CN1129576C - 用作环氧酶－2抑制剂的苯基杂环化合物 - Google Patents

用作环氧酶－2抑制剂的苯基杂环化合物 Download PDF

Info

Publication number
CN1129576C
CN1129576C CN00100981A CN00100981A CN1129576C CN 1129576 C CN1129576 C CN 1129576C CN 00100981 A CN00100981 A CN 00100981A CN 00100981 A CN00100981 A CN 00100981A CN 1129576 C CN1129576 C CN 1129576C
Authority
CN
China
Prior art keywords
phenyl
methylsulfonyl
compound
alkyl
fluorophenyl
Prior art date
Legal status (The legal status 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 status listed.)
Expired - Fee Related
Application number
CN00100981A
Other languages
English (en)
Other versions
CN1295065A (zh
Inventor
Y·杜查米
J·Y·高蒂埃
P·普拉西
Y·勒布朗
Z·-Y·王
S·利格
M·特里恩
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mike Frost Co
Original Assignee
Merck Frosst Canada Ltd
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
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=26767192&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=CN1129576(C) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Merck Frosst Canada Ltd filed Critical Merck Frosst Canada Ltd
Publication of CN1295065A publication Critical patent/CN1295065A/zh
Application granted granted Critical
Publication of CN1129576C publication Critical patent/CN1129576C/zh
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • 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
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • 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
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • 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
    • 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
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/46—Y being a hydrogen or a carbon atom
    • 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
    • C07C311/48—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 having nitrogen atoms of sulfonamide groups further bound to another hetero atom
    • C07C311/49—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 having nitrogen atoms of sulfonamide groups further bound to another hetero atom to nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/24—Sulfones; Sulfoxides having sulfone or sulfoxide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/26—Radicals substituted by 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
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon 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
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/58—One oxygen atom, e.g. butenolide
    • 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
    • C07D333/06—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/18—Radicals substituted by singly bound hetero atoms other than halogen by sulfur atoms
    • 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Virology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pulmonology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Communicable Diseases (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Oncology (AREA)
  • Biomedical Technology (AREA)
  • Rheumatology (AREA)
  • Endocrinology (AREA)
  • Dermatology (AREA)
  • Pain & Pain Management (AREA)
  • Hospice & Palliative Care (AREA)
  • Hematology (AREA)
  • Reproductive Health (AREA)
  • Immunology (AREA)
  • Diabetes (AREA)
  • Molecular Biology (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Furan Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

本发明公开了式A化合物，其中R1选自：(a)S(O)2CH3，(b)S(O)2NH2，R2选自一或二取代的苯基，其中取代基选自：(1)氢，(2)卤素，(3)C1-4烷氧基，(4)C1-4烷硫基，(5)CN，(6)CF3，(7)C1-4烷基，(8)N3，和(9)-C(R5)(R6)-OH；R5和R6各自独立地选自：(a)氢，(b)甲基或乙基，或R5和R6与它们所连的碳原子一起形成4、5或6个原子的饱和碳环。

