ring system” include aromatic rings, as well as non-aromatic rings which can be saturated, partially saturated or fully saturated non-aromatic rings.
  • heterocyclic ring system includes ring structures wherein all of the rings contain at least one hetero atom as well as structures having less than all of the rings in the ring structure containing at least one hetero atom, for example bicyclic ring structures wherein one ring is a benzene ring and one of the rings has one or more hetero atoms are included within the term "heterocyclic ring systems” as well as bicyclic ring structures wherein each of the two rings has at least one hetero atom.
  • the ring structures described herein may be attached to one or more indicated pendant groups via any hetero atom or carbon atom which results in a stable structure.
  • substituted means that one or more of the hydrogen atoms on the ring carbon atom(s) or nitrogen atom(s) of the each of the rings in the ring structures described herein may be replaced by one or more of the indicated substituents if such replacement(s) would result in a stable compound.
  • Nitrogen atoms in a ring structure may be quaternized, but such compounds are specifically indicated or are included within the term "a pharmaceutically acceptable salt” for a particular compound.
  • the total number of O and S atoms in a single heterocyclic ring is greater than 1, it is preferred that such atoms not be adjacent to one another. Preferably, there are no more that 1 O or S ring atoms in the same ring of a given heterocyclic ring structure.
  • Examples of monocylic and bicyclic heterocylic ring systems, in alphabetical order, are acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2- dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, ind
  • Preferred heterocyclic ring structures include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, imidazolyl, indolyl, benzimidazolyl, lH-indazolyl, oxazolinyl, or isatinoyl. Also included are fused ring and spiro compounds containing, for example, the above heterocylic ring structures.
  • aromatic heterocyclic ring system has essentially the same definition as for the monocyclic and bicyclic ring systems except that at least one ring of the ring system is an aromatic heterocyclic ring or the bicyclic ring has an aromatic or non-aromatic heterocyclic ring fused to an aromatic carbocyclic ring structure.
  • halo or halogen as used herein refer to Cl, Br, F or I substituents.
  • haloalkyl refers to an aliphatic carbon radicals having at least one hydrogen atom replaced by a Cl, Br, F or I atom, including mixtures of different halo atoms.
  • Trihaloalkyl includes trifluoromethyl and the like as preferred radicals, for example.
  • salts includes salts of compounds derived from the combination of a compound and an organic or inorganic acid. These compounds are useful in both free base and salt form. In practice, the use of the salt form amounts to use of the base form; both acid and base addition salts are within the scope of the present invention.
  • “Pharmaceutically acceptable acid addition salt” refers to salts retaining the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicyclic acid and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like
  • organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid
  • “Pharmaceutically acceptable base addition salts” include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts.
  • Salts derived from pharmaceutically acceptable organic nontoxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, polyamine resins and the like.
  • Particularly preferred organic nontoxic bases are isopropylamine, diethylamine, ethanolamine, trimethamine, dicyclohexylamine, choline, and caffeine.
  • Bio property for the purposes herein means an in vivo effector or antigenic function or activity that is directly or indirectly performed by a compound of this invention that are often shown by in vitro assays. Effector functions include receptor or ligand binding, any enzyme activity or enzyme modulatory activity, any carrier binding activity, any hormonal activity, any activity in promoting or inhibiting adhesion of cells to an extracellular matrix or cell surface molecules, or any structural role. Antigenic functions include possession of an epitope or antigenic site that is capable of reacting with antibodies raised against it.
  • the compounds of this invention carbon atoms bonded to four non- identical substituents are asymmetric. Accordingly, the compounds may exist as diastereoisomers, enantiomers or mixtures thereof.
  • the syntheses described herein may employ racemates, enantiomers or diastereomers as starting materials or intermediates. Diastereomeric products resulting from such syntheses may be separated by chromatographic or crystallization methods, or by other methods known in the art. Likewise, enantiomeric product mixtures may be separated using the same techniques or by other methods known in the art.
  • Each of the asymmetric carbon atoms when present in the compounds of this invention, may be in one of two configurations (R or S) and both are within the scope of the present invention.
