WO1999048878A1 - Composes heterocycliques regulateurs de coagulation - Google Patents

Composes heterocycliques regulateurs de coagulation Download PDF

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Publication number
WO1999048878A1
WO1999048878A1 PCT/DK1999/000138 DK9900138W WO9948878A1 WO 1999048878 A1 WO1999048878 A1 WO 1999048878A1 DK 9900138 W DK9900138 W DK 9900138W WO 9948878 A1 WO9948878 A1 WO 9948878A1
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Prior art keywords
phenyl
benzo
oxazin
difluoro
benzoxazin
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PCT/DK1999/000138
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English (en)
Inventor
Egon Persson
Palle Jakobsen
Helle Worsaae
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Novo Nordisk A/S
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Priority to AU28260/99A priority Critical patent/AU2826099A/en
Publication of WO1999048878A1 publication Critical patent/WO1999048878A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
    • C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D265/20—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 4
    • C07D265/22—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/536—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to reagents useful as anticoagulants. More specifically, the invention relates to the use of compounds having the formula I, and pharmaceutical salts - thereof, as anticoagulants.
  • the compounds inhibit the ability of factor Vila (fVlla) in complex with tissue factor (TF) to cleave a low-molecular weight substrate and/or factor X and, as a result, blood coagulation initiated by tissue factor is inhibited.
  • the invention further relates to the use of compound I as an inhibitor of clotting activity, and methods of inhibiting clotting activity, tissue factor activity, and FVlla activity as well as methods for treatment of coagulation related diseases states.
  • the invention also relates to novel compounds with anticoagulative effect and pharmaceutical compositions comprising such compounds.
  • Blood coagulation is a process consisting of a complex interaction of various blood components, or factors, which eventually gives rise to a fibrin clot.
  • the blood components which participate in what has been referred to as the coagulation "cascade” are proenzymes or zymogens, enzymatically inactive proteins, which are converted to proteolytic enzymes by the action of an activator, itself an activated clotting factor.
  • Coagulation factors that have undergone such a conversion and generally referred to as "active factors”, and are designated by the addition of the letter "a" to the name of the coagulation factor (e.g. fVlla).
  • Activated factor X is required to convert prothrombin to thrombin, which then converts fibrinogen to fibrin as a final stage in forming a fibrin clot.
  • the "intrinsic pathway” refers to those reactions that lead to thrombin formation through utilisation of factors present only in plasma.
  • a series of protease-mediated activations ultimately generates factor IXa, which, in conjunction with factor Villa, cleaves factor X into Xa.
  • An identical proteolysis is effected by fVlla and its cofactor TF in the "extrinsic pathway" of blood coagulation.
  • TF is a membrane bound protein and does not normally circulate in plasma.
  • FVII is a trace plasma glycoprotein that circulates in blood as a single-chain zymogen.
  • the zymogen is catalytically inactive (Williams et al., J. Biol. Chem. 264:7536- - 7543 (1989); Rao et al., Proc. Natl. Acad. Sci. USA. 85:6687-6691 (1988)).
  • Single-chain fVII may be converted to two-chain fVlla by factor Xa, factor Xlla, factor IXa, fVlla or thrombin in vitro.
  • Factor Xa is believed to be the major physiological activator of fVII.
  • fVII is dependent on vitamin K for its activity, which is required for the gamma-carboxylation of multiple glutamic acid residues that are clustered in the amino terminus of the protein. These gamma-carboxylated glutamic acids are required for the metal-associated interaction of fVII with phospholipids.
  • the conversion of zymogen fVII into the activated two-chain molecule occurs by cleavage of an internal Arg152-lle153 peptide bond (Hagen et al., Proc. Natl. Acad. Sci. USA 83: 2412-2416 (1986); Thim et al., Biochemistry 27:7785-7793 (1988)).
  • the two-chain fVlla rapidly activates factor X or factor IX by limited proteolysis. It is often desirable to selectively block or inhibit the coagulation cascade in a patient.
  • Anticoagulants such as heparin, coumarin, derivatives of coumarin, indandione derivatives, thrombin inhibitors, factor Xa inhibitors, modified fVII or other agents may be used.
  • Inhibition of coagulation is beneficial in a number of diseased states, for example during kidney dialysis, or to treat deep vein thrombosis, disseminated intravascular coagulation (DIC) and a host of other medical disorders.
  • heparin treatment or extracorporeal treatment with citrate ions U.S. Patent 4, 500, 309 may be used in dialysis to prevent coagulation during the course of treatment.
  • Heparin is also used in preventing deep vein thrombosis in patients undergoing surgery.
  • Treatment with heparin and other anticoagulants may, however, have undesirable side effects.
  • Available anticoagulants generally act throughout the body, rather than acting specifically at the site of injury, i. e. the site at which the coagulation cascade is active.
  • Heparin may cause severe bleedings. Furthermore, with a half-life of approximately 80 minutes, heparin is rapidly cleared from the blood, necessitating frequent administrating. Because heparin acts as a 3 cofactor for antithrombin III (AT III), and AT 111 is rapidly depleted in DIC treatment, it is often difficult to maintain the proper heparin dosage, necessitating continuous monitoring of AT III and heparin levels. Heparin is also ineffective if AT III depletion is extreme. Further, prolonged use of heparin may also increase platelet aggregation and reduce platelet count, and has been implicated in the development of osteoporosis. Indandione derivatives may also have toxic side effects.
  • AT III antithrombin III
  • anticoagulants comprise thrombin and factor Xa inhibitors derived from bloodsucking organisms.
  • Antithrombins, hirudin, hirulog and hirugen are recombinant proteins or peptides derived from the leach Hirudo medicinalis.
