WO2000064430A1 - Inhibiteurs de l'apoptose - Google Patents

Inhibiteurs de l'apoptose Download PDF

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Publication number
WO2000064430A1
WO2000064430A1 PCT/JP2000/002471 JP0002471W WO0064430A1 WO 2000064430 A1 WO2000064430 A1 WO 2000064430A1 JP 0002471 W JP0002471 W JP 0002471W WO 0064430 A1 WO0064430 A1 WO 0064430A1
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Prior art keywords
dimethylethyl
butyl
group
difluorobenzamide
chloro
Prior art date
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PCT/JP2000/002471
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English (en)
Japanese (ja)
Inventor
Kazuhito Ikeda
Tohru Tatsuno
Chikao Nakayama
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Sumitomo Pharmaceuticals Co., Ltd.
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Priority to AU36798/00A priority Critical patent/AU3679800A/en
Publication of WO2000064430A1 publication Critical patent/WO2000064430A1/fr

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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/65—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • 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
    • C07D213/82—Amides; Imides in position 3
    • 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
    • C07D213/89—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 with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to an apoptosis inhibitor useful as a therapeutic agent for a disease associated with enhanced apoptosis.
  • Landscape technology
  • N-t-butyl-benzamide, N-t-butyl-4-bromobenzamide, N-t-butyl-4-nitrobenzamide, etc. are neurodegenerative diseases such as Parkinson's disease, multiple sclerosis, and Alzheimer's disease It is known that it is useful as a therapeutic agent for the disease (WO 95/28153, WO 96/31462).
  • N-t-butyl-3-chloro-2-oxopyridinecarboxamide and N_ (2-hydroxy-1,1-dimethylethyl) -16-chloro-2-pyridinecarboxamide are useful as herbicides. It is known that there are (JP-A-48-26918, JP-A-60-72803, JP-A-61-151174).
  • Apoptosis is a cell that exhibits morphological characteristics such as a decrease in cell volume due to cytoplasmic condensation, a collapse of the nucleus due to nuclear chromatin condensation fragmentation, and the formation of cell body fragments (apoptotic bodies) covered by cell membranes. It is a form of death that plays an essential role in many life phenomena, including morphogenesis during ontogeny, maintaining normal tissue structure, and removing unwanted cells.
  • apoptosis is also involved in the pathological cell death of many diseases.
  • Various pathological conditions or diseases can be caused by abnormally increasing or suppressing apoptosis. It is known that apoptosis is associated with the following diseases (Science, 261, 1456-1462 (1995), Biotherapy, 11, 836-844 (1997), History of Medicine 187.463 -538 (1998)).
  • apoptosis is enhanced by viral infection, and the typical type of disease is AIDS (acquired immunodeficiency syndrome). HIV infection induces apoptosis of CD4 + T cells.
  • autoimmune diseases such as multiple sclerosis
  • CTLs cytotoxic T lymphocytes
  • Apoptosis of cardiomyocytes is thought to be involved in the pathogenesis of ischemic diseases such as post-ischemia reperfusion injury, myocardial infarction, and cardiomyopathy, as well as cardiovascular diseases.
  • liver diseases such as colic hepatitis, hepatocellular death due to typical apoptosis is observed, and hepatic dysfunction occurs.
  • diabetes is caused by apoptosis of Teng / 3 cells.
  • vascular endothelial damage occurs, often leading to microvascular disorders such as nephropathy and complications such as obstructive atherosclerosis, but vascular endothelial cell death due to hyperglycemia is due to apoptosis I know that.
  • Apoptosis is thought to be involved in the development and progression of renal diseases such as mesangial proliferative nephritis. It has been suggested that apoptosis of bronchial and alveolar epithelial cells is involved in the pathogenesis of lung diseases such as pulmonary fibrosis.
  • Atherosclerosis is a complex lesion in which cell migration, proliferation, and death coexist.
  • arteriosclerosis lesions associated with hyperlipidemia apoptosis of macrophage-derived foam cells is observed.
  • Oxidative stress such as hyperlipidemia and smoking is known as a risk factor for arteriosclerosis, but oxidized denatured lipoprotein produced under such conditions induces apoptosis in macrophage-derived foam cells.
  • the present invention seeks to provide an apoptosis inhibitor.
  • the present invention provides a therapeutic agent for a disease associated with enhanced apoptosis.
  • the present invention relates to the following inventions [1] to [5].
  • Ar represents a phenyl group which may have a substituent or an aromatic heterocyclic group which may have a substituent.
  • n represents an integer 0, 1 or 2.
  • R 1 is a hydrogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, Represents alkynyl, alkoxycarbonyl, alkamoyl, alkanoyl or cyano which may be exchanged.
