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WO2001098301A1 - Composes de pyrazolopyridine et utilisation de ces derniers en tant que medicaments - Google Patents

Composes de pyrazolopyridine et utilisation de ces derniers en tant que medicaments Download PDF

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Publication number
WO2001098301A1
WO2001098301A1 PCT/JP2001/005187 JP0105187W WO0198301A1 WO 2001098301 A1 WO2001098301 A1 WO 2001098301A1 JP 0105187 W JP0105187 W JP 0105187W WO 0198301 A1 WO0198301 A1 WO 0198301A1
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Prior art keywords
group
amino
urea
isopropyl
pyridin
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PCT/JP2001/005187
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English (en)
Japanese (ja)
Inventor
Hisashi Kawasaki
Koichi Ozawa
Kazuhiko Yamamoto
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Japan Tobacco Inc
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Japan Tobacco Inc
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Priority claimed from JP2000185067A external-priority patent/JP2004123537A/ja
Priority claimed from JP2001070593A external-priority patent/JP2004123539A/ja
Application filed by Japan Tobacco Inc filed Critical Japan Tobacco Inc
Priority to AU2001264313A priority Critical patent/AU2001264313A1/en
Publication of WO2001098301A1 publication Critical patent/WO2001098301A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • 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
    • 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
    • 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 pyrazo′-mouth pyridine compound having a sphingosin-1-phosphate (hereinafter, referred to as “Sph-11-P”) antagonistic activity and a pharmaceutical use thereof. Furthermore, the present invention relates to a therapeutic agent for fibrosis, comprising a compound having Sph-1-P receptor antagonistic activity or a pharmaceutically acceptable salt thereof as an active ingredient. More specifically, the present invention relates to a new conjugate having a therapeutic effect on arterial sclerosis due to fibrosis of the liver, kidney, and lung and hypertrophy of vascular smooth muscle, and a pharmaceutical use thereof.
  • Sph-11-P sphingosin-1-phosphate
  • the lipids that make up the cell membrane are divided into glycemic phospholipids, cholesterol and sphingolipids.
  • the sphingolipids are composed of two major types. It is a variety of glycolipids in which sugar chains such as sphingomyelin, which is one of the main phosphorus essences, and gangliosides are linked to a ceramide skeleton.
  • sphingolipids When sphingolipids are stimulated from the outside, they are degraded in cell membranes or lysosomes by sphingomyelinase or endglycanase by the enzymatic action of sphingomyelinase and converted to ceramide, and further sphingosine by the action of ceramidase. Is metabolized to This sphingosine is phosphorylated at the hydroxyl group of C1 by the action of sphingosine kinase to form Sph-1-1: P. This S ph-1-: P also does not normally accumulate in cells, but is immediately degraded by lyase and converted to phosphoethanolamine and palmitaldehyde. In recent years, attention has been paid to the fact that substances generated in the metabolic degradation pathway of cell membrane sphingolipids are factors that regulate various functions.
  • ceramide and sphingosine are important second messengers for cell proliferation, differentiation and apoptosis. «It has been known for a long time that he is involved in Noh.
  • Sph-1-P was found to be accumulated in platelets that did not contain lyase, a degrading enzyme, and released with activation.
  • the released Sph-1P functions as a cell motility regulator that strongly inhibits PDGF-dependent cell motility of cancer cells such as melanoma cells and vascular smooth muscle cells, or to fibroblasts. It was elucidated to have a growth promoting effect. Furthermore, it has been elucidated that it triggers various complex cellular reactions, releases Ca + from intracellular stores, regulates actin polymerization, inhibits cell death, and regulates the MAP kinase signaling pathway.
  • Sph-1-P acts via extracellular receptors via cell surface
  • the function of so-called intercellular messengers is being elucidated.
  • Sp - 1 one P is to mobilize calcium from sites different from one to the IP 3 in cells
  • pe rtussis toxi n-sensitive G protein-dependent and -independent both cell Organization exist, they It was found that the site of action was mediated not by intracellular cells but by cell surface receptors through activation of MAP kinase and promotion of DA synthesis.
  • Edg-1, Edg-3, Edg-5 (AG Rl6 / H218), Edg-6 and Edg-8 genes have recently been cloned, and these have been identified as specific Sph-1-P Was reported to be a receptor for Subsequent studies have revealed that Edg-5 is specifically distributed in vascular fibres, heart, kidney, lung, liver, and others.
  • the present inventors further conducted a study on Sph-11P, and found that an increase in Edg-5 mRNA level was observed with the progression of the disease state in a disease state model for these organs.
  • the compound represented by is disclosed, but the compound is Sph-1 There is no description that it specifically has an antagonistic effect on P receptors or that it is useful as a therapeutic agent for fibrosis, and there is no disclosure of data suggesting them.
  • the reference discloses a herbicide as a use, but does not disclose and suggest a therapeutic agent for fibrosis.
  • Japanese Patent Application Laid-Open No. 61-197580 discloses that
  • the compounds have specific antagonism to Sph-11P receptor as described in the present application, and they are useful as therapeutic agents for fibrosis. There is no statement at all, nor is there any overnight disclosure suggesting them.
  • the reference discloses a herbicide as a use, but does not disclose and suggest a therapeutic agent for fibrosis.
  • an object of the present invention is to treat a disease associated with the sphingosine-11-monophosphate receptor (Edg-5) by specifically antagonizing the receptor.
  • a disease associated with the sphingosine-11-monophosphate receptor Edg-5
  • the purpose is to do.
  • a birazolopyridine compound represented by the following general formula (1) and a pharmaceutically acceptable salt thereof have been replaced by sufingosine mono-monophosphate. It has been found that hepatic fibrosis, pulmonary fibrosis, renal fibrosis and arteriosclerosis can be treated by specifically antagonizing the receptor (Edg-5), leading to the completion of the present invention.
  • Edg-5 antagonizing the receptor
  • R 1 is hydrogen atom, - 8 alkyl group or - COR 7 (wherein, R 7 is (8 Al kill group, an optionally substituted Ariru group, an optionally substituted Ararukiru group, C i one 6 an alkoxy group, an optionally substituted aryloxy group or a substituted V, which may be an arylalkyloxy group);
  • R 3 represents a hydrogen atom, C ⁇ - 8 alkyl group - 6 alkoxy groups, C 2 - 6 alkoxy force carbonyl haloalkyl group, a C 3 _ 7 cycloalkyl or optionally substituted good I Ariru group;
  • R 4 is a hydrogen atom or an alkyl group
  • R 5 and R 6 are the same or different, a hydrogen atom, an alkyl group, ( ⁇ _ 6 alkoxy group, C 2 - 6 alkoxycarbonyl group, a carboxyl group, C 2 _ 6 alkynyl group, a halogen atom, Shiano group, Nitro group, haloalkyl group, alkylamino di (C ⁇ -salkyl) amino group, acyl group, hydroxyl group, optionally substituted aryloxy group, optionally substituted aralkyloxy group, optionally substituted Good aryl group optionally substituted aralkyl group, alkoxyalkyl group or -CONHR 8 (where R 8 is optionally substituted aryl group or optionally substituted aralkyl group) And;
  • Z is one C—one, one CS—, one CH 2 —, one 0— or a single bond
  • W is -N (R 14 )-(where R 14 is a hydrogen atom, an 8 alkyl group, an optionally substituted aralkyloxycarbonyl, an optionally substituted aryloxy Carbonyl group or heteroarylalkyl group), 10-, 1C
  • Ring A is optionally substituted Ariru group, Heteroari Ichiru group or C 3 - 7 Vila oxazolidinedione compound or a pharmaceutically acceptable salt thereof represented by cycloalkyl is a group].
  • R 1 represents a hydrogen atom, (1 -6 Arukiru group or one €; 01 ⁇ 7 (wherein, R 7 is, C, one 6 Arukinore group, ⁇ Li Ichiru group, Ararukiru CI- e alkoxy group , An aryloxy group or an aralkyloxy group);
  • R 2 is — 6 alkyl or aryl
  • R 3 represents a hydrogen atom, an alkyl group, ( ⁇ _ 6 alkoxy groups, C 2 - be 6 alkoxy force carbonyl group, a haloalkyl group, C 3 _ 7 cycloalkyl group or Ariru group;
  • R 4 is a hydrogen atom or an alkyl A group;
  • R 5 and R 6 are the same or different, a hydrogen atom, - 6 alkyl group, 6 alkoxy group C 2 - 6 alkoxycarbonyl group, a carboxyl group, C 2 - 6 alkynyl group, a halogen atom, Shiano group, a nitro group A haloalkyl group, an alkylamino group, a di-6alkyl) amino group, an acyl group, a hydroxyl group, an aryloxyaralkyloxy group or one C0NHR 8 (where R 8 is an aryl group or an aralkyl group);
  • Z is one CO—, _CS—, one CH 2 —, one 0— or a single bond
  • W is one N (R 14) i (where,: R 14 is a hydrogen atom, (vii 6 alkyl group, Araru Kill O alkoxycarbonyl group, Teroari Ichiru C Bok ⁇ Li one Ruo alkoxycarbonyl group, or the 6 An alkyl group), — 0—, — CO—, —C0NH— (however, the nitrogen atom is bonded to ring A), — CH 2 —, —NHCH 2- (where the carbon atom is bonded to ring A) Is a double bond or a single bond; or is a single bond;
  • Ring A is Ariru group, Heteroariru group or C 3 - a cycloalkyl group, the above SL 1.
