WO2003022277A1 - Arylsulfonamide derivatives for use as ccr3 antagonists in the treatment of inflammatory and immunological disorders - Google Patents

Arylsulfonamide derivatives for use as ccr3 antagonists in the treatment of inflammatory and immunological disorders Download PDF

Info

Publication number
WO2003022277A1
WO2003022277A1 PCT/EP2002/009873 EP0209873W WO03022277A1 WO 2003022277 A1 WO2003022277 A1 WO 2003022277A1 EP 0209873 W EP0209873 W EP 0209873W WO 03022277 A1 WO03022277 A1 WO 03022277A1
Authority
WO
WIPO (PCT)
Prior art keywords
branched
straight
hydrogen
ring
sulfonyl
Prior art date
Application number
PCT/EP2002/009873
Other languages
French (fr)
Inventor
Yingfu Li
Akihiko Watanabe
Timothy B. Lowinger
Kevin Bacon
Norihiro Kawamura
Takuya Shintani
Tetsuo Kikuchi
Toshiya Moriwaki
Klaus Urbahns
Keiko Fukushima
Noriko Nunami
Takashi Yoshino
Toshiki Murata
Megumi Yamauchi
Hiroko Yoshino
Original Assignee
Bayer Healthcare Ag
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 Bayer Healthcare Ag filed Critical Bayer Healthcare Ag
Priority to US10/489,029 priority Critical patent/US7700586B2/en
Priority to JP2003526406A priority patent/JP4517047B2/en
Priority to EP02772265A priority patent/EP1461038B9/en
Priority to CA002459432A priority patent/CA2459432C/en
Priority to DE60221569T priority patent/DE60221569T2/en
Publication of WO2003022277A1 publication Critical patent/WO2003022277A1/en
Priority to US12/763,072 priority patent/US8242118B2/en

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
    • C07D213/60—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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • 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
    • A61P11/02—Nasal agents, e.g. decongestants
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A61P5/16—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4 for decreasing, blocking or antagonising the activity of the thyroid hormones
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/64—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton
    • C07C323/67—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton containing sulfur atoms of sulfonamide groups, bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
    • C07D207/48—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C07D211/28—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/96—Sulfur 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • C07D213/71—Sulfur atoms to which a second hetero atom is attached
    • 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
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • 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
    • C07D213/72—Nitrogen atoms
    • C07D213/76—Nitrogen atoms to which a second hetero atom is attached
    • 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
    • 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
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • 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
    • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/194—Radicals derived from thio- or thiono carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/26—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/14—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the present invention relates to a sulfonamide derivative which is useful as an active ingredient of pharmaceutical preparations.
  • the sulfonamide derivatives of the present invention have CCR3 (CC type chemokine receptor 3) antagonistic activity, and can be used for the prophylaxis and treatment of diseases associated with CCR3 activity, in particular for the treatment of asthma, atopic dermatitis, allergic rhinitis 10 and other inflammatory/immuno logical disorders.
  • CCR3 CC type chemokine receptor 3
  • Chemokmes are chemotactic cytokines of which major functions are migration of 15 inflammatory cells that express relevant chemokine receptors on their surfaces to sites of inflammation, and activation of inflammatory cells.
  • eotaxin is an 8.4 kDa (74 amino acid) polypeptide and binds with high affinity solely to the receptor CCR3.
  • eotaxin causes chemotaxis of inflammatory cells expressing CCR3 [Eisner J., Hochstetter R., Kimming D. and Kapp A.: Human eotaxin represents a potent activator of the respiratory burst of human eosinophils. Eur. J. Immunol., 26: 1919-
  • the chemokine receptor CCR3 is a G protein-coupled, seven transmembrane domain receptor (GPCR) which binds to known ligands, in addition to eotaxin, including eotaxin-2 (CCL24), RANTES (CCL5), MCP-3 (CCL7) and MCP-4 (CCL13).
  • GPCR G protein-coupled, seven transmembrane domain receptor
  • CCR3 30 is expressed on inflammatory cells relevant to the chronic asthma pathology.
  • Such inflammatory cells include Eosinophils [Sabroe I., Conroy D.M., Gerard N.P., Li Y., Collins P.D., Post T.W., Jose P.J., Williams TJ., Gerard C.J., Ponath P.D. J. Immunol.
  • mice showed decreased eosinophilia after antigen challenge [Rothenberg M.E., MacLean J.A., Pearlman E., Luster A.D. and Leder P. J. Exp.
  • CCR3 and related chemokine including eotaxin has been implicated as being important mediators of inflammatory and immunoregulatory disorders and diseases, including asthma, rhinitis, and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis, Grave's disease, and atherosclerosis.
  • CCR3 and related chemokine binding of CCR3 and related chemokine is an important factor of virus infections including HIV [(Marone G, de Paulis A, Florio G, Petraroli A, Rossi F, Triggiani M.: Int Arch Allergy Immunol 2001 Jun;125(2)/89- 95), (Li Y et al.,: Blood 2001 Jun 1; 97(l l):3484-90), and (Marone G, Florio G,
  • CCR3 is an important target and antagonism of CCR3 is likely to be effective in the treatment of such inflammatory and immunoregulatory disorders and diseases.
  • WO 00/76514 and WO 00/76513 disclose cyclopentyl modulators of chemokine receptors including CCR3 activity represented by the general formula:
  • X x, y, R 1 ', R 2 ', R 3 ', R 4 ' R 5 ', R 6 ' R 7 ' and R 8 ' are defined in the application.
  • This invention is to provide novel sulfonamide derivatives shown by the following formula (I), its tautomeric and stereoisomeric form, and the salts thereof.
  • X represents phenyl, which is substituted by 0 to 5 substituents independently selected from the group consisting of R 1 , R 2 , R 3 ,R 4 and R° or pyridine, which is substituted by 0 to 5 substituents independently selected from the group consisting of R 1 , R 2 , R 3 and R 4
  • R 1 is hydrogen, halogen, hydroxy, straight- or branched- C ⁇ -6 alkyl optionally substituted by mono, di or tri halogen, straight- or branched- C ⁇ -6 alkoxy, straight- or branched- C 1-6 alkoxy carbonyl, amino, straight- or branched- C] -6 alkylamino, di(straight- or branched- C ⁇ -6 alkyl)amino, straight- or branched- Cj -6 alkanoyl, nitro, or phenyl
  • R 2 is hydrogen, halogen, straight- or branched- C ⁇ -6 alkyl optionally substi-tuted by mono, di or tri halogen, straight- or branched-C 1-6 alkoxy, or cyano,
  • R 1 and R 2 together form benzene ring or C 5-8 cycloalkyl fused to the adjacent phenyl or pyridine,
  • R 3 is hydrogen, halogen, or straight- or branched- C 1-6 alkyl
  • R 4 is hydrogen, halogen, or straight- or branched- C 1-6 alkyl
  • R° is hydrogen, halogen, or straight- or branched- C 1-6 alkyl
  • Y represents O, ML NCH 3 S, S(O), or SO 2 ;
  • Z 1 represents CH or N
  • Z 2 represents CH or N
  • R .5 represents hydrogen, halogen, hydroxy, straight- or branched- C] -6 alkyl optionally substituted by mono, di or tri halogen or hydroxy, straight- or branched- C 1-6 alkoxy, straight- or branched- C 1-6 alkoxycarbonyl, amino, straight- or branched- C ⁇ -6 alkanoylamino, phenyl- (CH 2 ) q -carbonylamino (wherein q represents an integer selected from 0 to 6), straight- or branched- C ⁇ -6 alkylbenzoylamino, naphfhyl- carbonylamino, thenoylamino, nitro, cyano, carboxy, straight- or branched- C 1-6 alkyl sulfonyl, oxazolidinonyl, or substituents represented by the formula, -SO 2 -NR 51 R 52 , or -CO-NR 51 R 52 ,
  • R 51 and R 52 are independently selected from the group consisting of hydrogen, straight- or branched- C ⁇ -6 alkyl optionally substituted by cyano or carbamoyl and tetrazolyl optionally substituted by C 1-6 alkylnitrile, or
  • R 51 and R 52 may form, together with the adjacent N, a saturated 5 to 8 membered ring optionally interrupted by NH,
  • R 6 represents hydrogen, halogen, straight or branched C ⁇ -6 alkyl optionally substituted by mono di or tri halogen, or straight or branched C 1-6 alkoxy, or
  • R 5 and R 6 may form a pyrrol ring fused to adjacent phenyl, or pyridine;
  • R 7 represents
  • n represents an integer selected from 1 to 3
  • m represents an integer selected from 0 to 3
  • R > 71 is hydrogen, C 3-8 cycloalkyl optionally interrupted by NH, N-CH 3 or O, straight- or branched C 1-6 alkoxycarbonyl, phenyl optionally substituted by straight- or branched C 1-6 alkyl, benzyl, formyl, or
  • straight- or branched C ⁇ -6 alkyl wherein the alkyl is optionally substituted by hydroxy, straight- or branched- C 1-6 alkoxy, hydroxy straight- or branched- C 1-6 alkoxy, carboxy, straight- or branched- C ⁇ -6 alkoxycarbonyl, straight- or branched- C ⁇ -6 alkylthio, di(straight- or branched- C 1-6 alkyl)amino, 5 mono, di or tri halogen, or C 3-8 cycloalkyl optionally interrupted by
  • R and R are independently selected from the group consisting of hydrogen, halogen, hydroxy, carboxy, cyano, straight-or branched C ⁇ -6
  • R 711a and R 711 are independently selected from the group consisting of hydrogen, straight- or branched- C 1-6 alkyl, straight- or branched- C 1-6 alkanoyl, and straight- or branched- C ⁇ -6 alkyl- sulfonyl, or
  • R and R may form, together with the adjacent N atom, a 5 to 8 membered saturated ring;
  • R is hydrogen, or straight- or branched- C ⁇ -6 alkyl
  • R is hydrogen, or straight- or branched- C 1-6 alkyl
  • R 74 is hydrogen, or straight- or branched- C 1-6 alkyl optionally substituted by phenyl, or R 73 and R 74 may form, together with adjacent N atom, a 5 to 8 membered saturated ring optionally substituted by C 1-6 alkyl and optionally interrupted by NH or O;
  • R 75 is straight- or branched- C ⁇ -6 alkylene or a 3 to 8 membered saturated or unsaturated ring;
  • p represents an integer selected from 0 to 4.
  • a ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom N A is the only hetero atom;
  • N B ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom N B is the only hetero atom;
  • C ring and D ring together form a 7 to 12 membered diazabicyclic ring.
  • a 7 to 12 membered diazabicyclic ring stands for a saturated bicyclic ring system consisting of 5 to 10 carbon atoms and 1 to 2 nitrogen atoms, wherein said bicyclic ring system does not exhibit a spiro ring connection.
  • This invention is also to provide a method for treating or preventing a CCR3 related disorder or disease in a human or animal subject, comprising administering to said subject a therapeutically effective amount of the sulfonamide derivative shown in the formula (I), its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof.
  • this invention is to provide a use of the sulfonamide derivative shown in the formula (I), its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof in the preparation of a medicament for treating or preventing a CCR3 related disorder or disease.
  • the compounds of the present invention surprisingly show excellent CCR3 antagonistic activity. They are, therefore suitable for the production of medicament or medical composition, which may be useful to treat CCR3 related diseases.
  • the compounds of the present invention antagonise CCR3, they are useful for treatment and prophylaxis of diseases as follows:
  • asthma wheezing a rhinitis
  • allergic diseases rhinitis
  • autoimmune pathologies such as rheumatoid arthritis, Grave's disease, and atherosclerosis.
  • CCR3 is an important target and antagonism of CCR3 is likely to be effective in the treatment and prophylaxis of such inflammatory and immunoregulatory disorders and diseases.
  • the compounds of the present invention are also useful for treatment and prophylaxis of diseases like virus infections including HIN, lung granuloma, and Alzheimer's diseases, since the diseases also relate to CCR3.
  • the compounds of formula (I) are those wherein:
  • X, Y, Z 1 , Z 2 , R 1 , R 2 , R 3 , R 4 , R° and R 7 are as defined above,
  • R is chloro, iodo, nitro, or cyano
  • R 6 is hydrogen
  • the compounds of formula (I) are those wherein: X, Y, Z 1 and Z 2 are as defined above,
  • R 1 is halogen, or straight- or branched- Cj -6 alkyl optionally substituted by mono, di or tri halogen;
  • R 2 is halogen, or straight- or branched- C ⁇ -6 alkyl optionally substituted by mono, di or tri halogen;
  • R 3 is hydrogen
  • R 4 is hydrogen
  • R is hydrogen
  • R , 5 is halogen, nitro, or cyano
  • R is hydrogen
  • R 7 represents
  • n an integer selected from 1 to 3
  • m represents an integer selected
  • R 71 is hydrogen, straight- or branched C ⁇ -6 alkyl optionally substituted by hydroxy or hydroxy straight- or branched- C ⁇ - 6 alkoxy, C 3-8 cycloalkyl, straight- or branched C 1-6 alkoxycarbonyl, phenyl optionally substituted by straight- or branched C 1-6 alkyl, benzyl, or formyl,
  • R 7U and R 712 are independently selected from the group consisting of hydrogen, halogen, carboxy, or straight-or branched C ⁇ -6 alkyl, or
  • R 71 and R 711 may form, together with the adjacent N atom, a 5 to 8 membered saturated ring;
  • R >72 is hydrogen, or straight- or branched- C 1-6 alkyl
  • R 73 is hydrogen, or straight- or branched- d. 6 alkyl
  • R 74 is hydrogen, or straight- or branched- C 1-6 alkyl,or
  • R 73 and R 74 may form, together with adjacent N atom, a 5 to 8 membered saturated ring optionally interrupted by NH or O;
  • R is straight- or branched- C 1-6 alkylene or a 3 to 8 membered saturated or unsaturated ring;
  • p represents an integer selected from 0 to 4.
  • a ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom N A is the only hetero atom;
  • N B ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom N B is the only hetero atom;
  • C ring and D ring together form a 7 to 12 membered diazabicyclic ring.
  • the compounds of formula (I) are those wherein:
  • X, Y, Z and Z are as defined above,
  • R and R are identical or different and represent chloro, or methyl
  • R is hydrogen or fluoro
  • R 4 is hydrogen; R° is hydrogen;
  • R » 5 is chloro, iodo, nitro, or cyano
  • R is hydrogen
  • R represents
  • n represents an integer selected from 1 to 3
  • m represents an integer selected from 0 to 3
  • R 71 is hydrogen, straight- or branched C ⁇ -6 alkyl optionally substituted by hydroxy or hydroxy straight- or branched- d -6 alkoxy, C 3-8 cycloalkyl, straight- or branched C 1-6 alkoxycarbonyl, phenyl optionally substituted by straight- or branched C 1-6 alkyl, benzyl, or formyl,
  • R 711 and R 712 are independently selected from the group consisting of hydrogen, halogen, carboxy, or straight-or branched C 1-6 alkyl, or
  • R 71 and R 711 may form, together with the adjacent N atom, a 5 to 8 membered saturated ring;
  • R is hydrogen, or straight- or branched- C 1-6 alkyl
  • R 73 is hydrogen, or straight- or branched- C ⁇ -6 alkyl
  • R >74 is hydrogen, or straight- or branched- C 1-6 alkyl,or
  • R and R may form, together with adjacent N atom, a 5 to 8 membered saturated ring optionally interrupted by NH or O;
  • R 75 is straight- or branched- C ⁇ -6 alkylene or a 3 to 8 membered saturated or unsaturated ring;
  • p represents an integer selected from 0 to 4.
  • a ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom N A is the only hetero atom; 2277
  • N B ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom N B is the only hetero atom;
  • C ring and D ring together form a 7 to 12 membered diazabicyclic ring.
  • the compounds of formula (I) are those wherein:
  • X, Y, Z 1 and Z 2 are as defined above,
  • R 1 is hydrogen, fluoro, chloro, bromo, methyl, isopropyl, butyl, tert-butyl, tri- fluoromethyl, methoxy, amino, dimethylamino, acetyl, or nitro;
  • R 2 is hydrogen, fluoro, chloro, methyl, isopropyl, tert-butyl, trifluoromethyl, methoxy, or cyano;
  • R 3 is hydrogen or fluoro
  • R 4 is hydrogen
  • R° is hydrogen
  • R 5 is chloro, iodo, nitro, or cyano
  • R 6 is hydrogen
  • R 7 represents
  • n an integer 1
  • n an integer selected from 1 or 2
  • R 71 represents hydrogen, methyl, ethyl or isopropyl
  • R , 711 represents hydrogen, methyl, or carboxy
  • R >712 represents hydrogen or methyl, or 2277
  • R 71 and R 711 may form, together with the adjacent N atom, a 5 membered saturated ring
  • R 72 is hydrogen, methyl, or ethyl
  • R 73 is hydrogen, or methyl
  • R 74 is hydrogen, methyl, or ethyl, or
  • R and R may form, together with adjacent N atom, piperidino, morpholino, or pyrrolidino;
  • R > 75 is phenyl
  • p represents an integer selected from 0 to 4.
  • a ring represents piperidino, or pyrrolidino
  • B ring represents pyrrolidino
  • C ring and D ring together form a 7 to 12 membered diazabicyclic ring.
  • R 1 is hydrogen, halogen, straight- or branched- C 1-6 alkyl optionally substituted by mono, di or tri halogen, straight- or branched- C 1-6 alkoxy, straight- or branched- C 1-6 alkoxy carbonyl, amino, straight- or branched- C ⁇ -6 alkylamino, di(straight- or branched- C ⁇ -6 alkyl)amino, straight- or branched-
  • R 2 is hydrogen, halogen, straight- or branched- C 1-6 alkyl optionally substituted by mono, di or tri halogen, straight- or branched-C 1-6 alkoxy, or cyano, or
  • R and R may form benzene ring or C 5-8 cycloalkyl fused to the adjacent phenyl;
  • R J is hydrogen or halogen
  • Y represents O, NH, NCH 3 , S, S(O), or SO 2 :
  • R is hydrogen, halogen, hydroxy, straight- or branched- C 1-6 alkyl optionally substituted by mono,di, or tri halogen or hydroxy, straight- or branched- C 1-6 alkoxy, straight- or branched- C 1-6 alkoxycarbonyl, amino, straight- or branched- C ⁇ -6 alkanoylamino, phenyl-(CH ) q -carbonylamino (wherein q represents an integer selected from 0 to 6), straight- or branched- C ⁇ -6 alkyl- benzoylamino, naphthylcarbonylamino, thenoylamino, nitro, cyano, carboxy, straight- or branched- C 1-6 alkyl sulfonyl, oxazolidinonyl, or substituents represented by the formula, -SO 2 -NR 51 R 52 , or -CO-NR 51 R 52 ,
  • R and R are identical or different and represent hydrogen, straight- or branched- C 1-6 alkyl optionally substituted by cyano or carbamoyl, tetrazolyl optionally substituted by C ⁇ -6 alkylnitrile, or R 51 and R 52 may form, together with the adjacent N, a saturated 5 to 8 membered ring optionally interrupted by NH,
  • R 6 is hydrogen, halogen, straight or branched Cj -6 alkyl optionally substituted by mono, di or tri halogen, or straight or branched C ⁇ -6 alkoxy, or
  • R and R may form a pyrrol ⁇ ng fused to adjacent phenyl
  • R 7 represents
  • n represents an integer selected from 1 to 3
  • m represents an integer selected from 0 to 3
  • R is hydrogen, straight- or branched C ⁇ -6 alkyl optionally substituted by hydroxy or hydroxy straight- or branched- C ⁇ -6 alkoxy, C 3-8 cycloalkyl, straight- or branched C 1-6 alkoxycarbonyl, phenyl optionally substituted by straight- or branched C ⁇ . 6 10 alkyl, benzyl, or formyl,
  • R and R are independently selected from the group consisting of hydrogen, halogen, hydroxy, carboxy, cyano, straight-or branched C ⁇ -6 alkyl optionally substituted by hydroxy, carboxy,
  • R 711a and R 711b are independently selected from the group consisting of hydrogen, straight- or branched- C ⁇ -6 alkyl, straight- or branched- C ⁇ -6 alkanoyl, or straight- or branched- C ⁇ -6 alkylsulfonyl, or R 71 and R 71! may form, together with the adjacent N atom, a 5 to 8 membered saturated ring;
  • R 72 is hydrogen, or straight- or branched- C 1-6 alkyl
  • R is hydrogen, or straight- or branched- C ⁇ -6 alkyl
  • R .74 is hydrogen, or straight- or branched- C 1-6 alkyl, or
  • R 73 and R 74 may form, together with adjacent N atom, a 5 to 8 membered saturated ring optionally interrupted by NH or O;
  • R is straight- or branched- C 1-6 alkylene or a 3 to 8 membered saturated or unsaturated ring;
  • p represents an integer selected from 0 to 4.
  • a ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom N A is the only hetero atom;
  • N B ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom N B is the only hetero atom;
  • C ring and D ring together form a 7 to 12 membered diazabicyclic ring.
  • R is hydrogen, halogen, straight- or branched- C ⁇ -6 alkyl optionally substituted by mono, di or tri halogen, straight- or branched- C 1-6 alkoxy, straight- or branched- C 1-6 alkoxy carbonyl, amino, straight- or branched- C ⁇ -6 alkylamino, di(straight- or branched- C 1-6 alkyl)amino, straight- or branched- C ⁇ -6 alkanoyl, or nitro,
  • R 2 is hydrogen, halogen, straight- or branched- C 1-6 alkyl optionally substituted by mono, di or tri halogen, straight- or branched-C 1-6 alkoxy, or cyano, or
  • R 1 and R 2 may form benzene ring or C 5-8 cycloalkyl fused to the adjacent phenyl;
  • R is hydrogen or halogen
  • Y represents O, NH, NCH 3 , S, S(O), or SO 2 ;
  • R 5 is chloro, iodo, nitro, or cyano
  • R is hydrogen
  • R 7 represents
  • n an integer selected from 1 to 3
  • m represents an integer selected
  • R 71 is hydrogen, straight- or branched C 1-6 alkyl optionally substituted by hydroxy or hydroxy straight- or branched- C ⁇ -6 alkoxy, C 3-8 cycloalkyl, straight- or branched C ⁇ -6 alkoxycarbonyl, phenyl optionally substituted by straight- or branched C ⁇ -6 alkyl, benzyl, or formyl,
  • R 711 and R 712 are independently selected from the group consisting of hydrogen, halogen, carboxy, or straight-or branched C ⁇ -6 alkyl, or
  • R 71 and R 711 may form, together with the adjacent N atom, a 5 to 8 membered saturated ring;
  • R 72 is hydrogen, or straight- or branched- C 1-6 alkyl;
  • R 73 is hydrogen, or straight- or branched- C 1-6 alkyl
  • R 74 is hydrogen, or straight- or branched- C 1-6 alkyl, or
  • R 73 and R 74 may fonn, together with adjacent N atom, a 5 to 8 membered saturated ring optionally interrupted by NH or O;
  • R 75 is straight- or branched- C 1-6 alkylene or a 3 to 8 membered saturated or unsaturated ring;
  • p represents an integer selected from 0 to 4.
  • a ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom N A is the only hetero atom;
  • N B ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom N B is the only hetero atom;
  • C ring and D ring together form a 7 to 12 membered diazabicyclic ring.
  • the compounds of formula (1-2) are those wherein :
  • R , ⁇ is hydrogen, halogen, or straight- or branched- C 1-6 alkyl optionally substituted by mono, di or tri halogen;
  • R is hydrogen,halogen, or straight- or branched- C 1-6 alkyl optionally substituted by mono, di or tri halogen;
  • R > 3 is hydrogen or halogen
  • Y is O, NH, NCH 3) S, S(O),or SO 2
  • R is halogen, nitro, or cyano
  • R is hydrogen
  • R represents
  • n represents an integer selected from 1 to 3
  • n an integer selected from 0 to 3
  • R 71 is hydrogen, straight- or branched C 1-6 alkyl optionally substituted by hydroxy or hydroxy straight- or branched- C 1-6 alkoxy, C 3-8 cycloalkyl, straight- or branched C 1-6 alkoxycarbonyl, phenyl optionally substituted by straight- or branched Cj -6 alkyl, benzyl, or formyl,
  • R represents hydrogen, methyl,or carboxy
  • R 712 represents hydrogen or methyl
  • R 71 and R 711 may form, together with the adjacent N atom, a 5 to 8 membered saturated ring;
  • R is hydrogen, or straight- or branched- C ⁇ -6 alkyl
  • R 73 is hydrogen, or straight- or branched- C ⁇ -6 alkyl
  • R 74 is hydrogen, or straight- or branched- C 1-6 alkyl, or
  • R 73 and R 74 may form, together with adjacent N atom, a 5 to 8 membered saturated ring optionally interrupted by NH or O;
  • R 75 is straight- or branched- C ⁇ -6 alkylene or a 3 to 8 membered saturated or unsaturated ring;
  • a ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom N A is the only hetero atom;
  • N B ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom N B is the only hetero atom;
  • C ring and D ring together form a 7 to 12 membered diazabicyclic ring.
  • the compounds of formula(I-2) are those wherein:
  • R , R and R are identical or different and represent hydrogen, chloro, or methyl
  • Y is O, NH, NCH 3 , S, S(O), or SO 2 ;
  • R ) 5 is chloro, iodo, nitro, or cyano
  • R is hydrogen
  • R represents
  • n an integer selected from 1 to 3
  • n an integer selected from 1 to 3
  • R 71 is hydrogen, straight- or branched C 1-6 alkyl optionally substituted by hydroxy or hydroxy straight- or branched- C 1-6 alkoxy, C 3-8 cycloalkyl, straight- or branched C 1-6 alkoxycarbonyl, phenyl optionally substi- tuted by straight- or branched C ⁇ -6 alkyl, benzyl, or formyl,
  • R 711 represents hydrogen, methyl,or carboxy or
  • R and R may form, together with the adjacent N atom, a 5 to 8 membered saturated ring;
  • R 72 is hydrogen, or straight- or branched- C ⁇ -6 alkyl
  • R is hydrogen, or straight- or branched- C ⁇ -6 alkyl
  • R 74 is hydrogen, or straight- or branched- C 1-6 alkyl
  • R 73 and R 74 may form, together with adjacent N atom, a 5 to 8 membered saturated ring optionally interrupted by NH or O;
  • R 75 is straight- or branched- C 1-6 alkylene or a 3 to 8 membered saturated or unsaturated ring;
  • p represents an integer selected from 0 to 4.
  • a ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom N A is the only hetero atom;
  • N B ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom N B is the only hetero atom;
  • C ring and D ring together form a 7 to 12 membered diazabicyclic ring.
  • the compounds of formula (1-2) are those wherein
  • R 1 is halogen, or straight- or branched- C 1-6 alkyl optionally substituted by mono, di or tri halogen;
  • R is halogen, or straight- or branched- C ⁇ -6 alkyl optionally substituted by mono, di or tri halogen;
  • R is hydrogen or fluoro
  • Y is O, NH, NCH 3 , S, S(O),or SO 2 ;
  • R 5 is hydrogen, fluoro, chloro, bromo, iodo, trifluoromethyl, hydroxy, methoxy, amino, acetylamino, isobutylcarbonylamino, tert-butylcarbonylamino, benzo- ylamino, benzylcarbonylamino, phenethylcarbonylamino, methylbenzoyl- amino, naphthylcarbonylammo, thenoylamino, mtro, cyano, methylsulfonyl, dimethyammosulfonyl, piperazmosulfonyl, dimethyaminocarbonyl, or piperazinocarbonyl;
  • R > 6 is hydrogen, methyl, or methoxy
  • R » 5 and R may form a pyrrol ring fused to adjacent phenyl
  • R 7 represents
  • n an integer 1
  • n an integer 1 or 2
  • R 71 is hydrogen, methyl, ethyl, isopropyl, sec-butyl, branched pentyl, hydroxyethyl, hydroxyethoxyethyl, cyclopentyl, cyclohexyl, tert- butoxycarbonyl, phenyl, tolyl, benzyl, or formyl,
  • R 711 represents hydrogen, methyl,or carboxy
  • R 712 represents hydrogen or methyl
  • R 71 and R 711 may form, together with the adjacent N atom, a 5 membered saturated ring
  • R , 72 is hydrogen, methyl, or ethyl
  • R > 73 is hydrogen, or methyl
  • R 74 is hydrogen, methyl, or ethyl, or
  • R 73 and R 74 may form, together with adjacent N atom, piperidino, morpholino, or pyrrolidino;
  • R 75 is phenyl;
  • p represents an integer selected from 0 to 4.
  • a ring represents piperidino, or pyrrolidino
  • B ring represents pyrrolidino
  • C ring and D ring together form a 7 to 12 membered diazabicyclic ring.
  • the compounds of formula (1-2) are those wherein;
  • R 1 is hydrogen, fluoro, chloro, bromo, methyl, isopropyl, butyl, tert-butyl, tri- fluoromethyl, methoxy, amino, dimethylamino, acetyl, or nitro;
  • R 2 is hydrogen, fluoro, chloro, methyl, isopropyl, tert-butyl, trifluoromefhyl, methoxy, or cyano;
  • R 3 is hydrogen or fluoro
  • Y is O, NH, NCH 3 , S, S(O), or SO 2 ;
  • R 5 is hydrogen, fluoro, chloro, bromo, iodo, trifluoromefhyl, hydroxy, methoxy, amino, acetylamino, isobutylcarbonylamino, tert-butylcarbonylamino, benzoyl- amino, benzylcarbonylamino, phenemylcarbonylamino, methylbenzoylamino, naphthylcarbonylammo, thenoylamino, nitro, cyano, methylsulfonyl, dimefhyl- aminosulfonyl, piperazmosulfonyl, dime ylaminocarbonyl, or piperazino- carbonyl;
  • R is hydrogen, methyl, or methoxy; or R and R may form a pyrrol ring fused to adjacent phenyl, and
  • R represents
  • n an integer 1
  • R 71 represents hydrogen, methyl, ethyl, isopropyl, sec-butyl, branched pentyl, hydroxyethyl, hydroxyethoxyethyl, cyclopentyl, cyclohexyl, tert-butoxycarbonyl, phenyl, tolyl, benzyl, or formyl,
  • R 711 represents hydrogen, methyl,or carboxy
  • R 712 represents hydrogen or methyl
  • R 71 and R 711 may form, together with the adjacent N atom, a 5 membered saturated ring
  • R ,72 is hydrogen, methyl, or ethyl
  • R >73 is hydrogen, or methyl
  • R )74 is hydrogen, methyl, or ethyl, or
  • R 73 and R 74 may form, together with adjacent N atom, piperidino, morpholino, or pyrrolidino;
  • R 75 is phenyl
  • p represents an integer selected from 0 to 4.
  • a ring represents piperidino, or pyrrolidino
  • B ring represents pyrrolidino
  • C ring and D ring together form a 7 to 12 membered diazabicyclic ring.
  • the compounds of formula (1-2) are those wherein; R is chloro, bromo, or methyl;
  • R >2 is hydrogen, chloro, bromo, or methyl
  • R ,3 is hydrogen or fluoro
  • Y represents O, S, or S(O);
  • R represents hydrogen, chloro, nitro, or cyano
  • R > 6 represents hydrogen
  • R 7 represents
  • R >71 represents hydrogen, methyl, ethyl or isopropyl
  • R 7n represents hydrogen, methyl,or carboxy
  • R 712 represents hydrogen or methyl
  • R 72 is hydrogen, methyl, or ethyl
  • R is hydrogen, methyl, or ethyl
  • R 74 is hydrogen, methyl, or ethyl
  • R 73 and R 74 may form, together with adjacent N atom, piperidino, or pyrrolidino,
  • R ⁇ 5 is phenyl
  • p represents integer 0 or 1 ;
  • a ring represents piperidino, or pyrrolidino
  • B ring represents pyrrolidino.
  • the preferable compounds of the present invention are as follows:
  • the compound of the formula (I) of the present invention can be prepared by combining various known methods.
