WO2001032610A1 - Derive d'uree, son procede de production, et produit pharmaceutique contenant ce derive d'uree - Google Patents

Derive d'uree, son procede de production, et produit pharmaceutique contenant ce derive d'uree Download PDF

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WO2001032610A1
WO2001032610A1 PCT/JP2000/007571 JP0007571W WO0132610A1 WO 2001032610 A1 WO2001032610 A1 WO 2001032610A1 JP 0007571 W JP0007571 W JP 0007571W WO 0132610 A1 WO0132610 A1 WO 0132610A1
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group
carbon atoms
formula
salt
atom
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Japanese (ja)
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Akihiko Okuyama
Satoru Ikegami
Tatsuhiro Harada
Tatsuya Maruyama
Yuzuru Matsumura
Naoya Nagata
Hideto Fukui
Kyouko Fujimoto
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Kaken Pharmaceutical Co., Ltd.
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Priority to AU79612/00A priority Critical patent/AU7961200A/en
Publication of WO2001032610A1 publication Critical patent/WO2001032610A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
    • C07C275/20—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C07C275/24—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
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    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/26—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/42—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C335/04—Derivatives of thiourea
    • C07C335/14—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C335/04—Derivatives of thiourea
    • C07C335/16—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C335/04—Derivatives of thiourea
    • C07C335/16—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C335/22—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • the present invention relates to a novel perea derivative, a method for producing the same, a pharmaceutical containing the perea derivative, and a therapeutic method for administering the perea derivative. More specifically, the present invention provides
  • the present invention relates to a medicament useful as an evening gonist, and a method for treating a disease through cell adhesion, which comprises administering the above-mentioned (Cho) perea compound or a salt thereof.
  • the adhesion phenomenon is indispensable for complex life phenomena caused by cell-cell interactions such as cell activation, migration, proliferation, and differentiation.
  • cell-cell or cell-extracellular matrix interactions involve cell adhesion molecules classified as integrin, immunoglobulin, selectin, cadherin, and the like. Integrins have a single heterodimer structure and fall into three major groups:> 51,? 2 and / or? 3 subfamilies.
  • VLA-4 integrin VLA-4 (hi 4 ⁇ 1)
  • integrin VLA-4 hi 4 ⁇ 1
  • lymphocytes eosinophils, basophils, and monocytes
  • VCAM-1 Fibronectin is the ligand. That is, VLA-4 plays an important role in cell-cell and cell-extracellular matrix interactions through VCAM-1 and fibronectin.
  • C Leukocytes function in inflamed tissues. Requires that white blood cells circulating in the blood must pass through endothelial cells and invade sites of inflammation.
  • VLA-4 and VCAM-1 binding is one of the most important mechanisms for strong adhesion between leukocytes and vascular endothelium. Inflammation such as T lymphocytes, B lymphocytes, monocytes and eosinophils Sex cells express VLA-4, and the VLA-4Z VCAM-1 mechanism is strongly involved in the invasion of these cells into inflammatory lesions. Adhesion molecules also play an important role in cell activation through cell-cell interaction, and the VCAM-1 / VLA-4 mechanism activates eosinophils to cause degranulation. Signaling via 4 has been shown to be involved in lymphocyte-specific proliferative activity o
  • VCAM-1 / VLA-4 mechanism in inflammation and the like, attempts have been made to inhibit the binding between these molecules by using a monoclonal antibody.
  • anti-VLA-4 monoclonal antibodies inhibit the attachment of VLA-4 expressing Ramos cells to human umbilical vein vascular endothelial cells (HUVEC) and VCAM-1 transgenic COS cells.
  • VLA-4 cell adhesion by VLA-4 plays a role in rheumatoid arthritis, nephritis, diabetes, systemic lupus erythematosus, late-onset allergy, multiple sclerosis, atherosclerosis, organ transplantation and various malignancies It was shown to fulfill.
  • VLA-4 blockade by an appropriate antagonist is effective for the treatment of the above-mentioned various diseases including inflammatory diseases.
  • VLA-4 antagonists Low molecular weight conjugates have already been proposed as VLA-4 antagonists. These compounds are disclosed in Patent Publications W096 / 22966, W097 / 03094, W098 / 04247, W099 / 61421, W098 / 538 U, W098 / 53817, W098 / 53818, W099 / 20272, W099 / 25685, W099 / 26615, W099 / 26921, W09 9/26922, W099 / 26923, W099 / 64395, W099 / 06390 3 W099 / 06431 3 W099 / 06432 3 W099 / 0643 3, W099 / 06434, W099 / 06435, W099 / 06436, W099 / 06437, W099 / 10312 ⁇ W099 / 10313, WOOO / 21929, W000 / 48988, W
  • VLA-4 antagonists with desirable properties for use in therapy and prophylaxis was desired. Indication during the light
  • a first object of the present invention is to provide a novel compound exhibiting VLA-4 antagonistic action which is excellent in oral absorption and in vivo kinetics.
  • the second object is to provide a method for efficiently producing this compound.
  • a third object is to provide a medicament useful as a VLA-4 antagonist containing the above compound as an active ingredient
  • a fourth object is to provide a disease through cell adhesion to which the above compound is administered. It is to provide a method of treatment.
  • the present inventors have conducted intensive studies to achieve the above object, and as a result, have found that a (thio) pera compound having a specific structure or a salt thereof has an excellent VLA-4 anion gonist action. Then, they found that they can be manufactured efficiently by a specific process, and based on this finding, completed the present invention.