  • the factor Xa inhibitor antistatin and the recombinant derivative rTAP are tick-derived proteins.
  • Inhibitors of platelet aggregation such as monoclonal antibodies or synthetic peptides, which interfere with the platelet receptor GPIIb/llla are also effective as anticoagulants.
  • Such anticoagulants comprise the physiological inhibitor TFPI (tissue factor pathway inhibitor) and modified fVII (fVllai), which is fVlla modified in such a way that it is catalytically inactive but still binds to TF and competes with active fVlla.
  • TFPI tissue factor pathway inhibitor
  • fVllai modified fVII
  • SMCs smooth muscle cells
  • treatment of atherosclerosis frequently includes the clearing of blocked vessels by angioplasty, endarterectomy or reduction atherectomy, or by bypass grafting, surgical procedures in which atherosclerotic plaques are compressed or removed through catheterization (angioplasty), stripped away from the arterial wall through an incision (endarterectomy) or bypassed with natural or synthetic grafts. These procedures remove the vascular endothelium, disturb the underlying intimal layer, and result in the death of medial SMCs.
  • This injury is followed by medial SMC 4 proliferation and migration into the intima, which typically occurs within the first few weeks and up to six months after injury and stops when the overlying endothelial cell layer is reestablished.
  • these lesions are composed of about 20% cells and 80% extracellular matrix.
  • endarterectomy or bypass grafts, thrombosis and/or SMC proliferation in the intima causes re-occlusion of the vessel and consequent failure of the reconstructive surgery. This closure of the vessel subsequent " to surgery is known as restenosis.
  • Modified FVlla (FVIlai) has been shown to effectively suppress the restenosis process possibly as a result of a decreased procoagulant activity and thrombin generation initially after treatment of the constricted vessel.
  • low-molecular-weight compounds which may be administered via a route other than intravenously and which have an inhibitory effect on fVlla-TF activity similar to that of fVllai.
  • JP 6157591 describes compounds based on TFPI-derived peptides with FVlla-TF antagonist activity
  • WO 90/03390, WO 95/00541 , WO 96/18653, and EP 500 800 describe compounds based on FVIIa-derived peptides with FVlla-TF antagonist activity
  • WO 91/15487 describes 5-substituted 4H-3J-benzoxazinone structures having substituted alkyl groups in the 2- position.
  • ⁇ BE 862,201 describe 2-phenylsubstituted quinazolin-4-one derivatives which are antiallergic agents
  • JP 55147279 describes 2-pyridylsubstituted quinazolin-4-one derivatives with antidepressant and inflammation inhibting effect.
  • the present invention fulfills this need by providing anticoagulants that act specifically on fVlla-TF at sites of injury, and further provides other related advantages such as its effect on the restenosis process.
  • the present invention has the advantage that it is a small 6 synthetic molecule suitable for oral administration and for prophylactic treatment of atherosclerotic patients at risk for thrombosis.
  • the present invention thus provides the use of a compound of the general formula I for the preparation of a pharmaceutical composition for the treatment and/or prevention of coagulation-related diseased states.
  • the present invention also provides novel compounds with the formula I.
  • the compounds are useful for the treatment of coagulation-related diseased states.
  • coagulation-related diseases include, but are not limited to, diseases such as deep vein thrombosis, pulmonary embolism, stroke, disseminated intravascular coagulation (DIC), vascular restenosis, platelet deposition, myocardial infarction, or the prophylactic treatment of mammals with atherosclerotic vessels at risk for thrombosis.
  • diseases such as deep vein thrombosis, pulmonary embolism, stroke, disseminated intravascular coagulation (DIC), vascular restenosis, platelet deposition, myocardial infarction, or the prophylactic treatment of mammals with atherosclerotic vessels at risk for thrombosis.
  • DIC disseminated intravascular coagulation
  • the mammal is preferably a human.
  • C 1 . 8 -alkyl As used herein: The term "C 1 . 8 -alkyl",”C 2 - 8 -al' ⁇ enyl", “C 2 - 8 -alkynyl” as used herein, alone or in combination, refers to a straight or branched, saturated or unsaturated hydrocarbon chain.
  • the C,. 8 -alkyl residues include aliphatic hydrocarbon residues, unsaturated aliphatic hydrocarbon residues, alicyclic hydrocarbon residues.
  • aliphatic hydrocarbon residues include saturated aliphatic hydrocarbon residues having 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.butyl, tert.butyl, n-pentyl, isopentyl, neopentyl, tert.pentyl, n-hexyl, isohexyl.
  • Example of the unsaturated aliphatic hydrocarbon residues include those having 2 to 6 carbon atoms such as ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4- pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl, ethynyl, 1- propionyl, 2-propionyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentenyl, 3-pentenyl, 4- pentenyl, 1-hexynyl, 3-hexynyl, 2,4-hexadiynyl, 5-hexynyl.
  • C 3 - 8 -cycloalkyl means an alicyclic hydrocarbon residue including saturated alicyclic hydrocarbon residues having 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cy- clopentyl, cyclohexyl; and C ⁇ unsaturated alicyclic hydrocarbon residues having 5 to 6 car- bon atoms such as 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2- cyclohexenyl, 3-cyclohexenyl.
  • C,. 6 -alkoxy refers to a straight or branched monovalent substituent comprising a C,. 6 -alkyl group linked through an ether oxygen having its free valence bond from the ether oxygen and having 1 to 6 carbon atoms e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy.
  • . 6 -alkylthio refers to a straight or branched monovalent substituent comprising a C ⁇ -alkyl group linked through an thioether sulfur atom having its free valence bond from the thioether sulfur and having 1 to 6 carbon atoms.
