EP1311473A2 - NEUE VERBINDUNGEN, DIE FAKTOR Xa-AKTIVITÄT INHIBIEREN - Google Patents

NEUE VERBINDUNGEN, DIE FAKTOR Xa-AKTIVITÄT INHIBIEREN

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Publication number
EP1311473A2
EP1311473A2 EP01976140A EP01976140A EP1311473A2 EP 1311473 A2 EP1311473 A2 EP 1311473A2 EP 01976140 A EP01976140 A EP 01976140A EP 01976140 A EP01976140 A EP 01976140A EP 1311473 A2 EP1311473 A2 EP 1311473A2
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EP
European Patent Office
Prior art keywords
groups
aryl
alkyl
heterocycloalkyl
heteroalkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP01976140A
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German (de)
English (en)
French (fr)
Inventor
Michael W. Cappi
Thilo Fuchs
Robert Eckl
Silke Schabbert
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Morphochem AG
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Morphochem AG
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Publication of EP1311473A2 publication Critical patent/EP1311473A2/de
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    • C07D295/00Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
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    • C07D295/16Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182Radicals derived from carboxylic acids
    • C07D295/185Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P35/00Antineoplastic agents
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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    • C07ORGANIC CHEMISTRY
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    • C07D211/00Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/30Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
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    • C07D211/00Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40Oxygen atoms
    • C07D211/44Oxygen atoms attached in position 4
    • C07D211/52Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
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    • C07D213/00Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
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    • C07D213/00Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72Nitrogen atoms
    • C07D213/74Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D217/00Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/06Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D295/00Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/24Oxygen atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D309/00Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10Oxygen atoms
    • C07D309/12Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic 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
    • C07D401/02Heterocyclic 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
    • C07D401/12Heterocyclic 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 linked by a chain containing hetero atoms as chain links
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    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to new compounds with anticoagulant activity (so-called anticoagulants) and their pharmacologically acceptable salts or solvates and hydrates, pharmaceutical compositions which contain them as an active ingredient, processes for the preparation of such compounds, salts and compositions and their use for prevention and / or treatment of thromboembolytic diseases. These compounds, salts and compositions are very effective factor Xa inhibitors.
  • the present invention also relates to pro-drugs, optically active forms, racemates and diastereomers of these compounds and salts.
  • Thromboembolytic diseases are based on an increased tendency to clot in people with risk factors, e.g. major operations, prolonged immobilization, broken bones of the lower extremities, obesity, blood lipid metabolism disorders, infections with Gram-negative organisms, cancer and older age.
  • risk factors e.g. major operations, prolonged immobilization, broken bones of the lower extremities, obesity, blood lipid metabolism disorders, infections with Gram-negative organisms, cancer and older age.
  • Venous thrombosis can cause the tissue removed from the affected vein to develop edema or inflammation.
  • Thrombosis of a deep vein can lead to serious complications such as Lead pulmonary embolism.
  • Arterial thrombosis can lead to ischemic necrosis of the tissue supplied by the affected artery, e.g. to myocardial infarction in the case of an affected coronary artery.
  • Other thromboembolytic diseases are e.g. Arteriosclerosis, apoplexy (stroke), angina pectoris, intermittent claudication.
  • the intrinsic blood coagulation pathway is initiated when blood comes into contact with non-physiological surfaces.
  • the extrinsic blood coagulation pathway is initiated by the injury to blood vessels.
  • Both blood coagulation paths lead to a common path in which the blood coagulation factor X, a serine proteinase, is converted into its active form (factor Xa).
  • Factor Xa together with factor Va and Ca 2+ in the so-called prothrombinase complex causes prothrombin to be converted into thrombin, which in turn releases fibrin monomers by cleaving peptides from fibrinogen, which are able to coagulate into fibrin fibers.
  • Factor XIII finally leads to cross-linking and thus stabilization of the fibrin fibers.
  • Anticoagulants are used both for the prevention and for the treatment of thromboembolytic diseases.
  • anticoagulants are differentiated from immediately effective heparin, which directly inhibits certain factors in blood clotting, from vitamin K antagonists (eg coumarin derivatives). The latter inhibit the production of certain coagulation factors in the liver, which is dependent on the presence of vitamin K, and only begin to take effect slowly.
