WO2002014272A1 - Derives de (thio)uree, procede de production correspondant et medicaments contenant ces derives - Google Patents

Derives de (thio)uree, procede de production correspondant et medicaments contenant ces derives Download PDF

Info

Publication number
WO2002014272A1
WO2002014272A1 PCT/JP2001/006833 JP0106833W WO0214272A1 WO 2002014272 A1 WO2002014272 A1 WO 2002014272A1 JP 0106833 W JP0106833 W JP 0106833W WO 0214272 A1 WO0214272 A1 WO 0214272A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
carbon atoms
alkyl group
hydrogen atom
atom
Prior art date
Application number
PCT/JP2001/006833
Other languages
English (en)
Japanese (ja)
Inventor
Hideto Fukui
Satoru Ikegami
Akihiko Okuyama
Original Assignee
Kaken Pharmaceutical Co., Ltd.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Kaken Pharmaceutical Co., Ltd. filed Critical Kaken Pharmaceutical Co., Ltd.
Priority to AU2001277720A priority Critical patent/AU2001277720A1/en
Publication of WO2002014272A1 publication Critical patent/WO2002014272A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic 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
    • C07D213/02—Heterocyclic 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
    • C07D213/04—Heterocyclic 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
    • C07D213/60—Heterocyclic 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/16—Central respiratory analeptics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • 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
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs 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