  • R 2 and R 3 each independently represent an alkyl group which may have a substituent. Or, R 2 combines with R ] or R 3 to form a cycloalkane ring with the carbon atom to which they are attached. The cycloalken ring may have a substituent.
  • R 4 and R 5 each independently represent a hydrogen atom or an alkyl group which may have a substituent.
  • R 6 represents a hydrogen atom, a hydroxyl group or an alkyl group.
  • an apoptosis inhibitor comprising a pharmaceutically acceptable salt thereof.
  • R represents a hydrogen atom or a modifying group
  • R 1 Q represents a hydrogen atom or an alkyl group which may have a substituent.
  • Ar, R 2 , R 3 , R 4 , R 5 , R 6 and n are as described above
  • an apoptosis inhibitor comprising a pharmaceutically acceptable salt thereof.
  • N-t-butyl-l-fluoro-l-methanesulfonylaminobenzamide N-tert-butyl-2-fluoro-4-phenylbenzamide
  • 2,4-difluorobenzamide ⁇ - (2- (3-carboxypropanoyloxy) — 1,1-dimethylethyl) 1,2,4-difluorobenzamide • N— (2-glycyloxy-1,1-dimethylethyl) 1,2,4-difluorobenzamide
  • Diseases associated with enhanced apoptosis are viral infections, myelodysplastic syndromes, blood diseases, autoimmune diseases, ischemic diseases, cardiovascular diseases, liver diseases, kidney diseases, lung diseases or arteriosclerosis
  • the substituent in the substituted phenyl or substituted aromatic heterocyclic group is a halogen atom, a cyano group, a nitro group, an alkyl group, a halogen-substituted alkyl group, an alkoxy group, a halogen-substituted alkoxy group, an alkoxycarbonyl group, an alkanoylamino Group, amino group, phenyl group, alkylaminocarbonylamino group, alkoxycarbonylamino group, alkylsulfonylamino group, rubamoyl group or alkyl-substituting rubamoyl group, substituted alkyl group, and substituted cycloalkane ring
  • the substituent in the above is a cycloalkyl group, an alkoxy group, a hydroxyl group, a halogen atom, an alkoxyalkoxy group, an alkanoyloxy group, an amino group, an alky
  • Ar is a phenyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, virazinyl group, 3-pyridazinyl group, 4-pyridazinyl group, 2-pyrimidinyl group, 4-pyrimidinyl group or 5 —Pyrimidinyl group (however, these groups Ar may be substituted with 1 to 3 halogen atoms, and the nitrogen atom of 2-pyridyl group, 3-pyridyl group and 4-pyridyl group may be oxidized)
  • the inhibitor according to any one of [1] to [6].
  • Ar is 2,4-difluorophenyl group, 2,4-dichlorophenyl group, 4-fluorophenyl group, 4-chlorophenyl group, 2-fluoro-4-chlorophenyl group, 2-fluoro-4 —Bromophenyl group, 2-fluoro-4-phenyl-phenyl group, 2,4,5-trifluorophenyl group, 5-chloro-2-pyridyl group, 5-fluoro-2-pyridyl group, 3-fluoro-2-pyridyl group , 2-Chloro-5-pyridyl group, 1-Oxido 2-pyridyl group, 1-Oxid 5-5-Chloro-2-pyridyl group, 1-Oxido 5-fluoro-2-pyridyl group, 1-Oxido 3-fluoro-
  • R 6 is a hydrogen atom [1] inhibitor according to any one of - [1 0].
  • the apoptosis inhibitor of the present invention includes, for example, viral infections such as AIDS, blood diseases such as myelodysplastic syndrome, aplastic anemia, autoimmune diseases such as multiple sclerosis, reperfusion injury after ischemia, and myocardial infarction. , Cardiomyopathy and other ischemic and cardiovascular diseases, fulminant hepatitis, liver diseases such as alcoholic hepatitis, diabetes and its complications, mesangial proliferation It is useful as a therapeutic agent for renal diseases such as inflammatory nephritis, pulmonary diseases such as pulmonary fibrosis, and arteriosclerosis.
  • the “modifying group” means a group that is eliminated in vivo to give a free hydroxyl group.
  • Representative examples of the “modifying group” include an acyl group, a phosphono group which may have a substituent, and an alkanoyloxymethyl group which may have a substituent.
  • acyl group examples include an alkanoyl group optionally having a substituent, an arylo group optionally having a substituent, an alkoxycarbonyl group optionally having a substituent, and a substituent. And an aminocarbonyl group which may be present.
  • alkanoyl group examples include straight-chain or branched-chain alkanoyl groups having 20 or less carbon atoms, and specific examples include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, vivaloyl, and 2-— Methylbutyryl, hexanoyl, lauroyl, myristoyl, nosolemitoyl, stearoyl and the like.
  • Examples of the “aroyl group” include groups having 10 or less carbon atoms, such as benzoyl, toluoyl, and naphthoyl.
