TWI444366B - 作為磷酸二酯酶抑制劑之１－苯基－２－吡啶烷基醇衍生物 - Google Patents

作為磷酸二酯酶抑制劑之１－苯基－２－吡啶烷基醇衍生物 Download PDF

Info

Publication number
TWI444366B
TWI444366B TW097130008A TW97130008A TWI444366B TW I444366 B TWI444366 B TW I444366B TW 097130008 A TW097130008 A TW 097130008A TW 97130008 A TW97130008 A TW 97130008A TW I444366 B TWI444366 B TW I444366B
Authority
TW
Taiwan
Prior art keywords
alkyl
group
substituted
halogen atoms
compound
Prior art date
Application number
TW097130008A
Other languages
English (en)
Other versions
TW200916440A (en
Inventor
Maurizio Delcanale
Gabriele Amari
Elisabetta Armani
Original Assignee
Chiesi Farma Spa
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chiesi Farma Spa filed Critical Chiesi Farma Spa
Publication of TW200916440A publication Critical patent/TW200916440A/zh
Application granted granted Critical
Publication of TWI444366B publication Critical patent/TWI444366B/zh

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • 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
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • 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
    • C07D213/61—Halogen atoms or nitro 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
    • C07D213/79—Acids; Esters
    • 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
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pulmonology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Description