  • the invention provides a compound of the general formulae (I) or (II):
  • A is a member selected from the group consisting of:
  • R lc is H, C 1-6 alkyl or C 3-8 cycloalkyl
  • R a and R b are independently H, -C 1-6 alkyl, -C 2-6 alkenyl, -C2-6alkynyl; or R a and R b taken together with the nitrogen to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and its oxidized forms, piperazinyl, 4-methyl-l -piperazinyl, morpholinylcarbaldehyde, piperazinylcarbaldehyde or thiomorpholinylcarbaldehyde and its oxidized forms;
  • Q is a member selected from the group consisting of:
  • R 1 is a H, Cl, F, Br, I, -C 1-6 alkyl, -OC 1-6 alkyl, -OhaloC ⁇ -6 alkyl, -SO 2 C 1-6 alkyl, - NR a Rb, or -SC ⁇ -6 alkyl, where Ra and Rb are as set forth above;
  • R 2 is a H, Cl, F, I, Br, -OC ⁇ -6 alkyl or -NRaR b , where R a and R b are as set forth above;
  • R 3 , R 4 ' R 5 , R 6 and R 7 are each H, -F, -Cl or -Br, Od. 6 alkyl, -OhaloC 1-6 alkyl, -NR a R b ;
  • Y is CH orN
  • X is O or S
  • A is a member selected from the group consisting of:
  • R lb and R 2a are each a C ⁇ -6 alkyl or C 3-8 cycloalkyl
  • R is a -Cl, -Br, -I or -F;
  • R 1 is a H, -OMe, OCF 3 , NH 2 , NHMe, NMe 2 , -Cl, -Br, -I or -F;
  • R 2 is a H, -Cl, -Br, -I , -F or -O-C ⁇ - 6 alkyl;
  • R 3 is a H, -Cl, -Br, -I, -F, -O-C ⁇ - 6 alkyl, -NH-d- 6 acyl, -NO 2 , -NHSO 2 -C ⁇ - 4 alkyl, -CN or -O-(CH 2 ) 1-4 -COOH;
  • X is -O- or -S-;
  • R 4 and R 5 are each independently H, -Cl, -Br, -I , -F or -O-d- 6 alkyl;
  • Q is a member selected from the group consisting of:
  • R 1 are each independently a H, Me, OMe, OCF 3 , NHMe, NMe 2 , -Cl, -Br, -I or -F, and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof.
  • the invention further provides a compound of formula (I) or (II), as set forth above, wherein: A is a member selected from the group consisting of:
  • R is a -Cl, -Br, -I or -F;
  • R 1 is a H, -Cl, -Br, -I or -F;
  • R 2 is a H, -Cl, -Br, -I, -F or -O-d- 6 alkyl;
  • R 3 is a H, -Cl, -Br, -I, -F or -O-C ⁇ - 6 alkyl;
  • R 4 is a H, -Cl, -Br, -I, -F, -O-C ⁇ - 6 al_kyl, -NH-d- 6 acyl, -NO 2 , -NHSO 2 -d- 4 alkyl, -CN and -O-(CH 2 ) 1-4 -COOH;
  • X is -O- or -S-;
  • R 6 and R 7 are each independently a H, -Cl, -Br, -I , -F or -O-d- ⁇ alkyl;
  • Q is a member selected from the group consisting of:
  • R 1 is a H, -Cl, -Br, -I or -F, and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof.
  • A is a member selected from the group consisting of:
  • R x is a H, -F, -Cl, -OMe, -Me, -OCF 3 , -SO 2 Me, -NMe 2 , or-SMe;
  • R 2 is a H, Cl, F, -OMe or -NMe 2 ;
  • R 3 is a H, Cl, F, -OMe or -NMe 2
  • R 4 is a H, -F, -Cl or -Br; -OMe, and
  • R is a -F, -Cl, or -Br, and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof.
  • the quinazolinone compounds may exist in equilibrium with hydrate compounds (uncyclized) as set forth below:
  • the invention also encompasses all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives of the compounds of the invention, as set forth herein.
  • the compounds of the invention can exist in various isomeric and tautomeric forms, and all such forms are meant to be included in the invention, along with pharmaceutically acceptable salts, hydrates, solvates and prodrug derivatives of such isomers and tautomers.
  • the compounds of the invention may be isolated as the free acid or base or converted to salts of various inorganic and organic acids and bases. Such salts are within the scope of the invention. Non-toxic and physiologically compatible salts are particularly useful although other less desirable salts may have use in the processes of isolation and purification.
  • a number of methods are useful for the preparation of the salts of the compounds as described above and are known to those skilled in the art.