  • aryl and “heteroaryl” as used herein refers to an aryl which can be optionally substituted or a heteroaryl which can be optionally substituted and includes phenyl, biphenyl, indene, fluorene, naphthyl (1-naphthyl, 2-naphthyl), anthracene (1-anthracenyl, 2- anthracenyl, 3-anthracenyl), thiophene (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl) , indolyl, oxadiazolyl, isoxazolyl, quinazolin, fluorenyl, xanthenyl, , isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazo
  • the invention also relates to partly or fully saturated analogues of the ring systems mentioned above
  • leaving group includes, but is not limited to, halogen, sulfonate or an acyl group. Suitable leaving groups will be known to a person skilled in the art.
  • Coupling agent means an agent suitable for formation of acid derivatives from acids or activated acids and amines, phenols, alcohols, or acids including, but not limited to hydroxy- benzotriazole (HOBt) and derivatives thereof and carbodiimides like dicyclohexylcarbodi- imide and ethyldimethylaminopropyl carbodiimide (DCC, EDAC). Suitable coupling agents will be known to the skilled person. Activated acids includes acid chlorides, acid anhydrides, esters, and similar derivatives.
  • Agent capable of introducing ring closure means an agent capable of introducing combined hydrolysis and ring closure under absorption of water including, but not limited to, acid anhydrides, both organic like acetic anhydride and inorganic like P 2 O 5 .mineral acids such as concentrated sulfuric acid, phosphoric acid and the like, acid chlorides like SOCI 2 , PCI 5 , and POCI 3 10
  • Halogen refers to fluorine, chlorine, bromine, and iodine.
  • Halo refers to fluoro, chloro, bromo and iodo.
  • Halo-alkyl means the group -R-halo in which R is alky!, and both alkyl and halo are as defined herein.
  • the alkyl group may bear one, two or three halo substituents; examples include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, di- " chloromethyl, trichloromethyl, chloroethyl, dichloroethyl, bromoethyl, iodoethyl, and the like.
  • aryl ... optionally substituted means that the aryl may or may not be substituted and that the description includes both unsubstituted aryls and aryls wherein there is substitution.
  • “Pharmaceutical acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with non-toxic acids, either inorganic acids such as hydrochloric acid, sulphuric acid and phosphoric acid, or organic acids such as formic acid, acetic acid, propi- onic acid, succinic acid, gluconic acid, lactic acid, citric acid, ascorbic acid, benzoic acid, embonic acid, methanesulphonic acid and malonic acid and the like.
  • inorganic acids such as hydrochloric acid, sulphuric acid and phosphoric acid
  • organic acids such as formic acid, acetic acid, propi- onic acid, succinic acid, gluconic acid, lactic acid, citric acid, ascorbic acid, benzoic acid, embonic acid, methanesulphonic acid and malonic acid and the like.
  • Treatment means the administration of an effective amount of a therapeutically active compound of the invention with the purpose of preventing any symptoms or disease state to develop or with the purpose of curing or easing such symptoms or disease states already developed.
  • treatment is thus meant to include prophylactic treatment.
  • Coagulation-related disease states Diseases or symptoms which are caused by unwanted blood coagulation, clotting activity, deposition of fibrin and/or platelets or TF-FVIIa activity.
  • diseases include, but are not limited to, deep vein thrombosis, pulmonary embolism, stroke, disseminated intravascular coagulation (DIC), vascular restenosis, platelet deposition, or myocardial infarction, or the prophylactic treatment of mammals with atherosclerotic vessels at risk for thrombosis.
  • Compounds which solely inhibit the proteolytic activity of FVlla-TF and/or prolong the coagulation time may do so by preventing the association of factor X with the FVlla-TF complex or by preventing the activation of factor X bound to the complex.
  • Modules of the TF-FVIIa pathway Compounds that modulate the coagulation process through an inhibitory action on the TF-FVIIa complex or on TF activity.
  • the activity of FVlla in complex with TF in particular its activation of factor X, can be inhibited by a low-molecular weight compound. By this action, the initiation and acceleration of the blood coagulation cascade upon exposure of TF to flowing blood is prevented.
  • “Pharmaceutically acceptable carriers” means any and all solvents , dispersion media, coatings, antifungal agents, preservatives, isotonic agents and the like.
  • Modulating and normalizing an impaired haemostatic balance means achieving an effect on the coagulation system measurable in in vitro assays and/or animal models which effect diminishes the risk for thrombosis or bleedings.
  • Certain of the compounds of the invention have chiral centers and exist as optical antipodes.
  • the invention described and claimed herein includes each of the individual enantiomers as well as their racemic modifications and the racemic mixture.
  • the present invention relates to the use of compounds of formula
  • X and Y is independently O, S or NH;
  • R 1 and R 2 independently are
  • R 3 is aryl or heteroaryl, each optionally substituted with one or more Ci- ⁇ -alkyl, C 2 . 8 alkenyl, C 2 . 8 alkynyl, or C 3 _ 6 cycloalkyl, each optionally substituted with halogen, OH, NH 2 , NHR 4 , N(R 4 ) 2 , NHCOR 4 , C M alkoxy , trifluoromethoxy , carbamoyi, CONHR 4 , or CON(R 4 ) 2 ; Halogen, CF 3 , C 1 J alkoxy, C,_ 6 alkylthio, OCF 3 , COOH, CN, CONH 2 , CONHR 4 , OH, NH 2 , 13 NHR 4 , N(R ) 2 , NHCOR 4 , CON(R ) 2 , CONHSO 2 R 4 , SO 2 NH 2 , SO 2 NHR 4 , C 1 - 4 alkoxycarbonyl ,
  • R 4 is C ⁇ -alkyl, C 2 . 4 alkenyl, C 2 . 4 alkynyl, C ⁇ cycloalkyl, or phenyl
  • R 1 and R 2 are: hydrogen, 4-fluoro, 5-methyl, 6-methyl, 6-fluoro , 5,8-dichloro, 6- chloro, 6-iodo,7-chloro, 5-nitro, 5-amino, 5-acetylamino, 6-nitro, 6-acetylamino, 6-carboxy.