  • the first object of the present invention is to provide a compound represented by the general formula (I):
  • R 1 represents a hydrogen atom, an alkyl group, a cycloalkyl group or an arylalkyl group
  • X represents a hydrogen atom, a halogen atom, an alkyl group, an aryl group, an arylsulfamoyl group or an arylamide group
  • Y represents oxygen.
  • R 1 is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, and a cycloalkyl group having 3 to 7 carbon atoms.
  • X represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms, or an arylsulfamoyl group having 6 to 10 carbon atoms.
  • R 2 independently represents the same meaning as R 1 above, and R 3 and R 4 each independently represent a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a carboxyl group, a carbon number of 1 Alkyl group having 10 to 10 carbon atoms, cycloalkyl group having 3 to 7 carbon atoms, alkoxy group having 1 to 6 carbon atoms, aryl group having 6 to 10 carbon atoms, aryl alkyl group having 7 to 13 carbon atoms, and 2 to 7 carbon atoms An alkoxycarbonyl group, an alkylthio group having 1 to 4 carbon atoms, an alkylsulfonyl group having 1 to 4 carbon atoms, an alkylsulfinyl group having 1 to 4 carbon atoms, — NR 2 ° R 21 , -NR 22 COR 23 or — NR 22 S0 in 2 R 23 (wherein, R zo,
  • R ⁇ R 8 , R 9 and R 1Q each independently represent a hydrogen atom or an alkyl group having 16 carbon atoms, and q represents an integer of 0 to 3.
  • q represents an integer of 0 to 3.
  • R 11 represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms
  • R 12 represents a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a carboxyl group, and an alkyl group having 1 to 0 carbon atoms.
  • a second object of the present invention is to (1) General formula (II-1)
  • Production Method I A method for producing a urea derivative represented by the following formula (hereinafter referred to as Production Method I):
  • a third object of the present invention is to provide a VLA-4 antenna composed of a perrea derivative represented by the general formula (I) or a salt thereof, and an optical system represented by the general formula (I-a)
  • a VLA-4 antagonist composed of an active urea derivative or a salt thereof, a pharmaceutical composition containing the urea derivative represented by the general formula (I) or a salt thereof as an active ingredient, and a pharmaceutical composition represented by the general formula (Ia): This is achieved by a pharmaceutical composition containing the optically active urea derivative or a salt thereof as an active ingredient.
  • a fourth object of the present invention is to provide a perrea derivative represented by the general formula (I) or a salt thereof, an optically active urea derivative represented by the general formula (Ia) or a salt thereof, — It is achieved by a method for treating a disease through cell adhesion, which comprises administering a 4th party gonist or the aforementioned pharmaceutical thread.
  • the urea derivative referred to in the present invention means a (thio) rare compound, that is, both a rare compound and a thiourea compound.
  • the perylene derivative of the present invention or a salt thereof has the general formula (I) ⁇ en
  • (Cho) is a rare compound or a salt thereof.
  • R 1 represents a hydrogen atom, an alkyl group, a cycloalkyl group or an arylalkyl group. Specifically, it represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms or an arylalkyl group having 7 to 13 carbon atoms.
  • X represents a hydrogen atom, a halogen atom, an alkyl group, an aryl group, an arylsulfamoyl group or an arylamide group.
  • R 2 independently represents the same meaning as R 1 above, and R 3 and R 4 each independently represent a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a carboxyl group, and a carbon atom of 1 Alkyl group having 10 to 10 carbon atoms, cycloalkyl group having 3 to 7 carbon atoms, alkoxy group having 1 to 6 carbon atoms, aryl group having 6 to 10 carbon atoms, aryl alkyl group having 7 to 13 carbon atoms, 2 to 7 carbon atoms An alkoxycarbonyl group, an alkylthio group having 1 to 4 carbon atoms, an alkylsulfonyl group having 1 to 4 carbon atoms, an alkylsulfinyl group having 1 to 4 carbon atoms, one NR 20 R 21 , — NR 22 COR 23 or one NR 22 S0 2 R 23 (wherein, R 20 , R 21 ,
  • Y represents an oxygen atom or a sulfur atom.
  • R 5 is an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an aryl group having 6 to 10 carbon atoms, ?
  • R ⁇ R 8 , R 9 and R 1Q each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and q represents an integer of 0 to 3.
  • q represents an integer of 0 to 3.
  • R 11 represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms
  • R 12 represents a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a carboxyl group, an alkyl group having 1 to 10 carbon atoms, An alkoxy group having 1 to 6 carbon atoms, — NR 29 R 3 °, -NR 31 COR 32 or one NR 31 S0 2 R 32 (wherein R 29 , R 3 °, R 31 and R 32 are each Independently has the same meaning as R 2Q .
  • S and r are each independently an integer from 0 to 3. ].
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • alkyl group having 1 to 10 carbon atoms include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a sec-butyl group, Examples thereof include linear or branched alkyl groups such as n-pentyl, tert-amyl, 3-methylbutyl, neopentyl, n-hexyl, n-octyl, and n-decyl.
  • cycloalkyl group having 3 to 7 carbon atoms examples include a cyclobutyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group.
  • alkoxy group having 1 to 6 carbon atoms include methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, tert-butoxy group, sec-butoxy group, n Linear or branched alkoxy groups such as —pentyloxy group, tert-amyloxy group, 3-methylbutoxy group, neopentyloxy group and n-hexyloxyl group.