  • R 3 is the h-position
  • R 4 is the i-position
  • N (1H—4-Isopropyl-1,3-dimethylbirazolo [3,4-b] pyridin-6-yl) amino-] NT— (2-chloro-6-((4-fluorophenyl) methyl) Pyridine-41-yl) urea,
  • a pharmaceutical composition comprising the pyrazo-mouth pyridine compound of any of 31 to 14 above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a sphingosine 1-1-phosphate receptor antagonist comprising as an active ingredient the birazolopyridine compound of any one of 1 to 14 or a pharmaceutically acceptable salt thereof.
  • a therapeutic agent for fibrosis comprising as an active ingredient the birazolopyridine conjugate of any one of the above 1. to 14. or a pharmaceutically acceptable salt thereof.
  • a therapeutic drug for hepatic fibrosis which comprises an acceptable salt as an active ingredient.
  • a remedy for pulmonary fibrosis comprising as an active ingredient the birazolopyridine compound of any one of 1 to 14 or a pharmaceutically acceptable salt thereof.
  • Sphingosine a therapeutic drug for fibrosis comprising, as an active ingredient, a compound having a 1-phosphate receptor antagonistic activity or a pharmaceutically acceptable salt thereof.
  • the sphingosin-1-phosphate receptor is Edg-5, according to the above item 20.
  • Sphingosine a therapeutic drug for hepatic fibrosis comprising, as an active ingredient, a compound having a monophosphate receptor antagonistic activity or a pharmaceutically acceptable salt thereof.
  • a remedy for pulmonary fibrosis comprising a compound having a sphingosine-11-monophosphate receptor antagonistic activity or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Halogen atom means chlorine atom, bromine atom, fluorine atom and iodine atom.
  • R 5 and R 6 are preferably chlorine atom, fluorine atom, iodine atom or bromine atom
  • ( 8 alkyl group) refers to a linear or branched alkyl group having 1 to 8, preferably 1 to 6 carbon atoms, such as a methyl group, an ethyl propyl group, an isopropynole group, and a butyl group. , Isobutyl group, sec-butyl tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, hexyl group, heptyl group, 3-methylhexyl group or octyl group, and the like.
  • a linear or branched alkyl group having 1 to 4 carbon atoms particularly preferably a methylethyl group or an isopropyl group, preferably a methyl group for R 1 , and a methyl group for R 2 .
  • R 3 is preferably a methyl group, an ethyl group, a tert-butyl group, or an isobutyl group.
  • An ethyl group or an isopropyl group, preferably in R 4 is a methyl group, and preferably a methyl Echiru group in R 6, a propyl group Isopuropiru group, butyl group, isobutyl group, tert - butyl pentyl group, isopentyl group, to A xyl group, a 3-methylhexyl group, a heptyl group or an octyl group, preferably a methyl group or an ethyl group in R 7 , and a C 4 alkyl group (particularly preferably a methyl group) in R 9 ;
  • R 1 1 is ( ⁇ _ 4 alkyl group (particularly preferably a methyl group)
  • R 1 2 is a methyl group
  • R 1 4 is a methyl group.
  • Alkoxy group means a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy.
  • Particularly preferred is a methoxy group or an ethoxy group.
  • R 3 is preferably a methoxy group
  • R 5 and R 6 are preferably a methoxy group or an ethoxy group
  • R 7 is preferably a methoxy group.
  • alkoxyalkyl group is an alkoxyalkyl group in which the alkoxy part has the same meaning as the above-mentioned alkoxy group and the alkyl part has the same meaning as the above-mentioned alkyl group, such as a methoxymethyl group, an ethoxymethyl group, a propoxymethyl group, Butoxymethyl group, pentyloxymethyl group, hexyloxymethyl group, ethoxyxethyl group and the like.
  • R 5 and R 6 are preferably a methoxymethyl group.
  • the "C 2 _ 6 alkoxycarbonyl group” methoxycarbonyl group, Etokishika carbonyl group, propoxy carboxymethyl group, isopropoxycarbonyl group, an alkyl portion or a butoxy carbonyl group, I Su Wu butoxycarbonyl group or a tert- butoxycarbonyl group Represents an alkoxycarbonyl group having 1 to 5 carbon atoms. Preferably, it is a methoxycarbonyl group, an ethoxycarbonyl group or a tert-butoxycarbonyl group.
  • R 3 , R 5 and R 6 are preferably a methoxycarbonyl group, and R 1 Q is preferably a methoxycarbonyl group or an ethoxycarbonyl group.
  • R 12 is preferably a methoxycarbonyl group or a tert-butoxycarbonyl group.
  • haloalkyl group is a group in which the above —8 alkyl group is substituted with the above halogen atom, for example, chloromethyl group, bromomethyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, trichloromethyl group, tribromomethyl group, And a trichloromethyl group, a penfluoromethyl group or a butylmethyl group, preferably a chloromethyl group, a bromomethyl group, a fluoromethyl group, a trifluoromethyl group or a trichloromethyl group. Particularly preferred is a trifluoromethyl group.
  • R 3 , R 5 and R 6 are preferably a trifluoromethyl group or a difluoromethyl group.
  • C 2 _ 6 alkynyl group is a good ⁇ Rukiniru groups be straight or branched having 2 to 6 carbon atoms, for example Echiniru group, propynyl group, heptynyl group, 2-pentynyl group, 3 —Pentynyl group, 2-hexynyl group, 3-hexynyl group and the like, preferably a straight-chain or branched alkynyl group having 2 to 4 carbon atoms.
  • R 5 and R 6 are preferably an ethynyl group.
  • alkylamino group refers to an amino group mono-substituted with an alkyl group having 1 to 8, preferably 1 to 6 carbon atoms, such as a methylamino group, a propylamino group, a propylamino group, and the like. Preferred are a methylamino group and an ethylamino group. R 5 and R 6 are preferably a methylamino group or an ethylamino group.
  • the “di (( ⁇ -8 alkyl) amino group” refers to an amino group disubstituted by an alkyl group having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, such as a dimethylamino group, a getylamino group, propyl amino Jibuchiruamino group, preferably a like Jimechiruamino group or Jechiruamino group. rather preferable in R 5 and R 6 are Jimechiruamino group or Jechiruamino group.
  • acyl group is a formyl group having 1 carbon atom; an alkanoyl group having 2 to 6 carbon atoms (for example, acetyl group, propionyl group, butyryl or bivalonole group, etc.), or 1 to 3 carbon atoms on the aryl group.
  • An arylo group which may have a substituent for example, a benzoyl group and the like; the substituent herein means the same as the substituent of the following “aryl group”.
  • Preferred are a formyl group, an acetyl group, a bivaloyl group and a benzoyl group.
  • R 5 and R 6 are preferably an acetyl group.
  • aryl group is, for example, a phenyl group, a naphthyl group, a biphenyl group or the like, preferably a phenyl group.
  • the aryl group may be substituted by 1 to 3 substituents.
  • the substituent in “may be substituted by 1 to 3 substituents” may be the same or different, and the position of the substituent is arbitrary and is particularly limited. is not.
  • Ci 6 alkyl group eg, methyl group, ethyl group, propyl group, isopropyl group, butyl group, tert-butyl group, etc.
  • hydroxyl group eg, methoxy group, ethoxy group , A propoxy group, a butoxy group, etc.
  • a halogen atom eg, a fluorine atom, a chlorine atom, a bromine atom, etc.
  • a nitro group a cyano group
  • an acyl group eg, a formyl group, an acetyl group, a propionyl group, etc.
  • a mercapto group C DOO 6 alkylthio group (e.g., methylthio group, Echiruchio propylthi
  • cyclopentyl group cyclohexylene
  • a phenyl group an acylamide group (eg, an acetoamide group, a propionylamide group, etc.), and preferably a hydroxyl-Cs alkyl group, a C 6 alkoxy group, a mercapto group, a —6 alkylthio group, a halogen atom, trifluoro Romechiru group, Ashiru group, c 2 _ 6 alkoxy months Boniru a group or Ashiruamido group.
  • an acylamide group eg, an acetoamide group, a propionylamide group, etc.
  • R ⁇ R 2 and R 3 are phenyl groups; preferably at R 8 is phenyl group substituted by phenyl group or a halogen atom (e.g., Puromofue such as a secondary le group), preferably in R 1 3 Substituted by phenyl group or halogen atom Been phenyl group (e.g., Buromofue sulfonyl chloride port Hue group, Jikurorofu etc. Eniru group), preferably in the ring A is a phenyl group, preferably a phenyl group in R 5 and R 6, black hole phenylene A methoxyphenyl group or a methoxycarbonylphenyl group.
  • a halogen atom e.g., Puromofue such as a secondary le group
  • Been phenyl group e.g., Buromofue sulfonyl chloride port Hue group, Jikurorofu
  • the “aralkyl group” means that the aryl moiety is a phenyl group (here, the phenyl group may be substituted by 1 to 3 with the substituent (s) described above for the aryl group), and the alkyl moiety is a carbon atom.