Description

用作环氧酶-2抑制剂的苯基杂环化合物
本申请是申请号为94192580.3、申请日为1994年6月9日、发明名称为“用作环氧酶-2抑制剂的苯基杂环化合物”的发明专利申请的分案申请。
本发明涉及用于治疗环氧酶介导的疾病的化合物和药物组合物及其治疗方法。
非甾类消炎药物通过抑制前列腺素G/H合成酶(也称为环氧酶)来发挥其大部分消炎、止痛和退热活性并抑制激素诱导的子宫收缩以及某些类型的癌生长。直到最近，仅有一种形式的环氧酶(它对应于环氧酶-1或组成酶)被描述为最初在牛精囊中发现。最近，第二种可诱导形式的环氧酶(环氧酶-2)的基因从鸡、鼠和人源中被克隆、定序和特征化。这种酶不同于已从羊、鼠和人源中被克隆、定序和特征化的环氧酶-1。第二种形式的环氧酶即环氧酶-2迅速而容易地被各种药剂包括有丝分裂原、内毒素、激素、细胞因子和生长因子诱导。因为前列腺素具有生理和病理作用，因此可推断出组成酶即环氧酶-1在很大程度上决定前列腺素的内源性基本释放，所以其生理功能如保持胃肠完整和肾血流动非常重要。相反，可推断出诱导形式的环氧酶-2主要决定前列腺素的病理作用，其中应答于这些药剂如发炎药、激素、生长因子和细胞因子发生酶的迅速诱导，因此，环氧酶-2的选择性抑制剂具有类似于常规非甾类消炎药的消炎、退热和止痛活性，另外，它能抑制激素诱导的子宫收缩和具有有效的抗癌作用，但其诱导某些机理基副作用的能力变小。特别是，这些化合物具有减小的胃肠毒性、减小的肾副作用、减少出血次数的作用和可能减少的诱导阿司匹林敏感的哮喘受治疗者哮喘发作的能力。
                    本发明的概述
本发明涉及用于治疗环氧酶-2介导的疾病的新的式I化合物：
本发明还涉及用于治疗环氧酶-2介导的疾病的某些药物组合物和方法，包括使用式I化合物。
                  本发明的详细描述
本发明涉及用于治疗环氧酶-2介导的疾病的新的式I化合物或其可药用盐：其中：当b边为双键，a边和c边为单键时，X-Y-Z-选自：           (a)-CH2CH2CH2-，
           (b)-C(O)CH2CH2-，
           (c)-CH2CH2C(O)-，
           (d)-CR5(R5′)-O-C(O)-，
           (e)-C(O)-O-CR5(R5′)-，
           (f)-CH2-NR3-CH2-，
           (g)-CR5(R5′)-NR3-C(O)-，
           (h)-CR4＝CR4′-S-，
           (i)-S-CR4＝CR4′-，
           (j)-S-N＝CH-，
           (k)-CH＝N-S-，
           (l)-N＝CR4-O-，
           (m)-O-CR4＝N-
           (n)-N＝CR4-NH-；
           (o)-N＝CR4-S-，
           (p)-S-CR4＝N-，
           (q)-C(O)-NR3-CR5(R5′)-；
           (r)-R3N-CH＝CH-，其条件是R1不是-S(O)2Me
           (s)-CH＝CH-NR3-，其条件是R1不是-S(O)2Me以及当a边和c边为双键，b边为单键时，X-Y-Z-选自：
           (a)＝CH-O-CH＝，
           (b)＝CH-NR3-CH＝，
           (c)＝N-S-CH＝，
           (d)＝CH-S-N＝，
           (e)＝N-O-CH＝，
           (e)＝CH-O-N＝，
           (g)＝N-S-N＝，
           (h)＝N-O-N＝；R1选自：
    (a)S(O)2CH3，
    (b)S(O)2NH2，
    (c)S(O)2HC(O)CF3，
    (d)S(O)(NH)CH3，
    (e)S(O)(NH)NH2，
    (f)S(O)(NH)NHC(O)CF3，
    (g)P(O)(CH3)OH，和
    (h)P(O)(CH3)NH2；R1选自：
(a)C1-C6烷基，
(b)C3、C4、C5、C6和C7环烷基，
(c)一、二或三取代的苯基或萘基，其中取代基选自：
    (1)氢，
    (2)卤素，
    (3)C1-6烷氧基，
    (4)C1-6烷硫基，
    (5)CN，
    (6)CF3，
    (7)C1-6烷基，
    (8)N3，
    (9)-CO2H，
    (10)-CO2-C1-4烷基，
    (11)-C(R5)(R6)-OH，
    (12)-C(R5)(R6)-O-C1-4烷基，以及
    (13)-C1-6烷基-CO2-R5；
(d)一、二或三取代的杂芳基，其中杂芳基为五个原子的单环芳环基，所述环具有一个为S、O或N的杂原子，并任选具有1、2或3个另外的N原子；或杂芳基为六个原子的单环基，所述环具有一个为N的杂原子，并任选具有1、2、3或4个另外的N原子；所述取代基选自：
    (1)氢，
    (2)卤素，包括氟、氯、溴和碘，
    (3)C1-6烷基，
    (4)C1-6烷氧基，
    (5)C1-6烷硫基，
    (6)CN，
    (7)CF3，
    (8)N3
    (9)-C(R5)(R6)-OH，以及
    (10)-C(R5)(R6)-O-C1-4烷基；
(e)苯并杂芳基，包括(d)的苯并稠和的类似基团；R3选自：
(a)氢，
(b)CF3，
(c)CN，
(d)C1-6烷基，
(e)羟基C1-6烷基，
(f)-C(O)-C1-6烷基，
(g)任选取代的
    (1)-C1-5烷基-Q，
    (2)-C1-3烷基-O-C1-3烷基-Q，
    (3)-C1-3烷基-S-C1-3烷基-Q，
    (4)-C1-5烷基-O-Q，或
    (5)-C1-5烷基-S-Q，
    其中取代基位于烷基上并且取代基为C1-3烷基；
(h) -Q；R4和R4′各自独立地选自：
(a)氢，
(b)CF3，
(c)CN，
(d)C1-6烷基，
(e)-Q，
(f)-O-Q；
(g)-S-Q，以及
(h)任选取代的
    (1)-C1-5烷基-Q，
    (2)-O-C1-5烷基-Q，
    (3)-S-C1-5烷基-Q，
    (4)-C1-3烷基-O-C1-3烷基-Q，
    (5)-C1-3烷基-S-C1-3烷基-Q，
    (6)-C1-5烷基-O-Q，
    (7)-C1-5烷基-S-Q，
其中取代基位于烷基上并且取代基为C1-3烷基；R5、R5′、R6、R7和R8各自独立地选自：
(a)氢，
(b)C1-6烷基，或R5和R6或R7和R8与它们所连的碳原子一起形成3、4、5、6或7个原子的饱和单环碳环；Q为CO2H、CO2-C1-4烷基、四唑基-5-基、C(R7)(R8)OH或C(R7)(R8)(O-C1-4烷基)；条件是当X-Y-Z为-S-CR4＝CR4′时，R4和R4′不为CF3。
一方面，在具体实施方案中，化合物为式I化合物或其可药用盐：
Figure C0010098100101
其中：当b边为双键，a边和c边为单键时，X-Y-Z-选自-C(O)-O-CR5(R5′)-，R1选自：
(a)S(O)2CH3，
(b)S(O)2NH2；R2选自：
(a)C1-C6烷基，
(b)C3、C4、C5、C6和C7环烷基，
(c)杂芳基，
(d)苯并杂芳基，
(e)一或二取代的苯基，其中取代基选自：
    (1)氢，
    (2)卤素，
    (3)C1-6烷氧基，
    (4)C1-6烷硫基，
    (5)CN，
    (6)CF3，
    (7)C1-6烷基，
    (8)N3，
    (9)-CO2H，
    (10)-CO2-C1-4烷基，
    (11)-C(R5)(R6)-OH，
    (12)-C(R5)(R6)-O-C1-4烷基，以及
    (13)-C1-6烷基-CO2-R5；R5、R5′和R6各自独立地选自：
(a)氢，
(b)C1-6烷基，或R5和R6与它们所连的碳原子一起形成3、4、5、6或7个原子的饱和单环碳环；
在上述具体实施方案中有一类式I化合物，其中：X-Y-Z-选自：
    (a)-CH2CH2CH2-，
    (b)-C(O)CH2CH2-，
    (c)-CH2CH2C(O)-，
    (d)-CR5(R5′)-O-C(O)-，
    (e)-C(O)-O-CR5(R5′)-，
    (f)-CH2-NR3-CH2-，
    (g)-CR5(R5′)-NR3-C(O)-，
    (h)-CR4＝CR4′-S-，
    (i)-S-CR4＝CR4′-，
    (j)-S-N＝CH-，
    (k)-CH＝N-S-，
    (l)-N＝CR4-O-，
    (m)-O-CR4＝N-
    (n)-N-CR4-NH-，
    (o)-N＝CR4-S-，
    (p)-S-CR4＝N-，
    (q)-C(O)-NR3-CR5(R5′)-，
    (r)-NR3-CH＝CH-，其条件是R1不是S(O)2Me，
    (s)-CH＝CH-NR3-，其条件是R1不是-S(O)2Me.
在该类化合物中，式I化合物的亚类如下所述，其中：R1选自：
    (a)S(O)2CH3，
    (b)S(O)2NH2，
    (c)S(O)2NHC(O)CF3，
    (d)S(O)NHCH3，
    (e)S(O)NHNH2，和
    (f)S(O)NHNHC(O)CF3；R2选自：
(a)C1-C4烷基，
(b)C3、C4、C5、C6和C7环烷基，
(c)一或二取代的苯基，其中取代基选自：
    (1)氢，
    (2)氟、氯和溴，
(3)C1-4烷氧基，
(4)C1-4烷硫基，
(5)CN，
(6)CF3，
(7)C1-4烷基，
(8)N3，
(9)-CO2H，
(10)-CO2-C1-3烷基，
(11)-C(R5)(R6)-OH-，以及
(12)-C(R5)(R6)-O-C1-3烷基，(d)一或二取代的杂芳基，选自：
(1)呋喃基，
(2)二嗪基、三嗪基和四嗪基，
(3)咪唑基，
(4)异噁唑基，
(5)异噻唑基，
(6)噁二唑基，
(7)噁唑基，
(8)吡唑基，
(9)吡咯基，
(10)噻二唑基，
(11)噻唑基，
(12)噻吩基，
(13)三唑基，以及
(14)四唑基，其中所述取代基选自：
(a)氢，
    (b)氯、氯和溴，
    (c)C1-4烷氧基，
    (d)C1-4烷硫基，
    (e)CN，
    (5)CF3，
    (6)C1-4烷基，
    (7)N3，
    (8)-C(R5)(R6)-OH，
    (9)-C(R5)(R6)-O-C1-4烷基。
在上述亚类中有一类式I化合物，其中：R2选自：
(a)环己基，
(b)一或二取代的苯基，其中取代基选自：
    (1)氢，
    (2)卤素，
    (3)C1-4烷氧基，
    (4)C1-4烷硫基，
    (5)CN，
    (6)CF3，
    (7)C1-4烷基，
    (8)N3，和
    (9)-C(R5)(R6)-OH；R3选自：
(a)氢，
(b)CF3，
(c)C1-3烷基和羟基C1-3烷基，
(d)CN；R4和R4′各自独立地选自：
(a)氢，
(b)CF3，
(c)C1-3烷基，
(d)CN，
(e)氯和氟；R5、R5′、R6各自独立地选自：
(a)氢，
(b)甲基或乙基，或R5和R6与它们所连的碳原子一起形成4、5或6个原子的饱和碳环。
在上述一类化合物中有一小类式I化合物，其中：X-Y-Z-选自：
    (a)-CH2-O-C(O)-，
    (b)-C(O)-O-CH2-，和
    (c)-CH2-NR3-C(O)-；R1选自：
    (a)S(O)2CH3，
    (b)S(O)2NH2，
    (c)S(O)NHCH3，和
    (d)S(O)NHNH2；R2选自一或二取代的苯基，其中取代基选自：
    (1)氢，
    (2)卤素，选自氟、氯和溴，
    (3)C1-3烷氧基，
    (4)C1-3烷硫基，
    (5)CN，和
    (6)C1-3烷基；R3选自：
(a)氢，
(b)CF3，
(c)C1-3烷基和羟基C1-3烷基。
在上述小类中有一组式I化合物，其中：X-Y-Z-选自：
    (a)-CH2-O-C(O)-，和
    (b)-C(O)-O-CH2-；R1选自：
    (a)S(O)2CH3，
    (b)S(O)2NH2，
    (c)S(O)NHCH3，和
    (d)S(O)NHNH2；R2为一或二取代的苯基，其中取代基选自：
    (1)氢，
    (2)卤素，选自氟、氯和溴，
    (3)甲氧基，和
    (4)甲基。
这组化合物中可更具体地限定为下述的式I化合物，其中：X-Y-Z-选自：
      (a)-CH2-O-C(O)-，和
      (b)-C(O)-O-CH2-；R1选自：
      (a)S(O)2CH3，和
      (b)S(O)2NH2；R2为一或二取代的苯基，其中取代基选自：
    (1)氢，
    (2)卤素，选自氟、氯和溴。
在上述亚类中有一类式I化合物，其中：R2为一或二取代的杂芳基，其中杂芳基选自：
    (1)呋喃基，
    (2)二嗪基、三嗪基、四嗪基，
    (3)咪唑基，
    (4)异噁唑基，
    (5)异噻唑基，
    (6)噁二唑基，
    (7)噁唑基，
    (8)吡唑基，
    (9)吡咯基，
    (10)噻二唑基，
    (11)噻唑基，
    (12)噻吩基，
    (13)三唑基，以及
    (14)四唑基，
其中所述取代基选自：
        (a)氢，
        (b)氟或氯，
        (c)C1-3烷氧基，
        (d)C1-6烷硫基，
        (e)CN，
        (5)CF3，
        (6)C1-3烷基，
        (7)-C(R5)(R6)-OH，以及
        (8)-C(R5)(R6)-O-C1-4烷基。
在此类化合物中有一小类式I化合物，其中：R2为一或二取代的杂芳基，其中杂芳基选自：
    (1)2-呋喃基，
    (2)3-呋喃基，
    (3)2-噻吩基，
    (4)3-噻吩基，
    (5)3-异噁唑基，
    (6)4-异噁唑基，
    (7)5-异噁唑基，
    (8)3-异噻唑基，
    (9)4-异噻唑基，
    (10)5-异噻唑基，
    (11)2-噁唑基，(12)4-噁唑基，(13)5-噁唑基，(14)2-噻唑基，(15)4-噻唑基，(16)5-噻唑基，(17)1，2，3-噻二唑-4-基，(18)1，2，3-噻二唑-5-基，(19)1，2，4-噻二唑-3-基，(20)1，2，4-噻二唑-5-基，(21)1，3，4-噻二唑-2-基，(22)1，2，5-噻二唑-3-基，(23)1，2，3-噁二唑-4-基，(24)1，2，3-噁二唑-5-基，(25)1，2，4-噁二唑-3-基，(26)1，2，4-噁二唑-5-基，(27)1，3，4-噁二唑-2-基，(28)1，2，5-噁二唑-3-基，(29)吡唑-4-基，(30)吡唑-5-基，(31)1，2，3-triadiazol-4-基，(32)1，2，3-triadiazol-5-基，(33)1，2，4-triadiazol-3-基，(34)1，2，4-triadiazol-5-基，(35)1，2-二嗪基，(36)1，3-二嗪基，(37)1，4-二嗪基，(38)1，2，3，4-四嗪-5-基，
(39)1，2，4，5-四嗪-4-基，
(40)1，3，4，5-四嗪-2-基，和
(41)1，2，3，5-四嗪-4-基。在此小类中有一组式I化合物，其中杂芳基选自：
(1)3-异噁唑基，
(2)4-异噁唑基，
(3)5-异噁唑基，
(4)3-异噻唑基，
(5)4-异噻唑基，
(6)5-异噻唑基，
(7)2-噁唑基，
(8)4-噁唑基，
(9)5-噁唑基，
(10)2-噻唑基，
(11)4-噻唑基，
(12)5-噻唑基，
(13)1，2，3-噻二唑-4-基，
(14)1，2，3-噻二唑-5-基，
(15)1，2，4-噻二唑-3-基，
(16)1，2，4-噻二唑-5-基，
(17)1，3，4-噻二唑-2-基，
(18)1，2，5-噻二唑-3-基，
(19)1，2，3-噁二唑-4-基，
(20)1，2，3-噁二唑-5-基，
(21)1，2，4-噁二唑-3-基，
(22)1，2，4-噁二唑-5-基，
(23)1，3，4-噁二唑-2-基，
(24)1，2，5-噁二唑-3-基，
(25)1，2-二嗪基，
(26)1，3-二嗪基，和
(27)1，4-二嗪基。这些杂芳基可被更具体地限定为选自：
(1)3-异噻唑基，
(2)4-异噻唑基，
(3)5-异噻唑基，
(4)2-噁唑基，
(5)4-噁唑基，
(6)5-噁唑基，
(7)2-噻唑基，
(8)4-噻唑基，
(9)5-噻唑基，
(10)1，2-二嗪基，
(11)1，3-二嗪基，和
(12)1，4-二嗪基，其中取代基选自：
(1)氢，
(2)氟或氯，
(3)C1-3烷氧基，
(4)C1-3烷硫基，
(5)CN，
(6)C1-3烷基，和
(7)-C(R5)(R6)-OH，
其中R5和R6各自独立地选自氢、甲基或乙基。
这些杂芳基可被进一步具体定义，给定这些更具体定义的杂芳基，式I化合物包括下述一组化合物，其中：X-Y-Z-选自：
    (a)-CH2-O-C(O)-，
    (b)-C(O)-O-CH2-，和
    (c)-CH2-NR3-C(O)-；R1选自：
    (a)S(O)2CH3，
    (b)S(O)2NH2，
    (c)S(O)NHCH3，和
    (d)S(O)NHNH2；R3选自：
(a)氢，
(b)CF3，
(c)C1-3烷基和羟基C1-3烷基。
(d)CN。
在上述具体实施方案中的第二类化合物为下述式I化合物，其中：X-Y-Z-选自：
    (a)＝CH-O-CH＝，
    (b)＝CH-NR3-CH＝，
    (c)＝N-S-CH＝，
    (d)＝CH-S-N＝，
       (e)＝N-O-CH＝，
       (f)＝CH-O-N＝，
       (g)＝N-S-N＝，
       (h)＝N-O-N＝.
在此类化合物中，式I化合物的亚类如下所述，其中：R1选自：
    (a)S(O)2CH3，
    (b)S(O)2NH2，
    (c)S(O)2NHC(O)CF3，
    (d)S(O)(NH)CH3，
    (e)S(O)(NH)NH2，和
    (f)S(O)(NH)NHC(O)CF3；R2选自：
(a)C1-C4烷基，
(b)C3、C4、C5、C6和C7环烷基，
(c)一或二取代的苯基，其中取代基选自：
    (1)氢，
    (2)氟、氯和溴，
    (3)C1-4烷氧基，
    (4)C1-4烷硫基，
    (5)CN，
    (6)CF3，
    (7)C1-4烷基，
    (8)N3，
    (9)-CO2H，
    (10)-CO2-C1-3烷基，
(11)-C(R5)(R6)-OH，和
(12)-C(R5)(R6)-O-C1-3烷基，(d)一或二取代的杂芳基，选自：
(1)呋喃基，
(2)二嗪基、三嗪基和四嗪基，
(3)咪唑基，
(4)异噁唑基，
(5)异噻唑基，
(6)噁二唑基，
(7)噁唑基，
(8)吡唑基，
(9)吡咯基，
(10)噻二唑基，
(11)噻唑基，
(12)噻吩基，
(13)三唑基，和
(14)四唑基，其中所述取代基选自：
(a)氢，
(b)氟、氯、溴，
(c)C1-4烷氧基，
(d)C1-4烷硫基，
(e)CN，
(5)CF3，
(6)C1-4烷基，
(7)N3，
(8)-C(R5)(R6)-OH，和
        (9)-C(R5)(R6)-O-C1-4烷基。
就本说明书而言，此亚类的杂芳基可按上述任一方式更具体地限定。
在此亚类中有一类式I化合物，其中：R2选自：
(a)环己基，和
(b)一或二取代的苯基，其中取代基选自：
    (1)氢，
    (2)卤素，
    (3)C1-4烷氧基，
    (4)C1-4烷硫基，
    (5)CN，
    (6)CF3，
    (7)C1-4烷基，
    (8)N3，和
    (9)-C(R5)(R6)-OH；R3选自：
(a)氢，
(b)CF3，
(c)C1-3烷基和羟基C1-3烷基，
(d)CN；R5、R5′、R6各自独立地选自：
(a)氢，
(b)甲基或乙基，或R5和R6与它们所连的碳原子一起形成4、5或6个原子的饱和碳环。
在此类中有一小类式I化合物，其中：X-Y-Z-选自：