  • one or more of the substituents, such as amino group, carboxyl group, and hydroxyl group of the compounds used as starting materials or intermediates are advantageously protected by a protecting group known to those skilled in the art. Examples of the protecting groups are described in "Protective Groups in Organic Synthesis (3rd Edition)" by Greene and Wuts, John Wiley and Sons, New York 1999.
  • the compound represented by the general formula (I-a) can be prepared by the Reaction A or A' below.
  • X, Z 1 , Z 2 and R 6 are as defined above, Y' is O, NH, or S, R 5 is nitro, C 1-6 alkyl, C 1-6 alkylsulfonyl, carboxy and R 7 is the same as R 7 as defined above or protected R 7 . 2277
  • L and L' are identical or different and represent leaving group, such as halogen atom e.g., fluorine, chlorine, bromine, or iodine atom; C ⁇ -io aryl- sulfonyloxy group e.g., benzenesulfonyloxy, or p-toluenesulfonyloxy; and C alkyl- sulfonyloxy group, e.g., trifluoromethanesulfonyloxy, methanesulfonyloxy and the
  • H-R can be reacted to obtain compound 2 in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2- dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide and N-methylpyr- rolidone; sulfoxides such as dimethyl sulfoxide, and others.
  • halogenated hydrocarbons such as dichloromethane, chloroform and 1,2- dichloroethane
  • ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane
  • the reaction temperature is usually, but not limited to, about -10°C to 200°C, and preferably about 10°C to 80°C.
  • the reaction may be carried out for, usually, 30 minutes to 48 hrs and preferably 1 hr to 24 hrs.
  • the reaction can be advantageously conducted in the presence of a base.
  • the examples of the base include an alkali metal hydride such as sodium hydride or potassium hydride; alkali metal alkoxide such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; alkali metal hydroxide such as sodium hydroxide and potassium hydroxide; carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; organic amines such as pyridine, triethylamine and N,N- diisopropylethylamine, and others.
  • Compound 3 (wherein L is identical or different and represent leaving group, such as halogen atom e.g., fluorine, chlorine, bromine, or iodine atom; C 6-10 arylsulfonyloxy group e.g., benzenesulfonyloxy, or p-toluenesulfonyloxy; and C 1-4 alkylsulfonyloxy group, e.g., trifluoromethanesulfonyloxy, methanesulfonyloxy and the like, W represents nitro, halogen, thiol, C 1-6 alkyl sulfinyl, sulfinic acid, sulfonic acid, sulfon- amide and the like) and HY'-X can be reacted to obtain compound 4 in a similar manner as that for the preparation of I-a from compound 2 and HY'-X.
  • leaving group such as halogen atom e.g
  • Compound 4 can be converted to compound 5 (wherein L'is as defined above) by known method in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N- dimethylacetamide and N-methylpyrrolidone; sulfoxides such as dimethylsulfoxide (DMSO); organic acid such as acetic acid; inorganic acid such as HC1 and H 2 SO 4 ; water and others.
  • a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethyl
  • the reaction temperature is usually, but not limited to about -10°C to 200°C, and preferably about 10°C to 80°C.
  • the reaction may be carried out for, usually, 30 minutes to 48 hrs and preferably 1 to 24 hrs.
  • the compound (I-a) can be further reacted to modify R 7 , e.g. to deprotect, or to mmooddiiffyy RR 55 ttoo oobbttaaiinn the compound having amino, halogen, hydroxy, cyano, C ⁇ -6 alkoxy or amide group
  • the compound represented by the general formula (I-b) can be prepared by the Reaction B below.
  • Reaction B is especially advantageous when R 5 is Br.
  • compound 6 and sulfonic acid halide e.g., chlorosulfonic acid
  • a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1 ,2-dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1 ,2-dimethoxyethane; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide and N-methylpyrrolidone; sulfoxides such as dimethylsulfoxide (DMSO), and others.
  • two or more of the solvents selected from the listed above can be mixed and used.
  • the reaction temperature is usually, but not limited to, about -10°C to 200°C, and preferably about 10°C to 80°C.
  • the reaction may be carried out for, usually, 30 minutes to 48 hrs and preferably 1 to 24 hrs.
  • Compound 8 can be prepared from compound 7 in two steps; (step 1) the reaction with H-R 7 and (step 2)deprotection of methoxy group, (step 1) The reaction of 2277
  • compound 7 and H-R 7 can be perforated in a similar manner as that for the
  • Step 2 The successive deprotection of methoxy group to obtain B-3 can be done by the reaction with Lewis acid such as, for example, BBr , in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2- dichloroethane; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide and N-methylpyrrolidone, and others.
  • Lewis acid such as, for example, BBr
  • a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2- dichloroethane; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide and N-methylpyrrolidone, and others.
  • a solvent including, for instance, halogenated hydrocarbons such as
  • the reaction temperature is usually, but not limited to about -10°C to 200°C, and preferably about 10°C to 80°C.
  • the reaction may be carried out for, usually, 30 minutes to 48 hrs and preferably 1 to 24 hrs.
  • compound 8 can be reacted with X-L"(wherein X is defined as above, L" represents leaving group, such as boronic acid, halogen atom e.g., fluorine, chlorine, bromine, or iodine atom) to obtain the compound (I-b).
  • L represents leaving group, such as boronic acid, halogen atom e.g., fluorine, chlorine, bromine, or iodine atom
  • the reaction can be performed in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide and N-methylpyrrolidone; sulfoxides such as dimethyl sulfoxide, and others.
  • halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane
  • ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF)
  • the reaction temperature is usually, but not limited to about -10°C to 200°C, and preferably about 10°C to 100°C.
  • the reaction may be carried out for, usually, 30 minutes to 48 hrs and preferably 1 to 24 hrs.
  • the reaction can be earned out in the presence of a catalyst, including for instance, cooper salts such as cooper(H) acetate, palladium salts such as palladium (It) acetate, and others.
  • the reaction can be advantageously conducted in the presence of a base.
  • the examples of the base include an alkali metal alkoxide such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; alkali metal hydroxide such as sodium hydroxide and potassium hydroxide; carbonates such as cesium carbonate, sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; organic amines such as pyridine, triethylamine and N,N-diisopropylethylamine, and others.
  • alkali metal alkoxide such as sodium methoxide, sodium ethoxide and potassium tert-butoxide
  • alkali metal hydroxide such as sodium hydroxide and potassium hydroxide
  • carbonates such as cesium carbonate, sodium carbonate and potassium carbonate
  • alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate
  • organic amines such as pyridine, triethylamine and N,N-diisopropylethyl
  • the compound (I-b) can be further reacted to modify R , e.g. to deprotect, or to modify R 5 to obtain the compound having amino, halogen, hydroxy, cyano, C ⁇ -6 alkoxy or amide group.
  • the compound (I-c) below can be advantageously prepared by the Reaction C below.
  • X, Z , Z and R are as defined above, Y" is NH or S, and R is the same as
  • R as defined above or protected R .
  • compound 8 which can be prepared as described in the Reaction B can be reacted with either trifluoromethanesulfomc anhydride or trifluoromethanesulfonic chloride to obtain compound 9.
  • the reaction can be performed in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile; amides such as N, N- dimethylformamide (DMF), N, N-dimethylacetamide and N-methylpyrrolidone; sulfoxides such as dimethyl sulfoxide, and others.
  • two or more of the solvents selected from
  • the reaction temperature is usually, but not limited to about -10°C to 200°C, and preferably about 0°C to 100°C.
  • the reaction may be carried out for, usually, 30 minutes to 48 hrs and preferably 1 to 24 hrs.
  • the reaction can be advantageously conducted in the presence of a base.
  • the examples of the base include organic amines such as pyridine, triethylamine and N,N-diisopropylethylamine, and others.
  • compound 9 and HY -X can be reacted to obtain compound (I-c) in a similar manner as that for I-a from compound 2 and HY -X.
  • the compound (I-c) can be further reacted to modify R 7 , e.g. to deprotect, or to modify R 5 to obtain the compound having amino, halogen, hydroxy, cyano, C 1-6 alkoxy or amide group.
  • the compound (I-d) below can be prepared by the Reaction D below.
  • X, Z 1 , Z 2 , R 5' and R 6 are as defined above, Y'" is SO or SO 2 and R 7' is the
  • the sulfoxide compounds of the formula (I-d') can be prepared by oxidation of compound (I-a') using appropriate oxidant including but not limited to, peroxide, such as hydrogen peroxide, t-butyl peroxide; peracids such as meta-chloroperbenzoic acid and the like.
  • peroxide such as hydrogen peroxide, t-butyl peroxide
  • peracids such as meta-chloroperbenzoic acid and the like.
  • the reaction can be performed in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloro- ethane; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N-dimethyl- acetamide and N-methylpyrrolidone, and others.
  • a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloro- ethane; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N-dimethyl- acetamide and N-methylpyrrolidone, and others.
  • DMF N-dimethylform
  • the sulfone compounds of the formula (I-d") can be prepared by oxidation of compound (I-a') with an oxidant such as,for example, sodium periodate (NaIO 4 ) or sodium hypochlorite (NaOCl) in the presence of catalyst such as, for instance, ruthenium (HI) chloride.
  • an oxidant such as,for example, sodium periodate (NaIO 4 ) or sodium hypochlorite (NaOCl) in the presence of catalyst such as, for instance, ruthenium (HI) chloride.
  • the reaction can be performed in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2- dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N- dimethylacetamide and N-methylpyrrolidone; water and others.
  • a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2- dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N- dimethylacetamide and N-methylpyrrolidone; water and others.
  • the sulfone compounds of the formula (I-d") can also be prepared by oxidation of compound (I-d') in a similar manner as that for the oxidation of compound (I-a').
  • the compound (I-d') and (I-d") can be further reacted to modify R 7 , e.g., to deprotect, or to modify R 5 to obtain the compound having amino, halogen, hydroxy, cyano, C 1-6 alkoxy or amide group.
  • Typical salts of the compound shown by the formula (I) include salts prepared by reaction of the compounds of the present invention with a mineral or organic acid, or an organic or inorganic base. Such salts are known as acid addition and base addition salts, respectively.
  • Acids to form acid addition salts include inorganic acids such as, without limitation, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid and the like, and organic acids, such as, without limitation, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • inorganic acids such as, without limitation, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid and the like
  • organic acids such as, without limitation, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • Base addition salts include those derived from inorganic bases, such as, without limitation, ammonium hydroxide, alkaline metal hydroxide, alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, and organic bases, such as, without limitation, ethanolamine, triethylamine, tris(hydroxymethyl)aminomethane, and the like.
  • inorganic bases include, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.
  • the compound of the present invention or a salts thereof, depending on its substituents, may be modified to form lower alkylesters or known other esters; and/or hydrates or other solvates. Those esters, hydrates, and solvates are included in the scope of the present invention.
  • the compound of the present invention may be administered in oral forms, such as, without limitation normal and enteric coated tablets, capsules, pills, powders, granules, elixirs, tinctures, solution, suspensions, syrups, solid and liquid aerosols and emulsions. They may also be administered in parenteral forms, such as, without limitation, intravenous, intraperitoneal, subcutaneous, intramuscular, and the like forms, well-known to those of ordinary skill in the pharmaceutical arts.
  • the compounds of the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal delivery systems well-known to those of ordinary skilled in the art.
  • the dosage regimen with the use of the compounds of the present invention is selected by one of ordinary skill in the arts, in view of a variety of factors, including, without limitation, age, weight, sex, and medical condition of the recipient, the severity of the condition to be treated, the route of administration, the level of metabolic and excretory function of the recipient, the dosage form employed, the particular compound and salt thereof employed.
  • the compounds of the present invention are preferably formulated prior to administration together with one or more pharmaceutically-acceptable excipients.
  • Excipients are inert substances such as, without limitation carriers, diluents, flavoring agents, sweeteners, lubricants, solubilizers, suspending agents, binders, tablet disintegrating agents and encapsulating material.
  • compositions of the present invention are pharmaceutical formulation comprising a compound of the invention and one or more pharmaceutically- acceptable excipients that are compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • Pharmaceutical formulations of the invention are prepared by combimng a therapeutically effective amount of the compounds of the invention together with one or more pharmaceutically-acceptable excipients therefore.
  • the active ingredient may be mixed with a diluent, or enclosed within a carrier, which may be in the form of a capsule, sachet, paper, or other container.
  • the carrier may serve as a diluent, which may be solid, semi-solid, or liquid material which acts as a vehicle, or can be in the form of tablets, pills powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
  • a diluent which may be solid, semi-solid, or liquid material which acts as a vehicle, or can be in the form of tablets, pills powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
  • the active ingredient may be combined with an oral, and non- toxic, pharmaceutically-acceptable carrier, such as, without limitation, lactose, starch, sucrose, glucose, sodium carbonate, mannitol, sorbitol, calcium carbonate, calcium phosphate, calcium sulfate, methyl cellulose, and the like; together with, optionally, disintegrating agents, such as, without limitation, maize, starch, methyl cellulose, agar bentonite, xanthan gum, alginic acid, and the like; and optionally, binding agents, for example, without limitation, gelatin, acacia, natural sugars, beta-lactose, corn sweeteners, natural and synthetic gums, acacia, tragacanth, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like; and, optionally, lubricating agents, for example, without limitation, magnesium stearate, sodium stearate, stearic acid, sodium oleate,
  • the carrier may be a finely divided solid which is in admixture with the finely divided active ingredient.
  • the active ingredient may be mixed with a carrier having binding properties in suitable proportions and compacted in the shape and size desired to produce tablets.
  • the powders and tablets preferably contain from about 1 to about 99 weight percent of the active ingredient which is the novel composition of the present invention.
  • Suitable solid carriers are magnesium carboxymefhyl cellulose, low melting waxes, and cocoa butter.
  • Sterile liquid formulations include suspensions, emulsions, syrups and elixirs.
  • the active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent, or a mixture of both sterile water and sterile organic solvent.
  • a pharmaceutically acceptable carrier such as sterile water, sterile organic solvent, or a mixture of both sterile water and sterile organic solvent.
  • the active ingredient can also be dissolved in a suitable organic solvent, for example, aqueous propylene glycol.
  • Other compositions can be made by dispersing the finely divided active ingredient in aqueous starch or sodium carboxymethyl cellulose solution or in suitable oil.
  • the formulation may be in unit dosage form, which is a physically discrete unit containing a unit dose, suitable for administration in human or other mammals.
  • a unit dosage form can be a capsule or tablets, or a number of capsules or tablets.
  • a "unit dose" is a predetermined quantity of the active compound of the present invention, calculated to produce the desired therapeutic effect, in association with one or more excipients.
  • the quantity of active ingredient in a unit dose may be varied or adjusted from about 0.1 to about 1000 milligrams or more according to the particular treatment involved.
  • Typical oral dosages of the present invention when used for the indicated effects, will range from about O.Olmg /kg/day to about 100 mg/kg/day, preferably from 0.1 mg/kg/day to 30 mg/kg/day, and most preferably from about 0.5 mg/kg/day to about 10 mg/kg/day.
  • parenteral administration it has generally proven advantageous to administer quantities of about 0.001 to lOOmg /kg/day, preferably from 0.01 mg/kg/day to 1 mg/kg/day.
  • the compounds of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses, two, three, or more times per day. Where delivery is via transdermal forms, of course, administration is continuous.
  • ⁇ NMR spectra were recorded using either Bruker DRX-300 (300MHz for 1H) spectrometer in CDC1 . Chemical shifts are reported in parts per million (ppm) with tetramethylsilane (TMS) as an internal standard at zero ppm. Coupling constant (J) are given in hertz and the abbreviations s, d, t, q, m, and br refer to singlet, doublet, triplet, quartet,multiplet, and broad, respectively.
  • Mass spectroscopy data were recorded on a FINNIGAN MAT 95. TLC was performed on a precoated silica gel plate (Merck silica gel 60 F-254). Silica gel (WAKO-gel C-200 (75-150 ⁇ m))was used for all column chromatography separations.
  • Human CCR3-transformed K562 cells were used.
  • the cloned CCR3 cDNA was constructed with pcDNA3 vector and transfected into a K562 cell line.
  • the human CCR3 -transformed K562 cells were maintained in RPMI-1640 (Cat.#22400-089, Life Technologies) supplemented with 10% FCS (Cat A- 1115-L, Hyclone), 55 ⁇ M 2-mercaptoethanol (Cat.#21985-023, Life Tech- nologies), 1 mM sodium pyruvate (Cat.#l 1360-070, Life Technologies),
  • culture medium 100 units/ml of penicillin G and 100 ⁇ g/ml of streptomycin (Cat.#15140-122, Life Technologies), and 0.4 mg/ml of Geneticin (Cat.#10131-035, Life Technologies) (hereinafter called "culture medium").
  • culture medium 100 units/ml of penicillin G and 100 ⁇ g/ml of streptomycin (Cat.#15140-122, Life Technologies), and 0.4 mg/ml of Geneticin (Cat.#10131-035, Life Technologies) (hereinafter called "culture medium”).
  • 5 mM sodium butyrate Cat.#193-01522, Wako
  • Butyrate-pretreated cells suspended in binding buffer (25 mM HEPES pH
  • [ 125 I] -labeled human eotaxin (Cat.#IM290 5 Amersham Pharmacia Biotech), diluted with the binding buffer at the concentration of 0.4 nM (final concentration;0.1 nM), was added into 30 ⁇ l/well in the polypropylene plate.
  • Total 120 ⁇ l/well of binding reaction mixture (60 ⁇ l/well of cell suspension, 30 ⁇ l/well of compound solution, and 30 ⁇ l/well of [ 125 I]-labeled eotaxin) were incubated in the polypropylene plate for 1 hour at room temperature after the incubation, 2277
  • 100 ⁇ l/well of the reaction mixture was transferred to a filtration plate (Cat.#MAFB-NOB, Millipore), and washed with the washing buffer (25 mM HEPES pH 7.6, 1 mM CaCl 2 , 5 mM MgCl 2 , 0.5% BSA, 0.1% NaN 3 , 0.5 M NaCl) twice.
  • the 96-well filtration plate was pretreated with 100 ⁇ l/well of 0.5%) polyethylenimine (Cat.#P-3143, Sigma) for 2-4 hours at room temperature and washed with the washing buffer twice before use.
  • the non-specific binding was determined by parallel incubation in the presence of 500 nM of non-labeled eotaxin (Cat.#23209, Genzyme Techne).
  • the radioactivities remained on the filter were measured by liquid scintillation counter (TopCountTM, Packard) after an addition of 45 ⁇ l/well of scintillant
  • Human CCR3 -transformed K562 cells were used.
  • the human CCR3- transformed K562 cells were maintained in RPMI-1640 supplemented with 10% FCS, 55 ⁇ M 2-mercaptoethanol (Cat.#21985-023, Life Technologies), 1 mM sodium pyruvate, 100 units/ml of penicillin G and 100 ⁇ g/ml of streptomycin and 0.4 mg/ml of Geneticin .
  • cells were pretreated with 5 mM sodium butyrate -containing the culture medium (2 x 10 5 cells/ml) for 20-24 hours to increase the expression ofCCR3. 2277
  • Butyrate-pretreated cells were loaded with Fluo-3AM (Cat.#F-1242, Molecular Probes) in loading buffer (Hanks' solution Cat.#05906 Nissui, 20 mM HEPES pH 7.6, 0.1% BSA, 1 mM probenecid Cat.#P-8761 Sigma, 1 ⁇ M
  • Human CCR3-transformed LI.2 cells were used. Human CCR3 -expressing
  • LI .2 stable transformant was established by electroporation, referring to the methods described in J. Exp. Med. 183:2437-2448, 1996.
  • the human CCR3- transformed LI .2 cells were maintained in RPMI-1640 supplemented with 10% FCS, 100 units/ml of penicillin G and 100 ⁇ g/ml of streptomycin , and 0.4 mg/ml of Geneticin.
  • FCS 10% FCS
  • penicillin G 100 ⁇ g/ml of streptomycin
  • Geneticin 0.4 mg/ml of Geneticin.
  • cells were 22277
  • Butyrate-pretreated cells were suspended in chemotaxis buffer (Hanks' solution Cat.#05906 Nissui, 20 mM HEPES pH 7.6, 0.1% human serum albumin Cat.#A-1887 Sigma) at a cell density of 1.1 x 10 7 cells /ml.
  • a mixture of 90 ⁇ l of cell suspension and 10 ⁇ l of compound solution diluted with chemotaxis buffer (10-times concentration of the final concentration) were preincubated for 10 minutes at 37°C.
  • the mixture of cells and compounds was added into the upper chamber of the 24-well chemotaxis chamber (TranswellTM, Cat.#3421, Costar, pore size;5 ⁇ m).
  • chemotaxis was performed in CO 2 incubator at 37°C for 4 hours. After 4hrs incubation, migrated cells were counted using FACScan (Becton Dickinson). The inhibition percent at the each concentration of compound was calculated, and IC50 values were determined from the inhibition curve.
  • Chemotaxis assay with the use of the obtained eosinophils was done by the same protocols as that using CCR3 stable transformants, LI .2 cells.
  • ketamine hydrochloride 7mg/kg, i.m.; Ketaset, Fort Dodge, IA
  • xylazine 1.2mg/kg, i.m.; Bayer Corp., Elkart, IN
  • Ketamine 5 mg/kg, i.m. was used to supplement anesthesia as needed.
  • Airway responsiveness (AR) to inhaled methachroline followed by bronchoalveolar lavage (BAL) to assess airway cellular composition (ACC) were determined 3 days before (day 0) and 3 days after (day 10) three alternate-day (days 3,5,7) inhalations of Ascaris suum extract. Animals were rested 6 to 8 weeks between studies to allow airway responsiveness and inflammation to return to baseline (pre-antigen) levels. Treatment studies were bracketed by vehicle control studies to assure that no changes in sensitivity to antigen occurred over time.
  • test compounds dissolved in Ethanol:PEG400:Water (10:50:40 v/v) were administered under light anesthetisia.
  • Aerosol Delivery Svstem and Inhalation Challenges Aerosol inhalation challenges were administered by intermittent positive pressure breathing with a Bird Mark 7A respirator and micronebulizer (model 8158). Each challenge consisted of 30 breaths
  • Ascaris suum extract (Greer Laboratories, Lenoir, NC) was diluted with PBS to a final threshold concentration previously determined for each animal and administered as an aerosol (particle size ⁇ 2 ⁇ m).
  • Methacholine (Sigma Chemical Co, St. Louis, Missouri) was dissolved in PBS at a concentration of 100 mg/ml and serial dilutions of 30, 10, 3, 1, 0.3 and
  • Methacholine Dose Response Determinations To assess airway responsiveness to inhaled methacholine, cumulative dose response curves were constructed by admimstering increasing concentrations of methacholine until increases in Rrs of between 100 and 200% were obtained. A vehicle control challenge was performed prior to the first dose of methacholine. Changes in Rrs were measured continuously over a 10 minute period post aerosol challenge. Aerosol challenges were separated by 5 to 10 minutes or until Rrs returned to baseline values.
  • Bronchoalveolar Lavage Following methacholine dose response determinations each monkey was placed in the supine position and a fiberoptic bronchoscope (Olympus Optical, model 3C-10, Lake Success, NY) was guided past the carina and wedged into a fifth to seventh generation bronchus. A total of 15 ml of bicarbonate buffered saline (pH 7.4) was infused and gently aspirated through a channel in the bronchoscope. Collected samples were immediately centrifuged at 2000 rpm for 10 minutes at 4°C. The resulting pellets were resuspended in Ca++ and Mg++ free Hank's balanced salt solution.
  • BAL was performed on alternating right and left lungs. Total white cells per milliliter of BAL fluid was obtained using a Coulter counter (Coulter Corp., Miami, FL). BAL cell composition was determined by counting a minimum of 200 cells from a Wright's stained cytospin slide preparation. Blood Samples: Blood samples were collected prior to and 30minutes, Jackpot and 2hr after the first dose of the test compounds (morning of day 2), immediately before each subsequent dose, and 30 minutes, Jackpot and 2hr after the final dose (evening of day 9). Blood was collected from the femoral vein into EDTA, centrifuged at
  • IC 50 A l ⁇ M ⁇ B 10 ⁇ M ⁇ C
  • the compounds of the present invention also show more than 100-fold selectivity against CCRl.
  • CCR5. CCR7.
  • the compounds of the present invention show dose-dependent inhibitory effect on eotaxin-induced chemotaxis of human eosinophils and strong activity in vivo assays. 63 -
  • Example 1-1 or 1-2 In the similar manner as described in Example 1-1 or 1-2 above, compounds in Example 1-3 to 1-100 as shown in Table 1 were synthesized.
  • Example 2- 2 to 2-24 as shown in Table 2 were synthesized.
  • Example 5-3 to 5-8 as shown in Table 5 were synthesized.
  • Example 6-1 or 6-2 In the similar manner as described in Example 6-1 or 6-2 above, compounds in Example 6-3, 6-4 and 6-5 as shown in Table 6 were synthesized.
  • Example 7- 2 to 7-9 as shown in Table 7 were synthesized.
  • Activity grade RBA A Activity grade Ca 2+ : A 22277
  • the mixture was made basic with IN aqueous NaOH solution.
  • the mixture was diluted with diethylether.
  • the mixture was filtered, then the organic layer was extracted with diethylether, was washed with brine, dried over anhydrous MgSO 4 , filtered, and concentrated in vacuo.
  • the residue was purified by column chromatography on silica gel (EtoAc/Hexane) to give tert- butyl 4- ⁇ [5-(3,5-dimethylphenoxy)-lH-indol-6-yl]sulfonyl ⁇ -l-piperazinecarb- oxylate (42.2 mg, 23.6 %) as a pale brown solid.
  • IC 50 (CCR3): 35 ⁇ M IC 50 (Ca 2+ ): 20 ⁇ M IC 50 (Chemotaxis): 8 ⁇ M
  • Activity grade RBA Activity grade Ca 2+ : A
  • Activity grade RBA A Activity grade Ca 2+ : A
  • the compounds according to the invention can be converted into pharmaceutical preparations as follows:
  • Example 1-1 100 mg of the compound of Example 1-1, 50 mg of lactose (monohydrate), 50 mg of maize starch (native), 10 mg of polyvinylpyrrolidone (PNP 25) (from BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.
  • the mixture of active component, lactose and starch is granulated with a 5% solution (m/m) of the PVP in water. After drying, the granules are mixed with magnesium stearate for 5 min. This mixture is moulded using a customary tablet press (tablet format, see above). The moulding force applied is typically 15 k ⁇ .
  • Example 1-1 1000 mg of the compound of Example 1-1, 1000 mg of ethanol (96%), 400 mg of Rhodigel (xanthan gum from FMC, Pennsylvania, USA) and 99 g of water.
  • a single dose of 100 mg of the compound according to the invention is provided by
  • Rhodigel is suspended in ethanol and the active component is added to the suspension.
  • the water is added with stirring. Stirring is continued for about 6h until the swelling of the Rhodigel is complete.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Pulmonology (AREA)
  • Rheumatology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Virology (AREA)
  • Vascular Medicine (AREA)
  • Psychiatry (AREA)
  • Oncology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Pain & Pain Management (AREA)
  • Communicable Diseases (AREA)
  • Molecular Biology (AREA)
  • Hospice & Palliative Care (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • AIDS & HIV (AREA)
  • Urology & Nephrology (AREA)
  • Otolaryngology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a sulfonamide derivative which is useful as an active ingredient of pharmaceutical preparations. The sulfonamide derivatives of the present invention have CCR3 (CC type chemokine receptor) antagonistic activity, and can be used for the prophylaxis and treatment of diseases associated with CCR3 activity, in particular for the treatment of asthma, atopic dermatitis, allergic rhinitis and other inflammatory/immunological disorders.