  • An arylalkyl group which is an alkyl group of 1 to 8, preferably 1 to 6, such as a benzyl group, a phenylethyl group, a phenylpropyl group, a phenylbutyl group or a phenylhexyl group; And the like, and preferably a benzyl group or a phenylethyl group.
  • R 7 , RR 12 and R 14 are preferably a benzyl group
  • R 5 and H 6 are preferably a phenylethyl group or a fluorobenzyl group.
  • aryloxy group is an aryloxy group in which the aryl group has the same meaning as the above aryl group, wherein the aryl group is substituted with 1 to 3 substituents described in the above aryl group. Is also good.
  • a phenoxy group, a naphthyloxy group and the like can be mentioned, and a phenoxy group is preferable.
  • R 5 , R 6 and R 7 are preferably a phenoxy group.
  • the “aralkyloxy group” is an aralkyloxy group in which the aryl moiety has the same meaning as the above aryl group, and the alkoxy moiety is an alkoxy group having 1 to 4 carbon atoms.
  • the moiety may be substituted with 1 to 3 substituents described above for the aryl group. Examples thereof include a benzyloxy group, a phenethyloxyphenylpropyloxy group, a phenylbutyloxy group and the like, and a benzyloxy group is preferable.
  • R 5 , R 6 and R 7 are preferably a benzyloxy group or a 2-phenylethyl group.
  • aryloxycarbonyl group is an aryloxycarbonyl group in which the aryl group has the same meaning as the above aryl group, wherein the aryl group is the same as the aryl group described above, and has 1 to 3 substituents. May be done.
  • a phenoxycarbonyl group, a naphthyloxycarbonyl group and the like can be mentioned, and a phenoxycarbonyl group is preferable.
  • R 12 and R 14 are preferably a phenoxycarbonyl group.
  • the “aralkyloxycarbonyl group” is an aralkyloxycarbonyl group in which the aryl moiety is the same as the above aryl group, and the alkoxy moiety is an alkoxy group having 1 to 4 carbon atoms.
  • the aryl portion may be substituted with 1 to 3 substituents described above for the aryl group.
  • a benzyloxycarbonyl group, a phenyloxycarbonyl group, a phenylpropyloxycarbonyl phenylbutyloxycarbonyl group and the like can be mentioned, and a benzyloxycarbonyl group is preferable.
  • R 12 and R 14 are preferably a benzyloxycarbonyl group.
  • ⁇ 3 _ 7 cycloalkyl group a cycloalkyl group having 3 to 7 carbon was meaning taste, specifically cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group consequent opening, 1- methylcyclohexane Hexyl, cycloheptyl group and the like.
  • a cycloalkyl group having 3 to 6 carbon atoms specifically, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.
  • Particularly preferred is a cyclopropyl group or a cyclohexyl group.
  • R 3 is preferably a cyclic propyl group.
  • Ring A is preferably a cyclohexyl group.
  • Heteroaryl group means a 5- or 6-membered aromatic heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom other than carbon atom as a ring-constituting atom
  • Rings and unsaturated heterocyclic rings mean condensed heterocycles in which these heterocycles and benzene rings are condensed, and specifically, a thiophen-12-yl group, a thiophen-13-yl group, a furan-12 —Yl group, furan-3-yl group, pyrroyl-11-yl group, pyrroyl-12-yl group, pyrroyl-3--3-imidazolyl-1-yl group , Imidazo-1-yl group, imidazo-1-yl group, pyrazo-1-yl pyrazo, one-loop 3-yl pyrazo-1-yl 4-yl group, thiazo-1-1-2 Group, thiazol-4-yl thiazol-15-yl
  • a pyridyl group for example, a pyridine-12-yl group, a pyridin-3-yl group, a pyridine-4-yl group, etc.
  • a benzoxazolyl-12-yl group and a morpholine-14f Radical
  • benzimidazoyl 2-yl group pyrimidine-12-yl group pyrimidine-14-yl phenyl group (for example, thiophen-12-yl group, thiophen-13-yl group, etc.), furan-1 2-yl, furan-3-yl, pyrroyl-2T, pyrroyl-3-yl, pyrazoyl-3-yl, thiazol-1-4
  • Benzyl thiazole-1-5-benzimidazole-2-ylbenzo, thiophen-12-yl, benzofuran-12-yl, and more preferably a pyridyl or phenyl group
  • Heteroaryl alkyl group means a heteroarylalkyl group in which the heteroaryl moiety is the above-described heteroaryl group, and the alkyl moiety is an alkyl group having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms.
  • a pyridylmethyl group for example, 2-pyridylmethyl group, 3-pyridylmethyl group, 4-pyridylmethyl group, etc.
  • a quinolinylmethyl group for example, 2-quinolinylmethyl group, etc.
  • an indolylmethyl group for example, 2-yne (Drillmethyl group, 3-indolylmethyl group, etc.
  • thiophene-2-ylmethyl group, thiophene-3-ylmethyl group 2-furanylmethyl group, 3-furanylmethyl group, 1H-benzimidazole-1-ylmethylbenzo Thiazole-2-ylmethyl group, 2- (thiophen-1-yl) ethyl group, 2--(furan-2-yl) Chinore is a group, and the like.
  • R 14 is preferably a 3-pyridylethyl group (eg, a 2- (pyridine-13-yl) ethyl group).
  • Prodrug is a chemically modified derivative of a drug molecule and is itself a physiological It shows no activity and shows a reversible drug effect on the original drug molecule in the body after administration.
  • “Pharmaceutically acceptable salts” include, for example, various inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, phosphate or nitrate; acetate, propionate, succinate, and glycosyl. Monolate, lactate, malate, oxalate, tartrate, citrate, maleate, fumarate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, Various organic acid addition salts such as tosylate or ascorbate; salts with various amino acids such as aspartate or glutamate, but are not limited thereto. In some cases, it may be a hydrate, hydrate or solvate.
  • General formula (1) General formula (1)
  • a pharmaceutically acceptable salt thereof specifically antagonizes the sphingosine-1 1-phosphate receptor (Edg-5). Therefore, it is useful as an excellent therapeutic agent for diseases related to the sphingosine-1-phosphate receptor Edg-5 (eg, arteriosclerosis; renal, pulmonary, and hepatic tissue fibrosis).
  • diseases related to the sphingosine-1-phosphate receptor Edg-5 eg, arteriosclerosis; renal, pulmonary, and hepatic tissue fibrosis.
  • R 3 is the h-position
  • R 4 is the i-position
  • the substituent represented by is preferably at the j-position.
  • R 1 is preferably a C ⁇ 6 alkyl group, particularly preferably a methyl group.
  • R 2 is preferably a C 6 alkyl group, particularly preferably a methyl group.
  • R 3 is preferably a C i — 6 alkyl group, a no-open alkyl group or a C 3 — 7 cycloalkyl group, and particularly preferably a C 6 alkyl group.
  • R 4 is preferably a hydrogen atom.
  • a hydrogen atom in R 5 and R 6, an alkyl group, ( ⁇ _ 6 an alkoxy group, C 2 _ 6 alkynyl group, a halogen atom, Shiano group, a nitro group, a haloalkyl group, - 6 alkylamino group, di (Ci —E alkyl) is an amino group, an acyl group, an aryloxy group or an aralkyloxy group.
  • Z it is preferably 1 CO—, 1 CS—, 1 CH 2 — or 10 0 —, and particularly preferably 1 CO—.
  • W is preferably 1 N (R 14 ) 1 (here, preferred examples of R 14 include: A hydrogen atom or a —6 alkyl group, particularly preferably a hydrogen atom) or a single bond, particularly preferably 1 NH—.
  • an aryl group or a heteroaryl group is preferable, and a phenyl group, a pyridinole group (pyridine-12-yl group, pyridine-13-yl group or pyridine-14 group) is particularly preferable. Group).
  • the compound of the present invention may be a hydrate or a solvate in some cases, and also encompasses its prodrug conjugates and metabolites.
  • the present invention is used as a therapeutic agent for liver fibrosis or the like, it is administered systemically or locally, orally or parenterally.
  • the dosage varies depending on the age, body weight, symptoms, therapeutic effect, etc., but is usually in the range of 10 mg to 1 g per adult, and is administered once to several times a day.
  • the compound of the present invention comprises a diluent, a dispersant, an adsorbent, a solubilizer, and the like suitable for preparing a solid composition and a liquid composition for oral administration, or a preparation such as an injection for parenteral administration. Can be mixed.
  • the compounds of the present invention can also be used in the treatment and prevention of fibrosis and arteriosclerosis in humans as well as non-human animals, particularly mammals.
  • the functional group other than the site may be protected in advance if necessary, and may be deprotected at an appropriate stage.
  • reaction may be performed by a usual method, and the isolation and purification may be performed by appropriately selecting or combining a commonly used method such as crystallization, recrystallization, column chromatography, or preparative HPLC. Just do it.