作為磷酸二酯酶抑制劑之1-苯基-2-吡啶烷基醇衍生物
本發明係關磷酸二酯酶4(PDE4)酵素之抑制劑。特定言之，本發明係關於屬於1-苯基-2-吡啶烷基醇之衍生物之化合物、此等化合物之製備方法、含有此等化合物之組成物及其治療用途。
呼吸道阻塞係為多種嚴重呼吸道疾病包括氣喘及慢性阻塞性肺疾(COPD)之特徵。導致呼吸道阻塞之事件包括呼吸道壁水腫、黏液產量增加及發炎。
呼吸道疾病諸如氣喘及COPD之治療用藥目前係經由吸入投予。吸入投藥途徑優於系統性投藥途徑之優點之一為可將藥物直接遞送於作用部位，避免任何系統性副作用，如此導致更為快速的臨床反應及更高治療比。
吸入性皮質類固醇為氣喘之目前首選的維持治療，且用於急性症狀的緩解可合併使用支氣管擴張劑β2 促效劑，二者構成目前該疾病治療上的基石。目前COPD的處理大半為根據症狀以吸入性抗膽鹼激性劑及吸入性β2 腎上腺受體激動劑利用支氣管擴張治療。但皮質類固醇用於COPD時係無法如同用於氣喘減低發炎反應。
另一類已經就其抗炎效果用於發炎性呼吸道疾病諸如氣喘及COPD的治療上廣為人研究的治療劑以酵素磷酸二酯酶(PDE)抑制劑為代表，特別為磷酸二酯酶第4型(後文稱作為PDE4)抑制劑。
先前技術已經揭示多種用作為PDE4抑制劑之化合物。但數種第一代PDE4抑制劑諸如洛利普蘭(rolipram)及皮拉米萊(piclamilast)之用途係受到非期望之副作用所限。該等副作用包括由於作用於中樞神經系統之PDE4造成噁心及嘔吐；以及由於對腸道壁細胞中PDE4之作用而導致胃酸分泌。
該等副作用之起因已經廣泛研究。
發現PDE4係以兩種表示不同組態的分別形式存在，被設計成為高親和力洛利普蘭結合位置或HPDE4，特別係存在於中樞神經系統及體壁細胞；以及低親和力洛利普蘭結合位置或LPDE4(Jacobitz，S等人Mol. Pharmacol，1996，50，891-899)，出現於免疫細胞及發炎細胞。雖然兩種形式皆具有催化活性，但其對抑制劑之敏感度有別。特別對LPDE4具有較高度親和力之化合物顯然較不容易誘發副作用，諸如噁心、嘔吐及增加胃酸分泌。
LPDE4靶定作用之效果係導致對第二代PDE4抑制劑諸如西洛米萊(cilomilast)及洛路米萊(roflumilast)之選擇性略為改良。但此等化合物仍然不具有對LPDE4之良好選擇性。
其他作為PDE4抑制劑之化合物類別已經揭示於先前技術。
舉例言之，EP 1634606揭示其中之酮衍生物，例如苯并呋喃或1,3-苯并二唑衍生物。
WO 9402465揭示其中係如下通式之酮衍生物等
其中R1 為低碳烷基及R2 為烷基、烯基、環烷基、環烷基、環烯基、環硫烷基或環硫烯基。
Celltech Therapeutics之WO 9535281係有關經三取代之苯基衍生物。
二案皆未述及有關使用HPDE4抑制作用相關之副作用問題，也未報告有關對HPDE4及LPDE4之親和力資料。
因此，雖然至目前為止已經揭示數種PDE4抑制劑，但仍然需要有更有效且耐受性更佳的化合物。
特別，提供更具選擇性化合物係非常有利的，例如相對於對HPDE4之親和力，具有對LPDE4更高的親和力俾便衰減或避開與其抑制相關之副作用。
本發明經由提供對LPDE4具有改良之選擇性之PDE4抑制劑而解決此等問題。
實際上，目前已發現提供帶有可與PDE4之活性位置交互作用之額外部分的一種PDE4抑制劑，其係改良對LPDE4抑制劑之選擇性。
本發明之PDE4抑制劑當吸入性投予時可有效發揮功效，且其特徵在於肺臟中之持續性良好及系統性作用時間短。
本發明係針對作為磷酸二酯酶4(PDE4)酵素抑制劑之化合物、該等化合物之製備方法、含有該等化合物之組成物及其治療用途。
特別，本發明係針對通式(I)之1-苯基-2-吡啶烷基醇衍生物
其中：Z係選自於由下列所組成之組群
(CH2 )m 其中m=0、1或2；(CH2 )n O其中n=1、2或3；O(CH2 )p 其中p=0、1、2或3；CH2 SO2 ；CHNR6 ；CH2 NR6 ；NR6 其中R6 為H或線性或分支(C1 -C4 )烷基；OCOR4 R5 ；及CR4 R5 其中R4 分別係選自H或線性或分支(C1 -C4 )烷基，較佳為甲基，視需要可經以(C1 -C4 )環烷基取代及R5 分別係選自於下列所組成之組群
-線性或分支(C1 -C4 )烷基，較佳為甲基；-苯基；-苄基；-NH2 ；及-HNCOOR’，其中R’為線性或分支(C1 -C4 )烷基，較佳為第三丁基；R1 及R2 為相異或相同，且分別係選自於由下列所組成之組群-H；-線性或分支(C1 -C6 )烷基，視需要可經以選自於(C3 -C7 )環烷基或(C5 -C7 )環烯基之一個或多個取代基取代；-(C3 -C7 )環烷基；-(C5 -C7 )環烯基；-線性或分支(C2 -C6 )烯基；及-線性或分支(C2 -C6 )炔基；R3 為分別選自於由H、CN、NO2 、CF3 及鹵原子中之一個或多個取代基；A為環系，其為單環系環或雙環系環，可為飽和、部分不飽和或不飽和，諸如芳基、(C3 -C8 )環烷基或雜芳基，該環系A含有5至10個環原子，其中至少一個環原子為雜原子(例如N、S或O)，其中於A環系上之任選的取代基Rx 可為一個或多個，可相同或相異，且分別係選自於由下列所組成之組群：-視需要可經以一個或多個(C3 -C7 )環烷基取代之線性或分支(C1 -C6 )烷基；-視需要可經以一個或多個(C3 -C7 )環烷基取代之線性或分支(C2 -C6 )烯基；-視需要可經以一個或多個(C3 -C7 )環烷基取代之線性或分支(C2 -C6 )炔基；-(C5 -C7 )環烯基；-苯基；-(C3 -C7 )雜環烷基；-OR7 其中R7 係選自於由下列所組成之組群-H；-視需要可經以一個或多個(C3 -C7 )環烷基取代之(C1 -C10 )烷基；-(C3 -C7 )環烷基；-(C1 -C4 )伸烷基-(C3 -C7 )雜環烷基；-CO(C1 -C6 )烷基；-COO(C1 -C6 )烷基；-苯基；-苄基；-(C1 -C10 )烷基-NR8 R9 其中R8 及R9 分別係選自於由H、線性或分支(C1 -C6 )烷基所組成之組群，且與其鏈接之氮原子形成飽和、部分飽和或不飽和環，較佳NR8 R9 係鏈接至(C1 -C10 )烷基形成例如飽和、部分飽和或不飽和哌啶環、環、咪唑環，其中此等環視需要可經以(C1 -C4 )烷基取代；及-鹵原子；-CN；-NO2 ；-NR10 R11 其中R10 及R11 為相異或相同，且分別係選自於由下列所組成之組群-H；-線性或分支(C1 -C6 )烷基，視需要可經以苯基或(C3 -C7 )環烷基取代；-COC6 H5 ；-CO-(C1 -C4 )烷基；-COO-(C1 -C4 )烷基；-CONH-(C1 -C6 )烷基-R12 ，其中R12 係選自於由下列所組成之組群-H；-(C1 -C4 )烷基；-OR4 R5 ；及-CONH(C1 -C4 )烷基-N(C1 -C4 )烷基；或其可與其鏈結之氮原子形成飽和環或部分飽和環，較佳為哌啶環；-(C1 -C4 )烷基-NR10 R11 ；-COR12 其中R12 為苯基或線性或分支(C1 -C6 )烷基；-酮基；-HNSO2 R13 其中R13 為(C1 -C4 )烷基或苯基視需要可經以鹵原子或經以(C1 -C4 )烷基取代；-SO2 R14 其中R14 為(C1 -C4 )烷基、OH或NR10 R11 其中R10 及R11 係如前文定義；-SOR15 其中R15 為苯基或(C1 -C4 )烷基；-SR16 其中R16 為H、苯基或(C1 -C4 )烷基；-COOR17 其中R17 為H、(C1 -C4 )烷基、苯基或苄基；及-(CH2 )q OR18 ，其中q=1、2、3或4及R18 為H或(C1 -C4 )環烷基；及其醫藥上可接受之鹽及於其吡啶環上之N氧化物。
本發明也涵蓋其醫藥上可接受之鹽及/或溶劑合物。
本發明進一步係有關於吡啶環上之相對應之N氧化物。
本發明進一步包含一種製備通式(I)化合物之方法。
本發明也提供單獨通式(I)化合物或與一種或多種醫藥上可接受之載劑混合所組成之醫藥組成物。
於又一態樣中，本發明提供通式(I)化合物作為藥物之用途。
於又一態樣中，本發明提供通式(I)化合物用於製造藥物之用途。
特別本發明提供通式(I)化合物用於特徵為磷酸二酯酶4(PDE4)活性過高之任何疾病及/或期望抑制PDE4活性之任何疾病之預防及/或治療。
特別，通式(I)化合物單獨或與其它活性成分組合可投予特徵為呼吸道阻塞之呼吸道疾病，諸如氣喘及COPD之預防及/或治療。