      (a)＝CH-O-CH＝，
      (b)＝N-S-N＝，
      (c)＝N-O-N＝；R1选自：
      (a)S(O)2CH3，和
      (b)S(O)2NH2；R2选自一或二取代的苯基，其中取代基选自：
(1)氢，
(2)卤素，选自氟、氯和溴，
(3)C1-3烷氧基，
(4)C1-3烷硫基，
(5)CF3，
(6)C1-3烷基；R3选自：
(a)氢，
(b)CF3，
(c)C1-3烷基和羟基C1-3烷基；R5和R6各自选自：
(a)氢，
(b)甲基或乙基，或R5、R5′和R6与它们所连的碳原子一起形成5、6或7个原子的饱和碳环。
就本说明书而言，烷基被定义为包括直链、支链和环袄结构，C1-6烷基包括甲基、乙基、丙基、2-丙基、仲丁基、叔丁基、丁基、戊基、己基、1，1-二甲基乙基、环丙基、环丁基、环戊基和环己基。与此类似，C1-6烷氧基是指包括1-6个碳原子的直链、支链或环状构型的烷氧基。低级烷氧基的实例包括甲氧基、乙氧基、丙氧基、异丙氧基、环丙氧基、环己氧基等。同样，C1-6烷硫基是指包括1-6个碳原子的直链、支链或环状构型的烷硫基。低级烷硫基的实例包括甲硫基、丙硫基、异丙硫基、环庚硫基等。为了说明，丙硫基表示-SCH2CH2CH3。
杂芳基包括呋喃、噻吩、吡咯、异噁唑、异噻唑、吡唑、噁唑、噻唑、咪唑、1，2，3-噁二唑、1，2，3-噻二唑、1，2，3-三唑、1，3，4-噁二唑、1，3，4-噻二唑、1，3，4-三唑、1，2，5-噁二唑、1，2，5-噻二唑、吡啶、哒嗪、嘧啶、吡嗪、1，2，4-三嗪、1，3，5-三嗪、1，2，4，5-四嗪基团等。
苯并杂芳基包括可与苯环稠合的上述杂芳基环。
本发明的实例为：
(a)3-(4-(氨基磺酰基)苯基)-2-(4-氟苯基)-5-(2-羟基-2-丙基)噻吩，
(b)3-(4-(氨基磺酰基)苯基)-2-(4-氟苯基)噻吩，
(c)3-(4-(氨基磺酰基)苯基)-2-(4-氟苯基)-5-(2-丙基)噻吩，
(d)3-(4-(氨基磺酰基)苯基)-2-环己基噻吩，
(e)5-(4-羧基苯基)-4-(4-(甲磺酰基)苯基)噻吩-2-羧酸，
(f)4-(4-氟苯基)-2-甲基-5-(4-(甲磺酰基)苯基)噻唑，
(g)2-(4-氟苯基)-3-(4-(甲磺酰基)苯基)-2-环戊烯-1-酮，
(h)4-(4-(甲磺酰基)苯基)-5-(4-氟苯基)异噻唑，
(i)3-(4-氟苯基)-4-(4-(甲磺酰基)苯基)-2-(5H)-呋喃酮，
(j)3-(4-氟苯基)-4-(4-(氨基磺酰基)苯基)-2-(5H)-呋喃酮，
(k)3-(4-氟苯基)-4-(4-(甲磺酰基)苯基)呋喃，
(l)5，5-二甲基-3-(4-氟苯基)-4-(4-(甲磺酰基)苯基)-2-(5H)-呋喃酮，
(m)2-(4-(氨基磺酰基)苯基)-3-(4-氟苯基)噻吩，
(n)3-(4-(三氟乙酰氨基磺酰基)苯基)-2-(4-氟苯基)噻吩，
(o)3-(3-氟苯基)-4-(4-(甲磺酰基)苯基)-2-(5H)-呋喃酮，
(p)5，5-二甲基-3-(3-氟苯基)-4-(4-(甲磺酰基)苯基)-2-(5H)-呋喃酮，
(q)5，5-二甲基-3-(3-氯苯基)-4-(4-(甲磺酰基)苯基)-2-(5H)-呋喃酮，
(r)3-(3，4-二氟苯基)-4-(4-(甲磺酰基)苯基)-2-(5H)-呋喃酮，
(s)3-(3，4-二氯苯基)-4-(4-(甲磺酰基)苯基)-2-(5H)-呋喃酮，
(t)5，5-二甲基-3-(3，4-二氟苯基)-4-(4-(甲磺酰基)苯基)-2-(5H)-呋喃酮，
(u)5，5-二甲基-3-(3，4-二氯苯基)-4-(4-(甲磺酰基)苯基)-2-(5H)-呋喃酮，
(v)5，5-二甲基-3-(4-氯苯基)-4-(4-(甲磺酰基)苯基)-2-(5H)-呋喃酮，
(w)3-(2-萘基)-4-(4-(甲磺酰基)苯基)-2-(5H)-呋喃酮，
(x)5，5-二甲基-3-(2-萘基)-4-(4-(甲磺酰基)苯基)-2-(5H)-呋喃酮，
(y)3-苯基-4-(4-(甲磺酰基)苯基)-2-(5H)-呋喃酮。
本发明进一步例举的化合物为：
(a)3-(3，4-二氟苯基)-4-(4-(甲磺酰基)苯基)-2-(5H)-呋喃酮，和
(b)3-苯基-4-(4-(甲磺酰基)苯基)-2-(5H)-呋喃酮，或其可药用盐。
本文所描述的一些化合物含有一个或多个不对称中心，因此可具有非对映体和旋光异构体。本发明包括这些可能的非对映体以及他们的外消旋体和拆分的对映体纯形式及其可药用盐。
本文所描述的一些化合物含有烯类双键，因此除非另有指明，这些化合物包括E和Z几何异构体。
在第二具体实施方案中，本发明涉及用于抑制环氧酶和治疗本文所述的环氧酶介导的疾病的药物组合物，它包括可药用载体和无毒的治疗有效量的上述式I化合物。
在此具体实施方案中，本发明涉及用于抑制环氧酶-2和治疗本文所述的环氧酶-2介导的疾病的药物组合物，它包括可药用载体和无毒的治疗有效量的上述式I化合物。
在第三具体实施方案中，本发明涉及抑制环氧酶和治疗环氧酶介导的疾病的方法，优选用选择性地抑制COX-2且优先于抑制COX-1的本文所公开的活性药剂治疗，该方法包括给需要这种治疗的患者施用无毒的治疗有效量的本文所公开的式I化合物。
就本说明书而言，如果COX-1抑制与COX-2抑制的IC50浓度之比为100或更大，则可以说化合物选择性地抑制COX-2优先于抑制COX-1。
本发明的药物组合物包括作为活性成分的式I化合物或其可药用盐，也可含有可药用载体以及任选的其它治疗成分。术语“可药用盐”是指由可药用的无毒碱(包括无机碱和有机碱)制备的盐。由无机碱得到的盐包括铝、铵、钙、铜、铁、亚铁、锂、镁、锰、二价锰、钾、钠、锌盐等，特别优选铵、钙、镁、钾和钠盐。由可药用的有机无毒碱得到的盐包括下列碱的盐：伯、仲和叔胺，取代的胺包括天然存在的取代的胺，环胺和碱性离子交换树脂，例如精氨酸、甜菜碱、咖啡因、胆碱、N，N-二苄基乙二胺、二乙胺、2-二乙氨基乙醇、2-二甲氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡糖胺、氨基葡糖、组氨酸、哈胺、异丙胺、赖氨酸、甲基葡糖胺、吗啉、哌嗪、哌啶、聚胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基三丁醇等。
应当理解在下面讨论的治疗方法中，涉及式I化合物时也包括可药用盐。
式I化合物可用于缓解各种疾病的疼痛、发热和炎症，这些疾病包括风湿热、与流行性感冒或其它病毒感染有关的症状、感冒、低背和颈疼痛、痛经、头痛、牙痛、扭伤和劳损、肌炎、神经痛、滑膜炎、关节炎包括类风湿性关节炎、变性关节疾病(骨关节炎)、痛风和关节强硬性脊椎炎、粘液囊炎、烧伤、损伤(外科手术和牙处理后)。另外，这些化合物还可抑制细胞肿瘤的转化和转移肿瘤的生长，因此可用于治疗癌症。式I化合物也可用于治疗痴呆包括早老性痴呆和老年性痴呆，特别是与阿尔茨海默病有关的痴呆(即阿尔茨海默痴呆)。
式I化合物通过阻止收缩的前列腺素类化合物的合成还可抑制前列腺素类化合物诱导的平滑肌收缩，因此可用于治疗痛经、早产和哮喘。
由于式I化合物具有如上所述的高环氧酶-2(COX-2)活性和/或对环氧酶-2优先于环氧酶-1(COX-1)的选择性，因此式I化合物可用作常规非甾类消炎药(NSAID’S)的替代物，特别是当这些非甾类消炎药可能对有下列情况的患者禁用时：患有消化溃疡、胃炎、局部回肠炎、溃疡性结肠炎、憩室炎或胃肠损害复发史；GI出血、凝固疾病包括贫血如血凝血酶原过少、血友病或其它出血问题(包括与血小板功能减少或削弱有关的出血)；肾病(例如肾功能减退)；在外科手术或采用抗凝血剂之前；对NSAID诱导的哮喘敏感者。
同样地，式I化合物可用作制剂中常规NSAID的部分或全部的替代物，其中它们可与其它药剂或成分共同给药。因此，另一方面，本发明包括用于治疗上述环氧酶-2介导的疾病的药物组合物，包括无毒的治疗有效量的上述的式I化合物和一种或多种成分如另外的疼痛缓解剂，包括acetominophen或非那西丁；增效剂，包括咖啡因；H2拮抗剂，氢氧化铝或氢氧化镁、二甲硅油；减充血剂，包括苯福林、苯丙醇胺、假麻黄碱、羟间、ephinephrine、盐酸萘甲唑啉、丁苄唑啉、环己丙甲胺或左旋去氧麻黄碱；antiitussive，包括可待因、二氢可待因酮、咳美芬、咳必清或右旋甲吗喃；利尿剂；镇静或非镇静的抗组胺药。另外，本发明包括治疗环氧酶介导的疾病的方法，包括给需要这种治疗的患者施用无毒的治疗有效量的式I化合物式I化合物可任选地与一种或多种上面刚刚所列的成分共同给药。
本发明的化合物为环氧酶-2抑制剂，因此可用于治疗上述环氧酶-2介导的疾病。其活性可通过选择性地抑制环氧酶-2超过抑制环氧酶-1的能力来说明。因此，在一个试验中，本发明的化合物治疗环氧酶介导的疾病的能力可通过测量在花生四烯酸、环氧酶-1或环氧酶-2和式I化合物存在下合成的前列腺素E2(PGE2)的量来确定。IC50值表示使PGE2合成达到未抑制的对照组的50％所需的抑制剂的浓度。关于这方面，我们发现实施例的化合物抑制COX-2的有效性超过抑制COX-1的100以上。另外，它们对COX-2的IC50为1nM-1μM。为了比较，布洛芬对COX-2的IC50为1μM，消炎痛对COX-2的IC50为大约100nM。为了治疗任何环氧酶介导的疾病，式I化合物可以含有常规无毒可药用载体、辅助剂和赋形剂的单位剂型经口服、局部、肠胃外给药或经吸入喷雾或直肠给药。本文所有的术语“肠胃外给药”包括皮下注射、静脉内、肌内、胸骨内注射或输注方法。除了治疗温血动物如小鼠、大鼠、马、牛、羊、狗、猫等外，本发明化合物可有效治疗人。
如上所述，治疗上述环氧酶-2介导的疾病的药物组合物可任选包括一种或多种上述成分。
含有活性成分的药物组合物可采用适合于口服使用的剂型，例如片剂、锭剂、糖锭剂、水悬浮液  或油悬浮液、可分散的粉剂或粒剂、乳剂、硬胶囊或软胶囊、糖浆剂或酏剂。用于口服使用的组合物可按本领域公知的制备药物组合物的任意方法制备，为了提供美观可口的药物制剂，这些组合物可含有一种或多种选自甜味剂、调味剂、着色剂和防腐剂的试剂。片剂含有活性成分以及与之混合的适合制备片剂的无毒可药用赋形剂。这些赋形剂例如为惰性稀释剂，例如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠；成粒剂和崩解剂，例如玉米淀粉或藻酸；粘合剂，例如淀粉、明胶或阿拉伯胶；润滑剂，例如硬脂酸镁，硬脂酸或滑石粉。片剂可不被包衣或用已知方法包衣，以便在胃肠道中延缓崩散和吸收，从而在较长的期限内提供持续的作用。例如可使用时间延缓物质，如甘油一硬脂酸酯或甘油二硬脂酸酯。也可用美国专利4,256,108、4,166,452和4,265,874所述方法包衣形成控制释放的渗透治疗片剂。
口服使用的制剂也可采用硬胶囊形式，其中活性成分与惰性固体稀释剂例如碳酸钙、磷酸钙或高岭土混合，或采用软胶囊形式，其中活性成分与水或油状介质例如花生油、液体石腊或橄榄油混合。
水悬浮液含有活性物质以及与之混合的适合制备水悬浮液的赋形剂。这些赋形剂为悬浮剂，例如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、聚乙烯吡咯烷酮、西黄著胶和阿拉伯胶；分散剂或湿润剂可以是天然存在的磷脂，例如卵磷脂，或氧化烯与脂肪酸的缩合产物，例如聚氧乙烯硬脂酸酯，或环氧乙烷与长链脂肪醇的缩合产物，例如十七乙烯氧基十六烷醇，或环氧乙烷与脂肪酸和己糖醇所得的部分酯的缩合产物，例如聚氧乙烯山梨糖醇单油酸酯，或环氧乙烷与脂肪酸和己糖醇酐所得的部分酯的缩合产物，例如聚乙烯山梨糖醇酐单油酸酯。水悬浮液也可含有一种或多种防腐剂，例如对羟基苯甲酸乙酯或正丙酯，一种或多种着色剂，一种或多种调味剂，以及一种或多种甜味剂，例如蔗糖、糖精或阿斯巴甜。
油悬浮液可通过将活性成分悬浮于植物油例如花生油、橄榄油、芝麻油、椰子油，或矿物油如液体石腊中来制备。油悬浮液可含有增稠剂，例如蜂蜡、硬石腊或鲸蜡醇。可加入如上所述的甜味剂和调味剂以得到可口的口服制剂。可通过加入抗氧化剂如抗坏血酸使这些组合物防腐。
适合于通过加入水制备水悬浮液的可分散的粉剂和粒剂含有活性成分以及与之混合的分散剂或湿润剂、悬浮剂和一种或多种防腐剂。合适的分散剂或湿润剂和悬浮剂如上面所列举的。也可含有其它赋形剂，例如甜味剂、调味剂和着色剂。
本发明的药物组合物也可以水包油的乳剂形式存在。油相可为植物油，例如橄榄油或花生油，或矿物油，如液体石腊或它们的混合物。合适的乳化剂可以是天然存在的磷脂，例如大豆，卵磷脂，脂肪酸和己糖醇酐所得的酯或部分酯，例如山梨糖醇酐单油酸酯，以及所述的部分酯与环氧乙烷的缩合产物，例如聚氧乙烯山梨糖醇酐单油酸酯。乳剂也可含有甜味剂和调味剂。
糖浆剂和酏剂可用甜味剂例如甘油、丙二醇、山梨糖醇或蔗糖配制。这些制剂也可含有缓和剂、防腐剂、调味剂和着色剂。药物组合物可采用无菌的可注射的含水或含油的悬浮液形式，该悬浮液可按照本领域公知的方法使用上述的合适的分散剂或湿润剂和悬浮剂来配制。无菌的可注射制剂也可为在无毒的肠胃外可接受的稀释剂或溶剂中的无菌的可注射溶液或悬浮液，例如在1，3-丁二醇中的溶液。在可使用的并且可接受的载体和溶剂中，可使用水、林格氏溶液和等渗的氯化钠溶液。另外，无菌的固定油通常用作溶剂或悬浮介质。为此目的，可使用任何温和的固定油，包括合成的一或二甘油酯。另外，脂肪酸如油酸也可用于注射制剂。
式I化合物也可以直肠给药的栓剂形式给药。这些组合物可通过将药物与合适的无刺激的赋形剂混合来制备，赋形剂在常温下为固体，但在直肠温度下为液体，因此在直肠中溶化释放出药物。这些物质为可可脂和聚乙二醇。
为局部使用，可使用含有式I化合物的乳油、软膏、凝胶、溶液或悬浮液等。(就本申请而言，局部应用包括漱口剂和含漱液。)
大约0.01mg至大约140mg/kg体重/天的剂量或大约0.5mg至大约7g/患者/天的剂量可用于治疗上述疾病。例如通过施用大约0.01至50mg化合物/kg体重/天或大约0.5mg至大约3.5g/患者/天优选2.5mg-1g/患者/天，可有效地治疗炎症。
可与载体物质混合制备单一剂型的活性成分的量随治疗的宿主和具体的给药方式而变化。例如，用于人口服给药的制剂可含有0.5mg-5g活性药剂，活性药剂与合适的和常规用量的载体物质混合，载体物质可为组合物总量的大约5至大约95％。单位剂型一般含有大约1mg至大约500mg活性成分，典型的有：25mg、50mg、100mg、200mg、300mg、400mg、500mg、600mg、800mg或1000mg。
然而，应当理解，对于任何具体患者的特定剂量取决于各种因素，包括年龄、体重、一般的健康状况、性别、饮食、给药时间、给药途径、排泄速度、药物的配合和所治疗的具体疾病的严重程度。合成方法
本发明的化合物可按下列方法制备。方法A
使用Weissenfels(Z.Chem.1966，6，471)所述的一般方法由酮II和Vilsmeier试剂(DMF-POCl3)可制得β-氯乙烯基醛III。使用Weissenfels(Z.Chem.1973，13，57)所述的一般方法由III制得噻吩化合物IV。用一当量的m-CPBA氧化化合物IV(Ra＝-SMe)，接着在回流下用TFAA处理所得的亚砜后可得到硫醇化合物V.然后可用Kharash的方法(J.Amer.Chem.Soc.1951，73，3240)形成氨磺酰基(VI)。将化合物VI水解并在喹啉中用青铜脱羧，得到化合物VII。可用卤化试剂如在乙酸中的溴处理化合物VII(R4＝H)来制备5-溴噻吩(VII，R4＝Br)。当需要在C-5上有腈基时，可由VI通过用Weinreb方法(Tetrahedron Letters，1977，4171)形成酰胺，接着用TFAA脱水来完成。可用Girard的方法(J.Org.Chem.1983，48，3220)的方法在VII的C-5上引入CF3。
在C-5上引入烷基可通过将VII(R4＝H)与酰基氯Cl-CO-低级烷基和催化剂如TiCl4进行Friedel-Crafts反应接着还原来达到。对于R4＝Me，可由酯(R4＝CO2Me)通  过DIBAL-H还原接着用Lau的方法(J.Org.Chem.1986，51，3038)脱氧合来达到。可由VI和MeMgBr得到叔醇(R4＝-C(CH3)2OH)。也可用Lau的方法使这些叔醇脱氧合。同样，可由酮VIII制备噻吩IX。
方法A
Figure C0010098100371
续方法A
Figure C0010098100381
方法B：
使用方法A中已描述的一般方法可将酮X转化为噻吩分合物XI。用n-BuLi金属取代XI，用甲基膦酰二氯终止反应，加入水或氨(X′＝OH或NH2)，可制得噻吩XII。同样，由酮XIII可制得另一区域异构体XIV。方法B
Figure C0010098100391
方法C
将酮II溴化得到α-溴酮XV，然后用硫代酰胺处理转化为噻唑XVI。同样，可将酮VIII转化为噻唑XVII。方法C 方法D
使用Brederick等人，Chem.Ber.1953，p.88所述的制备方法，用甲酰胺处理可将酮XV转化为咪唑化合物XVIII。方法D
Figure C0010098100402
方法E
使用Friedman等人，J.Org.Chem.1965，30，p.854，K.Dimroth等人，Ber.1956，56，2602，K.Dimroth等人，Ann.1961，634，102的一般方法，可由二酮XIX制得吡咯化合物XX。可在碱如Et3N存在下用CI-CO-低级烷基酰化吡咯的游离NH。使用烷基卤作为试剂和碱如NaH也可制得烷基化产物。方法E
Figure C0010098100411
方法F
式XXV化合物可由容易得到的4-取代的苯基乙酰氯XXIa制备。使二(3-丁烯基)镉与4-取代的苯基乙酰氯反应得到酮XXI。将XXI臭氧分解得到酮醛XXIb，用碱环化得到环戊烯酮XXII。溴化芳基镁或芳基锂与XXII加成得到烯丙醇XXIV。用氯铬酸吡啶鎓氧化XXIV得到所需的2，3-二取代的环戊烯酮XXV。为制备化合物XXV(R1＝SO2Me)，使用4-甲硫基苯基锂，接着用一过氧邻苯二甲酸(MMPP)或间氯过氧苯甲酸(mCPBA)的镁盐氧化以在XXV中引入所需的甲磺酰基。方法F
Figure C0010098100421
方法G
方法G的顺序与方法F相近，所不同的是用含有R1的酰氯作为原料。在后面的步骤中通过羰基加成反应接着进行PCC氧化引入R2。方法G
Figure C0010098100431
方法H
按B.Schulze等人，Helvetica Chimica Acta，1991，74，1059所描述的一般方法可制备4，5-二取代的异噻唑和异噻唑-3(2H)-酮-1，1-二氧化物。用过量的NH4SCN在回流的丙酮中处理醛III(Ra＝SO2Me)或XXVII，得到相应的4，5-二取代的异噻唑XXX和XXVIII，然后用过氧化氢氧化得到XXXI和XXIX。方法H
Figure C0010098100441
方法I
在溶剂如乙腈中，在碱如三乙胺存在下，使适当取代的芳基溴甲基酮与适当取代的芳基乙酸反应，然后用1，8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)处理，得到内酯XXXIII或XXXV。方法I
Figure C0010098100451
(R2为一或二取代的苯基或一或二取代的杂芳基)方法J
在-78℃下，使在溶剂如THF中的内酯XXXIII或XXXV与还原剂如氢化二异丁基铝或硼氢化锂反应，得到呋喃XXXVI。方法J 方法K
除使用合适的酰胺XXXVIII外，可按与方法I所述相同的反应，制备内酰胺XXXVII和XXXIX。
方法K
Figure C0010098100462
方法L
用TMSCl将2-羟基异丁酸甲酯甲硅烷基化得到TMS醚XLI，然后用4-甲硫基苯基锂处理得到酮XLII。脱甲硅烷基化后接着酰化，得到酮-酯XLIV，然后用碱催化环化得到内酯XLV。用MMPP或mCPBA氧化XLV，得到所需的产物XLVI。
方法L
Figure C0010098100471
方法M
羟基酮XLIII的另一制备方法是将公知的(J.Org.Chem. 1991  56，5955-8；Sulfur Lett. 1991， 12，123-32)酮XLVII氧化。将XLVII、含水碱如NaOH、有机溶剂如四氯化碳/甲苯和相转移催化剂如ALIQUAT336的混合物在空气中在室温下搅拌得到XLIII。化合物XLIII已被描述在US4,321,118和Org.Coat. 1986， 6，175-95中。方法N
在合适的催化剂存在下，使炔XLVIII与一氧化碳和水反应得到化合物XXXIII及其异构体XXXV的混合物。可用本领域的常规方法如色谱法或结晶法分离异构体。可用的催化剂和条件的实例为在含HCl和EtOH中的PdCl2，在50-150℃和50-150个大气压下加热，或在含有三烷基胺的含水THF(或丙酮、乙腈、苯、甲苯、EtOH、MeOH)中的Rh4(CO)12(或Rh6(CO)16)，在50-150℃和20-300个大气压下加热。参见Takahashi等人，Organometallics 1991，10，2493-2498；和Tsuji等人，J.Am.Chem.Soc.1966，88，1289-1292。方法O