  • isolation and purification may be performed by appropriately selecting or combining a commonly used method such as crystallization, recrystallization, column chromatography, or preparative HPLC. Just do it. Manufacturing method 1 to 3
  • N CN RN ⁇ 2 processes
  • R ⁇ R 2 , R 4 , R 5 , R 6 and A are as defined above, and X 1 is a halogen atom
  • the compound represented by the general formula (4) can be prepared by the method disclosed in Helv. Chim. Acta 16, 306 (1958X Angew. Chem. 86, 237 (1974) or JP-A-5-140113). Can be obtained similarly.
  • a compound represented by the general formula (4) and a compound represented by the general formula (5) in the presence of an acidic catalyst for example, sulfuric acid, hydrochloric acid, formic acid, acetic acid, propionic acid, tosylic acid, and maleic sulfonic acid.
  • an acidic catalyst for example, sulfuric acid, hydrochloric acid, formic acid, acetic acid, propionic acid, tosylic acid, and maleic sulfonic acid.
  • Step 1-2 the conjugated compound represented by the general formula (6) is reacted with a halogenoacetic acid derivative represented by the general formula: X 1 CH 2 C 0 OMe, and then the methoxy group is further removed.
  • the compound in which the substituent represented by is substituted at the h-position of the pyridine ring includes a compound represented by the general formula (4) and a compound represented by the general formula (5) (where R 3 is an alkoxy group) In the case of a group)
  • the target compound can be obtained by subjecting this compound to a reaction similar to that of Production Methods 2-2 to 2-4 described below.
  • Radical scavenger eg, benzene, toluene, anisol, etc.
  • an aprotic solvent eg, tetrahydrofuran, 1,4-dioxane, benzene, toluene, anisol, acetonitrile, N, N-dimethylformamide, etc.
  • a compound represented by the general formula (6) is converted to a phosphorus oxyhalide (for example, phosphorus oxychloride, phosphorus oxybromide, etc.) or a phosphorus halide (for example,
  • the compound represented by the general formula (7) can be obtained by reacting the compound with phosphorus pentabromide.
  • a compound represented by the general formula (6) is added to a solution of phosphorus oxyhalide or a reaction solvent of phosphorus halide, and the mixture is heated and stirred.
  • the compound represented by the general formula (7) By reacting the compound represented by the general formula (7) with a hydrazine compound (eg, hydrazine) in a polar solvent (eg, methanol, ethanol, isopropanol, dimethyl sulfoxide, etc.) under heating to reflux, thus, the compound shown in (8) can be obtained.
  • a compound represented by the general formula (7) is added to a solution of a hydrazine compound in a reaction solvent, and the mixture is heated and stirred.
  • the compound represented by the general formula (9) is converted to an azidating agent (eg, diphtheria).
  • an azidating agent eg, diphtheria
  • DPPA enyl phosphoryl azide
  • an azidating agent is added to a solution of a reaction solvent of the compound represented by the general formula (9) and a base, and the mixture is stirred.
  • the compound represented by the general formula (10) can also be obtained by introducing the compound represented by the general formula (9) into an acid anhydride or an acid halide and then reacting the compound with an azidating agent. be able to. Furthermore, the compound can be obtained by introducing the compound represented by the general formula (9) into hydrazide, followed by diazotization.
  • the compound represented by the general formula (9) a commercially available product or, for example, a compound synthesized by the following methods A to L can be used.
  • the compound (carboxylic acid derivative) represented by the general formula (9) can be obtained by subjecting the ester derivative to acidic or alkaline hydrolysis.
  • Alkoxyalkyl benzoic acid is desired: ⁇ includes, for example, an alkyl benzoate ester of N— according to the method described in the document Helv. Chim. Acta, 19_ (1996) 1967.
  • the reaction is carried out with halogenosuccinimide under heating in an ester solvent such as methyl formate or ethyl acetate; or in a solvent such as carbon tetrachloride in the presence of a light or 2,2-azobisisobutyronitrile catalyst.
  • the obtained halogenoalkyl benzoate ester is converted to an alcohol solvent such as methyl alcohol; an ether solvent such as tetrahydrofuran or dioxane; or a metal alkoxide or the like in a solvent such as N, N-dimethylformamide or dimethylsulfoxide. Reaction with nucleating agent at room temperature or under heating.
  • the desired alkoxyalkyl benzoic acid can be obtained by subjecting the obtained alkoxyalkyl benzoate to the method of A.
  • 2,6-dihalogenopyridine-14-carboxylic acid is converted to an alcoholic solvent such as methyl alcohol; tetrahydrofuran, dioxane or the like.
  • a nucleophilic agent such as a metal alkoxide at room temperature or under heating in a solvent such as an ether solvent or N, N-dimethylformamide, dimethylsulfoxide, or toluene to obtain a desired 2-halogeno-6-alkoxy.
  • Pyridine-1-carboxylic acid can be obtained.
  • methyl ketone having a corresponding alkyl or aryl group is converted to an alcoholic solvent such as methyl alcohol; tetrahydrofuran, dioxane, etc.
  • solvents such as N, N-dimethylformamide, dimethylsulfoxide, and toluene
  • a base such as triethylamine, piperidine, potassium carbonate,
  • 2-hydro-3-cyano-16-alkyl or arylpyridine_4 carboxylic acid ester is decyanolated with heating with a strong acid such as concentrated hydrochloric acid or sulfuric acid to give 2-hydroxy-6.
  • a strong acid such as concentrated hydrochloric acid or sulfuric acid
  • 2-hydroxy-6 is obtained.
  • 2-hydroxy-16-alkyl or arylpyridine-14-carboxylic acid is converted to oxyphosphorus chloride, phosphorous trichloride, in the presence of a catalyst such as triethylamine, dimethylaniline, tetraalkylammonium halide, N, N-dimethylformamide, etc.
  • the desired 2-halogeno-6-alkyl or arylpyridine-4-carboxylate By reacting with a halogenating agent such as phosphorus pentachloride, oxyphosphorus bromide, phosphorus tribromide, pentabromide phosphorus, etc. under heating, the desired 2-halogeno-6-alkyl or arylpyridine-4-carboxylate can be obtained. An acid can be obtained.
  • a halogenating agent such as phosphorus pentachloride, oxyphosphorus bromide, phosphorus tribromide, pentabromide phosphorus, etc.
  • the corresponding thioamide having an alkyl or aryl group can be converted to an alcohol-based compound such as methyl keto ⁇ -halogenocarboxylic acid ester and methyl alcohol.
  • the desired 2-alkyl or arylthiazole-4-carboxylic acid can be obtained by subjecting the obtained 2-alkyl or arylthiazole-4-carboxylate to the method of A.
  • a 2-thiophenone derivative When a 2-thiophenone derivative is desired, the corresponding 2-hydrothiophene is converted to a hydrocarbon solvent such as hexane; an ether solvent such as tetrahydrofuran or dioxane; or a solvent such as dimethyl sulfoxide. Under a strong base such as butyllithium and sodium metal, 2-methylthiophene is produced under cooling. By adding carbon dioxide thereto, a desired thiophene-121-ruvonic acid derivative can be obtained.
  • a hydrocarbon solvent such as hexane
  • an ether solvent such as tetrahydrofuran or dioxane
  • a solvent such as dimethyl sulfoxide
  • the 2-formylthiophene derivative can be chlorinated in aqueous solution, silver nitrate or weakly basic aqueous solution. It can also be obtained by the action of sodium acid.
  • Thiophene-l-Three-carboxylic acid derivative if desired, is obtained by reacting the corresponding 3-formylthiophene derivative with sodium chlorite under an aqueous alkaline solution, under a nitric or weakly basic aqueous solution. be able to.
  • the corresponding 2-hydrothiophene-14-carboxylic acid or an ester thereof may be added to a halogenating agent such as sulfuryl chloride or peridianidropyridinium.
  • a halogenating agent such as sulfuryl chloride or peridianidropyridinium.
  • 2-halogenothiophene-14-monorubonic acid or an ester thereof When an ester is used, the desired 2-halogenothiophene-4-carboxylic acid derivative can be obtained by subjecting it to the method of A.
  • the 2-halogenothiophene-14-carboxylic acid derivative obtained by the method of H. can be used to convert carbon dioxide using the reaction conditions of F. It can be obtained by using N, N-dimethylformamide instead.
  • the corresponding pyrazo-1-ol 3-carboxylic acid ester is converted to an alcohol solvent such as methyl alcohol; an ether solvent such as tetrahydrofuran or dioxane.
  • Solvents ketone solvents such as acetone, or N, N-dimethylformamide, dimethylsulfoxide, etc.
  • aprotic solvent eg, ethyl acetate, chloroform, benzene, toluene, etc.
  • Curtius rearrangement occurs, and the compound represented by the general formula (11)
  • the compounds represented can be obtained. Specifically, for example, a solution of the compound represented by the general formula (10) in a reaction solvent is heated and stirred.
  • the compound represented by the general formula (11) can also be obtained by reacting a compound represented by the following general formula (18) with a phosgene derivative (for example, phosgene, diphosgene, or the like).
  • the compound represented by the general formula (11) can be used in the next step without isolation.
  • the compound represented by the general formula (8) is converted to a compound represented by the general formula (11)
  • a compound represented by the general formula (1-1) By reacting with the compound represented by the formula (1), a compound represented by the general formula (1-1), which is one of the target compounds, can be obtained.