  • Preferred R 3 are: 2,6-difluorophenyl, 2-fluoro, 6-chlorophenyl, 2-fluorophenyl, 2,3- dichlorophenyl, 2-bromophenyl, 2-bromo-5-methoxyphenyl, 2-trifluoromethoxyphenyl, 7- benzofuranyl, 2-thienyl, 2-furanyl, 5-chloro-2-methoxyphenyl, 5-nitrofuranyl ,2-piperidyl, 3- chloro-5-trifluoromethyl-2-pyridyl.
  • Preferred R 4 are: Methyl, ethyl, isopropyl, propyl ,cyclopropyl, cyclopentyl, cyclohexyl, phenyl.
  • R 3 is an ortho-substituted aryl or a heteroaryl ring.
  • the present invention relates to the use of compounds with the general formula I, or pharmaceutical acceptable salts thereof, for the manufacture of a medicament for treatment of coagulation-related diseases, or for modulating and normalizing an impaired haemostatic balance in a mammal.
  • the invention relates to the use as an inhibitor of blood coagulation in a mammal , or for use as an inhibitor of clotting activity in a mammal, or for use as an inhibitor of deposition of fibrin in a mammal, or for use as an inhibitor of platelet deposition in a mammal.
  • the coagulation-related diseases comprises diseases such as deep vein thrombo- sis, pulmonary embolism, stroke, disseminated intravascular coagulation (DIC), vascular restenosis, platelet deposition, or myocardial infarction, or for the prophylactic treatment of mammals with atherosclerotic vessels at risk for thrombosis. 14
  • the compounds have the general formula I, wherein X is O, and Y is O, S or NH.
  • the compounds have the general formula I, wherein X is S, and Y is
  • the compounds have the general formula I, wherein X is NH, and Y is O, S or NH. In another embodiment, the compounds have the general formula
  • the compounds have the general formula I, wherein X is O, and Y is S. In another embodiment, the compounds have the general formula I, wherein X is O, and Y is NH. In another embodiment, the compounds have the general formula I, wherein X is S, and Y is O. In another embodiment, the compounds have the general formula I, wherein X is S, and Y is S. In another embodiment, the compounds have the general formula I, wherein X is S, and Y is NH. In another embodiment, the compounds have the general formula I, wherein X is NH, and Y is O. In another embodiment, the compounds have the general formula I, wherein X is NH, and Y is S. In another embodiment, the compounds have the general formula I, wherein X is NH, and Y is NH.
  • the invention relates to the use of compounds with the general formula I for the manufacture of a medicament for modulating and normalizing an impaired haemostatic balance in a mammal.
  • the invention relates to the use of compounds with the general formula I for the manufacture of a medicament for treatment of mammals suffering from deep vein thrombosis, pulmonary embolism, stroke, disseminated intravascular coagulation (DIC), vascular restenosis, platelet deposition and associated disorders and myocardial infarction, and in the prophylactic treatment of mammals with atherosclerotic vessels at risk for thrombosis.
  • DIC disseminated intravascular coagulation
  • vascular restenosis vascular restenosis
  • platelet deposition and associated disorders and myocardial infarction and in the prophylactic treatment of mammals with atherosclerotic vessels at risk for thrombosis.
  • the invention also relates to a method for modulating and normalizing an impaired haemo- static balance in a mammal, and to a method for treatment of coagulation-related diseased states in a mammal, which methods comprise administering an effective amount of a compound with formula I, in combination with a pharmaceutical acceptable excipient and/ or carrier to the mammal in need of such a treatment.
  • the invention relates to a method for treatment of mammals suffering from deep vein thrombosis, pulmonary embolism, stroke, disseminated intravascular coagulation (DIC), vascular restenosis, platelet deposition and associated disorders and myocardial infarction, and in the prophylactic treatment of mammals with atherosclerotic vessels at risk for thrombosis, as well as modulating and normalizing an impaired haemostatic balance in a mammal, and a method for inhibiting blood coagulation in a mammal, or inhibiting clotting activity in a mammal, or inhibiting deposition of fibrin in a mammal, or inhibiting fibrin in a mammal, 16
  • the invention in another aspect, relates to a method for inhibiting tissue factor activity in a mammal which method comprises administering an effective amount of a compound with formula I, in combination with a pharmaceutical acceptable excipient and/ or carrier to the mammal in need of such a treatment.
  • the compounds with formula I are selected from the compounds listed in table 1 and table 2, and pharmaceutical acceptable salts thereof.
  • the invention in another aspect, relates to a method for inhibiting factor VII activity by substantially reducing the ability of activated factor VII to catalyze tissue factor-enhanced activation of factors X and IX comprising administering a compound with formula I, in combination with a pharmaceutical acceptable excipient and/ or carrier to a mammal in need of such a treatment.
  • the invention relates to the use of a compound with formula I for modulating and normalizing an impaired haemostatic balance in a mammal, such as a human, or for the use of a compound with formula I for the treatment of coagulation-related diseased states.
  • the coagulation-related diseased states are deep vein thrombosis, pulmonary embolism, stroke, disseminated intravascular coagulation (DIC), vascular restenosis, platelet deposition and associated disorders or myocardial infarction, or the prophylactic treatment of mammals with atherosclerotic vessels at risk for thrombosis.