  • aryl group having 6 to 10 carbon atoms refers to an unsubstituted or 1 to 3 substituted carbon number 6 to: monocyclic or bicyclic aromatic hydrocarbon group having L 0, and specific examples thereof include: Examples include phenyl, 0-tolylyl, 2-methoxyphenyl, 3-chlorophenyl, 11-naphthyl, 2-naphthyl and the like.
  • substituents examples include an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, an aryloxy group having 6 to 10 carbon atoms, an alkylamino group having 1 to 6 carbon atoms, and a carbon atom having 1 to 6 carbon atoms. And an alkylamide group having 6 to 6 carbon atoms or an arylamide group having 6 to 10 carbon atoms.
  • the “C 6-10 aryloxy group” refers to an unsubstituted or 1-3-substituted monocyclic or bicyclic aromatic hydrocarbon group having 6-10 carbon atoms, and specific examples thereof include: Phenoxy, 3-chlorophenoxy or 1-naphthyloxy And so on.
  • substituent include an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, an aryloxy group having 6 to 10 carbon atoms, an alkylamino group having 1 to 6 carbon atoms, and a carbon number.
  • Examples thereof include an alkylamide group having 1 to 6 or an arylamide group having 6 to 10 carbon atoms.
  • alkylamino group having 1 to 6 carbon atoms include straight-chain or branched alkylamino groups such as a methylamino group, an ethylamino group, an isopropylamino group, an n-butylamino group, a dimethylamino group and a getylamino group. And an alkylamino group.
  • alkylamide group having 1 to 6 carbon atoms include linear or branched alkylamide groups such as an acetamido group, an n-butylamide group, a tert-butylamide group, and an n-hexylamide group. can give.
  • arylamide group having 6 to 10 carbon atoms refers to an amide group having an unsubstituted or 1 to 3 substituted monocyclic or bicyclic aromatic hydrocarbon group having 6 to 10 carbon atoms, Specific examples include a benzamide group, a 3-chlorobenzamide group, and a 1-naphthylamide group.
  • substituents examples include an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, an aryloxy group having 6 to 10 carbon atoms, an alkylamino group having 1 to 6 carbon atoms, Examples thereof include an alkylamide group having 1 to 6 carbon atoms and an arylamide group having 6 to 10 carbon atoms.
  • arylsulfamoyl group having 6 to 10 carbon atoms refers to an unsubstituted or 1 to 3 substituted monocyclic aromatic hydrocarbon sulfamoyl group having 6 to 10 carbon atoms.
  • substituents examples include an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, an aryloxy group having 6 to 10 carbon atoms, an alkylamino group having 1 to 6 carbon atoms, and a carbon number.
  • substituents include alkylamide groups of 1 to 6 or arylamide tombs of 6 to 10 carbon atoms.o
  • C1-C13 arylalkyl refers to an unsubstituted or 1-3-substituted monocyclic or bicyclic araliphatic hydrocarbon group having 7-13 carbon atoms.
  • benzyl group phenethyl group, 1-phenylethyl group, 1-phenyl Examples include a propyl group, a 1-naphthylmethyl group and a 2-naphthylmethyl group.
  • substituents examples include an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, an aryloxy group having 6 to 10 carbon atoms, an alkylamino group having 1 to 6 carbon atoms, and a carbon number.
  • substituents include an alkylamide group having 1 to 6 or an arylamide group having 6 to 10 carbon atoms.
  • alkoxycarbonyl group having 2 to 7 carbon atoms examples include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, sec-butoxycarbonyl and the like. Or a straight-chain or branched alkoxycarbonyl group such as a tert-butoxycarbonyl group.
  • alkylthio group having 1 to 4 carbon atoms include linear groups such as methylthio group, ethylthio group, n-propylthio group, isopropylthio group, n-butylthio group, sec-butylthio group and tert-butylthio group. Or a branched alkylthio group.
  • alkylsulfonyl group having 1 to 4 carbon atoms include a methanesulfonyl group, an ethanesulfonyl group, an n-propylsulfonyl group, an isopropylsulfonyl group, an n-butylsulfonyl group, and a sec-butylsulfonyl group. Or a straight-chain or branched alkylsulfonyl group such as a tert-butylsulfonyl group.
  • alkylsulfinyl group having 1 to 4 carbon atoms include a methanesulfinyl group, an esulfinyl group, an n-propylsulfinyl group, an isopropylsulfinyl group, an n-butylsulfinyl group, a sec-butylsulfinyl group and the like. And a straight-chain or branched alkylsulfinyl group such as a tert-butylsulfinyl group.
  • heteroaryl group having 2 to 10 carbon atoms refers to a 5- to 10-membered monocyclic or 5-membered monocyclic or ring containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom.
  • Basic Throw refers to a 5- to 10-membered monocyclic or 5-membered monocyclic or ring containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom.
  • heteroarylalkyl group having 3 to 11 carbon atoms refers to a nitrogen atom in the ring: a 5- to 10-membered monocyclic ring containing 1 to 3 hetero atoms selected from an oxygen atom or a sulfur atom or Represents an alkyl group having a bicyclic heterocyclic ring, and specific examples thereof include a furylmethyl group, a chenylmethyl group, an imidazolylmethyl group, a thiazolylmethyl group, a benzofuranylmethyl group, a benzimidazolylmethyl group, and a benzoxoxa group. Zolylmethyl group and the like.