Figure C0010098100491
在铜盐存在下使XLIX与4-甲硫基苯基有机金属试剂L进行1，4-加成反应，并用三烷基甲硅烷基氯如TMSCl或TIPSCl捕获所得的烯醇酯得到烯酮缩醛LI。然后用Ito的方法，用催化量的在MeOH中的Pd2(OAc)2和Cu(OAc)2和O2，或用Magnus的方法，用在MeOH中的Cu(OAc)2和O2，或用Magnus的方法，用PhIO/TMSN3和Bu4NF氧化烯酮缩醛得到取代的丁烯羟酸内酯。碘的引入可通过在吡啶存在下用I2处理LII得到LIII来完成。LIII与合适的芳基或烷基参与物如硼酸LIV的钯催化的Susuki或Stille偶合得到丁烯羟酸内酯LV。可用各种氧化剂如过乙酸、MPPM、MMPP或H2O2将硫醚氧化为砜，得到所需的化合物LVI。参见Y.Ito等人，J.Am.Chem.Soc.1979，101，494；和P.Magnus等人，Tet.Lett.1992，2933。
因此，本发明的另一方面涉及制备式XXXIII化合物的方法：
Figure C0010098100501
该方法包括：
(a1)在有机溶剂中使式XXXII′化合物
Figure C0010098100511
与溴试剂反应得到式XXXII化合物：
Figure C0010098100512
就本说明书而言，所定义的有机溶剂包括但不限于二氯甲烷、氯仿、四氯化碳和乙酸。同样，所定义的溴试剂包括但不限于溴、过溴化吡啶鎓氢溴酸盐、CuBr2和N-溴琥珀酰亚胺。
(a2)在非水极性溶剂中在碱存在下使式XXXII化合物与下式化合物反应：
Figure C0010098100513
得到式A化合物：
Figure C0010098100521
(a3)在非水极性溶剂中用强碱处理式A化合物，得到式XXXIII化合物。
就本说明书而言，所定义的非水极性溶剂包括但不限于乙腈、丙腈、丙酮、2-丁酮和四氢呋喃。同样，所定义的碱包括但不限于三C1-3烷基胺如三乙胺。另外，所定义的强碱包括但不限于脒、胍、二异丙基氨基化锂和双(三甲基甲硅烷基)氨基化锂。
另外，本发明涉及另一种制备式XXXIII化合物的方法：
Figure C0010098100522
该方法包括：
(b1)在合适的催化剂存在下，使式XLVIII的乙炔化合物与一氧化碳和水反应，得到化合物XXXIII和XXXV：
Figure C0010098100532
就本说明书而言，合适的催化剂包括但不限于在含水THF或丙酮、乙腈、苯、甲苯、甲醇或乙醇中的Ru4(CO)12、Co2(CO)8或PdCl2。
此外，本发明涉及另一种制备式XXXIII化合物的方法：
Figure C0010098100533
该方法包括：
(c1)在含水溶剂如苯、甲苯、THF、MeOH、DME或EtOH中，在合适的钯催化剂存在下，使式LIII化合物
Figure C0010098100541
与式(HO)2BR2试剂反应，得到式LV化合物：
Figure C0010098100542
(c2)氧化式LV化合物得到式XXXIII化合物。
就本说明书而言，所定义的催化剂包括但不限于钯催化剂。同样，所定义的溶剂包括但不限于苯、甲苯、THF、MeOH、DME或EtOH。
在所有的方法方案中，R1和R2如上面涉及式I化合物的详细描述和权利要求中所定义。代表性的化合物
表I和II列举了式I化合物。表I实施例         方法 表I(续)
Figure C0010098100561
实施例          方法7                F
Figure C0010098100562
表I(续)实施例       方法
Figure C0010098100571
表I(续)
Figure C0010098100581
实施例         方法15     I
Figure C0010098100582
表I(续) 实施例       方法20            I
Figure C0010098100592
表I(续)
Figure C0010098100601
实施例        方法25            I
Figure C0010098100602
表I(续)
Figure C0010098100611
实施例           方法30              I
Figure C0010098100612
表I(续)
Figure C0010098100621
实施例        方法35            I
Figure C0010098100622
表I(续) 实施例          方法40              I
Figure C0010098100632
表I(续)
Figure C0010098100641
实施例          方法I45             I 表I(续) 实施例         方法50            I
Figure C0010098100652
表I(续)实施例            方法
Figure C0010098100661
表I(续)实施例              方法
Figure C0010098100671
表II 表II(续)
Figure C0010098100691
表II(续)
Figure C0010098100701
表II(续)
Figure C0010098100711
表II(续) 表II(续)
Figure C0010098100731
表II(续) 表II(续)
Figure C0010098100751
表II(续)
Figure C0010098100761
表II(续)
Figure C0010098100771
表II(续)
Figure C0010098100781
表II(续)
Figure C0010098100791
测定生物活性的试验
使用下列测定式I化合物的环氧酶-2的抑制活性的测定试验式I化合物。环氧酶活性的抑制
以全细胞和微粒体环氧酶测定试验化合物作为环氧酶活性抑制剂。这两个试验用放射免疫测定法测定应答于花生四烯酸的前列腺素E2(PGE2)的合成。全细胞试验所用的细胞和由此制备的用于微粒体试验的微粒体的细胞为人骨肉瘤143细胞(特别表达环氧酶-2)和人U-937细胞(特别表达环氧酶-1)。在这些测定中，100％活性定义为在没有加入花生四烯酸和在花生四烯酸存在下前列腺素E2合成的差值。IC50值表示使PGE2合成达到未抑制的对照样的50％所需的假定的抑制剂的浓度。代表性的结果列于表III中。代表性的大鼠爪水肿试验-原始记录
将雄性Sprague-Dawley大鼠(150-200g)禁食过夜，然后在9-10am口服载体(5％吐温80或1％methocel)或试验化合物。1小时后，用永久性标志在一后爪的踝关节以上画线确定所测的爪的面积。根据排水原理，用体积描记器(Ugo-Basile，Italy)测量爪的体积(Voh)。使用带有25计量的针的胰岛素注射器将50μl 1％角叉菜胶的盐水溶液(FMC Corp，Maine)从动物的足底下注射入爪(即每只爪500g角叉菜胶)。三小时后，测量爪的体积(V3h)并且计算爪体积(V3h-Voh)的增加值。用CO2使动物无痛苦窒息致死，并且评价是否有胃的损伤。胃的评价表示为总损伤之和(mm)。将爪水肿数据与载体对照组比较，并以对照组的值作为100％计算抑制百分率。因为用标准的NSAID得到的最大值为60-70％抑制率(爪水肿)，则用ED30值作比较。所有的处理组都进行编号以消除观察偏差。用这样的原始试验，消炎痛的ED30为1.0mg/kg。代表性的结果列于表IV中。
                                  表III*
                          全细胞                                微粒体
  实施例   浓度(nM)   COX-2抑制％   COX-1抑制％   浓度(nM)   COX-2抑制％  COX-1抑制％
  1   100   96   12   100   53   8
  2   10   69   0   10   49   25
  3   10   42   10   33   19
  3   100   100   100   76   12
  4   10   47   2
5 10 0 0 10 43 31
  6   100   78   100    19   16
  7   100   74     0   1000     58   16
  8   10   41
  8   100   89
  9   100   83   100   37   9
  10   100   95   100   71   12
  11   100   39   100   46   7
  12   100   54
  13   10   41   10   52   7
  13   100   84   10   58   10
  14   10   73   10   45   29
  14   1000   89   100   63   0
  14   1000   101   1000   69   0
    实施例     浓度(nM)     COX-2抑制％ COX-1抑制％ Conc.(nM) COX-2抑制％ COX-1抑制％
    15     20     39
    15     80     76
    15     160     95
    16     20     41
    16     40     50
    16     160     85
    17     40     41
    17     160     77
    18     40     24
    18     160     58
    19     40     21
    19     160     59
    20     10     70
    20     40     91
    21     10     50
    21     40     94
    22     20     39
    22     160     98
    23     20     50
    23     160     88
    24     40     43
    24     160     78
    25     160     40
    26     80     27
    26     160     39
    27     20     38
    27     160     97
    实施例     浓度(nM)     COX-2抑制％   COX-1抑制％   Conc.(nM)   COX-2抑制％   COX-1抑制％
    28     20     48
    28     160     69
    29     20     78
    29     160     85
    30     160     30
    31     20     49
31 160 87
    32     5     43
    32     10     73
    32     40     92
    32     80     99
    33     160     6
    34     10     30
    34     40     80
    34     160     102
    35     20     32
    35     40     57
    35     160     83
    36     10     11
    36     40     50
    36     160     89
    37     10     53
    37     40     82
    37     160     93
    38     10     25
    38     40     63
    38     160     88
    39     10     17
   实施例     浓度(nM)     COX-2抑制％   COX-1抑制％   Conc.(nM)   COX-2抑制％   COX-1抑制％
    39     160     84
    40     10     43
    40     40     72
    40     160     96
    41
    41
    42     20     10
    42     160     44
    43     10     78
    43     40     101
    44     20     14
    44     40     55
    44     160     106
    45     10     16
    45     40     61
    45     160     101
46 10 76
    46     40     94
    46     160     97
    47     10     61
    47     40     74
    47     160     101
    48     10     7
    48     160     47
    49     10     53
    49     40     91
    49     80     99
    50     80     42
    实施例     浓度(nM)     COX-2抑制％   COX-1抑制％   Conc.(nM)   COX-2抑制％   COX-1抑制％
    51     5     49
    51     20     95
    51     40     102
    52     10     50
    52     40     82
    52     160     102
    53     10     54
    53     40     96
    53     160     102
    54     10     81
    54     80     91
    54     160     99
    55     10     48
    55     80     59
    55     160     65
*在全细胞测定中，布洛芬对于COX-1的IC50为1000nM，对于COX-2的IC50为3000nM.同样，消炎痛对于COX-1的IC50为100nM，对于CON-2的IC50为10nM。表IV
Figure C0010098100861
Figure C0010098100871
Figure C0010098100901
Figure C0010098100911
Figure C0010098100921
Figure C0010098100941
Figure C0010098100951
Figure C0010098100971
Figure C0010098100981
Figure C0010098100991
现在用下列非限定实施例来说明本发明，除非另有说明，其中：(i)所有操作都在室温或环境温度下进行，即在18-25℃的温度下进行；使用旋转蒸发器在减压(600-4000帕：4.5-30mm.Hg)且浴温不高于60℃的条件下蒸发溶剂；反应过程用薄层色谱法(TLC)监测，所给的反应时间仅是用于说明；熔点未经校正，‘d’表示分解；所给的熔点为所制备的物质得到的熔点；在某些制备中具有不同熔点的物质的分离可能产生多晶体；用至少一种下列方法测定所有最终产物的结构和纯度：TLC，质谱，核磁共振(NMR)谱或微量分析数据；所给的产率仅是用于说明；在300MHz或400MHz下使用指定的溶剂测定的NMR数据是以主要鉴定质子的δ值形式且按相对于四甲基甲硅烷(TMS)的每百万分之份数(ppm)给出；用于信号峰的常规缩写为：s.单峰；d.双峰；t.三峰；m.多重峰；br.宽峰等；另外，“Ar”表示芳香族信号；化学符号具有其通用含义；还使用下列缩写：v(体积)，w(重量)，b.p.(沸点)，m.p.(熔点)，L(升)，mL(毫升)，g(克)，mg(毫克)，mol(摩尔)，mmol(毫摩尔)，eq(当量)。
下列缩写具有指定的含义：
Ac＝乙酰基
Bn＝苄基
DBU＝1，8-二氮杂双环[5.4.0]十一碳-7-烯
DIBAL＝氢化二异丁基铝
DMAP＝4-(二甲氨基)吡啶DMF＝N，N-二甲基甲酰胺Et3N＝三乙胺LDA＝二异丙基氨基化锂m-CPBA＝间氯过苯甲酸MMPP＝单过氧邻苯二甲酸MPPM＝单过氧邻苯二甲酸镁6H2OMs＝甲磺酰基＝SO2MeMsO＝甲磺酸酯NSAID＝非甾类消炎药OXONE_＝2KHSO5·KHSO4·K2SO4PCC＝氯铬酸吡啶鎓PDC＝二铬酸吡啶鎓Ph＝苯基Phe＝苯二基Pye＝吡啶二基r.t.＝室温rac.＝外消旋SAM＝氨基磺酰基或氨磺酰或SO2NH2TBAF＝氟化四正丁铵Th＝2-或3-噻吩基TFAA＝三氟乙酸酐THF＝四氢呋喃Thi＝噻吩二基TLC＝薄层色谱法TMS-CN＝三甲基甲硅烷基氰化物Tz＝1H(或2H)-四唑-5-基C3H5＝烯丙基烷基的缩写Me＝甲基Et＝乙基n-Pr＝正丙基i-Pr＝异丙基n-Bu＝正丁基i-Bu＝异丁基s-Bu＝仲丁基t-Bu＝叔丁基c-Pr＝环丙基c-Bu＝环丁基c-Pen＝环戊基c-Hex＝环己基
                实施例1 3-(4-氨基磺酰基)苯基)-2-(4-氧苯基)-5-(2-羟基- 2-丙基)噻吩 步骤1： 1-(4-氟苯基)-2-(4-(甲硫基)苯基)乙酮
向4-氟苯甲醛(5.40g)的1，2-二氯乙烷(43.50mL)溶液中加入TMS-CN(4.32g)和ZnI2(44mg)。室温下0.5小时后，真空除去溶剂。在-78℃下向所得的TMS氰醇(9.20g)的THF(42.0mL)溶液中滴加0.51M的LDA的THF(88.9mL)溶液。0.5小时后，在0.5小时内，滴加4-(氯甲基)硫代苯甲醚(9.93g)的THF溶液(30.0mL).在+5℃下18小时后，所得的混合物用TBAF(57.5mL)处理，接着用25％NH4OAc水溶液(100mL)处理，并用EtOAc(2×150mL)萃取。蒸发后，将10∶1的Et2O和己烷的混合物(200mL)加到粗酮中。搅拌10h并过滤后，过滤得到固体标题产物(2.40g)。
1HNMR(CD3COCD3)：δ2.45(3H，s)，4.34(2H，s)，7.19-7.29(6H，m)，
8.14(2H，q).步骤2： 顺，反-3-氯-3-(4-氯苯基)-2-(4-(甲硫基) 苯基)丙烯醛
向1-(4-氟苯基)-2-(4-(甲硫基)苯基)乙酮(2.50g)的1，2-二氯乙烷(27.0mL)溶液中加入3.3MVilsmeier试剂(Aldrich catalog，1992-1993)(11.6mL)和DMAP(1.17g)。在80℃下4小时后，用EtOAc和25％NH4OAc的水溶液萃取反应混合物。真空蒸发并干燥数小时后，得到的标题产物用于下一步骤。1H NMR(CD3COCD3)：δ2.40和2.48(3H，2s，6.90-7.80(SH，m)，9.55(1H，s).步骤3： 5-(4-氟苯基)-4-(4-(甲硫基)苯基)噻吩- 2-甲酸甲酯
向顺，反-3-氯-3-(4-氟苯基)-2-(4-(甲硫基)苯基)丙烯醛(3.00g)的吡啶(12.0mL)溶液中加入硫代甘醇酸甲酯(1.16mL)和Et3N(4.09mL)。然后将所得的混合物在80℃下加热2小时，用EtOAc萃取，并用3NHCl洗涤，用快速色谱法纯化(30％EtOAc/己烷)标题产物(2.00g)。1H NMR(CD3COCD3)：δ2.48(3H，s)，3.88(3H，s)，7.11(2H，t)，7.21(4H，s)，7.37(2H，q)，7.80(1H，s).步骤4： 5-(4-氟苯基)-4-(4-(甲亚磺酰基)苯基)噻 吩-2-甲酸甲酯
在0℃下，向5-(4-氟苯基)-4-(4-(甲硫基)苯基)噻吩-2-甲酸甲酯(5.60g)的CH2Cl2(84.0mL)溶液中分批加入50-60％的m-CPBA(5.39g)。TLC表明反应己完成(50％EtOAc的己烷溶液)，反应混合物用饱和的NaHCO3萃取、用Na2SO4干燥，过滤并蒸发至干，得到白色泡沫状的标题化合物(5.00g)。1H NMR(CD3COCD3)：δ2.75(3H，s)，3.92(3H，s)，7.15(2H，t)，7.40(2H，q)，7.52(2H，d)，7.66(2H，d)，7.90(1H，s).步骤5： 4-(4-(氨基磺酰基)苯基)-5-(4-氨苯基)噻 吩-2-甲酸甲酯