  • the free acid or free base form of a compound of one of the formulae above can be reacted with one or more molar equivalents of the desired acid or base in a 5 solvent or solvent mixture in which the salt is insoluble, or in a solvent like water after which the solvent is removed by evaporation, distillation or freeze drying.
  • the free acid or base form of the product may be passed over an ion exchange resin to form the desired salt or one salt form of the product may be converted to another using the same general process.
  • prodrug derivatives of the compounds contained herein.
  • prodrug refers to a pharmacologically inactive derivative of a parent drug molecule that requires biotransformation, either spontaneous or enzymatic, within the organism to release the active drug.
  • Prodrugs are variations or derivatives of the compounds of the invention which have groups
  • Prodrugs become the compounds of the invention which are pharmaceutically active in vivo, when they undergo solvolysis under physiological conditions or undergo enzymatic degradation.
  • Prodrug compounds of the invention may be called single, double, triple etc., depending on the number of biotransformation steps required to release the active drug within the
  • Prodrug forms often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985 and Silverman, The Organic Chemistry of Drug Design and Drug Action, pp. 352-401, Academic Press, San Diego, CA,
  • Prodrugs commonly known in the art include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acids with a suitable alcohol, or amides prepared by reaction of the parent acid compound with an amine, or basic groups reacted to form an acylated base derivative.
  • the prodrug derivatives of the invention may be combined
  • the compounds of the present invention may also be used alone or in combination or in combination with other therapeutic or diagnostic agents.
  • the compounds of the invention may be coadministered along with other compounds typically prescribed for these conditions according to generally accepted medical practice such as anticoagulant agents, thrombolytic agents, or other antithrombotics, including platelet aggregation inhibitors, tissue plasminogen activators, urokinase, prourokinase, streptokinase, heparin, aspirin, or warfarin.
  • the compounds of the present invention may act in a synergistic fashion to prevent reocclusion following a successful thrombolytic therapy and/or reduce the time to reperfusion.
  • the compounds of the invention can be utilized in vivo, ordinarily in mammals such as primates (e.g. humans), sheep, horses, cattle, pigs, dogs, cats, rats and mice, or in vitro.
  • the biological properties of the compounds of the present invention can be readily characterized by methods that are well known in the art, for example by the in vitro protease activity assays and in vivo studies to evaluate antithrombotic efficacy, and effects on hemostasis and hematological parameters, such as are illustrated in the examples. Diagnostic applications of the compounds of the invention will typically utilize formulations in the fonn of solutions or suspensions.
  • the compounds of the invention may be utilized in compositions such as tablets, capsules or elixirs for oral administration, suppositories, sterile solutions or suspensions or injectable administration, and the like, or incorporated into shaped articles.
  • Subjects in need of treatment (typically mammalian) using the compounds of the invention can be administered dosages that will provide optimal efficacy.
  • the dose and method of administration will vary from subject to subject and be dependent upon such factors as the type of mammal being treated, its sex, weight, diet, concurrent medication, overall clinical condition, the particular compounds employed, the specific use for which these compounds are employed, and other factors which those skilled in the medical arts will recognize.
  • the compounds of the present invention may be synthesized by standard organic chemical synthetic methods as described and referenced in standard textbooks. These methods are well known in the art. See, e.g., Morrison and Boyd, "Organic Chemistry", Allyn and Bacon, Inc., Boston, 1959, et seq.
  • Reactions are carried out in standard laboratory glassware and reaction vessels under reaction conditions of standard temperature and pressure, except where otherwise indicated.
  • Non-limiting exemplary synthesis schemes are outlined directly below, and specific steps are described in the Examples.
  • the reaction products are isolated and purified by conventional methods, typically by solvent extraction into a compatible solvent.
  • the products may be further purified by column chromatography or other appropriate methods.
  • the titled compound was made by the procedure similar to that described in example 1 except the following two steps.
  • Stepl A solution of l-methyl-5-nitro-lH-pyrazole-4-carboxylic acid (340 mg) in 10 mL of dichloromethane was treated with 3 mL of (COCl) 2 and 2 drops of DMF at rt for 2h. The volatile was evaporated and the residue was dissolved in 15 mL of dichloromethane. To the solution was added 256 mg (1 equiv) of 2-amino-5- chloropyridine and 2 mL of pyridine.