  • Other anticoagulants are fibrinolytics, which cause direct or indirect activation of the fibrinolytic system, and Platelet aggregation inhibitors such as acetylsalicylic acid.
  • a less common procedure is the lowering of the fibrinogen level in the blood by the enzyme Ancrod.
  • the aim of using anticoagulant agents is to prevent the formation of a vaso-occlusive blood clot or to dissolve it again after it has formed.
  • the vitamin K antagonists such as Warfarin show - presumably genetically determined - a different effectiveness from patient to patient. In addition to the slow onset of action mentioned above, this has the disadvantage that the patient must be monitored and an individual dose adjustment is required.
  • thrombin inhibitors Other known anticoagulants belong to the group of thrombin inhibitors.
  • Current overviews of the relevant research activities in this field can be found, for example, in Jules A. Shafer, Current Opinion in Chemical Biology, 1988, 2: 458-485, Joseph P. Vacca, Current Opinion in Chemical Biology, 2000, 4: 394- 400 and Fahad Al-Obeidi and James A. Ostre, DDT, Vol. 3, No. 5, May 1998: 223-231.
  • a decisive disadvantage of thrombin inhibitors is that in order to achieve the desired effect, such a strong suppression of thrombin activity in vivo is required that the tendency to bleed can increase, which makes dosing difficult.
  • factor Xa inhibitors suppress the formation of new thrombin from prothrombin, while they do not impair existing thrombin activity, which is required for primary hemostasis.
  • An object of the present invention was to provide new compounds with useful properties, in particular anticoagulant activity.
  • Suitable pharmaceutical compositions should also be provided. These compounds or compositions should in particular be administrable orally.
  • Another object of the present invention was to provide a process for the preparation of these new compounds. Furthermore, these new compounds should be suitable for use in the prevention and / or treatment of thromboembolytic diseases.
  • the present invention describes anticoagulant compounds, their pharmacologically acceptable salts or solvates and hydrates and formulations which are new, have high activity and selectivity and which can be administered orally.
  • the present invention further relates to pro-drugs, optically active forms, racemates and diastereomers of these compounds and salts. Said compounds and salts can themselves be pro-drugs that are only activated by metabolism. Also described are pharmaceutical compositions which contain the said compounds or salts etc. as an active ingredient.
  • several direct and simple syntheses of the compounds, pro-drugs, salts and compositions as well as intermediates according to the invention are described which are useful in such syntheses.
  • the use of these active ingredients for the prevention and / or treatment of thromboembolytic diseases is described.
  • the present invention relates to a compound of the general formula (I):
  • Ar is arylene, heteroarylene, heteroarylalkylene or aralkylene, where X is directly linked to the aromatic ring system;
  • R 3 is H, alkyl such as C 1 -C 4 alkyl, heteroalkyl or aralkyl;
  • the groups R * independently of one another are alkyl groups which can be substituted by one or more -OH or -NH 2 radicals, heteroalkyl groups, carbocyclic groups, heterocycloalkyl groups, aryl groups, heteroaryl groups or aralkyl groups , where these groups can be substituted with one or more unsubstituted groups selected from alkyl, heteroalkyl such as alkyloxy, acyl or acyloxy, a carbocyclic group, heterocycloalkyl, aryl, heteroaryl or aralkyl, or are hydroxyl groups or glycosyloxy groups;
  • R 5 is H, alkyl, heteroalkyl, a carbocyclic group, heterocycloalkyl, aryl, heteroaryl, heteroarylalkyl or aralkyl;
  • R 6 and R 7 independently of one another are H, alkyl, heteroalkyl, a carbocyclic group, heterocycloalkyl such as, for example, aryl-heterocycloalkyl, aryl, heteroaryl, aralkyl or Are heteroarylalkyl, these groups being substituted by one or more preferably unsubstituted groups selected from alkyl, heteroalkyl such as alkoxy, acyl or acyloxy, a carbocyclic group, heterocycloalkyl, aryl, heteroaryl, heteroarylalkyl, aralkyl, -OH or -NH 2 can, or together part of a heterocycloalkyl ring system, especially an aryl heterocycloalkyl ring system such as.
