Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
  • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
• • 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
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • 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
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
• • 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
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • 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
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • 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]
  • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• Yet another aspect of the invention relates to a method of selectively modulating to nAChR activity, for example ⁇ .7 nAChR activity.
• the method is useful for treating and/or preventing conditions and disorders related to ⁇ .7 nAChR activity modulation in mammals.
• Stereoisomers may exist as stereoisomers wherein, asymmetric or chiral centers are present. These stereoisomers are “R” or “S” depending on the configuration of substituents around the chiral element.
• R and “S” used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45: 13-30.
• Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers.
• Quinuclidine ethers of formula (14), wherein Ar 1 is a nitrogen-containing heteroaryl, for example pyridazine, and Ar 2 is as defined for formula (I), can be prepared as shown in Scheme 2.
• Potassium quinuclidinoxide (10) can be reacted with a dihaloaromatic ring, for example, dichloropyridazine, of formula (11 ) to obtain a quinuclidine ether of formula (12).
• the quinuclidine ether can be reacted with a suitable tin or boron reagent, as described in Scheme 1 , to provide a fused bicycloheterocycle substituted quinuclidine ether of formula (14).
• Compounds of formula (29) also can be treated with a hexamethylditin or diboron reagent of formula (9), such as bis(pinacolato)diboron and bis(catecholato)diboron, in the presence of a palladium catalyst to provide the corresponding tin or boronic acid of formula (30), which is reacted with a desired halide of an amine-substituted fused bicycloheterocycle represented by Ar 2 of formula (46), wherein X 1 is bromide, chloride, or iodide, to provide compounds of formula (69).
• a hexamethylditin or diboron reagent of formula (9), such as bis(pinacolato)diboron and bis(catecholato)diboron in the presence of a palladium catalyst to provide the corresponding tin or boronic acid of formula (30), which is reacted with a desired halide of an amine-substituted fused bi
• Aminobenzothiazole-substituted quinuclidines of formula (82) can be obtained as shown in Scheme 13.
• Amino-substituted quinuclidine ethers, thioethers, and amines of formula (80) are obtained by methods described in Schemes 6-12.
• Compounds of formula (80) are reacted with bromine and KSCN in acetic acid to provide aminobenzothiazole-substituted quinuclidines of formula (81 ).
• N-(4-lodophenyl)quinuclidin-3-amine 3-Quinuclidinone hydrochloride (Aldrich, 3.22 g, 20 mmol) was treated with 4- iodo-aniline (Aldrich, 2.19 g, 10 mmol), Na 2 SO 4 (anhydrous, Aldrich, 7.40 g, 50 mmol) and NaBH(OAc) 3 (Aldrich, 3.16 g, 15 mmol) in HOAc (25 mL) at ambient temperature for 15 h. After the reaction was complete, the reaction mixture was slowly poured into a flask containing 75 mL of saturated NaHCO 3 and stirred for 20 min.
• Example 24B The product of Example 24B (25.Og, 100 mmol) was stirred in POCI 3 (Aldrich, 200 ml_) at 100 0 C for 18 h. Most of POCI 3 was then distilled off (around 150 mL was collected). The residue was then poured into 300 ml_ of ice/water and stirred vigorously for 1 h. The solid was filtered off. The filtrate was washed with water (2 x 50 ml_) and dried under vacuum to give the title compound (26.2 g, 98%).
• POCI 3 Aldrich, 200 ml_
• Example 27A 5-(6-f(3R)-1 -Qxy-1 -Aza-bicvclof2.2.21oct-3-yloxy1-Pyridazin-3-yl)-1 ,3-dihvdro-indol-2- one
• Example 36A The product of Example 36A (40 mg, 0.10 mmol) was treated with HCI (Aldrich, 4M in dioxane, 0.25 ml_, 1.0 mmol) in EtOAc (3 ml_) at ambient temperature for 1 hour to afford the title compound as yellow solid (20.0 mg, 92%).
• Example 4A The product of Example 4A (127 mg, 1 mmol ) was coupled with 3-(6-chloro- pyridazin-3-yl)-1 H-indole (Bionet, 229 mg, 1 mmol) according to the procedure of Example 39. The title compound was obtained as solid (208.3 mg, yield, 35%).

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• General Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Public Health (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• Neurology (AREA)
• Biomedical Technology (AREA)
• Neurosurgery (AREA)
• Psychiatry (AREA)
• Reproductive Health (AREA)
• Cardiology (AREA)
• Pain & Pain Management (AREA)
• Heart & Thoracic Surgery (AREA)
• Rheumatology (AREA)
• Hospice & Palliative Care (AREA)
• Urology & Nephrology (AREA)
• Psychology (AREA)
• Dermatology (AREA)
• Gynecology & Obstetrics (AREA)
• Pregnancy & Childbirth (AREA)
• Vascular Medicine (AREA)
• Endocrinology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Priority Applications (1)

Applications Claiming Priority (1)

Publications (1)

Family

ID=34960429

Family Applications (1)

Country Status (6)

Families Citing this family (27)

Family Cites Families (7)

• 2004
  • 2004-12-10 WO PCT/US2004/041471 patent/WO2006065233A1/en active Application Filing
  • 2004-12-10 EP EP04813737A patent/EP1824848A1/de not_active Withdrawn
  • 2004-12-10 CA CA002551486A patent/CA2551486A1/en not_active Abandoned
  • 2004-12-10 AU AU2004325725A patent/AU2004325725A1/en not_active Abandoned
  • 2004-12-10 JP JP2007545431A patent/JP2008523058A/ja not_active Ceased
  • 2004-12-10 CN CNA2004800419490A patent/CN1922176A/zh active Pending

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events