将5-(4-氟苯基)-4-(4-(甲亚磺酰基)苯基)噻吩-2-甲酸甲酯(0.500g)溶于TFAA(10.0mL)中，回流0.5小时。然后真空除去溶剂，所得的残余物与Et3N-MeOH溶液(1∶1)(100.0mL)共蒸发10次，并泵抽几小时后得到粘性油状物。将油状物溶于HOAc(10.0mL)中，在+10℃下用在HOAc中的Cl2(1.9M)(3.5mL)处理。20分钟后，在减压下除去溶剂，泵抽后，将THF(20.0mL)加到所得的产物中。在0℃下鼓泡通入NH3几分钟，在室温下将反应混合物搅拌0.5小时。用EtOAc-25％NH4OAc溶液萃取并且用快速色谱法纯化(30-40％EtOAc的己烷溶液)，得到白色固体状标题化合物(0.210g)。  1H NMR(CD3COCD3)：δ3,90(3H，s)，6.55(2H，bs)，7.13(2H，t)，7.40(2H，q)，7.46(2H，d)，7.83(2H，d)，7.90(1H，s).步骤6： 3-(4-氨基磺酰基)苯基)-2-(4-氧苯基)-5- (2-羟基-2-丙基)噻吩
在0℃下向4-(4-(氨基磺酰基)苯基)-5-(4-氟苯基)噻吩-2-甲酸甲酯(0.460g)的THF(5.70mL)溶液中加入MeMgBr(1.4M)的甲苯-THF溶液(5.00mL)，然后在室温下将混合物搅拌几小时。加入25％NH4OAc溶液终止反应，用EtOAc萃取并且用Na2SO4干燥。用快速色谱法纯化(40-50％EtOAc的己烷溶液)标题化合物(0.300g)。1H NMR(CD3COCD3)：δ1.65(6H，s)，4.52(1H，s)，6.55(2H，bs)，7.09(3H，m)，7.34(2H，dd)，7.30(2H，m)，7.43(2H，d)，7.82(2H，d).元素分析
计算值：C19H18FNO3S2；C，58.31；H，4.60；C，3.58.实测值：C，57.94；H，4.66；N，3.44
                   实施例2 3-(4-(氨基磺酰基)苯基)-2-(4-氟苯基)噻吩 步骤1： 4-(4-(氨基磺酰基)苯基)-5-(4-氟苯基)噻 吩-2-甲酸
向4-(4-(氨基磺酰基)苯基)-5-(4-氟苯基)噻吩-2-甲酸甲酯(实施例1，步骤5)(0.210g)的THF(2.0mL)溶液中加入MeOH(1.0mL)、NaOH 1N(1.0mL)和几滴10NNaOH。将所得的混合物在45℃下加热2小时，然后将反应混合物在EtOAc和HCl(3N)之间分配，得到白色固体状标题产物(0.200g)。1H NMR(CD3COCD3)δ6.60(2H，s)，7.15(2H，t)，7.35(2H，q)，7.45(2H，d)，7.82(2H，d)，7.87(1H，s).步骤2： 3-(4-(氨基磺酰基)苯基)-2-(4-氟苯基)噻 吩
向3-(4-(氨基磺酰基)苯基)-2-(4-氟苯基)噻吩-2-甲酸(0.280g)的喹啉(4.0mL)溶液中加入青铜(0.300g)。在氮气氛、180℃下0.5小时后，反应混合物用EtOAc和3NHCl萃取，用Na2SO4干燥，用快速色谱法纯化(30％EtOAc的己烷溶液)，得到白色固体状标题化合物(0.180g)。
1H NMR(CD3COCD3)：δ6.60(2H，bs)，7.15(2H，t)，7.29(1H，d)，7.35
(2H，q)，7.45(2H，d)，7.60(1H，d)，7.83(2H，d).
元素分析 计算值：C16H12FNO2S2；
        C，57.65；H，3.60；N，4.20.
实测值：C，57.62；H，3.59；N，4.15.
                  实施例3 3-(4-(氨基磺酰基)苯基)-2-(4-氟苯基)-5-(2-丙 基)噻吩
1H NMR(CD3COCD3)δ1.40(6H，d)，3.25(1H，septuplet)，6.58(2H，bs)，
7.05(1H，s)，7.15(2H，t)，7.32(2H，dd)，7.46(2H，d)，7.80(2H，d).
元素分析 计算值 C19H18FNO2S2.
        C，60.80；H，4.80；N，3.73.
实测值：C，60.59；H，4.45；N，3.60
               实施例4 3-(4-(氨基磺酰基)苯基)-2-环己基噻吩 1H NMR(CD3)2)CO)δ1.24-1.40(3H，m)，1.40-1.56(2H，m)，1.65-1.85(3H，m)，1.90-2.0(2H，m)，3.18(1H，m)，6.58(2H，bs)，7.05(1H，d)，7.37(1H，d)，7.58(2H，d)，7.97(2H，d).
               实施例5 5-(4-羧基苯基)-4-(4-(甲磺酰基)苯基)噻吩-2-甲酸 步骤1： 4-(2-(4-甲硫基苯基)-1-氧代乙基)苯甲酸甲 酯
在室温下向4-甲酰基苯甲酸甲酯(10.30g)的1，2-二氯乙烷溶液中加入TMS-CN(6.58mL)和ZnI2(2.00g)，在室温下0.5小时后，真空除去溶剂。在-78℃下向所得的TMS氰醇(5.00g)的THF(22.0mL)溶液中滴加0.87M的LDA的TFF(26.2mL)溶液。0.5小时后，在0.5小时内，滴加4-(氯甲基)硫代苯甲醚的THF溶液(10.0mL)。然后使温度慢慢升至-20℃，然后升到+5℃2小时，加入1M TBAF的THF(50.0mL)溶液。加入25％NH4OAc的水溶液后，反应混合物用EtOAc萃取，用NASO4干燥，真空蒸发，用快速色谱法纯化(20-30％EtOAc的己烷溶液)，得到白色固体状标题化合物(7.00g)。步骤2： 4-(1-氧代-2-(4-(甲磺酰基)苯基)乙基)苯 甲酸甲酯
在0℃下向7.10g4-(2-(4-甲硫基苯基)-1-氧代乙基)苯甲酸甲酯的MeOH(100ml)溶液中加入过硫酸氢钾制剂(21.0g)的H2O(20.0mL)溶液。在室温下几小时后，用EtOAc和H2O萃取反应混合物，用快速色谱法纯化(50-100％EtOAc的己烷溶液)后，得到白色固体状标题产物(3.20g)。
1H NMR(CD3COCD3)δ3.10(3H，s)，3.95(3H，s)，4.65(2H，s)，7.60
(2H，d)，7.96(2H，d)，8.20(4H，q).步骤3： 顺，反4-(1-氧-3-氧代-2-(4-(甲磺酰基)苯 基)-1-丙烯基)苯甲酸甲酯
向4-(1-氧代-2-((4-甲磺酰基)苯基)乙基)苯甲酸(1.70g)的1，2-二氯乙烷(15.0mL)溶液中加入3.3M(6.2mL)的Vilsmeier试剂和DMAP(0.624g)。在80℃下将反应混合物加热4小时，然后用25％NH4OAc和EtOAc的水溶液萃取反应混合物，用Na2SO4干燥并蒸发，得到油状的标题产物，原样用于下一步骤。步骤4： 5-(4-(甲氧基羰基)苯基)-4-(4-(甲磺酰基) 苯基)噻吩-2-甲酸甲酯
按实施例1步骤3的方法，由4-(1-氯-3-氧代-2-(4-甲磺酰基)苯基)-1-丙烯基)苯甲酸甲酯制备标题化合物。1H NMR(CD3COCD3)δ3.13(3H，s)，3.85 and 3.92(6H，2s)，7.50(2H，d)，7.55(2H，d)，7.90(2H，d)，7.92(1H，s)，7.92(2H，d).步骤5： 5-(4-(羧基苯基)-4-(4-(甲基)磺酰基)苯 基)噻吩-2-甲酸
按实施例2步骤1的方法，由5-(4-(甲氧基羰基)苯基)-4-(4-(甲基)磺酰基)苯基)噻吩-2-甲酸甲酯制备标题化合物。1H NMR(CD3COCD3)δ3.15(3H，s)，7.50(2H，d)，7.62(2H，d)，7.95(2H，d)，7.98(1H，s)，8.05(2H，d).
元素分析，计算值：C19H14O6S2·0.1H2O：
               C，56.46；H，3.51.
       实测值：C，56.18；H，3.51.
             实施例6 4-(4-氟苯基)-2-甲基-5-(4-(甲磺酰基)苯基)噻唑 步骤1： 1-(4-氟苯基)-2-(4-(甲磺酰基)苯基)乙酮
在0℃下，向实施例1步骤1的1-(4-氟苯基)-2-(4-(甲硫基)苯基)乙酮(17.9g)在CH2Cl2-MeOH溶液(272.0mL/27.0mL)中的溶液中加入MPPM(28.0g)。然后撤去冷却浴，将反应混合物在室温下搅拌1小时。在0℃下，再加入MPPM(28.0g)，在室温下将反应混合物保持1.5小时。过滤出不溶物，接着蒸发溶剂，然后用CH2Cl2-NaHCO3萃取残余物。真空蒸发后，用乙醚-己烷(1∶1)洗涤所得的固体，并过滤得到标题化合物16.8g。1H NMR(CD3COCD3)δ3.13(3H，s)，3.58(2H，s)，7.29(2H，t)，7.55(2H，d)，7.88(2H，d)，8.20(2H，dd).步骤2： 2-溴-1-(4-氟苯基)-2-(4-(甲磺酰基)苯基) 乙酮
向1-(4-氟苯基)-2-(4-(甲磺酰基)苯基)乙酮(1.00g)含有CHCl3(1.0mL)和CCl4(1.0mL)的CH2Cl2中的溶液中加入溴(0.614g)。光照1小时后，用Na2S2O4终止反应，用CH2Cl2萃取，用Na2SO4干燥并蒸发，得到标题化合物(1.10g)，原样用于下一步骤。1H NMR(CD3COCD3)δ3.10(3H，s)，7.05(1H，s)，7.30(2H，t)，7.87(2H，d)，7.95(2H，d)，8.25(2H，dd).步骤3： 4-(4-氟苯基)-2-甲基-5-(4-(甲磺酰基)苯 基)噻唑
向2-溴-1-(4-氟苯基)-2-(4-(甲基磺酰基)苯基)乙酮(1.10g)的乙醇(15.0mL)溶液中加入硫代乙酰胺(0.266g)和吡啶(0.300mL)。回流2小时后，反应混合物用EtOAc、25％NH4OAc萃取，用快速色谱法纯化(50％EtOAc的己烷溶液，然后90％Et2O的己烷溶液)，得到标题产物(0.320g)。1H NMR(CD3COCD3)δ2.72(3H，s)，3.15(3H，s)，7.09(2H，t)，7.52(2H，dd)，7.60(2H，d)，7.92(2H，d).
元素分析计算值：C17H14FNO2S2：
        C，58,78；H，4.03；N，4.03.
实测值：C，58.71，H，4.17；N，3.85.
                    实施例7 2-(4-氟苯基)-3-(4-(甲磺酰基)苯基)-2-环戊烯-1- 酮 步骤1： 1-(4-氟苯基)-5-己烯-2-酮
向冷却至0℃的14.6g(80mmol)CdCl2在200mL乙醚中的悬浮液中滴加115mL 1.3M的3-丁烯-1-溴化镁。将混合物回流1小时，然后蒸馏除去乙醚。加入苯(500mL)，接着加入17.5g(100mmol)4-氟苯基乙酰氯的溶液。回流1小时后，用200mL饱和的NH4Cl水溶液、50mL 1N HCl骤冷反应混合物，用200mL 1∶1的己烷/EtOAc萃取，用MgSO4干燥有机相并浓缩。残余物用快速色谱法纯化，用4∶1的己烷/EtOAc洗脱，得到15g标题产物。1H NMR(CDCl3)δ2.40(2H，t)，2.53(2H，t)，3.63(2H，s)，4.90-4.98(2H，m)，5.67-5.78(1H，m)，6.98(2H，t)，7.13(2H，m).步骤2： 1-(4-氟苯基)-5-氧代-2-戊酮
将14g 1-(4-氟苯基)-5-己烯-2-酮在200mL 3∶1的CH2Cl2/MeOH中的溶液冷却至-78℃，用过量的过硫酸氢钾制剂处理。所得的混合物用15g三苯膦处理，并在室温下搅拌1小时。浓缩反应混合物并且用3∶1的己烷/EtOAc进行快速色谱法纯化，得到8g标题的酮醛。
1H NMR(CDCl3)δ2.72(4H，s)，3.71(2H，s)，6.99(2H，t)，7.14(2H，m)，
9.73(1H，s).步骤3： 2-(4-氯苯基)-2-环戊烯-1-酮
用2g NaOMe处理8g 1-(4-氟苯基)-5-氧代-2-戊酮在300mL MeOH中的溶液。将混合物搅拌2小时，然后用5mL HOAc骤冷。蒸发溶剂，残余物用快速色谱法纯化，用3∶1的己烷/EtOAc洗脱，得到7g标题产物。
1H NMR(CDCl3)δ2.57(2H，m)，2.68(2H，m)，7.04(2H，J＝8.8Hz，t)，
7.67(2H，J＝8.8，5.5Hz，dd)，7.77(1H，m).步骤4： 1-(4-(甲硫基)苯基)-2-(4-氟苯基)-2-环戊 烯-1-醇
向冷却至-78℃的3.86g(19mmol)4-溴硫代苯甲醚在90mL Et2O中的溶液中滴加22mL 1.7M t-BuLi(38mmol)的戊烷溶液。在-78℃下将反应混合物搅拌15分钟，加入2.23g 2-(4-氟苯基)-2-环戊烯-1-酮在10mlEt2O中的溶液。在-78℃下搅拌15分钟后，将反应混合物温热至0℃，用50mL饱和的NH4Cl溶液骤冷，用100mL EtOAc萃取产物，用Na2SO4干燥，用快速色谱法纯化，用4∶1的己烷/EtOAc洗脱，得到3.4g所需的产物。
1H NMR(CDCl3)2.12(1H，s)，2.34(2H，m)，2.44(3H，s)，2.45-2.52
(1H，m)，2.56-2.65(1H，m)，6.37(1H，m)，6.84(2H，J＝8.7Hz，t)，7.17
(2H，J＝8.3Hz，d)，7.24-7.33(4H，m).步骤5： 2-(4-氟苯基)-3-(4-(甲硫基)苯基)-2-环 戊烯-1-酮
向PCC(4.5g，20.9mmol)和10g无水的4A分子筛在150mLCH2Cl2中的悬浮液中加入2.2g(7.3mmol)的1-(4-(甲硫基)苯基)-2-(4-氟苯基)-2-环戊烯-1-醇在20mLCH2Cl2中的溶液。混合物在室温下搅拌1小时，然后用300ml Et2O稀释。过滤并且浓缩后，残余物用快速色谱法纯化，用2∶1的己烷/EtOAc洗脱，得到1.5g标题产物。
1H NMR(CDCl3)δ2.45(3H，s)，2.68(2H，m)，3.00(2H，m)，7.02(2H，
J＝8.6Hz，t)，7.11(2H，J＝8.6Hz，d)，7.15-7.23(4H，m).步骤6： 2-(4-氯苯基)-3-(4-(甲磺酰基)苯基)-2- 环戊烯-1-酮
向50mg(0.17mmol)2-(4-氟苯基)-3-(4-(甲硫基)苯基)-2-环戊烯-1-酮在8ml 10∶1的CH2Cl2/MeOH中的溶液中加入124mg(0.2mmol)MPPM。将反应混合物在室温下搅拌2小时，然后用10ml 1∶1的己烷/EtOAc稀释。过滤并且浓缩后，残余物用快速色谱法纯化，用2∶1的EtOAc/己烷洗脱，得到45mg标题产物。1H NMR(丙酮-d6)δ2.67(2H，m)，3.14(3H，s)，3.16(2H，m)，7.05-7.10(2H，m)，7.20-7.25(2H，m)，7.63(2H，d)，7.93(2H，d).
               实施例8 4-(4-(甲磺酰基)苯基)-5-(4-氟苯基)异噻唑
向338mg(1mmol)的顺，反3-氯-3-(4-氟苯基)-2-(4-(甲磺酰基)苯基)丙烯醛在5mL丙酮中的溶液中加入230mg(3mmol)NH4SCN。将反应混合物回流3小时，然后用20mL饱和的NaHCO3骤冷，产物用100mLEtOAc萃取，用Na2SO4干燥，浓缩，用快速色谱法纯化，用3∶2的己烷/EtOAc洗脱，得到250mg标题产物。1H NMR(CDCl3)δ8.57(1H，s)，7.93(3H，d)，7.50(2H，d)，7.30(2H，t)，7.08(2H，t).
                实施例9 3-(4-氯苯基)-4-(4-(甲磺酰基)苯基)-2-(5H)- 呋喃酮 步骤1： 2-溴-1-(4-(甲磺酰基)苯基)乙酮
在30分钟内，向197g 4-(甲硫基)苯乙酮(参见：JACS，1952，74，p.5475)700mLMeOH和3500mLCH2Cl2中的溶液中加入881gMMPP。在室温下3小时后，过滤反应混合物，用2L饱和的NaHCO3水溶液和1L盐水洗涤滤液，再用2LCH2Cl2萃取水相。合并的萃取液用Na2SO4干燥，浓缩得到240g白色固体状4-(甲磺酰基)苯乙酮。
向冷却(-5℃)的174g 4-(甲磺酰基)苯乙酮在2.5LCHCl3中的溶液中加入20mgAlCl3，接着加入40mLBr2在300mLCHCl3中的溶液。然后用1.5L水处理反应混合物，分离出CHCl3层。用1LEtOAc萃取水层，合并的萃取液用Na2SO4干燥并浓缩。粗产物用50/50EtOAc/己烷重结晶，得到210g白色固体状2-溴-1-(4-(甲磺酰基)苯基)乙酮。步骤2：
向溶于乙腈(4mL)中的步骤1的产物(216mg)中加入Et3N(0.26mL)，接着加入4-氟苯基乙酸(102mg)。在室温下1.5小时后，加入0.23mLDBU，将反应混合物再搅拌45分钟，然后用5mL1N HCl处理。产物用EtOAc萃取，用Na2SO4干燥并浓缩。残余物用快速色谱法纯化(40％EtOAc的己烷溶液)，得到150mg固体标题化合物。1H NMR(CD3COCD3)δ3.15(3H，s)，5.36(3H，s)，7.18(2H，J＝8.9Hz，t)，7.46(2H，m)，7.7(2H，J＝8.65Hz，d)，7.97(2H，J＝8.68，d).
                实施例10 3-(4-氟苯基)-4-(4-(氧基磺酰基)苯基)-2-(2H) -呋喃酮
 1H NMR(CD3COCD3)δ5.34(2H，s)，6.67(2H，bd)，7.18(2H，m)，7.46
 (2H，m)，7.61(2H，m)，7.90(2H，m).
 M.P.187-188℃(d).
               实施例11 3-(4-氟苯基)-4-(4-(甲磺酰基)苯基)呋喃 步骤1：
在-78℃下，将实施例10的产物(0.2g)的THF(5mL)和甲苯(3mL)溶液缓慢加入DIBAL(0.72mL，1M的甲苯溶液)中。15分钟后，将溶液温热至0℃并且维持15分钟，然后将混合物倾入冷却的酒石酸钠钾和EtOAc的水溶液中。将有机层与一些樟脑磺酸晶体一起搅拌0.5小时，然后浓缩该溶液并用快速色谱法纯化，得到标题化合物。1H NMR(CDCl3)_3.1(3H，s)，7.02(2H，J＝8.9，t)，7.18(2H，m)，7.4(2H，J＝8.8Hz，d)，7.58(1H，s)，7.68(1H，s)，7.85(2H，J＝8.8Hz，d)
                     实施例12 5，5-二甲基-3-(4-氟苯基)-4-(4-甲磺酰基苯基)-2- (5H)-呋喃酮 步骤1： 2-三甲基甲硅烷氧基异丁酸甲酯
向1.2mL(10.4mmol) 2-羟基异丁酸甲酯在50mLCH2CL2中的溶液中加入1.2g(17.6mmol)咪唑和2.1mL(16.6mmol)TMSCl。在室温下将混合物搅拌1.5小时，用20mLH2O骤冷。用MgSO4干燥有机层，浓缩并且通过硅胶短柱，用9∶1的己烷/EtOAc洗脱。蒸发溶剂得到1.27g无色油状标题化合物。
1H NMR(CD3COCD3)80.08(9H，s)，1.38(6H，s)，3.67(3H，s).步骤2： 2-三甲基甲硅烷氧基-4′-(甲硫基)异丙基苯基 甲酮
将204mg(1.0mmol)4-溴硫代苯甲醚在2.5mLTHF中的溶液冷却至-78℃，用0.42mL2.5M n-BuLi的己烷溶液处理。在-78℃下搅拌1小时后，加入380mg(2.0mmol)2-三甲基甲硅烷氧基异丁酸甲酯在2mLTHF中的溶液。将混合物在-78℃下搅拌2小时，然后用NH4OAc缓冲液骤冷，产物用EtOAc萃取，用MgSO4干燥并且浓缩。残余物用快速色谱法纯化，用19∶1的己烷/EtOAc洗脱，得到95mg标题产物。1H NMR(CD3COCD3)δ0.05(9H，s)，1.52(6H，s)，2.53(3H，s)，7.33(2H，d)，8.12(2H，d).步骤3： 2-羟基-4′-(甲硫基)异丙基苯基甲酮
向40mg(0.14mmol)2-三甲基甲硅烷氧基-4′-(甲硫基)异丙基苯基甲酮在2mLTHF中的溶液中加入0.2mL1M n-Bu4NF的THF溶液。将所得的混合物搅拌30分钟，然后用10ml NH4OAc缓冲液骤冷。产物用EtOAc萃取，用MgSO4干燥并且浓缩。残余物用快速色谱法纯化，用4∶1的己烷/EtOAc洗脱，得到25mg标题产物。1H NMR(CD3COCD3)δ1.50(6H，s)，2.54(3H，s)，4.68(1H，s)，7.30(2H，d)，8.15(2H，d).步骤4： 2-(4-氟苯基乙酰氢基)-4′-(甲硫基)异丙 基苯基甲酮