於又一態樣中，本發明提供通式(I)化合物用於製備以非期望的發炎性免疫反應為特徵或相關聯，或由TNF-α及PDE4過度分泌所誘生的或相關聯的發炎性疾病、病症或症狀之預防及/或治療用藥物之用途。
此外，本發明提供一種治療及/或預防其中需要PDE4抑制之任何疾病之方法，該方法包含對有需要該治療之病人投予治療有效量之通式(I)化合物。
(定義)
如此處使用「鹵原子」一詞包括氟、氯、溴及碘，較佳為氯。
如此處使用「線性或分支(C1 -Cx )烷基」其中x為大於1之整數所示，係指其中組成碳原子數目係於1至x之範圍之直鏈及分支烷基。特別烷基為甲基、乙基、正丙基、異丙基及第三丁基。
於該等基團中，一個或多個氫原子視需要可為鹵原子，較佳為氯或氟所置換。
衍生之所示「(C2 -C6 )烯基」及「(C2 -C6 )炔基」係以類似方式解譯。
如此處使用「(C3 -Cx )環烷基」所示，此處x為大於3之整數，係指含有3個至x個環碳原子之環狀非芳香族烴基。實例包括環丙基、環丁基、環戊基、環己基及環庚基。
於該等基團中，一個或多個氫原子視需要可由鹵原子、較佳為氯或氟取代。
如此處使用「(C3 -C7 )雜環烷基」所示係指視需要可經以一個或多個(C1 -C4 )烷基取代之含有一個或多個雜原子(例如N、S或O)之環狀非芳香族烴基。
衍生之所示「(C1 -Cx )環烷氧基」係以類似方式解譯。
衍生之所示「(C5 -Cx )環烯基」，此處x為大於5之整數，係以類似方式解譯。
如此處使用「環系」所示係指可為飽和、部分不飽和或不飽和之單環或雙環環系，諸如芳基、(C3 -C8 )環烷基或含5至10個環原子其中至少一個環原子為雜原子(例如N、S或O)之雜芳基。
適當單環系之實例包括苯基、吡啶基、哌基、哌啶基、啉基、環戊基、環己基、環己烯基、環庚基、二、咪唑及咪唑啶。
適當二環系之實例包括萘基、喹啉基、異喹啉基、茚基、芴基、苯并咪唑基、苯并咪唑啶基、黃嘌呤基及其部分氫化或全部氫化衍生物。
本發明係針對一類用作為磷酸二酯酶4(PDE4)酵素抑制劑之化合物。
該類化合物抑制環狀核苷酸特別為環狀腺苷單磷酸(cAMP)轉換成為其無活性5’-單核苷酸形式。
於呼吸道中，對環狀核苷酸特別為cAMP之胞內濃度升高之生理反應，導致免疫細胞及前發炎細胞諸如肥大細胞、巨噬細胞、T細胞、嗜伊紅球及嗜中性球之活性受抑制，結果導致發炎媒介物質的釋放減少，該等發炎媒介物質包括細胞激素類諸如IL-1、IL-3及腫瘤壞死因子-α(TNF-α)。
其亦導致呼吸道平滑肌鬆弛及水腫減輕。
先前已經識出PDE4之催化位置：主要包含存在有兩個凹槽次級結構諸如S0 及S1 之疏水區，及含有金屬離子Zn2+ 及Mg2+ 之親水區，其又包含環繞金屬離子展開的凹槽次級結構S2 及由該疏水性凹槽中央分支約90度之凹槽次級結構S3 。
大部分先前技術化合物設有一個可與疏水區凹槽次級結構S0 及S1 交互作用之部分，諸如經取代之兒茶酚基；及有另一個與S2 凹槽次級結構之金屬離子間接交互作用之部分，例如雜環諸如吡啶或吡咯啶。
本發明係針對下述化合物，該化合物係設計成可藉經取代之兒茶酚部分維持與凹槽次級結構S0 及S1 之交互作用，以及藉吡啶環維持於金屬離子區交互作用，此點係類似其它已知之PDE4抑制劑，但差異在於存在有可與凹槽次級結構S3 建立額外交互作用之額外基團。
特別，本發明係關於通式(I)1-苯基-2-吡啶烷基醇衍生物
藥學上可接受之鹽包括經由作為鹼之主要化合物與無機酸或有機酸反應形成鹽所得者，例如鹽酸鹽、硫酸鹽、磷酸鹽、甲磺酸鹽、樟腦磺酸鹽、草酸鹽、順丁烯二酸鹽、丁二酸鹽及檸檬酸鹽。
熟諳技藝人士顯然易知通式(I)化合物可含有非對稱中心。因此本發明也包括其光學立體異構物及其混合物。
當根據本發明之化合物具有至少一個非對稱中心時，如此可呈對映異構物存在。當根據本發明之化合物擁有兩個或多個非對稱中心時，可額外呈非對映異構物存在。須了解全部此等異構物及其呈任一種比例之混合物係涵蓋於本發明之範圍。
通式(I)化合物顯示試管內對PDE4酶之抑制活性係於nM之範圍，顯然當經由氣管內投予COPD動物研究模型時於肺臟具有良好活性。
於某些情況下，也具有於肺臟之維持濃度，但未見任何可檢測得之血漿濃度，此乃系統性作用時間短的指標。
此等化合物對LPDE4比較對HPDE4具有出乎意外的高選擇性之一項解釋為其皆具有一個特徵部分，可經由A取代基而嵌合入PDE4酵素之催化位置之S3 凹槽次級結構。
由實施例13報告之結果可知，本發明之代表性化合物對LPDE4之選擇性確實為對HPDE4之1319倍。
通式(I)化合物之較佳組群為其中根據通式(II)，2-吡啶基環於3及5位置經以兩個氯原子取代者
其中R1 、R2 、Z及A係如前文定義。
較佳當R1 或R2 為H時，於兒茶酚基上之另一個取代基非為H。
較佳R1 及R2 皆非為H。
更佳通式(II)化合物之第一組群為其中：R1 及R2 係如前文定義；Z為(CH2 )n 其中n為0；及A係如前文定義。
更佳之第二組群為其中：R1 及R2 係如前文定義；Z為CHR5 其中R5 為線性或分支(C1 -C4 )烷基，較佳為甲基；及A係如前文定義。
更佳化合物之第三組群為其中：R1 及R2 係如前文定義；Z為CR4 R5 其中R4 及R5 皆為線性或分支(C1 -C4 )烷基，且與其鏈接之碳原子形成一個具有3、4、5或6個碳原子，較佳具有3個碳原子之環；以及A係如前文定義。
於較佳具體例中之一者，A為經取代及Rx 係選自於由線性或分支(C1 -C6 )烷基、線性或分支(C2 -C6 )烯基、線性或分支(C2 -C6 )炔基或OR7 ，其中R7 係如前文定義所組成之組群。
於另一個較佳具體例中，A為經取代及Rx 為可改良整個分子之水中溶解度之基團，諸如NR10 R11 或HNSO2 R13 ，其中R10 、R11 及R13 係如前文定義。
於本發明之特定具體例中，當A為雜芳基環時，該環較佳係選自於由吡咯、吡唑、呋喃、噻吩、咪唑、唑、異唑、噻唑、吡啶、嘧啶、吡及哌喃、咪唑、咪唑啶所組成之組群，及更佳為吡啶。
根據較佳具體例，本發明提供如下報告之化合物：
較佳本發明化合物之特徵為經由其IC50 測定得知，具有對LPDE4之選擇性高於對HPDE4之選擇性。
於LPDE4之情況下，IC50 為如Corti jo J et al Br J Pharmacol 1993，108：562-568所述，評估IC50 為可產生抑制50%cAMP消失之試驗化合物之莫耳濃度；而於HPDE4之情況下，如Duplantier AJ et al J Med Chem 1996；39：120-125所述，評估IC50 為可產生抑制50%[H3 ]洛利普蘭結合作用之試驗化合物之莫耳濃度。
較佳本發明化合物之HPDE4/LPDE4之IC50 比係高於5，較佳高於10，更佳高於20，及又更佳高於100。
通式(I)化合物習知可根據技藝界揭示之方法製備。可使用之若干方法說明如下，報告於如下反應式中且不可視為限制可用於製備本發明化合物之合成方法之範圍。
舉例言之，根據本發明之特定具體例(反應式)，通式(5)化合物可根據一種方法製備，該方法包含下列步驟：
第1步驟-還原通式(1)乙酮衍生物，獲得通式(2)乙醇衍生物(途徑A)。
該反應可經由使用硼氫化鈉(NaBH4 )於溶劑諸如甲醇，於室溫於氮氣氣體下進行。
第2步驟-添加式AZCOOH之適當酸至通式(2)醇衍生物溶液，獲得通式(5)化合物。
該反應係於適當強鹼諸如二異丙基醯胺鋰(LDA)、NaH、二甲基胺基吡啶(DMAP)存在下，以及於縮合劑諸如1-乙基-3-[3-二甲基胺基丙基]甲二醯亞胺鹽酸鹽(EDC)及N-羥基苯并***(HOBT)存在下，於溶劑諸如二氯甲烷於氮氣氣體下進行。可使用其它溶劑，諸如二甲基甲醯胺(DMF)、四氫呋喃(THF)、氯仿、二及任何其它技藝界人士已知之非質子性溶劑。於特定具體例中，反應也可於無溶劑存在下進行。
於羧酸A-Z-COOH具有反應性基團例如羥基、羧基、硫基或胺基之情況下，需要藉保護基諸如第三丁氧基羰基、苄基、苄氧基羰基、甲基、三甲基矽烷基等保護，且於合成之某個步驟，經由去保護而再度獲得自由態反應性基團；然後已去保護之基團可與適當反應劑例如烷化劑、醯化劑、磺化劑等反應。
官能基之保護及去保護係說明於「Protective Groups in Organic Chemistry」第三版,T. W. Greene and P. G. M. Wuts,Wiley-Interscience(1999)及「Protecting Groups」,P. J. Kocienski,Georg Thieme Verlag(1994)。