  • a solution of a reaction solvent of the compound represented by the general formula (8) is added to a solution of a reaction solvent of the compound represented by the general formula (11), and the mixture is stirred.
  • a compound having a different W from the compound represented by the general formula (1-1) can be produced by the following production method.
  • Compounds of the general formula (1) in which W is a single bond and ring A is a pyridyl group include aprotic solvents such as tetrahydrofuran, 1,4-dioxane, benzene, toluene, acetonitrile, N, N-dimethyl Formamide, etc.) in the general formula (8)
  • aprotic solvents such as tetrahydrofuran, 1,4-dioxane, benzene, toluene, acetonitrile, N, N-dimethyl Formamide, etc.
  • the compound of the general formula (1) in which W is a single bond and ring A is a phenyl group is prepared by using a base in an aprotic solvent (for example, tetrahydrofuran, benzene, chloroform, N, N-dimethylformamide, etc.) (For example, pyridine, triethylamine, etc.) in the presence of a compound represented by the general formula (8)
  • the compound of the general formula (1) in which W is —CONH— is prepared by reacting a base (eg, sodium hydroxide, lithium hydroxide) in a reaction solvent (eg, tetrahydrofuran, 1,4-dioxane, benzene, toluene, methanol, etc.) , Sodium hydride, lithium hydrogen chloride, sodium methylate, etc.) in the presence of a compound represented by the general formula (8)
  • the compound of the general formula (1) in which one X—Y— is —NH—NH— and Z and W are single bonds is a compound of the general formula (8) which has high reactivity.
  • -Halide for example, 2-halogenobenzimidazole
  • a compound represented by the general formula (1-1) with an oxidizing agent (eg, N-promosuccinimide, bromine, etc.) in the presence of pyridine, sodium hydroxide, etc. it can.
  • the step 117 can be carried out using a compound represented by the general formula (19) and an equivalent thereof instead of the compound represented by the general formula (11).
  • a strong base such as butyllithium or sodium hydrogen chloride
  • a cycloformylamide with triphosgene an equivalent of the compound represented by the general formula (19) is obtained.
  • the compound (1-1) can be obtained.
  • aprotic solvents for example, tetrahydrofuran, 1,4-dioxane, ethyl ether, hexane, etc.
  • strong bases for example, n-butyllithium, tert-butyllithium, sec-butyllithium, etc.
  • alcohols for example, n-butyllithium, tert-butyllithium, sec-butyllithium, etc.
  • a compound represented by general formula (7) is converted to a formylating agent (eg, N, N-dimethylformamide, formylpiperidine, hexamethylenetetramine, etc.) with a formylating agent.
  • the compound represented by the general formula (12) can be obtained by shading. Specifically, for example, after adding a strong base or an alkali metal to a solution of a reaction solvent of the compound represented by the general formula (7), a formylidani is added. And heat and stir.
  • Step 2-1 the obtained compound represented by the general formula (12) is reduced with a reducing agent (for example, sodium, borohydride, etc.), and then reduced with a compound represented by the general formula (11).
  • a reducing agent for example, sodium, borohydride, etc.
  • a compound represented by the general formula (11) By reacting, a compound of the general formula (1) in which X is one CH 2 —, Y is —CO—, Z is —CO—, and W is —NH— can be obtained.
  • a base eg, potassium carbonate, sodium carbonate
  • a hydroxylamine compound eg, hydroxylamine hydrochloride
  • a solution of a reaction solvent between the compound represented by the general formula (12) and a base is stirred.
  • Step 2-2 the obtained compound represented by the general formula (13) is converted into acyl halide or the anilide represented by the general formula (11) in the presence of a base (for example, pyridine, triethylamine or the like).
  • a base for example, pyridine, triethylamine or the like.
  • the compound represented by the general formula (14) can be obtained by reducing the compound represented by the general formula (13) by a conventional method. There are various reduction methods, for example,
  • Production method 3 Production method of compound of general formula (1) where X is —0—, Y is —NH—, Z is —CO—, and Z is —NH—
  • a strong base eg, potassium tert-butoxide, sodium methoxide, sodium hydroxide, water
  • a compound represented by the general formula (7) is converted to an N-protected hydroxyamine compound (eg, ethyl N-hydroxyacetimidate).
  • N-protected hydroxyamine compound eg, ethyl N-hydroxyacetimidate
  • a polar solvent for example, methanol, ethanol, tetrahydrofuran, etc.
  • an acid for example, hydrochloric acid, sulfuric acid, phosphoric acid, etc.
  • the compound represented by the general formula (16) can be obtained.
  • an acid is added to a solution of the compound represented by the general formula (15) in a reaction solvent, followed by stirring.
  • RRR 3 , RRRA and X 1 are the same as above, Ph is a phenyl group, R 12 ′ is a C 2 _ 6 alkoxycarbonyl group, a substituted or unsubstituted aralkyloxycarbonyl group or Aryloxy which may be substituted A carbonyl group, R 14 'is ( ⁇ alkyl group or the Teroari Ichiru of over 8 ( ⁇ is an 8 Al kill group, R 14 "is ⁇ Lal Kill optionally substituted O propoxycarbonyl sulfonyl group Or a substituted or unsubstituted aryloxycarbonyl group)
  • W is - method of manufacturing NH-, compound
  • a compound represented by the general formula (14) is converted into a compound (Synth. Commun. 26, 331 (1996)) by reacting with the compound represented by the general formula (19) obtained by the same method as that described in (1-15), which is one of the target compounds A compound can be obtained.
  • a compound represented by the general formula (19) instead of the compound represented by the general formula (19), for example, a compound represented by the general formula (22) (twenty two)
  • a compound represented by the general formula (1-2) is converted into a base (eg, n-butyllithium, sec-butyllithium, tert-butyllithium), and then reacted with an acylating agent represented by the general formula (20) to obtain a compound represented by the general formula (1-6), which is one of the target compounds. Can be obtained.
  • a base eg, n-butyllithium, sec-butyllithium, tert-butyllithium
  • Production method 7 —X in general formula (1) is —CH 2 —; Y is —N (R 14 ) — (R 14 is as defined above) or one NH—; Z is one CO— A process for producing a compound wherein W is -N (R 14 ")-(R 14 " is as defined above)
  • Aprotic solvent for example, tetrahydrofuran, 1,4-dioxane, benzene, toluene, etc.
  • a strong base for example, lithium tetramethyldisilazide
  • this is reacted with an acylating agent represented by the general formula (21) to obtain an amide compound represented by the general formulas (117) and (1-7).
  • a strong base for example, lithium tetramethyldisilazide
  • n—Pen means n—pentyl group
  • i—P "en” isopentyl group
  • n-Hex is n-hexyl group
  • n-Hep is n-heptyl group
  • n-Oct is n-octyl group
  • Ph is The phenyl group
  • Ac means an acetyl group
  • Bn means a benzyl group.
  • Step 1-2 b) 1H-6-Hydroxy-1-4-isopropyl-1,3-dimethylpyrazo [3,4-b] pyridine (6)
  • Step 1-3 c) 1H-6-promo 4-isopropyl-1- 1,3-dimethylpyrazolo [3,4-b] pyridine (7)
  • Step 1-4 d) 1H-6-hydrazino-1-isopropyl-1,3-dimethylpyrazo [3,4-b] pyridine (8)
  • Step 1-5 e) 2,6-Dichrolic pyridine-1-4-carbonylazide (10)
  • 2,6-Dichloroisonicotinic acid (9) 40.45 g
  • triethylamine (38 mL) are dissolved in ethyl acetate (4 ° OmL), and DPPA (50 mL) is added dropwise to this solution under ice-cooling. Then, the mixture was stirred at room temperature for 20 hours. After adding ethyl acetate and diluting, the mixture was washed with water and saturated saline. This was dried over magnesium sulfate and then concentrated to obtain a crude product (70.80 g) of 2,6-dichloromouth pyridine-14-carbonylazide (10). The crude crystals were dissolved in ethyl acetate and treated with activated carbon to give 2,6-dichloropyridine-14-carbonylazide (10) (45.67 g) as crystals.
  • Steps 1-6 and 1-7 f) N- (1H—4-Isopropyl-1,3-dimethylpyrurazolo [3,4-b] pyridin-6-yl) amino-1 'N'-(2,6- Dichloropyridine-1-yl) urea (1-1) 2,6-Dichrolic pyridine_4-carbonylazide (10) (42.41 g) obtained in e) of Example 1 was dissolved in toluene (41 OmL), and the solution was stirred at 100 ° C for 4 hours. (11).
  • Example 1-2-1-235 The compound of Example 1-2-1-235 was obtained in the same manner as in Example 1. The obtained compounds are shown in Tables 1 to I3.
  • Example 1-2 in Steps 1-4 of the above-mentioned general production method (hereinafter, “general production method” is omitted and only the process number is shown), X is obtained by using methylhydrazine instead of hydrazine.
  • the target compounds were obtained by using benzyl isocyanate compounds instead of the compounds (11) in Steps 1-7.