Description

ARYLSULFONAMIDE DERIVATIVES FOR USE AS CCR3 ANTAGONISTS IN THE TREATMENT OF
INFLAMMATORY AND IMMUNOLOGICAL DISORDERS
SULFONAMIDE DERIVATIVES
TECHNICAL FIELD
5 The present invention relates to a sulfonamide derivative which is useful as an active ingredient of pharmaceutical preparations. The sulfonamide derivatives of the present invention have CCR3 (CC type chemokine receptor 3) antagonistic activity, and can be used for the prophylaxis and treatment of diseases associated with CCR3 activity, in particular for the treatment of asthma, atopic dermatitis, allergic rhinitis 10 and other inflammatory/immuno logical disorders.
BACKGROUND ART
Chemokmes are chemotactic cytokines of which major functions are migration of 15 inflammatory cells that express relevant chemokine receptors on their surfaces to sites of inflammation, and activation of inflammatory cells. There are two classes of chemokmes, C--X--C (.alpha.) and C— C (i), depending on whether the first two cysteines are separated by a single amino acid (C— X--C) or are adjacent (C— C).
20 One of the C-C family of chemokines, eotaxin, is an 8.4 kDa (74 amino acid) polypeptide and binds with high affinity solely to the receptor CCR3. In vitro and in vivo eotaxin causes chemotaxis of inflammatory cells expressing CCR3 [Eisner J., Hochstetter R., Kimming D. and Kapp A.: Human eotaxin represents a potent activator of the respiratory burst of human eosinophils. Eur. J. Immunol., 26: 1919-
25 1925, 1996.].
The chemokine receptor CCR3 is a G protein-coupled, seven transmembrane domain receptor (GPCR) which binds to known ligands, in addition to eotaxin, including eotaxin-2 (CCL24), RANTES (CCL5), MCP-3 (CCL7) and MCP-4 (CCL13). CCR3 30 is expressed on inflammatory cells relevant to the chronic asthma pathology. Such inflammatory cells include Eosinophils [Sabroe I., Conroy D.M., Gerard N.P., Li Y., Collins P.D., Post T.W., Jose P.J., Williams TJ., Gerard C.J., Ponath P.D. J. Immunol. 161: 6139-6147, 1998], basophils [Uguccioni M., Mackay C.R., Ochensberger B., Loetscher P., Rhis S., LaRosa G.J., Rao P., Ponath P.D., Baggiolini M., Dahinden CA. J. Clin. Invest. 100: 1137-1143, 1997], Th2 cells [Sallusto R, Mackay C.R., Lanzavecchia A. Science. 277: 2005-2007, 1997], alveolar macrophages [Park I.W., Koziel H., Hatch W., Li X., Du B., Groopman J.E. Am. J. Respir. Cell Mol. Biol. 20:864-71, 1999] and mast cells[Oliveira S.H. and Lukacs N.W. Inflamm. Res. 50: 168-174. 2001]. Very recently, it was reported that BEAS- 2B, an epithelial cell line, stimulated with TNF-α and JJFN-γ, expressed CCR3 [Stellato C, Brummet M.E., Plitt J.R., Shahabuddin S., Baroody F.M., Liu M.,
Ponath P.D., and Beck L.A. J. Immunol., 166: 1457-1461, 2001.].
In animal models, eotaxin-knockout mice showed decreased eosinophilia after antigen challenge [Rothenberg M.E., MacLean J.A., Pearlman E., Luster A.D. and Leder P. J. Exp. Med., 185: 785-790, 1997] and in IL5-/eotaxin- double knock-out mice there is no eosinophilia or AHR in response to antigen challenge [Foster P.S., Mould A.W., Yang M., Mackenzie J., Mattes J., Hogan S.P., Mahalingam S., Mckenzie A.N.J., Rothenberg M.E., Young I.G., Matthaei K.I. and Webb D.C. Immunol. Rev., 179, 173-181, 2001]. Clinically, expression of eotaxin and CCR3 mRNA and protein is observed in the lung tissues of atopic asthmatics and is associated with AHR, reduced FENi and lung eosinophilia [Ying S., Robin D.S., Meng Q., Rottman J., Kennedy R., Ringler D.J., Mackay C.R., Daugherty B.L., Springer M.S., Durham S.R., Williams T . and Kay A.B.: Enhanced expression of eotaxin and CCR3 mRΝA and protein in atopic asthma. Association with airway hyperresponsiveness and predominant colocalization of eotaxin mRΝA to bronchial epithelial and endothelial cells. Eur. J. Immunol., 27, 3507-3516, 1997; Lamkhioued Renzi P.M., AbiYounes S., GarciaZepada E.A., Allakhverdi Z., Ghaffar O., Rothenberg M.D., Luster A.D. and Hamid Q.: Increased expressions of eotaxin in bronchoalveolar lavage and airways of asthmatics contributes to the chemotaxis of eosinophils to the site of inflammation. J.Immunol., 159: 4593-4601, 1997; Jahnz-
Royk K., Plusa T. and Mierzejewska J.: Eotaxin in serum of patients with asthma or chronic obstructive pulmonary disease: relationship with eosinophil cationic protein and lung function. Mediators of Inflammation, 9: 175-179, 2000]. In addition, in allergic rhinitis, CCR3 -expressing Th2 lymphocytes co-localize with eosinophils in nasal polyps in close proximity to eotaxin-expressing cells [Gerber B.O., Zanni M.P., Uguccioni M., Loetscher M., Mackay C.R., Pichler W.J., Yawalkar N., Baggiolini M. and Moser B.: Functional expression of the eotaxin receptor CCR3 in T lymphocytes co-localizing with eosinophils. CURRENT BIOLOGY 7: 836-843, 1997]. Moreover, viral infections (RSV, influenza virus) which are known risk factors in asthma, result in increased eotaxin expression in lung tissue which is correlated with tissue eosinophilia [Matsukura S., Kokubo F., Kubo H., Tomita T., Tokunaga H., Kadokura
M., Yamamoto T., Kuroiwa Y., Ohno T., Suzaki H. and Adachi M.: Expression of RANTES by normal airway epithelial cells after influenza virus A infection. Am. J. Respir. Cell and Mol. Biol., 18: 255-264, 1998; Saito T., Deskin R.W., Casola A., Haeberle H., Olszewska B., Ernest P.B., Alam R., Ogra P.L. and Garofalo R.: Selective regulation of chemokine production in human epithelial cells. J. Infec. Dis.,
175: 497-504, 1997].
Thus the binding of CCR3 and related chemokine including eotaxin has been implicated as being important mediators of inflammatory and immunoregulatory disorders and diseases, including asthma, rhinitis, and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis, Grave's disease, and atherosclerosis. It is also implicated that binding of CCR3 and related chemokine is an important factor of virus infections including HIV [(Marone G, de Paulis A, Florio G, Petraroli A, Rossi F, Triggiani M.: Int Arch Allergy Immunol 2001 Jun;125(2)/89- 95), (Li Y et al.,: Blood 2001 Jun 1; 97(l l):3484-90), and (Marone G, Florio G,
Petraroli A, Triggiani M, de Paulis A: Trends Immunol 2001 May;22 (5):229-32)], lung granuloma (Ruth JH, Lukacs NW, Warmington KS, Polak TJ, Burdick M, Kunkel SL, Strieter RM, Chensue SW:J Immunol 1998 Oct 15; 161 (8):4276-82), and Alzheimer's diseases (Xia MQ, Qin SX, Wu LJ, Mackay CR, and Hyman BT: Am J Pathol 1998 Jul;153 (l):31-37). Therefore, CCR3 is an important target and antagonism of CCR3 is likely to be effective in the treatment of such inflammatory and immunoregulatory disorders and diseases.
WO 00/76514 and WO 00/76513 disclose cyclopentyl modulators of chemokine receptors including CCR3 activity represented by the general formula:
Figure imgf000005_0001
wherein
X", x, y, R1', R2', R3', R4' R5', R6' R7' and R8' are defined in the application.
Other applications also disclose CCR3 modulators.
However, none of the reference and other reference discloses simple sulfonamide derivatives having CCR3 antagonistic activity.
The development of a compound having effective CCR3 antagonistic activity and can be used for the prophylaxis and treatment of diseases associated with CCR3 activity has been desired. 2277
- 5 -
SUMMARY OF THE INVENTION
As the result of extensive studies on chemical modification of sulfonamide derivatives, the present inventors have found that the compounds of the structure related to the present invention have unexpectedly excellent CCR3 antagonistic activity. The present invention has been accomplished based on these findings.
This invention is to provide novel sulfonamide derivatives shown by the following formula (I), its tautomeric and stereoisomeric form, and the salts thereof.
Figure imgf000006_0001
X represents phenyl, which is substituted by 0 to 5 substituents independently selected from the group consisting of R1, R2, R3 ,R4 and R° or pyridine, which is substituted by 0 to 5 substituents independently selected from the group consisting of R1, R2, R3 and R4
wherein
R1 is hydrogen, halogen, hydroxy, straight- or branched- Cι-6 alkyl optionally substituted by mono, di or tri halogen, straight- or branched- Cι-6 alkoxy, straight- or branched- C1-6 alkoxy carbonyl, amino, straight- or branched- C]-6 alkylamino, di(straight- or branched- Cι-6 alkyl)amino, straight- or branched- Cj-6 alkanoyl, nitro, or phenyl, R2 is hydrogen, halogen, straight- or branched- Cι-6 alkyl optionally substi-tuted by mono, di or tri halogen, straight- or branched-C1-6 alkoxy, or cyano,
or
R1 and R2 together form benzene ring or C5-8 cycloalkyl fused to the adjacent phenyl or pyridine,
R3 is hydrogen, halogen, or straight- or branched- C1-6 alkyl,
R4 is hydrogen, halogen, or straight- or branched- C1-6 alkyl,
R° is hydrogen, halogen, or straight- or branched- C1-6 alkyl,
Y represents O, ML NCH3 S, S(O), or SO2;
Z1 represents CH or N;
Z2 represents CH or N
with the proviso that both Z1 and Z2 cannot be N at the same time;
R .5 represents hydrogen, halogen, hydroxy, straight- or branched- C]-6 alkyl optionally substituted by mono, di or tri halogen or hydroxy, straight- or branched- C1-6 alkoxy, straight- or branched- C1-6 alkoxycarbonyl, amino, straight- or branched- Cι-6 alkanoylamino, phenyl- (CH2)q -carbonylamino (wherein q represents an integer selected from 0 to 6), straight- or branched- Cι-6 alkylbenzoylamino, naphfhyl- carbonylamino, thenoylamino, nitro, cyano, carboxy, straight- or branched- C1-6 alkyl sulfonyl, oxazolidinonyl, or substituents represented by the formula, -SO2-NR51R52, or -CO-NR51R52 ,
wherein
R51 and R52 are independently selected from the group consisting of hydrogen, straight- or branched- Cι-6 alkyl optionally substituted by cyano or carbamoyl and tetrazolyl optionally substituted by C1-6 alkylnitrile, or
R51 and R52 may form, together with the adjacent N, a saturated 5 to 8 membered ring optionally interrupted by NH,
R6 represents hydrogen, halogen, straight or branched Cι-6 alkyl optionally substituted by mono di or tri halogen, or straight or branched C1-6 alkoxy, or
R5 and R6 may form a pyrrol ring fused to adjacent phenyl, or pyridine; and
R7 represents
Figure imgf000008_0001
Figure imgf000008_0002
Figure imgf000009_0001
Figure imgf000009_0002
Figure imgf000009_0003
or
Figure imgf000009_0004
wherein
n represents an integer selected from 1 to 3, m represents an integer selected from 0 to 3,
R > 71 is hydrogen, C3-8 cycloalkyl optionally interrupted by NH, N-CH3 or O, straight- or branched C1-6 alkoxycarbonyl, phenyl optionally substituted by straight- or branched C1-6 alkyl, benzyl, formyl, or
straight- or branched Cι-6 alkyl wherein the alkyl is optionally substituted by hydroxy, straight- or branched- C1-6 alkoxy, hydroxy straight- or branched- C1-6 alkoxy, carboxy, straight- or branched- Cι-6 alkoxycarbonyl, straight- or branched- Cι-6 alkylthio, di(straight- or branched- C1-6 alkyl)amino, 5 mono, di or tri halogen, or C3-8 cycloalkyl optionally interrupted by
NH or O,
71 1 71
R and R are independently selected from the group consisting of hydrogen, halogen, hydroxy, carboxy, cyano, straight-or branched Cι-6
10 alkyl optionally substituted by hydroxy, carboxy, or mono, di or tri halogen, carbamoyl, di (straight-or branched C]-6 alkyl)amino carb- onyl, and -NR711aR71 ,b
wherein
15
R711a and R711 are independently selected from the group consisting of hydrogen, straight- or branched- C1-6 alkyl, straight- or branched- C1-6 alkanoyl, and straight- or branched- Cι-6 alkyl- sulfonyl, or
20
R and R may form, together with the adjacent N atom, a 5 to 8 membered saturated ring;
79
R is hydrogen, or straight- or branched- Cι-6 alkyl;
25
R is hydrogen, or straight- or branched- C1-6 alkyl,
R74 is hydrogen, or straight- or branched- C1-6 alkyl optionally substituted by phenyl, or R73 and R74 may form, together with adjacent N atom, a 5 to 8 membered saturated ring optionally substituted by C1-6 alkyl and optionally interrupted by NH or O;
R75 is straight- or branched- Cι-6 alkylene or a 3 to 8 membered saturated or unsaturated ring;
p represents an integer selected from 0 to 4;
A ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom NA is the only hetero atom;
B ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom NB is the only hetero atom; and
C ring and D ring together form a 7 to 12 membered diazabicyclic ring.
A 7 to 12 membered diazabicyclic ring stands for a saturated bicyclic ring system consisting of 5 to 10 carbon atoms and 1 to 2 nitrogen atoms, wherein said bicyclic ring system does not exhibit a spiro ring connection. Preferred are 8 to 10 membered ring systems.
This invention is also to provide a method for treating or preventing a CCR3 related disorder or disease in a human or animal subject, comprising administering to said subject a therapeutically effective amount of the sulfonamide derivative shown in the formula (I), its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof.
Further this invention is to provide a use of the sulfonamide derivative shown in the formula (I), its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof in the preparation of a medicament for treating or preventing a CCR3 related disorder or disease.
The compounds of the present invention surprisingly show excellent CCR3 antagonistic activity. They are, therefore suitable for the production of medicament or medical composition, which may be useful to treat CCR3 related diseases.
More specifically, since the compounds of the present invention antagonise CCR3, they are useful for treatment and prophylaxis of diseases as follows:
asthma, rhinitis, and allergic diseases, and autoimmune pathologies such as rheumatoid arthritis, Grave's disease, and atherosclerosis.
Therefore, CCR3 is an important target and antagonism of CCR3 is likely to be effective in the treatment and prophylaxis of such inflammatory and immunoregulatory disorders and diseases.
The compounds of the present invention are also useful for treatment and prophylaxis of diseases like virus infections including HIN, lung granuloma, and Alzheimer's diseases, since the diseases also relate to CCR3.
In another embodiment, the compounds of formula (I) are those wherein:
X, Y, Z1, Z2, R1, R2, R3, R4, R° and R7 are as defined above,
R is chloro, iodo, nitro, or cyano, and
R6 is hydrogen.
In another embodiment, the compounds of formula (I) are those wherein: X, Y, Z1 and Z2 are as defined above,
R1 is halogen, or straight- or branched- Cj-6 alkyl optionally substituted by mono, di or tri halogen;
R2 is halogen, or straight- or branched- Cι-6 alkyl optionally substituted by mono, di or tri halogen;
R3 is hydrogen;
R4 is hydrogen;
R is hydrogen;
R , 5 is halogen, nitro, or cyano;
R is hydrogen; and
R7 represents
Figure imgf000013_0001
Figure imgf000013_0002
227
13
Figure imgf000014_0001
Figure imgf000014_0002
or
Figure imgf000014_0003
wherein
n represents an integer selected from 1 to 3, m represents an integer selected
Figure imgf000014_0004
R 71 is hydrogen, straight- or branched Cι-6 alkyl optionally substituted by hydroxy or hydroxy straight- or branched- Cι-6 alkoxy, C3-8 cycloalkyl, straight- or branched C1-6 alkoxycarbonyl, phenyl optionally substituted by straight- or branched C1-6 alkyl, benzyl, or formyl,
R7U and R712 are independently selected from the group consisting of hydrogen, halogen, carboxy, or straight-or branched Cι-6 alkyl, or
R71 and R711 may form, together with the adjacent N atom, a 5 to 8 membered saturated ring;
R >72 is hydrogen, or straight- or branched- C1-6 alkyl, R73 is hydrogen, or straight- or branched- d.6 alkyl,
R74 is hydrogen, or straight- or branched- C1-6 alkyl,or
R73 and R74 may form, together with adjacent N atom, a 5 to 8 membered saturated ring optionally interrupted by NH or O;
R is straight- or branched- C1-6 alkylene or a 3 to 8 membered saturated or unsaturated ring;
p represents an integer selected from 0 to 4;
A ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom NA is the only hetero atom;
B ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom NB is the only hetero atom; and
C ring and D ring together form a 7 to 12 membered diazabicyclic ring.
In another embodiment, the compounds of formula (I) are those wherein:
X, Y, Z and Z are as defined above,
I 9
R and R are identical or different and represent chloro, or methyl;
R is hydrogen or fluoro;
R4 is hydrogen; R° is hydrogen;
R » 5 is chloro, iodo, nitro, or cyano;
R is hydrogen; and
R represents
Figure imgf000016_0001
Figure imgf000016_0002
Figure imgf000016_0003
or
Figure imgf000016_0004
wherein n represents an integer selected from 1 to 3, m represents an integer selected from 0 to 3,
R71 is hydrogen, straight- or branched Cι-6 alkyl optionally substituted by hydroxy or hydroxy straight- or branched- d-6 alkoxy, C3-8 cycloalkyl, straight- or branched C1-6 alkoxycarbonyl, phenyl optionally substituted by straight- or branched C1-6 alkyl, benzyl, or formyl,
R711 and R712 are independently selected from the group consisting of hydrogen, halogen, carboxy, or straight-or branched C1-6 alkyl, or
R71 and R711 may form, together with the adjacent N atom, a 5 to 8 membered saturated ring;
79
R is hydrogen, or straight- or branched- C1-6 alkyl;
R73 is hydrogen, or straight- or branched- Cι-6 alkyl,
R >74 is hydrogen, or straight- or branched- C1-6 alkyl,or
R and R may form, together with adjacent N atom, a 5 to 8 membered saturated ring optionally interrupted by NH or O;
R75 is straight- or branched- Cι-6 alkylene or a 3 to 8 membered saturated or unsaturated ring;
p represents an integer selected from 0 to 4;
A ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom NA is the only hetero atom; 2277
- 17 -
B ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom NB is the only hetero atom; and
C ring and D ring together form a 7 to 12 membered diazabicyclic ring.
In another embodiment, the compounds of formula (I) are those wherein:
X, Y, Z1 and Z2 are as defined above,
R1 is hydrogen, fluoro, chloro, bromo, methyl, isopropyl, butyl, tert-butyl, tri- fluoromethyl, methoxy, amino, dimethylamino, acetyl, or nitro;
R2 is hydrogen, fluoro, chloro, methyl, isopropyl, tert-butyl, trifluoromethyl, methoxy, or cyano;
R3 is hydrogen or fluoro;
R4 is hydrogen;
R° is hydrogen;
R5 is chloro, iodo, nitro, or cyano;
R6 is hydrogen; and
R7 represents
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000019_0002
Figure imgf000019_0003
or
Figure imgf000019_0004
wherein
n represents an integer 1,
m represents an integer selected from 1 or 2,
R71 represents hydrogen, methyl, ethyl or isopropyl;
R , 711 represents hydrogen, methyl, or carboxy
R >712 represents hydrogen or methyl, or 2277
- 19 -
R71 and R711 may form, together with the adjacent N atom, a 5 membered saturated ring;
R72 is hydrogen, methyl, or ethyl;
R73 is hydrogen, or methyl,
R74 is hydrogen, methyl, or ethyl, or
R and R may form, together with adjacent N atom, piperidino, morpholino, or pyrrolidino;
R >75 is phenyl;
p represents an integer selected from 0 to 4;
A ring represents piperidino, or pyrrolidino;
B ring represents pyrrolidino; and
C ring and D ring together form a 7 to 12 membered diazabicyclic ring.
Yet other preferred compounds of formula (I) represent formula (1-2) and are those
Figure imgf000020_0001
wherein
R1 is hydrogen, halogen, straight- or branched- C1-6 alkyl optionally substituted by mono, di or tri halogen, straight- or branched- C1-6 alkoxy, straight- or branched- C1-6 alkoxy carbonyl, amino, straight- or branched- Cι-6 alkylamino, di(straight- or branched- Cι-6 alkyl)amino, straight- or branched-
C1-6 alkanoyl, or nitro,
R2 is hydrogen, halogen, straight- or branched- C1-6 alkyl optionally substituted by mono, di or tri halogen, straight- or branched-C1-6 alkoxy, or cyano, or
1 9
R and R may form benzene ring or C5-8 cycloalkyl fused to the adjacent phenyl;
RJ is hydrogen or halogen,
Y represents O, NH, NCH3, S, S(O), or SO2 :
R is hydrogen, halogen, hydroxy, straight- or branched- C1-6 alkyl optionally substituted by mono,di, or tri halogen or hydroxy, straight- or branched- C1-6 alkoxy, straight- or branched- C1-6 alkoxycarbonyl, amino, straight- or branched- Cι-6 alkanoylamino, phenyl-(CH )q -carbonylamino (wherein q represents an integer selected from 0 to 6), straight- or branched- Cι-6 alkyl- benzoylamino, naphthylcarbonylamino, thenoylamino, nitro, cyano, carboxy, straight- or branched- C1-6 alkyl sulfonyl, oxazolidinonyl, or substituents represented by the formula, -SO2-NR51R52, or -CO-NR51R52 ,
wherein
R and R are identical or different and represent hydrogen, straight- or branched- C1-6 alkyl optionally substituted by cyano or carbamoyl, tetrazolyl optionally substituted by Cι-6 alkylnitrile, or R51 and R52 may form, together with the adjacent N, a saturated 5 to 8 membered ring optionally interrupted by NH,
R6 is hydrogen, halogen, straight or branched Cj-6 alkyl optionally substituted by mono, di or tri halogen, or straight or branched Cι-6 alkoxy, or
R and R may form a pyrrol πng fused to adjacent phenyl; and
R7 represents
Figure imgf000022_0001
Figure imgf000022_0002
Figure imgf000022_0003
or
Figure imgf000023_0001
wherein
n represents an integer selected from 1 to 3, m represents an integer selected from 0 to 3, 5
71
R is hydrogen, straight- or branched Cι-6 alkyl optionally substituted by hydroxy or hydroxy straight- or branched- Cι-6 alkoxy, C3-8 cycloalkyl, straight- or branched C1-6 alkoxycarbonyl, phenyl optionally substituted by straight- or branched Cι.6 10 alkyl, benzyl, or formyl,
711 71
R and R are independently selected from the group consisting of hydrogen, halogen, hydroxy, carboxy, cyano, straight-or branched Cι-6 alkyl optionally substituted by hydroxy, carboxy,
15 or mono, di or tri halogen, carbamoyl, di (straight-or branched
Ci-β alkyl)amino carbonyl, or-NR7! laR711b
wherein
20 R711a and R711b are independently selected from the group consisting of hydrogen, straight- or branched- Cι-6 alkyl, straight- or branched- Cι-6 alkanoyl, or straight- or branched- Cι-6 alkylsulfonyl, or R71 and R71! may form, together with the adjacent N atom, a 5 to 8 membered saturated ring;
R72 is hydrogen, or straight- or branched- C1-6 alkyl;
R is hydrogen, or straight- or branched- Cι-6 alkyl,
R .74 is hydrogen, or straight- or branched- C1-6 alkyl, or
R73 and R74 may form, together with adjacent N atom, a 5 to 8 membered saturated ring optionally interrupted by NH or O;
e
R is straight- or branched- C1-6 alkylene or a 3 to 8 membered saturated or unsaturated ring;
p represents an integer selected from 0 to 4;
A ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom NA is the only hetero atom;
B ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom NB is the only hetero atom; and
C ring and D ring together form a 7 to 12 membered diazabicyclic ring.
Yet other preferred compounds of formula (1-2) are those wherein:
R is hydrogen, halogen, straight- or branched- Cι-6 alkyl optionally substituted by mono, di or tri halogen, straight- or branched- C1-6 alkoxy, straight- or branched- C1-6 alkoxy carbonyl, amino, straight- or branched- Cι-6 alkylamino, di(straight- or branched- C1-6 alkyl)amino, straight- or branched- Cι-6 alkanoyl, or nitro,
R2 is hydrogen, halogen, straight- or branched- C1-6 alkyl optionally substituted by mono, di or tri halogen, straight- or branched-C1-6 alkoxy, or cyano, or
R1 and R2 may form benzene ring or C5-8 cycloalkyl fused to the adjacent phenyl;
R is hydrogen or halogen,
Y represents O, NH, NCH3, S, S(O), or SO2 ;
R5 is chloro, iodo, nitro, or cyano;
R is hydrogen; and
R7 represents
Figure imgf000025_0001
Figure imgf000025_0002
25
Figure imgf000026_0001
Figure imgf000026_0002
or
Figure imgf000026_0003
wherein
n represents an integer selected from 1 to 3, m represents an integer selected
Figure imgf000026_0004
R 71 is hydrogen, straight- or branched C1-6 alkyl optionally substituted by hydroxy or hydroxy straight- or branched- Cι-6 alkoxy, C3-8 cycloalkyl, straight- or branched Cι-6 alkoxycarbonyl, phenyl optionally substituted by straight- or branched Cι-6 alkyl, benzyl, or formyl,
R711 and R712 are independently selected from the group consisting of hydrogen, halogen, carboxy, or straight-or branched Cι-6 alkyl, or
R71 and R711 may form, together with the adjacent N atom, a 5 to 8 membered saturated ring; R72 is hydrogen, or straight- or branched- C1-6 alkyl;
R73 is hydrogen, or straight- or branched- C1-6 alkyl,
R74 is hydrogen, or straight- or branched- C1-6 alkyl, or
R73 and R74 may fonn, together with adjacent N atom, a 5 to 8 membered saturated ring optionally interrupted by NH or O;
R75 is straight- or branched- C1-6 alkylene or a 3 to 8 membered saturated or unsaturated ring;
p represents an integer selected from 0 to 4;
A ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom NA is the only hetero atom;
B ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom NB is the only hetero atom; and
C ring and D ring together form a 7 to 12 membered diazabicyclic ring.
In another embodiment, the compounds of formula (1-2) are those wherein :
R ,ι is hydrogen, halogen, or straight- or branched- C1-6 alkyl optionally substituted by mono, di or tri halogen;
R is hydrogen,halogen, or straight- or branched- C1-6 alkyl optionally substituted by mono, di or tri halogen;
R > 3 is hydrogen or halogen, Y is O, NH, NCH3) S, S(O),or SO2
.5
R is halogen, nitro, or cyano;
R is hydrogen; and
R represents
Figure imgf000028_0001
Figure imgf000028_0002
Figure imgf000028_0003
Figure imgf000028_0004
or
Figure imgf000028_0005
wherein n represents an integer selected from 1 to 3,
m represents an integer selected from 0 to 3,
R71 is hydrogen, straight- or branched C1-6 alkyl optionally substituted by hydroxy or hydroxy straight- or branched- C1-6 alkoxy, C3-8 cycloalkyl, straight- or branched C1-6 alkoxycarbonyl, phenyl optionally substituted by straight- or branched Cj-6 alkyl, benzyl, or formyl,
711
R represents hydrogen, methyl,or carboxy,
R712 represents hydrogen or methyl, or
R71 and R711 may form, together with the adjacent N atom, a 5 to 8 membered saturated ring;
79
R is hydrogen, or straight- or branched- Cι-6 alkyl;
R73 is hydrogen, or straight- or branched- Cι-6 alkyl,
R74 is hydrogen, or straight- or branched- C1-6 alkyl, or
R73 and R74 may form, together with adjacent N atom, a 5 to 8 membered saturated ring optionally interrupted by NH or O;
R75 is straight- or branched- Cι-6 alkylene or a 3 to 8 membered saturated or unsaturated ring;
p represents an integer selected from 0 to 4; A ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom NA is the only hetero atom;
B ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom NB is the only hetero atom; and
C ring and D ring together form a 7 to 12 membered diazabicyclic ring.
In another embodiment, the compounds of formula(I-2) are those wherein:
1 9 • •
R , R and R are identical or different and represent hydrogen, chloro, or methyl;
Y is O, NH, NCH3, S, S(O), or SO2 ;
R ) 5 is chloro, iodo, nitro, or cyano;
R is hydrogen; and
n
R represents
Figure imgf000030_0001
Figure imgf000030_0002
Figure imgf000030_0003
Figure imgf000031_0001
or
Figure imgf000031_0002
wherein
n represents an integer selected from 1 to 3,
m represents an integer selected from 1 to 3,
R71 is hydrogen, straight- or branched C1-6 alkyl optionally substituted by hydroxy or hydroxy straight- or branched- C1-6 alkoxy, C3-8 cycloalkyl, straight- or branched C1-6 alkoxycarbonyl, phenyl optionally substi- tuted by straight- or branched Cι-6 alkyl, benzyl, or formyl,
R711 represents hydrogen, methyl,or carboxy or
R and R may form, together with the adjacent N atom, a 5 to 8 membered saturated ring;
R72 is hydrogen, or straight- or branched- Cι-6 alkyl;
R is hydrogen, or straight- or branched- Cι-6 alkyl; R74 is hydrogen, or straight- or branched- C1-6 alkyl; or
R73 and R74 may form, together with adjacent N atom, a 5 to 8 membered saturated ring optionally interrupted by NH or O;
R75 is straight- or branched- C1-6 alkylene or a 3 to 8 membered saturated or unsaturated ring;
p represents an integer selected from 0 to 4;
A ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom NA is the only hetero atom;
B ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom NB is the only hetero atom; and
C ring and D ring together form a 7 to 12 membered diazabicyclic ring.
In another embodiment, the compounds of formula (1-2) are those wherein
R1 is halogen, or straight- or branched- C1-6 alkyl optionally substituted by mono, di or tri halogen;
R is halogen, or straight- or branched- Cι-6 alkyl optionally substituted by mono, di or tri halogen;
R is hydrogen or fluoro;
Y is O, NH, NCH3, S, S(O),or SO2; R5 is hydrogen, fluoro, chloro, bromo, iodo, trifluoromethyl, hydroxy, methoxy, amino, acetylamino, isobutylcarbonylamino, tert-butylcarbonylamino, benzo- ylamino, benzylcarbonylamino, phenethylcarbonylamino, methylbenzoyl- amino, naphthylcarbonylammo, thenoylamino, mtro, cyano, methylsulfonyl, dimethyammosulfonyl, piperazmosulfonyl, dimethyaminocarbonyl, or piperazinocarbonyl;
R > 6 is hydrogen, methyl, or methoxy; or
R » 5 and R may form a pyrrol ring fused to adjacent phenyl; and
R7 represents
Figure imgf000033_0001
Figure imgf000033_0002
Figure imgf000033_0003
R 4-iB B ring -(CH2)p — N — or
Figure imgf000034_0001
wherein
n represents an integer 1,
m represents an integer 1 or 2,
R71 is hydrogen, methyl, ethyl, isopropyl, sec-butyl, branched pentyl, hydroxyethyl, hydroxyethoxyethyl, cyclopentyl, cyclohexyl, tert- butoxycarbonyl, phenyl, tolyl, benzyl, or formyl,
R711 represents hydrogen, methyl,or carboxy,
R712 represents hydrogen or methyl, or
R71 and R711 may form, together with the adjacent N atom, a 5 membered saturated ring;
R , 72 is hydrogen, methyl, or ethyl;
R > 73 is hydrogen, or methyl,
R74 is hydrogen, methyl, or ethyl, or
R73 and R74 may form, together with adjacent N atom, piperidino, morpholino, or pyrrolidino; R75 is phenyl;
p represents an integer selected from 0 to 4;
A ring represents piperidino, or pyrrolidino;
B ring represents pyrrolidino; and
C ring and D ring together form a 7 to 12 membered diazabicyclic ring.
In another embodiment, the compounds of formula (1-2) are those wherein;
R1 is hydrogen, fluoro, chloro, bromo, methyl, isopropyl, butyl, tert-butyl, tri- fluoromethyl, methoxy, amino, dimethylamino, acetyl, or nitro;
R2 is hydrogen, fluoro, chloro, methyl, isopropyl, tert-butyl, trifluoromefhyl, methoxy, or cyano;
R3 is hydrogen or fluoro;
Y is O, NH, NCH3, S, S(O), or SO2;
R5 is hydrogen, fluoro, chloro, bromo, iodo, trifluoromefhyl, hydroxy, methoxy, amino, acetylamino, isobutylcarbonylamino, tert-butylcarbonylamino, benzoyl- amino, benzylcarbonylamino, phenemylcarbonylamino, methylbenzoylamino, naphthylcarbonylammo, thenoylamino, nitro, cyano, methylsulfonyl, dimefhyl- aminosulfonyl, piperazmosulfonyl, dime ylaminocarbonyl, or piperazino- carbonyl;
R is hydrogen, methyl, or methoxy; or R and R may form a pyrrol ring fused to adjacent phenyl, and
R represents
Figure imgf000036_0001
Figure imgf000036_0002
Figure imgf000036_0003
Figure imgf000036_0004
or
Figure imgf000036_0005
wherein
n represents an integer 1,
m represents an integer 1 or 2 R71 represents hydrogen, methyl, ethyl, isopropyl, sec-butyl, branched pentyl, hydroxyethyl, hydroxyethoxyethyl, cyclopentyl, cyclohexyl, tert-butoxycarbonyl, phenyl, tolyl, benzyl, or formyl,
R711 represents hydrogen, methyl,or carboxy
R712 represents hydrogen or methyl, or
R71 and R711 may form, together with the adjacent N atom, a 5 membered saturated ring;
R ,72 is hydrogen, methyl, or ethyl,
R >73 is hydrogen, or methyl,
R )74 is hydrogen, methyl, or ethyl, or
R73 and R74 may form, together with adjacent N atom, piperidino, morpholino, or pyrrolidino;
R75 is phenyl;
p represents an integer selected from 0 to 4;
A ring represents piperidino, or pyrrolidino;
B ring represents pyrrolidino; and
C ring and D ring together form a 7 to 12 membered diazabicyclic ring.
her embodiment, the compounds of formula (1-2) are those wherein; R is chloro, bromo, or methyl;
R >2 is hydrogen, chloro, bromo, or methyl;
R ,3 is hydrogen or fluoro;
Y represents O, S, or S(O);
R represents hydrogen, chloro, nitro, or cyano;
R >6 represents hydrogen;
R7 represents
Figure imgf000038_0001
Figure imgf000038_0002
Figure imgf000038_0003
or
Figure imgf000039_0001
wherein
R >71 represents hydrogen, methyl, ethyl or isopropyl;
R7n represents hydrogen, methyl,or carboxy;
R712 represents hydrogen or methyl;
R72 is hydrogen, methyl, or ethyl;
R is hydrogen, methyl, or ethyl;
R74 is hydrogen, methyl, or ethyl; or
R73 and R74 may form, together with adjacent N atom, piperidino, or pyrrolidino,
R ι 5 is phenyl;
p represents integer 0 or 1 ;
A ring represents piperidino, or pyrrolidino; and
B ring represents pyrrolidino. The preferable compounds of the present invention are as follows:
l-{[2-(3,5-dimethylphenoxy)-5-nitrophenyl]sulfonyl}-4-ethylpiperazine, l-{[2-(3,5-dichlorophenoxy)-5- nitrophenyl]sulfonyl}piperazine, 1 - { [2-(3 ,5 -dimethylphenoxy)-5-nitrophenyl] sulfonyl} -4-isopropylpiperazine,
4-(3,5-dimethylphenoxy)-3-(l-piperazinylsulfonyl)benzonitrile, l-{[5-chloro-2-(3,5-dimethylphenoxy)phenyl]sulfonyl}-4-ethylpiperazine, l-{[2-(3,5-dichlorophenoxy)-5-nitrophenyl]sulfonyl}-4-(l-pyrrolidinyl)piperidine;, 4-(3,5-dichlorophenoxy)-3-{[4-(l-pyrrolidinyl)-l-piperidinyl]sulfonyl}benzonitrile, 4-(3,5-dichlorophenoxy)-3-(l-piperazinylsulfonyl)benzonitrile, l-{[2-(3,5-dichlorophenoxy)-5-nitrophenyl]sulfonyl}-N,N-diethyl-3-pyrrolidinamine,
(2S)-l-{[2-(3,5-dichlorophenoxy)-5-nitrophenyl]sulfonyl}-2-(l-pyrrolidinylmethyl)- pyrrolidine,
3 - [(4aR, 7aR)-o ctahydro-6H-p yrrolo [3 ,4-b]pyridin-6-ylsulfonyl] -4-(3 , 5 -dichloro- phenoxy)benzonitrile,
4- [(3 , 5 -dichlorophenyl)sulfanyl] -3 -( 1 -pip erazinylsulfonyl) b enzonitrile, 4-[(3,5-dichlorophenyl)sulfinyl]-3-(l-piperazinylsulfonyl) benzonitrile, 1 - {[2-(3,5-dibromophenoxy)-5-nitrophenyl]sulfonyl}piperazine, l-{[2-(3,5-dichloro-2-fluorophenoxy)-5-nitrophenyl]sulfonyl}piperazine5 l-{[5-cyano-2-(3,5-dichlorophenoxy)phenyl]sulfonyl}-2-piperazinecarboxylic acid, l-{[2-(3,5-dichlorophenoxy)-5-nitrophenyl]sulfonyl}-2-piperazinecarboxylic acid, 1 - { [2-(3 , 5 -dimethylphenoxy)-5 -nitrophenyl] sulfonyl} - 1 ,4-diazep ane, l-{[2-(3,5-dichlorophenoxy)-5-nitrophenyl]sulfonyl}-l,4-diazepane, l-{[2-(3,5-dichlorophenoxy)-5-nitrophenyl]sulfonyl}-3,5-dimethylpiperazine, 3-(l,4-diazepan-l-ylsulfonyl)-4-(3,5-dichlorophenoxy) benzonitrile, r-{[2-(3,5-dichlorophenoxy)-5-nitrophenyl]sulfonyl}-l,3'-bipyrrolidine,
3-(l,3'-bipyrrolidin-r-ylsulfonyl)-4-(3,5-dichlorophenoxy)benzonitrile,
1 -({2-[(3,5-dicl lorophenyl)sulfanyl]-5-nitrophenyl} sulfonyl)-4-(l -pyrrohdmyl)piperidine,
4-(3,5-dichlorophenoxy)-3-(hexahydropyrrolo[l,2-a]pyrazin-2(lH)-ylsulfonyl)benzo- nitrile, and
3-(l,4-diazepan-l-ylsulfonyl)-4-[(3,5-dichlorophenyl)sulfanyl]benzonitrile, and their tautomeric and stereoisomeric form, and physiologically acceptable salts thereof.
The compound of the formula (I) of the present invention can be prepared by combining various known methods. In some embodiments, one or more of the substituents, such as amino group, carboxyl group, and hydroxyl group of the compounds used as starting materials or intermediates are advantageously protected by a protecting group known to those skilled in the art. Examples of the protecting groups are described in "Protective Groups in Organic Synthesis (3rd Edition)" by Greene and Wuts, John Wiley and Sons, New York 1999.