  • DIC disseminated intravascular coagulation
  • vascular restenosis vascular restenosis
  • platelet deposition and associated disorders or myocardial infarction or the prophylactic treatment of mammals with atherosclerotic vessels at risk for thrombosis.
  • the invention also relates to novel benzoxazin-4-one derivatives which is selected from a list of
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically active amount of said novel compounds, or a pharmaceutical acceptable salt thereof, in combination with a pharmaceutical acceptable excipient and/ or carrier.
  • the pharmaceutical composition is for oral administration.
  • the compounds with general formula I may be prepared by methods which comprise:
  • Such agents can be carboxylic acid anhydrides such as acetic anhydride, concentrated sul- furic acid, POCI 3 . P 2 O 5 or similar agents.
  • This ring closure might be performed directly after an amide formation as described above or from amides of the formula III prepared by other routes or purchased. or
  • agents capable of introducing ring closure to form a structure of the formula I.
  • agents can be carboxylic acid anhydrides such as acetic anhydride, concentrated sul- furic acid, POCI 3 . P 2 O 5 or similar agents.
  • This ring closure might be performed directly after an amide formation as described above or from amides of the formula III prepared by other routes or purchased, or D) reaction of a structure of the formula IV
  • R 1 , R 2 , and R 3 has the meaning described above and R 4 is an C,. 8 alkyl group with an agent capable of introducing ring closure like cone.
  • H 2 SO 4 or similar agents which can 25 introduce combined hydrolysis and ring closure under absorption of water.
  • compositions comprising the compounds and a pharmaceutically acceptable carrier or diluent.
  • pharmaceutically acceptable carriers include water, physiological saline, ethanol, polyols, e.g., glycerol or propylene glycol, or vegetable oils.
  • pharmaceutically acceptable carriers also encompasses any and all solvents, dispersion media, coatings, antifungal agents, preservatives, isotonic agents and the like. Except insofar as any conventional medium is incompatible with the active ingredient and its intended use, its use in the compositions of the present invention is contemplated.
  • compositions containing the compounds of this invention may be prepared by conventional techniques and appear in conventional forms, for example, capsules, tablets, solutions or suspensions.
  • the pharmaceutical carrier employed may be a conventional solid or liquid carrier.
  • solid carriers are lactose, terra alba, sucrose, talc, gelatine, agar, pectin, acacia, magnesium stearate and stearic acid.
  • liquid carriers are syrup, peanut oil, olive oil and water.
  • the carrier or diluent may include any time delay material known to the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the preparation can be tabletted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g.
  • the preparation may be in the form of a syrup, emulsion, soft gela- tine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution. 29
  • the compounds of this invention are dispensed in unit dosage form comprising 50- 200 mg of active ingredient in or together with a pharmaceutically acceptable carrier per unit dosage.
  • the dosage range of the compound for a small mammal, such as a rabbit is 15-50 mmoles per kg of body weight; for larger mammals, such as humans, 5-50 mmoles, preferably about 10-20 mmoles, per kg of body weight, is useful. This corresponds to about 2-25 mg/kg body weight.
  • a preferred dosage range is from 1 to about - 100 mg/day, or from about 1 to about 100 mg per dose when administered to patients, e.g. humans, as a drug.
  • a typical tablet which may be prepared by conventional tabletting techniques contains
  • Active compound (as free compound 100 mg or salt thereof)
  • the route of administration may be any route which effectively transports the active compound to the appropriate or desired site of action, such as oral or parenteral, e.g., rectal, transdermal, subcutaneous, intranasal, intramuscular, topical, intravenous, intraurethral, ophthalmic solution or an ointment, the oral route being preferred.
  • oral or parenteral e.g., rectal, transdermal, subcutaneous, intranasal, intramuscular, topical, intravenous, intraurethral, ophthalmic solution or an ointment, the oral route being preferred.
  • the compounds of the invention may be administered to a subject, e.g. a living animal body, in need of such treatment, elimination, alleviation, or amelioration of an indication such as prolonged bleeding or disorders related to the haemostatic balance, often preferably in the form of an alkali metal or earth alkali metal salt thereof, 30 concurrently, simultaneously, or together with a pharmaceutically acceptable carrier or diluent, especially and preferably in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parenteral (including subcutaneous) route, in an effective amount.
  • a pharmaceutically acceptable carrier or diluent especially and preferably in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parenteral (including subcutaneous) route, in an effective amount.
  • Suitable dosage ranges varies as indicated above depending as usual upon the exact mode of ad- ministration, form in which administered, the indication towards which the administration is directed, the subject involved and the body weight of the subject involved, and the preference and experience of the physician or veterinarian in charge.
  • Inhibitory compounds are identified in a fX activation assay:
  • the compounds are dissolved in DMSO and mixed with a solution of fVlla in Ca 2+ -containing buffer (1+5). 30 ⁇ l of this mixture was then mixed with 45 ⁇ l TF (relipidated in PC/PS vesicles) and 25 ⁇ l of a solution containing fX, all in Ca 2+ -containing buffer. This gives final concentrations of 100 pM fVlla, 5 pM TF, 175 nM fX and various concentrations of the compounds. After a 5-min incubation, the fVlla/TF-catalyzed activation of fX is terminated by the addition of 50 ⁇ l buffer containing enough EDTA to give an excess over the Ca 2+ ions pres- ent.
  • fXa substrate 50 ⁇ l of a 2-mM solution of S-2765 (fXa substrate) is then added and the fXa formed is allowed to hydrolyze the substrate for 10 minutes during which the absorbance at 405 nm is continuously monitored in a SPECTRAmaxTM 340 plate reader. The slope of the absorption curve is compared to that of a control where DMSO alone was added to fVlla/TF/fX.