  • aryl or heteroaryl-piperazinyl, or a heteroaryl ring system these systems having one or more preferably unsubstituted groups selected from alkyl, heteroalkyl such as alkoxy, acyl or acyloxy, a carbocyclic group, heterocycloalkyl, aryl, Heteroaryl, heteroarylalkyl, aralkyl, -OH or -NH 2 may be substituted; and i
  • R 8 is H, alkyl, heteroalkyl, a carbocyclic group, heterocycloalkyl, aryl, heteroaryl, heteroarylalkyl or aralkyl or together with R5 is part of a heterocycloalkyl ring system;
  • alkyl refers to a saturated or at least partially unsaturated, straight-chain or branched hydrocarbon group which has, for example, 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms, for example the methyl, ethyl, n-propyl, isopropyl, . n-butyl, isobutyl, tert-butyl, n-hexyl, 2, 2-dimethylbutyl, n-octyl, allyl, isoprenyl or hexa-2-enyl group.
  • heteroalkyl refers to an alkyl group in which one or more carbon atoms are replaced by at least one oxygen, nitrogen, phosphorus or sulfur atom, with oxygen and nitrogen being preferred, e.g. an alkyloxy group such as e.g. Methoxy or ethoxy, or a methoxymethyl, cyano or 2,3-dioxyethyl group.
  • the term heteroalkyl also refers to a carboxylic acid or a group derived from a carboxylic acid such as e.g. Acyl, acyloxy, carboxyalkyl, carboxyalkyl esters e.g. Methyl carboxyalkyl ester, carboxyalkylamide, alkoxycarbonyl or alkoxycarbonyloxy.
  • carbocyclic group refers to a saturated or partially unsaturated cyclic group that has one or more rings that form a skeleton, e.g. Contains 3 to 14 carbon atoms, preferably 5 or 6 to 10 carbon atoms, e.g. the cyclopropyl, cyclohexyl, tetralin or cyclohex-2-enyl group.
  • a heterocycloalkyl group can be substituted by an unsubstituted alkyl, heteroalkyl, heteroaryl or aryl group.
  • heterocycloalkyl refers to a carbocyclic group in which one or more carbon atoms are independently replaced by an oxygen, nitrogen, phosphorus or sulfur atom.
  • a heterocycloalkyl group can be substituted by an unsubstituted alkyl, heteroalkyl, heteroaryl or aryl group and can represent, for example, the piperidine, morpholine, N-methylpiperazine or N-phenylpiperazine group.
  • aryl refers to an aromatic cyclic group that has one or more rings and through a scaffold is formed which contains, for example, 5 to 14 carbon atoms, preferably 5 or 6 to 10 carbon atoms.
  • an aryl group can be substituted by unsubstituted alkyl or heteroalkyl groups, OH, CN, N0 or NH and can be, for example, a phenyl, naphthyl, 2-, 3- or 4-methoxyphenyl, 2-, 3- or 4-ethoxyphenyl, 4-carboxyphenylalkyl or 4-hydroxyphenyl group.
  • heteroaryl refers to an aryl group in which one or more carbon atoms are independently replaced by an oxygen, nitrogen, phosphorus or sulfur atom. Preferably only 1 or 2 carbon atoms are replaced. Examples of such groups are the 4-pyridyl, 2-imidazolyl, 3-pyrazolyl and isoquinolinyl groups.
  • aralkyl refers to groups which include both aryl and alkyl groups and / or carbocyclic groups, e.g. Benzyl or tetrahydronaphthalene groups.
  • heteroarylalkyl refers to aralkyl groups in which one or more carbon atoms are independently replaced by oxygen, nitrogen, phosphorus or sulfur atoms, e.g. the tetrahydroisoquinolinyl, 2- or 3-ethyl-indolyl or 4-methylpyridino group.
  • alkyl, heteroalkyl, carbocyclic group, heterocycloalkyl, aryl, heteroaryl, heteroarylalkyl and aralkyl also refer to groups in which one or more hydrogen atoms of such groups are represented by fluorine, chlorine, bromine or iodine atoms or by -OH, NH 2 , or SH residues are replaced. These terms continue to refer to appropriate groups using unsubstituted alkyl, heteroalkyl, aralkyl or aralkyloxy groups are substituted.
  • arylene, heteroarylene, heteroarylalkylene and aralkylene refer to disubstituted aryl, heteroaryl, heteroarylalkyl and aralkyl groups, i.e. on groups bearing at least two substituents other than H.
  • glycosyloxy group refers to a saccharide bonded via a - or ⁇ -O-glycosyl bond, in particular a monosaccharide, preferably glucose or fructose.
  • R 1 H, OH or C 1 -C 4 alkyloxy, such as mehoxy or ethoxy.
  • Ar is a para to X by an OH-, NH-, C x -C 4 -alkyloxy- (for example methoxy-), C ⁇ C ⁇ -alkylamino-, C 2 -C 6 dialkylamino group or a halogen atom (eg chlorine or fluorine) substituted meta-phenylene.
  • a halogen atom eg chlorine or fluorine
  • R 4 are independent of one another are an OH, -OCH 2 COOH, -COOH, C j -C ⁇ alkyloxy, a glycosyloxy group or a halogen atom such as F or Cl.
  • R 4 is particularly preferably a —OCH 2 COOH, —COOH or a ⁇ -D-glucosyloxy group.
  • R 5 is H, C 1-8 alkyl, C 1-8 heteroalkyl or the side chain of a natural amino acid.
  • R 5 is particularly preferably H or methyl.
  • R ⁇ and R 7 together form part of an aryl or heteroaryl piperazinyl ring (particularly preferably a 4-aryl or 4-heteroaryl piperazinyl ring).
  • R 8 H or C 1 -C 6 -alkyl, such as methyl.
  • R 1 is H, OH or C ⁇ C ⁇ alkyloxy such as methoxy or ethoxy; R 4 is independently OH, -0CH 2 C00H,
  • Examples of pharmacologically acceptable salts of the compounds of the formulas (I) or (II) are salts of physiologically acceptable mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid; or salts of organic acids such as methanesulfonic acid, p-toluenesulfonic acid, lactic acid, acetic acid, trifluoroacetic acid, citric acid, succinic acid, fumaric acid, maleic acid and salicylic acid.
  • Compounds of the formulas (I) or (II) can be solvated, in particular hydrated. The hydration can e.g. occur during the manufacturing process or as a result of the hygroscopic nature of the initially anhydrous compounds of formula (I) or (II).
  • compositions according to the present invention contain at least one compound of the formulas (I) or (II) as an active ingredient and optionally excipients and / or adjuvants.
  • the pro-drugs which are also the subject of the present invention, consist of a compound of the formulas (I) or (II) and at least one pharmacologically acceptable protective group which is split off under physiological conditions, e.g. an alkoxy, aralkyloxy, acyl or acyloxy group, e.g. an ethoxy, benzyloxy, acetyl or acetyloxy group.
  • a solvent such as dirnethylformamide
  • a coupling reagent such as carbonyldiimidazole or dicyclohexylcarbodiimide and 1-hydroxybenzotriazole.
  • compounds of formula (III) can be synthesized by reacting an ⁇ -bromic acid with a base such as sodium hydroxide, evaporating the solvent and adding an excess of an amine of formula (V) and the resulting mixture at a preferred temperature of 80 is heated to 120 ° C over a period of several hours.
  • Compounds of formula (III) may alternatively also be reacted by reacting an aldehyde such as 3-cyanobenzaldehyde with an amino acid in an aqueous solution of a base such as sodium hydroxide and adding e.g. Sodium cyanoborohydride are preferably synthesized at a temperature below 5 ° C.
  • compounds of formula (III) are synthesized by an aryl bromide such as. B. 3-bromo-benzonitrile with a phenylglycine derivative such as. B. (S) -phenylglycine is implemented.
  • This synthesis can e.g. B. analogous to that in: D. Ma et al. J. Am. Chem. Soc. 1998, 120: 12459-12467.
  • Compounds of formula (IV) can be synthesized by synthesizing an N-Boc protected amino acid with an amine of formula (XI) using standard coupling methods with a coupling reagent such as carbonyldiimidazole or dicyclohexylcarbodiimide and 1-hydroxybenztriazole.
  • a coupling reagent such as carbonyldiimidazole or dicyclohexylcarbodiimide and 1-hydroxybenztriazole.