  • compositions or formulations of the compounds of the invention are prepared for storage or administration by mixing the compound having a desired degree of purity with physiologically acceptable carriers, excipients, stabilizers etc., and may be provided in sustained release or timed release formulations.
  • Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical field, and are described, for example, in Remington 's Pharmaceutical Sciences, Mack Publishing Co., (A.R. Gennaro edit. 1985).
  • Such materials are nontoxic to the recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, acetate and other organic acid salts, antioxidants such as ascorbic acid, low molecular weight (less than about ten residues) peptides such as polyarginine, proteins, such as serum albumin, gelatin, or immunoglobulins, hydrophilic polymers such as polyvinylpyrrolidinone, amino acids such as glycine, glutamic acid, aspartic acid, or arginine, monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, glucose, mannose or dextrins, chelating agents such as EDTA, sugar alcohols such as mannitol or sorbitol, counterions such as sodium and/or nonionic surfactants such as Tween®, Pluronics® or polyethyleneglycol.
  • buffers such as phosphate, citrate, acetate and other organic acid salts
  • antioxidants such
  • Dosage formulations of the compounds of the invention to be used for therapeutic administration must be sterile. Sterility is readily accomplished by filtration through sterile membranes such as 0.2 micron membranes, or by other conventional methods. Formulations typically will be stored in lyophilized form or as an aqueous solution.
  • the pH of the preparations of the invention typically will be between about 3 and about 11, more preferably from about 5 to about 9 and most preferably from about 7 to about 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of cyclic polypeptide salts.
  • While the preferred route of administration is by injection, other methods of administration are also anticipated such as intravenously (bolus and/or infusion), subcutaneously, intramuscularly, colonically, rectally, nasally or intraperitoneally, employing a variety of dosage forms such as suppositories, implanted pellets or small cylinders, aerosols, oral dosage formulations and topical formulations such as ointments, drops and dermal patches.
  • dosage forms such as suppositories, implanted pellets or small cylinders, aerosols, oral dosage formulations and topical formulations such as ointments, drops and dermal patches.
  • the compounds of the invention are desirably incorporated into shaped articles such as implants which may employ inert materials such as biodegradable polymers or synthetic silicones, for example, Silastic, silicone rubber or other polymers commercially available.
  • the compounds of the invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of lipids, such as cholesterol, stearylamine orphosphatidylcholines.
  • the compounds of the invention may also be delivered by the use of antibodies, antibody fragments, growth factors, hormones, or other targeting moieties, to which the compound molecules are coupled.
  • the compounds of the invention may also be coupled with suitable polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxy- propyl-methacrylamide-phenol, polyhydroxyethyl-aspartamide-phenol, or polyetliyleneoxide-polylysine substituted with palmitoyl residues.
  • the factor Xa inhibitors of the invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels.
  • Polymers and semipermeable polymer matrices may be formed into shaped articles, such as valves, stents, tubing, prostheses and the like.
  • Therapeutic compound liquid formulations generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by hypodermic injection needle.
  • Therapeutically effective dosages may be determined by either in vitro or in vivo methods. For each particular compound of the present invention, individual determinations may be made to determine the optimal dosage required.
  • the range of therapeutically effective dosages will naturally be influenced by the route of administration, the therapeutic objectives, and the condition of the patient. For injection by hypodermic needle, it may be assumed the dosage is delivered into the body's fluids. For other routes of administration, the absorption efficiency must be individually determined for each inhibitor by methods well known in pharmacology. Accordingly, it may be necessary for the therapist to titer the dosage and modify the route of administration as required to obtain the optimal therapeutic effect.
  • the determination of effective dosage levels that is, the dosage levels necessary to achieve the desired result, will be within the ambit of one skilled in the art.
  • a typical dosage of the compounds and compositions of the invention range from about 0.001 mg/kg to about 1000 mg/kg, preferably from about 0.01 mg/kg to about 100 mg/kg, and more preferably from about 0.10 mg/kg to about 20 mg/kg.
  • the compounds of the invention may be administered several times daily. Other dosage regimens may also be useful (e.g. single daily dose and/or continuous infusion).
  • a compound or mixture of compounds of the invention is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, dye, flavor, etc., as called for by accepted pharmaceutical practice.
  • a physiologically acceptable vehicle carrier, excipient, binder, preservative, stabilizer, dye, flavor, etc.
  • the amount of active ingredient in these compositions is such that a suitable dosage in the range indicated is obtained.