  • the compound of the present invention represented by the general formula (I) has at least one asymmetric carbon, and has two or more asymmetric carbons in a racemic form, an individual optically active substance, and a molecule. In some cases, any of the diastereoisomers is included. When a geometric isomer is present, it includes any of the (E) -form, the (Z) -form and mixtures thereof. In these, the general formula (I- a)
  • the optically active substance represented by is particularly preferable.
  • R 1 is preferably a hydrogen atom
  • X is preferably an arylamide group
  • the salt of the compound of the present invention represented by the general formula (I) is not particularly limited as long as it is a pharmacologically acceptable salt.
  • a salt with an inorganic base examples thereof include salts with mechanical acids, salts with inorganic acids, and salts with amino acids.
  • Examples of the salt with an inorganic base include an alkali metal salt such as a sodium salt and a potassium salt, and an ammonium salt.
  • Examples of the salt with an organic base include a triethylamine salt, a pyridine salt, an ethanolamine salt, a cyclohexylamine salt, and a dicyclohexylamine salt.
  • salts with organic acids include formate, acetate, tartrate, maleate, succinate, methanesulfonate, and the like.
  • salts with inorganic acids include hydrochlorides, hydrobromides, nitrates and the like.
  • salts with amino acids include glycine salt, alanine salt, arginine salt, glutamate, and aspartate.
  • This reaction is usually performed in the presence of an inorganic or organic base.
  • Suitable inorganic bases include sodium bicarbonate, sodium carbonate, carbonated sodium carbonate, sodium hydroxide, potassium hydroxide, and the like.
  • Preferred organic bases include triethylamine, N, N-diisopropylethylamine. Min, 4-methylmorpholine, pyridine and the like.
  • the reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, and the reaction is carried out in water, methanol, ethanol, isopropyl alcohol, tetrahydrofuran, dioxane or a mixed solvent thereof.
  • the reaction temperature is not particularly limited, and the reaction is usually performed at 0 to 100 ° C, and the reaction time is preferably 2 to 10 hours. Manufacturing method H
  • R represents a lower alkyl group
  • X, Y, ⁇ , and * represent the same meaning as described above.
  • step 1 a compound represented by the general formula (II-12) or a salt thereof, a compound represented by the general formula (IV) is reacted with a reagent for introducing a carbonyl group or a thiocarbonyl group.
  • a reagent for introducing a carbonyl group or a thiocarbonyl group is reacted with a reagent for introducing a carbonyl group or a thiocarbonyl group.
  • a compound represented by the general formula (1-2) As the lower alkyl group represented by R, a methyl group and an ethyl group can be preferably exemplified.
  • Examples of the reagent for introducing a carbonyl group include carbonyldiimidazole, triphosgene, and phosgene, and examples of the reagent for introducing a thiocarbonyl group include thiocarbonyldiimidazole and thiophosgene.
  • This reaction can be performed in the presence of a base depending on the type of the raw material. Suitable bases in this case include pyridine, triethylamine, ⁇ , ⁇ -diisoprovirethylamine, ⁇ -methylmorpholine and the like.
  • the reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, but dichloromethane, dichloroethane, chloroform, tetrahydrofuran, dioxane and the like are preferable.
  • the reaction temperature is not particularly limited, and the reaction is usually performed at 0 to 100 ° C, and the reaction time is preferably 2 to 10 hours.
  • step 2 the compound (1-2) obtained as described above is hydrolyzed under alkaline conditions to produce a compound (1-3).
  • This alkaline strip The hydrolysis treatment under the conditions may use a known method, and examples of the aqueous solution include lithium hydroxide, sodium hydroxide, and potassium hydroxide.
  • the reaction solvent is not particularly limited as long as it is an organic solvent miscible with water, but is preferably methanol, ethanol, tetrahydrofuran, dimethoxyethane, or a mixed solvent thereof.
  • the reaction temperature is not particularly limited, and is usually 0 to: 0 CTC, and the reaction time is preferably 30 minutes to 3 hours.
  • the compound of the present invention produced by the above-mentioned production method can be produced as a free compound, a salt thereof, a hydrate thereof, or various solvates such as ethanolate or a polymorphic substance.
  • the pharmacologically acceptable salt of the compound of the present invention can be produced by a conventional salt formation reaction. Isolation and purification are performed by applying chemical operations such as extraction fractionation, crystallization, and various types of fractional chromatography.
  • the optical isomer can be converted to a stereochemically pure isomer by selecting an appropriate starting compound or by an optical resolution method of a racemic compound.
  • the amino compound (Z, H) represented by the general formula (V-1) used as one of the raw materials for producing the compound of the present invention is represented by the following reaction formula:
  • R 5 represents the same meaning as described above, and R 33 represents a hydrogen atom, an alkyl group having 1 to 9 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an aryl group having 6 to 10 carbon atoms or a carbon atom.
  • Prime? Represents ⁇ reel alkyl group of ⁇ 12, R 34 is a hydrogen atom, ⁇ alkyl group having 1 to 9 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, Ariru group having 6 to 10 carbon atoms, carbon number?
  • the compound represented by the general formula (V-1) or a salt thereof is a compound represented by the general formula (V-2) or a salt thereof, and a compound represented by the general formula (V-3): It can be produced by a reductive amination reaction. This reaction is usually performed in the presence or absence of an acid, and the acid is preferably an organic or inorganic acid, and examples thereof include formic acid, acetic acid, trifluoroacetic acid, and P-toluenesulfonic acid.