Definitions

  • the present invention relates to a novel (thio) urea derivative, a method for producing the same, a drug containing the (thio) urea derivative, and a therapeutic method for administering the (thio) perrea derivative. More specifically, the present invention relates to a novel (thio) peria derivative or a salt thereof exhibiting VLA-4 antagonistic action, a method for efficiently producing the same, and a method for effectively producing the (thio) peria derivative or a salt thereof.
  • the present invention relates to a medicament useful as a VL A-4 amino gonist, which is contained as an ingredient, and a method for treating a disease through cell adhesion, which comprises administering the (thio) perrea derivative 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 integrins, immunoglobulins, selectins, cadherins, and the like. Integrins have a single heterodimeric structure and fall into one of three main groups: the subfamilies of / 1, ⁇ 2 and / 53.
  • VLA protein one of which, integrin VL A-4 ( ⁇ 4-1), is expressed on lymphocytes, eosinophils, basophils and monocytes, and — 1 and fibronectin are ligands. That is, VLA-4 plays an important role in VCAM-1 and fibronectin-mediated cell-cell and cell-extracellular matrix interactions.
  • circulating leukocytes In order for leukocytes to function in inflamed tissue, circulating leukocytes must pass through endothelial cells and infiltrate the site of inflammation.
  • VLA-4 and VCAM-1 binding is most critical for strong adhesion between leukocytes and vascular endothelium. This is one of the key mechanisms. Inflammatory cells such as T lymphocytes, B lymphocytes, monocytes and eosinophils express VLA-4, and VLA-4 / VCAM-1 mechanism is strongly involved in the invasion of these cells into inflammatory foci. I have. The adhesion molecules also play an important role in cell activation through cell-cell interaction, and the VLA-4 / VCAM-1 mechanism activates eosinophils to cause degranulation. VLA-4 mediated signaling has also been shown to be involved in i) W-specific proliferation activation of lymphocytes.
  • 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 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, arteriosclerosis, 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 A peptide compound or a peptide-like compound has been proposed as an antagonist, but all of these compounds have problems such as lack of bioavailability in oral administration and easy degradability in vivo. Dots are left. Therefore, a VLA-4 antagonist with desirable properties for therapeutic and prophylactic use was desired. Censoring the launch
  • 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) perrea derivative 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, an arylalkyl group or a heterocyclic alkyl group
  • X 1 represents a single bond or a formula
  • R 2 and R 3 each independently represent the same meaning as described above, and A 1 represents an oxygen atom, a sulfur atom or —NR 4 — (wherein, R 4 has the same meaning as R 1 ) And A 2 represents a carbonyl group, a thiocarbonyl group, a sulfonyl group, or — (CH 2 ) p 1 (wherein, P represents an integer of 0 to 5).
  • X 2 represents a group represented by the formula:
  • R 5 and R 6 are each independently a hydrogen atom, a substituent having no organic group, a bond directly to a carbon atom of a heterocyclic ring, or an oxygen atom
  • RRR 11 and R 12 represent the same it independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms,:.
  • R represents an integer of 0-3) or formula
  • R 13 and R 14 represent the same meaning as R 1, and s and t each independently represent an integer of 0 to 3.
  • a second object of the present invention is to provide a compound represented by the general formula (II)
  • a third object of the present invention is to provide a medicament containing the (thio) perrea derivative represented by the above general formula (I) or a salt thereof as an active ingredient, and a pharmaceutical composition comprising the (thio) urea derivative or a salt thereof. Achieved by the inclusion of VL A-4 as an ingredient.
  • a fourth object of the present invention is to provide a cell adhesion comprising administering the (thio) urea derivative represented by the general formula (I) or a salt thereof, the drug or the VLA-4 antagonist. Is achieved by a method of treating a disease as described above.
  • the (thio) peria derivative means both a perrea derivative and a thioperea derivative. ⁇ for transportation
  • R 1 represents a hydrogen atom, an alkyl group, a cycloalkyl group, an arylalkyl group or a heterocyclic alkyl group.
  • a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, and a 7 to 7 carbon atoms Represents an arylalkyl group of 13 or a heterocyclic alkyl group having 1 to 6 carbon atoms.
  • X 1 is a single bond or a formula
  • R 3 independently represent the same meaning as H 1 above, and ⁇ 1 represents an oxygen atom, a sulfur atom or one NR 4 _ (wherein, R 4 has the same meaning as R 1 A 2 represents a carbonyl group, a thiocarbonyl group, a sulfonyl group or 1 (CH 2 ) p ⁇ (where p represents an integer of 0 to 5). ].