  • Typical adjuvants which may be incorporated into tablets, capsules and the like are a binder such as acacia, corn starch or gelatin, and excipient such as microcrystalline cellulose, a disintegrating agent like corn starch or alginic acid, a lubricant such as magnesium stearate, a sweetening agent such as sucrose or lactose, or a flavoring agent.
  • a dosage form is a capsule, in addition to the above materials it may also contain a liquid carrier such as water, saline, a fatty oil.
  • Other materials of various types may be used as coatings or as modifiers of the physical form of the dosage unit.
  • Sterile compositions for injection can be formulated according to conventional pharmaceutical practice.
  • dissolution or suspension of the active compound in a vehicle such as an oil or a synthetic fatty vehicle like ethyl oleate, or into a liposome may be desired.
  • a vehicle such as an oil or a synthetic fatty vehicle like ethyl oleate
  • Buffers, preservatives, antioxidants and the like can be incorporated according to accepted pharmaceutical practice.
  • the preferred compounds of the present invention are characterized by their ability to inhibit thrombus formation with acceptable effects on classical measures of coagulation parameters, platelets and platelet function, and acceptable levels of bleeding complications associated with their use.
  • Conditions characterized by undesired thrombosis would include those involving the arterial and venous vasculature.
  • abnormal thrombus formation characterizes the rupture of an established atherosclerotic plaque which is the major cause of acute myocardial infarction and unstable angina, as well as also characterizing the occlusive coronary thrombus formation resulting from either thrombolytic therapy or percutaneous transluminal coronary angioplasty (PTCA).
  • PTCA percutaneous transluminal coronary angioplasty
  • abnormal thrombus formation characterizes the condition observed in patients undergoing major surgery in the lower extremities or the abdominal area who often suffer from tlirombus formation in the venous vasculature resulting in reduced blood flow to the affected extremity and a predisposition to pulmonary embolism.
  • Abnormal thrombus formation further characterizes disseminated intravascular coagulopathy commonly occurs within both vascular systems during septic shock, certain viral infections and cancer, a condition wherein there is rapid consumption of coagulation factors and systemic coagulation which results in the formation of life-threatening thrombi occurring throughout the microvasculature leading to widespread organ failure.
  • the compounds of the invention are useful for the treatment or prophylaxis of those diseases which involve the production and/or action of factor
  • Xa/prothrombinase complex The compounds of this present invention, selected and used as disclosed herein, find utility as a diagnostic or therapeutic agent for preventing or treating a condition in a mammal characterized by undesired thrombosis or a disorder of coagulation.
  • Disease states treatable or preventable by the administration of compounds of the invention include, without limitation, occlusive coronary tlirombus formation resulting from either thrombolytic therapy or percutaneous transluminal coronary angioplasty, thrombus formation in the venous vasculature, disseminated intravascular coagulopathy, the treatment of reocclusion or restenosis of reperfused coronary arteries, thromboembolic complications of surgery and peripheral arterial occlusion, a condition wherein there is rapid consumption of coagulation factors and systemic coagulation which results in the formation of life-threatening thrombi occurring throughout the microvasculature leading to widespread organ failure, hemorrhagic stroke, renal dialysis, blood oxygenation, and cardiac catheterization.
  • the invention provides a method for preventing or treating a condition in a mammal characterized by undesired thrombosis which administers to a mammal a therapeutically effective amount of a compound of the invention, as described herein.
  • Conditions for prevention or treatment include, for example, (a) the treatment or prevention of any thrombotically mediated acute coronary syndrome including myocardial infarction, unstable angina, refractory angina, occlusive coronary thrombus occurring post-thrombolytic therapy or post-coronary angioplasty, (b) the treatment or prevention of any thrombotically mediated cerebrovascular syndrome including embolic stroke, thrombotic stroke or transient ischemic attacks, (c) the treatment or prevention of any thrombotic syndrome occurring in the venous system including deep venous thrombosis or pulmonary embolus occurring either spontaneously or in the setting of malignancy, surgeiy or trauma, (d) the treatment or prevention of any coagulopathy including disseminated intra
  • Anticoagulant therapy is also useful to prevent coagulation of stored whole blood and to prevent coagulation in other biological samples for testing or storage.