  • the reducing agent include palladium, zinc, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and the like.
  • the reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, but methanol, ethanol, isopropanol, ethyl acetate, benzene, toluene, xylene and the like are preferable.
  • the reaction temperature is not particularly limited, and the reaction is usually performed at 0 to 100 ° C., and the reaction time is preferably 1 to 12 hours.
  • the urea derivative of the present invention or a salt thereof exhibits excellent VLA-4 antagonistic action, and is used for treatment or prevention of a disease caused by leukocyte adhesion and infiltration or a disease in which a VLA-4 dependent adhesion process plays a role.
  • a disease caused by leukocyte adhesion and infiltration or a disease in which a VLA-4 dependent adhesion process plays a role For example, rheumatoid arthritis, nephritis, inflammatory bowel disease, systemic lupus erythematosus, inflammatory diseases of the central nervous system, asthma, allergies (late allergies, etc.), multiple sclerosis Disease, cardiovascular disease, arteriosclerosis, diabetes, various malignancies, prevention of damage to transplanted organs, inhibition of tumor growth or metastasis, and the like.
  • the compounds of the present invention can be administered orally or parenterally (eg, intravenous injection, subcutaneous injection, rectal administration, etc.), and may be systemic or topical. Of these, oral administration is desirable.
  • the dosage form is also not particularly limited and can be conveniently selected depending on the administration route. For example, tablets, troches, sublingual tablets, dragees, capsules, pills, powders, granules, solutions, emulsions, syrups Preparations, inhalants, eye drops, nasal drops, injections, suppositories and the like. These preparations are prepared by blending organic or inorganic solid or liquid excipients, preservatives, wetting agents, emulsifiers, stabilizers, solubilizing agents, and other pharmacologically acceptable additives. be able to.
  • the dose of the compound of the present invention may be appropriately determined depending on conditions such as the administration subject, administration route, and symptoms.
  • the compound of the present invention as an active ingredient is usually administered in a single dose.
  • L 0 mg / kg preferably The dose may be in the range of 1 to 3 OmgZkg, and it is preferably administered once to three times a day.
  • TMS tetramethylsilane
  • Me is a methyl group
  • Et is an ethyl group
  • Pr is a propyl group
  • Bu is a butyl group
  • Ph is a phenyl group
  • Ac is an acetyl group
  • Ms is a methanesulfonyl group
  • Boc is represents a t-butoxycarbonyl group.
  • Step 1 Isobutyraldehyde (2.3 ml, 32.6 mol) was added to a benzene solution (200 ml) of aniline (2.0 g, 21.5 mmol), and the mixture was refluxed with heating for 3 hours. After the reaction, the solvent was concentrated under reduced pressure. Next, the obtained residue was dissolved in methanol (20 ml), sodium borohydride (0.82 g, 21.6 mmol) was added at 0 ° C, and the mixture was stirred for 3 hours.
  • Step 3 3- [4- (2,6-dicyclobenzoylamino) phenyl] -12 (S) -1- (3-isobutyl-13-phenylthioureide) produced in Step 2 Methyl propionate
  • methanol-Z tetrahydrofuran volume ratio 1: 1, 2 ml
  • lml sodium hydroxide aqueous solution
  • Step 1 To a solution of triphosgene (38 mg, 0.13 mmol 1) in dichloromethane (2 ml) at 0 ° C. was added 4- (2,6-dichlorobenzenebenzoylamino) 1 L-phenyl-2-alanine methyl ester (0.1%). A solution of 14 g, 0.38 mmol) and N, N-diisopropylethylamine (0.08 ml, 0.42 mmol) in dichloromethane (3 ml) was slowly added dropwise over 30 minutes.
  • N-isobutylaniline (85 mg, 0.38 mmol 1) prepared in Step 1 of Example 1 and N, N-diisoprovirethylamine (0.08 ml, 0.42 mmol) were prepared.
  • a dichloromethane solution (2 ml) of 1) was added, and the mixture was stirred at room temperature for 2 hours.
  • the solvent was concentrated under reduced pressure, ethyl acetate (20 ml) was added to the residue, and the mixture was washed with an aqueous solution of potassium hydrogen sulfate (20 ml), an aqueous solution of sodium hydrogen carbonate (20 ml) and saturated saline, and sulfuric acid was removed. Dried over magnesium.
  • Step 2 3- [4- (2,6-dicyclobenzoylamino) phenyl] —2
  • Example 24 In the same manner as in Example 23, the results are shown in Examples 24-26, 76-80, 82-: 103, 105-: 116, 118, 150-155, 174, 176, 187 and 206-208.
  • the compound was prepared. Table 1, Table 2, Table 3, Table 4, Table 5, and Table 7 show the physical properties of the obtained compound.
  • Step 1 To a solution of (S) — 1-phenylethylamine (10.9 g, 90 mmol) in ethyl acetate (60 ml), add isobutyraldehyde (7.1 g, 9 Ommo) 1), acetic acid (0.5 ml) and anhydrous magnesium sulfate (20 g) were added, and the mixture was stirred for 4 hours. After the reaction, the inorganic salts were filtered through celite. At C, sodium borohydride (5. lg, 135 mmo 1) was added, and the mixture was stirred at room temperature for 3 hours.