  • X 2 is the formula
  • R 5 and R 6 each independently represent a hydrogen atom, a substituent having no organic group, a bond directly to a carbon atom of a heterocycle, or an oxygen atom. , a sulfur atom, O alkoxycarbonyl group, a hydrocarbon group bonded through a sulfonyl group or a sulfinyl group, one NR 15 R 16, - NR 15 COR 16 or a NR 15 S 0 2 R 16
  • R 15 and R 16 each independently represent a hydrogen atom, a hydrocarbon group, a hydrocarbyloxy group, a heterocyclic group or a heterocyclic alkyl group.
  • R 5 and R 6 are each independently a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a carboxyl group, an alkyl group having 1 to 6 carbon atoms, and a cycloalkyl having 3 to 7 carbon atoms.
  • alkoxy group having 1 to 6 carbon atoms aryl group having 6 to 10 carbon atoms, arylalkyl group having 7 to 13 carbon atoms, aryl alkoxy group having 7 to 13 carbon atoms, carbon number 2-7 alkoxycarbonyl group, an alkylthio group having 1 to 4 carbon atoms, an alkylsulfonyl group having 1 to 4 carbon atoms, alkylsulfinyl group having 1-4 carbon atoms, one NR 15 R 16, one NR 15 COR 16 or a NR 15 SO 2 R 16 (wherein, R 15 and R 16 are each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, and a cyclo group having 3 to 7 carbon atoms.
  • Y represents an oxygen atom or a sulfur atom.
  • Z is one NR 7 R 8 wherein R 7 and R 8 are each independently a hydrogen atom, a hydrocarbon group, a heterocyclic group, a heterocyclic alkyl group, — CR 17 R 18 — (CH 2 ) q— CONR ls R 20 , — CR 17 R 18 — (CH 2 ) q — NR 19 COR 2 .
  • R 17 and R 18 are each independently a hydrogen atom, an alkyl group, a cycloalkyl group, a hydroxyalkyl group, an aminoalkyl group, an arylalkyl group or a heterocyclic alkyl R 19 , R 2fl and R 21 each independently represent the same meaning as R 15 , V represents a carbonyl group or a thiocarpoxyl group, and q represents an integer of 0 to 5.
  • R 9 , R 1D , R 11 and R 12 each independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, and r represents an integer of 0 to 3) or
  • R 13 and R 14 have the same meaning as R 1, and s and t each independently represent an integer of 0 to 3.
  • R 7 and R 8 are each independently a hydrogen atom and a carbon number:! 6 to 6 alkyl groups, 3 to 7 carbon atoms, cycloalkyl group, 6 to 10 carbon atoms, aryl group, carbon number? ⁇ 13 aryl alkyl Group, a heterocyclic group, heterocyclic alkyl group to the 1 to 6 carbon atoms, -CR l7 R 18 - (CH 2) q- CONR 19 R 2. , — CR 17 R 18 — (CH 2 ) q — NR 13 COR 2 .
  • R 17 and R 18 are each Independently, a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a hydroxyalkyl group having 1 to 5 carbon atoms, an amino amino group having 1 to 5 carbon atoms, and 7 to 13 carbon atoms Represents an arylalkyl group or a heterocyclic alkyl group having 1 to 6 carbon atom
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • alkyl group having 1 to 6 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, and a n-butyl group.
  • Examples include a linear or branched alkyl group such as a pentyl group, a tert-amyl group, a 3-methylbutyl group, a neopentyl group, and an n-hexyl group.
  • cycloalkyl group having 3 to 7 carbon atoms include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group.
  • alkoxyl 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 alkoxyl groups such as —pentyloxy group, tert-amyloxy group, 3-methylbutoxy group, neopentyloxy group and n-hexyloxy group.
  • hydroxyalkyl group having 1 to 5 carbon atoms include hydroxymethyl And a 1-hydroxyethyl group, a 2-hydroxyethyl group and a hydroxypropyl group.
  • aminoalkyl group having 1 to 5 carbon atoms include an aminomethyl group, a 2-aminoethyl group, a 3-aminopropyl group, and a 4-aminobutyl group.
  • the amino group may be substituted, and examples of the substituent include a methyl group, an ethyl group, a benzyl group, an acetyl group, a benzoyl group, a methoxycarbonyl group, a benzyloxycarbonyl group, and a tert-butoxycarbonyl group. And the like.
  • the “aryl group having 6 to 10 carbon atoms” refers to a mono- or di-substituted aromatic hydrocarbon group having 6 to: L 0 unsubstituted or 1 to 3 substituted carbon atoms. Phenyl, 0-tolyl, 2-methoxyphenyl, 3-chlorophenyl, 11-naphthyl, 2-naphthyl and the like. Examples of the substituent include an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, and an aryloxy group having 6 to 10 carbon atoms.
  • C7-C13 arylalkyl group refers to an unsubstituted or 1-3-substituted monocyclic or bicyclic araliphatic hydrocarbon group having 7-13 carbon atoms. Examples thereof include a benzyl group, a phenethyl group, a 1 (S) -phenylethyl group, a 1 (R) -phenylethyl group, a 1-phenylpropyl group, a 1-naphthylmethyl group, a 2-naphthylmethyl group and the like.
  • the aromatic ring of the araliphatic hydrocarbon may combine with the aliphatic chain to form a ring, and specific examples thereof include an indanyl group, and a 1,2,3,4-tetrahydronaphthyl group.
  • the substituent include an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, and an aryloxy group having 6 to 10 carbon atoms.