  • test compounds 20 mM in DMSO
  • DMSO dimethyl methoxysulfoxide
  • 55 ⁇ l sample compound in plasma
  • thromboplastin Innovin, Dade
  • the clotting reaction is started by adding 55 ⁇ l of a 25-mM CaCI 2 solution, yielding a final com- 31 pound concentration of 0,33 mM.
  • the clotting time is measured using an ACL 300 R coagu- lometer. The ratio between the clotting time in the presence and absence of test compound is used to quantify the anticoagulant efficiency.
  • the compounds with general formula I have interesting pharmacological properties.
  • the compounds of this invention can be used to modulate and normalize an impaired haemostatic balance in mammals caused by deficiency or malfunction of blood clotting fac- ⁇ tors or their inhibitors.
  • the fVlla and in particular the fVlla/TF activity plays an important role in the control of the coagulation cascade, and modulators of this key regulatory activity such as the present invention can be used in the treatment of coagulation-related diseased states.
  • the pharmaceutical composition is administered by the oral route.
  • the route of administration of the compositions containing a compound of formula I may be any route which effectively transports the active compound to its site of action, such as transdermal, pulmonal, subcutaneous, rectal, etc.
  • the pharmaceutical composition comprising compounds with formula I may be useful for modulating and normalizing an impaired haemostatic balance in a mammal.
  • the pharmaceutical composition may be useful for the treatment of coagulation-related diseased states. More particularly the pharmaceutical composition may be useful as an inhibitor of blood coagulation in a mammal, as an inhibitor of clotting activity in a mammal, as an inhibitor of deposition of fibrin in a mammal, as an inhibitor of platelet deposition in a mammal, in the treatment of mammals suffering from deep vein thrombosis, pulmonary embolism, stroke, disseminated intravascular coagulation (DIC), vascular restenosis, platelet deposition and associated disorders, myocardial infarction, and in the prophylactic treatment of mammals with atherosclerotic vessels at risk for developing thrombosis.
  • mammal is also intended to comprise a human.
  • the regimen for any patient to be treated with the compositions according to the present invention should be determined by those skilled in the art.
  • the daily dose to be administered in therapy can be determined by a physician and will depend on the particular compound employed, on the route of administration and on the age and the condition of the patient.
  • the daily dose comprises an effective amount (i.e. a therapeutically effective amount) of a compound according to the invention wherein the amount can be determined by a physician 32 and will depend on the particular compound employed, on the route of administration and on the age and the condition of the patient.
  • a convenient daily dosage can be in the range of from about OJ ⁇ mol to about 0.2 mmol of the active ingredient.
  • the invention relates to a method for inhibiting TF activity in a mammal which method comprises administering an effective amount of a compound of formula I, in combination with a pharmaceutical acceptable excipient and/ or carrier to the mammal in need of such a treatment.
  • the invention also relates to a method for inhibiting fVlla activity by substantially reducing the ability of activated fVlla to catalyze TF-enhanced activation of factors X and IX comprising administering a compound with formula I, in combination with a pharmaceutical acceptable excipient and/ or carrier to a mammal in need of such a treatment.
  • the invention also relates to a method for substantially inhibiting the binding of fVII/fVlla to TF which method comprises administering an effective amount of a compound of formula I, in combination with a pharmaceutical acceptable excipient and/ or carrier to the mammal in need of such a treatment.
  • compositions with formula I are particularly useful in methods for treating patients when formulated into pharmaceutical compositions, where they may be given by oral administration to individuals suffering from a variety of diseased states to treat coagulation- related conditions.
  • compositions of the invention are particular useful in prophylactic treatment of patients with atherosclerotic vessels at risk for thrombosis.
  • the compositions can also be used to inhibit vascular restenosis and platelet deposition and associated disorders.
  • compositions typically for oral administration to humans will comprise one or more compounds of the invention and pharmaceutically acceptable carriers and buffers. 33
  • Examples of pharmaceutically acceptable salts are pharmaceutically acceptable acid addition salts with non-toxic acids, either inorganic acids such as hydrochloric acid, sulphuric acid and phosphoric acid, or organic acids such as formic acid, acetic acid, propionic acid, succinic acid, gluconic acid, lactic acid, citric acid, ascorbic acid, benzoic acid, embonic acid, methanesulphonic acid and malonic acid.
  • inorganic acids such as hydrochloric acid, sulphuric acid and phosphoric acid
  • organic acids such as formic acid, acetic acid, propionic acid, succinic acid, gluconic acid, lactic acid, citric acid, ascorbic acid, benzoic acid, embonic acid, methanesulphonic acid and malonic acid.
  • compositions which comprise at least one compound of formula I or a pharmaceutically acceptable acid addition salt thereof in connection with a pharmaceutically acceptable carrier may be in the form of powders, solutions, or suspensions, which may or may not be divided in unit dosage form or in the form of capsules or tablets.
  • a preferred composition is in the form of an composition for oral administering.
  • compositions comprising a compound with formula I or a pharmaceutical acceptable salt thereof may further comprise carriers, diluents, absorption enhancers, tablet disintegrating agents and other ingredients which are conventionally used in the art.
  • the powders and tablets preferably contain from 5 to 99%, more preferred from 10 to 90 of the active ingredient.
  • solid carriers are magnesium carbonate, magnesium stearate, dextrin, lactose, sugar, talc, gelatin, pectin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melting waxes and cocoa butter.
  • Liquid compositions include sterile solutions, suspensions and emulsions suitable for parenteral injection.
  • compositions of this invention are prepared by methods known per se by the skilled art worker (see, for example, Remington: The Science and Practice of Pharmacy, 1995).