  • Compounds of formula (IV) can also be synthesized using the mixed anhydrides or 4-nitro ⁇ henyl esters of the corresponding N-Boc protected amino acids. Removal of the protective group on the amine group by treatment with an acid such as hydrochloric acid, trifluoroacetic acid or formic acid in water or dichloromethane leads to the end compounds of the formula (IV).
  • reaction described can be catalyzed by adding Bronsted acids such as p-toluenesulfonic acid or 2,4-dinitrobenzenesulfonic acid or Lewis acids such as zinc dichloride, iron trichloride, boron trifluoroetherate or ytterbium triflate.
  • Bronsted acids such as p-toluenesulfonic acid or 2,4-dinitrobenzenesulfonic acid
  • Lewis acids such as zinc dichloride, iron trichloride, boron trifluoroetherate or ytterbium triflate.
  • a solvent such as methanol, dichloromethane or dimethylformamide or also without a solvent e.g. is implemented at room temperature or a temperature up to 80 ° C (see K. Matsumoto et al., Synthesis, 1997, 249-250).
  • the starting nitrile can be dissolved in a solvent such as ethanol or methanol or a solvent mixture such as chloroform and methanol or chloroform and ethanol and this solution can be dissolved in a Expose anhydrous hydrogen chloride flow at a temperature below 10 ° C.
  • a reaction time of several hours to days the intermediate product is precipitated with ether and filtered off.
  • This intermediate can be dissolved in water and extracted with a solvent such as dichloromethane, chloroform or acetic acid ester after neutralization with a base such as sodium carbonate or hydroxide.
  • the material obtained is then reacted with anhydrous ammonia or an ammonium salt such as ammonium chloride in a solvent such as methanol or ethanol, preferably at a temperature up to 80 ° C.
  • a solvent such as methanol or ethanol
  • the filtered intermediate can be reacted immediately with anhydrous ammonia or an ammonium salt such as ammonium chloride in a solvent such as methanol or ethanol.
  • a solvent such as dirnethylformamide or ethanol
  • a base such as sodium, sodium hydride or triethylamine and hydroxylamine or a hydroxylamine salt such as hydroxylamine hydrochloride
  • a solvent e.g. dirnethylformamide or ethanol, preferably at a temperature below 5 ° C
  • R 1 alkyloxy
  • This compound is then step by dissolving in a solvent such as ethanol or acetic acid with a catalyst such as palladium or palladium on carbon or Platinum or Raney nickel hydrogenated in a hydrogen atmosphere.
  • a solvent such as ethanol or acetic acid
  • a catalyst such as palladium or palladium on carbon or Platinum or Raney nickel hydrogenated in a hydrogen atmosphere.
  • a compound or pharmaceutical composition of the present invention can be used for the inhibition of factor Xa activity, for the prevention and / or treatment of thrombo-embolitic diseases, arterial restenosis, blood poisoning, cancer, acute inflammation or other diseases caused by factor X a -Activity are mediated, and in particular of venous thrombosis, edema or inflammation, of "deep vein thrombosis", pulmonary embolism, thromboembolytic complications after major operations, during vascular surgery, prolonged immobilization, broken bones of the lower extremities etc., of arterial thrombosis , especially the coronary arteries in myocardial infarction, as well as arteriosclerosis, apoplexy, angina pectoris, intermittent claudication, to name just a few indications.
  • the active compounds according to the invention should have the highest possible inhibitory activity against factor Xa with the highest possible selectivity.
  • the selectivity was in the present case estimated by comparing the inhibitory effect against factor Xa and tryptase and thrombin (two further serine proteinases).
  • the present invention also relates to the use of these active compounds for the production of medicaments for the prevention and / or treatment of thromboembolytic diseases.
  • compounds of formula (I) or (II) are administered using known and acceptable modes, either individually or in combination with any other therapeutic agent.
  • Such therapeutically useful agents can be administered in one of the following ways: orally, for example as dragées, coated tablets, pills, semi-solids, soft or hard capsules, solutions, emulsions or suspensions; parenterally, for example as an injectable solution; rectally as suppositories; by inhalation, for example as a powder formulation or spray, transdermally or intranasally.
  • the therapeutically usable product can be mixed with pharmacologically inert, inorganic or organic drug carrier substances, for example with lactose, sucrose, glucose, gelatin, malt, silica gel, starch or derivatives thereof , Talc, stearic acid or its salts, dry skimmed milk and the like.
  • drug carriers such as vegetable oils, petroleum, animal or synthetic oils, wax, fat, polyols can be used.
  • drug carriers such as water, alcohols, aqueous salt solution, aqueous dextrose, polyols, glycerin, vegetable oils
  • solvents such as oxygen, nitrogen and carbon dioxide
  • the pharmaceutically usable agents can also contain additives for preservation, stabilization, emulsifiers, sweeteners, flavorings, salts for changing the osmotic pressure, buffers, coating additives and antioxidants.
  • Combinations with other therapeutic agents may include other agents that are commonly used to prevent and / or treat thromboembolytic disorders such as e.g. Warfarin etc.
  • the dose of the biologically active compound according to the invention can vary within wide limits and can be adjusted to the individual need. In general, a dose of 0.1 ⁇ g to 10 mg / kg body weight per day is suitable, with a preferred dose being 0.5 to 4 mg / kg per day. In suitable cases, the dose can also be below or above the values given above.
  • a 0.05 molar solution of 2- (3, 4, 5-trihydroxy-6-hydroxy-methyl-tetrahydropyran-2-yloxy) benzaldehyde (helicin), a 0.05 molar solution of 3-aminobenzamidine dihydrochloride and one 0.05 molar solution of 2-isocyano-l- [4- (2-methoxyphenyl) piperazin-1-yl] ethanone in methanol was reacted in a sealed vessel at room temperature for 24 hours. After evaporation of the solvent, the product was subjected to liquid chromatography and mass spectroscopy to demonstrate the structure of the final product.
  • EXAMPLE 7 Analogously to Example 1 and using the appropriate suitable starting materials, 2 - [(3-cyano-phenylamino] -N- ⁇ 2- [4- (2-methoxy-phenyl) -piperazin-1-yl] -2-oxo -ethyl ⁇ -2- [2- (3,4,5-trihydroxy-6-hydroxymethyl-tetrahyro-dro-pyran-2-yloxy) phenyl] acetamide was obtained.
  • Example 7 0.8 mmol of the product from Example 7 was added to a methanol solution containing equimolar amounts of hydroxylamine hydrochloride. and contained a suitable base such as triethylamine or sodium methoxide and was stirred at room temperature for 24 hours. After the evaporation of all volatile components, the compound was purified by liquid chromatography in analogy to Example 1.
  • EXAMPLE 48 In analogy to Example 1 and using the appropriate suitable starting materials, (3- ⁇ (3-carbamimidoylphenylamino) - [2- (6, 7-dimethoxy-3, 4-dihydro-1H-isoquinolin-2-yl ) -2-oxo-ethylcarbamoyl] methyl ⁇ phenoxy) acetic acid obtained.
  • Chromogenic peptide substrates were used to show the inhibitory activity against factor Xa activity.
  • the inhibition of the amidolytic activity of factor Xa by the compounds described above was shown as follows. The measurements were carried out in microtiter plates at room temperature. The compounds were dissolved in dimethyl sulfoxide and 5 ul of this solution became a 1 nM solution of human recombinant factor Xa
  • Kj . IC 50 / (1+ [S] / K m ])
  • Kj . IC 50 / (1+ [S] / K m ]
  • IC 50 values of the above examples are in the range from 1 nM to I ⁇ M.