  • arylalkoxy group having 7 to 13 carbon atoms means an unsubstituted or 1 to 3 substituted carbon atom having 7 to: monocyclic or bicyclic aromatic hydrocarbon alkoxyl group having L3.
  • Examples include benzyloxy, 1-phenylethoxy, 2-phenylethoxy, 1-phenylpropoxy, 1-naphthylmethoxy, 2-naphthylmethoxy, and the like.
  • substituent include an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, and a carbon atom having 6 to 10 carbon atoms.
  • Aryloxy group and the like are examples of the substituent.
  • aryloxy group having 6 to 10 carbon atoms refers to an unsubstituted or 1 to 3 substituted monocyclic or bicyclic aromatic hydrocarbon group having 6 to 10 carbon atoms.
  • Examples include phenoxy, 2-methylphenoxy, 4-methoxyphenoxy, 3,5-dichlorophenoxy, 11-naphthyloxy, 2-naphthyloxy, and the like.
  • Examples of the substituent include an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, and a halogen atom.
  • alkoxycarbonyl group having 2 to 7 carbon atoms examples include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, sec-butoxycarbonyl, tert- A linear or branched alkoxycarbonyl group such as a butoxycarbonyl group is exemplified.
  • alkylthio group having 1 to 4 carbon atoms include straight-chain 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 methanesulfonyl group, ethanesulfonyl group, n-propylsulfonyl group, isopropylsulfonyl group, n-butylsulfonyl group, sec-butylsulfonyl group, A straight-chain or branched alkylsulfonyl group such as a tert-butylsulfonyl group is exemplified.
  • alkylsulfinyl group having 1 to 4 carbon atoms include a methanesulfinyl group, an ether sulfinyl group, an ⁇ -propylsulfinyl group, an isopropylsulfinyl group, an ⁇ -butylsulfinyl group, a sec-butylsulfinyl group, Examples thereof include a linear or branched alkylsulfinyl group such as a tert-butylsulfinyl group.
  • Hetero group refers to a 5- to 7-membered monocyclic heterocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom or a sulfur atom in a ring.
  • Furyl, chenyl, imidazolyl, thiazolyl, oxazolyl Examples include a pyridyl group, a bilazinyl group, a vilolidinyl group, a piperidinyl group, a piperazinyl group, a homopiperazinyl group, a morpholinyl group, and a dioxanyl group.
  • a bicyclic or tricyclic fused heterocyclic group in which the monocyclic heterocyclic ring and a benzene ring or the monocyclic heterocyclic ring are fused and specific examples thereof include a benzofuranyl group, a benzothenyl group, an indolyl group, and a benzimidazolyl group.
  • substituents include an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, an aryloxy group having 6 to 10 carbon atoms, a hydroxyl group, And an amino group.
  • substituent include an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, an aryloxy group having 6 to 10 carbon atoms, a hydroxyl group, And an amino group.
  • heterocycle an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, an aryloxy group having 6 to 10 carbon atoms, a hydroxyl group, And an amino group.
  • heterocyclic alkyl group having 1 to 6 carbon atoms refers to an alkyl group having 1 to 6 carbon atoms substituted with the above “heterocyclic group”, and specific examples thereof include imidazolylmethyl group and indolyl Examples include a methyl group, a benzothiazolylmethinole group, a pyridinolemethyl group, a 1-pyridylethyl group, a 2-pyridylethyl group, a 3-phenylphenyl group, and a 2-pyridinoethyl group.
  • any of its racemate, diastereoisomer and individual optically active compound is included in the present invention. Yes, and when geometric isomers are present, the (E) -form, the (Z) -form and mixtures thereof are all included in the present invention.
  • 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 a salt with an organic base, an organic acid And salts with inorganic acids and salts with amino acids.
  • the salt with an inorganic base include an alkali metal salt such as a sodium salt, a potassium salt, and a calcium 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, a dicyclohexylamine salt, and the like.
  • salts with organic acids include formate, acetate, tartrate, maleate, succinate, and methanesulfonate.
  • salts with inorganic acids include hydrochlorides, hydrobromides, nitrates and the like.
  • Examples of the salt with an amino acid include glycine salt, alanine salt, arginine salt, glutamate, and aspartate.
  • the thio (uree) derivative of the present invention represented by the general formula (I) can be efficiently produced by the method of the present invention described below. That is, according to the method of the present invention, general formula (II)
  • the (thio) urea derivative of the present invention can be obtained by the following production method 1 and production method 2.
  • Compound (1-1) can be produced by the reaction of the following steps 1 and 2.
  • Step 1 compound ( ⁇ -1-a) can be produced by reacting compound ( ⁇ ), compound (III) and a reagent for introducing a thiocarbonyl group.
  • the reagent for introducing a thiocarbonyl group include thiocarbonyldiimidazole and thiophosgene.