  • the column was eluted with a linear gradient of 5-90% acetonitrile, 85-0% water and 10% trifluoroacetic acid (0.1%).
  • ELS The purity estimated from the electrospray (positive ion) measurement.
  • 6-Nitroanthranilic acid (0.6 g) , 2,6-difluorobenzoyl chloride (0.93 mL) and triethyl amine/toluene (1/1) (18 mL) were reacted as described under (10). Reaction time 2 days. Extraction between ethyl acetate (100 mL) and HCl (2NJ00 mL) , followed by separation of the organic layer, drying over MgSO4, filtering and evaporation gave a crude product which was dissolved in warm THF (20 mL) and precipitated with hexane.
  • 6-Chloroanthranilic acid 0.566 g
  • 2,6-difluorobenzoyl chloride (0.93 mL)
  • triethyl amine/toluene (1/1) (18 mL) were reacted as described under (10).
  • Reaction time 2 days.
  • Extraction between ethyl acetate (100 mL) and HCl (2NJ00 mL) , followed by separation of the organic layer, drying over MgSO4, filtering and evaporation gave a crude product which was dissolved in warm THF (20 mL) and precipitated with hexane.
  • the resulting mixture was further purified on a silicagel column using dichloromethane as eluent.
  • 6-Nitro-2-(2,6-difluoro-phenyl)-benzo[d][1 ,3]oxazin-4-one 50 mg was dissolved in acetic acid (5 mL) under N2, PtO2 ( 2.5 mg) was added and the mixture was hydrogenated with H2 gas. Reaction time 2 h. The reaction mixture was filtered through Hyflo®, which was rinsed afterwards with ethyl acetate. The combined organic phases were evaporated to dryness and subsequently treated three times with toluene followed by evaporation.
  • the resulting mixture was further purified on a silicagel column using dichloromethane as eluent.
  • the isolated fraction (80 mg) was hydrolysed with 1 % HCl in ethanol by stirring for 2 days at RT, and further hydrolysis after addition of HCl (4N, 5 mL) and ethyl acetate (10 mL). 45
  • the organic layer was separated, evaporated and dried resulting in 2-(2,6-difluoro-phenyl)- 8-hydroxy-benzo[d][1 ,3]oxazin-4-one (32 mg) , mp.190-198 .
  • LC-MS showed the purity 86% with the corresponding O-triisopropylsilylated product as the impurity.
  • IC50 TF/FVII/FX The IC50 value in ⁇ M found from the FX activation assay described above
  • Clot Ratio % The clot ratio found in the clotting assay described above.

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Abstract

L'invention se rapporte à l'utilisation de composés représentés par la formule (I) en tant qu'inhibiteurs du complexe facteur VII-facteur tissulaire ainsi qu'à de nouveaux dérivés benzoxazines. On a montré que les composés représentés par la formule (I) et leurs sels pharmaceutiquement acceptables sont des inhibiteurs de l'activité du facteur VIIa-facteur tissulaire. Ces composés possèdent des propriétés anticoagulantes. Lesdits composés s'avèrent utiles au traitement des anomalies des facteurs de coagulation sanguine ou des effets d'inhibiteurs sur les facteurs de coagulation sanguine. L'invention se rapporte également à des procédés d'inhibition de l'activité de coagulation.
PCT/DK1999/000138 1998-03-24 1999-03-17 Composes heterocycliques regulateurs de coagulation WO1999048878A1 (fr)

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AU28260/99A AU2826099A (en) 1998-03-24 1999-03-17 Heterocyclic compounds regulating clotting

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DK41398 1998-03-24
DK0413/98 1998-03-24
DK46498 1998-04-02
DK0464/98 1998-04-02
DKPA199801559 1998-11-26
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* Cited by examiner, † Cited by third party
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WO2000030646A1 (fr) * 1998-11-26 2000-06-02 Novo Nordisk A/S Composes heterocycliques regulant la coagulation
WO2001030333A2 (fr) * 1999-10-27 2001-05-03 Sunol Molecular Corporation Antagonistes de facteur tissulaire et leurs procedes d'utilisation
US6313122B1 (en) 1997-06-26 2001-11-06 Eli Lilly And Company Antithrombotic agents
US6372759B1 (en) 1997-06-26 2002-04-16 Eli Lilly And Company Antithrombotic agents
US6417200B1 (en) 1997-06-26 2002-07-09 Eli Lilly And Company Antithrombotic agents
WO2003007955A2 (fr) * 2001-07-20 2003-01-30 Cancer Research Technology Limited Nouvelle utilisation
WO2003016292A1 (fr) * 2001-08-13 2003-02-27 Ciba Specialty Chemicals Holding Inc. Absorbeurs de lumiere ultraviolette
WO2003035735A1 (fr) * 2001-10-22 2003-05-01 Cytec Technology Corp. Absorbeurs uv a base de benzoxazinone a faible teneur en sodium et a faible indice de coloration et procede de fabrication de ces absorbeurs