向72mg(0.34mmol)2-羟基-4′-(甲硫基)异丙基苯基甲酮在1.7mLCH2Cl2中的溶液中加入0.2mL吡啶和140mg(0.81mmol)4-氟苯基乙酰氯。将混合物在室温下搅拌过夜，然后用NH4OAc缓冲液骤冷，产物用EtOAc萃取，用MgSO4干燥并且浓缩。粗产物用快速色谱法纯化，用8∶1的己烷/EtOAc洗脱，得到95mg标题产物。
1H NMR(CD3COCD3)51.62(3H，s)，1.67(3H，s)，2.48(3H，s)，3.79
(2H，s)，7.0-7.3(6H，m)，7.78(2H，d).步骤5： 5，5-二甲基-3-(4-氟苯基-4-(4-甲硫基苯基) -2-(5H)-呋喃酮
向95mg2-(4-氟苯基乙酰氧基)-4′-(甲硫基)异丙基苯基甲酮在4mLCH2Cl2中的溶液中加入0.2mL1，8-二氮杂双环(5.4.0)十一碳-7-烯。将混合物搅拌4小时，然后用NH4OAc缓冲液稀释。产物用EtOAc萃取，用MgSO4干燥并且浓缩。残余物用快速色谱法纯化，用20∶1的甲苯/EtOAc洗脱，得到75mg标题产物。
1H NMR(CD3COCD3)δ1.58(6H，s)，2.50(3H，s)，7.03(2H，dd)，7.25-
7.35(4H，m)，7.41(2H，dd).步骤6： 5，5-二甲基-3-(4-氟苯基)-4-(4-甲磺酰基 苯基)-2-(5H)-呋喃酮
向81mg 5，5-二甲基-3-(4-氟苯基-4-(4-甲硫基苯基)-2-氧代-2H-二氢呋喃在1.8mLCH2Cl2和0.2mLMeOH中的溶液中加入250mgMPPM。将反应混合物在室温下搅拌1小时，然后用NaHCO3水溶液骤冷。产物用EtOAc萃取，用MgSO4干燥并浓缩。粗产物用快速色谱法纯化，用1∶1的己烷/EtOAc洗脱，得到73mg标题产物。1H NMR(CD3COCD3)δ1.62(6H，s)，3.15(3H，s)，7.02(2H，dd)，7.40(2H，dd)，7.65(2H，d)，8.03(2H，d).
                实施例13 2-((4-氧基磺酰基)苯基)-3-(4-氟苯基)噻吩 1H NMR(CD3COCD3)δ6.60(2H，bs)，7.12(2H，t)，7.25(1H，d)，7.35(2H，m)，7.45(2H，d)，7.65(1H，d)，7.85(2H，d).
元素分析：计算值：C16H12FNS2O2
        C，57.65；H，3.60；N，4.20
实测值：C，57.55；H，3.79；N，4.03
                  实施例14 3-(4-(三氟乙酰氨基磺酰基)苯基)-2-(4-氟苯基)噻 吩
1H NMR(300MHz，CD3COCD3)δ7.15(2H，t)，7.30(3H，m)，7.45(2H，
d)，7.65(1H，d)，7.95(2H，d).
                  实施例15 3-(2，4-二氟苯基)-4-(4-(甲磺酰基)苯基)-2-(5H) -呋喃酮
    元素分析：计算值 C17H12F2O4S
            C，58.28；H，3.45；S，9.15
    实测值：C，58.27；H，3.50；S，9.27
                  实施例16 3-(3，4-二氟苯基)-4-(4-(甲基磺酰基)苯基)-2- (5H)-呋喃酮
在室温下，向3，4-二氟苯基乙酸(ALDRICHCHEMICAL)(10g)和2-溴-1-(4-(甲磺酰基)苯基)乙酮(实施例9，步骤1)(17.3g)的乙腈(200mL)溶液中缓慢加入三乙胺(20.2mL)。在室温下1小时后，在冰浴中冷却反应混合物，用17.4mLDBU处理。在0℃下2小时后，用200mL 1N HCl处理混合物，产物用EtOAc萃取，用Na2SO4干燥并浓缩。将残余物加到硅胶柱的顶部(烧结玻璃板漏斗)，用75％EtOAc/己烷洗脱，蒸发溶剂，用乙酸乙酯洗涤，得到10g标题化合物。
 元素分析 计算值 C17H12F2O4S
          C，58.28；H，3.45；S，9.15
 实测值   C，58.02；H，3.51；S，9.35
                  实施例17 3-(2，6-二氟苯基)-4-(4-(甲磺酰基)苯基)-2-(5H) -呋喃酮
     元素分析 计算值 C17H12F2O4S
            C，58.28；H，3.45；S，9.15
     实测值 C，58.18；H，3.50；S，9.44
                  实施例18 3-(2，5-二氟苯基)-4-(4-(甲磺酰基)苯基)-2-(5H) -呋喃酮
     元素分析 计算值 C17H12F2O4S
            C，58.28；H，3.45；S，9.15
     实测值 C，58.89；H，3.51；S，9.11
                  实施例19 3-(3，5-二氟苯基)-4-(4-(甲磺酰基)苯基)-2-(5H) -呋喃酮
     元素分析 计算值 C17H12F2O4S
            C，58.28；H，3.45；S，9.15
     实测值 C，58.27；H，3.62；S，9.32
                  实施例20 3-(4-溴苯基)-4-(4-(甲磺酰基)苯基)-2-(5H)- 呋喃酮
元素分析 计算值   C17H13BrO4S
       C，51.94；H，3.33；S，8.16
实测值 C，51.76；H，3.42；S，8.21
                 实施例21 3-(4-氯苯基)-4-(4-(甲磺酰基)苯基)-2-(5H)- 呋喃酮 1H NMR(300MHz，CDCl3)δ7.93(2H，d)，7.49(2H，d)，7.35(4H，m)，5.16(2H，s)，3.06(3H，s)
                 实施例22 3-(4-甲氧基苯基)-4-(4-(甲磺酰基)苯基)-2-(5H) -呋喃酮
元素分析  计算值 C18H16O5S
       C，62.78 H，4.68；S，9.31
实测值 C，62.75；H，4.72；S，9.39
                 实施例23 3-(苯基)-4-(4-(甲磺酰基)苯基)-2-(5H)-呋喃酮
在25℃下，向苯基乙酸(27.4g，201mmol)和2-溴-1-(4-(甲磺酰基)苯基)乙酮(实施例9，步骤1)(60g，216mmol，1.075eq.)的乙腈(630mL)溶液中缓慢加入三乙胺(30.8mL，1.1eq.)。将混合物在室温下搅拌20分钟，然后在冰浴中冷却。缓慢加入DBU(60.1mL，3eq.)。在冰浴中搅拌20分钟后，反应完成，用1N HCl酸化混合物(颜色从棕黑色变为黄色)，然后加入2.4L冰和水，搅拌几分钟后，过滤出沉淀，用水冲洗(得到64g粗湿产物)。将固体溶于750mL二氯甲烷中(用MgSO4干燥，过滤)，加入300g硅胶。蒸发溶剂至近干(硅胶稍有粘性)，将残余物加到硅胶柱顶部(烧结玻璃板漏斗)，用10％EtOAc/CH2Cl2洗脱，蒸发溶剂，用乙酸乙酯洗涤，得到36.6g(58％)标题化合物。
 元素分析  计算值    C17H14O4S
         C，64.95；H，4.49；S，10.20
 实测值  C，64.63；H，4.65；S，10.44
                 实施例24 3-(2-氯苯基)-4-(4-(甲磺酰基)苯基)-2-(5H)- 呋喃酮
 元素分析 计算值 C17H13ClO4S
         C，58.54；H，3.76；S，9.19
 实测值  C，58.59；H，3.80；S，9.37
                 实施例25 3-(2-溴-4-氟苯基)-4-(4-(甲磺酰基)苯基)-2-(5H) -呋喃酮
 元素分析 计算值 C17H12BrFO4S
         C，49.75；H，2.93
 实测值  C，49.75；H，3.01
               实施例26 3-(2-溴-4-氯苯基)-4-(4-(甲磺酰基)苯基)-2-(5H) -呋喃酮
1H NMR(300MHz，丙酮-d6)δ7.95(2H，d)，7.85(1H，d)，7.63(2H，
dd)，7.55(1H，dd)，7.45(1H，d)，5.50(2H，s)，3.15(3H，s)
               实施例27 3-(4-氨-2-氨苯基)-4-(4-(甲磺酰基)苯基)-2-(5H) -呋喃酮
1H NMR(300MHz，丙酮-d6)δ8.0(2H，d)，7.7O(2H，d)，7.50-7.30(3H，
m)，5.35(2h，s)，3.15(3H，s)
               实施例28 3-(3-溴-4-氟苯基)-4-(4-(甲磺酰基)苯基)-2-(5H) -呋喃酮
 元素分析 计算值 C17H12BrFO4S
        C，49.75；H，2.93
 实测值 C，49.44；H，2.98
               实施例29 3-(3-氨苯基)-4-(4-(甲磺酰基)苯基)-2-(5H)- 呋喃酮
 元素分析 计算值 C17H13ClO4S
         C，58.54；H，3.76
 实测值  C，58.29；H，3.76
               实施例30 3-(2-氯-4-氟苯基)-4-(4-(甲磺酰基)苯基)-2-(5H) -呋喃酮
元素分析 计算值 C17H12ClFO4S
         C，55.67；H，3.30
实测值   C，55.67；H，3.26
               实施例31 3-(2，4-二氯苯基)-4-(4-(甲磺酰基)苯基)-2-(5H) -呋喃酮
元素分析计算值 C17H12Cl2O4S
        C，53.28；H，3.16；S，8.37
实测值  C，52.89；H，3.23；S，8.58
               实施例32 3-(3，4-二氯苯基)-4-(4-(甲磺酰基)苯基)-2-(5H) -呋喃酮
元素分析 计算值 C17H12Cl2O4S
        C，53.28；H，3.16；S，8.37
实测值  C，53.07；H，3.32；S，8.51
               实施例33 3-(2，6-二氯苯基)-4-(4-(甲磺酰基)苯基)-2-(5H) -呋喃酮
元素分析 计算值 C17H12Cl2O4S
        C，53.28；H，3.16；S，8.37
实测值  C，52.99；H，3.22；S，8.54
                实施例34 3-(3-氯-4-氟苯基)-4-(4-(甲磺酰基)苯基)-2-(5H) -呋喃酮 1H NRR(300MHz，丙酮 -d6)d 8.O(2H，d)，7.70(2H，d)，7.60(1H，d)，7.25-7.40(2H，m)，5.35(2H，s)，3.15(3H，s)
                实施例35 3-(4-三氟甲基苯基)-4-(4-(甲磺酰基)苯基)-2-(5H) -呋喃酮
1H NMR(CD3COCD3)δ8.10(2H，d)，7.82-7.93(4H，m)，7.75(2H，d)，
5.55(2H，s)，3.30(3H，s)
                实施例36 3-(3-氟-4-甲氧基苯基)-4-(4-(甲磺酰基)苯基)-2- (5H)-呋喃酮
      元素分析 计算值 C18H15FO5S
             C，59.66；H，4.17
      实测值 C，59.92；H，4.37
                实施例37 3-(3-氯-4-甲氧基苯基)-4-(4-(甲磺酰基)苯基)-2- (5H)-呋喃酮
      元素分析 计算值 C18H15ClO5S
             C，57.07；H，3.99
      实测值 C，57.29；H，4.15
             实施例38 3-(3-溴-4-甲氧基苯基)-4-(4-(甲磺酰基)苯基)-2- (5H)-呋喃酮
 元素分析  计算值   C18H15BrO5S
        C，51.08；H，3.57
 实测值 C，51.38；H，3.62
             实施例39 3-(2-氟苯基)-4-(4-(甲磺酰基)苯基)-2-(5H)- 呋喃酮
 元素分析  计算值   C17H13FO4S
        C，61.44；H，3.94
 实测值 C，61.13；H，3.85
                实施例40 3-(4-甲硫基苯基)-4-(4-(甲磺酰基)苯基)-2-(5H) -呋喃酮
1H NMR(300MHz，丙酮  -d6)d 8.0(2H，d)，7.70(2H，d)，7.35(2H，d)，
7.25(2H，d)，5.35(2H，s)，3.15(3H，s)，2.55(3H，s)
                实施例41 3-(3-氟苯基)-4-(4-(甲磺酰基)苯基)-2-(5 H)- 呋喃酮
1H NMR(300MHz，CDCl3)d 7.93(2H，d)，7.49(2H，d)，7.35(1H，m)，
7.12(3H，m)，5.18(2H，s)，3.06(3H，s)
                 实施例42 3-(2-氯-6-氟苯基)-4-(4-(甲磺酰基)苯基)-2-(5H) -呋喃酮 1H NMR(300MHz，丙酮 -d6)，d8.0(2H，d)，7.70(2H；d)，7.55-7.65(1H，m)，7.40(1H，d)，7.30(1H，m)，5.60(2H，s)，3.15(3H，s)
                 实施例43 3-(3-溴-4-甲基苯基)-4-(4-(甲磺酰基)苯基)-2-(5H) -呋喃酮
  元素分析 计算值 C18H15BrO4S
          C，53.08；H，3.71
  实测值：C，53.06；H，3.83
                 实施例44 3-(4-溴-2-氟苯基)-4-(4-(甲磺酰基)苯基)-2-(5H) -呋喃酮
   元素分析 计算值 C17H12BrFO4S
           C，49.65；H，2.94
   实测值：C，49.76；H，3.00
                 实施例45 3-( 3，4-二溴苯基)-4-(4-(甲磺酰基)苯基)-2-(5H) -呋喃酮 1H NMR(300MHz，丙酮-d6)δ8.0(2H，d)，7.80(1H，d)，7.75(3H，m)，7.25(1H，d)，5.35(2H，s)，3.15(sH，s)
               实施例46 3-(4-氯-3-氟苯基)-4-(4-(甲磺酰基)苯基)-2-(5H) -呋喃酮
    元素分析  计算值 C17H12ClFO4S
           C，55.67；H，3.30
    实测值 C，55.45；H，3.30
               实施例47 3-(4-溴-3-氟苯基)-4-(4-(甲磺酰基)苯基)-2-(5H) -呋喃酮
    元素分析 计算值   C17H12BrFO4S
           C，49.66；H，2.94；S，7.80
    实测值 C，49.79；H，3.01；S，7.51
               实施例48 3-(4-溴-2-氯苯基)-4-(4-(甲磺酰基)苯基)-2-(5H) -呋喃酮
    元素分析  计算值   C17H12BrClO4S
           C，47.74；H，2.83；S，7.50
    实测值 C，47.92；H，2.84；S，7.42
               实施例49 3-(2-萘基)-4-(4-(甲磺酰基)苯基)-2-(5H)-呋 喃酮
    元素分析  计算值 C21H16O4S
           C，69.22；H，4.43
    实测值 C，69.22；H，4.46
              实施例50 3-(7-喹啉基)-4-(4-(甲磺酰基)苯基)-2-(5H)- 呋喃酮
元素分析  计算值 C20H15NO4S
       C，65.74；H，4.14；N，3.83
实测值 C，65.34；H，4.40；N，3.80M.S.(DCI，CH4)计算值 M+，365
          实测值 M++1，366
                  实施例51 3-(3，4-二氯苯基)-4-(4-(氨基磺酰基)苯基)-2- (2H)-呋喃酮 1H NMR(400MHz，CD3COCD3)δ7.92(2H，dd)，7，64(3H，dm)，7.60(1H，dd)，7.32(1H，dd)，6.70(1H，bs)，5.38(2H，s)
                  实施例52 3-(3，4-二氟苯基)-4-(4-(氨基磺酰基)苯基)-2- (2H)-呋喃酮 1H NMR(400MHZ，CD3COCD3)δ7.92(2H，dd)，7，64(2H，dd)，7.30-7.45(2H，m)，7.22(1H，m)，6.68(2H，bs)，5.37(2H，s)
                  实施例53 3-(3-氯-4-甲氧基苯基)-4-(4-(氨基磺酰基)苯基)- 2-(2H)-呋喃酮
元素分析  计算值   C17H14ClNO5S
       C，53.76；H，3.72，N，3.69
实测值 C，53.32；H，3.84，N，3.59M.S.(DCI，CH4)计算值   M+，379
          实测值M  ++1，380
           实施例54 3-(3-溴-4-甲氧基苯基)-4-(4-(氨基磺酰基)苯基)- 2-(2H)-呋喃酮
元素分析  计算值    C17H14BrNO5S
       C，48.13；H，3.33，N，3.30
实测值 C，48.26；H，3.40，N，3.28M.S.(DCI，CH4) 计算值  M+，423
          实测值   M++1，424
           实施例55 3-(苯基)-4-(4-(甲磺酰基)苯基)-2-(5H)-呋喃酮
在氮气氛下向20ml玻璃安瓿瓶中加入1g2-(4-(甲磺酰基)苯基)苯基乙炔、20mgRh4(CO)12、1.5gEt3N、10mLTHF、1ml水；将安瓿瓶放入100ml不锈钢的高压釜中。用CO冲洗反应体系3次，然后在室温下使初始的CO压力为100atm。反应在100℃下进行5小时，然后溶液用50ml苯稀释，并用盐水、1N HCl洗涤。用Na2SO4干燥苯溶液并浓缩，粗产物用硅胶柱色谱法分离，用2∶1EtOAc/己烷洗脱，得到标题化合物及其区域异构体。
                实施例56 3-(苯基)-4-(4-(甲磺酰基)苯基)-2-(5H)-呋喃酮 步骤1： 2-三甲基甲硅烷氧基-4-(4-甲硫基)苯基)-3， 4-二氢呋喃
向在-78℃下冷却的3.86g(19mmol)4-溴硫代苯甲醚在90mLEt2O中的溶液中滴加入22ml1.7M t-BuLi的戊烷溶液(38mmol)。将反应混合物在-78℃下搅拌15分钟，加入3.8gCuI，然后在30分钟内使反应混合物温热至-40℃。加入1.7g2(5H)-呋喃酮在10mlTHF中的溶液，搅拌1小时后，滴加2ml新蒸馏的TMSCl。然后用2mlEt3N和50ml饱和NaHCO3溶液处理反应混合物，并用100ml乙醚萃取。用Na2SO4干燥乙醚层并浓缩得到粗标题化合物，不经进一步纯化即用于下一步骤。步骤2： 4-(4-甲硫基)苯基)-2-(5H)-呋喃酮
在氮气氛、室温下，向4g Pd(OAc)2在100ml乙腈中的溶液中滴加入步骤1的粗产物(5g)。在室温下10小时后，在减压下浓缩混合物，残余物用硅胶快速色谱法纯化，用2∶1己烷/EtOAc洗脱，得到标题化合物。步骤3： 3-碘-4-(4-甲硫基)苯基)-2-(5H)-呋喃酮
向3g步骤2的产物在30ml吡啶中的溶液中加入3.7gI2，将混合物搅拌24小时，然后用200ml乙醚稀释，用100ml5N HCl和50ml 5N Na2S2O3洗涤。用Na2S2O4干燥乙醚层并浓缩，得到标题化合物。步骤4： 3-(苯基)-4-(4-(甲硫基)苯基)-2-(5H) -呋喃酮
将4g步骤3的产物、3.7gPhB(OH)2、4gPh3As、0.4gPdCl2(PhCN)2在100ml苯和15ml2N NaOH中的混合物回流6小时，然后加入乙醚(200ml)，用100ml饱和的NaHCO3溶液洗涤混合物，用MgSO4干燥有机层并浓缩。残余物用硅胶快速色谱法纯化，用4∶1己烷/EtOAc洗脱，得到标题化合物。步骤5： 3-(苯基)-4-(4-(甲磺酰基)苯基)-2-(5H) -呋喃酮
向3g步骤4的产物在80ml 10∶1 CH2Cl2/MeOH中的溶液中加入5.5gMPPM，将反应混合物在室温下搅拌2小时，然后用100ml 1∶1己烷/EtOAc稀释。过滤并浓缩后，将残余物用快速色谱法纯化，用2∶1 EtOAc/己烷洗脱，得到标题产物。