  • the reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, but dichloromethane, dichloroethane, tetrahydrofuran 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 3 to 72 hours.
  • Step 2 the compound ( ⁇ -1-a) obtained in Step 1 is treated under alkaline conditions.
  • the compound (1-1) can be produced by the following hydrolysis reaction.
  • a known reaction may be used for the hydrolysis reaction under alkaline conditions, and examples of the aqueous solution include lithium hydroxide, sodium hydroxide, potassium hydroxide and the like.
  • 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 the like.
  • the reaction temperature is not particularly limited, and is usually 0 to: L 0 ° C, and the reaction time is preferably 30 minutes to 3 hours. '
  • Compound (1-2) (wherein, X 1 , X 2 , Y, Z, R 1 and R have the same meanings as described above.)
  • Compound (1-2) is produced by the reaction of the following steps 1 and 2. can do.
  • Step 1 compound (1-2-a) can be produced by reacting compound (II), compound (III) and a reagent for introducing a carbonyl group.
  • the reagent for introducing a carbonyl group include carbonyldiimidazole, triphosgene and phosgene. This reaction is usually performed in the presence of a base. Suitable bases include pyridine, triethylamine, N, N-diisopro Pyruetylamine, N-methylmorpholine and the like.
  • the reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, and preferred are dichloromethane, dichloroethane, chloroform, tetrahydrofuran, dioxane and the like.
  • the reaction temperature is not particularly limited, and the reaction is usually performed at 0 to 100 ° C, and the reaction time is preferably 30 minutes to 24 hours.
  • Step 2 compound (1-2) can be produced from compound (I-2-a) obtained in step 1 by the same reaction as in step 2 of production method 1.
  • Z is - if it is NHR 7, for example can be the production of (Chio) Urea derivatives of the present invention by the production method 3 below.
  • Compound (1-3) or a salt thereof can be produced by reacting compound (II-1) or a salt thereof with compound (IV). This reaction is usually performed in the presence of an inorganic or organic base. Suitable inorganic bases include sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, and the like. Preferred organic bases include triethylamine, N, N-diisopropylethylamine, —Methylmorpholine, pyridine and the like.
  • the reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, but 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.
  • the (thio) perrea derivative of the present invention produced by the above-mentioned production method is a free compound, It is isolated and purified as various solvates such as salts, hydrates or ethanol solvates, or crystalline polymorphs.
  • the pharmacologically acceptable salt of the (thio) perylene derivative 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 obtained as a stereochemically pure isomer by selecting an appropriate starting compound or by optical resolution of a racemic compound.
  • the (Cho) perrea derivative of the present invention or a salt thereof exhibits excellent VLA-4 antagonistic action, and is 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 the treatment or prophylaxis of, for example, autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, Scheigren's syndrome, and various organ inflammations, asthma, and atby associated therewith.
  • autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, Scheigren's syndrome, and various organ inflammations, asthma, and atby associated therewith.
  • Allergic diseases such as atopic dermatitis, nasal congestion, rhinitis, inflammatory bowel diseases including Crohn's disease, nephritis, hepatitis, inflammatory diseases of the central nervous system, cardiovascular diseases, arteriosclerosis, diabetes, various Malignant tumors, prevention of transplanted organ damage, prevention of tumor growth or metastasis, etc.
  • the (thio) perrea derivative or a salt thereof of the present invention is administered systemically or locally by a method such as oral, intravenous injection, subcutaneous injection, or rectal administration, with oral administration being preferred.
  • the dosage form can be conveniently selected according to the route of administration, for example, tablets, troches, sublingual tablets, dragees, capsules, pills, powders, granules, solutions, emulsions, syrups, inhalants Preparations, eye drops, nasal drops, injections, suppositories and the like.
  • These preparations can be produced by mixing excipients, preservatives, wetting agents, emulsifiers, stabilizers, dissolution aids and the like.
  • the dose of the (thio) perrea derivative or a salt thereof of the present invention may be appropriately determined depending on conditions such as the administration subject, administration route and symptoms. For example, when administered orally to an adult patient, it is effective.
  • the compound of the present invention is usually administered in a single dose of about 0.1 to 10 Omg / kg, preferably 1 to 3 OmgZkg, and it is preferable to administer 1 to 3 times. .
  • H-NMR proton nuclear magnetic resonance
  • Et represents an ethyl group