  • the compounds of the invention can be added to or contacted with any medium containing or suspected to contain factor Xa and in which it is desired that blood coagulation be inhibited, e.g., when contacting the mammal's blood with material such as vascular grafts, stents, orthopedic prostheses, cardiac stents, valves and prostheses, extra corporeal circulation systems and the like.
  • the compounds of the invention also find utility in a method for inhibiting the coagulation of biological samples by administration of a compound of the invention.
  • the compounds of the present invention are dissolved in buffer to give solutions containing concentrations such that assay concentrations range from about 0 to 100 ⁇ M.
  • concentrations such that assay concentrations range from about 0 to 100 ⁇ M.
  • a synthetic chromogenic substrate is added to a solution containing test compound and the 10 enzyme of interest and the residual catalytic activity of that enzyme is determined spectrophotometrically.
  • the IC50 of a compound is determined from the substrate turnover.
  • the IC50 is the concentration of test compound giving 50% inhibition of the substrate turnover.
  • the compounds of the present invention desirably have an IC50 of less than about 500 nM in the factor Xa assay, preferably less than about
  • the compounds of the present invention desirably have an IC50 of less than about 4.0 ⁇ M in the prothrombinase assay, preferably less than 200 nM, and more preferred compounds have an IC50 of about 10 nM or less in the prothrombinase assay.
  • the compounds of the present invention desirably have an 20 IC50 of greater than about 1.0 ⁇ M in the thrombin assay, preferably greater than about 10.0 ⁇ M, and more preferred compounds have an IC50 of greater than about
  • Amidolytic Assays for determining protease inhibition activity 25 The factor Xa and thrombin assays are performed at room temperature, in
  • the activity of the prothrombinase complex is determined by measuring the time course of thrombin generation using the p- nitroanilide substrate Chromozym TH.
  • the assay consists of preincubation ( 5 minutes) of selected compounds to be tested as inhibitors with the complex formed from factor Xa (0.5 nM), factor Na (2 nM), phosphatidyl serine:phosphatidyl choline (25:75, 20 ⁇ M) in 20 mM Tris-HCl buffer, pH 7.5, containing 0.15 M ⁇ aCl, 5 mM CaCl2 and 0.1 % bovine serum albumin.
  • Rabbits are anesthetized with I.M. injections of Ketamine, Xylazine, and Acepromazine cocktail.
  • a standardized protocol consists of insertion of a thrombogenic cotton thread and copper wire apparatus into the abdominal vena cava of the anesthetized rabbit.
  • a non-occlusive thrombus is allowed to develop in the central venous circulation and inhibition of thrombus growth is used as a measure of the antithrombotic activity of the studied compounds.
  • Test agents or control saline are administered through a marginal ear vein catheter.
  • a femoral vein catheter is used for blood sampling prior to and during steady state infusion of test compound.
  • Initiation of thrombus formation begins immediately after advancement of the cotton thread apparatus into the cential venous circulation.
  • the rabbits are euthanized and the thrombus excised by surgical dissection and characterized by weight and histology. Blood samples are analyzed for changes in hematological and coagulation parameters.

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Abstract

Cette invention a trait à de nouveaux composés contenant une nouvelle pyrimidine-4-one bicyclique, correspondant à la formule (I) ou à la formule (II), ainsi qu'à leurs isomères, leurs sels, leurs hydrates, solvates ou promédicaments, acceptables du point de vue pharmaceutique, lesquelles substances font montre d'une action à l'encontre du facteur mammalien Xa. Elle concerne également des compositions renfermant ces composés. Ces derniers ainsi que les compositions selon l'invention se révèlent des plus utiles, in vitro comme in vivo, pour prévenir ou traiter chez des mammifères des états pathologiques se caractérisant par une thrombose indésirable.