  • Examples of the “substituent” of the substituted alkanoyl group and the substituted aryloyl group include an amino group, an alkylamino group, a dialkylamino group, an alkanoylamino group, an aryloamino group, a carboxy group, an alkoxycarbonyl group, and an aryloxycarbonyl group.
  • substituted alkoxycarbonyl group examples include an alkyl group, an arylalkyl group, and an aryl group.
  • the “substituent” of the substituted aminocarbonyl group includes an alkyl group, an arylalkyl group and an aryl group.
  • a dialkylamino group two alkyls which substitute for an amino group are bonded to each other or via an oxygen atom, and are combined with an amino amino atom to form, for example, pentayl or pyrrolidyl or morpholyl.
  • a 6-membered saturated heterocyclic ring may be formed.
  • Preferred alkyl groups include alkanoyl groups, substituted alkanoyl groups (for example, aminoalkanoyl groups, carboxyalkanoyl groups), aroyl groups, optionally substituted alkoxycarbonyl groups, optionally substituted aminocarbonyl groups, and the like.
  • Specific examples of the acetyl group include formyl, acetyl, propionyl, butyrinole, isobutyryl, norrelyl, isovaleryl, vivaloyl, 2-methylbutyryl, hexanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, and 3-alpha.
  • Minopropionyl 3-dimethylaminopropionyl, 2-dimethylaminobutyryl, 3-dimethylaminobutyryl, 4-dimethylaminobutyryl, 5-dimethylaminovaleryl, ethylaminoacetyl, getylaminoacetyl, Pyraminoacetyl, (1-pyrrolidyl) acetyl, (1-piperidyl) acetyl, morpholinoacetyl, ⁇ -amino acid acyl group (for example, glycyl, aranil, fenylalanil, arginyl, lysyl, ⁇ -aspartyl, / 3 —Aspal Tyl, ⁇ -glutamyl, ⁇ -glutamyl, methylaminoacetyl, dimethylaminoacetyl, 2-dimethylaminopropionyl, 2-dimethylamino-2-methylpropion
  • the substituted phosphono group an alkyl group, an arylalkyl group, an aryl group and the like can be mentioned.
  • Specific examples of the phosphono group which may have a substituent include phosphono, dimethylphosphono, getylphosphono and the like.
  • the ⁇ substituent '' of the alkanoyloxymethyl group which may have a substituent is present on the alkanol group, examples of the substituent and the substituted alkanoyl group are the same as those described above. Can be.
  • the “methyl” part of the alkanoyloxymethyl group may have a substituent such as an alkyl group.
  • aryl group examples include groups having 10 or less carbon atoms, such as phenyl, tolyl, and naphthoyl.
  • aromatic heterocyclic group for example, a 5- or 6-membered aromatic heterocycle containing 1 to 3 heteroatoms arbitrarily selected independently from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom And the like.
  • the nitrogen atom or sulfur atom constituting the ring may be oxidized.
  • the five-membered aromatic heterocyclic group is arbitrarily selected independently from the group consisting of nitrogen, sulfur and oxygen, such as pyrrolyl, phenyl, phenyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, thiazolifre and oxazolyl. And a five-membered aromatic heterocyclic group containing one or two hetero atoms.
  • Examples of the six-membered aromatic heterocyclic group include a six-membered aromatic heterocyclic group containing 1 to 3 nitrogen atoms.
  • pyridyl 1-oxydopyridyl
  • pyrazinyl pyrimidinyl
  • Pyridazinyl triazinyl and the like.
  • Examples of the “substituent” in the substituted phenyl group, the substituted aromatic heterocyclic group, the substituted 5-membered aromatic heterocyclic group and the substituted 6-membered aromatic heterocyclic group include, for example, a halogen atom, a cyano group, a nitro group, an alkyl group, Halogen-substituted alkyl group, alkoxy group, halogen-substituted alkoxy group, alkoxycarbonyl group, alkanoylamino group, amino group, phenyl group, alkylaminocarbonylamino group, alkoxycarbonylamino group, alkylsulfonylamino group, carbamoyl And an alkyl-substituting rubamoyl group, which may be independently substituted by one or more.
  • Preferred substituents in the substituted phenyl group include a halogen atom, a cyano group, a nitro group, a halogen-substituted alkyl group, a halogen-substituted alkoxy group, an alkoxycarbonyl group, an alkanoylamino group, an amino group, a phenyl group, and an alkylaminocarbonylamino group.
  • substituents include electron-withdrawing substituents such as a halogen atom, a cyano group, a nitro group, and trifluoromethyl, and more preferably a halogen atom. Particularly preferred is a fluorine atom.