The compound represented by the general formula (I-a) can be prepared by the Reaction A or A' below.
Figure imgf000041_0001
wherein
X, Z1, Z2 and R6 are as defined above, Y' is O, NH, or S, R5 is nitro, C1-6 alkyl, C1-6 alkylsulfonyl, carboxy and R7 is the same as R7 as defined above or protected R7. 2277
41
Reaction A
Figure imgf000042_0001
Compound 1 (wherein L and L' are identical or different and represent leaving group, such as halogen atom e.g., fluorine, chlorine, bromine, or iodine atom; Cβ-io aryl- sulfonyloxy group e.g., benzenesulfonyloxy, or p-toluenesulfonyloxy; and C alkyl- sulfonyloxy group, e.g., trifluoromethanesulfonyloxy, methanesulfonyloxy and the
7* • • • like) and H-R can be reacted to obtain compound 2 in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2- dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide and N-methylpyr- rolidone; sulfoxides such as dimethyl sulfoxide, and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.
The reaction temperature is usually, but not limited to, about -10°C to 200°C, and preferably about 10°C to 80°C. The reaction may be carried out for, usually, 30 minutes to 48 hrs and preferably 1 hr to 24 hrs.
The reaction can be advantageously conducted in the presence of a base. The examples of the base include an alkali metal hydride such as sodium hydride or potassium hydride; alkali metal alkoxide such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; alkali metal hydroxide such as sodium hydroxide and potassium hydroxide; carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; organic amines such as pyridine, triethylamine and N,N- diisopropylethylamine, and others.
Then compound 2 and HY'-X (wherein X and Y' are the same as defined above) can be reacted in a similar manner as that of the reaction of A-1 and H-R7 to obtain the compound (I-a).
Reaction A'
Figure imgf000043_0001
Figure imgf000043_0002
Compound 3 (wherein L is identical or different and represent leaving group, such as halogen atom e.g., fluorine, chlorine, bromine, or iodine atom; C6-10 arylsulfonyloxy group e.g., benzenesulfonyloxy, or p-toluenesulfonyloxy; and C1-4 alkylsulfonyloxy group, e.g., trifluoromethanesulfonyloxy, methanesulfonyloxy and the like, W represents nitro, halogen, thiol, C1-6 alkyl sulfinyl, sulfinic acid, sulfonic acid, sulfon- amide and the like) and HY'-X can be reacted to obtain compound 4 in a similar manner as that for the preparation of I-a from compound 2 and HY'-X.
Compound 4 can be converted to compound 5 (wherein L'is as defined above) by known method in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N- dimethylacetamide and N-methylpyrrolidone; sulfoxides such as dimethylsulfoxide (DMSO); organic acid such as acetic acid; inorganic acid such as HC1 and H2SO4; water and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.
The reaction temperature is usually, but not limited to about -10°C to 200°C, and preferably about 10°C to 80°C. The reaction may be carried out for, usually, 30 minutes to 48 hrs and preferably 1 to 24 hrs.
7'
Then compound 5 and H-R can be reacted to obtain (I-a) in a similar manner as that
7' for the preparation of compound 2 from compound 1 and H-R .
The compound (I-a) can be further reacted to modify R7 , e.g. to deprotect, or to mmooddiiffyy RR55 ttoo oobbttaaiinn the compound having amino, halogen, hydroxy, cyano, Cι-6 alkoxy or amide group
Alternatively, the compound represented by the general formula (I-b) can be prepared by the Reaction B below.
Figure imgf000044_0001
(I-b) wherein
X, Z1 and Z2 are as defined above, R5 is halogen, carboxy or nitro and R7 is the same as R7 as defined above or protected R7. Reaction B
Figure imgf000045_0001
7 of methoxy group
Figure imgf000045_0002
Reaction B is especially advantageous when R5 is Br.
First, compound 6 and sulfonic acid halide (e.g., chlorosulfonic acid) or equivalent thereof can be reacted to obtain compound 7 (wherein L'is as defined above) in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1 ,2-dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1 ,2-dimethoxyethane; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide and N-methylpyrrolidone; sulfoxides such as dimethylsulfoxide (DMSO), and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.
The reaction temperature is usually, but not limited to, about -10°C to 200°C, and preferably about 10°C to 80°C. The reaction may be carried out for, usually, 30 minutes to 48 hrs and preferably 1 to 24 hrs.
Compound 8 can be prepared from compound 7 in two steps; (step 1) the reaction with H-R7 and (step 2)deprotection of methoxy group, (step 1) The reaction of 2277
- 45 -
compound 7 and H-R7 can be perforated in a similar manner as that for the
7* preparation of compound 2 from compound 1 and H-R .
(Step 2) The successive deprotection of methoxy group to obtain B-3 can be done by the reaction with Lewis acid such as, for example, BBr , in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2- dichloroethane; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide and N-methylpyrrolidone, and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.
The reaction temperature is usually, but not limited to about -10°C to 200°C, and preferably about 10°C to 80°C. The reaction may be carried out for, usually, 30 minutes to 48 hrs and preferably 1 to 24 hrs.
Then compound 8 can be reacted with X-L"(wherein X is defined as above, L" represents leaving group, such as boronic acid, halogen atom e.g., fluorine, chlorine, bromine, or iodine atom) to obtain the compound (I-b). The reaction can be performed in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide and N-methylpyrrolidone; sulfoxides such as dimethyl sulfoxide, and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.
The reaction temperature is usually, but not limited to about -10°C to 200°C, and preferably about 10°C to 100°C. The reaction may be carried out for, usually, 30 minutes to 48 hrs and preferably 1 to 24 hrs. The reaction can be earned out in the presence of a catalyst, including for instance, cooper salts such as cooper(H) acetate, palladium salts such as palladium (It) acetate, and others. The reaction can be advantageously conducted in the presence of a base. The examples of the base include an alkali metal alkoxide such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; alkali metal hydroxide such as sodium hydroxide and potassium hydroxide; carbonates such as cesium carbonate, sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; organic amines such as pyridine, triethylamine and N,N-diisopropylethylamine, and others.
7'
The compound (I-b) can be further reacted to modify R , e.g. to deprotect, or to modify R5 to obtain the compound having amino, halogen, hydroxy, cyano, Cι-6 alkoxy or amide group.
The compound (I-c) below can be advantageously prepared by the Reaction C below.
Figure imgf000047_0001
wherein
X, Z , Z and R are as defined above, Y" is NH or S, and R is the same as
7 7
R as defined above or protected R .
Figure imgf000047_0002
9 (I-c) First, compound 8, which can be prepared as described in the Reaction B can be reacted with either trifluoromethanesulfomc anhydride or trifluoromethanesulfonic chloride to obtain compound 9. The reaction can be performed in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile; amides such as N, N- dimethylformamide (DMF), N, N-dimethylacetamide and N-methylpyrrolidone; sulfoxides such as dimethyl sulfoxide, and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.
The reaction temperature is usually, but not limited to about -10°C to 200°C, and preferably about 0°C to 100°C. The reaction may be carried out for, usually, 30 minutes to 48 hrs and preferably 1 to 24 hrs. The reaction can be advantageously conducted in the presence of a base. The examples of the base include organic amines such as pyridine, triethylamine and N,N-diisopropylethylamine, and others.
Then compound 9 and HY -X can be reacted to obtain compound (I-c) in a similar manner as that for I-a from compound 2 and HY -X.
The compound (I-c) can be further reacted to modify R7 , e.g. to deprotect, or to modify R5 to obtain the compound having amino, halogen, hydroxy, cyano, C1-6 alkoxy or amide group.
The compound (I-d) below can be prepared by the Reaction D below.
Figure imgf000048_0001
2277
- 48
wherein
X, Z1, Z2, R5' and R6 are as defined above, Y'" is SO or SO2 and R7' is the
7 7 same as R as defined above or protected R .
Reaction D
Figure imgf000049_0001
The sulfoxide compounds of the formula (I-d') can be prepared by oxidation of compound (I-a') using appropriate oxidant including but not limited to, peroxide, such as hydrogen peroxide, t-butyl peroxide; peracids such as meta-chloroperbenzoic acid and the like. The reaction can be performed in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloro- ethane; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N-dimethyl- acetamide and N-methylpyrrolidone, and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used. The reaction temperature is usually, but not limited to about — 10°C to 200°C, and preferably about 0°C to 100°C. The reaction may be carried out for, usually, 30 minutes to 48 hrs and preferably 1 to 24 hrs.
The sulfone compounds of the formula (I-d") can be prepared by oxidation of compound (I-a') with an oxidant such as,for example, sodium periodate (NaIO4) or sodium hypochlorite (NaOCl) in the presence of catalyst such as, for instance, ruthenium (HI) chloride.
The reaction can be performed in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2- dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N- dimethylacetamide and N-methylpyrrolidone; water and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used. The reaction temperature is usually, but not limited to about -10°C to 200°C, and preferably about 0°C to 100°C. The reaction may be carried out for, usually, 30 minutes to 48 hrs and preferably 1 to 24 hrs.
The sulfone compounds of the formula (I-d") can also be prepared by oxidation of compound (I-d') in a similar manner as that for the oxidation of compound (I-a').
The compound (I-d') and (I-d")can be further reacted to modify R7 , e.g., to deprotect, or to modify R5 to obtain the compound having amino, halogen, hydroxy, cyano, C1-6 alkoxy or amide group.
When the compound shown by the formula (I) or a salt thereof has tautomeric isomers and/or stereoisomers (e.g, geometrical isomers and conformational isomers), each of their separated isomer and mixtures are also included in the scope of the present invention. 2277
- 50 -
When the compound shown by the formula (I) or a salt thereof has an asymmetric carbon in the structure, their optically active compounds and racemic mixtures are also included in the scope of the present invention.
Typical salts of the compound shown by the formula (I) include salts prepared by reaction of the compounds of the present invention with a mineral or organic acid, or an organic or inorganic base. Such salts are known as acid addition and base addition salts, respectively.
Acids to form acid addition salts include inorganic acids such as, without limitation, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid and the like, and organic acids, such as, without limitation, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
Base addition salts include those derived from inorganic bases, such as, without limitation, ammonium hydroxide, alkaline metal hydroxide, alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, and organic bases, such as, without limitation, ethanolamine, triethylamine, tris(hydroxymethyl)aminomethane, and the like. Examples of inorganic bases include, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.
The compound of the present invention or a salts thereof, depending on its substituents, may be modified to form lower alkylesters or known other esters; and/or hydrates or other solvates. Those esters, hydrates, and solvates are included in the scope of the present invention.
The compound of the present invention may be administered in oral forms, such as, without limitation normal and enteric coated tablets, capsules, pills, powders, granules, elixirs, tinctures, solution, suspensions, syrups, solid and liquid aerosols and emulsions. They may also be administered in parenteral forms, such as, without limitation, intravenous, intraperitoneal, subcutaneous, intramuscular, and the like forms, well-known to those of ordinary skill in the pharmaceutical arts. The compounds of the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal delivery systems well-known to those of ordinary skilled in the art.
The dosage regimen with the use of the compounds of the present invention is selected by one of ordinary skill in the arts, in view of a variety of factors, including, without limitation, age, weight, sex, and medical condition of the recipient, the severity of the condition to be treated, the route of administration, the level of metabolic and excretory function of the recipient, the dosage form employed, the particular compound and salt thereof employed.
The compounds of the present invention are preferably formulated prior to administration together with one or more pharmaceutically-acceptable excipients. Excipients are inert substances such as, without limitation carriers, diluents, flavoring agents, sweeteners, lubricants, solubilizers, suspending agents, binders, tablet disintegrating agents and encapsulating material.
Yet another embodiment of the present invention is pharmaceutical formulation comprising a compound of the invention and one or more pharmaceutically- acceptable excipients that are compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Pharmaceutical formulations of the invention are prepared by combimng a therapeutically effective amount of the compounds of the invention together with one or more pharmaceutically-acceptable excipients therefore. In making the compositions of the present invention, the active ingredient may be mixed with a diluent, or enclosed within a carrier, which may be in the form of a capsule, sachet, paper, or other container. The carrier may serve as a diluent, which may be solid, semi-solid, or liquid material which acts as a vehicle, or can be in the form of tablets, pills powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
For oral administration, the active ingredient may be combined with an oral, and non- toxic, pharmaceutically-acceptable carrier, such as, without limitation, lactose, starch, sucrose, glucose, sodium carbonate, mannitol, sorbitol, calcium carbonate, calcium phosphate, calcium sulfate, methyl cellulose, and the like; together with, optionally, disintegrating agents, such as, without limitation, maize, starch, methyl cellulose, agar bentonite, xanthan gum, alginic acid, and the like; and optionally, binding agents, for example, without limitation, gelatin, acacia, natural sugars, beta-lactose, corn sweeteners, natural and synthetic gums, acacia, tragacanth, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like; and, optionally, lubricating agents, for example, without limitation, magnesium stearate, sodium stearate, stearic acid, sodium oleate, sodium benzoate, sodium acetate, sodium chloride, talc, and the like.
In powder forms, the carrier may be a finely divided solid which is in admixture with the finely divided active ingredient. The active ingredient may be mixed with a carrier having binding properties in suitable proportions and compacted in the shape and size desired to produce tablets. The powders and tablets preferably contain from about 1 to about 99 weight percent of the active ingredient which is the novel composition of the present invention. Suitable solid carriers are magnesium carboxymefhyl cellulose, low melting waxes, and cocoa butter.
Sterile liquid formulations include suspensions, emulsions, syrups and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent, or a mixture of both sterile water and sterile organic solvent. The active ingredient can also be dissolved in a suitable organic solvent, for example, aqueous propylene glycol. Other compositions can be made by dispersing the finely divided active ingredient in aqueous starch or sodium carboxymethyl cellulose solution or in suitable oil.
The formulation may be in unit dosage form, which is a physically discrete unit containing a unit dose, suitable for administration in human or other mammals. A unit dosage form can be a capsule or tablets, or a number of capsules or tablets. A "unit dose" is a predetermined quantity of the active compound of the present invention, calculated to produce the desired therapeutic effect, in association with one or more excipients. The quantity of active ingredient in a unit dose may be varied or adjusted from about 0.1 to about 1000 milligrams or more according to the particular treatment involved.
Typical oral dosages of the present invention, when used for the indicated effects, will range from about O.Olmg /kg/day to about 100 mg/kg/day, preferably from 0.1 mg/kg/day to 30 mg/kg/day, and most preferably from about 0.5 mg/kg/day to about 10 mg/kg/day. In the case of parenteral administration, it has generally proven advantageous to administer quantities of about 0.001 to lOOmg /kg/day, preferably from 0.01 mg/kg/day to 1 mg/kg/day. The compounds of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses, two, three, or more times per day. Where delivery is via transdermal forms, of course, administration is continuous.
EXAMPLES
The present invention will be described in detail below in the form of examples, but they should by no means be construed as defining the metes and bounds of the present invention.
In the examples below, all quantitative data, if not stated otherwise, relate to percentages by weight.
Η NMR spectra were recorded using either Bruker DRX-300 (300MHz for 1H) spectrometer in CDC1 . Chemical shifts are reported in parts per million (ppm) with tetramethylsilane (TMS) as an internal standard at zero ppm. Coupling constant (J) are given in hertz and the abbreviations s, d, t, q, m, and br refer to singlet, doublet, triplet, quartet,multiplet, and broad, respectively. Mass spectroscopy data were recorded on a FINNIGAN MAT 95. TLC was performed on a precoated silica gel plate (Merck silica gel 60 F-254). Silica gel (WAKO-gel C-200 (75-150μm))was used for all column chromatography separations.
All chemicals were reagent grade and were purchased from Sigma- Aldrich, Wako pure chemical industries, Ltd., Tokyo kasei kogyo Co., Ltd., Nacalai tesque, Inc.,
Watanabe Chemical Ind. Ltd., Maybridge pic, Lancaster Synthesis Ltd., Merck KgaA, Kanto Chemical Co., Ltd.
The effects of the present compounds were examined by the following assays and pharmacological tests. 2277
- 55 -
[Determination of IC50 values of compounds in receptor binding assay]
(1) cell
Human CCR3-transformed K562 cells were used. The cloned CCR3 cDNA was constructed with pcDNA3 vector and transfected into a K562 cell line. The human CCR3 -transformed K562 cells were maintained in RPMI-1640 (Cat.#22400-089, Life Technologies) supplemented with 10% FCS (Cat A- 1115-L, Hyclone), 55 μM 2-mercaptoethanol (Cat.#21985-023, Life Tech- nologies), 1 mM sodium pyruvate (Cat.#l 1360-070, Life Technologies),
100 units/ml of penicillin G and 100 μg/ml of streptomycin (Cat.#15140-122, Life Technologies), and 0.4 mg/ml of Geneticin (Cat.#10131-035, Life Technologies) (hereinafter called "culture medium"). Before the receptor binding assay, cells were pretreated with 5 mM sodium butyrate (Cat.#193-01522, Wako)-containing the culture medium (2 x 105 cells/ml) for 20-24 hours to increase the expression of CCR3.
(2) Receptor binding assay (RBA)
Butyrate-pretreated cells, suspended in binding buffer (25 mM HEPES pH
7.6, 1 mM CaCl2, 5 mM MgCl2, 0.5% BSA, 0.1% NaN3) at a cell density of 2 x 106 cells/ml, were added into 60 μl/well in the 96-well round bottom polypropylene plate (Cat.#3365, Costar). Compounds, diluted with the binding buffer (4-times higher concentration of the final concentration), were added into 30 μl/well in the polypropylene plate. [125I] -labeled human eotaxin (Cat.#IM2905 Amersham Pharmacia Biotech), diluted with the binding buffer at the concentration of 0.4 nM (final concentration;0.1 nM), was added into 30 μl/well in the polypropylene plate. Total 120 μl/well of binding reaction mixture (60 μl/well of cell suspension, 30 μl/well of compound solution, and 30 μl/well of [125I]-labeled eotaxin) were incubated in the polypropylene plate for 1 hour at room temperature after the incubation, 2277
- 56 -
100 μl/well of the reaction mixture was transferred to a filtration plate (Cat.#MAFB-NOB, Millipore), and washed with the washing buffer (25 mM HEPES pH 7.6, 1 mM CaCl2, 5 mM MgCl2, 0.5% BSA, 0.1% NaN3, 0.5 M NaCl) twice. The 96-well filtration plate was pretreated with 100 μl/well of 0.5%) polyethylenimine (Cat.#P-3143, Sigma) for 2-4 hours at room temperature and washed with the washing buffer twice before use. The non-specific binding was determined by parallel incubation in the presence of 500 nM of non-labeled eotaxin (Cat.#23209, Genzyme Techne). The radioactivities remained on the filter were measured by liquid scintillation counter (TopCount™, Packard) after an addition of 45 μl/well of scintillant
(Microscint20, Cat.#6013621, Packard). The inhibition percent at each concentration of compound was calculated, and IC50 values were determined from the inhibition curve.
[Determination of IC50 values of compounds in calcium mobilization assay] (IC50
Ca2+)
(1) cell
Human CCR3 -transformed K562 cells were used. The human CCR3- transformed K562 cells were maintained in RPMI-1640 supplemented with 10% FCS, 55 μM 2-mercaptoethanol (Cat.#21985-023, Life Technologies), 1 mM sodium pyruvate, 100 units/ml of penicillin G and 100 μg/ml of streptomycin and 0.4 mg/ml of Geneticin . Before the calcium mobilization assay, cells were pretreated with 5 mM sodium butyrate -containing the culture medium (2 x 105 cells/ml) for 20-24 hours to increase the expression ofCCR3. 2277
- 57 -
(2) Calcium mobilization assay
Butyrate-pretreated cells were loaded with Fluo-3AM (Cat.#F-1242, Molecular Probes) in loading buffer (Hanks' solution Cat.#05906 Nissui, 20 mM HEPES pH 7.6, 0.1% BSA, 1 mM probenecid Cat.#P-8761 Sigma, 1 μM
Fluo-3AM, 0.01% pluronic F-127 Cat.#P-6866 Molecular Probes) at a cell density of 1 x 107 cells/ml. Then, cells were washed with calcium assay buffer (Hanks' solution Cat.#05906 Nissui, 20 mM HEPES pH 7.6, 0.1% BSA, 1 mM Probenecid Cat.#P-8761 Sigma). The cell suspension (3.3 x 10° cells/ml) was added into 60 μl/well in the 96-well clear bottom black plate
(Cat.#3904, Costar). Compounds, diluted (5-times concentration of the final concentration) with the calcium assay buffer, were added into 20 μl/well in the plate 10 minutes before assay. Human recombinant eotaxin , diluted with the calcium assay buffer at the concentration of 50 nM (final concen- tration;10 nM), was added into in a polypropylene plate (Cat.#3365, Costar).
Mobilization of cytoplasmic calcium was measured by FDSS-6000 or FDSS- 3000(Hamamatsu Photonics) over 60 sec after the stimulation with lO nM eotaxin. The inhibition percent at the each concentration of compound was calculated, and IC50 values were determined from the inhibition curve.
[Determination of IC50 values of compounds in chemotaxis assay]
(1) cell
Human CCR3-transformed LI.2 cells were used. Human CCR3 -expressing
LI .2 stable transformant was established by electroporation, referring to the methods described in J. Exp. Med. 183:2437-2448, 1996. The human CCR3- transformed LI .2 cells were maintained in RPMI-1640 supplemented with 10% FCS, 100 units/ml of penicillin G and 100 μg/ml of streptomycin , and 0.4 mg/ml of Geneticin. One day before the chemotaxis assay, cells were 22277
- 58 -
pretreated with 5 mM sodium butyrate -containing culture medium (5 x 105 cells/ml) for 20-24 hours to increase the expression of CCR3.
(2) Chemotaxis assay
Butyrate-pretreated cells were suspended in chemotaxis buffer (Hanks' solution Cat.#05906 Nissui, 20 mM HEPES pH 7.6, 0.1% human serum albumin Cat.#A-1887 Sigma) at a cell density of 1.1 x 107 cells /ml. A mixture of 90 μl of cell suspension and 10 μl of compound solution diluted with chemotaxis buffer (10-times concentration of the final concentration) were preincubated for 10 minutes at 37°C. The mixture of cells and compounds was added into the upper chamber of the 24-well chemotaxis chamber (Transwell™, Cat.#3421, Costar, pore size;5 μm). 0.5 ml of 10 nM of human recombinant eotaxin(Cat.#23209, Genzyme Techne) solution, diluted with chemotaxis buffer, was added into the lower chamber of the chemotaxis plate.
Then, chemotaxis was performed in CO2 incubator at 37°C for 4 hours. After 4hrs incubation, migrated cells were counted using FACScan (Becton Dickinson). The inhibition percent at the each concentration of compound was calculated, and IC50 values were determined from the inhibition curve.
[Selectivity test]
Selectivity test was done in calcium mobilization assay and in receptor binding assay by using CCRl, CCR2, CCR4, CCR5, CCR7, CCR8, CXCRl and PAR-1 (peptidase activate receptor) stable transformants. Methods for the test are the same as that of
CCR3. Only the difference is that different stable transformants were used for these selectivity tests. [Determination of IC50 values of compounds in chemotaxis assay with the use of human eosinophils]
Human eosinophils were purified from peripheral blood. Twenty five ml of heparinized blood was layered on 15 ml of Mono-Poly Resolving Medium (#16-980-
49DN, ICN Biomedicals Co. Ltd, Japan) in 50 ml tube (#2335-050, Iwaki, Japan) gently and then centrifuged at 400G, for 20 min, at room temperature. After centrifu- gation, red blood cells were removed by hypotonic lysis. The polymorphonuclear leukocyte pellet was incubated with anti-human CD16 Microbeads (#130-045-701, Milteynyi Biotec GmbH, Germany) for 30 min at 4°C. After washing the cells, magnetically labeled neutrophils were then depleted by applying the cell suspension to BS columns (#130-041-304, Milteynyi Biotec GmbH, Germany) attached to VarioMACS (#130-090-282, Milteynyi Biotec GmbH, Germany).
Chemotaxis assay with the use of the obtained eosinophils was done by the same protocols as that using CCR3 stable transformants, LI .2 cells.
[Primate Chronic Asthma Model: Protocol]
Materials and Methods: The animals used in this study were wild caught, adult male cynomolgus monkeys (Macaca fascicularis) weighing 4.0 to 9.0 kg ( Charles River BRF, Inc.). All animals studied demonstrated a naturally occurring respiratory sensitivity to inhaled Ascaris suum extract. Animals were housed individually in environmentally controlled rooms in open mesh cages and provided food twice daily and water ad libitum. Each animal was fasted for approximately 12 hours prior to the day of study. For each study the animals were anesthetized with ketamine hydrochloride (7mg/kg, i.m.; Ketaset, Fort Dodge, IA) and xylazine (1.2mg/kg, i.m.; Bayer Corp., Elkart, IN), incubated with a cuffed endotracheal tube (5.0 mm ID; Mallinckrodt Critical Care, Glen Falls, NY) and seated in a specially designed support chair. Ketamine (5 mg/kg, i.m.) was used to supplement anesthesia as needed. Study Protocol: Airway responsiveness (AR) to inhaled methachroline followed by bronchoalveolar lavage (BAL) to assess airway cellular composition (ACC) were determined 3 days before (day 0) and 3 days after (day 10) three alternate-day (days 3,5,7) inhalations of Ascaris suum extract. Animals were rested 6 to 8 weeks between studies to allow airway responsiveness and inflammation to return to baseline (pre-antigen) levels. Treatment studies were bracketed by vehicle control studies to assure that no changes in sensitivity to antigen occurred over time.
The test compounds dissolved in Ethanol:PEG400:Water (10:50:40 v/v) were administered under light anesthetisia.
Aerosol Delivery Svstem and Inhalation Challenges: Aerosol inhalation challenges were administered by intermittent positive pressure breathing with a Bird Mark 7A respirator and micronebulizer (model 8158). Each challenge consisted of 30 breaths
(maximum inspiratory pressure=20 cmH2O). Ascaris suum extract (Greer Laboratories, Lenoir, NC) was diluted with PBS to a final threshold concentration previously determined for each animal and administered as an aerosol (particle size <2 μm). Methacholine (Sigma Chemical Co, St. Louis, Missouri) was dissolved in PBS at a concentration of 100 mg/ml and serial dilutions of 30, 10, 3, 1, 0.3 and
0.1 mg/ml were subsequently prepared for nebulization.
Measurement of Respiratory System Resistance (Rrs): The animal was connected to a Harvard Ventilator (Harvard Apparatus, S. Natick, MA) via the endotracheal tube and ventilated at a rate between 30-35 breaths per minute. Airflow was measured by a Fleisch (Hans Rudolph) pneumotachograph and thoracic pressure was measured by a validyne pressure transducer (as the difference between the pressure at the distal end of the endotracheal tube and room pressure). The pneumotachograph and validyne were connected to a pre-amplifier and then into an MI2 respiratory analyzer (Malvern, PA). Using the primary signals of flow and pressure the analyzer 22277
- 61 -
computed airway resistance and compliance (as well as a number of other respiratory parameters).
Methacholine Dose Response Determinations: To assess airway responsiveness to inhaled methacholine, cumulative dose response curves were constructed by admimstering increasing concentrations of methacholine until increases in Rrs of between 100 and 200% were obtained. A vehicle control challenge was performed prior to the first dose of methacholine. Changes in Rrs were measured continuously over a 10 minute period post aerosol challenge. Aerosol challenges were separated by 5 to 10 minutes or until Rrs returned to baseline values.
Determination of P Cu Values: The resistance obtained with PBS was set as zero. The percentage increase in resistance above zero at each dose of methacholine was entered into the computer and the program used an algorithm to determine the exact methacholine concentration which caused an increase in resistance of 100% above baseline (PCioo)- Differences (day 10-day 0) in PC10o values were calculated as logs (base 10 ) to normalize the data and account for the large variation in absolute values for the PC10o between animals.
Bronchoalveolar Lavage: Following methacholine dose response determinations each monkey was placed in the supine position and a fiberoptic bronchoscope (Olympus Optical, model 3C-10, Lake Success, NY) was guided past the carina and wedged into a fifth to seventh generation bronchus. A total of 15 ml of bicarbonate buffered saline (pH 7.4) was infused and gently aspirated through a channel in the bronchoscope. Collected samples were immediately centrifuged at 2000 rpm for 10 minutes at 4°C. The resulting pellets were resuspended in Ca++ and Mg++ free Hank's balanced salt solution. To avoid possible effects of the BAL procedure on lung cellular composition, BAL was performed on alternating right and left lungs. Total white cells per milliliter of BAL fluid was obtained using a Coulter counter (Coulter Corp., Miami, FL). BAL cell composition was determined by counting a minimum of 200 cells from a Wright's stained cytospin slide preparation. Blood Samples: Blood samples were collected prior to and 30minutes, Ihr and 2hr after the first dose of the test compounds (morning of day 2), immediately before each subsequent dose, and 30 minutes, Ihr and 2hr after the final dose (evening of day 9). Blood was collected from the femoral vein into EDTA, centrifuged at
1500 rpm for 15minutes at 4°C and the plasma stored at -70°C until assayed for the test compounds.
Statistical Analysis: All data were evaluated statistically with the use of students t- test where a p value <0.05 was considered statistically significant.
Results of receptor binding assay (RBA), Ca2+ mobilization assay (Ca2+) are shown in Examples and tables of the Examples below. The data corresponds to the compounds as yielded by solid phase synthesis and thus to levels of purity of about 40 to 90%. For practical reasons, the compounds are grouped in three classes of activity as follows:
IC50 = A lμM < B 10 μM < C
The compounds of the present invention also show more than 100-fold selectivity against CCRl. CCR5. CCR7. CCR8 and CXCRl in receptor binding assays.
The compounds of the present invention show dose-dependent inhibitory effect on eotaxin-induced chemotaxis of human eosinophils and strong activity in vivo assays. 63 -
Example 1-1
Figure imgf000064_0001
(1) To the solution of 2-chloro-5-nitrobenzenesulfonyl chloride (3.84 g, 15 mmol) in dry THF (30 ml) was added dropwise the mixture of Boc- piperazine (3.07 g, 16.5 mmol) and N, N-diisopropylethylamine (2.33 g, 18 mmol) in dry THF (10 ml) at 0°C with stirring. The mixture was then stirred at room temperature for 3 hrs. The solvent was evaporated and CH2C12 was added to the residue. The mixture was washed with 0.5 N aqueous HC1, brine, saturated aqueous NaHCO3, brine, successively, dried over MgSO4. The solvent was evaporated to give tert-butyl 4-[(2-chloro-5-nitrophenyl)- sulfonyl]-l-piperazinecarboxylate as white powder (5.80g, 95.3%).
Figure imgf000064_0002
(2) To the solution of 3,5-dimethylphenol (1.92 g, 15.72 mmol) in DMF (50 ml) was added NaH (60%, 0.629g, 15.72 mmol) at 0°C with stirring. tert-Butyl 4-[(2- cUoro-5-mfrophenyl)sulfonyl]-l-piperazinecarboxylate (5.80 g, 14.29 mmol) was added to the mixture after 30 min. The mixture was stirred at room temperature for 2 hrs. 100 ml of ice water was added, the precipitate was collected by filtration, washed with water and dried in vacuo to give tert-butyl 4-{[2- (3,5-dimethylphenoxy)-5-nitrophenyl]sulfonyl}-l-piperazinecarboxylate as white powder (6.90 g, 98.2%): mp 232-233°C; IH NMR (500 MHz, CDC13). 1.45 (9H, s), 2.35 (6H, s), 3.35 (4H, t, J = 5 Hz), 3.51 (4H, t, J = 5 Hz), 6.72 (2H, s), 6.91-6.95 (2H, m), 8.26 (IH, t), 8.86 (IH, s);HPLC-MS (ESI): Calcd for C23H29N3O7S [M + H]+ 492, Found: 492.
Molecular weight: 491.5675 Activity grade RB A: C Activity grade Ca2+: C
Example 1-2
Figure imgf000065_0001
(1) To the suspension of te7't-butyl 4-{[2-(3,5-dimethylphenoxy)-5-nitrophenyl]- sulfonyl} -1-piperazinecarboxylate (620 mg, 1.26 mmol) which was prepared in the Example 1-1 in CH2C12 (3ml) was added trifluoloacetic acid (2 ml) at 0°C, the mixture was stirred at 0°C for 3 hrs. The solvent was evaporated in vacuo and 20 ml of toluene was added, the solvent was evaporated in vacuo again. To the residue was added CH C12 (15 ml), and the mixture was cooled 22277
- 65 -
to 0°C. 4 N HCl solution in 1,4-dioxane (2 ml)was added and the mixture was stirred for 15 min at 0°C. The solvent was evaporated, and diethyl ether (5 ml) was added to the residue. The precipitate was collected by filtration and dried to give l-{[2-(3,5-dimethylphenoxy)-5-nitrophenyl]sulfonyl} pi- perazine hydrochloride
(480 mg, 88.9%): mp 264-266°C; IH NMR (300 MHz, OMSO-d6) δ 2.33 (6H, s), 3.18 (4H, br), 3.56 (4H, br), 6.96 (2H, s), 7.03-7.05 (2H, m), 8.45 (IH, q, J = 9.2 Hz), 8.60 (H, d, J = 2.8 Hz), 9.38 (2H, br); HPLC-MS (ESI): Calcd for C18H21N3O5S [M + H]+ 392, Found: 392.