PCT/US2001/030335 2000-09-29 2001-10-01 Inhibiteurs du facteur xa à base de pyrimidine-4-one bicyclique Ceased WO2002026718A2 (fr)

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WO2003007955A3 (fr) * 2001-07-20 2003-05-01 Cancer Rec Tech Ltd Nouvelle utilisation
WO2006047516A3 (fr) * 2004-10-26 2006-10-12 Irm Llc Composes et compositions servant d'inhibiteurs d'activite de recepteur cannabinoide de type 1
EP1553947A4 (fr) * 2002-10-21 2006-11-29 Bristol Myers Squibb Co Quinazolinones et derives de celles-ci comme inhibiteurs du facteur xa
WO2007000655A3 (fr) * 2005-06-28 2007-03-22 Orchid Res Lab Ltd Nouveaux dérivés de pyrazolopyrimidinone
US7390908B2 (en) 2001-08-17 2008-06-24 Astrazeneca Ab Compounds effecting glucokinase
US8003656B2 (en) 2006-08-23 2011-08-23 Neurogen Corporation 2-phenoxy pyrimidinone analogues
JP2012514631A (ja) * 2009-01-08 2012-06-28 レスバーロジックス コーポレイション 心血管疾患の予防および治療のための化合物
CN106795103A (zh) * 2014-07-03 2017-05-31 赛尔基因昆蒂赛尔研究公司 赖氨酸特异性脱甲基酶‑1的抑制剂
US9840498B2 (en) 2013-07-24 2017-12-12 Novartis Ag Substituted quinazolin-4-one derivatives

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KR101346902B1 (ko) 2005-07-09 2014-01-02 아스트라제네카 아베 당뇨병 치료에 있어 ｇｌｋ 활성화제로서 사용하기 위한헤테로아릴 벤즈아미드 유도체

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NZ192392A (en) * 1978-12-19 1983-02-15 M Ishikawa 3-(substituted (phenyl or pyridyl)) -3,4-dihydroquinazolin-4-ones
DE19816983A1 (de) * 1998-04-17 1999-10-21 Boehringer Ingelheim Pharma Bicyclen, deren Herstellung und deren Verwendung als Arzneimittel

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WO2003007955A3 (fr) * 2001-07-20 2003-05-01 Cancer Rec Tech Ltd Nouvelle utilisation
US7390908B2 (en) 2001-08-17 2008-06-24 Astrazeneca Ab Compounds effecting glucokinase
EP1553947A4 (fr) * 2002-10-21 2006-11-29 Bristol Myers Squibb Co Quinazolinones et derives de celles-ci comme inhibiteurs du facteur xa
US8158634B2 (en) 2004-10-26 2012-04-17 Irm Llc Compounds and compositions as inhibitors of cannabinoid receptor 1 activity
RU2431635C2 (ru) * 2004-10-26 2011-10-20 Айрм Ллк Соединения и композиции в качестве ингибиторов активности каннабиноидного рецептора 1
WO2006047516A3 (fr) * 2004-10-26 2006-10-12 Irm Llc Composes et compositions servant d'inhibiteurs d'activite de recepteur cannabinoide de type 1
KR100919524B1 (ko) * 2004-10-26 2009-10-01 아이알엠 엘엘씨 칸나비노이드 수용체 １ 활성 억제제로서의 화합물 및조성물
AU2005299421B2 (en) * 2004-10-26 2010-01-28 Novartis Ag Compounds and compositions as inhibitors of Cannabinoid Receptor 1 activity
CN102241680A (zh) * 2004-10-26 2011-11-16 Irm责任有限公司 作为大麻素受体1活性抑制剂的化合物和组合物
JP2011190281A (ja) * 2004-10-26 2011-09-29 Irm Llc カンナビノイド受容体１活性阻害剤としての化合物および組成物
JP2008518016A (ja) * 2004-10-26 2008-05-29 アイアールエム・リミテッド・ライアビリティ・カンパニー カンナビノイド受容体１活性阻害剤としての化合物および組成物
WO2007000655A3 (fr) * 2005-06-28 2007-03-22 Orchid Res Lab Ltd Nouveaux dérivés de pyrazolopyrimidinone
US8003656B2 (en) 2006-08-23 2011-08-23 Neurogen Corporation 2-phenoxy pyrimidinone analogues
US8759361B2 (en) 2006-08-23 2014-06-24 Neurogen Corporation 2-phenoxy pyrimidinone analogues
JP2012514631A (ja) * 2009-01-08 2012-06-28 レスバーロジックス コーポレイション 心血管疾患の予防および治療のための化合物
US9840498B2 (en) 2013-07-24 2017-12-12 Novartis Ag Substituted quinazolin-4-one derivatives
CN106795103A (zh) * 2014-07-03 2017-05-31 赛尔基因昆蒂赛尔研究公司 赖氨酸特异性脱甲基酶‑1的抑制剂
CN106795103B (zh) * 2014-07-03 2019-07-12 赛尔基因昆蒂赛尔研究公司 赖氨酸特异性脱甲基酶-1的抑制剂

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