  • Pr represents a propyl group
  • Bu represents a butyl group
  • Ph represents a phenyl group.
  • Step 1 To a solution of triphosgene (53 mg, 0.18 mmol 1) in dichloromethane (2 ml) at 0 ° C. was added 4-[(3,5-dichloropyridine-1-4-carbonyl) amino] 1-L-phenylalanine A dichloromethane solution (2 ml) of methyl ester (200 mg, 0.54 mmol) and N, N-diisopropylethylamine (0.12 ml, 0.70 mmol) was added dropwise over 20 minutes.
  • Step 2 3- [4 — [(3,5-dichloropyridine-14-carbonyl) amino] phenyl] 1-2 (S) — [3-isobutyl-3— [1 (S) — obtained in Step 1 [Phenylethyl] perido] Propionic acid methyl ester (217 mg, 0.38 mmo 1) is dissolved in methanol (4 ml) and tetrahydrofuran (1 ml), and a 2 mol / l aqueous lithium hydroxide solution (1.34 ml, 2.63 mmo 1) is dissolved. Was added and stirred at room temperature for 1 hour.
  • Step 1 4-[(3,5-Dichloromouth pyridine 4-carbonyl) amino] 1 L 1-Fenylalanine methyl ester (98 mg, 0.27 mmol) in tetrahydrofuran (1.5 ml) ), Add thiocarbonyldiimidazole (52 mg, 0.29 mmo 1), stir at room temperature for 2 hours, and add N-isobutyl-1 (S) -phenylethylamine (57 mg, 0.32 mmo 1) was added and the mixture was stirred for 48 hours.
  • Step 2 3- [4-[(3,5-Dichloropyridine-4-carbonyl) amino] phenyl] obtained in Step 1 1 2 (S) 1 [3-Isoptyl-3- [1 (S)- [Phenylethyl] thioperido] Propionic acid methyl ester (145 mg, 0.25 mmo 1) was dissolved in methanol (4 ml), and a 2 mol / l lithium hydroxide aqueous solution (0.62 ml, 1.23 mmo 1) was added. Time stirring did. After the reaction, pH was adjusted to 3 by adding 2 mol ZL hydrochloric acid at 0 C, and the solvent was concentrated under reduced pressure. Water was added to the residue, and the mixture was collected by filtration to give the title compound (11 mg, 78%) as a pale-yellow powder. The physical properties are shown below.
  • the inhibitory activity of the compounds of the present invention on the adhesion between Chinese hamster ovary cells (CH0 cells) transfected with human VCAM-1 gene and human promyelocytic cell line HL-60 cells expressing VLA-4 is shown below. Was evaluated using the method described above.
  • the HL-60 cells were resuspended in 0.4% by weight of serum albumin (BSA) -containing phenol-containing solution, and 5M of 2 ', 7'-bis (, carboxyethyl) -5 (6) -carboxyfluorescein penta acetoxymethyl Label with the addition of ester (BCECF-AM).
  • BSA serum albumin
  • BCECF-AM 2 ', 7'-bis (, carboxyethyl) -5 (6) -carboxyfluorescein penta acetoxymethyl Label with the addition of ester
  • VCAM - 1 expression CH0 cells and 2 chi [pi) 5 or layer per well in 96-well plates were cultured, adhere for 5 minutes at 37 ° C. Then weigh the plate 0.4 weight. /. Fill with BSA Hank's solution, cover with plates, invert the plate, and incubate for another 15 minutes. After washing, the cells are destroyed by adding PBS containing 1% by weight of NP-40, and the fluorescence intensity of the obtained supernatant is measured using a cytoFluor OO fluorescence measurement system (Millipore).
  • test results were obtained by measuring the number of cells adhering to VCAM-1 expressing CH0 cells by adding a control substance and a test substance using a calibration curve created from the measurement of the standard. calculate.
  • Table 6 shows the 50% inhibitory concentration of the compound of the present invention obtained in this test.
  • Table 6 Example 50% inhibitory concentration (nM)
  • the (thio) perrea derivative of the present invention or a salt thereof exhibits an excellent VLA-4 antagonistic action, and plays a role in diseases caused by leukocyte adhesion and infiltration or in a VLA-4 dependent adhesion process. It is useful as a medicament for treating or preventing a disease mediated by VLA-4, such as a disease.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Pulmonology (AREA)
  • Diabetes (AREA)
  • Rheumatology (AREA)
  • Hematology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Urology & Nephrology (AREA)
  • Neurology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Endocrinology (AREA)
  • Transplantation (AREA)
  • Obesity (AREA)
  • Biomedical Technology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Neurosurgery (AREA)
  • Vascular Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Emergency Medicine (AREA)
  • Dermatology (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des dérivés de (thio)urée de formule générale (I) ou des sels desdits composés, ainsi qu'un procédé de production de ces dérivés ou de ces sels. Dans cette formule, chaque symbole est tel que défini dans la description. Ces dérivés ou ces sels sont des nouveaux composés présentant un antagonisme VLA-4. Ils peuvent être utilisés dans des médicaments comme antagonistes VLA-4.
PCT/JP2001/006833 2000-08-09 2001-08-08 Derives de (thio)uree, procede de production correspondant et medicaments contenant ces derives WO2002014272A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001277720A AU2001277720A1 (en) 2000-08-09 2001-08-08 (thio)urea derivatives, process for their production and medicines containing the derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2000-241657 2000-08-09
JP2000241657 2000-08-09