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EP01976140A 2000-08-23 2001-08-23 NEUE VERBINDUNGEN, DIE FAKTOR Xa-AKTIVITÄT INHIBIEREN Withdrawn EP1311473A2 (de)

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DE10041402A DE10041402A1 (de) 2000-08-23 2000-08-23 Neue Verbindungen, die Faktor Xa-Aktivität inhibieren
DE10041402 2000-08-23
PCT/EP2001/009753 WO2002016312A2 (de) 2000-08-23 2001-08-23 NEUE VERBINDUNGEN, DIE FAKTOR Xa-AKTIVITÄT INHIBIEREN

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DE19939910A1 (de) * 1999-08-23 2001-03-01 Morphochem Ag Neue Verbindungen, die Tryptase-Aktivität hemmen
AU2002254907A1 (en) * 2001-02-23 2002-09-12 Morphochem Aktiengesellschaft Fur Kombinatorische Chemie Diamides which inhibit tryptase and factor xa activity
DE60224805T2 (de) 2001-07-26 2009-01-22 Eli Lilly And Co., Indianapolis 1-glycinyl-4-(1-methylpiperidin-4-yl)piperazine und -piperidine als faktor-xa-antagonisten
DE10204072A1 (de) * 2002-01-31 2003-08-14 Morphochem Ag Komb Chemie Neue Verbindungen, die Faktor Xa-Aktivität inhibieren
DE10300049A1 (de) * 2003-01-03 2004-07-15 Morphochem AG Aktiengesellschaft für kombinatorische Chemie Neue Verbindungen, die Faktor VIIa inhibieren
BR0307266A (pt) * 2002-01-31 2004-12-07 Morphochem Ag Komb Chemie Compostos que inibem a atividade do fator xa
KR20060027801A (ko) 2003-06-05 2006-03-28 제넨테크, 인크. B 세포 장애에 대한 조합 요법
WO2007062090A2 (en) 2005-11-23 2007-05-31 Genentech, Inc. Methods and compositions related to b cell assays
US7601844B2 (en) * 2006-01-27 2009-10-13 Bristol-Myers Squibb Company Piperidinyl derivatives as modulators of chemokine receptor activity
US7615556B2 (en) 2006-01-27 2009-11-10 Bristol-Myers Squibb Company Piperazinyl derivatives as modulators of chemokine receptor activity
JP2011500715A (ja) 2007-10-16 2011-01-06 ザイモジェネティクス, インコーポレイテッド 自己免疫疾患の治療のためのBLyS阻害剤および抗CD20剤の組合せ
WO2009132058A2 (en) 2008-04-25 2009-10-29 Zymogenetics, Inc. Levels of bcma protein expression on b cells and use in diagnostic methods
US8003335B2 (en) 2008-04-30 2011-08-23 Universite Paris-SUD11 Levels of APRIL in serum and use in diagnostic methods
SI2291657T1 (sl) 2008-05-01 2016-09-30 Zymogenetics, Inc. Nivoji blys/april heterotrimerjev v serumu in uporaba pri diagnostičnih postopkih
TWI433838B (zh) 2008-06-25 2014-04-11 必治妥美雅史谷比公司 作為趨化因子受體活性調節劑之六氫吡啶衍生物
WO2010075249A2 (en) 2008-12-22 2010-07-01 Genentech, Inc. A method for treating rheumatoid arthritis with b-cell antagonists
MX353186B (es) 2009-09-03 2018-01-05 Genentech Inc Metodos para el tratamiento, diagnosis y monitoreo de artritis reumatoide.
US8642622B2 (en) 2010-06-16 2014-02-04 Bristol-Myers Squibb Company Piperidinyl compound as a modulator of chemokine receptor activity
RU2013140975A (ru) 2011-02-28 2015-04-10 Дженентек, Инк. Биологические маркеры и способы прогнозирования восприимчивости к антагонистам в-клеток
US9775890B2 (en) 2012-01-25 2017-10-03 Université Catholique de Louvain Factor Xa inhibitor used with liver-derived progenitor cells
EP3078378B1 (en) 2015-04-08 2020-06-24 Vaiomer Use of factor xa inhibitors for regulating glycemia

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Publication number Priority date Publication date Assignee Title
DE19653036A1 (de) * 1996-12-19 1998-06-25 Merck Patent Gmbh Cyclopeptidderivate
IL134394A0 (en) * 1997-08-27 2001-04-30 Kissei Pharmaceutical 3-amidinoaniline derivatives, activated blood coagulation factor x inhibitors, and intermediates for producing both
PT921116E (pt) 1997-12-04 2003-11-28 Hoffmann La Roche Derivados de n-(4-carbamimido-fenil)-glicinamida
DE19939910A1 (de) 1999-08-23 2001-03-01 Morphochem Ag Neue Verbindungen, die Tryptase-Aktivität hemmen

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Title
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DE10041402A1 (de) 2002-03-14
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