Molecular weight: 427.9101 Activity grade RB A: A Activity grade Ca2+: A
In the similar manner as described in Example 1-1 or 1-2 above, compounds in Example 1-3 to 1-100 as shown in Table 1 were synthesized.
Table 1
EX.No molstructure MW M+1 mp RBA Ca2+
1-3 505.47344 392 120-125 A
1-4 435.83682 400 273-274 A A
1-5 459.90894 424 211-213
1-6 535.85272 500 188-191 A
1-7 512.07268 476 141-143
Figure imgf000067_0001
/022277
67 -
1-8 455.96432 420 182-185 A
1-9 441.93723 406 168-170
Figure imgf000068_0001
-10 424.86584 389 265-267 B
-11 449.9165 414 196-198
-12 413.88305 378 167-169
Figure imgf000068_0002
Figure imgf000069_0001
/022277
69
Figure imgf000070_0001
Figure imgf000071_0001
71
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
/022277
78
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
0
82
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
/022277
85
-98 504.34918 504 200-201
Figure imgf000086_0001
-99 468.74602 432 247-250
Figure imgf000086_0002
-100 468.74602 432 256-258 A A
Figure imgf000086_0003
86 -
Example 2-1
Figure imgf000087_0001
(1) To the solution of 3,5-dimethylthiophenol (82.94 mg, 0.60 mmol) in dry THF
(5ml) was added NaH (60%, 24 mg, 0.60 mmol). tert-Butyl 4-[(2-chloro-5- nitrophenyl)sulfonyl]-l-piperazinecarboxylate (162mg, 0.4 mmol), which was prepared in the step(l) of Example 1-1, was added to the solution after lOmin. The resulting mixture was stirred at room temperature overnight. 60 mg of K2CO3 was added and the mixture was stirred at room temperature for 6hrs.
EtoAc was added and the mixture was washed by 10% aqueous Na2CO3, brine, successively. The organic layer was dried over MgSO4. The solvent was evaporated to 3 ml, the produced white crystal was collected by filtration and dried to give tert-butyl 4-({2-[(3,5-dimethylphenyl)sulfanyl]-5-nitrophenyl}- sulfonyl)- 1-piperazinecarboxylate (148 mg , 72.9%).
Figure imgf000087_0002
(2) To the solution of tert-butyl 4-({2-[(3,5-dimethylphenyl)sulfanyl]-5-nitro- phenyl} sulfonyl)- 1-piperazinecarboxylate (100 mg, 0.20 mmol) in dry CH2C1 (3 ml) was added 4 N HCl (0.5 ml) solution in 1,4-dioxane, the mixture was stirred overnight at room temperature. The solvent was evaporated, and 5ml of diethyl ether was added to the residue. The precipitate was collected by filtration and dried to give l-({2-[(3,5-dimethylphenyl)- sulfanyl]-5-mtroρhenyl}sulfonyl)piperazine hydrochloride (82 mg, 93.8%): mp 225-227°C; IH NMR (300 MHz, OMSO-d6) δ 2.34 (6H, s), 3.18 (4H, br), 3.63 (4H, br), 7.09 (IH, d, J = 9Hz), 7.25 (IH, s), 7.31 (2H, s), 8.30 (IH, q, J = 9 Hz), 8.54 (IH, d, J = 2), 9.57 (2H, br); HPLC-MS (ESI): Calcd for
C18H21N3O4S2 [M + H]+ 408, Found: 408.
Molecular weight: 443.9747 Activity grade RBA: A Activity grade Ca2+: A
In the similar manner as described in Example 2-1 above, compounds in Example 2- 2 to 2-24 as shown in Table 2 were synthesized.
O 03/022277
88-
Table 2
Figure imgf000089_0001
Figure imgf000090_0001
O 03/022277
90
Figure imgf000091_0001
0
91
Figure imgf000092_0001
03/022277
-92-
Figure imgf000093_0001
2277
- 93 -
Example 3-1
Figure imgf000094_0001
(1) To the solution of 3,5-dimethylaniline (96.9 mg, 0.80 mmol) in dry THF
(15 ml) was added NaH (60%, 24 mg, 0.6 mmol) followed by tert-butyl 4-[(2- chloro-5-nitrophenyl)sulfonyl]-l-piperazinecarboxylate (162.3 mg, 0.40 mmol), which was prepared in the step (1) of Example 1-1 and the mixture was stirred at 80°C for 2 hrs. The solvent was evaporated and 15 ml of ice water was added to the residue. The mixture was extracted with CH C12. The combined extract was washed with saturated aqueous NaHCO3, brine, successively, dried over MgSO4. The solvent was evaporated and 10 ml of diethyl ether was added to the residue, the produced precipitate was collected by filtration and dried to give tert-butyl 4-({2-[(3,5-dimethylphenyl)amino]-5-nitrophenyl}- sulfonyl)- 1 -piperazinecarboxylate (110 mg, 56.1%).
Figure imgf000094_0002
2277
94
(2) To the suspension of te?'t-bu.tyl 4-({2-[(3,5-dimethylphenyl)amino]-5-nitro- phenyl} sulfonyl)- 1-piperazinecarboxylate (150 mg, 0.31 mmol) in CH2C12 (2 ml) was added 4N HCl solution in 1,4-dioxane (1ml), the mixture was stirred for 2 hrs at room temperature. The mixture was filtered. The filtrate was evaporated, and 5ml of diethyl ether was added to the residue. The precipitate was collected by filtration and dried to give N-(3,5-dimethyl- phenyl)-4-nitro-2-(l-piperazinylsulfonyl)aniline dihydrochloride (115 mg, 81.2%) : mp 175-179°C; IH NMR (300 MHz, OMSO-dT) δ 2.30 (6H, s), 3.18 (4H, t, J = 5.3 Hz), 3.44 (4H, q, J = 5.3 Hz), 6.97 (3H, s), 7.10 (IH, d, J = 9.4 Hz), 8.25 (IH, q, J = 9.4 Hz), 8.34 (IH, d, J = 2.64 Hz), 8.47 (IH, s),
9.23 (2H, br); HPLC-MS (ESI): Calcd for C18H22N4O S [M + H]+ 391, Found: 391.
Molecular weight: 463.3864 Activity grade RBA: A
In the similar manner as described in Example 3-1 above, compounds in Example 3- 2 to 3-12 as shown in Table 3 were synthesized.
Table 3
Figure imgf000096_0001
3/022277
96
Figure imgf000097_0001
Figure imgf000098_0001
2277
- 98 -
Example 4-1
Figure imgf000099_0001
(1) To the solution of 2-chloro-5-nirrobenzenesulfonyl chloride (2.05g, 8 mmol) in THF (60 ml) was added the solution of 4-(l-pyrrolidinyl)piperidine (1.23 g, 8 mmol) and NEt3 (0.89g, 8.8 mmol) in THF (15 ml) dropwise. The mixture was stirred at room temperature for 2hrs. 3,5-Dichlorophenol (1.96 g, 12 mmol) was added to the above mixture followed by NaH (60%, 0.96 g, 12 mmol). The resulting mixture was stirred at 65°C for 8 hrs, and cooled to room temperature. The precipitate was collected by filtration and washed with THF, Et2O, and water, successively, dried in vacuo to give l-{[2-(3,5- dichlorophenoxy)-5-nitroρhenyl]sulfonyl}-4-(l-pyrrolidinyl)piperidine as white powder (3.2 g, 79.9%): mp 217-218°C; IH NMR (500 MHz, CDC13) δ 1.26 (2H, s), 1.63 (4H, d, J = 10 Hz), 1.77 (4H, s), 1.92 (2H, d, J = 6.1Hz),
2.15 (IH, m), 2.34 (6H, s), 2.97 (2H, p, J = 10 Hz), 3.86 (2H, q, J = 9.3 Hz), 6.74 (2H, s), 6.90 (IH, d, J = 9.1 Hz), 6.94 (IH, s), 8.24 (IH, q, J = 9.1 Hz), 8.86 (IH, d, J = 2.85 Hz); HPLC-MS (ESI): Calcd for C21H23Cι2N3O5S [M + H]+ 501, Found: 500 and 502 Molecular weight: 500.4046 IC50 (CCR3): 8 μM IC50 (Ca2+): 7 μM IC50 (Chemotaxis): 5 μM
In the similar manner as described in Example 4-1 above, compounds in Example 4- 2 to 4-41 as shown in Table 4 were synthesized.
Table 4
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
03/022277
-104-
Figure imgf000105_0001
-28 491.63268 492 143-144
-29 514.43165 515 173-174 A
-30 531.46226 531 98-99 A
-31 503.40808 503 138-140 A
-32 529.44632 529 167-169
Figure imgf000106_0001
-106-
Figure imgf000107_0001
Figure imgf000108_0001
- 108 -
Example 5-1
Figure imgf000109_0001
(1) The mixture of tert-butyl 4-{[2-(3,5-dimethylphenoxy)-5-nitrophenyl]- sulfonyl}- 1-piperazinecarboxylate (6.80g, 13.83 mmol), which was prepared in the step (2) of Example 1-1 and 10% Pd-C (1) in methanol (600 ml) was stirred at room temperature under 1 ATM of H2 for 5 hrs. The Pa-C was filtered off. The filtrate was evaporated to 30 ml. The produced crystals was collected by filtration to give tert-butyl 4-{[5-amino-2-(3,5-dimethyl- phenoxy)phenyl] sulfonyl} -1-piperazinecarboxylate (6.0 g, 94.0%).: HPLC- MS (ESI): Calcd for C23H3ιN3O5S [M + H]+ 462, Found: 462.
Molecular weight: 461.5846 Activity grade RB A: C
Activity grade Ca2+: C
Example 5-2
Figure imgf000110_0001
(1) To the mixture of copper(I) chloride (39.6 mg, 0.4 mmol) and tert-butyl nitrite (41.2 mg, 0.4 mmol) in CH3CN (10 ml) was added tert-butyl 4-{[5- amino-2-(3,5-dimethylphenoxy)phenyl]sulfonyl}-l-piperazinecarboxylate (92.3 mg, 0.2 mmol) which was prepared in the Example 5-1 at 60°C. The mixture was stirred at 65-70°C for 2hrs, and cooled to room temperature. The solvent was evaporated. CH2C12 was added to the residue and the mixture was washed with 15 ml of 4N NaOH, 30 ml of brine, successively, dried over MgSO4. The solvent was evaporated, and the residue was purified by preparative TLC on silica gel (CH2Cl2/CH3OH =35/1) to give tert-butyl-4- {[5-chloro-2-(3,5-dimethylphenoxy)phenyl]sulfonyl}-l-piperazinecarboxylate (56.0 mg, 58.2%) .
Figure imgf000110_0002
22277
- 110 -
(2) To the suspension of tert-butyl 4-{[5-chloro-2-(3,5-dimethylphenoxy)phen- yl] sulfonyl} -1-piperazinecarboxylate (40.0 mg, 0.08 mmol) in dry CH2C1 (1.5 ml) was added 0.3 ml of 4N hydrogen chloride solution in 1,4-dioxane, the mixture was stirred for 5 hrs at room temperature. The solvent was evaporated, and diethyl ether (5 ml) was added to the residue. The produced precipitate was collected by filtration and dried to give l-{[5-chloro-2-(3,5- dimethylphenoxy)phenyl]sulfonyl}piperazine hydrochloride (24.0 mg, 69.2%): mp 202-204 °C; IH NMR (300 MHz, OMSO-d6) 8 2.30 (6H, s), 3.14 (4H, be), 3.50 (4H, br), 6.82 (2H, s), 6.91 (IH, s), 6.97 (IH, d, J = 8.7 Hz), 7.70 (IH, t, J = 8.7 Hz), 7.82 (IH, d, J = 2.3 Hz), 9.57 (2H, br); HPLC-
MS (ESI): Calcd for C18H21ClN2O3S [M + H]+ 381, Found: 381.
Molecular weight: 417.3576 Activity grade RBA: A Activity grade Ca2+: A
In the similar manner as described in Example 5-1 or 5-2 above, compounds in Example 5-3 to 5-8 as shown in Table 5 were synthesized.
Table 5
Figure imgf000112_0001
77
Figure imgf000113_0001
Example 6-1
Figure imgf000114_0001
(1) To the solution of tert-butyl 4-{[5-amino-2-(3,5-dimethylphenoxy)phenyl]- sulfonyl}-l-piperazinecarboxylate (138.5mg, 0.30 mmol) prepared in the step (1) of Example 5-1 in CH2C12 (5 ml) was added nitrosonium tetrafluoroborate (38.5 mg, 0.33 mmol) at 0 °C and the solution was stirred at 0°C for 30 min. The solvent was evaporated. The residue was dissolved in methanol (5 ml) and the solution of Cu2O (64.4 mg, 0.45 mmol) and CuSO4.3H2O (724.8 mg,
3 mmol) in 10ml of water was added to the above solution at 0°C. The mixture was stirred at 0°C for 30 min. The solvent was evaporated and ethyl acetate was added. The mixture was washed with 1 N aqueous NaOH, brine, successively and dried over MgSO4. The solvent was evaporated and the residue was purified by preparative TLC on silica gel (CH2Cl2/CH3OH =
20/1) to give tert-butyl 4-{[2-(3,5-dimethylphenoxy)-5-hydroxyphenyl]- sulfonyl}- 1-piperazinecarboxylate (39.0 mg , 28.1%).
114
Figure imgf000115_0001
(2) To the suspension of tert-butyl 4-{[2-(3,5-dimethylphenoxy)-5-hydroxy- phenyl] sulfonyl} -1-piperazinecarboxylate (12.0 mg, 0.03 mmol) in dry CH2C12 (1ml) was added 4 N HCl solution in 1,4-dioxane (0.18 ml), the mixture was stirred 5hrs at room temperature. The solvent was evaporated, and 3ml of diethyl ether was added to the residue. The precipitate was collected by filtration and dried to give 4-(3,5-dimethylphenoxy)-3-(l- ρiperazinylsulfonyl)phenol hydrochloride (9.0 mg, 87.0%): mp >286; IH NMR (300 MHz, DMSO-ΛJ) δ 2.24 (6H, s), 3.12 (4H, br), 3.36 (4H, br), 6.56 (2H, s), 6.76 (IH, s), 6.96 (IH, d, J = 9 Hz), 7.08 (IH, q, J = 9 Hz), 7.25 (IH, d, J = 2.6 Hz), 9.03 (2H, br), 10.06 (IH, s); HPLC-MS (ESI): Calcd for C18H22N2O4S [M + H]+ 363, Found: 363.
Molecular weight: 398.9120
Activity grade RB A: C
Activity grade Ca 2+. : C
Example 6-2
Figure imgf000116_0001
(1) To the solution of tert-butyl 4-{[2-(3,5-dimethylphenoxy)-5-hydroxyphenyι]- sulfonyl}- 1-piperazinecarboxylate (20.0 mg, 0.04 mmol), which was prepared in the step (1) of Example 6-1 in dry DMF (1ml) was added methyl iodide (30.7 mg, 0.22 mmol) and K2CO3 (12.0 mg, 0.09 mmol). The mixture was stirred at room temperature for 3 hrs. The solvent was evaporated in vacuo and 3ml of ice water was added. The white precipitate was collected by filtration and washed with 1 N aqueous NaOH, water and dried to give tert- butyl 4- { [2-(3 , 5 -dimethylphenoxy)-5 -methoxyphenyl] sulfonyl} - 1 -piperazine- carboxylate as white powder (20.0 mg, 97.1%).
Figure imgf000116_0002
22277
- 116 -
(2) To the solution of tert-butyl 4-{[2-(3,5-dimethylphenoxy)-5-methoxyphenyl]- sulfonyl}- 1-piρerazinecarboxylate (18.0 mg, 0.04 mmol) in dry CH2C12 (1 ml) was added 4 N HCl (0.2 ml) solution in 1,4-dioxane, the mixture was stirred 5 hrs at room temperature. The solvent was evaporated, and 3 ml of diethyl ether was added to the residue. The precipitate was collected by filtration and dried to give 4-(3,5-dimethylphenoxy)-3-(l-piρerazinylsulfonyl)phenol hydrochloride (12.0 mg, 76.9%): mp 175-177°C; IH NMR (300 MHz, DMSO-d6) δ 2.25 (6H, s), 3.12 (4H, t, J = 4.5 Hz), 3.40 (4H, d, J = 4.5 Hz), 3.82 (3H, s), 6.62 (2H, s), 6.80 (IH, s), 7.04 (IH, d, J = 9.1 Hz), 7.27 (IH, q, J = 9.1 Hz), 7.33 (IH, d, J = 3.0 Hz), 9.24 (2H, br);
HPLC-MS (ESI): Calcd for C19H24N2O4S [M + H]+ 377, Found: 377. Molecular weight: 412.9391 Activity grade RBA: A Activity grade Ca2+: B
In the similar manner as described in Example 6-1 or 6-2 above, compounds in Example 6-3, 6-4 and 6-5 as shown in Table 6 were synthesized.
Table 6
Figure imgf000118_0001
Example 7-1
Figure imgf000119_0001
(1) To the mixture of tert-butyl 4-{[5-amino-2-(3,5-dimethylphenoxy)phenyl]- sulfonyl}- 1-piperazinecarboxylate (369 mg, 0.80 mmol), which was prepared in the step (1) of Example 5-1, and triethylamine (97 mg, 0.96 mmol) in dry CH2C12 (20 ml) was added dropwise the solution of phenylacetyl chloride (130 mg, 0.84 mmol) in THF (5 ml) at 0°C with stirring. The mixture was then stirred at RT for 3 hrs, and CH2C12 was added. The mixture was washed with 0.5 N aqueous HCl, brine, saturated aqueous NaHCO , brine, successively, dried over MgSO4. The solvent was evaporated. Dry CH2C12 (15 ml) was added to the residue. 4 N HCl solution in 2,4-dioxane (1ml) was added to the solution at 0°C with stirring. The mixture was then stirred at room temperature for 3 hrs. The obtained precipitate was collected to give product as HCl salt. The HCl salt was suspended in 10 ml of ice water and the PH of the mixture was adjusted to 8 by addition of saturated aqueous NaHCO3, extracted by CH2C12. The combined extract was washed with saturated aqueous NaHCO3, brine, successively, dried over MgSO4. The solvent was evaporated. 5 ml of methanol was added to the residue and the white precipitate was collected by filtration and washed with ether and dried to give 22277
- 119 -
N- [4-(3 , 5 -dimethylphenoxy)-3 -( 1 -piperazinylsulfonyl)phenyl] -2-phenylacet- amide (330 mg , 86.0%): mp 228-230°C; IH NMR (300 MHz, CDC13). 2.28 (6H, s), 2.87 (4H, br), 3.24 (4H, br), 3.74 (2H,s), 6.62 (2H, s), 6.79 (IH, s), 6.87 (IH, d, J = 8.8 Hz), 7.34-7.62 (6H, m), 7.62 (IH, s), 7.95 (IH, q, J = 8.8 Hz); HPLC-MS (ESI): Calcd for C26H29N3O4S [M + H]+ 480, Found: 480.
Molecular weight: 479.6027 Activity grade RBA: C Activity grade Ca2+: C
In the similar manner as described in Example 7-1 above, compounds in Example 7- 2 to 7-9 as shown in Table 7 were synthesized.
O 03/022277
120
Table 7
Figure imgf000121_0001
Figure imgf000122_0001
Example 8-1
Figure imgf000123_0001
(1) To a solution of 4-bromoanisole (2.00 g, 10.7 mmol) in CHC13 (20 ml) was added chlorosulfonic acid (1.49 ml, 22.5 mmol) at 0°C. This mixture was stirred at room temperature for 2 hrs, and then poured into ice water (50 ml). This mixture was extracted with CH2C12. The combined organic extracts were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to give crude 5-bromo-2-methoxybenzenesulfonyl chloride (0.760 g, 24.9%).
Figure imgf000123_0002
(2) To a solution of 5-bromo-2-methoxybenzenesulfonyl chloride (760 mg,
2.66 mmol) and Et3N (445 μl, 3.19 mmol) in CH2C12 (20 ml) was added l-(t- butoxycarbonyl)piperazine (521 mg, 2.80 mmol) at 0°C. This mixture was stirred at room temperature for 6 hrs, and then diluted with Et2O, washed with 10%) citric acid solution, aqueous NaHCO3, and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give crude sulfonamide (716 mg). 22277
- 123
To a solution of the sulfonamide (716 mg, 1.65 mmol) in CH2C12 (5 ml) was added IM BBr3 solution in CH2C12 (3.30 ml, 3.30 mmol) at 0°C. This mixture was stirred at 0°C for 1 hr. After basifing with 3M aqueous NaOH (20 ml), THF (15 ml) and Di-t-butyl dicabonate (718 mg, 3.29 mmol) were added to the mixture at 0°C. The mixture was stirred at room temperature overnight. This mixture was extracted with Et O. The organic extract was dried over anhydrous Na2SO4, filtered, and concentrated to give di(Boc)- compound. To hydrolize t-butyl carbonate, the residue was treated with K2CO3 (455 mg, 3.29 mmol) in MeOH (10 ml) at room temperature for 5 hrs. After removing MeOH by evaporation, the residue was acidified with 10% citric acid solution. This aqueous mixture was extracted with EtoAc. The organic extract was dried over anhydrous Na2SO4, filtered, and concentrated to give tert-butyl 4-[(5-bromo-2-hydroxyphenyl)sulfonyl]-l-piperazinecarb- oxylate (526 mg, 47.0%).
Figure imgf000124_0001
(3) To a mixture of tert-butyl 4-[(5-bromo-2-hydroxyphenyl)sulfonyl]- 1-piperazinecarboxylate (410 mg, 0.973 mmol), 3,5-dimethylphenylbronic acid (219 mg, 1.46 mmol), Cu(OAc)2 (177 mg, 0.973 mol), and powdered 4A molecular sieves (820 mg) in CH2C12 (10 ml) was added Et3N (0.678 ml,
4.87 mmol) at room temperature. This mixture was stirred at room temperature under ambient atmosphere overnight. The resulting slurry was filtered through Celite. The filtrate was diluted with EtoAc, and washed with aqueous NH4C1, NaHCO3, and brine. The organic layer was dried over anhy- drous Na SO , filtered, and concentrated. Et2O was added to the residue. The resulting precipitate was collected by filtration, and washed with Et2O. This solid was purified by column chromatography on silica gel (CHCl3/MeOH=99/l) to give tert-butyl 4-{[5-bromo-2-(3,5-dimethyl- phenoxy)phenyl] sulfonyl} -1-piperazinecarboxylate (320 mg, 62.6%).
Figure imgf000125_0001
(4) To a solution of tert-butyl 4-{[5-bromo-2-(3,5-dimethylphenoxy)phenyl]- sulfonyl}- 1-piperazinecarboxylate (25.0 mg, 48.0 μmol) in CH2C12 (1.0 ml) was added 4M HCl solution in 1,4-dioxane (100 μl, 400 μmol) at 0°C. This mixture was stirred at room temperature overnight. Solvents were removed by evaporation. The resulting residue was suspended in Et O, and collected by filtration to give a white amorphous, l-{[5-bromo-2-(3,5-dimethyl- phenoxy)phenyl]sulfonyl}piperazine hydrochloride (20.0 mg, 90.2%): 1H NMR (300 MHz, CDC13) δ 2.31 (6 H, s), 3.12-3.38 (4H, br), 3.60-3.84 (4H, br), 6.72 (2H, s), 6.75 (IH, d, J= 8.7 Hz), 6.87 (IH, s), 7.54 (IH, dd, J= 2.3, 8.7 Hz), 8.05 (IH, d, J = 2.3 Hz), 9.79-10.40 (2H, br); HPLC-MS (ESI): Calcd for Cι8H21BrN2O3S [M + H]+ 425 and 427, Found: 425 and 427.
Molecular weight: 461.8086
Activity grade RBA: A Activity grade Ca2+: A 22277
125
Example 9-1
Figure imgf000126_0001
(1) A mixture of tert-butyl 4-{[5-bromo-2-(3,5-dimethylphenoxy)phenyl]sulfon- yl}- 1-piperazinecarboxylate (95.0 mg, 181 μmol), which was prepared in the step (3) of Example 8-1, CuCN (32.4 mg, 362 μmol), and Pd(PPh3)4 (20.9 mg, 18.1 μmol) in DMF (2 ml) was heated at 150°C overnight. After cooling to room temperature, this mixture was diluted with CH C1 , and washed with ammonia solution and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (Hexane/EtoAc=3/l~2/l) to give tert- butyl 4- {[5-cyano-2-(3,5-dimethylphenoxy)phenyl]sulfonyl} - 1 -piperazine- carboxylate (14.0 mg, 16.4%).
Figure imgf000126_0002
(2) To a solution of tert-butyl 4-{[5-cyano-2-(3,5-dimethylphenoxy)phenyl]- sulfonyl}- 1-piperazinecarboxylate (14.0 mg, 29.7 μmol) in CH2C1 (1.0 ml) 22277
- 126
was added 4M HCl solution in dioxane (0.2 ml) at room temperature. This mixture was stirred at room temperature overnight. Dioxane was removed by evaporation. The residue was suspended in Et O. The resulting precipitate was collected by filtration to give 4-(3,5-dimethylphenoxy)-3-(l-piperazinyl- sulfonyl)benzonitrile hydrochloride (6.0 mg, 49.6 %): 1H NMR (300 MHz, CDC13) δ 2.34 (6 H, s), 3.28-3.47 (4H, br), 3.67-3.83 (4H, br), 6.78 (2H, s), 6.89 (IH, d, J = 8.6 Hz), 6.95 (IH, s), 7.69 (IH, dd, J = 1.9, 8.6 Hz), 8.24 (IH, d, J = 1.9 Hz), 9.97-10.32 (2H, br); HPLC-MS (ESI): Calcd for C19H2]N3O3S [M + H]+ 372, Found: 372.
Molecular weight: 407.9225 Activity grade RBA: A Activity grade Ca2+: A
Example 10-1
Figure imgf000127_0001
(1) To 4-chlorobenzoic acid (1.00 g, 6.39 mmol) was added chlorosulfonic acid (2.55 ml, 38.3 mmol) at room temperature dropwise. This mixture was heated at 150°C for 6 hrs. After cooling to room temperature, the mixture was diluted with CH2C1 . This solution was added to ice water. Two phases were separated. The organic phase was washed with brine, and then dried over anhydrous MgSO4, filtered, and concentrated to give crude 4-chloro-3- (chlorosulfonyl)benzoic acid (0.720 g, 43.9%).
Figure imgf000128_0001
(2) To a solution of 4-chloro-3-(chlorosulfonyl)benzoic acid (200 mg, 0.784 mmol) and Et3N (130 μl, 0.938 mmol) in CH2C12 (5 ml) was added 1- (t-butoxycarbonyl)piperazine (161 mg, 0.864 mmol) at 0°C. This mixture was stirred at room temperature overnight, and then diluted with CH2C12, washed with 10% citric acid solution. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was suspended in Et2O, and the precipitate was collected by filtration to give crude 3-{[4-(tert- butoxycarbonyl)-l-piperazinyl]sulfonyl} -4-chlorobenzoic acid (200 mg, 63.0%).
Figure imgf000128_0002
(3) To a mixture of 3-{[4-(tert-butoxycarbonyl)-l-piperazinyl]sulfonyl}-4- chlorobenzoic acid (340 mg, 0.840 mmol), dimethylammonium chloride (137 mg, 1.68 mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (193 mg, 1.01 mmol), and HOBT (136 mg, 1.01 mmol) in CH2C12 was added Et3N (410 μl, 2.96 mmol) at 0°C. This mixture was stirred at room temperature for two days. The mixture was diluted with EtoAc, and washed with 10% citric acid solution, aqueous NaHCO3, and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (EtoAc) to give tert-butyl 4-( {2-chloro-5 - [(dimethylamino)carbonyl]phenyl} sulfonyl)- 1 - piperazinecarboxylate (258 mg, 71.1%).
Figure imgf000129_0001
(4) To a mixture of tert-butyl 4-({2-chloro-5-[(dimethylamino)carbonyl]phen- yl} sulfonyl)- 1-piperazinecarboxylate (248 mg, 0.574 mmol) and 3,5-dimethylphenol (140 mg, 0.859 mmol) in DMF (2 ml) was added t-BuOK (129 mg, 1.15 mmol) at room temperature. This mixture was heated at 150°C for two days. After cooling to room temperature, ice water (10 ml) was added to the mixture. Two phases were separated. The aqueous phase was extracted with CH2C12. The combined organic layers were washed with aqueous NaHCO3 and brine, dried over anhydrous Na2SO , filtered, and concentrated. This residue was purified by column chromatography on silica gel (Hexane/-
EtoAc=l/2) to give tert-butyl 4-({2-(3,5-dichlorophenoxy)-5-[(dimethyl- amino)-carbonyl]phenyl} sulfonyl)- 1-piperazinecarboxylate (182 mg, 56.8%).
Figure imgf000130_0001
(5) To a solution of tert-butyl 4-({2-(3,5-dichlorophenoxy)-5-[(dimethylamino)- carbonyl]phenyl} sulfonyl)- 1-piperazinecarboxylate (150 mg, 0.269 mmol) in CH2C12 was added 4M HCl solution in dioxane (0.300 ml, 1.20 mmol) at 0°C. This mixture was stirred at room temperature overnight. Solvents were removed by evaporation. The resulting residue was suspended in Et2O and collected by filtration to give 4-(3,5-dichlorophenoxy)-N,N-dimethyl-3-(l- piperazinylsulfonyl)benzamide hydrochloride (50.0 mg, 37.6%): mp 197- 199°C; HPLC-MS (ESI): Calcd for C19H21Cl2N3O4S [M + H]+ 458, Found: 458.
Molecular weight: 494.8279 Activity grade RBA: B Activity grade Ca2+: B
In the similar manner as described in Example 10-1 above, compound in Example 10-2 as shown in Table 10 was synthesized. Table 10
Figure imgf000131_0001
Example 11-1
Figure imgf000132_0001
(1) To a mixture of 5-fluoro-2-nitrotoluene (1.00 g, 6.45 mmol) in CHC13 (10 ml) was added chlorosulfonic acid (0.86 ml, 12.9 mmol) dropwise. The mixture was refluxed overnight. After the mixture was cooled to room temperature, the mixture was diluted with CHC13, then ice water was added to the mixture. The organic layer was extracted with CHC13 and was washed with brine. The extracted organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give a pale yellow oil.
The oil was dissolved in THF (50 ml). To the solution was added tert-butyl 1-piperazinecarboxylate (1.20 g, 6.45 mmol), and N,N-diisopropylethylamine (1.12 ml, 6.45 mmol) successively. The mixture was stirred at room temperature for 4 hrs. The mixture was concentrated in vacuo. The residue was diluted with ethylacetate and was washed with brine. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtoAc/Hexane) to give tert-butyl 4-[(2-fluoro-4-methyl-5-nitrophenyl)sulfonyl]-l-piperazine- carboxylate (1.00 g, 38.4 %) as a pale brown solid. 03/022277
- 132
Figure imgf000133_0001
(2) To a solution of 3,5-dimethylphenol (33.3mg, 0.27 mmol) in 1,4-dioxane (1 ml) was added sodium hydride (60 % oil suspension, 11.9 mg, 0.30 mmol) portionwise. The mixture was stirred at room temperature for 30 minutes. To the mixture was added a solution of tert-butyl 4-[(2-fluoro-4-methyl-5- nitrophenyl)sulfonyl]-l-piρerazinecarboxylate (100 mg, 0.25 mmol) in 1,4- dioxane (1 ml) slowly. The mixture was stirred at 70°C overnight. After the mixture was cooled to room temperature, the mixture was concentrated in vacuo. The residue was washed with ice water, then was dried in vacuo to give tert-butyl 4- {[2-(3,5-dimethylphenoxy)-4-methyl-5-nitrophenyl]sulfon- yl}- 1-piperazinecarboxylate (92.8 mg, 74.1 %) as a white solid.
Figure imgf000133_0002
(3) tert-butyl 4- {[2-(3 ,5-dimethylphenoxy)-4-methyl-5-nitrophenyl] sulfonyl} - 1 - piperazinecarboxylate (186 mg, 0.368 mmol) was placed in a frame-dried two-necked flask. It was dried in vacuo, then was purged with argon. To the flask was added dry DMF, dimethylformamide dimethyl acetal (0.0585 ml, 22277
133
0.441 mmol), and pyrrolidine 0.0369 ml, 0.441 mmol). The mixture was stirred at 110°C for 3 hrs. Additional pyrrolidine (0.0185 ml, 0.22 mmol) was added to the mixture. The mixture was stirred at 110°C for additional 1 hr. After the mixture was cooled to room temperature, the mixture was transferred to a solution of 4 M aqueous ammonium acetate in DMF, using additional DMF to rinse the mixture into the reaction flask. To the solution was added 20 % w/v aqueous titanium (IH) chloride (1.50 ml, 1.98 mmol) dropwise. The suspension was stirred at room temperature for 15 minutes. The mixture was made basic with IN aqueous NaOH solution. The mixture was diluted with diethylether. The mixture was filtered, then the organic layer was extracted with diethylether, was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtoAc/Hexane) to give tert- butyl 4-{[5-(3,5-dimethylphenoxy)-lH-indol-6-yl]sulfonyl}-l-piperazinecarb- oxylate (42.2 mg, 23.6 %) as a pale brown solid.
Figure imgf000134_0001
(4) To a solution of tert-butyl 4-{[5-(3,5-dimethylphenoxy)-lH-indol-6-yl]- sulfonyl} -1-piperazinecarboxylate (15.4 mg, 0.0317 mmol) in CH2C12 (1 ml) was added trifluoroacetic acid (0.10 ml) at 0°C. The mixture was stirred at
0°C for 2 hrs. Toluene was added to the mixture, then was concentrated in vacuo. The residue was triturated with diethylether to give 5-(3,5-dimethyl- 22277
134
phenoxy)-6-(l-piperazinylsulfonyl)-lH-indole trifluoroacetate (12.7 mg,
80.2%).
HPLC-MS (ESI): Calcd for C2oH23N3O3S [M+H]+ 368, Found: 368.
Molecular weight: 499.5129
Activity grade RBA: C Activity grade Ca2+: C
Exampl e l2-l
Figure imgf000135_0001
(1) 4-Fluorobenzoic acid (5.0 g, 35.7 mmol) was added to chlorosulfonic acid (31.5 g, 0.27 mol), and the mixture was stirred at 150°C for 2hrs. After cooling to room temperature, the mixture was poured into ice-water dropwise with cooling. The resulting white precipitate was collected by filtration. The solid was washed with water, and dried in vacuo to give 3-(chlorosulfonyl)-4- fluorobenzoic acid (6.33 g, 74.3%).
Figure imgf000135_0002
(2) To a solution of 3-(chlorosulfonyl)-4-fluorobenzoic acid (1.0 g, 4.19 mmol) in THF (10 ml) was added N-tert-butyl 1-homopiperazinecarboxylate (0.92 g, 4.61 mmol) in THF (5 ml) dropwise at 0°C, followed by Et3Ν (1.08 ml, 6.28 mmol). The mixture was stirred at room temperature for 6hrs. After quenched by water, the solvent was removed by evaporation. The resulting residue was dissolved in IN NaOH (24 ml), and washed with Et2O two times. Then the aqueous layer was acidified to pH 3-4 by IN HCl, then extracted with EtOAc 3 times. The organic layer was dried over anhydrous Na2SO4, the solvent was evaporated in vacuo to give 3-{[4-(tert-butoxycarbonyl)-l,4- diazepan-1-yl] sulfonyl} -4-fluorobenzoic acid as a colorless form (1.12 g, 66.4%):
Figure imgf000136_0001
(3) To a solution of 3-{[4-(tert-butoxycarbonyl)-l,4-diazepan-l-yl]sulfonyl}-4- fluorobenzoic acid (250 g, 0.62 mol) in THF (2000 ml) was added CDI
(125 g, 0.77 mol) at 0°C under Ar. The mixture was stirred at 0°C for Ihr. Then NH3 gas was bubbled into the mixture for 2 hrs. White precipitate was filtered off, and the filtrate was extracted with EtOAc, washed with IN HCl, and sat. NaHCO3 solution, and brine. The organic extracts were dried over anhydrous Na2SO4, the solvent was evaporated in vacuo to give tert-butyl 4-
{ [5-(aminocarbonyl)-2-fluorophenyl] sulfonyl} - 1 ,4-diazepane- 1 -carboxylate as a white solid (240 g, 96.2%)
Figure imgf000136_0002
22277
136
(4) To a solution of tert-butyl 4-{[5-(aminocarbonyl)-2-fluorophenyι]sulfonyl}- 1,4-diazepane-l-carboxylate (5.0 g, 12.5 mmol) in dry CH2C1 (150 ml) was added Et3N (6.94 ml, 49.8 mmol) under Ar. Then the solution was cooled to - 5°C (dry ice/t-PrOH). (CF3SO2)2O (3.14 ml, 18.7 mmol) was added to the mixture dropwise, cooling under 5°C. After 1.5hrs, the reaction was quenched by water, then extracted with CH2C12, and washed with water and brine. The organic extract was dried over anhydrous Na2SO4. The solvent was evaporated in vacuo. The resulting residue was purified by column chromatography on silica-gel (Hexane/EtoAc=l/l) to give tert-butyl 4-[(5-cyano-2- fluoroρhenyl)sulfonyl]-l,4-diazepane-l-carboxylate as a brown oil (4.12 g, 86.3%)
Figure imgf000137_0001
(5) To a solution of tert-butyl 4-[(5-cyano-2-fluorophenyl)sulfonyl]-l,4-diaze- pane-1-carboxylate (4.12 g, 10.75 mmol) and 3,5-dichlorophenol (5.25 g, 32.2 mmol) in dioxane (100 ml) was added NaH (1.54 g, 37.6 mmol). The mixture was stirred under reflux for Ihr. After cooled to room temperature, the mixture was quenched by water, and extracted with CH2C12 and washed with IN NaOH, and brine. The organic extract was dried over anhydrous
Na2SO4, the solvent was evaporated in vacuo. The resulting residue was purified by column chromatography on silica-gel (Hexane/EtoAc=l/l) to give tert-butyl 4-{[5-cyano-2-(3,5-dichlorophenoxy)phenyl]sulfonyl}-l,4-diaze- pane-1-carboxylate as a white solid (3.08 g, 54.5%)
Figure imgf000138_0001
(6) To a solution of tert-butyl 4-{[5-cyano-2-(3,5-dichlorophenoxy)phenyl]- sulfonyl}-l,4-diazepane-l-carboxylate (3.1 g, 5.89 mmol) in CH2C12 (60 ml) was added 4N HCl in dioxane (60 ml). The mixture was stirred at room temperature for 2hrs. After the solvent was removed by evaporation, the resulting white solid was washed with CH3CN to give 3-(l,4-diazepan-l- ylsulfonyl)-4-(3,5-dichlorophenoxy)benzonitrile hydrochloride as a white solid (2.13 g, 78.2%): mp 278-280°C; 1H NMR (500 MHz, DMSO-rf6) δ 1.99- 2.02 (2H, m), 3.19-3.24 (4H, m), 3.41-3.43 (2H, m), 3.64-3.66 (2H, m), 7.29 (IH, d, J = 8.5 Hz), 7.41 (2H, m), 7.59 (IH, m), 8.12 (IH, dd, J = 2.2, 8.8 Hz), 8.30 (IH, d, J = 1.9 Hz), 8.99 (IH, br); HPLC-MS (ESI): Calcd for C18H18Cl3N3O3S [M+H]+ 426 and 428, found: 426 and 428.
Molecular weight: 462.785
IC50 (CCR3): 35 μM IC50 (Ca2+): 20 μM IC50 (Chemotaxis): 8 μM
hi the similar manner as described in Example 12-1 above, compounds in Example
12-2 and 12-3 as shown in Table 12 were synthesized. Table12
Figure imgf000139_0001
22277
139 -
Example 13-1
Figure imgf000140_0001
(1) To a mixture of 4-fluoro-3-nitrobenzoic acid (10.00 g, 54.02 mmol) and 3,5- dichlorophenol (13.21 g, 81.03 mmol) in THF (300 ml) was added NaH (5.40 g, 135.05 mmol) at room temperature. The reasulting mixture was heated to 70°C. After 2 hrs, the reaction mixture was poured into water and 6N HCl (15ml) was added. The resulting mixture was extracted with EtOAc. The extract was washed with brine, and dried over MgSO4ι the solvent was evaporated in vacuo. The residue was collected by filtration and washed with hexane to give 4-(3,5-dichlorophenoxy)-3-nitrobenzoic acid as a slight yellow powder (15.29 g 86.3%).
Figure imgf000140_0002
(2) To a cooled solution of 4-(3,5-dichlorophenoxy)-3-nitrobenzoic acid (15.29 g, 46.60 mmol) in THF (300 ml), was added CDI (11.33 g, 69.90 mmol) and 22277
140 -
resulting mixture was allowed to warm to room temperature. After 2 hrs, the mixture was cooled with ice-bath and then NH3 gas was introduced directly into the reaction mixture. After 2 hrs, the reaction mixture was condensed under reduce pressure. The residue was dissolved in water and the resulting mixture was extracted with EtOAc. The extract was washed with IN NaOH, IN HCl, and brine, dried over MgSO . The solvent was evaporated in vacuo. The crude product was collected by filtration and washed with MeCN to give 4-(3,5-dichloroρhenoxy)-3-nitrobenzamide as a white powder (15.72 g, quantitative).
Figure imgf000141_0001
(3) The solution of 4-(3,5-dichlorophenoxy)-3-nitrobenzamide (15.50 g, 47.38 mmol) and i-Pr2EtN (49.52 ml, 284.30 mmol) in CH2C12 (500 ml) was cooled to -5°C with dry-ice/i-PrOH bath. Tf2O(16.04 ml, 94.77 mmol) was added dropwise to the mixture below 0°C and then additional i-Pr2EtN
(24.76 ml, 142.15 mmol) and Tf2O (12.03 ml, 71.08 mmol) was added. The mixture was stirred at 0°C for 30 min. Water was added into the reaction mixture and the resulting mixture was condensed under reduced pressure. The obtained residue was partitioned between water and EtOAc and the resulting mixture was extracted with EtOAc. The extract was washed with IN
HCl and brine, dried over MgSO4. The solvent was evaporated in vacuo. The residue was purified by column chromatography on silica-gel (CHCl3/EtoAc = 100/0 to 95/5) to give 5-cyano-2-(3,5-dichlorophenoxy)nitrobenzene as a white powder (4.08 g, 27.9 %).
Figure imgf000142_0001
(4) The mixture of 5-cyano-2-(3,5-dichlorophenoxy)nitrobenzene (4.08 g, 13.20 mmol) and Tin(H) chloride dihydrate (17.87 g, 79.20 mmol) in EtOAc (200 ml) was heated to reflux for 3hrs. After cooled to room temperature, the reaction mixture was poured into sat. NaHCO3. The mixture was extracted with EtOAc. The extract was washed with brine, and dried over MgSO4. The solvent was evaporated in vacuo to give 5-cyano-2-(3,5-dichlorophenoxy)- aniline (3.53 g, 95.8 %).
Figure imgf000142_0002
022277
142
(5) 5-Cyano-2-(3,5-dichlorophenoxy)aniline (3.53 g, 12.65 mmol) was dissolved in the mixture of cone. HCl (6.33 ml) and AcOH 2.53 ml). The solution was cooled to 0°C and sodium nitrite (0.96 g, 13.91 mmol) in water (1.27 ml) was added dropwise with stirring. After 30 min, the reaction mixture was added dropwise to the suspended mixture of CuCl (0.63 g, 6.32 mmol) in saturated solution of SO in AcOH (25.32 ml) at 5°C. The reaction mixture was stirred at 10°C for 30 min, poured into water and the resulting mixture was extracted with EtOAc. The extract was washed with sat. NaHCO3, brine, and dried over MgSO4. The solvent was evaporated in vacuo to give 5-cyano-2-(3,5- dichlorophenoxy)phenylsulfonylchloride as a brown powder (4.45 g, 97 %).
Figure imgf000143_0001