  • the target compound was obtained by using the corresponding 4-morpholinylcarbonyl chloride in the presence of triethylamine instead of compound (11) without going through Steps 1-6. .
  • Example 125 the target compound was obtained by appropriately performing the method in Step 117 using 3-chlorophenylphenylacetic acid in place of the compound (11).
  • the target compound was obtained by subjecting the compound (8) obtained in the step 1-4 to the process 5-1 in place of the compound of the aforementioned general formula (14).
  • the corresponding carbonic acid diester derivative is used in place of the carbonic acid amide derivative of the general formula (19).
  • Example 1-1 For Examples 61 and 62, a benzoyl chloride compound was used in place of the compound (11) in Step 117, and similarly for Compounds 170 and 71, 3-pyridine was used. The objective compound was obtained using carbonyl chloride.
  • the target compound was obtained by condensation reaction with dicyclohexylcarbodiimide in the presence of hydroxybenztriazole in N, N-dimethylformamide using the compound of the formula
  • the target compound was obtained by reacting the compound represented by the general formula (19) with the compound (8) having a single bond of Y used in Examples 15 to 15.
  • the compound (8) was reacted with ethyl ethyl chloroformate in tetrahydrofuran in the presence of triethylamine.
  • the target compound was obtained by subjecting to —7.
  • the compound of the general formula (7) and 3-amino-2-hydroxybenzoic acid methyl ester were prepared by adding trisdibenzylideneacetondipalladium, 2,2′-bis (diphenylphosphino) By reacting with heating in toluene and tetrahydrofuran in the presence of 1,1,1-binaphthyl and sodium tert-butoxy, methyl benzoate was obtained. This derivative was hydrolyzed with alkali to obtain a benzoic acid derivative. Further, this benzoic acid derivative was condensed with a compound represented by the general formula (18) with dicyclohexylcarbodiimide in dimethylformamide in the presence of hydroxybenztriazole to obtain a target compound.
  • Example 2 In the same manner as in Example 2, the compounds of Examples 2-2 to 2-24 were obtained. The obtained compounds are shown in Tables 14 and 15.
  • Example 3 1H-4 monoisopropyl-1,3, dimethyldimethylazo [3,4-b] pyridine-16-ylaldehyde obtained in a) of Example 3 (12) (3.65 g) Hydroxylamamine hydrochloride (2. 41 g) and potassium carbonate (2.4 g) were dissolved in a mixed solvent of ethanol (70 mL) and water (35 mL), and the mixture was stirred at room temperature for 3 days. Ethyl acetate was added thereto, and washed with water and saturated saline.
  • Step 2-3 c) 1H-6-Aminomethyl-1-41-isopropyl-1,3-dimethylvirazolo [3,4-b] pyridine (14)
  • the concentrate is diluted with ethyl acetate, washed with 1N potassium carbonate and saturated aqueous sodium hydrogen carbonate, dried over magnesium sulfate, and concentrated to give 1H-6-aminomethyl-4 monoisopropyl-1,3,3-dimethylpyrazolo [3, 4-b] pyridine (14) (0.
  • Step 2-4 (1)] ⁇ -(111-4-isopropyl-l, 3-dimethylbirazolo [3,4-b] pyridine-l-6-yl) methyl-lN '-(2,6-dichloropyridine
  • ⁇ -(111-4-isopropyl-l, 3-dimethylbirazolo [3,4-b] pyridine-l-6-yl) methyl-lN '-(2,6-dichloropyridine One four one) urea (one two)
  • Example 3 In the same manner as in Example 3, the compounds of Examples 2-2 to 3-33 were obtained. The obtained compounds are shown in Tables 16 and 17.
  • an acrylic ester derivative was obtained by carrying out a Heck reaction with the compound of the general formula (7) and ethyl acrylate. This is hydrolyzed with an alcohol to give an acrylic acid derivative, and this derivative and the compound of the general formula (18) are combined with N, N-dimethylformamide in the presence of hydroxybenztriazole in dicyclohexane.
  • the desired compound was obtained by a condensation reaction with hexyl carposimide.
  • the target compounds can be obtained by subjecting the compounds obtained in Examples 3-9 and 310 to hydrogenation reaction, respectively.
  • the compound of general formula (14) was converted to sodium methoxide
  • the compound was reacted with paraformaldehyde in the presence of and immediately reduced with sodium borohydride to obtain an N-methylated compound of the general formula (14). This was subjected to Step 2-4 to obtain the desired compound.
  • Example 3-19 the compound obtained in Example 3-6 was reacted with n-butyllithium in tetrahydrofuran under cooling, and then reacted with compound (11) in the system. The compound was obtained.
  • an acetylpyrazo-opened pyridine derivative was obtained in step 2-1 by using dimethylacetoamide in place of N, N-dimethylformamide.
  • This derivative and hydroxylamine hydrochloride were reacted under heating in aqueous ethanol in the presence of potassium carbonate to obtain an oxime derivative.
  • This derivative was reduced with zinc powder in an acetic acid solvent to obtain an ethylamine derivative.
  • the target compound was obtained by subjecting this ethylamine derivative to Steps 2-4.
  • the compound of formula (19) was synthesized using N- (2- (3-pyridyl) ethyl) -3,5-dichloroaniline. By subjecting to 1, the target compound was obtained.
  • Step 3-2 b) 1- (1H-4-isopropyl-1,3-dimethylbirazolo [3,4-b] pyridin-6-yl) hydroxylamine (16)
  • Step 3-3 c) N— (1H—4-Isopropyl-1,3-dimethylbirazolo [3,4-b] pyridine-16-yl) oxy_N, 1- (2,6-dichloromouth pyridine) One four one) urea (1-3)
  • Example 4-15 4-6 and 417, the target compound was obtained in step 3-3 using 2 equivalents of the compound (11).
  • Examples 4-18, 4-19 and 4-110 were carried out in step 3-1 by using N-benzyl-2- (tert-butoxycarbonyl) hydroxylamine as the N-protected hydroxylamine in the general formula (15) An analog of the compound was obtained, which was subsequently subjected to Steps 2-2 and 3-3 to obtain the desired compound.
  • Example 4-11, 4-1 12 and 4-13 first, the compound of the general formula (6) and ethyl bromoacetate were added to dimethylformamide in the presence of potassium t-butoxy at room temperature or under cooling. And then hydrolyzed with an alcohol to obtain a hydroxyacetic acid compound. This was combined with the compound of the general formula (18) in dimethylformamide in the presence of hydroxybenztriazole to obtain dicyclohexylcarbodiyl. The target compound was obtained by condensing with a amide.
  • Step 3-1 an analog of the compound of the general formula (15) was obtained in Step 3-1 by using N-methyl-N- (tert-butoxycarbonyl) hydroxylamine as the N-protected hydroxylamine. This was subsequently subjected to Steps 3-1 and 3-3 to obtain the desired compound.
  • Uz co modified Eagle MEM low glucose, 10% ⁇ shea calf serum, 1 O. g / ml puromycin
  • I c 50 was determined from the inhibition rate of ⁇ r activity.
  • Test example (3) Sph-1—P-stimulated human normal lung fibroblast (HLF) proliferation inhibition test
  • HLF 2000cels / 200 / l / we11
  • RPMI 1640 10% fetal serum medium Thereafter, the cells were washed with PBS (Phosphat e Buf ferd Saline), replaced with RPMI medium not containing fetal calf serum, and cultured for 1 day.
  • the test substance (final concentration 10- 3 M ⁇ : L 0- 5 M , final DMSO concentration 0.1%) was added Caro the 8 ⁇ 1, Sph-1- ⁇ (final concentration 1 / M) was added to 50 ⁇ 1.
  • Tables 20 and 21 show the test results of the above test examples (1) to (3).
  • Test example (4) DMN hepatitis test
  • OH-Proline quantitative measurement was performed as follows. Defatted for more than 2 days in Aceton.Fi1 ⁇ 2jc, dried in vacuum desiccator overnight, and measured dry weight Liver sections were placed in glass tubes with Teflon liner caps and hydrolyzed at 118 ° C for 24 hours with the addition of 5 ml of 6N HCl. After bubbling nitrogen gas while spraying nitrogen gas at 65 ° C. while evaporating to dryness, HC1 was evaporated to dryness and dissolved in 1 mL of pure water to obtain a sample for quantitative determination of 0H—Pro1ine.
  • 0.5 ml of the sample solution was mixed with 3 ml of citrate-phosphate buffer solution and 0.5 ml of periodate solution, and mixed, and then 1.75 ml of toluene extract was added, followed by 1 hour at room temperature. After shaking, the mixture was centrifuged at 1500 rpm for 10 minutes. 0.6 ml of the organic layer was placed in a test tube, 0.15 ml of the Ehrlich's reagent was added, the mixture was allowed to stand at room temperature for 45 minutes, and the absorbance at 565 nm was measured. The OH-Pro 1 ine content was shown as a value corrected by the dry weight of the tissue sample. Table 22 shows the test results of Test Example (4).
  • the novel birazolopyridination of the present invention and a pharmaceutically acceptable salt thereof selectively act on Edg-5 receptor.
  • the proliferation of human normal lung fibroblasts stimulated by Sph-1- ⁇ was significantly suppressed.