通式(5)化合物之製備方法可經由將通式A-Z-COCl之適當醯基氯或通式A-Z-NCO之適當異氰酸酯添加至通式(2)醇衍生物溶液，使用化學計算量或催化量之適當鹼根據熟諳技藝人士眾所周知之程序製備。
通式(2)之醇衍生物另外可經由式(3)苄醛與式(4)甲基吡啶衍生物(途徑B)使用貳(三甲基矽烷基)-醯胺鋰(LiHMDS)或類似之強鹼及溶劑諸如四氫呋喃(THF)或其它非質子性溶劑反應而製備。
通式(3)及(4)中間物為市面上可購得或可根據參考文獻可得且為熟諳技藝人士眾所周知之方法製備。
通式(5)化合物之2-吡啶基環上之N-氧化物可根據參考文獻可得且為熟諳技藝人士眾所周知之方法製備。例如其製法係經由將通式(5)化合物溶解於二氯甲烷或氯仿，然後添加氧化劑諸如間氯過苯甲酸(mCPBA)至所得溶液。其它可使用之氧化劑為過氧化氫、過苯甲酸及過乙酸。
用於該等化合物中A為經以對氧化敏感之官能基取代之環，當對應之N-氧化物另外可經由於途徑A之第2個步驟之前進行氧化步驟而製備。
本發明提供通式(I)化合物混合一種或多種醫藥上可接受之載劑之醫藥組成物，例如述於Remington’s Pharmaceutical Sciences Handbook,XVIIEd.,Mack Pub.,N. Y.,U.S.A.。
本發明化合物之投予可根據病人需要而達成，例如經口、經鼻、經腸道外(皮下、靜脈、肌肉、胸骨內及藉輸注投予)、藉吸入、經直腸、經***、局部外用、局部、經皮、及經眼球投予。多種固體口服劑型可用於投予本發明化合物包括錠劑、軟膠囊劑、膠囊劑、橢圓片劑、粒劑、***錠及散劑等固體劑型。本發明化合物可單獨投予或組合技藝界已知之多種醫藥上可接受之載劑、稀釋劑(諸如蔗糖、甘露糖醇、乳糖、澱粉)及賦形劑投予，包括但非限於懸浮劑，增溶劑、緩衝劑、黏結劑、崩散劑、保藏劑、著色劑、矯味劑、潤滑劑等。定時釋放膠囊劑、錠劑及膠漿劑用於投予本發明之化合物亦屬較佳。
多種液體口服劑型也可用於投予本發明化合物，包括水性溶液劑及非水性溶液劑、乳液、懸浮液、糖漿及酏劑。此等劑型也可含有技藝界已知之適當惰性稀釋劑，諸如水及技藝界已知之賦形劑諸如保藏劑、濕潤劑、甜味劑、矯味劑以及用於乳化及/或懸浮本發明化合物之作用劑。本發明化合物例如可呈等張無菌溶液劑劑型靜脈注射。其它製劑亦屬可能。
用於經直腸投予本發明化合物之栓劑可經由混合本發明化合物之適當賦形劑諸如可可脂、水楊酸酯類及聚乙二醇類而製備。
經***藥用之調配物可呈乳膏、膠漿、糊劑、發泡劑、或噴霧劑調配物劑型，其除了活性成分之外，含有諸如技藝界已知之適當載劑。
用於經局部投藥，醫藥組成物可呈乳膏劑、軟膏劑、擦劑、洗劑、乳液、懸浮液、膠漿、溶液、糊劑、散劑、噴霧劑及適合用於投予皮膚、眼、耳或鼻之滴劑等劑型。局部投藥也涉及透過諸如經皮貼片等手段而經皮投予。
用於呼吸道疾病之治療，根據本發明之化合物較佳係藉吸入投予。
吸入式製劑包括吸入式散劑、含推進劑之計量式噴霧劑或不含推進劑之吸入式調配物。
用於呈乾燥散劑投予，可利用先前已知之單劑式吸入器或多劑式吸入器。於該種情況下，散劑可填充於明膠、塑膠或其它膠囊、卡匣或泡胞罩杯包裝或填充於貯器內。
稀釋劑或載劑通常為無毒且對本發明呈化學惰性，例如乳糖劑或任何其它適合用於改良可吸入分量之添加劑皆可添加至本發明之粉狀化合物。
含有推進劑氣體諸如氫氟烷類之吸入式噴霧劑可含有呈溶液形式或分散形式之本發明化合物。藉推進劑推進之調配物也含有其它成分諸如助溶劑，安定劑及任選地其它賦形劑。
包含本發明化合物之不含推進劑之吸入式調配物可呈於水性介質、醇系介質或水醇介質之溶液或懸浮液形式，可藉熟諳技藝人士已知之噴射霧化器或超音波霧化器或藉軟霧噴霧器諸如遞送。
本發明化合物可調配作為唯一活性劑，或組合其它醫藥上活性劑投予，包括目前用於治療呼吸道病症之醫藥活性劑，例如β2 -促效劑、皮質類固醇及抗膽鹼激性劑或抗蕈毒鹼劑。
本發明化合物之劑量取決於多項因數包括欲治療之特定疾病、症狀嚴重程度、投藥途徑、投藥間隔頻率所使用之特定化合物，化合物之功效、毒理數據、及化合物之藥動學數據資料。
較佳，通式(I)化合物例如可以劑量0.001至1000毫克/日，較佳為0.1至500毫克/日投予。
當藉吸入途徑投予時，通式(I)化合物之劑量較佳為0.01至20毫克/日，較佳為0.1至10毫克/日。
較佳單獨通式(I)化合物或組合其它活性成分可投予用於任何阻塞性呼吸道疾病諸如氣喘、慢性支氣管炎及慢性阻塞性肺疾(COPD)之預防及/或治療。
但通式(I)化合物可用於預防及/或治療任何需要抑制PDE4之疾病。該等疾病包括：過敏疾病狀態諸如異位性皮膚炎、蕁麻疹、過敏性鼻炎、過敏性結膜炎、春季型結膜炎、嗜伊紅性肉芽腫、乾癬、炎性關節炎、類風濕性關節炎、敗血性休克、潰瘍性大腸炎、克隆氏病、心肌及腦之再灌流傷害、慢性腎小球性腎炎、內毒性休克、囊性纖維維化、動脈再狹窄、動脈粥狀硬化、角化症、類風濕性脊柱炎、骨關節炎、胃灼熱、糖尿病、塵肺病、毒性及過敏性接觸性濕疹、異位性濕疹、脂漏性濕疹、單純苔癬、曬傷、會陰部搔癢、斑禿、肥厚性瘢痕、盤狀紅斑性狼瘡、系統性紅斑性狼瘡、濾泡性及廣面積性膿皮病、內生性痤瘡及外生性痤瘡、酒渣鼻、貝歇特氏病(Beghet’s disease)、過敏性紫瘢、腎炎、炎性腸病、白血病、多發性硬化、胃腸病、自體免疫病等。
該等疾病也包括神經病症及精神病症諸如阿茲海默氏病、多發性硬化、脊萎縮性脊側索硬化(ALS)、多重系統萎縮(MSA)、精神***症、帕金森氏病、杭丁頓氏病、皮克氏病、憂鬱症、中風、及脊索受傷。
現在將藉下列非限制性實施例進一步說明本發明。
[實施例] [實施例1]
3,5-二氯-4-甲基吡啶(反應式之中間物(4))之製備
二異丙基胺(70毫升，500毫莫耳)溶解於無水四氫呋喃(THF)(500毫升)，溶液冷卻至-10℃及於攪拌下逐滴添加丁基鋰(2.5N於己烷，210毫升，525毫莫耳)。30分鐘後，溶液冷卻至-20℃及逐滴加入3,5-二氯吡啶(66.6克，450毫莫耳)於四氫呋喃(200毫升)。溶液於-10℃攪拌30分鐘，冷卻至-70℃及逐滴添加碘甲烷(50毫升，1.6莫耳)於四氫呋喃(100毫升)。讓反應混合物溫熱至室溫，以水(100毫升)淬熄及以***(3×100毫升)萃取；組合有機層以硫酸鈉(5克)脫水及蒸發至乾。粗產物由水性乙醇結晶，然後由己烷結晶，獲得3,5-二氯-4-甲基吡啶(49.9克，306毫莫耳，68%產率)呈白色固體。
MS/ESI+ 162-164-166m/z[MH]+ 。
[實施例2]
2-(3,5-二氯-吡啶-4-基)-1-(3,4-二甲氧基-苯基)-乙酮(反應式之中間物(1)之製備)
3,5-二氯-4-甲基-吡啶(2.06克，12.7毫莫耳)於無水四氫呋喃(30毫升)之溶液冷卻至-78℃，然後於攪拌下逐滴添加1.8M二異丙基醯胺鋰於四氫呋喃之溶液(7.4毫升，13.3毫莫耳)，溫度維持低於-70℃。所得溶液攪拌30分鐘，然後逐滴加入3,4-二甲氧基-苯甲醯氯(2.55克，12.7毫莫耳)於無水四氫呋喃(20毫升)之溶液，溫度維持低於-70℃。攪拌15分鐘後，添加冰(20克)，接著又添加500毫升水。混合物以乙酸乙酯(2×50毫升)萃取，組合有機層以硫酸鈉脫水及於減壓下蒸發獲得油，油藉急速層析術純化(洗提劑：乙酸乙酯/石油醚由10/90至30/70v:v)。
獲得2.1克(6.4毫莫耳，52%產率)標題化合物呈白色固體。
MS/ESI+ 326-328-330m/z[MH]+ ;1 H NMR(CDCl3 調校於7.26ppm)3.91及3.95(2s,6H),4.62(s,2H),6.91-6.95(d,1H),7.53-7.54(d,1H),7.67-7.75(dd,1H),8.49(s,2H).
下列中間物係使用該途徑之適當溶劑製備：
[實施例3]
2-(3,5-二氯-吡啶-4-基)-1-(3,4-二甲氧基-苯基)-乙醇(反應式之中間物(2)之製備)
(途徑A)
硼氫化鈉NaBH4 (45.2毫克，2.5當量)於室溫於氮氣氣體下添加至2-(3,5-二氯-吡啶-4-基)-1-(3,4-二甲氧基-苯基)-乙醇(150毫克，1當量)於甲醇(5毫升)之懸浮液。混合物於室溫攪拌隔夜，然後反應以水淬熄及以乙酸乙酯萃取。有機層以硫酸鈉脫水及蒸發去除溶劑。粗產物於矽氧凝膠上以由石油醚/乙酸乙酯9/1v/v至石油醚/乙酸乙酯7/3v/v之梯度洗提，藉急速層析術純化，獲得75毫克標題化合物(50%產率)。
MS/ESI+ 328-330-332[MH]+ 。
下列中間物係使用該途徑以適當溶劑製備：
[實施例4]
2-(3,5-二氯-吡啶-4-基)-1-(3,4-二甲氧基-苯基)-乙醇(反應式之中間物(2)之製備)