(6) To a solution of 5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonylchloride (0.03 g 0.08 mmol) in THF (1 ml), (3S)-(tert-butoxycarbonylamino)pyr- rolidine (0.05 g, 0.25 mmol) was added. The reaction mixture was stirred at room temperature overnight, then poured into water and the resulting mixture was extracted with EtOAc. The extract was washed with brine, and dried over MgSO4. The solvent was evaporated in vacuo. The residue was purified by preparative TLC on silica gel (CH2Cl2/CH3OH = 25/1) to give l-{5-cyano-
2- (3,5-dicMorophenoxy)phenylsulfonyl}-(3S)-(tert-butoxycarbonylamino)- pyrolidine as an oil (0.02 g, 47%).
Figure imgf000144_0001
(7) To the solution of l-{5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonyl}-(3S)- (tert-butoxycarbonylamino)pyrrolidine (0.03 g, 0.04 mmol) in 1,4-dioxane (1 ml) was added 4N HCl (1 ml) in 1,4-dioxane. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo. The obtained residue was dissolved in THF followed by addition of ether. The produced precipitate was collected by filtration, washed with ether and dried in vacuo to give l-{5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonyl}-(3S)- aminopyrrolidine hydrocloride as a white powder (13.4 mg, 77%): mp 276°C; 1H NMR (500 MHz, DMSO-d6) δ 1.92-1.97 (IH, m), 2.15-2.22 (IH, m), 3.34-3.41 (2H, m), 3.51-3.56 (IH, m), 3.63-3.67 (IH, m), 3.79-3.83 (IH, m), 7.34 (IH, d, J= 8.8 Hz), 7.39 (2H, dd, J= 1.6, 1.9 Hz), 8.13 (IH, dd, J= 8.5, 2.2 Hz), 8.21 (3H, br), 8.29 (IH, d, J = 1.9); HPLC-MS (ESI): calcd for C17H15Cl2N3O3S [M+H]+ 411 and 413, Found: 411 and 413.
Molecular weight: 448.758 Activity grade Ca2+: A
In the similar manner as described in Example 13-1 above, compounds in Example
13-2 to 13-12 as shown in Table 13 were synthesized. Table 13
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Example 14-1
Figure imgf000148_0001
(1) To a cold (10°C) solution of 3-{[4-(tert-butoxycarbonyl)-l-piperazinyl]- sulfonyl}-4-fluorobenzoic acid (0.200 g, 0.515 mmol) and 3,5-dimethylphenol (0.063 g, 0.515 mmol) in 1,4-dioxane (1.0 ml) was added NaH (0.041 g, 1.030 mmol), and the stirring was continued for 15 min. The mixture was heated at 120°C for 3 hrs. N-Methyl-2-pyrollidone (1.0 ml) was added to the mixture, which was then heated at 120°C overnight. After cooled to room temperature, the mixture was quenched with water and then extracted with a 1 : 1 mixture of EtOAc and hexane. The aqueous phase was separated, and the organic phase was extracted with water. The combined aqueous phase was acidified to pH 3-4 with IN HCl, and then extracted with EtOAc. The separated organic phase was washed with water and brine, dried over Na2SO .
The solvent was evaporated in vacuo. The residue was suspended in boiled MeOH for 1 h. After cooling to room temperature, the precipitate was collected by filtration, washed with MeOH and dried in vacuo to give 3-{[4- (tert-butoxycarbonyl)-l-piperazinyl]sulfonyl}-4-(3,5-dimethylphenoxy)- benzoic acid (0.101 g, 40.0%): HPLC-MS (ESI): Calcd for C24H30N2O7S [M
+ H]+ 491, Found: 391(-Boc) 148
Figure imgf000149_0001
(2) To a solution of 3-{[4-(tert-butoxycarbonyl)-l-piperazinyl]sulfonyl}-4-(3,5- dimethylphenoxy)benzoic acid (0.030 g, 0.061 mmol) in 1,4-dioxane (0.5 ml) was added 4N HCl in 1,4-dioxane (1.5 ml). The mixture was further stirred at room temperature for 3 hrs, and then concentrated in vacuo. The residue was washed twice with CH3CN and dried in vacuo to give 4-(3,5-dirnethylphen- oxy)-3-(l-piperazinylsulfonyl)benzoic acid hydrochloride (0.027 g, quantitative): 1H NMR (500 MHz, DMSO-^) δ 2.31 (6H, s), 3.17 (4H, br), 3.47 (4H, br), 6.87 (IH, s), 6.96 (IH, s), 6.98 (IH, br), 8.15 (IH, dd, J= 2.2, 8.8 Hz), 8.39 (IH, d, J= 2.2 Hz), 9.19 (IH, br), 13.36 (IH, br); HPLC-MS (ESI): Calcd for C19H22N2O5S [M + H]+ 391, Found: 391.
Molecular weight: 426.922 Activity grade Ca2+:A
In the similar manner as described in Example 14-1 above, compounds in Example 14-2 to 14-4 as shown in Table 14 were synthesized. Table 14
Figure imgf000150_0001
Example 15-1
Figure imgf000151_0001
(1) To a solution of 3-{[4-(tert-butoxycarbonyl)-l-piperazinyl]sulfonyl}-4-(3,5- dimethylphenoxy)benzoic acid (0.100 g, 0.204 mmol) in THF (1.0 ml) was added l,l'-carbonylimidazole (0.041 g, 0.255 mmol), and the mixture was stirred at room temperature. After 3 hrs, 0.5M NH3 in 1,4-dioxane was added, and the stirring was continued overnight. The resultant mixture was concen- trated in vacuo, and the residue was partitioned between EtOAc and saturated
NaHCO3. The separated organic phase was washed with water and brine, dried over Na SO4. The solvent was evaporated in vacuo. The solid obtained was washed with EtOH and dried in vacuo to give tert-butyl 4-{[5-(amino- carbonyl)-2-(3,5-dimethylphenoxy)phenyl]sulfonyl}-l-piperazinecarboxylate (0.071 g, .71.1%).
Figure imgf000151_0002
(2) To a suspension of tert-butyl 4-{[5-(aminocarbonyl)-2-(3,5-dimethylphenoxy)- phenyl] sulfonyl} -1-piperazinecarboxylate (0.057 g, 0.116 mmol) in 1,4-dioxane 22277
151 -
(1.0 ml) was added 4N HCl in 1,4-dioxane (3.0 ml), and the mixture was stirred at room temperature for 2 hrs. The mixture was concentrated in vacuo, washed twice with CH3CN and dried in vacuo to give 4-(3,5-dimethylphenoxy)-3-(l- piperazinylsulfonyl)benzamide hydrochloride (0.047 g, 94.8%): 1H NMR (500 MHz, DMSC /tf) δ 2.30 (6H, s), 3.16 (4H, br), 3.45 (4H, br), 6.83 (IH, s), 6.94 (IH, s), 6.95 (IH, d, J = 8.8 Hz), 7.51 (IH, s), 8.11 (IH, dd, J = 2.2, 8.5 Hz), 8.18 (IH, s), 8.37 (IH, d, J= 2.2 Hz), 9.22 (2H, s); HPLC-MS (ESI): Calcd for Cι9H23N3O4S [M + H]+ 390, Found: 390.
Molecular weight: 425.937
Activity grade RBA: Activity grade Ca2+: A
Example 15-2
Figure imgf000152_0001
(1) To a mixture of 3-{[4-(tert-butoxycarbonyl)-l-piperazinyl]sulfonyl}-4-(3,5- dimethylphenoxy)benzoic acid (0.300 g, 0.612 mmol), K2CO3 (0.169 g, 1.223 mmol) and DMF (3.0 ml) was added Mel (0.174 g, 1.223 mmol), and the stirring was continued at room temperature overnight. The mixture was quenched with water, and extracted with EtOAc. The separated organic phase was washed with water and brine, dried over Na2SO4. The solvent was evaporated in vacuo. The residue was recrystallized from MeOH to give tert- butyl 4-{[2-(3,5-dimethylphenoxy)-5-(methoxycarbonyl)phenyl]sulfonyl}-l- piperazinecarboxylate (0.276 g, 89%).
Figure imgf000153_0001
(2) To a suspension of tert-butyl 4-{[2-(3,5-dimethylphenoxy)-5-(methoxy- carbonyl)phenyl] sulfonyl} -1-piperazinecarboxylate (0.030 g, 0.059 mmol) in 1,4-dioxane (1.0 ml) was added 4N HCl in 1,4-dioxane (3.0 ml). The resulting clear solution was stirred at room temperature for 3 hrs. The mixture was concentrated in vacuo, washed twice with Et O and dried in vacuo to give methyl 4-(3,5-dimethylphenoxy)-3-(l-piperazinylsulfonyl)benzoate hydrochloride (0.027 g, quantative): mp 120°C; 1H NMR (500 MHz, DMSO- ) δ 2.31 (6H, s), 3.16 (4H, br), 3.48 (4H, br), 3.88 (3H, s), 6.89 (2H, s), 6.97 (IH, d, J= 2.3 Hz), 6.98 (IH, s), 8.17 (2H, dd, J= 2.3, 9.0 Hz), 8.40 (IH, d, J = 2.3 Hz), 9.22 (2H, br); HPLC-MS (ESI): Calcd for C2oH24N2O5S [M + H]+ 405, Found: 405.
Molecular weight: 440.949
Activity grade Ca 2+. : A
In the similar manner as described in Example 15-1 or 15-2 above, compounds in Example 15-3 and 15-4 as shown in Table 15 were synthesized. Table 15
Figure imgf000154_0001
Example 16-1
Figure imgf000155_0001
(1) To a cold (0°C) solution of 4-{[2-(3,5-dimethylphenoxy)-5-(methoxycarb- onyl)phenyl] sulfonyl} -1-piperazinecarboxylate (0.227 g, 0.450 mmol) in THF (3.0 ml) was added LiBH4 (0.012 g, 0.540 mmol). The mixture was stirred at room temperature for 3 hrs, and at 60°C for 4 hrs. After cooled to room temperature, the mixture was quenched with saturated NH4C1, and extracted with EtOAc. The separated organic phase was washed with water and brine, dried over Na2SO4. The solvent was evaporated in vacuo. The residue was purified by recrystallization from CH3CN to give tert-butyl 4-{[2-(3,5- dimethylphenoxy)-5-(hydroxymethyl)phenyl]sulfonyl}-l-piperazinecarb- oxylate (0.156 g, 72.8%).
Figure imgf000155_0002
(2) To a solution of tert-butyl 4-{[2-(3,5-dimethylphenoxy)-5-(hydroxymethyl)- phenyl]sulfonyl}-l-piperazinecarboxylate (0.027 g, 0.057 mmol) in 1,4- dioxane (1.0 ml) was added 4N HCl in 1,4-dioxane (3.0 ml). The mixture was stirred at room temperature for 3 hrs. The mixture was concentrated in vacuo, washed twice with Et2O and dried in vacuo to give [4-(3,5-dimethylphenoxy)- 3-(l-piperazinylsulfonyl)phenyl]methanol hydrochloride (0.020 g, 85.5%): mp 160°C 1H NMR (500 MHz, DMSO-d<j) δ 2.27 (6H, s), 3.14 (4H, br), 3.39 (4H, br), 4.53 (2H, d, J= 5.7 Hz), 5.42 (IH, t, J= 5.7 Hz), 6.71 (2H, s), 6.86 (IH, s), 6.96 (IH, d, J= 8.5 Hz), 7.57 (IH, dd, J= 2.2, 8.5 Hz), 7.83 (IH, d, J = 1.9 Hz), 9.12 (2H, br); HPLC-MS (ESI): Calcd for C19H24N2O4S [M + H]+ 377, Found: 377.
Molecular weight: 412.939
Activity grade Ca 2+. : A
Example 17-1
Figure imgf000156_0001
(1) To a stirred suspension of NaH (60%, 0.015 g, 0.375 mmol) in 1,4-dioxane (2.0 ml) was added 3,5-dichlorothiophenol (0.067 g, 0.374 mmol). After 15 min, tert-butyl 4-[(5-cyano-2-fluorophenyl)sulfonyl]- 1-piperazinecarboxylate (0.100 g, 0.271 mmol) was added, and the suspension was stirred at room temperature for 10 min. THF (0.5 ml) was added, and the stirring was continued for 2 hrs. The mixture was quenched with water, and extracted with EtOAc and saturated aqueous NaHCO3 solution. The separated organic phase was washed with water and brine, dried over Na2SO4. The solvent was evaporated in vacuo. The residue was recrystallized from CH3CN to give tert- butyl 4-({5-cyano-2-[(3,5-dichlorophenyl)sulfanyl]phenyl}sulfonyl)-l-pip- erazinecarboxylate (0.088 g, 61.5%).
Figure imgf000157_0001
(2) To a solution of tert-butyl 4-({5-cyano-2-[(3,5-dichlorophenyl)sulfanyl]- phenyl} sulfonyl)- 1-piperazinecarboxylate (0.020 g, 0.038 mmol) in 1,4- dioxane (1.0 ml) was added 4N HCl in 1,4-dioxane (3.0 ml), and the stirring was continued for 3 hrs. The mixture was concentrated in vacuo. The residue was recrystalhzed from diisopropylether. The solid obtained was washed with diisopropylether, dried in vacuo to give 4-[(3,5-dichlorophenyl)sulfanyl]-3-(l- piperazinylsulfonyl)benzonitrile hydrochloride (0.017 g, 96.6%): mp 82°C 1H NMR (500 MHz, OMSO-d6) δ 3.19 (4H, br), 3.53 (4H, br), 7.18 (IH, d, J = 8.5 Hz), 7.73 (IH, d, J= 1.9 Hz), 7.87 (IH, t, J= 1.9 Hz), 7.97 (IH, dd, J = 1.3, 8.5 Hz), 8.3 (IH, d, J = 1.6 Hz), 8.99 (2H, br); HPLC-MS (ESI): Calcd for C17H15Cl2N3O2S2 [M + H]+ 428, Found: 428.
Molecular weight:464.823 IC50 (CCR3): 3 μM ICso (Ca2+): 2 μM IC5o (Chemotaxis): 2 μM
In the similar manner as described in Example 17-1 above, compounds in Example 17-2 and 17-3 as shown in Table 17 were synthesized. Table 17
Figure imgf000158_0001
Example 18-1
Figure imgf000159_0001
(1) To a stirred mixture of tert-butyl 4-({5-cyano-2-[(3,5-dichlorophenyl)- sulfanyl]phenyl} sulfonyl)- 1-piperazinecarboxylate (0.011 g, 0.020 mmol), CC14 (0.4 ml), CH3CN (0.4 ml) and water (0.8 ml) was added NaIO4 (0.030 g, 0.142 mmol) followed by RuCl3 (0.003 g, 0.014 mmol). The mixture was stirred at room temperature for 4 hrs. The mixture was partitioned between EtOAc and water. The separated organic phase was washed with saturated aqueous NaHCO3 solution and brine, dried over Na2SO4. The solvent was evaporated in vacuo. The residue was dissolved in hot CH3CN, and allowed to cool to room temperature. The precipitate was collected by filtration, washed with CH3CN, and dried in vacuo to give tert-butyl 4-({5-cyano-2- [(3 ,5-dichlorophenyl)sulfonyl]phenyl} sulfonyl)- 1 -piperazinecarboxylate
(0.016 g, 60.3%).
Figure imgf000160_0001
(2) To a suspension of tert-butyl 4-({5-cyano-2-[(3,5-dichlorophenyl)sulfonyl]- phenyl} sulfonyl)- 1-piperazinecarboxylate (0.011 g) in 1,4-dioxane (0.5 ml) was added 4N HCl in 1,4-dioxane (1.5 ml), and the stirring was continued for 3 hrs. The mixture was concentrated in vacuo, and recrystalhzed with diisopropylether. The obtained solid was washed with diisopropylether, and dried in vacuo to give 4-[(3,5-dichlorophenyl)sulfonyl]-3-(l-piperazinylsulfonyl)- benzonitrile hydrochloride (0.008 g, 82%):mp 258°C 1H NMR (500 MHz, OMSO-d6) δ 3.15 (4H, br), 3.57 (4H, br), 7.94 (2H, d, J= 1.9 Hz), 8.05 (IH, t, J = 1.9 Hz), 8.52 - 8.55 (2H, m), 8.72 (IH, d, J = 8.5 Hz), 8.96 (2H, br); FAB-MS: Calcd for C17H15Cl2N3O4S2 [M + H]+ 460, Found: 460.
Molecular weight: 496.821 IC50 (CCR3): l,2 μM
IC50 (Ca2+): 7 μM
Example 19-1
Figure imgf000161_0001
(1) To a cold (0°C) solution of tert-butyl 4-({5-cyano-2-[(3,5-dichlorophenyl)- sulfanyl]phenyl} sulfonyl)- 1-piperazinecarboxylate (0.022 g, 0.042 mmol) in CH2C12 (0.6 ml) was added m-chloroperbenzoic acid (0.022 g, 0.062 mmol), and the stirring was continued for 1 h. The mixture was allowed to warm to room temperature, and stirred for 30 min. The mixture was quenched with 10% Na2SO3 solution, and extracted with EtOAc. The extract was washed with saturated NaHCO3, water and brine, dried over Na SO4. The solvent was evaporated in vacuo. The solid obtained was washed twice with MeOH and dried in vacuo to give tert-butyl 4-({5-cyano-2-[(3,5-dichlorophenyl)sulfmyl]- phenyl} sulfonyl)- 1-piperazinecarboxylate (0.022 g, 97.1%).
Figure imgf000161_0002
(2) To a suspension of tert-butyl 4-({5-cyano-2-[(3,5-dichlorophenyl)sulfinyl]- phenyl} sulfonyl)- 1-piperazinecarboxylate (0.017 g, 0.031 mmol) in 1,4- dioxane (1.0 ml) was added 4N HCl in 1,4-dioxane (3.0 ml). The mixture was stirred at room temperature for 3 hrs, and then concentrated in vacuo. The residue was washed twice with CH3CN, and dried in vacuo to give 4-[(3,5- dichlorophenyl)sulfinyl]-3-(l-piperazinylsulfonyl)benzonitrile hydrochloride (0.008 g, 53.3%): mp 219°C 1H NMR (500 MHz, DMSO-^) δ 3.20 - 3.24 (4H, m), 3.43 - 3.46 (4H, m), 7.74 (IH, d, J = 1.9 Hz), 7.85 (IH, t, J = 1.9 Hz), 8.42 (IH, d, J= 1.6 Hz), 8.47 (IH, dd, J= 1.6, 8.2 Hz), 8.52 (IH, d, J= 8.2 Hz), 8.87 (2H, br); FAB-MS: Calcd for C17H15C,2N3O3S2 [M + H]+ 444, Found: 444.
Molecular weight: 480.822 Activity grade Ca2+:B
Example 20-1
Figure imgf000162_0001
(1) A solution of tert-butyl 4-[(5-cyano-2-fluorophenyl)sulfonyl]-l-piperazine- carboxylate (0.100 g, 0.271 mmol) in THF (2.0 ml) was cooled with a water bath, and KOtBu (0.033 g, 0.298 mmol) was added with stirring. The mixture was heated at reflux for 7 hrs. After cooled to room temperature, KOtBu (0.030 g, 0.267 mmol) was added, and the mixture was heated at reflux overnight. After cooled to room temperature, the mixture was quenched with saturated NH4C1, and extracted with EtOAc. The separated organic phase was washed with water and brine, dried over Na2SO4. The solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel (Hexane/ EtOAc=4/l). The product obtained was suspended in hexane including a small amount of EtOAc, collected by filtration, washed with hexane including a small amount of EtOAc, and dried in vacuo to give tert- butyl 4-({5-cyano-2-[(3,5-dichlorophenyl)amino]phenyl}sulfonyl)-l-pip- erazinecarboxylate (0.087 g, 62.8%).
Figure imgf000163_0001
(2) To a solution of tert-butyl 4-({5-cyano-2-[(3,5-dichlorophenyl)amino]- phenyl} sulfonyl)- 1-piperazinecarboxylate (0.035 g, 0.068 mmol) in 1,4- dioxane (0.5 ml) was added 4N HCl in 1,4-dioxane (1.5 ml), and the stirring was continued for 3 hrs. The mixture was concentrated in vacuo. The residue was crystallized from CH3CN, washed with CH3CN, and dried in vacuo to give 4- [(3 , 5 -dichlorophenyl)amino] -3 -( 1 -piperazinylsulfonyl)benzonitrile hydrochloride (0.030 g, 97.9%): 1H NMR (500 MHz, DMSO- ) δ 3.13 - 3.16 (4H, m), 3.34 - 3.37 (4H, m), 7.37 (IH, d, J= 8.8 Hz), 7.39 - 7.41 (IH, m), 7.41 (2H, s), 7.93 (IH, dd, J = 2.2, 8.8 Hz), 8.13 (IH, d, J = 2.2 Hz), 8.41
(IH, s), 8.87 (2H, br); FAB-MS: Calcd for C17H16Cl2N4O2S [M + H]+ 411, Found: 411. Molecular weight: 447.773 Activity grade RBA: A Activity grade Ca2+: A
Example 21-1
Figure imgf000164_0001
(1) To a cold (0°C) solution of tert-butyl 4-({5-cyano-2-[(3,5-dichlorophenyl)- amino]phenyl} sulfonyl)- 1-piperazinecarboxylate (0.049 g, 0.096 mmol) in DMF (1.5 ml) including Mel (0.041 g, 0.287 mmol) was added NaH (0.005 g, 0.115 mmol), and the stirring was continued for 1 h. The mixture was allowed to warm to room temperature, and the stirred was continued for 2 hrs. The mixture was cooled with ice-water bath, quenched with saturated NH4C1 solution, and extracted with EtOAc and water. The separated organic phase was washed with brine, dried over Na SO4. The solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel (Hexane/ EtOAc=4/l) to give tert-butyl 4-({5-cyano-2-[(3,5-dichlorophenyl)- (methyl)amino]phenyl}sulfonyl)-l-piperazinecarboxylate (0.048 g, 95.3%>).
Figure imgf000165_0001
(2) To a suspension of tert-butyl 4-({5-cyano-2-[(3,5-dichlorophenyl)(methyl)- aminojphenyl} sulfonyl)- 1-piperazinecarboxylate (0.043 g, 0.082 mmol) in 1,4-dioxane (1.0 ml) was added 4N HCl in 1,4-dioxane (3.0 ml). The mixture was stirred at room temperature for 2 hrs, and then concentrated in vacuo. The residue was washed twice with Et2O, and dried in vacuo to give 4-[(3,5- dichlorophenyl)(methyl)amino]-3-(l-piperazinylsulfonyl)benzonitrile hydrochloride (0.037 g, 97.9%): mp 163°C1H NMR (500 MHz, OMSO-d6) δ 2.98 (4H, br), 3.18 (3H, s), 3.29 (4H, br), 6.53 (2H, d, J= 1.6 Hz), 6.97 (IH, t, J = 1.6 Hz), 7.71 (IH, d, J= 8.2 Hz), 8.31 (IH, dd, J= 2.2, 8.2 Hz), 8.39 (IH, d, J = 1.9 Hz), 8.92 (2H, br); FAB-MS: Calcd for C,8H18Cl2N4O2S [M + H]+ 425, Found:
Molecular weight: 461.800
Activity grade Ca2+:B
In the similar manner as described in Example 21-1 above, compounds in Example 21-2 as shown in Table 21 were synthesized. Table 21
Figure imgf000166_0001
Example 22-1
Figure imgf000167_0001
(1) To a cold (0°C) mixture of 3-{[4-(tert-butoxycarbonyl)-l-piperazinyl]sulfon- yl}-4-(3,5-dimethylphenoxy)benzoic acid (0.450 g, 0.917 mmol), 3-amino- propionitrile (0.072 g, 1.009 mmol), HOBt (0.186 g, 1.376 mmol) and DMF (5.0 ml) was added l-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.211 g, 1.101 mmol). After 15 min, the mixture was allowed to warm to room temperature, and the stirring was continued overnight. The mixture was partitioned between EtOAc and water. The separated organic phase was washed with saturated NaHCO3 solution, water and brine, dried over Na2SO4. The solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel (Hexane/ EtOAc=l/2) to give tert- butyl 4- {[5- {[(2-cyanoethyl)amino] carbonyl} -2-(3,5-dimethylphenoxy)phen- yl] sulfonyl} -1-piperazinecarboxylate (0.490 g, 98.4%).
Figure imgf000167_0002
(2) To a solution of tert-butyl 4-{[5-{[(2-cyanoethyl)amino]carbonyl}-2-(3,5-di- methylphenoxy)phenyl]sulfonyl}-l-piperazinecarboxylate (0.030 g, 0.055 mmol) in 1,4-dioxane (1.0 ml) was added 4N HCl in 1,4-dioxane (3.0 ml). The mixture was stirred at room temperature for 1.5 hrs, and then concentrated in vacuo. The residue was crystallized from Et O, washed with Et2O and dried in vacuo to give N-(2-cyanoemyl)-4-(3,5-dimethylphenoxy)-3-(l-piperazinylsulfonyl)benzamide hydrochloride (0.025 g, 94.4%): mp 101°C 1H NMR (500 MHz, DMSO-^) δ 2.30 (6H, s), 2.79 (2H, t, J= 6.4 Hz), 3.14 - 3.18 (4H, m), 3.42 - 3.45 (4H, m), 3.47 - 3.54 (2H, m), 6.82 (2H, s), 6.95 (IH, s), 7.02 (IH, d, J = 8.7 Hz), 8.10 (IH, dd, J - 2.3, 8.7 Hz), 8.38 (IH, d, J = 2.3 Hz), 9.02 (2H, br), 9.84 (IH, t, J= 6.0 Hz); HPLC-MS (ESI): Calcd for C22H26N4O4S [M + H]+ 443, Found: 443.
Molecular weight: 479.001
Activity grade Ca 2+. :A
Example 22-2
Figure imgf000168_0001
(1) A mixture of tert-butyl 4-{[5-{[(2-cyanoethyl)amino]carbonyl}-2-(3,5-dimeth- ylphenoxy)phenyl] sulfonyl} -1-piperazinecarboxylate (0.040 g, 0.074 mmol) and 4 N HCl in 1,4-dioxane (3.0 ml) was stirred for 1.5 hrs. 5N HCl was added, and the stirring was continued for 3 days. The mixture was concentrated in vacuo, and the residue was recrystalhzed from CH3CN. The solid obtained was 2277
168
washed twice with CH3CN and dried in vacuo to give N-[4-(3,5-dimeth- ylphenoxy)-3-(l-piperazinylsulfonyl)benzoyl]-beta-alanineamide hydrochloride (0.036 g, 98.3%):mp 121°C Η NMR (500 MHz, ΩMSO-d6) δ 2.30 (6H, s), 2.36 (2H, t, J= 7.3 Hz), 3.16 (4H, br), 3.42 - 3.46 (6H, m), 6.81 (2H, s), 6.83 (IH, s), 6.94 (IH, s), 6.98 (IH, d, J= 8.5 Hz), 7.36 (IH, s), 8.08 (IH, dd, J = 2.2, 8.8 Hz), 8.35 (IH, d, J= 2.2 Hz), 8.76 (IH, t, J= 5.7 Hz), 9.13 (2H, br): HPLC-MS (ESI): Calcd for C22H28N4O5S [M + H]+ 461, Found: 461.
Molecular weight:497.017
Activity grade Ca 2+ :. A
Example 22-3
Figure imgf000169_0001
(1) To a solution of tert-butyl 4-{[5-{[(2-cyanoethyl)amino]carbonyl}-2-(3,5-di- methylphenoxy)phenyl]sulfonyl}-l-piperazinecarboxylate (0.396 g, 0.730 mmol) in CH3CN (3.0 ml) was added triphenylphosphine (0.230 g, 0.876 g). The mixture was gently heated with a heat gun until a clear solution resulted. The mixture was cooled with an ice- water bath, and diethyl azodicarboxylate (0.138 ml, 0.876 mmol) and azidotrimethylsilane (0.116 ml, 0.876 mmol) were added successively. The mixture was allowed to warm to room temperature, and the stirring was continued overnight. A solution of triphenylphosphine (0.115 g, 0.438 mmol), diethyl azodicarboxylate (0.069 ml, 0.438 mmol) and azidotrimethylsilane (0.058 ml, 0.437 mmol) were added successively, and the 3/022277
169
mixture was stirred for 3 days. The mixture was diluted with EtOAc, and washed with water. The separated organic phase was washed with saturated
NaHCO3 solution, water and brine, dried over Na SO4. The solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel (Hexane/EtOAc=l/l) to give tert-butyl 4- {[5-[l -(2-cyanoethyl)- 1H- tetraazol-5-yl]-2-(3,5-dimethylphenoxy)phenyl]sulfonyl}-l-piperazinecarb- oxylate (0.338 g, 81.6%).
Figure imgf000170_0001
(2) To a solution of tert-butyl 4-{[5-[l-(2-cyanoethyl)-lH-tetraazol-5-yl]-2-(3,5-di- methylphenoxy)phenyl]sulfonyl}-l-piperazinecarboxylate (0.030 g, 0.053 mmol) in 1,4-dioxane (1.0 ml) was added 4N HCl in 1,4-dioxane (3.0 ml). The mixture was stirred at room temperature for 2 hrs, then concentrated in vacuo. The residue was recrystalhzed from Et O, washed with Et2O and dried in vacuo to give 3- {5-[4-(3,5-dimethylphenoxy)-3-(l -piperazinylsulfonyl)phenyl]-lH- tetraazol-l-yl}propanenitrile hydrochloride (0.021 g, 78.8%):mp 125°C ]H NMR (500 MHz, DMSO-^) δ 2.32 (6H, s), 3.18 (4H, br), 3.23 (2H, t, J = 6.3 Hz), 3.50 (4H, br), 4.76 (2H, t, J = 6.3 Hz), 6.89 (2H, s), 6.99 (IH, s), 7.10 (IH, d, J= 8.5 Hz), 8.04 (IH, dd, J= 1.9, 8.5 Hz), 8.26 (IH, d, J= 1.9 Hz), 9.05 (2H, br); HPLC-MS (ESI): Calcd for C22H25N7O3S [M + H]+ 468,
Found: 468.
Molecular weight:504.014
Activity grade Ca 2+ :. A 22277
170
Example 22-4
Figure imgf000171_0001
(1) To a solution of tert-butyl 4-{[5-[l-(2-cyanoethyl)-lH-tetraazol-5-yl]-2-(3,5-di- methylphenoxy)phenyl]sulfonyl}- 1-piperazinecarboxylate (0.150 g, 0.264 mmol) in CH2C1 (2.0 ml) was added DBU (0.119 ml, 0.793 mmol), and the mixture was stirred at room temperature for 2.5 hrs. The mixture was diluted with EtOAc, and washed with IN HCl. The separated organic phase was washed with water and brine, dried over Na SO . The solvent was evaporated in vacuo. The residue was recrystalhzed from Et O. The solid was collected by filtration, washed with Et O and dried in vacuo to give tert-butyl 4-{[2-(3,5-dimethylphenoxy)-5-(lH-tetra- azol-5-yl)phenyl]sulfonyl}-l-piperazinecarboxylate (0.096 g, 70.6%).
Figure imgf000171_0002
(2) To a solution of tert-butyl 4-{[2-(3,5-dimethylphenoxy)-5-(lH-tetraazol-5- yl)phenyl]sulfonyl}-l-piperazinecarboxylate (0.050 g, 0.097 mmol) in 1,4- dioxane (1.0 ml) was added 4N HCl in 1,4-dioxane (3.0 ml). The mixture was stirred at room temperature for 2 hrs. The precipitate was collected by filtration, washed with 1,4-dioxane and Et2O, dried in vacuo to give l-{[2- (3 , 5 -dimethylphenoxy)-5 -( 1 H-tetraazol-5 -yl)phenyl] sulfonyl } piperazine hydrochloride (0.037 g, 84.4%):mp 213°C ]H NMR (500 MHz, OMSO-d6) δ 2.31 (6H, s), 3.18 (4H, br), 3.48 (4H, br), 6.86 (2H, s), 6.96 (IH, s), 7.14 (IH, d, J= 8.8 Hz), 8.29 (IH, dd, J= 2.2, 8.8 Hz), 8.56 (IH, d, J= 2.2 Hz), 9.07 (2H, br); HPLC-MS (ESI): Calcd for Cι9H22N6O3S [M + H]+ 415, Found: 415.
Molecular weight:450.950
Activity grade Ca 2+. : A
Example 23-1
Figure imgf000172_0001
(1) 2-(3,5-dimethylphenoxy)-4-nitrobenzic acid was prepared by the same procedure of 4-(3,5-dichlorophenoxy)-3-nitrobenzoic acid (Example 13-(1)).
Figure imgf000173_0001
(2) The mixture of 2-(3,5-dimethylphenoxy)-4-nitrobenzic acid (1.72 g, 6.00 mmol), diphenyl phosphoroazidate (1.98 g, 7.20 mmol) and triethylamine (1.00 ml, 7.20 mmol) in tert-butanol was heated to 80°C overnight. After cooled to room temperature, the reaction mixture was poured into water and the resulting mixture was extracted with EtOAc. The extract was washed with brine, and dried over MgSO4. The solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel (CHC13/Hexane = 65/35) to give a colorless oil. The obtained oil was dissolve into 4N HCl in 1,4-dioxane and the resulting mixture was stirred overnight. Then the reaction mixture was condensed under reduced pressure. The obtained material was dissolved in THF followed addition of ether. The precipitate was collected by filtration, washed with ether and dried in vacuo to give 2-(3,5- dimethylphenoxy)-4-nitro aniline hydrochloride as yellow powder. (0.18 g, 10%)
Figure imgf000173_0002
- 173
(3) 2-(3,5-dimethylphenoxy)-4-nitrobenzensulfonylchloride was prepared by the same procedure of 5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonylchloride (Example 13-(5)).
Figure imgf000174_0001
(4) tert-Butyl 4-{2-(3,5-dimethylphenoxy)-4-nitrophenylsulfonyl}-l-piperazine- carboxylate was prepared by the same procedure of l-{5-cyano-2-(3,5- dichlorophenoxy)phenylsulfony}-(3S)-(tert-butoxycarbonylamino)pyrrolidine (Example 13-1(6)).
Figure imgf000174_0002
(5) 1 - {2-(3,5-dimethylphenoxy)-4-nitrophenylsulfonyl}piperazine hydrochloride was prepared by the same procedure of l-{5-cyano-2-(3,5-dichlorophenoxy)- phenylsulfonyl}-(3S)-aminopyrrolidine hydrochloride (Example 13-(7)):mp 284°C
1H NMR (500 MHz, DMSO-d6) D; 2.32 (6H, s), 3.18-3.19 (4H, m), 3.51-3.53 (4H, m), 6.92 (2H, s), 7.01 (IH, s), 7.52 (IH, d, J= 1.9 Hz), 8.08 (IH, dd, J= 8.5, 2.2 Hz), 8.15 (IH, d, J= 8.5 Hz), 9.28 (2H, br); HPLC-MS (ESI): calcd for C18H22ClFN2O3S [M+H]+ 392, Found: 392.
Molecular weight: 427.910
Activity grade Ca 2+. : A
Example 24-1
Figure imgf000175_0001
(1) To a vigorously stirred mixture of rø-nitrobenzenesulfonyl chloride (3.00 g, 13.5 mmol), trifluoroacetic acid (6.5 ml, 84.4 mmol) and cone, sulfuric acid (2.6 ml, 47.8 mmol) was added N-bromosuccinimide (3.61 g, 20.3 mmol) in portions over an hour period. This mixture was stirred at 45°C for 88 hrs. The mixture was poured into 25 ml of ice-water, the organic layer was separated, and the aqueous layer was extracted with CH2C12 to remove very small amount of 3-bromo-5-nitrobenzenesulfonyl chloride. The aqueous layer was concentrated to give a mixture of 3-bromo-5-nitrobenzenesulfonic acid, 3- nitrobenzenesulfonic acid and sulfuric acid. To the mixture was added 8Ν NaOH and the resulting precipitate was collected by filtration and washed with water to give sodium 3-bromo-5-nitrobenzenesulfonate (256 mg, 6.2%).
Figure imgf000175_0002
22277
175
(2) A suspension of sodium 3-bromo-5-nitrobenzenesulfonate (140 mg, 0.46 mmol) in phosphorus oxychloride (1.0 ml, 10.7 mmol) was refluxed for 1 hr. Phosphorus pentachloride (192 mg, 0.92 mmol) was added and the mixture was stirred at 150°C for additional 1 hr. After cooling to room temperature, the mixture was evaporated. The resulting residue was neutralized with 4N NaOH and the product was extracted with EtOAc. The organic layer was dried over anhydrous MgSO4. The solvent was evaporated in vacuo to give 3-bromo-5-nitrobenzenesulfonyl chloride (103 mg, 74%).
Figure imgf000176_0001
(3) To a mixture of 3-bromo-5-nitrobenzenesulfonyl chloride (100 mg, 0.33 mmol) and N,N-diisopropylethylamine (0.069 ml, 0.40 mmol) in THF (3 ml) was added dropwise the solution of tert-butyl 1-piperazinecarboxylate
(68 mg, 0.37 mmol) in THF (2 ml) at 0°C. The mixture was stirred at room temperature for 1 hr. Solvent was removed by evaporation. The resulting residue was diluted with CH2C12 and washed with 0.5 Ν HCl, brine, aqueous ΝaHCO3, and brine, then dried over anhydrous MgSO4. The solvent was removed by evaporation and the residue was purified by preparative TLC on silica gel (Hexane/EtOAc=2/l) to give tert-butyl 4-[(3-bromo-5-nitrophenyl)- sulfonyl]- 1-piperazinecarboxylate (116 mg, 77%); MS (FAB): Calcd for C15H20BrN3O6S [M+H]+ 450 and 452, Found: 350 and 352 (-Boc).
Figure imgf000177_0001
(4) To a suspension of sodium hydride (6.7 mg, 0.17 mmol) in DMF (2 ml) was added 3,5-dimethylphenol (20 mg, 0.17 mmol) at 0°C. This mixture was stirred for 10 min. tert-butyl 4-[(3-bromo-5-nitrophenyl)sulfonyl]-l-piper- azinecarboxylate (50 mg, 0.11 mmol) was added to and the mixture was stirred at 90°C for 2.5 hrs. The reaction mixture was diluted with EtOAc and washed with aqueous NaHCO3 and brine. The organic layer was dried over anhydrous MgSO . The solvent was evaporated in vacuo. The residue was purified by preparative TLC on silica gel (Hexane/EtoAc=2/l). The resulting solid was suspended in ether/hexane/CHCl3 and collected by filtration to give tert-butyl 4- { [3 -bromo-5 -(3,5 -dimethylphenoxy)phenyl] sulfonyl} - 1 -piper- azinecarboxylate (19.5 mg, 33%): mp 155 °C; HPLC-MS (ESI): Calcd for C23H29BrN2O5S [M+H]+ 525 and 527, Found: 425 and 427 (-Boc).
Figure imgf000177_0002
(5) A solution of tert-butyl 4-{[3-bromo-5-(3,5-dimethylphenoxy)phenyl]- sulfonyl}- 1-piperazinecarboxylate (17 mg, 0.032 mmol) in 4N HCl solution in 1,4-dioxane (2 ml, 8 mmol) was stirred at room temperature overnight. Solvent was removed by evaporation to give l-{[3-bromo-5-(3,5-dimethyl- 22277
177
phenoxy)phenyl]sulfonyl}piρerazine hydrochloride (14.9 mg, 99%): mp >84°C (decomposed); Η NMR (500 MHz, DMSO-d6) δ 2.30 (6H, s), 3.20 (8H, br), 6.79 (2H, s), 6.93 (IH, S), 7.25 (IH, s), 7.60 (IH, d, J=2.0 Hz), 7.66 (IH, s), 8.99 (IH, br); HPLC-MS (ESI): Calcd for C18H2ιBrN2O3S [M+H]+ 425 and 427, Found: 425 and 427.
Molecular weight: 461.808
Activity grade Ca 2+. : A
Example 25-1
Figure imgf000178_0001
(1) To a mixture of 4-hydroxypyridine-3 -sulfonic acid (1.00 g, 5.71 mmol) and phosphorus pentachloride (2.38 g, 11.4 mmol) was added phosphorus oxychloride (1.06 ml, 11.4 mmol) dropwise at 0°C. The mixture was refluxed for 5 hrs. After the mixture was cooled to room temperature, cooled aqueous NaHCO3 was added to the mixture carefully. The mixture was extracted with CHC13. The organic layer was dried over anhydrous MgSO4. The solvent was evaporated in vacuo to give 4-chloro-3-pyridinesulfonyl chloride as colorless oil (0.97 g, 80.1 %).
Figure imgf000178_0002
(2) A mixture of 4-chloro-3-pyridinesulfonyl chloride (0.97 g, 4.57 mmol), tert- butyl 1-piperazinecarboxylate (0.94 g, 5.03 mmol), and N,N-diisopropyl- ethylamine (0.88 ml, 5.03 mmol) in THF (50 ml) was stirred at room temperature overnight. The mixture was concentrated in vacuo. The residue was washed with ice water, then was dried in vacuo to give tert-butyl 4-[(4- chloro-3-pyridinyl)sulfonyl]-l-piperazinecarboxylate as a pale yellow solid
(1.51 g, 91.3 %).
Figure imgf000179_0001
(3) To a solution of 3,5-dimethylphenol (37.1 mg, 0.30 mmol) in 1,4-dioxane (lml) was added sodium hydride (60 % oil suspension, 13.3 mg, 0.33 mmol) portionwise. The mixture was stirred at room temperature for 30 min. To the mixture was added a solution of tert-butyl 4-[(4-chloro-3-pyridinyl)sulfonyl]- 1-piperazinecarboxylate (100 mg, 0.28mmol) in 1,4-dioxane (lml) slowly. The mixture was stirred at 70°C overnight. After the mixture was cooled to room temperature, the mixture was concentrated in vacuo. The residue was washed with ice water, dried in vacuo to give tert-butyl 4-{[4-(3,5-dimethyl- phenoxy)-3-pyridinyl]sulfonyl}-l-piperazinecarboxylate (110 mg, 88.9 %) as a white solid. 22277
- 179
Figure imgf000180_0001
(4) To a solution of tert-butyl 4-{[4-(3,5-dimethylphenoxy)-3-pyridinyl]sulfon- yl}- 1-piperazinecarboxylate (23.4 mg, 0.0523 mmol) in CH2C12 (lml) was added 4N HCl in 1,4-dioxane (0.25 ml). The mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo. The residue was triturated with diethylether, dried in vacuo to give l-{[4-(3,5-dimethyl- phenoxy)-3-pyridinyl]sulfonyl}piperazine hydrochloride (17 mg, 76 %) as a white solid: mp 220°C; IH NMR (300 MHz, DMSO-d6) δ 2.33 (6H, s), 3.19 (4H, m), 3.52 (4H, m), 6.84 (IH, d, J = 6 Hz), 7.00 (2H, s), 7.03 (1H„ s), 8.65 (IH, d, J = 6 Hz), 8.88 (IH, s), 9.35 (2H, br); HPLC-MS (ESI): Calcd for C17H21N3O3S [M+H]+ 348, Found: 348.
Molecular weight: 420.361 Activity grade RB A: B
Activity grade Ca2+: A
In the similar manner as described in Example 25-1 above, compounds in Example 25-2 as shown in Table 25 were synthesized. Table 25
Figure imgf000181_0001
Example 26-1
Figure imgf000182_0001
(1) To a suspension of sodium hydride (4.5 mg, 0.11 mmol) in THF (2 ml) was added 2-[(3 ,5-dichlorophenyl)sulfanyl]-5-nitro-N-[2-(l -piperidinyl)ethyl]benzenesulfon- amide (50 mg, 0.10 mmol) at 0°C. The mixture was stirred at 0°C for 10 min. Methyl iodide (0.01 ml, 0.15 mmol) was added and the mixture was stirred at 0°C for 30 min then room temperature overnight. The reaction mixture was diluted with EtOAc and washed with aqueous ΝaHCO3 and brine. The organic layer was dried over anhydrous MgSO4. The solvent was evaporated in vacuo.
The residue was purified by preparative TLC on silica gel (CHCl3/MeOH=9/l) to give 2-[(3,5-dichlorophenyl)sulfanyl]-N-methyl-5-nitro-N-[2-(l-piperidinyl)- ethyl]benzenesulfonamide (18 mg, 35.0%): mp 113-114 °C; ]H ΝMR (300 MHz, CDC13) δ 1.42 (2H, m), 1.52 (4H, m), 2.41 (4H, m), 2.57 (2H, t, J=7.0 Hz), 3.03 (3H, s), 3.47 (2H, t, J=7.0 Hz), 7.07 (IH, d, J=8.7 Hz), 7.45 (2H, m), 7.51 (IH, t, J=1.9 Hz), 8.14 (IH, dd, J-2.3, 8.7 Hz), 8.79 (IH, d, J=2.3 Hz); HPLC-MS (ESI): Calcd for C20H23C12Ν3O4S2 [M+H]+ 504 and 506, Found: 504 and 506.
Molecular weight: 504.458
Activity grade RBA: A Activity grade Ca2+: A
In the similar manner as described in Example 26-1 above, compounds in Example 26-2 and 26-3 as shown in Table 26 were synthesized. Table 26
Figure imgf000183_0001
Operative examples relating to pharmaceutical compositions
The compounds according to the invention can be converted into pharmaceutical preparations as follows:
Tablet
Composition
100 mg of the compound of Example 1-1, 50 mg of lactose (monohydrate), 50 mg of maize starch (native), 10 mg of polyvinylpyrrolidone (PNP 25) (from BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.
Tablet weight 212 mg, diameter 8 mm, curvature radius 12 mm.
Preparation
The mixture of active component, lactose and starch is granulated with a 5% solution (m/m) of the PVP in water. After drying, the granules are mixed with magnesium stearate for 5 min. This mixture is moulded using a customary tablet press (tablet format, see above). The moulding force applied is typically 15 kΝ.
Orally administrable suspension
Composition
1000 mg of the compound of Example 1-1, 1000 mg of ethanol (96%), 400 mg of Rhodigel (xanthan gum from FMC, Pennsylvania, USA) and 99 g of water.
A single dose of 100 mg of the compound according to the invention is provided by
10 ml of oral suspension. Preparation
The Rhodigel is suspended in ethanol and the active component is added to the suspension. The water is added with stirring. Stirring is continued for about 6h until the swelling of the Rhodigel is complete.