Publications (1)

Publication Number Publication Date
WO2002014272A1 true WO2002014272A1 (fr) 2002-02-21

Family

ID=18732817

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2001/006833 WO2002014272A1 (fr) 2000-08-09 2001-08-08 Derives de (thio)uree, procede de production correspondant et medicaments contenant ces derives

Country Status (2)

Country Link
AU (1) AU2001277720A1 (fr)
WO (1) WO2002014272A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
EP1500650A1 (fr) * 2002-04-26 2005-01-26 Ishihara Sangyo Kaisha, Ltd. Composes pyridine ou sels de ces derniers et herbicides les contenant

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997036859A1 (fr) * 1996-03-29 1997-10-09 G.D. Searle & Co. Derives d'acide phenylpropanoique para-substitues, utilises comme antagonistes de l'integrine
JP2000344748A (ja) * 1999-03-29 2000-12-12 Welfide Corp ３−芳香族置換プロピオン酸またはアクリル酸化合物
WO2001014328A2 (fr) * 1999-08-20 2001-03-01 Merck & Co., Inc. Urees substituees inhibiteurs d'adhesion cellulaire
WO2001032610A1 (fr) * 1999-10-29 2001-05-10 Kaken Pharmaceutical Co., Ltd. Derive d'uree, son procede de production, et produit pharmaceutique contenant ce derive d'uree