(途徑B)
3,5-二氯-4-甲基吡啶(500毫克，1當量)於氮氣氣體下於-60℃溶解於無水THF(2毫升)。經注射器逐滴添加LiN(TMS)2 (1.0M於THF，3.38毫升，1.1當量)，維持溫度低於-55℃。混合物轉成黃色，於-60℃攪拌約30分鐘。然後經注射器逐滴添加3,4-二甲氧基苄醛(513毫克，1當量)於無水THF(2毫升)之溶液，維持溫度低於-55℃。於添加後，混合物徐緩溫熱至室溫，及於室溫攪拌約2小時。然後以水淬熄及以乙酸乙酯萃取。有機層以硫酸鈉脫水及蒸發去除溶劑。粗產物以***濕磨，及過濾獲得741毫克標題化合物，呈白色固體(73%產率)。MS/ESI+ 328-330-332[MH]+ 。
[實施例5]
(S)-2-(4-異丁基-苯基)-丙酸2-(3,5-二氯-吡啶-4-基)-1-(3,4-二甲氧基-苯基)乙酯(化合物1)之製備
(1-乙基-3-[3-二甲基胺基丙基]甲二醯二亞胺鹽酸鹽)(EDC. HCl)(345毫克，3當量)於室溫於氮氣氣體下添加至2-(3,5-二氯-吡啶-4-基)-1-(3,4-二甲氧基-苯基)-乙醇(200毫克，1當量)，(S)-2-(4-異丁基-苯基)-丙酸(148毫克，1.2當量)及4-二甲基胺基吡啶(DMAP)(37毫克，0.5當量)於無水二氯甲烷(8毫升)之溶液。混合物於室溫攪拌隔夜，然後以飽和氯化銨(20毫升)處理，及以乙酸乙酯(2×20毫升)萃取。組合有機層以硫酸鈉脫水及蒸發去除溶劑。粗產物於二氧化矽凝膠上以梯度洗提(由石油醚/乙酸乙酯9/1v/v至石油醚/乙酸乙酯7/3v/v)藉急速層析術純化，獲得259毫克純化合物。
下列化合物係使用該途徑以適當反應劑製備：
[表3]
[實施例6]
(S)-2-(4-異丁基-苯基)-丙酸2-(3,5-二氯-1-氧基-吡啶-4-基)-1-(3,4-二甲氧基-苯基)乙酯(化合物13)之製備
化合物1(51.5毫克，0.1毫莫耳)溶解於二氯甲烷(1毫升)。添加間氯過苯甲酸(mCPBA，15毫克，0.12毫莫耳)，所得溶液於室溫攪拌2小時。然後混合物以二氯甲烷(5毫升)稀釋及以1N氫氧化鈉(5毫升)萃取。有機相以硫酸鈉脫水及蒸發去除溶劑。粗產物藉製備性HPLC純化，獲得37毫克標題化合物。
下列化合物係遵照相同程序使用適當反應劑製備：
下列化合物係以類似先前各實施例所述方法，以適當選用反應劑及根據先前說明之大致合成方法而製備：
[實施例7]
2-(4-胺基-苯基)-丙酸2-(3,5-二氯-吡啶-4-基)-1-(3,4-二甲氧基-苯基)乙酯(化合物16)之製備
化合物10(50毫克，0.1毫莫耳)溶解於二甲基甲醯胺(DMF)(3毫升)。添加氯化錫(SnCl2 ×2H2 O，113毫克，0.5毫莫耳)，所得混合物於室溫攪拌17小時。然後混合物以水(15毫升)稀釋及以***(2×30毫升)萃取。有機相以硫酸鈉脫水及蒸發去除溶劑。粗產物藉製備性HPLC純化，獲得10毫克標題化合物。
[實施例8]
2-(4-甲磺醯胺基-苯基)-丙酸2-(3,5-二氯-吡啶-4-基)-1-(3,4-二甲氧基-苯基)乙酯(化合物17)之製備
化合物16(26毫克，0.05毫莫耳)於氮氣氣體下溶解於無水二氯甲烷(10毫升)。溶液冷卻至0℃及加入三乙基胺(0.009毫升，0.066毫莫耳)及甲磺醯氯(0.0052毫升，0.06毫莫耳)。然後讓混合物於室溫反應17小時。然後反應混合物以水(15毫升)稀釋及以乙酸乙酯(2×30毫升)萃取。有機相以硫酸鈉脫水及蒸發去除溶劑。粗產物藉製備性HPLC純化，獲得10毫克標題化合物呈非鏡像異構物之混合物。
[實施例9]
1-(3-環丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯(化合物18)之製備
中間物2b(100毫克，0.25毫莫耳)溶解於氯仿(3毫升)。
加入間氯過苯甲酸(mCPBA，80毫克，0.46毫莫耳)及所得溶液於0℃維持隔夜。
然後混合物以氯仿(5毫升)稀釋，及以1N氫氧化鈉(5毫升)洗滌。有機相以硫酸鈉脫水，及蒸發去除溶劑。
粗產物藉以乙醇結晶而純化。白色固體經過濾出及以石油醚洗滌，獲得70毫克標題化合物。
下列化合物係使用適當反應劑遵照相同程序製備：
[實施例10]
4-(2-哌啶-1-基-乙氧基)-苯甲酸1-(3-環丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯鹽酸鹽(化合物25)之製備
(1-乙基-3-[3-二甲基胺基丙基]甲二醯二亞胺鹽酸鹽)(EDC. HCl)(55毫克，當量)於室溫於氮氣氣體下添加至化合物18(60毫克，0.14毫莫耳)，4-(2-哌啶-1-基-乙氧基)-苯甲酸(81毫克，0.28當量)及4-二甲基胺基吡啶(DMAP)(37毫克，0.5當量)於無水DMF(4毫升)之溶液。混合物於室溫攪拌隔夜，然後以飽和氯化銨溶液(20毫升)處理及以乙酸乙酯(2×20毫升)萃取。組合有機層以硫酸鈉脫水及蒸發去除溶劑。粗產物藉製備性HPLC純化。油性殘餘物溶解於乙酸乙酯(2毫升)及添加微過量之1M無水鹽酸於乙酸乙酯溶液。於蒸發去除溶劑後，殘餘物由甲醇/***結晶獲得14毫克鹽酸鹽。
(說明)
*NMR
s=單峰
d=雙峰
t=三峰
q=四峰
dd=雙峰之雙峰
m=多峰
br=寬
ESI=電噴灑
(本發明化合物之藥理活性)
[實施例11]
測定試管內不含細胞之檢定分析中PDE4抑制活性
U937人類單核細胞株作為PDE4酶之來源。細胞經培養、收穫及上清液部分大致上為Torphy TJ et al J. Pharmacol. Exp. Ther. 1992；263：1195-1205所述製備。
藉檢定分析cAMP由培養混合物中消失，測定於細胞上清液之PDE4活性。於終體積200微升，於1.6μM cAMP存在下，使用或未使用試驗化合物(50微升)，50微升細胞上清液於30℃培養30分鐘。
試驗化合物濃度係於10-12 M至10-6 M之範圍。藉加熱鈍化(於100℃2.5分鐘)終止反應，及殘餘cAMP使用基於電化學發光(ECL)免疫檢定分析測定。
結果以可產生50% cAMP抑制消失(IC50 )之試驗化合物之莫耳濃度之平均值±95%信度極限報告於實施例12之表9。
假設於無抑制劑存在下cAMP消失為100%及於熱鈍化樣本中之cAMP消失為0%，計算PDE4活性之抑制百分比。
本發明之代表性試驗化合物之全部IC50 值係小於0.2μM。
[實施例12]
測定試管內周邊血液單核細胞(PBMC)檢定分析中PDE4抑制活性
藉PDE4抑制劑對周邊血液單核細胞(PBMC)中之脂多醣(LPS)誘導腫瘤壞死因子-α(TNF-α)釋放已知發揮抑制活性之檢定分析係根據前述方法進行(Hatzelmann A et al J. Pharmacol. Exp. Ther. 2001；297:267-279；Draheim R et al J. Pharmacol. Exp. Ther. 2004；308：555-563)。
低溫保存之人類PBMC(100微升/孔)於有或無(50微升)由10-12 M至10-6 M濃度範圍之試驗化合物存在下，於96孔孔板(105 細胞/孔)培養30分鐘。隨後添加LPS(3奈克/毫升)。
於37℃，於濕化孵育器內於95%空氣及5%二氧化碳之氣體下孵育18小時後，收集培養基及藉ELISA測定TNF-α。
結果，以可產生LPS誘導TNF-α釋放之50%抑制之試驗化合物濃度(IC50 )之平均值±95%信度極限表示且報告於表9。
假設於無抑制劑化合物存在下，LPS誘導TNF-α製造為100%，及於無LPS存在下PBMC之基本TNF-α製造為0%，以TNF-α釋放之抑制百分比計算試驗化合物之功效。
[實施例13]
抑制低度親和力LPDE4之能力相對於競爭高度親和力HPDE4之能力之評估
對LPDE4及HPDE4之親和力係如先前分別說明於Corti jo J et al Br J Pharmacol 1993，108：562-568及Duplantier AJ et al J Med Chem 1996；39：120-125之方法評估。
試驗化合物濃度係於10-12 M至10-5 M之範圍。
以IC50 表示之結果報告於表10。
於LPDE4之情況下，IC50 為可產生cAMP消失之50%抑制之試驗化合物之莫耳濃度；於HPDE4之情況下，IC50 為可產生[H3 ]洛利普蘭之結合50%抑制之試驗化合物之莫耳濃度。
結果指示本發明化合物可以次奈莫耳濃度之親和力抑制LPDE4，且對LPDE4相對於對HPDE4具有顯著更高選擇性。

Claims (19)

  1. 一種通式(I)化合物， 及其醫藥上可接受之鹽及於其吡啶環上之N氧化物，其中，Z係選自於由下列所組成之組群：(CH2 )m ，其中m=0、1或2；(CH2 )n O，其中n=1、2或3；O(CH2 )p ，其中p=0、1、2或3；CH2 SO2 ；CHNR6 ；CH2 NR6 ；NR6 ，其中R6 為H或視需要可經以一或多個鹵原子取代之線性或分支(C1 -C4 )烷基；OCOR4 R5 ；及CR4 R5 ，其中R4 係分別選自H或視需要可經以一或多個鹵原子或(C1 -C4 )環烷基取代之線性或分支(C1 -C4 )烷基，及R5 係分別選自於下列所組成之組群：-視需要可經以一或多個鹵原子取代之線性或分支(C1 -C4 ) 烷基；-苯基；-苄基；-NH2 ；及-HNCOOR’，其中R’為視需要可經以一或多個鹵原子取代之線性或分支(C1 -C4 )烷基；R1 及R2 為相異或相同且係分別選自於由下列所組成之組群：-H；-線性或分支(C1 -C6 )烷基，視需要可經以選自於鹵原子或(C3 -C7 )環烷基之一個或多個取代基取代；-(C3 -C7 )環烷基；R3 為分別選自於由H、CN、NO2 、CF3 及鹵原子中之一個或多個取代基；A為視需要可經以一個或多個Rx 基取代之苯基，或A為視需要可經以一個或多個Rx 基取代之雜芳基環，其中，A為選自於由吡咯、吡唑、呋喃、噻吩、咪唑、唑、異唑、噻唑、吡啶、嘧啶、吡、嗒及哌喃所組成之組群之雜芳基環，其中於A環系上之任選的取代基Rx 可為一個或多個，可相同或相異，且係分別選自於由下列所組成之組群：-視需要可經以一個或多個鹵原子或(C3 -C7 )環烷基取代之線性或分支(C1 -C6 )烷基；-苯基； -(C3 -C7 )雜環烷基；-OR7 其中R7 係選自於由下列所組成之組群：-H；-視需要可經以一個或多個鹵原子或(C3 -C7 )環烷基取代之(C1 -C10 )烷基；-(C3 -C7 )環烷基；-(C1 -C4 )伸烷基-(C3 -C7 )雜環烷基；-CO(C1 -C6 )烷基，其中(C1 -C6 )烷基視需要可經以一或多個鹵原子取代；-COO(C1 -C6 )烷基，其中(C1 -C6 )烷基視需要可經以一或多個鹵原子取代；-苯基；-苄基；-(C1 -C10 )烷基-NR8 R9 ，其中R8 及R9 係分別選自於由H、視需要可經以一或多個鹵原子取代之線性或分支(C1 -C6 )烷基所組成之組群，或與其鏈接之氮原子形成飽和、部分飽和或不飽和環；及-鹵原子；-CN；-NO2 ；-NR10 R11 ，其中R10 及R11 為相異或相同且係分別選自於由下列所組成之組群： -H；-線性或分支(C1 -C6 )烷基，視需要可經以一或多個鹵原子、苯基或(C3 -C7 )環烷基取代；-COC6 H5 ；-CO-(C1 -C4 )烷基，其中(C1 -C4 )烷基視需要可經以一或多個鹵原子取代；-COO-(C1 -C4 )烷基，其中(C1 -C4 )烷基視需要可經以一或多個鹵原子取代；-CONH-(C1 -C6 )烷基-R12 ，其中R12 係選自於由下列所組成之組群：-H；視需要可經以一或多個鹵原子取代之(C1 -C4 )烷基；-OR4 R5 ；及-CONH(C1 -C4 )烷基-N(C1 -C4 )烷基，其中N(C1 -C4 )烷基視需要可經以一或多個鹵原子取代；或其可與其鏈結之氮原子形成飽和環或部分飽和環；-(C1 -C4 )烷基-NR10 R11 ；-COR12 ，其中R12 為苯基或視需要可經以一或多個鹵原子取代之線性或分支(C1 -C6 )烷基；-酮基；-HNSO2 R13 ，其中R13 為視需要可經以一或多個鹵原子取代之(C1 -C4 )烷基或視需要可經以鹵原子或經以視需要可經以一或多個鹵原子 取代之(C1 -C4 )烷基取代之苯基；-SR16 ，其中R16 為H、苯基或視需要可經以一或多個鹵原子取代之(C1 -C4 )烷基；-COOR17 ，其中R17 為H、視需要可經以一或多個鹵原子取代之(C1 -C4 )烷基、苯基或苄基；及-(CH2 )q OR18 ，其中q=1、2、3或4及R18 為H或(C1 -C4 )環烷基。
  2. 如申請專利範圍第1項之化合物，其中，視需要取代該(C1 -C4 )烷基、(C1 -C6 )烷基及(C1 -C10 )烷基之該一或多個鹵原子係選自一或多個氯原子或氟原子。
  3. 如申請專利範圍第1項之化合物，其中，R3 為鹵原子。
  4. 如申請專利範圍第3項之化合物，其中，R3 為氯。
  5. 如申請專利範圍第4項之化合物，具有通式(II)
  6. 如申請專利範圍第5項之化合物，其中，Z為(CH2 )m 而m等於0。
  7. 如申請專利範圍第6項之化合物，其為3-環丙基甲氧基-4-二氟甲氧基-苯甲酸1-(3-環丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)乙酯(化合物14)。
  8. 如申請專利範圍第6項之化合物，其為3-環丙基甲氧基-4-二氟甲氧基-苯甲酸1-(3-環丙基甲氧基-4-二氟甲氧基-苯 基)-2-(3,5-二氯-吡啶-4-基)乙酯(化合物11)。
  9. 如申請專利範圍第5項之化合物，其中，Z為CHR5 ，此處R5 為線性或分支C1 -C4 烷基。
  10. 如申請專利範圍第5項之化合物，其中，Z為CR4 R5 ，此處R4 及R5 二者皆為視需要可經以一或多個鹵原子取代之線性或分支C1 -C4 烷基，且與其所鏈接之碳原子形成一個含3、4、5或6個碳原子之環。
  11. 一種式(2)化合物， 及於其吡啶環上之N氧化物，其中，R1 、R2 及R3 係如申請專利範圍第1項中所定義。
  12. 一種製備申請專利範圍第1至10項中任一項之化合物之方法，包含將式AZCOOH酸或式AZCOC1醯氯或式AZNCO異氰酸酯，其中A及Z係如申請專利範圍第1項之式(I)定義，添加至通式(2)之醇衍生物之溶液 其中R1 、R2 及R3 係如申請專利範圍第1項之式(I)定義。
  13. 一種醫藥組成物，包含申請專利範圍第1至10項中任一項之化合物作為活性成分，混合一種或多種醫藥上可接受之載劑及/ 或賦形劑。
  14. 如申請專利範圍第13項之醫藥組成物，其適合藉吸入投藥。
  15. 如申請專利範圍第13或14項之醫藥組成物，其中，該組成物進一步包含選自於β2 促效劑、皮質類固醇及抗膽鹼激性劑或抗蕈毒鹼劑之類別之額外活性成分。
  16. 一種申請專利範圍第1至10項中任一項之化合物之用途，其係用於製造藥物。
  17. 一種申請專利範圍第1至10項中任一項之化合物之用途’其係用於製造治療以磷酸二酯酶4(PDE4)活性過高為特徵及/或其中期望抑制PDE4活性之任一種疾病之藥物。
  18. 如申請專利範圍第17項之用途，其中，該疾病為以氣道阻塞為特徵之呼吸道疾病。
  19. 如申請專利範圍第18項之用途，其中，該疾病係選自於由氣喘或慢性支氣管炎或慢性阻塞性肺疾所組成之組群。
TW097130008A 2007-08-08 2008-08-07 作為磷酸二酯酶抑制劑之１－苯基－２－吡啶烷基醇衍生物 TWI444366B (zh)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
EP07114019A EP2022783A1 (en) 2007-08-08 2007-08-08 "Derivatives of 1-phenyl-2-pyridinyl alkyl alcohols as phosphodiesterase inhibitors"