Claims

22277- 185 -CLAIMS
1. A sulfonamide derivative of the formula (I), its tautomeric or stereoisomeric form, or a salt thereof:
Figure imgf000186_0001
X represents phenyl, which is substituted by 0 to 5 substituents independently selected from the group consisting of R1, R2, R3 ,R4 and R° or pyridine , which is substituted by 0 to 5 substituents independently selected from the group consisting of R1, R2, R3 and R4
wherein
R1 is hydrogen, halogen, hydroxy, straight- or branched- Cι-6 alkyl optionally substituted by mono, di or tri halogen, straight- or branched- Cι-6 alkoxy, straight- or branched- Cι-6 alkoxy carbonyl, amino, straight- or branched- -6 alkylamino, di(straight- or branched- C1-6 alkyl)amino, straight- or branched- Cι-6 alkanoyl, nitro, or phenyl,
R is hydrogen, halogen, straight- or branched- C1-6 alkyl optionally substituted by mono, di or tri halogen, straight- or branched- C1-6 alkoxy, or cyano, or
1
R and R together form benzene ring or C5-8 cycloalkyl fused to the adjacent phenyl or pyridine, R is hydrogen, halogen, or straight- or branched- C1-6 alkyl,
R4 is hydrogen, halogen, or straight- or branched- C1-6 alkyl,
R° is hydrogen, halogen, or straight- or branched- Cj-6 alkyl,
Y represents O, NH, NCH3 S, S(O), or SO2;
Z1 represents CH or N;
Z2 represents CH or N
with the proviso that both Z1 and Z2 cannot be N at the same time;
R > 5 represents hydrogen, halogen, hydroxy, straight- or branched -Cι-6 alkyl optionally substituted by mono, di or tri halogen or hydroxy, straight- or branched -C1-6 alkoxy, straight- or branched -Cι-6 alkoxycarbonyl, amino, straight- or branched- Cι-6 alkanoylamino, phenyl-(CH2)q -carbonylamino (wherein q represents an integer selected from 0 to 6), straight- or branched- C1-6 alkylbenzoylamino, naphthylcarbonylammo, thenoylamino, nitro, cyano, carboxy, straight- or branched- C1-6 alkyl sulfonyl, oxazolidinonyl, or substituents represented by the formula, -SO2-NR51R52, or -CO-NR5IR52 ,
wherein
R
Figure imgf000187_0001
are independently selected from the group consisting of hydrogen, straight- or branched- Cι-6 alkyl optionally substi- tuted by cyano or carbamoyl and tetrazolyl optionally substituted by Ci-6 alkylnitrile, or R and R may form, together with the adjacent N, a saturated 5 to 8 membered ring optionally interrupted by NH,
R6 represents hydrogen, halogen, straight or branched C1-6 alkyl optionally substituted by mono di or tri halogen, or straight or branched C1-6 alkoxy, or
R5 and R6 may form a pyrrol ring fused to adjacent phenyl, or pyridine; and
R7 represents
Figure imgf000188_0001
Figure imgf000188_0002
Figure imgf000188_0003
Figure imgf000189_0001
or
Figure imgf000189_0002
wherein
n represents an integer selected from 1 to 3,
5 m represents an integer selected from 0 to 3,
71
R is hydrogen, C3-8 cycloalkyl optionally interrupted by NH, N- CH3 or O, straight- or branched C1-6 alkoxycarbonyl, phenyl optionally substituted by straight- or branched C1-6 alkyl, 10 benzyl, formyl, or
straight- or branched C1-6 alkyl
wherein the alkyl is optionally substituted by hydroxy, straight- 15 or branched- Cι-6 alkoxy, hydroxy straight- or branched- Cι-6 alkoxy, carboxy, straight- or branched- Cι-6 alkoxycarbonyl, straight- or branched- C1-6 alkylthio, di (straight- or branched- Cι-6 alkyl)amino, mono, di or tri halogen, or C3-8 cycloalkyl optionally interrupted by NH or O, 20 R711 and R712 are independently selected from the group consisting of hydrogen, halogen, hydroxy, carboxy, cyano, straight-or branched C1-6 alkyl optionally substituted by hydroxy, carboxy, or mono, di or tri halogen, carbamoyl, di (straight-or branched
5 Ci-6 alkyl)amino carbonyl, and -NR711aR711b
wherein
R7Ua and R7U are independently selected from the group 10 consisting of hydrogen, straight- or branched- C1-6 alkyl, straight- or branched- C1-6 alkanoyl, and straight- or branched- Ci-6 alkylsulfonyl, or
R71 and R711 may form, together with the adjacent N atom, a 5 to 8
15 membered saturated ring;
R is hydrogen, or straight- or branched- C1-6 alkyl;
nn
R is hydrogen, or straight- or branched- C1-6 alkyl,
20
R74 is hydrogen, or straight- or branched- C1-6 alkyl optionally substituted by phenyl, or
R73 and R74 may form, together with adjacent N atom, a 5 to 8 25 membered saturated ring optionally substituted by C1-6 alkyl and optionally interrupted by NH or O;
R is straight- or branched- C1-6 alkylene or a 3 to 8 membered saturated or unsaturated ring; 30 p represents an integer selected from 0 to 4; A ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom NΛ is the only hetero atom;
B ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom NB is the only hetero atom; and
C ring and D ring together form a 7 to 12 membered diazabicyclic ring.
2. The sulfonamide derivative of the formula (I), its tautomeric or stereoisomeric form, or a salt thereof as claimed in claim 1,
wherein
R5 is chloro, iodo, nitro, or cyano; and
R is hydrogen.
3. The sulfonamide derivative of the formula (I), its tautomeric or stereoisomeric form, or a salt thereof as claimed in claim 1,
wherein
R1 is halogen, or straight- or branched- Cι-6 alkyl optionally substituted by mono, di or tri halogen;
R is halogen, or straight- or branched- C1-6 alkyl optionally substituted by mono, di or tri halogen;
R is hydrogen; R4 is hydrogen;
R° is hydrogen;
Y is O, NH, NCH3, S, S(O),or SO2;
R5 is halogen, nitro, or cyano;
R is hydrogen; and
R7 represents
Figure imgf000192_0002
(CH2)p - A ring NJ
Figure imgf000192_0003
Figure imgf000192_0004
or
Figure imgf000193_0001
wherein
n represents an integer selected from 1 to 3,
5 m represents an integer selected from 0 to 3,
71
R is hydrogen, straight- or branched Cι-6 alkyl optionally substituted by hydroxy or hydroxy straight- or branched- Cι-6 alkoxy, C3-8 cycloalkyl, straight- or branched C1-6 alkoxycarbonyl, 10 phenyl optionally substituted by straight- or branched Cj-6 alkyl, benzyl, or formyl,
R711 and R712 are independently selected from the group consisting of hydrogen, halogen, carboxy, and straight-or branched Cι-6 15 alkyl, or
R71 and R711 may form, together with the adjacent N atom, a 5 to 8 membered saturated ring;
77
20 R is hydrogen, or straight- or branched- Cι-6 alkyl,
R73 is hydrogen, or straight- or branched- C1-6 alkyl,
R > 74 is hydrogen, or straight- or branched- C1-6 alkyl,or
25 2277
- 193 -
R73 and R74 may form, together with adjacent N atom, a 5 to 8 membered saturated ring optionally interrupted by NH or O;
R is straight- or branched- Cι-6 alkylene or a 3 to 8 membered saturated or unsaturated ring;
p represents an integer selected from 0 to 4;
A ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom NA is the only hetero atom;
B ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom NB is the only hetero atom; and
C ring and D ring together form a 7 to 12 membered diazabicyclic ring.
4. The sulfonamide derivative of the formula (I), its tautomeric or stereoisomeric form, or a salt thereof as claimed in claim 1,
wherein
1 7
R and R are identical or different and represent chloro, or methyl;
R is hydrogen or fluoro;
R is hydrogen;
R is hydrogen;
Y is O, NH, NCH3, S, S(O), or SO2 ; R ,5 is chloro, iodo, nitro, or cyano;
R is hydrogen; and
R represents
Figure imgf000195_0001
Figure imgf000195_0002
Figure imgf000195_0003
Figure imgf000195_0004
or
Figure imgf000195_0005
wherein
n represents an integer selected from 1 to 3, m represents an integer selected from 0 to 3,
R71 is hydrogen, straight- or branched C1-6 alkyl optionally substi- tuted by hydroxy or hydroxy straight- or branched- Cj_6 alkoxy,
C3-8 cycloalkyl, straight- or branched C1-6 alkoxycarbonyl, phenyl optionally substituted by straight- or branched Cι-6 alkyl, benzyl, or formyl,
71 1 71 7 R and R are independently selected from the group consisting of hydrogen, halogen, carboxy, and straight-or branched C1-6 alkyl, or
R and R may form, together with the adjacent N atom, a 5 to 8 membered saturated ring;
77
R is hydrogen, or straight- or branched- C1-6 alkyl;
R is hydrogen, or straight- or branched- Cι-6 alkyl,
R7 is hydrogen, or straight- or branched- Cι-6 alkyl,or
R73 and R74 may form, together with adjacent N atom, a 5 to 8 membered saturated ring optionally interrupted by NH or O;
R75 is straight- or branched- C1-6 alkylene or a 3 to 8 membered saturated or unsaturated ring;
p represents an integer selected from 0 to 4; A ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom NΛ is the only hetero atom;
B ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom NB is the only hetero atom; and
C ring and D ring together form a 7 to 12 membered diazabicyclic ring.
The sulfonamide derivative of the formula (I), its tautomeric or stereoisomeric form, or a salt thereof as claimed in claim 1,
wherein
R1 is hydrogen, fluoro, chloro, bromo, methyl, isopropyl, butyl, tert-butyl, trifluoromethyl, methoxy, amino, dimethylamino, acetyl, or nitro;
R2 is hydrogen, fluoro, chloro, methyl, isopropyl, tert-butyl, trifluoromethyl, methoxy, or cyano;
R is hydrogen or fluoro;
R is hydrogen;
R is hydrogen;
Y is O, NH, NCH3, S, S(O),or SO2;
R5 is chloro, iodo, nitro, or cyano;
R is hydrogen; and R7 represents
Figure imgf000198_0001
Figure imgf000198_0002
Figure imgf000198_0003
or
Figure imgf000198_0004
wherein
n represents an integer 1,
m represents an integer selected from 1 or 2, 71
R represents hydrogen, methyl, ethyl or isopropyl;
711
R represents hydrogen, methyl,or carboxy;
71
R represents hydrogen or methyl, or
R71 and R711 may form, together with the adjacent N atom, a 5 membered saturated ring;
R is hydrogen, methyl, or ethyl;
R >73 is hydrogen, or methyl,
R >74 is hydrogen, methyl, or ethyl, or
R73 and R74 may form, together with adjacent N atom, piperidino, morpholino, or pyrrolidino;
ne t
R is phenyl;
p represents an integer selected from 0 to 4;
A ring represents piperidino, or pyrrolidino;
B ring represents pyrrolidino; and
C ring and D ring together form a 7 to 12 membered diazabicyclic ring.
The sulfonamide derivative its tautomeric or stereoisomeric form, or a salt thereof according to claim 1 which has the general formula (1-2):
Figure imgf000200_0001
wherein
R1 is hydrogen, halogen, straight- or branched- C1-6 alkyl optionally substituted by mono, di or tri halogen, straight- or branched- C1-6 alkoxy, straight- or branched- C1-6 alkoxy carbonyl, amino, straight- or branched- C1-6 alkylamino, di(straight- or branched- C1-6 alkyl)amino, straight- or branched- C1-6 alkanoyl, or nitro,
R2 is hydrogen, halogen, straight- or branched- Cι-6 alkyl optionally substituted by mono, di or tri halogen, straight- or branched-C1-6 alkoxy, or cyano, or
1 7 R and R may form benzene ring or C5-8 cycloalkyl fused to the adjacent phenyl;
R is hydrogen or halogen,
Y represents O, NH, NCH3, S, S(O), or SO2 ;
R5 is hydrogen, halogen, hydroxy, straight- or branched- C1-6 alkyl optionally substituted by mono,di, or tri halogen or hydroxy, straight- or branched- C1-6 alkoxy, straight- or branched- C1-6 alkoxycarbonyl, amino, straight- or branched- Cι-6 alkanoylamino, phenyl-(CH2)q -carbonylamino (wherein q represents an integer selected from 0 to 6), straight- or branched- C1-6 alkylbenzoylamino, naphthylcarbonylammo, thenoylamino, nitro, cyano, carboxy, straight- or branched- C1-6 alkyl sulfonyl, oxazolidinonyl, or substituents represented by the formula, -SO2-NR51R52, or -CO-NR51R52 ,
wherein
R51 and R52 are independently selected from the group consisting of hydrogen, straight- or branched- C1-6 alkyl optionally substituted by cyano or carbamoyl, tetrazolyl optionally substituted by C1-6 alkylnitrile, or R51 and R52 may form, together with the adjacent N, a saturated 5 to 8 membered ring optionally interrupted by NH,
R is hydrogen, halogen, straight or branched C1-6 alkyl optionally substituted by mono, di or tri halogen, or straight or branched C -6 alkoxy, or
e £
R and R may form a pyrrol ring fused to adjacent phenyl; and
R7 represents
Figure imgf000201_0001
Figure imgf000202_0001
or
Figure imgf000202_0002
wherein
n represents an integer selected from 1 to 3,
m represents an integer selected from 0 to 3,
R 71 is hydrogen, straight- or branched C1-6 alkyl optionally substituted by hydroxy or hydroxy straight- or branched- C1-6 alkoxy, C3-8 cycloalkyl, straight- or branched C1-6 alkoxycarbonyl,
10 phenyl optionally substituted by straight- or branched C1-6 alkyl, benzyl, or formyl, R711 and R712 are independently selected from the group consisting of hydrogen, halogen, hydroxy, carboxy, cyano, straight-or branched C1-6 alkyl optionally substituted by hydroxy, carboxy, or mono, di or tri halogen, carbamoyl, di (straight-or branched
5 C1-6 alkyl)amino carbonyl, or -NR7UaR711b
wherein
R7Ua and R711 are independently selected from the group 10 consisting of hydrogen, straight- or branched- Cι-6 alkyl, straight- or branched- Cι-6 alkanoyl, or straight- or branched- Ci-6 alkylsulfonyl, or
R71 and R711 may form, together with the adjacent N atom, a 5 15 to 8 membered saturated ring;
R >72 is hydrogen, or straight- or branched- C1-6 alkyl;
R is hydrogen, or straight- or branched- Cj-6 alkyl,
20
R74 is hydrogen, or straight- or branched- Cι-6 alkyl, or
R73 and R74 may form, together with adjacent N atom, a 5 to 8 membered saturated ring optionally interrupted by NH 25 or O;
R is straight- or branched- C1-6 alkylene or a 3 to 8 membered saturated or unsaturated ring;
30 p represents an integer selected from 0 to 4; A ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom N is the only hetero atom;
B ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom NB is the only hetero atom; and
C ring and D ring together form a 7 to 12 membered diazabicyclic ring. ■
7. The sulfonamide derivative of the formula (1-2), its tautomeric or stereoisomeric form, or a salt thereof as claimed in claim 6,
wherein
R5 is chloro, iodo, nitro, or cyano; and
R6 is hydrogen.
8. The sulfonamide derivative of the formula (1-2), its tautomeric or stereo- isomeric form, or a salt thereof as claimed in claim 6,
wherein
R1 is hydrogen, halogen, or straight- or branched- Cι-6 alkyl optionally substituted by mono, di or tri halogen;
R2 is hydrogen, halogen, or straight- or branched- d-6 alkyl optionally substituted by mono, di or tri halogen;
R is hydrogen or halogen, is O, NH, NCH3, S, S(O),or SO2;
R >5 is halogen, nitro, or cyano;
R is hydrogen; and
R7 represents
Figure imgf000205_0001
Figure imgf000205_0002
(CH2)p-f-Aring Nf
Figure imgf000205_0003
Figure imgf000205_0004
or
Figure imgf000205_0005
wherein n represents an integer selected from 1 to 3,
m represents an integer selected from 0 to 3,
71
R is hydrogen, straight- or branched C1-6 alkyl optionally substituted by hydroxy or hydroxy straight- or branched- Cι-6 alkoxy, C3-8 cycloalkyl, straight- or branched C1-6 alkoxycarbonyl, phenyl optionally substituted by straight- or branched -6 alkyl, benzyl, or formyl,
711
R represents hydrogen, methyl,or carboxy,
R712 represents hydrogen or methyl, or
R71 and R711 may form, together with the adjacent N atom, a 5 to membered saturated ring;
R72 is hydrogen, or straight- or branched- Cι-6 alkyl;
R73 is hydrogen, or straight- or branched- C1-6 alkyl,
R74 is hydrogen, or straight- or branched- Cι-6 alkyl, or
R73 and R74 may form, together with adjacent N atom, a 5 to 8 membered saturated ring optionally interrupted by NH or O;
R75 is straight- or branched- C1-6 alkylene or a 3 to 8 membered saturated or unsaturated ring;
represents an integer selected from 0 to 4; A ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom NA is the only hetero atom;
B ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom NB is the only hetero atom; and
C ring and D ring together form a 7 to 12 membered diazabicyclic ring.
The sulfonamide derivative of the formula (1-2), its tautomeric or stereoisomeric form, or a salt thereof as claimed in claim 6,
wherein
R1, R2 and R3 are independently selected from the group consisting of hydrogen, chloro, or methyl;
Y is O, NH, NCH3, S, S(O), or SO2 ;
R5 is chloro, iodo, nitro, or cyano;
R is hydrogen; and
R7 represents
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000208_0002
or
Figure imgf000208_0003
wherein
n represents an integer selected from 1 to 3,
m represents an integer selected from 1 to 3,
10 R 71 is hydrogen, straight- or branched C1-6 alkyl optionally substituted by hydroxy or hydroxy straight- or branched- Cι-6 alkoxy, C3-8 cycloalkyl, straight- or branched C1-6 alkoxycarbonyl, phenyl optionally substituted by straight- or branched C1-6 alkyl, benzyl, or formyl,
15
R ) 711 represents hydrogen, methyl,or carboxy or R71 and R711 may form, together with the adjacent N atom, a 5 to 8 membered saturated ring;
R >72 is hydrogen, or straight- or branched- C1-6 alkyl;
R is hydrogen, or straight- or branched- C1-6 alkyl;
R74 is hydrogen, or straight- or branched- C1-6 alkyl; or
R73 and R74 may form, together with adjacent N atom, a 5 to 8 membered saturated ring optionally interrupted by NH or O;
R75 is straight- or branched- C1-6 alkylene or a 3 to 8 membered saturated or unsaturated ring;
p represents an integer selected from 0 to 4;
A ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom NA is the only hetero atom;
B ring represents a 3 to 8 membered saturated ring, in which the nitrogen atom NB is the only hetero atom; and
C ring and D ring together form a 7 to 12 membered diazabicyclic ring.
10. The sulfonamide derivative of the formula (1-2), its tautomeric or stereoisomeric form, or a salt thereof as claimed in claim 6,
wherein R1 is halogen, or straight- or branched- C1-6 alkyl optionally substituted by mono, di or tri halogen;
R2 is halogen, or straight- or branched- C1-6 alkyl optionally substituted by mono, di or tri halogen;
R is hydrogen or fluoro;
Y is O, NH, NCH3, S, S(O),or SO2;
R5 is hydrogen, fluoro, chloro, bromo, iodo, trifluoromethyl, hydroxy, methoxy, amino, acetylamino, isobutylcarbonylamino, tert-butyl- carbonylamino, benzoylamino, benzylcarbonylamino, phenethylcarb- onylamino, methylbenzoylamino, naphthylcarbonylammo, thenoyl- amino, nitro, cyano, methylsulfonyl, dimethyammosulfonyl, piperazmosulfonyl, dimethyaminocarbonyl, or piperazinocarbonyl;
R is hydrogen, methyl, or methoxy; or
R5 and R6 may form a pyrrol ring fused to adjacent phenyl; and
R represents
Figure imgf000210_0001
Figure imgf000211_0001
Figure imgf000211_0002
or
Figure imgf000211_0003
wherein
n represents an integer 1,
m represents an integer 1 or 2,
10 R >71 is hydrogen, methyl, ethyl, isopropyl, sec-butyl, branched pentyl, hydroxyethyl, hydroxyethoxyethyl, cyclopentyl, cyclo- hexyl, tert-butoxycarbonyl, phenyl, tolyl, benzyl, or formyl,
R >71 represents hydrogen, methyl,or carboxy,
15
R , 712 represents hydrogen or methyl, or R71 and R711 may form, together with the adjacent N atom, a 5 membered saturated ring;
77
R is hydrogen, methyl, or ethyl;
R , 73 is hydrogen, or methyl,
R > 74 is hydrogen, methyl, or ethyl, or
R73 and R74 may form, together with adjacent N atom, piperidino, morpholino, or pyrrolidino;
R75 is phenyl;
p represents an integer selected from 0 to 4;
A ring represents piperidino, or pyrrolidino;
B ring represents pyrrolidino; and
C ring and D ring together form a 7 to 12 membered diazabicyclic ring.
11. The sulfonamide derivative of formula (1-2), its tautomeric or stereoisomeric form, or a salt thereof as claimed in claim 6,
wherein
R1 is hydrogen, fluoro, chloro, bromo, methyl, isopropyl, butyl, tert-butyl, trifluoromethyl, methoxy, amino, dimethylamino, acetyl, or nitro; R2 is hydrogen, fluoro, chloro, methyl, isopropyl, tert-butyl, trifluoro- methyl, methoxy, or cyano;
R3 is hydrogen or fluoro;
Y is O, NH, NCH3, S, S(O), or SO2;
R5 is hydrogen, fluoro, chloro, bromo, iodo, trifluoromethyl, hydroxy, methoxy, amino, acetylamino, isobutylcarbonylammo, tert-butyl- carbonylamino, benzoylamino, benzylcarbonylamino, phenethyl- carbonylamino, methylbenzoylamino, naphthylcarbonylamino, thenoylamino, nitro, cyano, methylsulfonyl, dimethyammosulfonyl, piperazmosulfonyl, dimethyaminocarbonyl, or piperazinocarbonyl;
R is hydrogen, methyl, or methoxy; or
R5 and R6 may form a pyrrol ring fused to adjacent phenyl, and
R7 represents
Figure imgf000213_0001
Figure imgf000213_0002
Figure imgf000214_0001
Figure imgf000214_0002
or
Figure imgf000214_0003
wherein
n represents an integer 1,
m represents an integer 1 or 2,
10 R 71 represents hydrogen, methyl, ethyl, isopropyl, sec-butyl, branched pentyl, hydroxyethyl, hydroxyethoxyethyl, cyclopentyl, cyclohexyl, tert-butoxycarbonyl, phenyl, tolyl, benzyl, or formyl,
15 R , 711 represents hydrogen, methyl,or carboxy,
R > 712 represents hydrogen or methyl, or R71 and R711 may form, together with the adjacent. N atom, a 5 membered saturated ring;
R72 is hydrogen, methyl, or ethyl,
R73 is hydrogen, or methyl,
R74 is hydrogen, methyl, or ethyl, or
R73 and R74 may form, together with adjacent N atom, piperidino, morpholino, or pyrrolidino;
R • 75 is phenyl;
p represents an integer selected from 0 to 4;
A ring represents piperidino, or pyπolidino;
B ring represents pyrrolidino; and
C ring and D ring together form a 7 to 12 membered diazabicyclic ring.
12. The sulfonamide derivative of formula (1-2), its tautomeric or stereoisomeric form, or a salt thereof as claimed in claim 6,
wherein
R1 is chloro, bromo, or methyl;
R2 is hydrogen, chloro, bromo, or methyl; R ,3 is hydrogen or fluoro;
Y represents O, S, or S(O);
R > 5 represents hydrogen, chloro, nitro, or cyano;
R >6 represents hydrogen;
R7 represents
Figure imgf000216_0001
(CH2)p-f- ring Nf
Figure imgf000216_0002
R t— [LB B ring J_(CH2)P_N— or
Figure imgf000217_0001
wherein
R71 represents hydrogen, methyl, ethyl or isopropyl; 5
R711 represents hydrogen, methyl,or carboxy;
R712 represents hydrogen or methyl;
10 R72 is hydrogen, methyl, or ethyl;
R ,73 is hydrogen, methyl, or ethyl;
R > 74 is hydrogen, methyl, or ethyl; or
15
R73 and R74 may form, together with adjacent N atom, piperidino, or pyrrolidino,
R75 is phenyl;
20 p represents integer 0 or 1;
A ring represents piperidino, or pyrrolidino; and
25 B ring represents pyrrolidino.
3. The sulfonamide derivative, its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof as claimed in claim 1, wherein said sulfonamide derivative is selected from the group consisting of:
l-{[2-(3,5-dimethylphenoxy)-5-nitrophenyl]sulfonyl}-4-ethylpiperazine,
1- {[2-(3,5-dichlorophenoxy)-5- nitrophenyl]sulfonyl}piperazine, l-{[2-(3,5-dimethylphenoxy)-5-nitrophenyl]sulfonyl}-4-isopropylpiperazine, 4-(3,5-dimethylphenoxy)-3-(l-piperazinylsulfonyl)benzonitrile, l-{[5-chloro-2-(3,5-dimethylphenoxy)phenyl]sulfonyl}-4-ethylpiperazine, l-{[2-(3,5-dicUorophenoxy)-5-nifrophenyl]sulfonyl}-4-(l-pyrroUdinyl)piperidine,
4-(3,5-dichlorophenoxy)-3-{[4-(l-pyrrolidinyl)-l-piperidinyl]sulfonyl}benzo- nitrile,
4-(3,5-dichlorophenoxy)-3-(l-piperazinylsulfonyl)benzonitrile, 1 - { [2-(3,5-dichlorophenoxy)-5-nitrophenyl] sulfonyl} -N,N-diethyl-3-pyr- rolidinamine,
(2S)-l-{[2-(3,5-dichlorophenoxy)-5-nitrophenyl]sulfonyl}-2-(l-pyrrolidinyl- methyl)pyrrolidine,
3-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-ylsulfonyl]-4-(3,5- dichlorophenoxy)b enzonitrile, 4- [(3 ,5 -dichlorophenyl)sulfanyl] -3 -( 1 -piperazinylsulfonyl) benzonitrile,
4-[(3,5-dichlorophenyl)sulfmyl]-3-(l-piperazinylsulfonyl) benzonitrile, 1 - { [2-(3 ,5 -dibromophenoxy)-5 -nitrophenyl] sulfonyl}piperazine, l-{[2-(3,5-dichloro-2-fluorophenoxy)-5-nitrophenyl]sulfonyl}piperazine, 1 - { [5-cyano-2-(3 ,5 -dichlorophenoxy)phenyl] sulfonyl} -2-piperazinecarboxylic acid, l-{[2-(3,5-dichlorophenoxy)-5-nitrophenyl]sulfonyl}-2-piperazinecarboxylic acid,
1 - {[2-(3,5-dimethylphenoxy)-5-nitrophenyl]sulfonyl} -1 ,4-diazepane, l-{[2-(3,5-dichlorophenoxy)-5-nitrophenyl]sulfonyl}-l,4-diazepane, 1 - {[2-(3,5-dichlorophenoxy)-5-nitrophenyl] sulfonyl} -3 ,5-dimethylpiperazine,
3-(l,4-diazepan-l-ylsulfonyl)-4-(3,5-dichlorophenoxy) benzonitrile, -{[2-(3,5-dichlorophenoxy)-5-nitrophenyl]sulfonyl}-l,3'-bipyrrolidine, 3-(l,3'-bipyrrolidin-r-ylsulfonyl)-4-(3,5-dichlorophenoxy)benzonitrile, 1 -( {2- [(3 , 5 -dichlorophenyl) sulfanyl] -5 -nitrophenyl } sulfonyl)-4-( 1 -pyr- rolidinyl)piperidine, 4-(3,5-dichlorophenoxy)-3-(hexahydropyrrolo[ 1 ,2-a]pyrazin-2(lH)-yl- sulfonyl)benzonitrile, and 3-(l,4-diazepan-l-ylsulfonyl)-4-[(3,5-dichlorophenyl)sulfanyl]benzonitrile.
14. A medicament comprising the sulfonamide derivative, its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof as claimed in claim 1 as an active ingredient.
15. A medicament as claimed in claim 14, further comprising one or more pharmaceutically acceptable excipients.
16. A medicament as claimed in claim 14, wherein said sulfonamide derivative, its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof is a CCR3 antagonist.
17. An anti-inflammatory agent comprising the sulfonamide derivative, its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof as claimed in claim 1 as an active ingredient.
18. An anti-inflammatory agent as claimed in claim 17;
wherein said agent is useful for treatment and prophylaxis of a disease selected from the group consisting of asthma, rhinitis, and allergic diseases, and autoimmune pathologies such as rheumatoid arthritis, Grave's disease, and atherosclerosis.
19. An agent to treat or prevent a disease selected from the group consisting of HIN, lung granuloma, and Alzheimer's diseases ;
comprising the sulfonamide derivative, its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof as claimed in claim 1 as an active ingredient.
20. A method for treating or preventing a CCR3 related disorder or disease in a human or animal subject, comprising administering to said subject a therapeutically effective amount of the sulfonamide derivative, its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof as claimed in claim 1.
21. The method of claim 20, wherein said disorder or disease is a inflammatory or immunoregulatory disorder or disease.
22. The method of claim 20, wherein said disorder or disease is selected from the group consisting of asthma, rhinitis, and allergic diseases, and autoimmune pathologies such as rheumatoid arthritis, Grave's disease, and atherosclerosis.
23. The method of claim 20, wherein said disorder or disease is selected from the group consisting of HIN, lung granuloma, and Alzheimer's diseases.
24. The method of claim 20, wherein said sulfonamide derivative is selected from the group consisting of:
1 - { [2-(3 , 5 -dimethylphenoxy)-5 -nitrophenyl] sulfonyl} -4-ethylpip erazine, l-{[2-(3,5-dichlorophenoxy)-5- nitrophenyl]sulfonyl}piperazine, l-{[2-(3,5-α ne ylphenoxy)-5-mfrophenyl]sulfonyl}-4-isopropylpiperazine, 4-(3 ,5-dimethylphenoxy)-3 -( 1 -piperazinylsulfonyl)benzonitrile, l-{[5-chloro-2-(3,5-dimethylphenoxy)phenyl]sulfonyl}-4-ethylpiperazine, l-{[2-(3,5-dichlorophenoxy)-5-nitrophenyl]sulfonyl}-4-(l-pyrrolidinyl)- piperidine,
4-(3,5-dichlorophenoxy)-3-{[4-(l-pyrrolidinyl)-l-piperidinyl]sulfonyl}- benzonitrile, 4-(3,5-dichlorophenoxy)-3-(l-piperazinylsulfonyl)benzonitrile, l-{[2-(3,5-dichlorophenoxy)-5-nitrophenyl]sulfonyl}-N,N-diethyl-3-pyr- rolidinamine,
(2S)-l-{[2-(3,5-dichlorophenoxy)-5-nitrophenyl]sulfonyl}-2-(l-pyr- rolidinylmethyl,)pyrrolidine, 3-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-ylsulfonyl]-4-(3,5- dichlorophenoxy)benzonitrile,
4- [(3 , 5 -dichlorophenyl) sulfanyl] -3 -( 1 -piperazinylsulfonyl) benzonitrile,
4-[(3,5-dichlorophenyl)sulfmyl]-3-(l-piperazinylsulfonyl) benzonitrile, l-{[2-(3,5-dibromophenoxy)-5-nitrophenyl]sulfonyl}piperazine, l-{[2-(3,5-dichloro-2-fluorophenoxy)-5-nitrophenyl]sulfonyl}piρerazine,
1 - {[5-cyano-2-(3 ,5-dichlorophenoxy)phenyl] sulfonyl} -2-piperazinecarboxylic acid, l-{[2-(3,5-dichlorophenoxy)-5-nitrophenyl]sulfonyl}-2-piperazinecarb- oxylic acid, 1 - { [2-(3 ,5-dimethylphenoxy)-5 -nitrophenyl] sulfonyl} - 1 ,4-diazepane, l-{[2-(3,5-dichlorophenoxy)-5-nitrophenyl]sulfonyl}-l,4-diazepane, l-{[2-(3,5-dichlorophenoxy)-5-nitrophenyl]sulfonyl}-3,5-dimethylpiper- azine,
3 -(1 ,4-diazepan- 1 -ylsulfonyl)-4-(3 ,5 -dichlorophenoxy) benzonitrile, -{[2-(3,5-dichlorophenoxy)-5-nitrophenyl]sulfonyl}-l,3'-bipyπolidine,
3-(l,3,-bipyrrolidin-r-ylsulfonyl)-4-(3,5-dichlorophenoxy)benzonitrile,
1 -( {2-[(3 ,5-dichlorophenyl)sulfanyl]-5-nitrophenyl} sulfonyl)-4-(l -pyr- rolidinyl)piperidine,
4-(3 ,5 -dichlorophenoxy)-3-(hexahydropyrrolo [ 1 ,2-a]pyrazin-2( 1 H)- ylsulfonyl)benzonitrile, and
3-(l,4-diazepan-l-ylsulfonyl)-4-[(3,5-dichlorophenyl)sulfanyl]benzonitrile.
25. The method of claim 20, wherein said sulfonamide derivative, its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof is administered with one or more pharmaceutically acceptable excipients.
26. Use of the sulfonamide derivative, its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof as claimed in claim 1 in the preparation of a medicament
27. Use of the sulfonamide derivative, its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof as claimed in claim 1 in the preparation of a medicament for treating or preventing a CCR3 related disorder or disease.
28. The use of claim 27, wherein said disorder or disease is a inflammatory or immunoregulatory disorder or disease.
29. The use of claim 27, wherein said disorder or disease is selected from the group consisting of asthma, rhinitis, and allergic diseases, and autoimmune pathologies such as rheumatoid arthritis, Grave's disease, and atherosclerosis.
30. The use of claim 27, wherein said disorder or disease is selected from the group consisting of HIN, lung granuloma, and Alzheimer's diseases.
31. The use of claim 27, wherein said sulfonamide derivative is selected from the group consisting of:
l-{[2-(3,5-dimethylphenoxy)-5-nitrophenyl]sulfonyl}-4-ethylpiperazine, l-{[2-(3,5-dichlorophenoxy)-5- nitrophenyl]sulfonyl}piperazine, 1 - { [2-(3 ,5-dimethylphenoxy)-5-nitrophenyl] sulfonyl} -4-isopropylpiperazine,
4-(3,5-dimethylphenoxy)-3-(l-piperazinylsulfonyl)benzonitrile, l-{[5-chloro-2-(3,5-dimethylphenoxy)phenyl]sulfonyl}-4-ethylpiperazine,
1 - {[2-(3 ,5-dichlorophenoxy)-5-nitrophenyl] sulfonyl} -4-(l -pyrrolidinyl)- piperidine,
4-(3,5-dichlorophenoxy)-3- {[4-(l -pyrrolidinyl)- 1 -piperidinyl] sulfonyl} - benzonitrile,
4-(3,5-dichlorophenoxy)-3-(l-piperazinylsulfonyl)benzonitrile, l-{[2-(3,5-dichlorophenoxy)-5-nitrophenyl]sulfonyl}-N,N-diethyl-3-pyr- rolidinamine,
(2S)- 1 - { [2-(3 ,5 -dichlorophenoxy)-5-nitrophenyl] sulfonyl} -2-( 1 -pynolidinyl- methyl,)pyrrolidine,
3-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-ylsulfonyl]-4-(3,5-di- chlorophenoxy)benzonitrile,
4-[(3,5-dichlorophenyl)sulfanyl]-3-(l-piperazinylsulfonyl) benzonitrile,
4-[(3,5-dichlorophenyl)sulfinyl]-3-(l-piperazinylsulfonyl) benzonitrile, l-{[2-(3,5-dibromophenoxy)-5-nitrophenyl]sulfonyl}piperazine, l-{[2-(3,5-dichloro-2-fluorophenoxy)-5-nitrophenyl]sulfonyl}piperazine, l-{[5-cyano-2-(3,5-dichlorophenoxy)phenyl]sulfonyl}-2-piperazinecarboxylic acid, l-{[2-(3,5-dichlorophenoxy)-5-nitrophenyl]sulfonyl}-2-piperazinecarboxylic acid,
1 - {[2-(3,5-dimethylphenoxy)-5-nitrophenyl]sulfonyl} -1 ,4-diazepane,
1 - {[2-(3 ,5-dichlorophenoxy)-5-nitrophenyl] sulfonyl} - 1 ,4-diazepane, l-{[2-(3,5-dichlorophenoxy)-5-nitrophenyl]sulfbnyl}-3,5-dimethylpiperazine,
3-(l,4-diazepan-l-ylsulfonyl)-4-(3,5-dichlorophenoxy) benzonitrile, 1 '- {[2-(3,5-dichlorophenoxy)-5-nitrophenyl]sulfonyl} -1 ,3'-bipyrrolidine,
3 -( 1 ,3 '-bipyπolidin- 1 '-ylsulfonyl)-4-(3 ,5-dichlorophenoxy)benzonitrile,
1 -( {2-[(3 ,5-dichlorophenyl)sulfanyl]-5-nitrophenyl} sulfonyl)-4-(l -pyr- ro lidinyl)pip eridine,
4-(3,5-dichlorophenoxy)-3-(hexahydropyrrolo[l,2-a]pyrazin-2(lH)- ylsulfonyl)benzonitrile, and
3 -(1 ,4-diazepan- 1 -ylsulfonyl)-4-[(3 ,5-dichlorophenyl)sulfanyl]benzonitrile.
2. The use of claim 27, wherein said sulfonamide derivative, its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof is fonnulated with one or more pharmaceutically acceptable excipients.
PCT/EP2002/009873 2001-09-07 2002-09-04 Arylsulfonamide derivatives for use as ccr3 antagonists in the treatment of inflammatory and immunological disorders WO2003022277A1 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
US10/489,029 US7700586B2 (en) 2001-09-07 2002-09-04 Arylsulfonamide derivatives for use as ccr3 antagonists in the treatment of inflammatory and immunological disorders
JP2003526406A JP4517047B2 (en) 2001-09-07 2002-09-04 Sulfonamide derivatives
EP02772265A EP1461038B9 (en) 2001-09-07 2002-09-04 Arylsulfonamide derivatives for use as ccr3 antagonists in the treatment of inflammatory and immunological disorders
CA002459432A CA2459432C (en) 2001-09-07 2002-09-04 Arylsulfonamide derivatives for use as ccr3 antagonists in the treatment of inflammatory and immunological disorders
DE60221569T DE60221569T2 (en) 2001-09-07 2002-09-04 ACRYLSULPHONAMIDE DERIVATIVES FOR USE AS CCR3 ANTAGONISTS IN THE TREATMENT OF INFLAMMATORY AND IMMUNOLOGICAL DISEASES
US12/763,072 US8242118B2 (en) 2001-09-07 2010-04-19 Arylsulfonamide derivatives for use as CCR3 antagonists in the treatment of inflammatory and immunological disorders