  • the amount of hydroxyproline (OH-Proline) contained in collagen was significantly suppressed.
  • the compound of the present invention can be used as a therapeutic agent for vascular smooth muscle, kidney, lung, and liver thread in which Edg-5 receptor is specifically present, and in particular, to prevent fibrils in these papers.

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Abstract

Des composés de pyrazolopyridine de formule (1) ou les sels pharmaceutiquement acceptables de ces derniers agissent spécifiquement sur Edg-5, qui est un récepteur de sphingosine-1-phosphate et sont par conséquent utiles en tant que substances thérapeutiques contre la fibrose. Dans la formule, R?1, R2 et R3¿ représentant chacun alkyle C¿1-8? ou autre; R?4¿ représente hydrogène ou autre; R5 et R6 représentent indépendamment hydrogène, alkyle C¿1-8?, alcoxy C1-6, halogéno ou autre ; X représente -NH-, -O-, -CH2 ou autre ; Y représente -NH- ou autre ; Z représente -CO- ou autre ; W représente -NH- ou autre et A représente aryle, hétéroaryle ou autre. Formule (1)
PCT/JP2001/005187 2000-06-20 2001-06-18 Composes de pyrazolopyridine et utilisation de ces derniers en tant que medicaments Ceased WO2001098301A1 (fr)

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JP2000-185067 2000-06-20
JP2000185067A JP2004123537A (ja) 2000-06-20 2000-06-20 ピラゾロピリジン化合物及びその医薬用途
JP2001070593A JP2004123539A (ja) 2001-03-13 2001-03-13 新規ピラゾロピリジン化合物及び医薬用途
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Cited By (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003020313A1 (fr) * 2001-09-04 2003-03-13 Ono Pharmaceutical Co., Ltd. Medicaments contre les maladies respiratoires renfermant un agent de regulation du recepteur de la sphingosine-1-phosphate
WO2004002531A1 (fr) 2002-06-26 2004-01-08 Ono Pharmaceutical Co., Ltd. Remedes pour les maladies provoquees par la contraction ou la dilatation vasculaire
WO2004074297A1 (fr) 2003-02-18 2004-09-02 Kyorin Pharmaceutical Co., Ltd. Derives d'acide aminophosphonique, leurs sels d'addition et des modulateurs de recepteurs s1p
WO2004089929A1 (fr) * 2003-04-14 2004-10-21 Astex Therapeutics Limited Derives de 5-amino-2-carbonylthiophene utilises en tant qu'inhibiteurs de la p38 map kinase dans le traitement des maladies inflammatoires
WO2005063704A1 (fr) 2003-12-25 2005-07-14 Ono Pharmaceutical Co., Ltd. Composes cycliques d'azetidine et medicaments les renfermant
US7064217B2 (en) 2001-01-30 2006-06-20 University Of Virginia Patent Foundation Agonists and antagonists of sphingosine-1-phosphate receptors
WO2007103308A2 (fr) 2006-03-07 2007-09-13 Array Biopharma Inc. Dérivés hétérobicycliques de pyrazole et méthodes d'utilisation
WO2007095561A3 (fr) * 2006-02-15 2007-10-11 Allergan Inc Composes amide d'acide indole-3-carboxylique, ester, thioamide et ester de thiol porteurs de groupes aryl ou heteroaryl presentant une activite biologique antagoniste sur le recepteur sphingosine-1-phosphate (s1p)
WO2008018427A1 (fr) 2006-08-08 2008-02-14 Kyorin Pharmaceutical Co., Ltd. Dérivé d'ester de l'acide aminophosphorique et modulateur du récepteur s1p contenant ledit dérivé en tant que principe actif
WO2008089015A1 (fr) 2007-01-11 2008-07-24 Allergan, Inc. Composé amide d'acide indole-3-carboxylique 6-substitué ayant une activité biologique d'antagoniste du récepteur de sphingosine-1-phosphate (s1p)
US7435731B2 (en) 2004-02-27 2008-10-14 Roche Palo Alto Llc Substituted pyrazolo[3,4-d]pyrimadines and methods of using the same
US7452880B2 (en) 2004-02-27 2008-11-18 Nidhi Arora Substituted pyrazolo [3,4-d] pyrimidines and methods of using the same
WO2008154470A1 (fr) * 2007-06-08 2008-12-18 University Of Connecticut Inhibiteur de l'activité récepteur du récepteur s1p1 permettant l'inhibition d'une angiogenèse pathologique dans l'œil
US7482491B2 (en) 2002-09-19 2009-01-27 Kyorin Pharmaceutical Co., Ltd. Amino alcohol derivative, addition salt thereof, and immunosuppressant
US7495015B2 (en) 2004-02-27 2009-02-24 Roche Palo Alto Llc Indazole derivatives and methods for using the same
US7563799B2 (en) 2005-08-25 2009-07-21 Roche Palo Alto Llc Substituted pyrazolo[3,4-D]pyrimidines as p38 map kinase inhibitors
WO2010030976A3 (fr) * 2008-09-12 2010-05-06 University Of Connecticut Procédés et compositions destinés à inhiber l'athérosclérose et une inflammation vasculaire
US7737173B2 (en) 2006-02-15 2010-06-15 Allergan, Inc. Indole-3-carboxylic acid amide, ester, thioamide and thiol ester compounds bearing aryl or heteroaryl groups having sphingosine-1-phosphate (S1P) receptor antagonist biological activity
US7781617B2 (en) 2004-07-16 2010-08-24 Kyorin Pharmaceutical Co., Ltd Effective use method of medicaments and method of preventing expression of side effect
US7795472B2 (en) 2004-10-12 2010-09-14 Kyorin Pharmaceutical Co., Ltd. Process for producing 2-amino-2-[2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl]-1,3-propanediol hydrochloride and hydrates thereof, and intermediates in the production thereof
WO2011076744A1 (fr) * 2009-12-21 2011-06-30 Novartis Ag Pyridines accolées à di-substitution hétéroaryle
US8048928B2 (en) 2005-10-07 2011-11-01 Kyorin Pharmaceutical Co., Ltd. Therapeutic agent for treating liver disease containing 2-amino-1,3-propanediol derivative as active ingredient, and method for treating liver disease
WO2011159864A1 (fr) * 2010-06-17 2011-12-22 Bracco Imaging S.P.A. Analogues de jte013 et leurs procédés de préparation et d'utilisation
US20120208840A1 (en) * 2009-09-29 2012-08-16 Allergan, Inc. Condensed Ring Pyridine Compounds As Subtype-Selective Modulators Of Sphingosine-1-Phosphate-2 (S1P2) Receptors
US8273748B2 (en) 2006-08-08 2012-09-25 Kyorin Pharmaceutical Co., Ltd. Amino alcohol derivative and immunosuppresive agent having same as an active ingredient
US8318811B2 (en) 2006-02-06 2012-11-27 Kyorin Pharmaceutical Co., Ltd. Method for treating an inflammatory bowel disease using 2-amino-2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl-1,3-propanediol or a salt thereof
US8404863B2 (en) 2008-01-03 2013-03-26 Allergan, Inc. Tetrahydroindoles having sphingosine-1-phosphate receptor activity
WO2013047701A1 (fr) * 2011-09-29 2013-04-04 小野薬品工業株式会社 Dérivé phényle
US8524917B2 (en) 2007-01-11 2013-09-03 Allergan, Inc. 6-substituted indole-3-carboxylic acid amide compounds having sphingosine-1-phosphate (S1P) receptor antagonist biological activity
EP2628724A4 (fr) * 2010-10-12 2014-02-26 Nippon Soda Co Composé aryloxyurée et agent de lutte contre des organismes nuisibles
US8785638B2 (en) 2009-05-15 2014-07-22 Katholieke Universiteit Leuven Thieno [2, 3-B] pyridine derivatives as viral replication inhibitors
WO2014157158A1 (fr) 2013-03-26 2014-10-02 小野薬品工業株式会社 Dérivé phénylique
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US8906906B2 (en) 2009-08-05 2014-12-09 Katholieke Universiteit Leuven Viral replication inhibitors
US20150141428A1 (en) * 2012-05-22 2015-05-21 Merck Sharp & Dohme Corp. TrkA Kinase Inhibitors, Compositions and Methods Thereof
JP2015524789A (ja) * 2012-03-26 2015-08-27 スウェンソン，ロルフ，イー 新規なスフィンゴシン１‐リン酸受容体アンタゴニスト
US9132129B2 (en) 2010-11-15 2015-09-15 Katholieke Universiteit Leuven Antiviral compounds
WO2016191872A1 (fr) * 2015-06-01 2016-12-08 Dalhousie University Antagonistes de s1pr2 et leurs utilisations
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WO2019002624A1 (fr) * 2017-06-30 2019-01-03 Kleuser, Burkhard Agents pour traiter des maladies intestinales inflammatoires
US10328053B2 (en) 2016-08-26 2019-06-25 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
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US10836769B2 (en) 2018-02-26 2020-11-17 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