US7244738B2 (en) 2003-07-02 2007-07-17 Roche Palo Alto Llc Arylamine-substituted quinazolinone compounds useful as alpha 1A/B adrenergic receptor antagonists
EP1829535A2 (fr) * 1999-10-27 2007-09-05 Tanox, Inc. Antagonistes de facteur de tissus et leurs procédés d'utilisation
TWI419884B (zh) * 2010-06-24 2013-12-21 Univ Chang Gung 苯并雜氧嗪酮衍生物，其製備方法以及包含有此等衍生物的藥學組成物
WO2015112081A1 (fr) 2014-01-23 2015-07-30 Sixera Pharma Ab Dérivés de benzoxazinone pour le traitement de maladies de la peau
WO2022253911A1 (fr) * 2021-06-01 2022-12-08 Sixera Pharma Ab Émulsion huile dans l'eau de 6-éthoxy-7-méthoxy-2-(2-méthylsulfanylphényle)-3,l-benzoxazin-4-one

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EP0206323A1 (fr) * 1985-06-25 1986-12-30 Syntex (U.S.A.) Inc. Dérivés de 2-oxy-4H-3,1-benzoxazin-4-one et composés apparentés
WO1996007648A1 (fr) * 1994-09-09 1996-03-14 Warner-Lambert Company 4H-3,1-BENZOXAZIN-4-ONES ET BENZTHIAZIN-4-ONES SUBSTITUES EN POSITION 2 INHIBITEURS DE LA PROTHEASE Clr DU COMPLEMENT POUR LE TRAITEMENT DES PROCESSUS INFLAMMATOIRES

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Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6677369B2 (en) 1997-06-26 2004-01-13 Eli Lilly And Company Antithrombotic agents
US6313122B1 (en) 1997-06-26 2001-11-06 Eli Lilly And Company Antithrombotic agents
US6605626B2 (en) 1997-06-26 2003-08-12 Eli Lilly And Company Antithrombotic agents
US6372759B1 (en) 1997-06-26 2002-04-16 Eli Lilly And Company Antithrombotic agents
US6417200B1 (en) 1997-06-26 2002-07-09 Eli Lilly And Company Antithrombotic agents
US6500851B2 (en) 1997-06-26 2002-12-31 Eli Lilly And Company Antithrombotic agents
WO2000030646A1 (fr) * 1998-11-26 2000-06-02 Novo Nordisk A/S Composes heterocycliques regulant la coagulation
WO2001030333A3 (fr) * 1999-10-27 2002-02-07 Sunol Molecular Corp Antagonistes de facteur tissulaire et leurs procedes d'utilisation
EP1829535A3 (fr) * 1999-10-27 2007-10-24 Tanox, Inc. Antagonistes de facteur de tissus et leurs procédés d'utilisation
EP1829535A2 (fr) * 1999-10-27 2007-09-05 Tanox, Inc. Antagonistes de facteur de tissus et leurs procédés d'utilisation
AU784426C (en) * 1999-10-27 2007-02-01 Tanox, Inc. Tissue factor antagonists and methods of use thereof
US6849617B2 (en) 1999-10-27 2005-02-01 Sunol Molecular Corporation Tissue factor antagonists and methods of use thereof
US6608066B1 (en) 1999-10-27 2003-08-19 Sunol Molecular Corporation Tissue factor antagonists and methods of use thereof
WO2001030333A2 (fr) * 1999-10-27 2001-05-03 Sunol Molecular Corporation Antagonistes de facteur tissulaire et leurs procedes d'utilisation
AU784426B2 (en) * 1999-10-27 2006-03-30 Tanox, Inc. Tissue factor antagonists and methods of use thereof
WO2003007955A2 (fr) * 2001-07-20 2003-01-30 Cancer Research Technology Limited Nouvelle utilisation
WO2003007955A3 (fr) * 2001-07-20 2003-05-01 Cancer Rec Tech Ltd Nouvelle utilisation
WO2003016292A1 (fr) * 2001-08-13 2003-02-27 Ciba Specialty Chemicals Holding Inc. Absorbeurs de lumiere ultraviolette
US7173128B2 (en) 2001-08-13 2007-02-06 Ciba Specialty Chemicals Corporation Ultraviolet light absorbers
US7244776B2 (en) 2001-08-13 2007-07-17 Ciba Specialty Chemicals Corporation Ultraviolet light absorbers
US6774232B2 (en) 2001-10-22 2004-08-10 Cytec Technology Corp. Low color, low sodium benzoxazinone UV absorbers and process for making same
WO2003035735A1 (fr) * 2001-10-22 2003-05-01 Cytec Technology Corp. Absorbeurs uv a base de benzoxazinone a faible teneur en sodium et a faible indice de coloration et procede de fabrication de ces absorbeurs
US7244738B2 (en) 2003-07-02 2007-07-17 Roche Palo Alto Llc Arylamine-substituted quinazolinone compounds useful as alpha 1A/B adrenergic receptor antagonists
TWI419884B (zh) * 2010-06-24 2013-12-21 Univ Chang Gung 苯并雜氧嗪酮衍生物，其製備方法以及包含有此等衍生物的藥學組成物
WO2015112081A1 (fr) 2014-01-23 2015-07-30 Sixera Pharma Ab Dérivés de benzoxazinone pour le traitement de maladies de la peau
CN106132941A (zh) * 2014-01-23 2016-11-16 西可斯拉制药公司 用于治疗皮肤病的苯并恶嗪酮衍生物
US9695194B2 (en) 2014-01-23 2017-07-04 Sixera Pharma Ab Benzoxazinone derivatives for treatment of skin diseases
EP3097085A4 (fr) * 2014-01-23 2017-08-09 Sixera Pharma AB Dérivés de benzoxazinone pour le traitement de maladies de la peau
CN106132941B (zh) * 2014-01-23 2018-04-06 西可斯拉制药公司 用于治疗皮肤病的苯并恶嗪酮衍生物
US10072024B2 (en) 2014-01-23 2018-09-11 Sixera Pharma Ab Benzoxazinone derivatives for treatment of skin diseases
WO2022253911A1 (fr) * 2021-06-01 2022-12-08 Sixera Pharma Ab Émulsion huile dans l'eau de 6-éthoxy-7-méthoxy-2-(2-méthylsulfanylphényle)-3,l-benzoxazin-4-one

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