Publications (2)

Publication Number Publication Date
TW200916440A TW200916440A (en) 2009-04-16
TWI444366B true TWI444366B (zh) 2014-07-11

Family

ID=38754730

Family Applications (1)

Application Number Title Priority Date Filing Date
TW097130008A TWI444366B (zh) 2007-08-08 2008-08-07 作為磷酸二酯酶抑制劑之１－苯基－２－吡啶烷基醇衍生物

Country Status (38)

Country Link
US (7) US7923565B2 (zh)
EP (3) EP2022783A1 (zh)
JP (3) JP2010535722A (zh)
KR (1) KR101200683B1 (zh)
CN (1) CN101796028B (zh)
AR (1) AR068057A1 (zh)
AU (1) AU2008286027B2 (zh)
BR (1) BRPI0814065B8 (zh)
CA (1) CA2695580C (zh)
CL (1) CL2008002330A1 (zh)
CO (1) CO6290760A2 (zh)
CY (2) CY1117324T1 (zh)
DK (2) DK2947068T3 (zh)
EA (1) EA017530B1 (zh)
ES (2) ES2563478T3 (zh)
GE (1) GEP20125537B (zh)
HK (1) HK1145686A1 (zh)
HR (2) HRP20160292T1 (zh)
HU (2) HUE027171T2 (zh)
IL (2) IL203712A (zh)
JO (1) JO3181B1 (zh)
LT (1) LT2947068T (zh)
MA (1) MA31586B1 (zh)
ME (1) ME00974B (zh)
MX (1) MX2010001544A (zh)
MY (1) MY152692A (zh)
NO (1) NO2947068T3 (zh)
NZ (1) NZ583103A (zh)
PE (1) PE20090698A1 (zh)
PL (2) PL2185515T3 (zh)
PT (2) PT2185515E (zh)
RS (2) RS54606B1 (zh)
SI (2) SI2947068T1 (zh)
TN (1) TN2010000044A1 (zh)
TW (1) TWI444366B (zh)
UA (1) UA99622C2 (zh)
WO (1) WO2009018909A2 (zh)
ZA (1) ZA201000832B (zh)

Families Citing this family (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2022783A1 (en) 2007-08-08 2009-02-11 CHIESI FARMACEUTICI S.p.A. "Derivatives of 1-phenyl-2-pyridinyl alkyl alcohols as phosphodiesterase inhibitors"
EP2216327A1 (en) * 2009-02-06 2010-08-11 CHIESI FARMACEUTICI S.p.A. Benzoic acid (1-phenyl-2-pyridin-4-yl)ethyl esters as phosphodiesterase inhibitors
RU2580312C2 (ru) 2010-04-21 2016-04-10 КЬЕЗИ ФАРМАЧЕУТИЧИ С.п.А. Способ получения частиц с пониженным электростатическим зарядом
KR101805958B1 (ko) * 2010-08-03 2017-12-07 키에시 파르마슈티시 엣스. 피. 에이. 포스포디에스테라제 억제제를 포함하는 건조 분말 제제
KR101803121B1 (ko) * 2010-08-03 2017-11-29 키에시 파르마슈티시 엣스. 피. 에이. 포스포디에스테라제 억제제를 포함하는 약학적 제제
WO2012041717A1 (en) * 2010-09-30 2012-04-05 Chiesi Farmaceutici S.P.A. Use of magnesium stearate in dry powder formulations for inhalation
UA111198C2 (uk) 2011-06-06 2016-04-11 К'Єзі Фармачеутічі С.П.А. Похідні 1-феніл-2-піридинілалкільних спиртів як інгібітори фосфодіестерази
CN103827088B (zh) 2011-09-26 2017-10-13 奇斯药制品公司 作为磷酸二酯酶抑制剂的1‑苯基‑2‑吡啶基烷基醇的衍生物
BR112014009471A2 (pt) * 2011-10-21 2017-04-18 Chiesi Farm Spa compostos, combinação de um composto, composição farmacêutica, uso de um composto, dispositivo e kit
BR112014029642A2 (pt) 2012-06-04 2017-06-27 Chiesi Farm Spa composto, combinação de um composto, composição farmacêutica, uso de um composto, dispositivo e kit
CA2893622A1 (en) 2012-12-05 2014-06-12 Chiesi Farmaceutici S.P.A. Novel compounds
CN104822669A (zh) * 2012-12-05 2015-08-05 奇斯药制品公司 作为pde-4抑制剂的苯基乙基吡啶衍生物
WO2014086865A1 (en) * 2012-12-05 2014-06-12 Chiesi Farmaceutici S.P.A. 1-phenyl-2-pyridinyl alkyl alcohol derivatives as phosphodiesterase inhibitors
BR112015012720A2 (pt) 2012-12-05 2017-07-11 Chiesi Farm Spa derivados de feniletilpiridina como inibidores de pde4
US9427376B2 (en) 2013-10-10 2016-08-30 Chiesi Farmaceutici S.P.A. Process for preparing pharmaceutical formulations for inhalation comprising a high-dosage strength active ingredient
PT3060551T (pt) * 2013-10-22 2019-12-09 Chiesi Farm Spa Processo para a preparação de um inibidor de pde4
AR098622A1 (es) 2013-12-05 2016-06-01 Chiesi Farm Spa Derivados de benzhidrilo
RU2016121854A (ru) * 2013-12-05 2017-12-07 КЬЕЗИ ФАРМАЧЕУТИЧИ С.п.А. Производные гетероарила
WO2015185130A1 (en) * 2014-06-04 2015-12-10 Chiesi Farmaceutici S.P.A. 3,5-dichloro,4-(3,4-(cyclo-)alkoxyphenyl)--2-carbonyloxy)ethyl)pyridine derivatives as pde-4 inhibitors
EP3152203A1 (en) * 2014-06-04 2017-04-12 Chiesi Farmaceutici S.p.A. 3,5-dichloro,4-(3,4-(cyclo-)alkoxyphenyl)- 2-carbonyloxy)ethyl)pyridine derivatives as pde-4 inhibitors
US9763924B2 (en) * 2014-06-05 2017-09-19 Chiesi Farmaceutici S.P.A. Aminoester derivatives
US9326976B2 (en) 2014-06-05 2016-05-03 Chiesi Farmaceutici S.P.A. Carbamate derivatives
AR104829A1 (es) * 2015-06-01 2017-08-16 Chiesi Farm Spa Derivados de aminoésteres
MA51413A (fr) 2017-12-28 2021-04-28 Chiesi Farm Spa Utilisation de dérivés d'alcool alkylique de 1-phényl-2-pyridinyl pour le traitement de la fibrose kystique
US11794466B2 (en) 2019-04-26 2023-10-24 Fuji Corporation Printing parameter acquisition device and printing parameter acquisition method
WO2023117985A1 (en) 2021-12-21 2023-06-29 Chiesi Farmaceutici S.P.A. Dry powder formulations filled in an inhaler with improved resistance to humidity
WO2023208982A1 (en) 2022-04-27 2023-11-02 Chiesi Farmaceutici S.P.A. Crystal form of a pde4 inhibitor
WO2024027901A1 (en) 2022-08-02 2024-02-08 Chiesi Farmaceutici S.P.A. Predictive biomarker of clinical response to a pde4 inhibitor
WO2024062007A1 (en) 2022-09-22 2024-03-28 Chiesi Farmaceutici S.P.A. Capsule inhaler for the administration of a phosphodiesterase-4 inhibitor
WO2024062006A1 (en) 2022-09-22 2024-03-28 Chiesi Farmaceutici S.P.A. Capsule inhaler for the administration of a phosphodiesterase-4 inhibitor
WO2024062005A1 (en) 2022-09-22 2024-03-28 Chiesi Farmaceutici S.P.A. Capsule inhaler for the administration of a phosphodiesterase-4 inhibitor