  • Step 1 Isobutyraldehyde in a solution of 1,2,3,4-tetrahydro-1-naphthylamine (1.0 g, 7.0 mmol) in methanol (40 ml) at 0 ° C
  • Step 2 In the same manner as in Step 2 of Example 1, 3- [4-1 (2,6-dichlorobenzoylamino) phenyl] -2 (S)-[3-isobutyl-3- (1,2, ⁇ ) , 4-tetrahydronaphthylene 11-yl) thioperide] methyl ester propionate was prepared. The physical properties are shown below.
  • Step 3 The title compound was produced in the same manner as in Step 3 of Example 1.
  • the physical properties are shown below.
  • Step 1 In the same manner as in Step 1 of Example 23, 3- [4- (2,6-dichlorobenzenebenzoylamino) phenyl] -2 (S) -1- [3-isobutyl-1-3- (1 (S)- H Enylethyl) [Reid] Probionic acid methyl ester was produced. The physical properties are shown below.
  • Step 2 The title compound was produced in the same manner as in Step 2 of Example 23.
  • Step 1 In the same manner as in Step 1 of Example 23, 3- [4- (2,6-dichroic benzoylamino) phenyl] -2 (S) 1- [3-isobutyl-1-3- (1,2,3 , 4-Tetrahydronaphthyl-1-yl) perido] propionic acid methyl ester was prepared. The physical properties are shown below. ' ⁇
  • Step 2 The title conjugate was produced in the same manner as in Step 2 of Example 23. The physical properties are shown below.
  • Step 1 To a solution of t-butoxycarbone-l-alanine (0.28 g, 1.5 mmol 1) in dimethylformamide (10 ml) at 0 ° 0, add 1 ⁇ -thiophen-2-ylmethylbenzylamine (0 ° C). 0.30 g, 1.5 mmol), 1-hydroxybenztriazole (0.40 g, 3. Ommo 1) and N-methylmorpholine (0.23 g, 2. lmmo 1) were added, and then 1-ethyl 3- (3-Dimethylaminopropyl) carbodiimide hydrochloride (0.34 g, 1.8 mmol) was added, and the mixture was stirred at room temperature for 12 hours. After the reaction, the solvent was concentrated under reduced pressure.
  • Step 2 [11- (benzylthiophene-2-ylmethylcarbamoyl) ethyl]
  • t-butyl ester of rubambanic acid (0.36 g, 96 mmol 1)
  • ethyl acetate 7 ml
  • hydrochloric acid / ethyl acetate 7 ml
  • the solvent was concentrated under reduced pressure, and the obtained residue was dissolved in methanol (20 ml).
  • Isobutyl aldehyde (70 mg, 1 mmol) and sodium triacetoxyborohydride (0.
  • Step 3 In the same manner as in Step 1 of Example 23, 2 (S) — [3- [1 (S) — (benzylthiophene-2-ylmethylcarbamoyl) ethyl] -13-isobutyl dirad] —3— [4- (2,6-Dichlorobenzoylamino) phenyl] propionic acid methyl ester was produced. The physical properties are shown below.
  • Step 1 To a solution of t-butoxycarbone-l-alanine (0.50 g, 2.6 mmo 1) in tetrahydrone (20 ml) at 0 ° C. was added N-methylmorpholine (0.38 g, 3.2 mmo 1). ) was added, and isobutyl chromate formate (0.38 g, 2.8 mmol) was added dropwise, followed by stirring for 30 minutes. After stirring, a solution of diisobutylamine (0.51 g, 3.9 mmol) in tetrahydrofuran (5 ml) was added, and the mixture was stirred at room temperature for 3 hours.
  • Step 2 N, N-Diisobutyl-2 (S) -isobutylaminobution pionamide was produced in the same manner as in Step 2 of Example 117.
  • the physical properties are shown below.
  • Step 4 The title compound was produced in the same manner as in Step 2 of Example 23.
  • the physical properties are shown below.
  • Step 1 To a solution of N, N-diisobutyl-12 (S) -isobutylaminobrobianamide (0.22 g, 0.8 mmol) prepared in Example 119 (Step 2) in tetrahydrone (10 ml) was added: A solution of borane-dimethylsulfide complex in tetrahydrofuran (1.2 ml, 0.9 mmol) was added, and the mixture was heated under reflux for 10 hours. After the reaction, add chloroform (20 ml), add sodium bicarbonate (30 ml) and saturate After washing with brine (30 ml), the organic layer was dried over magnesium sulfate. After drying, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain N, N, N 5 , -triisobutylpropane 1:: -diamine (0.12 g, yield 57%).
  • Step 2 In the same manner as in Step 1 of Example 23, 3- [4- (2,6-dichlorobenzoylamino) phenyl] -2 (S) — [3- (2-diisobutylamino-1 (S) — Methylethyl) -3-isobutylureide] Probionic acid methyl ester was produced. The physical properties are shown below.
  • Step 1 In the same manner as in Step 2 of Example 1, 3- [4- (2,6-dichlorobenzenebenzoylamino) phenyl] -1 2 (S)-[(3,4-dihydroquinoline-1-yl) Monocarbothioyl) amino] Probionic acid methyl ester was produced.
  • the physical properties are shown below.
  • Step 2 The title compound was produced in the same manner as in Step 3 of Example 1. Physical properties are shown below.
  • Step 1 3- [4- (2,6-Dichroic benzoylamino) phenyl] —2 (S) — [(2,3,4,5-tetrahydrobenzazebine) in the same manner as in Step 1 of Example 23. — 1-ylcarbonyl) amino] Probionic acid methyl ester was produced. The physical properties are shown below.