  • Preferred substituents in the substituted aromatic heterocyclic group, the substituted 5-membered aromatic heterocyclic group and the substituted 6-membered aromatic heterocyclic group include a halogen atom, a cyano group, a nitro group, an alkyl group, a halogen-substituted alkyl group, and an alkoxy group.
  • the number of the substituents is, for example, 1, 2 or 3, preferably 1 or 2, and more preferably 2.
  • a preferred substitution position of the substituent is 4-position, and when it has a plurality of substituents, 2- and 4-positions are mentioned.
  • the substituted aromatic heterocyclic group the substituted 5-membered aromatic heterocyclic group and the substituted 6-membered aromatic heterocyclic group, the number of the substituents is, for example, 1, 2 or 3, and preferably 1 or 2. And more preferably 1.
  • alkyl group examples include straight-chain or branched-chain alkyl groups having 6 or less carbon atoms, and specifically, methyl, ethyl, propyl, 1-methylethyl, butyl, 2-methylpropyl, pentyl, Examples include 1,2-dimethylpropyl, hexyl, and 3-methylpentyl.
  • alkyl group is a part of another group, that is, for example, as an alkyl moiety in a halogen-substituted alkyl group, an alkylaminocarbonyl group, an alkylsulfonylamino group, an alkylamino group, a dialkylamino group, etc. Can be exemplified.
  • alkoxy group examples include straight-chain or branched-chain alkoxy groups having 6 or less carbon atoms. Specific examples include methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 2-methylpropoxy, and pentyloxy. , 1,2-dimethylpropoxy, hexyloxy, 3-methylpentoxy and the like.
  • Alkoxyalkoxy group means an alkoxy group substituted with alkoxy.
  • Alkoxycarbonyl group means a carbonyl group substituted with alkoxy.
  • Halogen-substituted alkyl group and “halogen-substituted alkoxy group” mean an alkyl and an alkoxy, respectively, substituted by one or more halogen atoms. Preferred examples thereof include, for example, trifluoromethyl and trifluoromethyl, respectively. Tokishi etc. are mentioned.
  • alkyl-substituted rubamoyl group includes a monoalkyl-substituted rubamoyl group and a dialkylcarbamoyl group, and examples of the alkyl portion thereof include the above-mentioned alkyl groups.
  • halogen atom for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like can be mentioned.
  • a fluorine atom, a chlorine atom and a bromine atom Preferred are a fluorine atom, a chlorine atom and a bromine atom, and particularly preferred is a fluorine atom.
  • cycloalkane ring examples include a cycloalkane ring having 3 to 8 carbon atoms. Specifically, a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cyclohexane ring, a cycloheptane ring, a cyclooctane And the like.
  • substituted alkyl and substituted cycloalkane rings examples include, for example, cycloalkyl, alkoxy, hydroxyl, halogen atom, alkoxyalkoxy, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino and the like.
  • aryl groups such as phenyl and tolyl, and complex ring groups such as pyrrolidino, piperidino, piperazino, 4-alkylpiperazino, and morpholino.One or more of these substituents are independently present. It may be.
  • cycloalkyl group examples include cycloalkyl groups having 8 or less carbon atoms, such as cyclopentyl and cyclohexyl.
  • R 2 and R 3 in the above formula preferably include an alkyl group which may be substituted, more preferably an alkyl group, particularly preferably methyl and ethyl.
  • R 1 and R 6 in the above formula preferably include a hydrogen atom.
  • n is preferably 0 or 1, and particularly preferably 0.
  • the compound represented by the formula 1 has a basic group or an acidic group, it can be converted into a salt with an acid or a base according to a conventional method.
  • Salts with pharmaceutically acceptable acids include addition salts with inorganic or organic acids.
  • the inorganic acid include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and the like.
  • the organic acid include acetic acid, oxalic acid, citric acid, malic acid, tartaric acid, maleic acid, fumaric acid and the like.
  • Salts with pharmaceutically acceptable bases include addition salts with inorganic or organic bases.
  • Inorganic bases include, for example, sodium hydroxide, potassium hydroxide, water Calcium oxide and the like.
  • examples of the organic base include basic amino acids such as arginine and lysine.
  • the compound represented by the formula 1 or a pharmaceutically acceptable salt thereof may be a solvate such as a hydrate, and when a tautomer, a geometric isomer or a stereoisomer exists, May be a mixture of these isomers or an isolated one.
  • the compound represented by the formula 1 can be produced as follows according to the method described in International Application PCT / JP98 / 04782 (WO 99/21543).
  • RG represents a hydrogen atom or a leaving group.
  • R 16 has the same meaning as R 6 described above, or represents a protected hydroxyl group.
  • a r, n, RR 2 , R 3 , R 4 , R 5 and R 6 are as defined above.
  • the leaving group in R Q means the “protecting group” in the above reaction or the same “modifying group” as in R above. That is, the compound of formula 1A can be produced by protecting the amino group with a protecting group, if necessary, and condensing it with the compound of formula 3.