US10858358B2 (en) 2015-06-01 2020-12-08 Dalhousie University S1PR2 antagonists and uses therefor
EP3808176A4 (fr) * 2018-05-25 2022-04-13 Kyoto University Procédé de suppression des dégâts par congélation et composition de prévention des dégâts par congélation
WO2023283921A1 (fr) * 2021-07-16 2023-01-19 北京深蓝泰医药科技有限公司 Inhibiteur de dpd, composition pharmaceutique et utilisation
WO2024077036A1 (fr) * 2022-10-07 2024-04-11 Scorpion Therapeutics, Inc. Méthodes de traitement du cancer

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3542793A (en) * 1966-01-12 1970-11-24 Ciba Geigy Corp 4-unsubstituted-5-amino- or 5-acylamino-pyrazolo(3,4-b)pyridines
US4260614A (en) * 1980-02-08 1981-04-07 E. R. Squibb & Sons, Inc. 4-(2-(1H-Imidazol-1-ylmethyl)-1,3-dioxolan-4-yl)methoxypyrazolo(3,4-b)pyridines
US4612318A (en) * 1982-09-22 1986-09-16 Gruppo Lepetit S.P.A. CNS-depressant and analgesic tricyclo-[pyrazolo-[3,4-6]-pyridine] derivatives and pharmaceutical compositions thereof
US4822799A (en) * 1988-01-27 1989-04-18 Sandoz Pharm. Corp. Pyrazolopyridine analogs of mevalonolactone and derivatives thereof useful for inhibiting cholesterol biosynthesis in mammals
US5024999A (en) * 1988-04-26 1991-06-18 Nissan Chemical Industries Ltd. Pyrazolopyridine type mevalonolactones useful as pharmaeuticals
EP0535548A1 (fr) * 1991-10-04 1993-04-07 Nissan Chemical Industries Ltd. Inhibiteur de l'épaississement atherosclerotique de l'intima
US6060480A (en) * 1996-08-30 2000-05-09 Yoshitomi Pharmaceutical Industries, Ltd. Preventives/remedies for muscle tissue degenerations

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3542793A (en) * 1966-01-12 1970-11-24 Ciba Geigy Corp 4-unsubstituted-5-amino- or 5-acylamino-pyrazolo(3,4-b)pyridines
US4260614A (en) * 1980-02-08 1981-04-07 E. R. Squibb & Sons, Inc. 4-(2-(1H-Imidazol-1-ylmethyl)-1,3-dioxolan-4-yl)methoxypyrazolo(3,4-b)pyridines
US4612318A (en) * 1982-09-22 1986-09-16 Gruppo Lepetit S.P.A. CNS-depressant and analgesic tricyclo-[pyrazolo-[3,4-6]-pyridine] derivatives and pharmaceutical compositions thereof
US4822799A (en) * 1988-01-27 1989-04-18 Sandoz Pharm. Corp. Pyrazolopyridine analogs of mevalonolactone and derivatives thereof useful for inhibiting cholesterol biosynthesis in mammals
US5024999A (en) * 1988-04-26 1991-06-18 Nissan Chemical Industries Ltd. Pyrazolopyridine type mevalonolactones useful as pharmaeuticals
EP0535548A1 (fr) * 1991-10-04 1993-04-07 Nissan Chemical Industries Ltd. Inhibiteur de l'épaississement atherosclerotique de l'intima
US6060480A (en) * 1996-08-30 2000-05-09 Yoshitomi Pharmaceutical Industries, Ltd. Preventives/remedies for muscle tissue degenerations

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DAVAILLE, JULIEN, ET.AL.: "Antiproliferative properties of Sphingosine 1-Phosphate in human hepatic myofibroblasts.", THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 275, no. 44, November 2000 (2000-11-01), pages 34628 - 34633, XP002945852 *
DE MELLO., ET AL.: "New derivatives of 1H-pyrazolo (3,4-b) pyridine heterocyclic system: synthesis and hydrogen and carbonassignments by 1D and 2D NMR.", QUIM. NOVA, vol. 22, no. 1, 1999, pages 26 - 30, XP002945851 *
MELANI, F. ET.AL.: "Dipyrazolo (5,4-b:3',4'-d) pyridines. Synthesis, inhibition of benzodiazepine receptor binding and structure-activity relationships.", IL FARMACO, vol. 44, no. 6, 1989, pages 585 - 594, XP002945850 *
SIDDIQI, SUHAIB M. ET.AL.: "A survey of nonxanthine derivatives as adenosine receptor ligands.", NUCLEOSIDES & NUCLEOTIDES, vol. 15, no. 1-3, 1996, pages 693 - 717, XP002945849 *

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WO2004002531A1 (fr) 2002-06-26 2004-01-08 Ono Pharmaceutical Co., Ltd. Remedes pour les maladies provoquees par la contraction ou la dilatation vasculaire
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US7482491B2 (en) 2002-09-19 2009-01-27 Kyorin Pharmaceutical Co., Ltd. Amino alcohol derivative, addition salt thereof, and immunosuppressant
US7759326B2 (en) 2003-02-18 2010-07-20 Kyorin Pharmaceutical Co., Ltd. Aminophosphonic acid derivative, salt thereof, and modulator of S1P receptor
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US7456157B2 (en) 2003-02-18 2008-11-25 Kyorin Pharmaceutical Co., Ltd. Aminophosphonic acid derivatives, addition salts thereof and S1P receptor modulators
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US8404863B2 (en) 2008-01-03 2013-03-26 Allergan, Inc. Tetrahydroindoles having sphingosine-1-phosphate receptor activity
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US20120208840A1 (en) * 2009-09-29 2012-08-16 Allergan, Inc. Condensed Ring Pyridine Compounds As Subtype-Selective Modulators Of Sphingosine-1-Phosphate-2 (S1P2) Receptors
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US9820980B2 (en) 2011-09-29 2017-11-21 Ono Pharmaceutical Co., Ltd. Phenyl derivative
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US9663511B2 (en) 2012-03-26 2017-05-30 Arroyo BioSciences, LLC Sphingosine 1-phosphate receptor antagonists
JP2015524789A (ja) * 2012-03-26 2015-08-27 スウェンソン，ロルフ，イー 新規なスフィンゴシン１‐リン酸受容体アンタゴニスト
US9181261B2 (en) * 2012-05-22 2015-11-10 Merck Sharp & Dohme Corp. TrkA kinase inhibitors, compositions and methods thereof
US20150141428A1 (en) * 2012-05-22 2015-05-21 Merck Sharp & Dohme Corp. TrkA Kinase Inhibitors, Compositions and Methods Thereof
US9642855B2 (en) 2012-06-29 2017-05-09 Pfizer Inc. Substituted pyrrolo[2,3-d]pyrimidines as LRRK2 inhibitors
WO2014157158A1 (fr) 2013-03-26 2014-10-02 小野薬品工業株式会社 Dérivé phénylique
US9676719B2 (en) 2013-03-26 2017-06-13 Ono Pharmaceutical Co., Ltd. Phenyl derivative
KR20140117301A (ko) 2013-03-26 2014-10-07 오노 야꾸힝 고교 가부시키가이샤 페닐 유도체를 함유하는 의약
US9695171B2 (en) 2013-12-17 2017-07-04 Pfizer Inc. 3,4-disubstituted-1 H-pyrrolo[2,3-b]pyridines and 4,5-disubstituted-7H-pyrrolo[2,3-c]pyridazines as LRRK2 inhibitors
US10058543B2 (en) 2014-06-02 2018-08-28 Dalhousie University Treatment of familial exudative vitreoretinopathy through S1PR2 inhibition
WO2016191872A1 (fr) * 2015-06-01 2016-12-08 Dalhousie University Antagonistes de s1pr2 et leurs utilisations
CN107849038A (zh) * 2015-06-01 2018-03-27 达尔豪西大学 S1pr2拮抗剂及其用途
US10858358B2 (en) 2015-06-01 2020-12-08 Dalhousie University S1PR2 antagonists and uses therefor
US10487082B2 (en) 2015-06-01 2019-11-26 Dalhousie University S1PR2 antagonists and uses therefor
US10039753B2 (en) 2015-09-14 2018-08-07 Pfizer Inc. Imidazo[4,5-c]quinoline and imidazo[4,5-c][1,5]naphthyridine derivatives as LRRK2 inhibitors
US10874640B2 (en) 2016-08-26 2020-12-29 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
US10328053B2 (en) 2016-08-26 2019-06-25 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
US12161625B2 (en) 2016-08-26 2024-12-10 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
WO2019002624A1 (fr) * 2017-06-30 2019-01-03 Kleuser, Burkhard Agents pour traiter des maladies intestinales inflammatoires
US10836769B2 (en) 2018-02-26 2020-11-17 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
US11420974B2 (en) 2018-02-26 2022-08-23 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
EP3808176A4 (fr) * 2018-05-25 2022-04-13 Kyoto University Procédé de suppression des dégâts par congélation et composition de prévention des dégâts par congélation
WO2023283921A1 (fr) * 2021-07-16 2023-01-19 北京深蓝泰医药科技有限公司 Inhibiteur de dpd, composition pharmaceutique et utilisation
WO2024077036A1 (fr) * 2022-10-07 2024-04-11 Scorpion Therapeutics, Inc. Méthodes de traitement du cancer

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