Claims (2)

1.式A化合物：
Figure C0010098100021
其中R1选自：
    (a)S(O)2CH3，
    (b)S(O)2NH2，R2选自一或二取代的苯基，其中取代基选自：
    (1)       氢，
    (2)       卤素，
    (3)       C1-4烷氧基，
    (4)       C1-4烷硫基，
    (5)      CN，
    (6)      CF3，
    (7)       C1-4烷基，
    (8)      N3，和
    (9)       -C(R5)(R6)-OH；R5和R6各自独立地选自：
    (a)       氢，
    (b)       甲基或乙基，或R5和R6与它们所连的碳原子一起形成4、5或6个原子的饱和碳环。
2.权利要求1的化合物，其中R1为甲磺酰基，R2为苯基。
CN00100981A 1993-06-24 2000-01-12 用作环氧酶－2抑制剂的苯基杂环化合物 Expired - Fee Related CN1129576C (zh)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US8219693A 1993-06-24 1993-06-24
US082196 1993-06-24
US08/179,467 US5474995A (en) 1993-06-24 1994-01-10 Phenyl heterocycles as cox-2 inhibitors
US082,196 1994-01-10
US179,467 1994-01-10
US179467 1994-01-10

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
CN94192580A Division CN1058008C (zh) 1993-06-24 1994-06-09 用作环氧酶－２抑制剂的苯基杂环化合物

Publications (2)

Publication Number Publication Date
CN1295065A CN1295065A (zh) 2001-05-16
CN1129576C true CN1129576C (zh) 2003-12-03

Family

ID=26767192

Family Applications (2)

Application Number Title Priority Date Filing Date
CN94192580A Expired - Fee Related CN1058008C (zh) 1993-06-24 1994-06-09 用作环氧酶－２抑制剂的苯基杂环化合物
CN00100981A Expired - Fee Related CN1129576C (zh) 1993-06-24 2000-01-12 用作环氧酶－2抑制剂的苯基杂环化合物

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CN94192580A Expired - Fee Related CN1058008C (zh) 1993-06-24 1994-06-09 用作环氧酶－２抑制剂的苯基杂环化合物

Country Status (36)

Country Link
US (5) US5474995A (zh)
EP (4) EP0980866A3 (zh)
JP (1) JP2977137B2 (zh)
KR (1) KR100215358B1 (zh)
CN (2) CN1058008C (zh)
AT (1) ATE165825T1 (zh)
AU (1) AU6967494A (zh)
BG (1) BG63161B1 (zh)
BR (1) BR9406979A (zh)
CA (5) CA2364039A1 (zh)
CY (1) CY2098B1 (zh)
CZ (1) CZ288175B6 (zh)
DE (1) DE69410092T2 (zh)
DK (1) DK0705254T3 (zh)
ES (1) ES2115237T3 (zh)
FI (2) FI112222B (zh)
HK (1) HK1027474A1 (zh)
HR (1) HRP940373A2 (zh)
HU (1) HU227913B1 (zh)
IL (3) IL123002A (zh)
LV (1) LV12209B (zh)
MX (1) MX9404749A (zh)
NO (1) NO307253B1 (zh)
NZ (1) NZ267386A (zh)
PL (1) PL178203B1 (zh)
RO (1) RO115354B1 (zh)
RU (1) RU2131423C1 (zh)
SA (1) SA94150039B1 (zh)
SG (1) SG52703A1 (zh)
SI (1) SI0705254T1 (zh)
SK (1) SK284114B6 (zh)
TW (1) TW326042B (zh)
UA (1) UA48939C2 (zh)
WO (1) WO1995000501A2 (zh)
YU (1) YU49053B (zh)
ZA (1) ZA944501B (zh)