  • Step 2 The title compound was produced in the same manner as in Step 2 of Example 23.
  • the physical properties are shown below.
  • the inhibitory activity of the compound of the present invention on the adhesion between Chinese hamster ovary cells (CH0 cells) transfected with human VCAM-1 gene and human promyelocytic cells expressing VLA-4 ⁇ HL-60 cells was determined by the following method. Was evaluated using
  • FCS BCECF labeled HL-60 cell suspension solution 180 ⁇ 1 was resuspended in 4 X 1 0 6 cells / ml in free RPMI1640 medium, the test substance solution at various concentrations in 2 0 1 Dzu' 3 7 added Pre-treat for 5 minutes.
  • the pretreated HL-60 cells are layered on a 96-well plate in which VCAM-1 expressing CH0 cells have been cultured, 2 ⁇ 10 5 per well and adhered at 37 ° C. for 5 minutes.
  • the cells are disrupted by adding PBS containing 1% by weight of NP-40, and the fluorescence intensity of the resulting supernatant is measured with a cytoFluor 2300 fluorescence measurement system (Millipore).
  • the test results were obtained by measuring the number of cells adhering to VCAM-1 expressing CH0 cells by the addition of the control and test substances using a calibration curve created from the measurement of standards, and calculating the cell adhesion inhibition rate (%) by the following formula. .
  • Cell adhesion inhibition rate (%) 100 X [1-(Number of adherent cells in test substance added group)
  • Table 8 shows the 50% inhibitory concentrations of the compounds of the present invention obtained in this test.
  • Table 8-1 Example No., 50 ⁇ 1 ⁇ 2 inhibitory concentration (nM)
  • the urea derivative of the present invention or a salt thereof exhibits excellent VLA-4 antagonistic action, and is used for VLA such as a disease caused by leukocyte adhesion and infiltration or a disease in which a VLA-4 dependent adhesion process plays a role. It is useful as a medicament for treating or preventing diseases mediated by 4.

Abstract

La présente invention concerne un dérivé d'urée représenté par la formule générale (I), ou un de ses sels. Dans la formule (I): R1 est hydrogène, alkyle, etc.; X est hydrogène, halogéno, alkyle aryle, arylamide, etc.; Y est oxygène ou soufre; et Z est un groupe hydrocarbure ou hétérocycle contenant un atome d'azote par lequel Z est lié à l'atome de carbone de C=Y. Le dérivé d'urée ou son sel est un nouveau composé ayant une activité d'antagoniste de VLA-4, et est utile dans un produit pharmaceutique en tant qu'antagoniste de VLA-4.
PCT/JP2000/007571 1999-10-29 2000-10-27 Derive d'uree, son procede de production, et produit pharmaceutique contenant ce derive d'uree WO2001032610A1 (fr)

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Cited By (21)

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WO2002014272A1 (fr) * 2000-08-09 2002-02-21 Kaken Pharmaceutical Co., Ltd. Derives de (thio)uree, procede de production correspondant et medicaments contenant ces derives
WO2002022563A1 (fr) * 2000-09-14 2002-03-21 Toray Industries, Inc. Derive d'uree et inhibiteur de molecule adhesive contenant celui-ci en tant que substance active
WO2003068753A1 (fr) * 2002-02-14 2003-08-21 Ono Pharmaceutical Co., Ltd. Composes a noyau fusionne contenant n-carbamoyle azote et medicaments contenant ces composes comme ingredients actifs
WO2004099126A1 (fr) * 2003-05-05 2004-11-18 Almirall Prodesfarma Sa Derives de n-(2-phenylethyl)sulfamide entant qu'antagonistes de l'integrine $g(a)4
US6960597B2 (en) 2000-06-30 2005-11-01 Orth-Mcneil Pharmaceutical, Inc. Aza-bridged-bicyclic amino acid derivatives as α4 integrin antagonists
EP1500650A4 (fr) * 2002-04-26 2006-08-23 Ishihara Sangyo Kaisha Composes pyridine ou sels de ces derniers et herbicides les contenant
US9351954B2 (en) 2009-12-04 2016-05-31 Sunovion Pharmaceuticals Inc. Multicyclic compounds and methods of use thereof
US9388161B2 (en) 2013-11-18 2016-07-12 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
US10196403B2 (en) 2016-07-29 2019-02-05 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US10377769B2 (en) 2013-11-18 2019-08-13 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US10780074B2 (en) 2017-08-02 2020-09-22 Sunovion Pharmaceuticals Inc. Compounds and uses thereof
US10815249B2 (en) 2018-02-16 2020-10-27 Sunovion Pharmaceuticals Inc. Salts, crystal forms, and production methods thereof
US11077090B2 (en) 2016-07-29 2021-08-03 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US11116760B2 (en) 2018-10-30 2021-09-14 Gilead Sciences, Inc. Quinoline derivatives
US11129807B2 (en) 2017-02-16 2021-09-28 Sunovion Pharmaceuticals Inc. Methods of treating schizophrenia
US11136304B2 (en) 2019-03-14 2021-10-05 Sunovion Pharmaceuticals Inc. Salts of a heterocyclic compound and crystalline forms, processes for preparing, therapeutic uses, and pharmaceutical compositions thereof