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2001272327A JP2003081937A (en) 2001-09-07 2001-09-07 Benzenesulfonamide derivative
JP2001-272327 2001-09-07

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US10489029 A-371-Of-International 2002-09-04
US12/763,072 Continuation US8242118B2 (en) 2001-09-07 2010-04-19 Arylsulfonamide derivatives for use as CCR3 antagonists in the treatment of inflammatory and immunological disorders

Publications (1)

Publication Number Publication Date
WO2003022277A1 true WO2003022277A1 (en) 2003-03-20

Family

ID=19097717

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2002/009873 WO2003022277A1 (en) 2001-09-07 2002-09-04 Arylsulfonamide derivatives for use as ccr3 antagonists in the treatment of inflammatory and immunological disorders

Country Status (15)

Country Link
US (2) US7700586B2 (en)
EP (2) EP1461038B9 (en)
JP (2) JP2003081937A (en)
AR (1) AR037235A1 (en)
CA (1) CA2459432C (en)
DE (2) DE60238149D1 (en)
ES (2) ES2354378T3 (en)
GT (1) GT200200178A (en)
HK (1) HK1109867A1 (en)
HN (1) HN2002000247A (en)
MY (1) MY133303A (en)
PE (1) PE20030440A1 (en)
SV (1) SV2004001225A (en)
TW (1) TWI262187B (en)
WO (1) WO2003022277A1 (en)

Cited By (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004084898A1 (en) * 2003-03-24 2004-10-07 Actimis Pharmaceuticals, Inc. 2-phenoxy- and 2-phenylsulfomamide derivatives with ccr3 antagonistic activity for the treatment of asthma and other inflammatory or immunological disorders
US7482363B2 (en) 2002-03-19 2009-01-27 Astrazeneca Ab Piperidine derivatives useful as modulators of chemokine receptor activity
US7495013B2 (en) 2003-04-01 2009-02-24 Astrazeneca Ab Chemical compounds
US7632829B2 (en) 2006-04-20 2009-12-15 Hoffmann-La Roche Inc. Diazepan derivatives
US7700586B2 (en) 2001-09-07 2010-04-20 Axikin Pharmaceuticals, Inc. Arylsulfonamide derivatives for use as ccr3 antagonists in the treatment of inflammatory and immunological disorders
WO2010123959A3 (en) * 2009-04-22 2011-02-17 Axikin Pharmaceuticals, Inc. 2,5-disubstituted arylsulfonamide ccr3 antagonists
WO2011109345A1 (en) 2010-03-02 2011-09-09 Axikin Pharmaceuticals, Inc. Isotopically enriched arylsulfonamide ccr3 antagonists
WO2010123960A3 (en) * 2009-04-22 2011-09-09 Axikin Pharmaceuticals, Inc. Arylsulfonamide ccr3 antagonists
WO2010123956A3 (en) * 2009-04-22 2011-09-09 Axikin Pharmaceuticals, Inc. 2,5-disubstituted arylsulfonamide ccr3 antagonists
KR101110457B1 (en) * 2002-12-17 2012-02-17 아스트라제네카 아베 Novel compounds having selective inhibiting effect at gsk3
US20120088769A1 (en) * 2010-10-11 2012-04-12 Axikin Pharmaceuticals, Inc. Salts of arylsulfonamide ccr3 antagonists
WO2011116161A3 (en) * 2010-03-17 2012-04-19 Axikin Pharmaceuticals Inc. Arylsulfonamide ccr3 antagonists
EP2448581A1 (en) * 2009-06-29 2012-05-09 Agios Pharmaceuticals, Inc. Therapeutic compositions and related methods of use
US8247442B2 (en) 2006-03-29 2012-08-21 Purdue Pharma L.P. Benzenesulfonamide compounds and their use
US8314127B2 (en) 2005-07-21 2012-11-20 Astrazeneca Ab Piperidine derivatives
US8399486B2 (en) 2007-04-09 2013-03-19 Purdue Pharma L.P. Benzenesulfonyl compounds and the use thereof
US8541588B2 (en) 2009-01-12 2013-09-24 Pfizer Limited Sulfonamide derivatives
WO2014039748A1 (en) 2012-09-07 2014-03-13 Axikin Pharmaceuticals, Inc. Isotopically enriched arylsulfonamide ccr3 antagonists
US8742119B2 (en) 2009-04-06 2014-06-03 Agios Pharmaceuticals, Inc. Pyruvate kinase M2 modulators, therapeutic compositions and related methods of use
US8765736B2 (en) 2007-09-28 2014-07-01 Purdue Pharma L.P. Benzenesulfonamide compounds and the use thereof
US8785450B2 (en) 2009-06-29 2014-07-22 Agios Pharmaceuticals, Inc. Therapeutic compounds and compositions
US8791264B2 (en) 2006-04-13 2014-07-29 Purdue Pharma L.P. Benzenesulfonamide compounds and their use as blockers of calcium channels
US8889667B2 (en) 2010-12-29 2014-11-18 Agios Pharmaceuticals, Inc Therapeutic compounds and compositions
US8937181B2 (en) 2006-04-13 2015-01-20 Purdue Pharma L.P. Benzenesulfonamide compounds and the use thereof
US9000174B2 (en) 2004-10-14 2015-04-07 Purdue Pharma L.P. 4-phenylsulfonamidopiperidines as calcium channel blockers
AU2012238285B2 (en) * 2003-03-24 2015-07-02 Axikin Pharmaceuticals, Inc. Benzenesulfonamide derivatives
US9096558B2 (en) 2010-07-09 2015-08-04 Pfizer Limited N-sulfonylbenzamide compounds
US9145407B2 (en) 2010-07-09 2015-09-29 Pfizer Limited Sulfonamide compounds
US9181231B2 (en) 2011-05-03 2015-11-10 Agios Pharmaceuticals, Inc Pyruvate kinase activators for use for increasing lifetime of the red blood cells and treating anemia
US9221792B2 (en) 2010-12-17 2015-12-29 Agios Pharmaceuticals, Inc N-(4-(azetidine-1-carbonyl) phenyl)-(hetero-) arylsulfonamide derivatives as pyruvate kinase M2 (PMK2) modulators
US9328077B2 (en) 2010-12-21 2016-05-03 Agios Pharmaceuticals, Inc Bicyclic PKM2 activators
US9365545B2 (en) 2013-03-15 2016-06-14 Agios Pharmaceuticals, Inc Therapeutic compounds and compositions
US9980961B2 (en) 2011-05-03 2018-05-29 Agios Pharmaceuticals, Inc. Pyruvate kinase activators for use in therapy
US11234976B2 (en) 2015-06-11 2022-02-01 Agios Pharmaceuticals, Inc. Methods of using pyruvate kinase activators

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7897776B2 (en) 2007-04-23 2011-03-01 Salutria Pharmaceuticals Llc Sulfonamide containing compounds for treatment of inflammatory disorders
TW201036941A (en) * 2009-03-30 2010-10-16 Sumitomo Chemical Co Method for producing sulfonamide compound
WO2010129351A1 (en) 2009-04-28 2010-11-11 Schepens Eye Research Institute Method to identify and treat age-related macular degeneration

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2275354A (en) * 1937-11-29 1942-03-03 May & Baker Ltd Preparation of new therapeutically useful heterocyclic compounds
US3819639A (en) * 1970-11-11 1974-06-25 Christiaens Sa A 2-metatrifluoromethylanilino-pyridine-5-n-acetyl sulfonamide
WO1999055324A1 (en) * 1998-04-27 1999-11-04 Smithkline Beecham Corporation Ccr-3 receptor antagonists
WO2000042003A1 (en) * 1999-01-13 2000-07-20 Warner-Lambert Company Benzenesulfonamide derivatives and their use as mek inhibitors
WO2001032604A1 (en) * 1999-11-05 2001-05-10 University College London Activators of soluble guanylate cyclase

Family Cites Families (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4233409A (en) 1979-07-05 1980-11-11 Monsanto Company Polymeric blend
JP2799327B2 (en) 1987-12-14 1998-09-17 ザ ダウ ケミカル カンパニー ABS composition with trimodal rubber particle distribution
US5041498A (en) 1990-01-02 1991-08-20 The Dow Chemical Company Trimodal ABS compositions having good gloss and reduced gloss sensitivity
DE4404749A1 (en) 1994-02-15 1995-08-17 Bayer Ag ABS polymer compositions with a uniform matt surface
US6057322A (en) * 1995-01-30 2000-05-02 Hoechst Aktiengesellschaft Basically-substituted benzoylguanidines, a process for preparing them, their use as a medicament or diagnostic agent, and a medicament containing them
DE19507749A1 (en) 1995-03-06 1996-09-12 Bayer Ag Thermoplastic molding compounds of the ABS type
DE19518025A1 (en) 1995-05-17 1996-11-21 Bayer Ag Thermoplastic ABS molding compounds
SI0874830T1 (en) * 1995-12-08 2003-08-31 Agouron Pharmaceuticals, Inc. A metalloproteinase inhibitor, a pharmaceutical composition containing it and the pharmaceutical use and method useful for the preparation thereof
GB9602166D0 (en) * 1996-02-02 1996-04-03 Zeneca Ltd Aminoheterocyclic derivatives
US6262113B1 (en) * 1996-03-20 2001-07-17 Smithkline Beecham Corporation IL-8 receptor antagonists
DE19649249A1 (en) 1996-11-28 1998-06-04 Bayer Ag Improved thermoplastic molding compounds of the ABS type
US6284923B1 (en) * 1997-08-22 2001-09-04 Tularik Inc Substituted benzene compounds as antiproliferative and cholesterol lowering action
AU5473800A (en) 1999-06-11 2001-01-02 Merck & Co., Inc. Cyclopentyl modulators of chemokine receptor activity
AU5600100A (en) 1999-06-11 2001-01-02 Merck & Co., Inc. Cyclopentyl modulators of chemokine receptor activity
DE10008419A1 (en) 2000-02-23 2001-08-30 Bayer Ag ABS-type polymer composition for production of molded parts, e.g. casings, contains two graft copolymers based respectively on fine and coarse polybutadiene lattices obtained by seed polymerisation
DE10008420A1 (en) 2000-02-23 2001-08-30 Bayer Ag ABS-type polymer composition for production of molded parts, e.g. casings, contains at least two graft copolymers based respectively on fine and coarse polybutadiene lattices obtained by seed polymerization
JP2003081937A (en) 2001-09-07 2003-03-19 Bayer Ag Benzenesulfonamide derivative
DE10145773A1 (en) 2001-09-17 2003-04-03 Bayer Ag ABS compositions with improved combinations of properties
EP1997495B1 (en) 2003-03-24 2013-01-02 Axikin Pharmaceuticals, Inc. 2-phenoxy- and 2-phenylsulfanyl-benzenesulfonamide derivatives with CCR3 antagonistic activity for the treatment of asthma and other inflammatory or immunological disorders

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2275354A (en) * 1937-11-29 1942-03-03 May & Baker Ltd Preparation of new therapeutically useful heterocyclic compounds
US3819639A (en) * 1970-11-11 1974-06-25 Christiaens Sa A 2-metatrifluoromethylanilino-pyridine-5-n-acetyl sulfonamide
WO1999055324A1 (en) * 1998-04-27 1999-11-04 Smithkline Beecham Corporation Ccr-3 receptor antagonists
WO2000042003A1 (en) * 1999-01-13 2000-07-20 Warner-Lambert Company Benzenesulfonamide derivatives and their use as mek inhibitors
WO2001032604A1 (en) * 1999-11-05 2001-05-10 University College London Activators of soluble guanylate cyclase

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
"Ambinter Screening Collection", 31 May 2001, AMBINTER, PARIS F-75016, FRANCE *
"Chemokine CCR3 antagonists", EXPERT OPINION ON THERAPEUTIC PATENTS, vol. 10, no. 8, 2000, pages 1455 - 1459, XP002219852 *
DATABASE CHEMCATS Chemical abstracts service, Columbus, Ohio, US; XP002219853 *
DATABASE CROSSFIRE BEILSTEIN [online] Beilstein Institut zur Förderung der Chemischen Wissenschaften, Frankfurt am Main, DE; XP002219854, Database accession no. BRN 491793 *
DATABASE CROSSFIRE BEILSTEIN [online] Beilstein Institut zur Förderung der Chemischen Wissenschaften, Frankfurt am Main, DE; XP002219855, Database accession no. BRN 590986 *
DELARGE, ANN. PHARM. FR., vol. 31, 1973, pages 467 - 469 *
MASTRUKOVA ET AL, TETRAHEDRON, vol. 19, 1963, pages 357 - 368 *
SAARI ET AL.: "Synthesis and evaluation of some nitrobenzenesulfonamides containing nitroisopropyl and (ureidooxy)methyl groups as novel hypoxic cell selective cytotoxic agents.", J. MED. CHEM., vol. 34, no. 10, 1991, pages 3132 - 3138, XP000605240 *

Cited By (87)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7700586B2 (en) 2001-09-07 2010-04-20 Axikin Pharmaceuticals, Inc. Arylsulfonamide derivatives for use as ccr3 antagonists in the treatment of inflammatory and immunological disorders
US8242118B2 (en) 2001-09-07 2012-08-14 Axikin Pharmaceuticals Inc. Arylsulfonamide derivatives for use as CCR3 antagonists in the treatment of inflammatory and immunological disorders
US7482363B2 (en) 2002-03-19 2009-01-27 Astrazeneca Ab Piperidine derivatives useful as modulators of chemokine receptor activity
KR101110457B1 (en) * 2002-12-17 2012-02-17 아스트라제네카 아베 Novel compounds having selective inhibiting effect at gsk3
US7674797B2 (en) 2003-03-24 2010-03-09 Axikin Pharmaceuticals, Inc. 2-phenoxy- and 2-phenylsulfonamide derivatives with CCR3 antagonistic activity for the treatment of asthma and other inflammatory or immunological disorders
AU2011202499B2 (en) * 2003-03-24 2012-07-05 Axikin Pharmaceuticals, Inc. Benzenesulfonamide derivatives
WO2004084898A1 (en) * 2003-03-24 2004-10-07 Actimis Pharmaceuticals, Inc. 2-phenoxy- and 2-phenylsulfomamide derivatives with ccr3 antagonistic activity for the treatment of asthma and other inflammatory or immunological disorders
US9206186B2 (en) 2003-03-24 2015-12-08 Axikin Pharmaceuticals, Inc. 2-phenoxy- and 2-phenylsulfonamide derivatives with CCR3 antagonistic activity for the treatment of inflammatory or immunological disorders
AU2012238285B2 (en) * 2003-03-24 2015-07-02 Axikin Pharmaceuticals, Inc. Benzenesulfonamide derivatives
EP1997495A1 (en) * 2003-03-24 2008-12-03 Actimis Pharmaceuticals, Inc., 2-phenoxy- and 2-phenylsulfanyl-benzenesulfonamide derivatives with ccr3 antagonistic activity for the treatment of asthma and other inflammatory or immunological disorders
CN1802159B (en) * 2003-03-24 2013-04-24 阿克西金药品公司 2-phenoxy- and 2-phenylsulfomamide derivatives with CCR3 antagonistic activity for the treatment of asthma and other inflammatory or immunological disorders
KR101109296B1 (en) * 2003-03-24 2012-02-08 액시킨 파마수티컬스 인코포레이티드 2-phenoxy- and 2-phenylsulfomamide derivatives with ccr3 antagonistic activity for the treatment of asthma and other inflammatory or immunological disorders
JP2006523627A (en) * 2003-03-24 2006-10-19 アクチミス ファーマシューティカルズ インコーポレーテッド Benzenesulfonamide derivatives
US7495013B2 (en) 2003-04-01 2009-02-24 Astrazeneca Ab Chemical compounds
US9000174B2 (en) 2004-10-14 2015-04-07 Purdue Pharma L.P. 4-phenylsulfonamidopiperidines as calcium channel blockers
US8314127B2 (en) 2005-07-21 2012-11-20 Astrazeneca Ab Piperidine derivatives
US8247442B2 (en) 2006-03-29 2012-08-21 Purdue Pharma L.P. Benzenesulfonamide compounds and their use
US8791264B2 (en) 2006-04-13 2014-07-29 Purdue Pharma L.P. Benzenesulfonamide compounds and their use as blockers of calcium channels
US8937181B2 (en) 2006-04-13 2015-01-20 Purdue Pharma L.P. Benzenesulfonamide compounds and the use thereof
US7632829B2 (en) 2006-04-20 2009-12-15 Hoffmann-La Roche Inc. Diazepan derivatives
US8399486B2 (en) 2007-04-09 2013-03-19 Purdue Pharma L.P. Benzenesulfonyl compounds and the use thereof
US8765736B2 (en) 2007-09-28 2014-07-01 Purdue Pharma L.P. Benzenesulfonamide compounds and the use thereof
US8541588B2 (en) 2009-01-12 2013-09-24 Pfizer Limited Sulfonamide derivatives
TWI494317B (en) * 2009-01-12 2015-08-01 Icagen Inc Sulfonamide derivatives
US8907101B2 (en) 2009-01-12 2014-12-09 Pfizer Limited Sulfonamide derivatives
TWI419897B (en) * 2009-01-12 2013-12-21 Icagen Inc Sulfonamide derivatives
US9657004B2 (en) 2009-04-06 2017-05-23 Agios Pharmaceuticals, Inc Pyruvate kinase M2 modulators, therapeutic compositions and related methods of use
US9938259B2 (en) 2009-04-06 2018-04-10 Agios Pharmaceuticals, Inc. Therapeutic compositions and related methods of use
US8742119B2 (en) 2009-04-06 2014-06-03 Agios Pharmaceuticals, Inc. Pyruvate kinase M2 modulators, therapeutic compositions and related methods of use
WO2010123956A3 (en) * 2009-04-22 2011-09-09 Axikin Pharmaceuticals, Inc. 2,5-disubstituted arylsulfonamide ccr3 antagonists
EP2727908A3 (en) * 2009-04-22 2014-08-20 Axikin Pharmaceuticals, Inc. 2,5-disubstituted arylsulfonamide CCR3 antagonists
CN102459177B (en) * 2009-04-22 2015-09-02 埃克希金医药品有限公司 The dibasic Arylsulfonamide ccr 3 antagonists of 2,5-
EP2502921A1 (en) * 2009-04-22 2012-09-26 Axikin Pharmaceuticals, Inc. Arylsulfonamide CCR3 antagonists
US8420639B2 (en) 2009-04-22 2013-04-16 Axikin Pharmaceuticals, Inc. Arylsulfonamide CCR3 antagonists
US8563544B2 (en) 2009-04-22 2013-10-22 Axikin Pharmaceuticals, Inc. 2,5-disubstituted arylsulfonamide CCR3 antagonists
US8399456B2 (en) 2009-04-22 2013-03-19 Axikin Pharmaceuticals, Inc. 2,5-disubstituted arylsulfonamide CCR3 antagonists
US8658642B2 (en) 2009-04-22 2014-02-25 Axikin Pharmaceuticals, Inc. Arylsulfonamide CCR3 antagonists
US8669247B2 (en) 2009-04-22 2014-03-11 Axikin Pharmaceuticals, Inc. 2,5-disubstituted arylsulfonamide CCR3 antagonists
AU2010239337B2 (en) * 2009-04-22 2015-07-16 Axikin Pharmaceuticals, Inc. 2,5-disubstituted arylsulfonamide CCR3 antagonists
CN102459177A (en) * 2009-04-22 2012-05-16 埃克希金医药品有限公司 2,5-disubstituted arylsulfonamide ccr3 antagonists
AU2010239340B2 (en) * 2009-04-22 2015-07-02 Axikin Pharmaceuticals, Inc. 2,5-disubstituted arylsulfonamide CCR3 antagonists
US8318747B2 (en) 2009-04-22 2012-11-27 Axikin Pharmaceuticals, Inc. 2,5-disubstituted arylsulfonamide CCR3 antagonists
AU2010239341B2 (en) * 2009-04-22 2015-07-02 Axikin Pharmaceuticals, Inc. Arylsulfonamide CCR3 antagonists
CN102459210B (en) * 2009-04-22 2015-09-02 埃克希金医药品有限公司 Arylsulfonamide ccr 3 antagonists
CN102459210A (en) * 2009-04-22 2012-05-16 埃克希金医药品有限公司 Arylsulfonamide ccr3 antagonists
RU2532515C2 (en) * 2009-04-22 2014-11-10 Аксикин Фармасьютикалз, Инк. 2,5-disubstituted arylsulphonamide ccr3 antagonists
WO2010123959A3 (en) * 2009-04-22 2011-02-17 Axikin Pharmaceuticals, Inc. 2,5-disubstituted arylsulfonamide ccr3 antagonists
CN104177313A (en) * 2009-04-22 2014-12-03 埃克希金医药品有限公司 2,5-disubstituted arylsulfonamide ccr3 antagonists
CN102459178A (en) * 2009-04-22 2012-05-16 埃克希金医药品有限公司 2,5-disubstituted arylsulfonamide ccr3 antagonists
US9187425B2 (en) 2009-04-22 2015-11-17 Axikin Pharmaceuticals, Inc. 2,5-disubstituted arylsulfonamide CCR3 antagonists
TWI473793B (en) * 2009-04-22 2015-02-21 Axikin Pharmaceuticals Inc Arylsulfonamide ccr3 antagonists
WO2010123960A3 (en) * 2009-04-22 2011-09-09 Axikin Pharmaceuticals, Inc. Arylsulfonamide ccr3 antagonists
US9115086B2 (en) 2009-06-29 2015-08-25 Agios Pharmaceuticals, Inc. Therapeutic compositions and related methods of use
EP2448581A1 (en) * 2009-06-29 2012-05-09 Agios Pharmaceuticals, Inc. Therapeutic compositions and related methods of use
EP2448581B1 (en) * 2009-06-29 2016-12-07 Agios Pharmaceuticals, Inc. Therapeutic compositions and related methods of use
US8785450B2 (en) 2009-06-29 2014-07-22 Agios Pharmaceuticals, Inc. Therapeutic compounds and compositions
US11866411B2 (en) 2009-06-29 2024-01-09 Agios Pharmaceutical, Inc. Therapeutic compounds and compositions
US10029987B2 (en) 2009-06-29 2018-07-24 Agios Pharmaceuticals, Inc. Therapeutic compounds and compositions
US10988448B2 (en) 2009-06-29 2021-04-27 Agios Pharmaceuticals, Inc. Therapeutic compounds and compositions
USRE49582E1 (en) 2009-06-29 2023-07-18 Agios Pharmaceuticals, Inc. Therapeutic compounds and compositions
AU2011223873B2 (en) * 2010-03-02 2015-06-25 Axikin Pharmaceuticals, Inc. Isotopically enriched arylsulfonamide CCR3 antagonists
WO2011109345A1 (en) 2010-03-02 2011-09-09 Axikin Pharmaceuticals, Inc. Isotopically enriched arylsulfonamide ccr3 antagonists
US8999995B2 (en) 2010-03-02 2015-04-07 Axikin Pharmaceuticals, Inc. Isotopically enriched arylsulfonamide CCR3 antagonists
JP2013522316A (en) * 2010-03-17 2013-06-13 アクシキン ファーマシューティカルズ インコーポレーテッド Arylsulfonamide CCR3 antagonist
CN102892754A (en) * 2010-03-17 2013-01-23 埃克希金医药品有限公司 Arylsulfonamide ccr3 antagonists
US8741894B2 (en) 2010-03-17 2014-06-03 Axikin Pharmaceuticals, Inc. Arylsulfonamide CCR3 antagonists
WO2011116161A3 (en) * 2010-03-17 2012-04-19 Axikin Pharmaceuticals Inc. Arylsulfonamide ccr3 antagonists
US9096558B2 (en) 2010-07-09 2015-08-04 Pfizer Limited N-sulfonylbenzamide compounds
US9145407B2 (en) 2010-07-09 2015-09-29 Pfizer Limited Sulfonamide compounds
CN103298786B (en) * 2010-10-11 2016-01-20 埃克希金医药品有限公司 Arylsulfonyl amine salt CCR3 antagonist
CN103298786A (en) * 2010-10-11 2013-09-11 埃克希金医药品有限公司 Salts of arylsulfonamide ccr3 antagonists
US20120088769A1 (en) * 2010-10-11 2012-04-12 Axikin Pharmaceuticals, Inc. Salts of arylsulfonamide ccr3 antagonists
AU2011313906B2 (en) * 2010-10-11 2015-08-13 Axikin Pharmaceuticals, Inc. Salts of arylsulfonamide CCR3 antagonists
US9221792B2 (en) 2010-12-17 2015-12-29 Agios Pharmaceuticals, Inc N-(4-(azetidine-1-carbonyl) phenyl)-(hetero-) arylsulfonamide derivatives as pyruvate kinase M2 (PMK2) modulators
US9328077B2 (en) 2010-12-21 2016-05-03 Agios Pharmaceuticals, Inc Bicyclic PKM2 activators
US10087169B2 (en) 2010-12-21 2018-10-02 Agios Pharmaceuticals, Inc. Bicyclic PKM2 activators
US8889667B2 (en) 2010-12-29 2014-11-18 Agios Pharmaceuticals, Inc Therapeutic compounds and compositions
US9199968B2 (en) 2010-12-29 2015-12-01 Agios Pharmaceuticals, Inc. Therapeutic compounds and compositions
US11793806B2 (en) 2011-05-03 2023-10-24 Agios Pharmaceuticals, Inc. Pyruvate kinase activators for use in therapy
US9181231B2 (en) 2011-05-03 2015-11-10 Agios Pharmaceuticals, Inc Pyruvate kinase activators for use for increasing lifetime of the red blood cells and treating anemia
US9980961B2 (en) 2011-05-03 2018-05-29 Agios Pharmaceuticals, Inc. Pyruvate kinase activators for use in therapy
US10632114B2 (en) 2011-05-03 2020-04-28 Agios Pharmaceuticals, Inc. Pyruvate kinase activators for use in therapy
WO2014039748A1 (en) 2012-09-07 2014-03-13 Axikin Pharmaceuticals, Inc. Isotopically enriched arylsulfonamide ccr3 antagonists
US9637460B2 (en) 2012-09-07 2017-05-02 Axikin Pharmaceuticals, Inc. Isotopically enriched arylsulfonamide CCR3 antagonists
US9156799B2 (en) 2012-09-07 2015-10-13 Axikin Pharmaceuticals, Inc. Isotopically enriched arylsulfonamide CCR3 antagonists
US9365545B2 (en) 2013-03-15 2016-06-14 Agios Pharmaceuticals, Inc Therapeutic compounds and compositions
US11234976B2 (en) 2015-06-11 2022-02-01 Agios Pharmaceuticals, Inc. Methods of using pyruvate kinase activators

Also Published As

Publication number Publication date
MY133303A (en) 2007-11-30
US8242118B2 (en) 2012-08-14
JP2005519024A (en) 2005-06-30
GT200200178A (en) 2003-05-23
JP2003081937A (en) 2003-03-19
SV2004001225A (en) 2004-02-24
TWI262187B (en) 2006-09-21
JP4517047B2 (en) 2010-08-04
ES2354378T3 (en) 2011-03-14
CA2459432C (en) 2009-05-26
US20050070582A1 (en) 2005-03-31
DE60238149D1 (en) 2010-12-09
HK1109867A1 (en) 2008-06-27
EP1849469A1 (en) 2007-10-31
DE60221569T2 (en) 2008-04-30
ES2294167T3 (en) 2008-04-01
HN2002000247A (en) 2003-11-24
EP1461038A1 (en) 2004-09-29
PE20030440A1 (en) 2003-06-26
EP1461038B1 (en) 2007-08-01
AR037235A1 (en) 2004-11-03
DE60221569D1 (en) 2007-09-13
EP1461038B9 (en) 2009-09-23
CA2459432A1 (en) 2003-03-20
EP1849469B1 (en) 2010-10-27
US7700586B2 (en) 2010-04-20
US20100204213A1 (en) 2010-08-12

Similar Documents

Publication Publication Date Title
US8242118B2 (en) Arylsulfonamide derivatives for use as CCR3 antagonists in the treatment of inflammatory and immunological disorders
US7674797B2 (en) 2-phenoxy- and 2-phenylsulfonamide derivatives with CCR3 antagonistic activity for the treatment of asthma and other inflammatory or immunological disorders
WO2006027680A1 (en) 3-(1-carbamoylcyclohexyl) propionic acid derivatives as inhibitors of neutral endopeptidase enzyme
EP1268396B1 (en) Diphenyl ether compounds useful in therapy
US20020052395A1 (en) Diphenyl ether compounds useful in therapy
NO178259B (en) Amidino Compounds, Pharmaceutical Preparations Containing Them, and Their Use in the Preparation of Pharmaceutical Preparations
JP5297386B2 (en) 5-Alkyloxy-indoline-2-one derivatives, their preparation and their application in therapy as selective ligands of the V2 vasopressin receptor
AU2012238285B2 (en) Benzenesulfonamide derivatives

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BY BZ CA CH CN CO CR CU CZ DE DM DZ EC EE ES FI GB GD GE GH HR HU ID IL IN IS JP KE KG KP KR LC LK LR LS LT LU LV MA MD MG MN MW MX MZ NO NZ OM PH PL PT RU SD SE SG SI SK SL TJ TM TN TR TZ UA UG US UZ VC VN YU ZA ZM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ UG ZM ZW AM AZ BY KG KZ RU TJ TM AT BE BG CH CY CZ DK EE ES FI FR GB GR IE IT LU MC PT SE SK TR BF BJ CF CG CI GA GN GQ GW ML MR NE SN TD TG AE AG AL AM AT AZ BA BB BG BR BY BZ CA CH CN CO CR CZ DE DK DM DZ EC EE ES FI GB GD GE GM HR HU ID IL IN IS JP KE KG KP KR KZ LK LR LS LT LU LV MA MD MG MK MN MX MZ NO NZ OM PH PL PT RO RU SD SE SI SK SL TJ TM TN TR TT TZ UA UG UZ VC YU ZA ZM ZW GH GM KE LS MW MZ SL SZ TZ UG ZM ZW

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 2002772265

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2459432

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2003526406

Country of ref document: JP

WWP Wipo information: published in national office

Ref document number: 2002772265

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 10489029

Country of ref document: US

WWG Wipo information: grant in national office

Ref document number: 2002772265

Country of ref document: EP