Family Cites Families (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5124455A (en) * 1990-08-08 1992-06-23 American Home Products Corporation Oxime-carbamates and oxime-carbonates as bronchodilators and anti-inflammatory agents
US5935978A (en) * 1991-01-28 1999-08-10 Rhone-Poulenc Rorer Limited Compounds containing phenyl linked to aryl or heteroaryl by an aliphatic- or heteroatom-containing linking group
PT652868E (pt) * 1992-07-28 2005-01-31 Aventis Pharma Ltd Inibidores da fosfodiesterase do amp ciclico
US5786354A (en) * 1994-06-21 1998-07-28 Celltech Therapeutics, Limited Tri-substituted phenyl derivatives and processes for their preparation
GB9412573D0 (en) 1994-06-22 1994-08-10 Celltech Ltd Chemical compounds
AU712869B2 (en) 1996-09-17 1999-11-18 Merck & Co., Inc. Method of preparing phosphodiesterase IV inhibitors
WO2000050402A1 (en) 1999-02-25 2000-08-31 Merck Frosst Canada & Co. Pde iv inhibiting compounds, compositions and methods of treatment
NZ542671A (en) 2003-03-12 2008-12-24 Celgene Corp 7-Amido-isoindolyl compounds and their pharmaceutical uses
TW200420554A (en) * 2003-03-31 2004-10-16 Kyowa Hakko Kogyo Kk A intra-airway administrating preparation
US7888381B2 (en) * 2005-06-14 2011-02-15 Bristol-Myers Squibb Company Modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity, and use thereof
EP2044023B1 (en) * 2006-07-14 2011-01-19 CHIESI FARMACEUTICI S.p.A. Derivatives of 1-phenyl-2-pyridynyl alkylene alcohols as phosphodiesterase inhibitors
EP2022783A1 (en) 2007-08-08 2009-02-11 CHIESI FARMACEUTICI S.p.A. "Derivatives of 1-phenyl-2-pyridinyl alkyl alcohols as phosphodiesterase inhibitors"
EP2070913A1 (en) 2007-12-14 2009-06-17 CHIESI FARMACEUTICI S.p.A. Ester derivatives as phosphodiesterase inhibitors
EP2110375A1 (en) 2008-04-14 2009-10-21 CHIESI FARMACEUTICI S.p.A. Phosphodiesterase-4 inhibitors belonging to the tertiary amine class
EP2216327A1 (en) 2009-02-06 2010-08-11 CHIESI FARMACEUTICI S.p.A. Benzoic acid (1-phenyl-2-pyridin-4-yl)ethyl esters as phosphodiesterase inhibitors
KR101803121B1 (ko) 2010-08-03 2017-11-29 키에시 파르마슈티시 엣스. 피. 에이. 포스포디에스테라제 억제제를 포함하는 약학적 제제
KR101805958B1 (ko) 2010-08-03 2017-12-07 키에시 파르마슈티시 엣스. 피. 에이. 포스포디에스테라제 억제제를 포함하는 건조 분말 제제
UA111198C2 (uk) 2011-06-06 2016-04-11 К'Єзі Фармачеутічі С.П.А. Похідні 1-феніл-2-піридинілалкільних спиртів як інгібітори фосфодіестерази
CN103827088B (zh) 2011-09-26 2017-10-13 奇斯药制品公司 作为磷酸二酯酶抑制剂的1‑苯基‑2‑吡啶基烷基醇的衍生物
BR112014009471A2 (pt) 2011-10-21 2017-04-18 Chiesi Farm Spa compostos, combinação de um composto, composição farmacêutica, uso de um composto, dispositivo e kit
BR112014029642A2 (pt) 2012-06-04 2017-06-27 Chiesi Farm Spa composto, combinação de um composto, composição farmacêutica, uso de um composto, dispositivo e kit

Also Published As

Publication number Publication date
EP2947068A1 (en) 2015-11-25
MX2010001544A (es) 2010-03-15
IL239466A0 (en) 2015-07-30
TN2010000044A1 (en) 2011-09-26
LT2947068T (lt) 2018-01-25
CO6290760A2 (es) 2011-06-20
RS56765B1 (sr) 2018-04-30
EP2947068B1 (en) 2017-11-08
NO2947068T3 (zh) 2018-04-07
EA201000149A1 (ru) 2010-08-30
CL2008002330A1 (es) 2009-03-20
RS54606B1 (en) 2016-08-31
EP2022783A1 (en) 2009-02-11
US8203000B2 (en) 2012-06-19
DK2947068T3 (en) 2018-01-15
JP2015163629A (ja) 2015-09-10
ZA201000832B (en) 2011-04-28
JP2010535722A (ja) 2010-11-25
JP2014037426A (ja) 2014-02-27
PE20090698A1 (es) 2009-07-06
HUE035557T2 (en) 2018-05-02
AR068057A1 (es) 2009-11-04
HRP20160292T1 (hr) 2016-04-22
CN101796028A (zh) 2010-08-04
AU2008286027A2 (en) 2010-04-01
US20110144070A1 (en) 2011-06-16
NZ583103A (en) 2012-03-30
TW200916440A (en) 2009-04-16
US20120116091A1 (en) 2012-05-10
US20110144075A1 (en) 2011-06-16
BRPI0814065B1 (pt) 2020-02-11
PT2947068T (pt) 2018-01-12
PL2947068T3 (pl) 2018-04-30
JP5746298B2 (ja) 2015-07-08
CY1117324T1 (el) 2017-04-26
US20090048220A1 (en) 2009-02-19
EP2185515A2 (en) 2010-05-19
MA31586B1 (fr) 2010-08-02
WO2009018909A3 (en) 2009-05-14
ES2563478T3 (es) 2016-03-15
EP2185515B1 (en) 2016-01-06
BRPI0814065A2 (pt) 2015-01-06
CA2695580C (en) 2016-10-04
US7923565B2 (en) 2011-04-12
IL203712A (en) 2016-08-31
JO3181B1 (ar) 2018-03-08
PT2185515E (pt) 2016-03-31
PL2185515T3 (pl) 2016-06-30
KR20100050501A (ko) 2010-05-13
US8383826B2 (en) 2013-02-26
MY152692A (en) 2014-11-28
SI2185515T1 (sl) 2016-04-29
SI2947068T1 (en) 2018-02-28
AU2008286027A1 (en) 2009-02-12
US9102619B2 (en) 2015-08-11
ES2655816T3 (es) 2018-02-21
JP6023846B2 (ja) 2016-11-09
KR101200683B1 (ko) 2012-11-13
HK1145686A1 (zh) 2011-04-29
US20150018321A1 (en) 2015-01-15
ME00974B (me) 2012-06-20
GEP20125537B (en) 2012-05-25
EA017530B1 (ru) 2013-01-30
CY1119669T1 (el) 2018-04-04
HUE027171T2 (en) 2016-10-28
BRPI0814065B8 (pt) 2021-05-25
US20130137648A1 (en) 2013-05-30
DK2185515T3 (en) 2016-02-29
US9000177B2 (en) 2015-04-07
US20140135301A1 (en) 2014-05-15
WO2009018909A2 (en) 2009-02-12
CA2695580A1 (en) 2009-02-12
UA99622C2 (ru) 2012-09-10
AU2008286027B2 (en) 2013-02-21
HRP20180212T1 (hr) 2018-03-09
CN101796028B (zh) 2013-07-10

Similar Documents

Publication Publication Date Title
TWI444366B (zh) 作為磷酸二酯酶抑制劑之１－苯基－２－吡啶烷基醇衍生物
EP2225205B1 (en) Ester derivatives as phosphodiesterase inhibitors
US8859778B2 (en) 1-phenyl-2-pyridinyl alkyl alcohol compounds as phosphodiesterase inhibitors
EP2044023B1 (en) Derivatives of 1-phenyl-2-pyridynyl alkylene alcohols as phosphodiesterase inhibitors
JP2000502675A (ja) Ｐｄｅ ｉｖインヒビターとして有用なトリ置換フェニル誘導体
EA007074B1 (ru) 2-амино-6-(2,4,5-замещенный фенил)пиридины для применения в качестве ингибиторов синтазы оксида азота