US11174256B2 (en) 2018-10-30 2021-11-16 Gilead Sciences, Inc. Imidazopyridine derivatives
US11179383B2 (en) 2018-10-30 2021-11-23 Gilead Sciences, Inc. Compounds for inhibition of α4β7 integrin
US11224600B2 (en) 2018-10-30 2022-01-18 Gilead Sciences, Inc. Compounds for inhibition of alpha 4 beta 7 integrin
US11578069B2 (en) 2019-08-14 2023-02-14 Gilead Sciences, Inc. Compounds for inhibition of α4 β7 integrin
US11738002B2 (en) 2020-04-14 2023-08-29 Sunovion Pharmaceuticals Inc. Methods of treating neurological and psychiatric disorders

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Cited By (34)

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Publication number Priority date Publication date Assignee Title
US6960597B2 (en) 2000-06-30 2005-11-01 Orth-Mcneil Pharmaceutical, Inc. Aza-bridged-bicyclic amino acid derivatives as α4 integrin antagonists
WO2002014272A1 (fr) * 2000-08-09 2002-02-21 Kaken Pharmaceutical Co., Ltd. Derives de (thio)uree, procede de production correspondant et medicaments contenant ces derives
WO2002022563A1 (fr) * 2000-09-14 2002-03-21 Toray Industries, Inc. Derive d'uree et inhibiteur de molecule adhesive contenant celui-ci en tant que substance active
WO2003068753A1 (fr) * 2002-02-14 2003-08-21 Ono Pharmaceutical Co., Ltd. Composes a noyau fusionne contenant n-carbamoyle azote et medicaments contenant ces composes comme ingredients actifs
US7368444B2 (en) 2002-02-14 2008-05-06 Ono Pharmaceutical Co., Ltd. N-carbamoyl nitrogen-containing fused ring compounds and drugs containing these compounds as the active ingredient
EP1500650A4 (fr) * 2002-04-26 2006-08-23 Ishihara Sangyo Kaisha Composes pyridine ou sels de ces derniers et herbicides les contenant
WO2004099126A1 (fr) * 2003-05-05 2004-11-18 Almirall Prodesfarma Sa Derives de n-(2-phenylethyl)sulfamide entant qu'antagonistes de l'integrine $g(a)4
JP2006525271A (ja) * 2003-05-05 2006-11-09 アルミラル プロデスファルマ ソシエダッド アノニマ インテグリンα４アンタゴニストとしてのＮ−（２−フェニルエチル）スルファミド誘導体
US10085968B2 (en) 2009-12-04 2018-10-02 Sunovion Pharmaceuticals Inc. Multicyclic compounds and methods of use thereof
US9351954B2 (en) 2009-12-04 2016-05-31 Sunovion Pharmaceuticals Inc. Multicyclic compounds and methods of use thereof
US10894033B2 (en) 2009-12-04 2021-01-19 Sunovion Pharmaceuticals Inc. Multicyclic compounds and methods of use thereof
US10336722B2 (en) 2013-11-18 2019-07-02 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
US9388161B2 (en) 2013-11-18 2016-07-12 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
US10377769B2 (en) 2013-11-18 2019-08-13 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US10611750B2 (en) 2013-11-18 2020-04-07 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as bet bromodomain inhibitors
US10703764B2 (en) 2013-11-18 2020-07-07 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US11111229B2 (en) 2013-11-18 2021-09-07 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
US11084831B1 (en) 2013-11-18 2021-08-10 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US11958862B2 (en) 2016-07-29 2024-04-16 Sumitomo Pharma America, Inc. Compounds and compositions and uses thereof
US10196403B2 (en) 2016-07-29 2019-02-05 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US10927124B2 (en) 2016-07-29 2021-02-23 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US11077090B2 (en) 2016-07-29 2021-08-03 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US11129807B2 (en) 2017-02-16 2021-09-28 Sunovion Pharmaceuticals Inc. Methods of treating schizophrenia
US11491133B2 (en) 2017-08-02 2022-11-08 Sunovion Pharmaceuticals Inc. Heteroaryl-isochroman compounds and uses thereof
US10780074B2 (en) 2017-08-02 2020-09-22 Sunovion Pharmaceuticals Inc. Compounds and uses thereof
US10815249B2 (en) 2018-02-16 2020-10-27 Sunovion Pharmaceuticals Inc. Salts, crystal forms, and production methods thereof
US11440921B2 (en) 2018-02-16 2022-09-13 Sunovion Pharmaceuticals Inc. Salts, crystal forms, and production methods thereof
US11116760B2 (en) 2018-10-30 2021-09-14 Gilead Sciences, Inc. Quinoline derivatives
US11174256B2 (en) 2018-10-30 2021-11-16 Gilead Sciences, Inc. Imidazopyridine derivatives
US11179383B2 (en) 2018-10-30 2021-11-23 Gilead Sciences, Inc. Compounds for inhibition of α4β7 integrin
US11224600B2 (en) 2018-10-30 2022-01-18 Gilead Sciences, Inc. Compounds for inhibition of alpha 4 beta 7 integrin
US11136304B2 (en) 2019-03-14 2021-10-05 Sunovion Pharmaceuticals Inc. Salts of a heterocyclic compound and crystalline forms, processes for preparing, therapeutic uses, and pharmaceutical compositions thereof
US11578069B2 (en) 2019-08-14 2023-02-14 Gilead Sciences, Inc. Compounds for inhibition of α4 β7 integrin
US11738002B2 (en) 2020-04-14 2023-08-29 Sunovion Pharmaceuticals Inc. Methods of treating neurological and psychiatric disorders

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