  • the compound in which RG in Formula 1A is a hydrogen atom or a “modifying group” corresponds to the compound of Formula 1 described above.
  • R 16 is a protected hydroxyl group and R G is a ⁇ protecting group ''
  • a conventional protecting group used in the field of organic synthetic chemistry can be used, and the introduction and removal of the protecting group can be performed according to a conventional method (for example, “Protective Groups in Organic Synthesis”). TW Greene, PM Wuts, dohn Wiley and Sons, 1991, pp. 10-142).
  • Examples of the protecting group for the hydroxyl group in R 16 include protecting groups usually used in the field of synthetic organic chemistry (eg, “Protective Groups in Organic Synthesis” TW Greene, PM Wuts, John Wiley and Sons, 1991, 10-). See page 142).
  • substituted silyl groups such as trimethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, getylisopropylsilyl, t-butyldimethylsilyl, diphenylmethylsilyl, tbutyldiphenylsilyl, and t—
  • substituted silyl groups such as trimethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, getylisopropylsilyl, t-butyldimethylsilyl, diphenylmethylsilyl, tbutyldiphenylsilyl, and t—
  • examples thereof include an optionally substituted methyl group such as butyl, benzyl, trityl, methoxymethyl, methylthiomethyl, benzyloxymethyl, methoxyethoxymethyl, and tetrahydroviranyl.
  • Preferable examples include t-butyl, benzyl, trityl, methoxymethyl, tetrahydroviranyl, benzyloxymethyl, methoxetoxymethyl and the like.
  • the condensation reaction between the compound of the formula 2 and the compound of the formula 3 can be carried out according to a known method in peptide chemistry (for example, see “Basic and Experimental Peptide Synthesis” by Nobuo Izumiya et al., Maruzen).
  • C-terminal activation method (acid halide method, acid azide method, mixed anhydride method, active ester method, symmetric acid anhydride, etc.), method using coupling reagent (N, N'-dicyclohexylcal) A method using a posiimide, etc.), N-terminal activation method (isocyanate method, phosphazo method, phosphite method, etc.).
  • acid halide method for example, a compound of the formula 2 is converted into an acid halide according to a conventional method, and then, in an inert solvent such as dichloromethane at 0 ° C. It can be carried out at room temperature by condensation with the compound of formula 5.
  • the base examples include an organic base such as triethylamine.
  • a coupling reagent for example, a compound of the formula 2 and a compound of the formula 3 are mixed with an N— (3-— compound in an inert solvent such as dichloromethane or N, N-dimethylformamide (DMF). Dimethylaminopropyl)-N'-Ethylcarbodiimid hydrochloride (WSC hydrochloride), etc., in the presence of 1-hydroxybenzotriazole (HOB t) if necessary in the presence of a coupling reagent Then, condensation can be performed at 0 ° C. to room temperature.
  • an inert solvent such as dichloromethane or N, N-dimethylformamide (DMF).
  • DMF dimethylaminopropyl)-N'-Ethylcarbodiimid hydrochloride
  • HOB t 1-hydroxybenzotriazole
  • an N-oxide compound can be produced by condensing the compound of the formula 4 and the compound of the formula 5 and then oxidizing the compound with an appropriate oxidizing agent.
  • oxidation can be performed at room temperature to reflux temperature using an oxidizing agent such as aqueous hydrogen peroxide.
  • R 16 is a protected hydroxyl group
  • the protecting group for the hydroxyl group can be deprotected according to a conventional method.
  • the protecting group is t-butyl, benzyl, trityl, methoxymethyl, tetrahydroviranyl, benzyloxymethyl, methoxetoxymethyl, etc.
  • deprotection is achieved by hydrogenolysis or hydrolysis using an acid catalyst. can do.
  • the compound represented by the formula (1) in which the length is ⁇ modifying group '' can be produced by modifying the compound represented by the formula (1) wherein R is a hydrogen atom, according to a usual method in the field of synthetic organic chemistry. .
  • a compound in which R is an acyl group can be produced by protecting a compound in which R is a hydrogen atom, if necessary, by protecting the active functional group with a suitable protecting group, and then acylating it according to a conventional method.
  • R is a phosphono group which may have a substituent or an alkanoyl group which may have a substituent
  • the compounds that are 'groups' can also be Can be manufactured. Further, the raw material of compound R G is "modifying group" in the formula 3 is also, similarly, can be produced by modifying the compound R Q is a hydrogen atom.
  • the compound obtained as described above can be purified by a usual method. For example, it can be purified by column chromatography, recrystallization and the like. Examples of the recrystallization solvent include alcohol solvents such as methanol, ethanol, and 2-propanol; ether solvents such as dimethyl ether; ester solvents such as ethyl acetate; aromatic solvents such as toluene; ketone solvents such as acetone; and hexane.
  • the apoptosis inhibitor of the present invention can be administered orally or parenterally (intramuscular or intravenous injection, rectal administration in the form of a suppository, application to the skin as an external preparation, eye drops, etc.).
  • parenterally intramuscular or intravenous injection, rectal administration in the form of a suppository, application to the skin as an external preparation, eye drops, etc.
  • it when administered orally, it can be in the form of tablets, capsules, syrups, suspensions, etc., and when administered as injections, solutions such as solutions, emulsions, suspensions, etc.
  • Such a dosage form can be produced according to a general method by mixing the active ingredient with a usual carrier, excipient, binder, stabilizer and the like.
  • a buffer When used in the form of an injection, a buffer, a solubilizing agent, an isotonic agent and the like can be added.
  • the dosage and frequency of administration vary depending on the symptoms, age, body weight, dosage form, etc., but for oral administration, the dose is usually in the range of 1 to 1000 mg, preferably 10 to 500 mg per day for adults. It can be administered once or in several divided doses. When administered as an injection, it can be administered in the range of 0.1 to 500 mg, preferably in the range of 3 to 100 mg, once or several times.
  • Wistar male rats (Charles Riva Japan) were purchased at the age of 6 weeks and bred for 1 week in a light-dark cycle (8: 00-20: 00 light period). Bred for a while.
  • the white light continuous irradiation obstruction device is a breeding box with a lid made of an acrylic plate with an inner surface of 1020 mm in length and 425 mm in width and 520 mm in height, all mirrored. Irradiation was performed continuously for 24 hours with a white fluorescent lamp from the top of the device. At this time, the average illuminance in the device is 174.2 foot candle. After breeding for 2 days, the rats were placed in a dark room and allowed to dark adapt for at least 4 hours.
  • Rats are fixed on a brain fixation device under ketamine-xylazine anesthesia, mydriatics are administered by instillation, electrodes are attached to the cornea, the forehead, and the lower part of the ear lobe, and ERG (electroretinogram) for light stimulation with constant intensity was measured.
  • ERG electroretinogram
  • the degree of retinal damage was evaluated based on the amplitude of a-wave of ERG derived from extraretinal granule cells (photoreceptor cells).
  • the test substance was administered by instillation immediately before being placed in the injured device (10:00) and at 13:00, 16:00, 19:00, and the same time the following day, and the protective effect was evaluated.
  • the compound of the present invention was dissolved in a 0.5% methylcellulose (MC) solution containing 0 to 5% Tween 80 using 5 rats, and 50 ⁇ l of the solution was instilled into both eyes at a time.
  • MC methylcellulose
  • MC administration group 0.5% MC solution was administered by instillation, and As a control group, rats raised on a normal 12-hour light-dark cycle were used.
  • the percentage of protection against retinal damage I was expressed as% protection and the results are shown in Table 1.
  • Test Example 2 Inhibition of extraretinal granule cell apoptosis by continuous white light irradiation
  • Test Example 27 The same test as in Test Example 2 was performed on the compound of Production Example 27. Oral administration (administered immediately before placing in the disordered device (10:00) and at the same time the following day) was examined. The number of TUNNEL-positive cells was counted at four sites of the retina per eye, and the average value of the number of positive cells per unit area was calculated.
  • Table 4 shows the results.
  • the administration of the compound of Production Example 27 reduced the number of apoptosis-positive cells in a dose-dependent manner.
  • Production example 2 7 ⁇ 0 mg / kg 2 5 5 1 Sat 3 2 0 5
  • Production example 2 7 0 mg / kg 8 3 8 Sat 1 9 0 5
  • the title compound (0.3996 g; 93) was obtained by performing the same reaction as in Production Example 1 using 3,5-difluorobenzoyl chloride (0.3555 g, 2.01 mmol) instead of 2,4-difluorobenzoyl chloride. %).
  • the title compound (0.4130 g; 97) was obtained by carrying out the same reaction as in Production Example 1 using 2,6-difluorobenzoyl chloride (0.3547 g, 2.01 mmol) instead of 2,4-difluorobenzoyl chloride. %).
  • the title compound (0.4794 g; 95) was obtained by performing the same reaction as in Production Example 1 using 4-bromobenzoyl chloride (0.4301 g, 1.97 mmol) instead of 2,4-difluorobenzoyl chloride. %).
  • the title compound (0.3611 g; 93) was obtained by performing the same reaction as in Production Example 1 using 4-methylbenzoyl chloride (0.3153 g, 2.04 mmol) instead of 2,4-difluorobenzoyl chloride. %).
  • the title compound (0.5017 g) was obtained by performing the same reaction as in Production Example 1 using 2,4-dichlorobenzoyl chloride (0.4169 g, 1.99 mmol) instead of 2,4-difluorobenzoyl chloride. ;> 99%).
  • the title compound (0.4204 g; 0.4204 g;) was obtained by performing the same reaction as in Production Example 1 except that 4,1-difluorobenzoyl chloride was used instead of 2,4-dibenzobenzoyl chloride. 99%).
  • 2,4-difluorobenzoyl chloride (0.3532 g, 2.00 mmol) was replaced with t-butylamine, isopropylamine (0.26 ml, 3.05 mmol).
  • the title compound (0.3804 g; 95%) was obtained by performing the same reaction as in Production Example 1 using the above compound.
  • the title compound (0.4278 g; was obtained by performing the same reaction as in Production Example 14 using 2-chloro-4 monofluorobenzoic acid (0.3492 g, 2.00 mmol) in place of 4 monochloro-2-fluorobenzoic acid. 93%).
  • the title compound (0.2966) was obtained by carrying out the same reaction as in Production Example 1 using nicotinoyl lauride chloride hydrochloride (0.3569 g, 2.00 mmol) instead of 2,4-difluorobenzoyl lauride. g; 83%).
  • the title compound (0.3109 g) was obtained by performing the same reaction as in Production Example 1 using picolinoyl chloride and hydrochloride (0.3624 g, 2.04 mmol) instead of 2,4-difluorobenzoyl chloride. ; 86%).
  • the title compound (0.4869 g; 95%) was obtained by performing the same reaction as in Production Example 14 using 4 monophenylbenzoic acid (0.3982 g, 2.01 mmol) in place of 4 monochloro-2-benzoic acid. Obtained.
  • the reaction mixture was concentrated, diluted with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate, 1N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated saline, and dried over magnesium sulfate.
  • the title compound was obtained by carrying out the same reaction as in Production Example 26 using 2-amino-2 monomethylpropanamide hydrochloride instead of 2-fluoro-1,1-dimethylethylamine hydrochloride.
  • the title compound was obtained by performing the same reaction as in Production Example 26 using 2-amino-2-methylpropionic acid methyl ester hydrochloride instead of 2-fluoro-1,1-dimethylethylamine hydrochloride. .
  • the extract layer was washed with a saturated saline solution and dried with magnesium sulfate.
  • the solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate 10/1) to obtain the title compound (0.38 g; 60%).
  • N- (2-hydroxy-1,1-dimethylethyl) -1,2,4-difluorobenzamide (6.2 g, 27 mmol) obtained in Production Example 27, triethylamine (8.2 g, 81 mmol) and dimethyl sulfoxide (A solution of a pyridine.sulfur trioxide complex (12.9 g, 81 mmol) and DMSO (60 ml) was added dropwise to a solution of DMSO) (60 ml) under ice cooling, and the mixture was stirred for 2 hours. The reaction solution was poured into ice water and extracted with ethyl acetate.
  • the extract layer was washed sequentially with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, and dried over sodium sulfate. After concentration under reduced pressure, the residue was recrystallized from hexane monoethyl acetate to obtain the title compound (5.05 g; 82%).
  • the extract layer was washed successively with 1 N hydrochloric acid, saturated aqueous sodium hydrogencarbonate and saturated saline, and dried over sodium sulfate.
  • the filtrate was concentrated under reduced pressure, and the residue was crystallized from hexane-ethyl acetate to give the title compound (0.24 g; 81%).
  • N— (1-Carboxy-1-methylethyl) -1,2,4-difluorobenzamide N_ (1—Methoxycarbonyl 1-methylethyl) obtained in Production Example 30
  • methanol 10 ml
  • methanol 10 ml
  • methanol 10 ml
  • the mixture was stirred at room temperature for 30 minutes.
  • methanol was distilled off
  • the mixture was acidified with 4 N hydrochloric acid, extracted with ethyl acetate, and the extracted layer was dried over sodium sulfate.
  • the solvent was distilled off under reduced pressure to obtain the title compound (1.42 g; 99%).
  • the title compound was obtained by carrying out the same reaction as in Production Example 27 using 1,1-dimethylpropargylamine in place of 2-amino-1-methyl-1-propanol.
  • AD-mix- ⁇ (Aldrich: 1.39 g) to a mixture of butanol and water (1: 1, 10 ml), cool with ice, and add 6-chloro-3-vinylpyridazine (0.14 g, l.Ommol ), And the mixture was gradually warmed to room temperature and stirred overnight.
  • 6-Chloro-3-pyridazinecarboxylic acid (0.12 g, 0.76 mmol) and dichloromethane (15 ml) in a solution of t-butylamine (0.21 ml, 2.0 mmol) and N, N-bis (2-oxo-13-oxazolidinyl) ) Phosphinic chloride (0.24 g, 0.93 mmol) was added and stirred overnight.
  • the mixture was extracted three times, and the collected organic layer was washed with saturated saline and dried with sodium sulfate.
  • Potassium carbonate (0.29 g, 2.1 mmol) was gradually added to a solution of sodium periodate (2.13 g, 9.98 mmol), potassium permanganate (0.065 g, 0.41 mmol) and water (10 ml).
  • butanol 5 ml
  • the 5-chloro-2- obtained above Vinyl pyridine (0.34 g, about 2 mmol) was gradually added, and the mixture was stirred for 1 hour.
  • Ethylene glycol (1 ml) was added thereto, and the mixture was further stirred for 1 hour.
  • the reaction mixture was added to a 5% aqueous potassium hydrogen sulfate solution, extracted three times with ethyl acetate, and dried over sodium sulfate.
  • the solvent was distilled off to obtain 0.31 g of the title compound.
  • the title compound was obtained by performing the same reaction as in Production Example 27 using 5-chloro-2-pyridinecarboxylic acid and t-butylamine instead of 2,4-difluorobenzoic acid and 2-amino-2-methyl-1-propanol. Obtained.
  • the extract layer was dried over sodium sulfate and the solvent was distilled off under reduced pressure to obtain a mixture of regioisomers of fluorocyanoviridine (0.9 g).
  • 10 ml of a 4N aqueous sodium hydroxide solution was added 10 ml of a 4N aqueous sodium hydroxide solution, and the mixture was heated under reflux for 2.5 hours. After allowing to cool, the mixture was acidified with concentrated hydrochloric acid, and then concentrated to dryness under reduced pressure. This residue was suspended in DMF (10 ml), t-butylamine (1.46 g, 20 mmol), WSC hydrochloride (3.1 g, 16 mmol) and HOBt (2.2 g, 16 mmol) were added, and the mixture was stirred overnight.
  • reaction mixture was diluted with water, extracted with ethyl acetate, and the extracted layer was washed with saturated aqueous sodium hydrogen carbonate and dried over sodium sulfate.
  • the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (hexane Z ethyl acetate 2 5/1) to give the title compound (0.19 g; 12%).
  • WSC was added to a mixture of 2-pyrazinecarboxylic acid (0.99 g, 8 mmol), 2-amino-2-methyl-1-propanol (0.80 g, 9 mmol), HOBt (1.36 g, lOmmol) and dichloromethane (30 ml). Hydrochloride (1.94 g, 10 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture is diluted with ethyl acetate, and then successively with saturated aqueous sodium hydrogen carbonate and saturated saline. After washing, it was dried over sodium sulfate and the solvent was distilled off.
  • the title compound was obtained by carrying out the same reaction as in Production Example 14 using 4-bromo-2-fluorobenzoic acid instead of 4-chloro-2-fluorobenzoic acid.
  • the title compound was obtained by carrying out the same reaction as in Production Example 14 using 2-bromo-4-fluorobenzoic acid instead of 4-chloro-2-fluorobenzoic acid.
  • the dichloromethane was distilled off under reduced pressure, diluted with ethyl acetate, washed sequentially with water, 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over sodium sulfate.

Abstract

L'invention concerne des inhibiteurs de l'apoptose contenant des composés représentés par la formule générale (1), ou des sels de ces composés, acceptables sur le plan pharmacologique. Dans cette formule Ar représente phényle, un hétérocycle aromatique, etc., n représente un nombre entier de 0, 1 ou 2, R représente hydrogène ou un modificateur, R1 représente hydrogène, alkyle, etc., et R2 et R3 représentent chacun alkyle, etc., ou bien R2 peut être lié à R1 ou R3 pour former un noyau cycloalcane éventuellement substitué, ensemble avec les (l') atome(s) de carbone auxquels ils sont liés, R4 et R5 représentent chacun hydrogène, alkyle, etc., et R6 représente hydrogène, hydroxy ou alkyle.
PCT/JP2000/002471 1999-04-23 2000-04-14 Inhibiteurs de l'apoptose WO2000064430A1 (fr)

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JP2004018524A (ja) * 2002-06-13 2004-01-22 Eucro European Contract Research Gmbh & Co Kg 動脈硬化症を処置するための方法
WO2007010350A1 (fr) * 2005-07-19 2007-01-25 Pfizer Products Inc. Synthèse d’éthers diphényliques à usage thérapeutique
CN110305032A (zh) * 2019-07-11 2019-10-08 常州永和精细化学有限公司 N-叔丁基-4-氨基苯甲酰胺的制备方法

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WO2007010350A1 (fr) * 2005-07-19 2007-01-25 Pfizer Products Inc. Synthèse d’éthers diphényliques à usage thérapeutique
CN110305032A (zh) * 2019-07-11 2019-10-08 常州永和精细化学有限公司 N-叔丁基-4-氨基苯甲酰胺的制备方法

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