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997036859A1 (fr) * 1996-03-29 1997-10-09 G.D. Searle & Co. Derives d'acide phenylpropanoique para-substitues, utilises comme antagonistes de l'integrine
JP2000344748A (ja) * 1999-03-29 2000-12-12 Welfide Corp ３−芳香族置換プロピオン酸またはアクリル酸化合物
WO2001014328A2 (fr) * 1999-08-20 2001-03-01 Merck & Co., Inc. Urees substituees inhibiteurs d'adhesion cellulaire
WO2001032610A1 (fr) * 1999-10-29 2001-05-10 Kaken Pharmaceutical Co., Ltd. Derive d'uree, son procede de production, et produit pharmaceutique contenant ce derive d'uree

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1500650A1 (fr) * 2002-04-26 2005-01-26 Ishihara Sangyo Kaisha, Ltd. Composes pyridine ou sels de ces derniers et herbicides les contenant
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

Also Published As

Publication number Publication date
AU2001277720A1 (en) 2002-02-25

Similar Documents

Publication Publication Date Title
JP6299591B2 (ja) ソマトスタチン受容体作動活性を有する化合物およびその医薬用途
JP6323629B1 (ja) Ｅｐ４拮抗薬と免疫チェックポイント阻害薬を含んでなる組み合わせ
US7402580B2 (en) Fused pyridazine derivative compounds and drugs containing these compounds as the active ingredient
KR20150128891A (ko) 인돌아민 2,3-디옥시게나제 (ido)의 억제제
CA2548849A1 (fr) Inhibiteurs de phenylamide et de pyridylamide de la beta-secretase, traitant la maladie d'alzheimer
US20040259897A1 (en) Spiro-hydantoin compounds useful as anti-inflammatory agents
KR20140040774A (ko) 이미다조피리딘 화합물
US9714224B2 (en) Heterocyclic compounds and methods of their use
CA2765678A1 (fr) Acides hydroxamiques substitues et leurs utilisations
WO2001032610A1 (fr) Derive d'uree, son procede de production, et produit pharmaceutique contenant ce derive d'uree
EP1535906A1 (fr) Composes contenant de l'azote
WO2006001463A1 (fr) Composé ayant une activité de liaison aux récepteurs s1p et utilisation de celui-ci
US10584116B2 (en) Heterocyclic sulfonamide derivative and medicine containing same
KR20150082616A (ko) 디히드로피라졸 gpr40 조절제
WO2019158070A1 (fr) Antagoniste du récepteur a2a et/ou a2b
CA3201054A1 (fr) Nouveaux composes en tant qu'inhibiteurs doubles du recepteur des androgenes et de la phosphodiesterase
JPWO2003024933A1 (ja) ２−フェニル−３−ヘテロアリールプロピオン酸誘導体またはその塩、それを用いた医薬
EA015974B1 (ru) Производные пирролизина, индолизина и хинолизина, их получение и их применение в терапии
JP2022546414A (ja) Ｐｅｒｋ阻害ピロロピリミジン化合物
WO2018028491A1 (fr) Inhibiteurs indoamine2, 3-dioxygénase et leurs utilisations en pharmacie
EP1667635A2 (fr) Sulfonylaminovalerolactames et leurs derives utilises comme inhibiteurs du facteur xa
WO2006095822A1 (fr) Compose sulfonamide et produit pharmaceutique le contenant
WO2002014272A1 (fr) Derives de (thio)uree, procede de production correspondant et medicaments contenant ces derives
CA3178647A1 (fr) Amides tricycliques substitues, analogues de ceux-ci et procedes les mettant en oeuvre
JP2002363163A (ja) ベンズアゼピン誘導体

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
ENP Entry into the national phase

Ref country code: JP

Ref document number: 2002 519417

Kind code of ref document: A

Format of ref document f/p: F

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase