Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • 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
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

• Drugs that are currently used for the initial treatment of ischemic stroke include intravenous thrombolytics, such as t-PA (Activase®) or Streptokinase; and anti-clotting agents such as Ancrod, Asprin, Aggrenox, Thienopyridines, and Warfarin.
• intravenous thrombolytics such as t-PA (Activase®) or Streptokinase
• anti-clotting agents such as Ancrod, Asprin, Aggrenox, Thienopyridines, and Warfarin.
• thienopyridines such as Ticlopidine (Ticlid®) have been associated with reversible lupus-like symptoms, reversible neutropenia and thrombocytopenia.
• the compounds of this invention are useful for treating, preventing, or lessening the severity of a variety of disorders, including neurodegenerative disorders, neurological disorders, inflammatory disorders, ischemic disorders, reperfusion/ischemia in stroke, heart disease, allergic disorders, organ hypoxia, and thrombin-induced platelet aggregation to name a few.
• neurodegenerative disorders including neurodegenerative disorders, neurological disorders, inflammatory disorders, ischemic disorders, reperfusion/ischemia in stroke, heart disease, allergic disorders, organ hypoxia, and thrombin-induced platelet aggregation to name a few.
• a cycloalkyl group may contain one or more substituents.
• Suitable substituents (R 5 ) for replacement of one or more hydrogen atoms on the saturated carbon of a cycloalkyl ring (as defined by R ) include one or more independent occurrences of: halogen, alkyl, -(CH 2 ) q OR 6 , -(CH 2 ) q SR , -(CH 2 ) q N(R 6 ) 2 , -(CH 2 ) q NR 6 C(O)R 6 , -(CH 2 ) q NR 6 C(O)N(R 6 ) 2 , -(CH 2 ) q NR 6 CO 2 R 6 , - (CH 2 ) q CO 2 R 6 , - (CH 2 ) q C(O)R 6 , -(CH 2 ) q C(O)N(R 6 ) 2 , -(CH 2 ) q OC(
• structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention.
• structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a 13 C- or l C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biological assays.
• R 1 is hydrogen or fluorine
• R 2 is substituted or unsubstituted cycloalkyl
• r is 0 or 1
• R 3 is alkyl, or -(CH 2 ) m OR 4
• m is 0, 1 or 2
• R 4 is hydrogen or alkyl
• n is 0, 1 or 2.
• the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
• a non-toxic parenterally-acceptable diluent or solvent for example as a solution in 1,3-butanediol.
• acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• Neurodegenerative diseases which may be treated or prevented by the compounds of this invention include, but are not limited to, Alzheimer's disease, Parkinson's disease, cerebral ischemias or neurodegenerative disease caused by traumatic injury.
• Example 12 Preparation of 1-8: 1H NMR (CDC1 3 , 500 MHz) ⁇ 8.13 (d, IH), 7.49
• Example 17 Preparation of N -CBz-(lR. 2R. 4S)-bicyclor2.2.11hept-2-ylamine and N -CBz-(lS, 2S. 4R)-bicyclor2.2.11hept-2-ylamine: [00116] Scheme 3:
• Example 24 Preparation of 1-17: (4-Methyl-cyclohexyl)-[4-(3-phenyl-5- piperidin-l-ylmethyl-isoxazol-4-yl)-pyrimidin-2-yl]-amine: 1H NMR (500 MHz, CDC1 3 ) ⁇ 8.05 (1 H, m), 7.4 (2 H, m), 7.30 (3 H, m), 6.25 (1 H, d), 5.22 (0.5 H, br s), 4.95 (0.5 H, br s), 3.95 (3 H, d), 3.55 (1 H, br s), 2.40 (4 H, br s), 1.95 (2 H, s), 1.90 (1 H, d), 1.65 (2 H, d), 1.50 (6 H, in), 1.35 (3 H, m), 1.10 (1 H, m), 0.90 (1 H, m); HPLC (Method A): 3.26 min; MS (ES + ): m/z 432.33 (M+H).
• rat brains were removed, and chilled on ice in IX PBS for 10 mins.
• Two mm thick coronal sections (7 sections per brain) were be stained by 2% TTC in IX PBS and post fixed overnight by 10% neutral buffered formalin.
• Body temperature was monitored throughout the surgery and maintained near normal values (36.8 - 37.5° C). Body temperature was documented at the time of MCAO, two hours into ischemia, at the beginning of treatment (2, 4 or 6 hr post ischemia), 24, 48 and 72 hr post ischemia (end of experiment).
• compounds are administered using the
• This protocol describes the procedure used to induce experimental ischemia by anoxia-re-oxygenation in cultured hippocampal neuronal cells.
• the neuroprotective effect of test compounds is evaluated against ischemic-induced neuronal cell injury and cell death
• Neurobasal/B27AO contains Neurobasal medium (Invitrogen Corp Cat # 21103-049) with 2x B27 minus AO supplement (Invitrogen Corp Cat #10889-038), 0.5 mM L-glutamine, and 0.25x Penicillin/Streptomycin] was pre-equilibrated overnight. [00155] The following steps were performed the day of the assay:

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• Chemical & Material Sciences (AREA)
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• Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Bioinformatics & Cheminformatics (AREA)
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• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Engineering & Computer Science (AREA)
• Vascular Medicine (AREA)
• Neurology (AREA)
• Cardiology (AREA)
• Heart & Thoracic Surgery (AREA)
• Diabetes (AREA)
• Hematology (AREA)
• Biomedical Technology (AREA)
• Urology & Nephrology (AREA)
• Neurosurgery (AREA)
• Pain & Pain Management (AREA)
• Rheumatology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

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• 2003
  • 2003-09-08 US US10/657,811 patent/US20040132755A1/en not_active Abandoned
  • 2003-09-08 JP JP2004534669A patent/JP2006502168A/ja active Pending
  • 2003-09-08 AU AU2003270350A patent/AU2003270350A1/en not_active Abandoned
  • 2003-09-08 WO PCT/US2003/027903 patent/WO2004022555A1/en not_active Ceased
  • 2003-09-08 EP EP03752038A patent/EP1546141A1/en not_active Withdrawn

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