Families Citing this family (466)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5663180A (en) * 1983-10-29 1997-09-02 G.D. Searle & Co. Substituted cyclopentenes for the treatment of inflammation
ES2111288T3 (es) * 1993-01-15 1998-03-01 Searle & Co Nuevos 3,4-diaril tiofenos y analogos de los mismos utiles como agentes antiinflamatorios.
US6492413B2 (en) 1993-01-15 2002-12-10 G.D. Searle & Co. 3.4-diaryl thiophenes and analogs thereof having use as antiinflammatory agents
GB9420616D0 (en) * 1994-10-12 1994-11-30 Merck Sharp & Dohme Method, compositions and use
US6090834A (en) * 1993-05-21 2000-07-18 G.D. Searle & Co. Substituted oxazoles for the treatment of inflammation
GB9602877D0 (en) * 1996-02-13 1996-04-10 Merck Frosst Canada Inc 3,4-Diaryl-2-hydroxy-2,5- dihydrofurans as prodrugs to cox-2 inhibitors
US5840746A (en) * 1993-06-24 1998-11-24 Merck Frosst Canada, Inc. Use of inhibitors of cyclooxygenase in the treatment of neurodegenerative diseases
US5474995A (en) * 1993-06-24 1995-12-12 Merck Frosst Canada, Inc. Phenyl heterocycles as cox-2 inhibitors
EP0739340A1 (en) * 1994-01-10 1996-10-30 Merck Frosst Canada Inc. Phenyl heterocycles as cox-2 inhibitors
CA2195847A1 (en) * 1994-07-27 1996-02-08 John J. Talley Substituted thiazoles for the treatment of inflammation
US6613789B2 (en) 1994-07-28 2003-09-02 G. D. Searle & Co. Heterocyclo-substituted imidazoles for the treatment of inflammation
US5620999A (en) * 1994-07-28 1997-04-15 Weier; Richard M. Benzenesulfonamide subtituted imidazolyl compounds for the treatment of inflammation
US5616601A (en) * 1994-07-28 1997-04-01 Gd Searle & Co 1,2-aryl and heteroaryl substituted imidazolyl compounds for the treatment of inflammation
US6426360B1 (en) * 1994-07-28 2002-07-30 G D Searle & Co. 4,5-substituted imidazolyl compounds for the treatment of inflammation
US6239172B1 (en) * 1997-04-10 2001-05-29 Nitrosystems, Inc. Formulations for treating disease and methods of using same
GB2294879A (en) * 1994-10-19 1996-05-15 Merck & Co Inc Cylcooxygenase-2 Inhibitors
US5849943A (en) * 1994-10-27 1998-12-15 Merck Frosst Canada, Inc. Stilbene derivatives useful as cyclooxygenase-2 inhibitors
JP2636819B2 (ja) 1994-12-20 1997-07-30 日本たばこ産業株式会社 オキサゾール系複素環式芳香族化合物
JPH10511089A (ja) * 1994-12-21 1998-10-27 メルク フロスト カナダ インコーポレーテツド Ｃｏｘ−２阻害剤としてのジアリール−２−（５ｈ）−フラノン
US5633272A (en) * 1995-02-13 1997-05-27 Talley; John J. Substituted isoxazoles for the treatment of inflammation
WO1996025405A1 (en) * 1995-02-13 1996-08-22 G.D. Searle & Co. Substituted isoxazoles for the treatment of inflammation
US5691374A (en) * 1995-05-18 1997-11-25 Merck Frosst Canada Inc. Diaryl-5-oxygenated-2-(5H) -furanones as COX-2 inhibitors
US5643933A (en) * 1995-06-02 1997-07-01 G. D. Searle & Co. Substituted sulfonylphenylheterocycles as cyclooxygenase-2 and 5-lipoxygenase inhibitors
WO1996038418A1 (en) 1995-06-02 1996-12-05 G.D. Searle & Co. Heterocyclo substituted hydroxamic acid derivatives as cyclooxygenase-2 and 5-lipoxygenase inhibitors
US6512121B2 (en) 1998-09-14 2003-01-28 G.D. Searle & Co. Heterocyclo substituted hydroxamic acid derivatives as cyclooxygenase-2 and 5-lipoxygenase inhibitors
US6515014B2 (en) 1995-06-02 2003-02-04 G. D. Searle & Co. Thiophene substituted hydroxamic acid derivatives as cyclooxygenase-2 and 5-lipoxygenase inhibitors
US6156776A (en) * 1995-06-08 2000-12-05 Yu; Dingwei Tim Diaryl substituted thiazoles useful in the treatment of fungal infections
EP0833622B8 (en) * 1995-06-12 2005-10-12 G.D. Searle & Co. Compositions comprising a cyclooxygenase-2 inhibitor and a 5-lipoxygenase inhibitor
CA2224563A1 (en) * 1995-06-12 1996-12-27 G.D. Searle & Co. Combination of a cyclooxygenase-2 inhibitor and a leukotriene b4 receptor antagonist for the treatment of inflammations
US5700816A (en) * 1995-06-12 1997-12-23 Isakson; Peter C. Treatment of inflammation and inflammation-related disorders with a combination of a cyclooxygenase-2 inhibitor and a leukotriene A4 hydrolase inhibitor
US6593361B2 (en) 1995-07-19 2003-07-15 Merck & Co Inc Method of treating colonic adenomas
US5968974A (en) * 1995-07-19 1999-10-19 Merck & Co., Inc. Method of treating colonic adenomas
US5837719A (en) * 1995-08-10 1998-11-17 Merck & Co., Inc. 2,5-substituted aryl pyrroles, compositions containing such compounds and methods of use
US5792778A (en) * 1995-08-10 1998-08-11 Merck & Co., Inc. 2-substituted aryl pyrroles, compositions containing such compounds and methods of use
US5786515A (en) * 1995-09-15 1998-07-28 Merck & Co., Inc. Synthesis of α-chloro or fluoro ketones
AU6981996A (en) * 1995-09-27 1997-04-17 Merck Frosst Canada Inc. Compositions for treating inflammation containing certain prostaglandins and a selective cyclooxygenase-2 inhibitor
US6083949A (en) * 1995-10-06 2000-07-04 Merck & Co., Inc. Substituted imidazoles having anti-cancer and cytokine inhibitory activity
US5717100A (en) * 1995-10-06 1998-02-10 Merck & Co., Inc. Substituted imidazoles having anti-cancer and cytokine inhibitory activity
US5981576A (en) * 1995-10-13 1999-11-09 Merck Frosst Canada, Inc. (Methylsulfonyl)phenyl-2-(5H)-furanones as COX-2 inhibitors
UA57002C2 (uk) * 1995-10-13 2003-06-16 Мерк Фросст Кенада Енд Ко./Мерк Фросст Кенада Енд Сі. Похідне (метилсульфоніл)феніл-2-(5н)-фуранону, фармацевтична композиція та спосіб лікування
US6020343A (en) * 1995-10-13 2000-02-01 Merck Frosst Canada, Inc. (Methylsulfonyl)phenyl-2-(5H)-furanones as COX-2 inhibitors
EP0859642A2 (en) * 1995-10-17 1998-08-26 G.D. Searle & Co. Method of detecting cyclooxygenase-2
DE69618820T2 (de) * 1995-10-30 2002-06-20 Merck Frosst Canada & Co., Halifax 3,4-diaryl-2-hydroxy-2,5-dihydrofurane als wirkstoffvorstufen von cox-2 inhibitoren
US6222048B1 (en) * 1995-12-18 2001-04-24 Merck Frosst Canada & Co. Diaryl-2-(5H)-furanones as Cox-2 inhibitors
DK0880504T3 (da) * 1996-01-26 2003-07-21 Searle & Co Heterocyclosubstituerede imidazoler til behandling af inflammation
US5789413A (en) * 1996-02-01 1998-08-04 Merck Frosst Canada, Inc. Alkylated styrenes as prodrugs to COX-2 inhibitors
US5733909A (en) * 1996-02-01 1998-03-31 Merck Frosst Canada, Inc. Diphenyl stilbenes as prodrugs to COX-2 inhibitors
ES2147973T3 (es) * 1996-02-01 2000-10-01 Merck Frosst Canada Inc Estirenos alquilatados como profarmacos de inhibidores de cox-2.
EP0882015B1 (en) * 1996-02-01 2000-12-27 Merck Frosst Canada & Co. Diphenyl stilbenes as prodrugs to cox-2 inhibitors
EP1640003A2 (en) * 1996-02-13 2006-03-29 G.D. SEARLE & CO. Compositions comprising a Cyclooxygenase-2 Inhibitor and a Leukotriene B4 receptor antagonist
WO1997029774A1 (en) 1996-02-13 1997-08-21 G.D. Searle & Co. Combinations, having immunosuppressive effects, containing a cyclooxygenase-2 inhibitor and a leukotriene a4 hydrolase inhibitor
DK0888127T3 (da) 1996-02-13 2002-04-08 Searle & Co Kombinationer med immunoundertrykkende virkninger indeholdende cyclooxygenase-2-inhibitorer og 5-lipooxygenaseinhibitortorer
HUP9902645A3 (en) * 1996-03-18 1999-12-28 Eisai Co Ltd Fused-ring carboxylic acid derivatives
AU706518B2 (en) * 1996-03-29 1999-06-17 Merck Frosst Canada & Co. Bisarylcyclobutene derivates as cyclooxygenase inhibitors
US5807873A (en) * 1996-04-04 1998-09-15 Laboratories Upsa Diarylmethylidenefuran derivatives and their uses in therapeutics
FR2747123B1 (fr) * 1996-04-04 1998-06-26 Union Pharma Scient Appl Nouveaux derives diarylmethylidene tetrahydrofurane, leurs procedes de preparation, et leurs utilisations en therapeutique
US6180651B1 (en) * 1996-04-04 2001-01-30 Bristol-Myers Squibb Diarylmethylidenefuran derivatives, processes for their preparation and their uses in therapeutics
US5908858A (en) 1996-04-05 1999-06-01 Sankyo Company, Limited 1,2-diphenylpyrrole derivatives, their preparation and their therapeutic uses
RO121338B1 (ro) 1996-04-12 2007-03-30 G.D. Searle & Co. Derivaţi de benzensulfonamidă, procedeu de preparare a acestora, compoziţie farmaceutică şi utilizarea ca inhibitori de cox-2
JP2000509032A (ja) * 1996-04-23 2000-07-18 メルク フロスト カナダ アンド カンパニー 選択的シクロオキシゲナーゼ―２阻害剤としてのピリジニル―２―シクロペンテン―１―オン
US5922742A (en) * 1996-04-23 1999-07-13 Merck Frosst Canada Pyridinyl-2-cyclopenten-1-ones as selective cyclooxygenase-2 inhibitors
HUP9902889A3 (en) * 1996-05-17 2002-04-29 Merck Frosst Canada & Co Kirkl The use of 3-phenyl-4-(4-methylsulphonyl)-phenyl-2-(5h)-furanone for producing anti inflammatory medicaments and such medicaments
AU775030B2 (en) * 1996-05-17 2004-07-15 Merck Frosst Company Compositions for a once a day treatment of cyclooxygenase-2 mediated diseases
CA2254121A1 (en) * 1996-05-17 1997-11-27 Bruno Hancock Compositions for a once a day treatment of cyclooxygenase-2 mediated diseases
HRP970289A2 (en) * 1996-05-31 1998-04-30 Merck & Co Inc Process for preparing phenyl heterocycles useful as cox-2 inhibitors
US6677364B2 (en) 1998-04-20 2004-01-13 G.D. Searle & Co. Substituted sulfonylphenylheterocycles as cyclooxygenase-2 and 5-lipoxygenase inhibitors
US5883267A (en) * 1996-05-31 1999-03-16 Merck & Co., Inc. Process for making phenyl heterocycles useful as cox-2 inhibitors
JP3418624B2 (ja) * 1996-06-10 2003-06-23 メルク エンド カンパニー インコーポレーテッド サイトカイン阻害活性を有する置換イミダゾール類
GB9615867D0 (en) * 1996-07-03 1996-09-11 Merck & Co Inc Process of preparing phenyl heterocycles useful as cox-2 inhibitors
US5677318A (en) * 1996-07-11 1997-10-14 Merck Frosst Canada, Inc. Diphenyl-1,2-3-thiadiazoles as anti-inflammatory agents
BR9711151A (pt) * 1996-08-14 1999-08-17 Searle & Co Forma cristalina de 4-¬5-metil-3-fenilsoxazol-4-il¾benzenossulfonamida
US8022095B2 (en) * 1996-08-16 2011-09-20 Pozen, Inc. Methods of treating headaches using 5-HT agonists in combination with long-acting NSAIDs
US6586458B1 (en) * 1996-08-16 2003-07-01 Pozen Inc. Methods of treating headaches using 5-HT agonists in combination with long-acting NSAIDs
US5939069A (en) * 1996-08-23 1999-08-17 University Of Florida Materials and methods for detection and treatment of immune system dysfunctions
FR2753449B1 (fr) * 1996-09-13 1998-12-04 Union Pharma Scient Appl Nouveaux derives 3,4-diaryloxazolone, leurs procedes de preparation, et leurs utilisations en therapeutique
DK0932402T3 (da) 1996-10-15 2004-11-08 Searle Llc Metode til anvendelse af cyclooxygenase-2-inhibitorer ved behandling og forebyggelse af neoplasi
US5776954A (en) * 1996-10-30 1998-07-07 Merck & Co., Inc. Substituted pyridyl pyrroles, compositions containing such compounds and methods of use
US5985930A (en) 1996-11-21 1999-11-16 Pasinetti; Giulio M. Treatment of neurodegenerative conditions with nimesulide
CA2273836A1 (en) * 1996-12-10 1998-06-18 G.D. Searle & Co. Substituted pyrrolyl compounds for the treatment of inflammation
EP0863134A1 (en) * 1997-03-07 1998-09-09 Merck Frosst Canada Inc. 2-(3,5-difluorophenyl)-3-(4-(methyl-sulfonyl)phenyl)-2-cyclopenten-1-one useful as an inhibitor of cyclooxygenase-2
US6004960A (en) * 1997-03-14 1999-12-21 Merck Frosst Canada, Inc. Pyridazinones as inhibitors of cyclooxygenase-2
DE69816047T2 (de) * 1997-03-14 2004-04-22 Merck Frosst Canada & Co, Kirkland (methylsulfonyl)phenyl-2-(5h)-furanone mit sauerstoff-bindung als cox-2-hemmer
JP2001514669A (ja) * 1997-03-14 2001-09-11 メルク フロスト カナダ アンド カンパニー シクロオキシゲナーゼ−２阻害薬としてのピリダジノン類
US6071954A (en) * 1997-03-14 2000-06-06 Merk Frosst Canada, Inc. (methylsulfonyl)phenyl-2-(5H)-furanones with oxygen link as COX-2 inhibitors
TW492959B (en) * 1997-04-18 2002-07-01 Merck & Co Inc Process for making 2-aryl-3-aryl-5-halo pyridines useful as cox-2 inhibitors
US6127545A (en) * 1997-04-18 2000-10-03 Merck & Co., Inc. Process for making 2-aryl-3-aryl-5-halo pyridines useful as COX-2 inhibitors
US6130334A (en) * 1998-04-15 2000-10-10 Merck & Co., Inc. Process for making 2-aryl-3-aryl-5-halo pyridines useful as COX-2 inhibitors
US20040072889A1 (en) * 1997-04-21 2004-04-15 Pharmacia Corporation Method of using a COX-2 inhibitor and an alkylating-type antineoplastic agent as a combination therapy in the treatment of neoplasia
US6307047B1 (en) * 1997-08-22 2001-10-23 Abbott Laboratories Prostaglandin endoperoxide H synthase biosynthesis inhibitors
US6525053B1 (en) 1997-08-22 2003-02-25 Abbott Laboratories Prostaglandin endoperoxide H synthase biosynthesis inhibitors
AU744997B2 (en) * 1997-09-05 2002-03-07 Glaxo Group Limited 2,3-diaryl-pyrazolo(1,5-B)pyridazines derivatives, their preparation and their use as cyclooxygenase 2 (COX-2) inhibitors
ES2239402T3 (es) * 1997-09-12 2005-09-16 MERCK FROSST CANADA & CO. 2-aminopiridinas como inhibidores de ciclooxigenasa-2.
US6004950A (en) * 1997-09-12 1999-12-21 Merck Frosst Canada, Inc. 2-aminopyridines as inhibitors of cyclooxygenase-2
RS49982B (sr) * 1997-09-17 2008-09-29 Euro-Celtique S.A., Sinergistička analgetička kombinacija analgetičkog opijata i inhibitora ciklooksigenaze-2
US6034089A (en) * 1997-10-03 2000-03-07 Merck & Co., Inc. Aryl thiophene derivatives as PDE IV inhibitors
US6020339A (en) * 1997-10-03 2000-02-01 Merck & Co., Inc. Aryl furan derivatives as PDE IV inhibitors
FR2769311B1 (fr) * 1997-10-07 1999-12-24 Union Pharma Scient Appl Nouveaux derives 3,4-diarylthiazolin-2-one ou -2-thione, leurs procedes de preparation et leurs utilisations en therapeutique
US5972986A (en) * 1997-10-14 1999-10-26 G.D. Searle & Co. Method of using cyclooxygenase-2 inhibitors in the treatment and prevention of neoplasia
US6080876A (en) * 1997-10-29 2000-06-27 Merck & Co., Inc. Process for making phenyl heterocycles useful as COX-2 inhibitors
WO1999023087A1 (en) * 1997-10-30 1999-05-14 Merck Frosst Canada & Co. Diaryl-5-alkyl-5-methyl-2(5h)-furanones as selective cyclooxygenase-2 inhibitors
US6133292A (en) * 1997-10-30 2000-10-17 Merck Frosst Canada & Co. Diaryl-5-alkyl-5-methyl-2-(5H)-furanones as selective cyclooxygenase-2-inhibitors
JP2001521889A (ja) * 1997-10-31 2001-11-13 ジー・ディー・サール・アンド・カンパニー 早期分娩の治療及び予防中における胎児動脈管の維持にシクロオキシゲナーゼ−２阻害剤を使用する方法
US6025353A (en) * 1997-11-19 2000-02-15 G.D. Searle & Co. Method of using cyclooxygenase-2 inhibitors as anti-angiogenic agents
US7041694B1 (en) 1997-12-17 2006-05-09 Cornell Research Foundation, Inc. Cyclooxygenase-2 inhibition
AU1703799A (en) * 1997-12-17 1999-07-05 Cornell Research Foundation Inc. Cyclooxygenase-2 inhibition
US6375957B1 (en) 1997-12-22 2002-04-23 Euro-Celtique, S.A. Opioid agonist/opioid antagonist/acetaminophen combinations
RS50070B (sr) 1997-12-22 2009-01-22 Euro-Celtique S.A., Oralni dozni oblik sa kombinacijom opijatnog agonista i antagonista
NZ333399A (en) * 1997-12-24 2000-05-26 Sankyo Co Cyclooxygenase-2 inhibitors (COX-2) for the prevention and treatment of tumors, cachexia and tumor-metastasis
FR2775477B1 (fr) * 1998-02-27 2000-05-19 Union Pharma Scient Appl Nouveaux derives diarylmethylene heterocycliques, leurs procedes de preparation et leurs utilisations en therapeutique
US6136804A (en) * 1998-03-13 2000-10-24 Merck & Co., Inc. Combination therapy for treating, preventing, or reducing the risks associated with acute coronary ischemic syndrome and related conditions
US6727238B2 (en) * 1998-06-11 2004-04-27 Pfizer Inc. Sulfonylbenzene compounds as anti-inflammatory/analgesic agents
US6294558B1 (en) 1999-05-31 2001-09-25 Pfizer Inc. Sulfonylbenzene compounds as anti-inflammatory/analgesic agents
TNSN99111A1 (fr) * 1998-06-11 2005-11-10 Pfizer Derives de sulfonylbenzene nouveaux, procede pour leur preparation et compositions pharmaceutiques les contenant.
CA2339140A1 (en) * 1998-08-31 2000-03-09 Merck & Co., Inc. Method of treating neurodegenerative diseases
DE19842833B4 (de) * 1998-09-18 2005-04-14 Merckle Gmbh 2-Arylalkylthio-imidazole, 2-Arylalkenylthio-imidazole und 2-Arylalkinylthio-imidazole als Entzündungs-Hemmstoffe und Hemmstoffe der Cytokin-Freisetzung
EP1124798A4 (en) * 1998-10-27 2002-08-28 Merck & Co Inc SYNTHESIS OF METHYLTHIOPHENYL HYDROXYKETONES
EP1126841B1 (en) * 1998-11-02 2004-12-15 Merck & Co., Inc. Combinations of a 5ht1b/1d agonist and a selective cox-2 inhibitor for the treatment of migraine
DE69919887T2 (de) 1998-11-03 2005-09-15 Glaxo Group Ltd., Greenford Pyrazolopyridin derivative als selektive cox-2 inhibitoren
SA99191255B1 (ar) * 1998-11-30 2006-11-25 جي دي سيرل اند كو مركبات سيليكوكسيب celecoxib
US6649645B1 (en) 1998-12-23 2003-11-18 Pharmacia Corporation Combination therapy of radiation and a COX-2 inhibitor for treatment of neoplasia
US20030013739A1 (en) * 1998-12-23 2003-01-16 Pharmacia Corporation Methods of using a combination of cyclooxygenase-2 selective inhibitors and thalidomide for the treatment of neoplasia
US20040122011A1 (en) * 1998-12-23 2004-06-24 Pharmacia Corporation Method of using a COX-2 inhibitor and a TACE inhibitors as a combination therapy
US6155267A (en) * 1998-12-31 2000-12-05 Medtronic, Inc. Implantable medical device monitoring method and system regarding same
CA2357525A1 (en) * 1999-01-27 2000-08-03 Cornell Research Foundation, Inc. Treating cancers associated with overexpression of her-2/neu
ATE261444T1 (de) 1999-02-27 2004-03-15 Glaxo Group Ltd Pyrazolopyridine
US6380187B2 (en) 1999-03-25 2002-04-30 Dingwei Tim Yu Class of thiomorpholino substituted thiazoles
KR20010094161A (ko) * 2000-04-04 2001-10-31 서경배 2,2-디메틸-4,5-디아릴-3(2ｈ)퓨라논의 유도체 및 이를함유하는 선택적인 시클로옥시게네이즈-2 저해제로서약제학적 조성물
DZ3265A1 (fr) * 1999-04-14 2000-10-19 Pacific Corp Derives de 4,5-diaryl-3(2h)-furanone comme inhibiteurs de cyclo-oxygenase-2
IL136025A0 (en) * 1999-05-14 2001-05-20 Pfizer Prod Inc Combination therapy for the treatment of migraine
CO5190664A1 (es) 1999-06-30 2002-08-29 Pfizer Prod Inc Terapia de combinacion para el tratamiento de migrana administracion de un receptor 5ht, cafeina y un inhibidor de ciclooxigenasa-2
US6066667A (en) * 1999-08-17 2000-05-23 Ashbrook; Charles D. Substituted furanones, compositions and antiarthritic use
AU6976400A (en) * 1999-09-08 2001-04-10 Merck Frosst Canada & Co. 1,2,3-thiadiazoles and their use as cox-2 inhibitors
EP1216037A2 (en) * 1999-09-21 2002-06-26 Emory University Methods and compositions for treating platelet-related disorders using mpl pathway inhibitory agents
EP1090915B1 (en) * 1999-10-08 2009-05-27 Merial Polymorphic B form of 3-(cyclopropylmethoxy)-4-¬-4-(methylsulfonyl)phenyl - 5,5-dimethyl-5H-furan-2-one
EP1099695A1 (en) * 1999-11-09 2001-05-16 Laboratoire Theramex S.A. 5-aryl-1H-1,2,4-triazole compounds as inhibitors of cyclooxygenase-2 and pharmaceutical compositions containing them
ES2193921T3 (es) 1999-12-03 2003-11-16 Pfizer Prod Inc Compuestos de sulfamoilheteroaril-pirazol como agentes antinflamatorios/analgesicos.
EP1104758B1 (en) 1999-12-03 2003-07-23 Pfizer Products Inc. Acetylene derivatives as anti-inflammatory/analgesic agents
EP1104759B1 (en) 1999-12-03 2003-10-22 Pfizer Products Inc. Heteroaryl phenyl pyrazole compounds as anti-inflammatory/analgesic agents
BR0016031A (pt) 1999-12-03 2002-07-23 Pfizer Prod Inc Derivados de heterociclo-alquilsulfonil pirazol como agentes antiinflamatórios/analgésicos
JP2003523954A (ja) 1999-12-08 2003-08-12 ファルマシア コーポレイション 治療効果が迅速に開始されるシクロオキシゲナーゼ−２阻害剤組成物
UA74539C2 (en) 1999-12-08 2006-01-16 Pharmacia Corp Crystalline polymorphous forms of celecoxib (variants), a method for the preparation thereof (variants), a pharmaceutical composition (variants)
ES2236011T3 (es) * 1999-12-08 2005-07-16 Pharmacia Corporation Formas cristalinas polimorficas de celecoxib.
GB9930358D0 (en) 1999-12-22 2000-02-09 Glaxo Group Ltd Process for the preparation of chemical compounds
NZ519781A (en) * 1999-12-23 2004-04-30 Nitromed Inc Nitrosated and nitrosylated cyclooxygenase-2 inhibitors, compositions and methods of use
DE10001166A1 (de) 2000-01-13 2001-07-19 Merckle Gmbh Anellierte Pyrrolverbindungen, diese enthaltende pharmazeutische Mittel und deren Verwendung
BR0108077A (pt) 2000-02-04 2002-10-22 Children S Hospital Res Founda Processo para reduzir placas ateroscleróticas em um mamìfero, método para tratamento da aterosclerose em um mamìfero, composição, métodos para prover proteìna ou polipeptìdeo hidrolisante de lipìdeo biologicamente ativo ou mistura deles, para células de um mamìfero tendo deficiência na proteìna ou polipeptìdeo hidrolisante de lipìdeo biologicamente ativo , para prover lipase de ácido lisossomal biologicamente ativa para células de um mamìfero tendo deficiência de lipase de ácido lisossomal biologicamente ativa, para prover lipase de ácido lisossoal biologicamente ativa para células de um mamìfero com aterosclerose, para tratamento da doença de wolman em um mamìfero, para tratamento de doença de armazenagem de colesteril éster em um mamìfero, e, para tratamento da aterosclerose em um mamìfero
EP2517710B1 (en) 2000-02-08 2015-03-25 Euro-Celtique S.A. Tamper-resistant oral opioid agonist formulations
EP1255547B1 (en) 2000-02-08 2008-08-20 Euro-Celtique S.A. Controlled-release compositions containing opioid agonist and antagonist
ES2166710B1 (es) * 2000-04-25 2004-10-16 J. URIACH & CIA, S.A. Nuevos compuestos heterociclicos con actividad antiinflamatoria.
JP2003531202A (ja) 2000-04-25 2003-10-21 ファルマシア・コーポレーション ３，４−ジ（カルボシクリルまたはヘテロシクリル）チオフェンの位置選択的合成
AU2001258677A1 (en) * 2000-05-22 2001-12-03 Dr. Reddy's Research Foundation Novel compounds having antiinflammatory activity: process for their preparation and pharmaceutical compositions containing them
RU2003100874A (ru) 2000-06-13 2004-06-27 Вайс (Us) Болеутоляющие и противовоспалительные составы, содержащие ингибиторы циклооксигеназы-2
US6465509B2 (en) 2000-06-30 2002-10-15 Merck Frosst Canada & Co. Pyrones as inhibitors of cyclooxygenase-2
CA2414674A1 (en) * 2000-07-13 2002-01-24 Pharmacia Corporation Use of cox-2 inhibitors in the treatment and prevention of ocular cox-2 mediated disorders
PE20020146A1 (es) * 2000-07-13 2002-03-31 Upjohn Co Formulacion oftalmica que comprende un inhibidor de ciclooxigenasa-2 (cox-2)
DK1303265T3 (da) * 2000-07-20 2007-11-12 Lauras As Anvendelse af COX-2-inhibitorer, som immunostimulerende midler ved behandling af HIV eller AIDS
US6716829B2 (en) 2000-07-27 2004-04-06 Pharmacia Corporation Aldosterone antagonist and cyclooxygenase-2 inhibitor combination therapy to prevent or treat inflammation-related cardiovascular disorders
PE20020506A1 (es) 2000-08-22 2002-07-09 Glaxo Group Ltd Derivados de pirazol fusionados como inhibidores de la proteina cinasa
WO2002017896A2 (en) * 2000-08-29 2002-03-07 Peter Van Patten Combination for the treatment of migraine comprising a cyclooxygenase-2 inhibitor and acetylsalicylic acid
GB0021494D0 (en) * 2000-09-01 2000-10-18 Glaxo Group Ltd Chemical comkpounds
US20030219461A1 (en) * 2000-09-12 2003-11-27 Britten Nancy J. Parenteral combination therapy for infective conditions
WO2002022124A1 (en) * 2000-09-18 2002-03-21 Merck & Co., Inc. Treatment of inflammation with a combination of a cyclooxygenase-2 inhibitor and an integrin alpha-v antagonist
DE10057366A1 (de) * 2000-11-18 2002-05-23 Mahle Gmbh Verfahren zur gießtechnischen Herstellung eines Kolbens mit einem gekühlten Ringträger
US6919352B2 (en) 2000-12-15 2005-07-19 Smithkline Beecham Corporation Pyrazolopyridinyl pyridine and pyrimidine therapeutic compounds
DE60112330T2 (de) 2000-12-15 2006-04-13 Glaxo Group Ltd., Greenford Pyrazolopyridinderivate
WO2002060378A2 (en) 2000-12-21 2002-08-08 Nitromed, Inc. Substituted aryl compounds as cyclooxygenase-2 selective inhibitors, compositions and methods of use
US7115565B2 (en) * 2001-01-18 2006-10-03 Pharmacia & Upjohn Company Chemotherapeutic microemulsion compositions of paclitaxel with improved oral bioavailability
AUPR283801A0 (en) * 2001-02-01 2001-03-01 Australian National University, The Chemical compounds and methods
JP2004522754A (ja) * 2001-02-02 2004-07-29 ファルマシア・コーポレーション 月経困難症の治療および予防のための組み合わせ治療としてシクロオキシゲナーゼ‐２阻害剤および性ステロイドを使用する方法
DE10107683A1 (de) 2001-02-19 2002-08-29 Merckle Gmbh Chem Pharm Fabrik 2-Thio-substituierte Imidazolderivate und ihre Verwendung in der Pharmazie
DE60201074T2 (de) 2001-03-08 2005-09-15 Smithkline Beecham Corp. Pyrazolopyridinderivate
WO2002078700A1 (en) 2001-03-30 2002-10-10 Smithkline Beecham Corporation Pyralopyridines, process for their preparation and use as therapteutic compounds
PE20021017A1 (es) 2001-04-03 2002-11-24 Pharmacia Corp Composicion parenteral reconstituible
WO2002083672A1 (en) 2001-04-10 2002-10-24 Smithkline Beecham Corporation Antiviral pyrazolopyridine compounds
US20030105144A1 (en) 2001-04-17 2003-06-05 Ping Gao Stabilized oral pharmaceutical composition
US6673818B2 (en) 2001-04-20 2004-01-06 Pharmacia Corporation Fluoro-substituted benzenesulfonyl compounds for the treatment of inflammation
US6756498B2 (en) 2001-04-27 2004-06-29 Smithkline Beecham Corporation Process for the preparation of chemical compounds
WO2002088124A2 (en) 2001-04-27 2002-11-07 Smithkline Beecham Corporation Pyrazolo'1,5-a!pyridine derivatives
UA81224C2 (uk) 2001-05-02 2007-12-25 Euro Celtic S A Дозована форма оксикодону та її застосування
WO2002089798A2 (en) * 2001-05-04 2002-11-14 Merck & Co., Inc. Method and compositions for treating migraines
CN1525851A (zh) 2001-05-11 2004-09-01 ������ҩ�����޹�˾ 抗滥用阿片样物质控释剂型
GB0112802D0 (en) * 2001-05-25 2001-07-18 Glaxo Group Ltd Pyrimidine derivatives
GB0112810D0 (en) * 2001-05-25 2001-07-18 Glaxo Group Ltd Pyrimidine derivatives
US20030153801A1 (en) * 2001-05-29 2003-08-14 Pharmacia Corporation Compositions of cyclooxygenase-2 selective inhibitors and radiation for inhibition or prevention of cardiovascular disease
PL367337A1 (en) * 2001-05-31 2005-02-21 Pharmacia Corporation Skin-permeable selective cyclooxygenase-2 inhibitor composition
DE10129320A1 (de) * 2001-06-19 2003-04-10 Norbert Mueller Verwendung von COX-2 Inhibitoren zur Behandlung von Schizophrenie, wahnhaften Störungen, affektiven Störungen oder Ticstörungen
US20060167074A1 (en) * 2001-06-19 2006-07-27 Norbert Muller Methods and compositions for the treatment of psychiatric disorders
CN1518550A (zh) 2001-06-21 2004-08-04 ʷ��˿�������ȳ�ķ���޹�˾ 用于预防和治疗疱疹病毒感染的咪唑并[1,2-a]吡啶衍生物
EP1273582B1 (en) 2001-07-05 2005-06-29 Pfizer Products Inc. Heterocyclo-alkylsulfonyl pyrazoles as anti-inflammatory/analgesic agents
ATE419039T1 (de) 2001-07-18 2009-01-15 Euro Celtique Sa Pharmazeutische kombinationen von oxycodon und naloxon
US20030068375A1 (en) 2001-08-06 2003-04-10 Curtis Wright Pharmaceutical formulation containing gelling agent
US20030157168A1 (en) 2001-08-06 2003-08-21 Christopher Breder Sequestered antagonist formulations
UA80682C2 (en) * 2001-08-06 2007-10-25 Pharmacia Corp Orally deliverable stabilized oral suspension formulation and process for the incresaing physical stability of thixotropic pharmaceutical composition
DE60232417D1 (de) 2001-08-06 2009-07-02 Euro Celtique Sa Opioid-agonist-formulierungen mit freisetzbarem und sequestriertem antagonist
US20030044458A1 (en) 2001-08-06 2003-03-06 Curtis Wright Oral dosage form comprising a therapeutic agent and an adverse-effect agent
GB0119477D0 (en) * 2001-08-09 2001-10-03 Glaxo Group Ltd Pyrimidine derivatives
AR038957A1 (es) 2001-08-15 2005-02-02 Pharmacia Corp Terapia de combinacion para el tratamiento del cancer
WO2003018575A1 (en) * 2001-08-24 2003-03-06 Wyeth Holdings Corporation 5-substituted-3(2h)-furanones useful for inhibition of farnesyl-protein transferase
US20030114483A1 (en) * 2001-09-18 2003-06-19 Pharmacia Corporation Compositions of chromene cyclooxygenase-2 selective inhibitors and acetaminophen for treatment and prevention of inflammation, inflammation-mediated disorders and pain
US20030236308A1 (en) * 2001-09-18 2003-12-25 Pharmacia Corporation Compositions of cyclooxygenase-2 selective inhibitors and acetaminophen for treatment and prevention of inflammation, inflammation-mediated disorders and pain
AP2004002999A0 (en) * 2001-09-26 2004-03-31 Pharmacia Corp Organoleptically acceptable intraorally disintegrating compositions
GT200200183A (es) 2001-09-28 2003-05-23 Procedimiento para preparar derivados de heterocicloalquilsulfonil pirazol
US7244740B2 (en) 2001-10-05 2007-07-17 Smithkline Beecham Corporation Imidazo-pyridine derivatives for use in the treatment of herpes viral infection
KR100824233B1 (ko) 2001-10-10 2008-04-24 씨제이제일제당 (주) 사이클로옥시게나제-2의 저해제로서 선택성이 뛰어난3,4-디하이드로-1ｈ-나프탈렌 유도체
KR100810468B1 (ko) 2001-10-10 2008-03-07 씨제이제일제당 (주) 사이클로옥시게나제-2의 저해제로서 선택성이 뛰어난1ｈ-인돌 유도체
WO2003037336A1 (en) 2001-11-02 2003-05-08 Pfizer Products Inc. 1-(5-sulfonyl-pyridin-2-yl)-5-(methylidene-cycloalkylmethoxy)-1h-pyrazole-4-carbonitrile derivatives and other compounds as cyclooxygenase inhibitors for the treatment of arthritis, neurodegeneration and colon cancer
CA2468266A1 (en) 2001-12-06 2003-06-19 Merck & Co., Inc. Substituted bicyclic pyrimidinones as a mitotic kinesin ksp inhibitors
FR2833164B1 (fr) * 2001-12-07 2004-07-16 Oreal Compositions cosmetiques antisolaires a base d'un melange synergique de filtres et utilisations
JP2005516916A (ja) 2001-12-11 2005-06-09 スミスクライン ビーチャム コーポレーション 抗ヘルペス薬としてのピラゾロ−ピリジン誘導体
DE10162120A1 (de) * 2001-12-12 2003-06-18 Berolina Drug Dev Ab Svedala Deuterierte substituierte Dihydrofuranone sowie diese Verbindungen enthaltende Arzneimittel
US20040082940A1 (en) * 2002-10-22 2004-04-29 Michael Black Dermatological apparatus and method
US20030212138A1 (en) * 2002-01-14 2003-11-13 Pharmacia Corporation Combinations of peroxisome proliferator-activated receptor-alpha agonists and cyclooxygenase-2 selective inhibitors and therapeutic uses therefor
US20030220374A1 (en) * 2002-01-14 2003-11-27 Pharmacia Corporation Compositions and methods of treatment involving peroxisome proliferator-activated receptor-gamma agonists and cyclooxygenase-2 selective inhibitors
US6667330B2 (en) 2002-01-31 2003-12-23 Galileo Pharmaceuticals, Inc. Furanone derivatives
US7985771B2 (en) * 2002-01-31 2011-07-26 Monsanto Technology Llc Furanone derivatives
DK2425824T5 (en) 2002-04-05 2018-02-12 Mundipharma As Pharmaceutical preparation containing oxycodone and naloxone
US7232821B2 (en) * 2002-04-08 2007-06-19 Glaxo Group Limited (2-((2-alkoxy)-phenyl) -cyclopent-1enyl) aromatic carbo and heterocyclic acid and derivatives
IL164163A0 (en) * 2002-04-09 2005-12-18 Pharmacia Corp Process for preparing a finely self-emulsifiable pharmaceutical composition
US7329401B2 (en) 2002-04-15 2008-02-12 The Regents Of The University Of California Cyclooxygenase-2 selective agents useful as imaging probes and related methods
AU2003230965B2 (en) 2002-04-17 2008-02-21 The Cleveland Clinic Foundation Systemic marker for monitoring anti-inflammatory and antioxidant actions of therapeutic agents
AU2003215867A1 (en) * 2002-04-22 2003-11-03 Pfizer Products Inc. Indol-2-ones as selective inhibitors of cyclooxygenase-2
GB0210121D0 (en) 2002-05-02 2002-06-12 Celltech R&D Ltd Biological products
EP3072978B1 (en) 2002-05-09 2018-07-11 The Brigham and Women's Hospital, Inc. 1l1rl-1 as a cardiovascular disease marker
US7273616B2 (en) * 2002-05-10 2007-09-25 The Trustees Of Columbia University In The City Of New York Genetically engineered cell lines and systems for propagating Varicella zoster virus and methods of use thereof
KR100804827B1 (ko) 2002-05-17 2008-02-20 씨제이제일제당 (주) 티아졸리딘-4-온 유도체, 그 제조방법 및 약제학적 조성물
US20030225054A1 (en) * 2002-06-03 2003-12-04 Jingwu Duan Combined use of tace inhibitors and COX2 inhibitors as anti-inflammatory agents
KR100478467B1 (ko) 2002-06-24 2005-03-23 씨제이 주식회사 피라졸-3-온 유도체, 그 제조방법 및 약제학적 조성물
KR100465455B1 (ko) 2002-06-24 2005-01-13 씨제이 주식회사 2-티옥소티아졸 유도체, 그 제조방법 및 약제학적 조성물
JP2006501179A (ja) * 2002-06-27 2006-01-12 ニトロメッド インコーポレーティッド シクロオキシゲナーゼ−２選択的阻害剤、組成物、および使用方法
AU2003279622A1 (en) * 2002-06-28 2004-01-19 Nitromed, Inc. Oxime and/or hydrazone containing nitrosated and/or nitrosylated cyclooxigenase-2 selective inhibitors, compositions and methods of use
AU2003248759A1 (en) * 2002-07-02 2004-01-23 Pharmacia Corporation Use of cyclooxygenase-2 selective inhibitors and thrombolytic agents for the treatment or prevention of a vaso-occlusive event
KR100467668B1 (ko) 2002-08-07 2005-01-24 씨제이 주식회사 1,2,4-트리아졸 유도체, 그 제조방법 및 약제학적 조성물
ES2263058T3 (es) * 2002-08-19 2006-12-01 Glaxo Group Limited Derivados de pirimidina como inhibidores selectivos de cox-2.
DE10238045A1 (de) 2002-08-20 2004-03-04 Merckle Gmbh Chem.-Pharm. Fabrik 2-Thio-substituierte Imidazolderivate und ihre Verwendung in der Pharmazie
UY27939A1 (es) 2002-08-21 2004-03-31 Glaxo Group Ltd Compuestos
GB0221443D0 (en) 2002-09-16 2002-10-23 Glaxo Group Ltd Pyridine derivates
EP2422772A3 (en) 2002-09-20 2012-04-18 Alpharma, Inc. Sequestering subunit and related compositions and methods
US8303511B2 (en) * 2002-09-26 2012-11-06 Pacesetter, Inc. Implantable pressure transducer system optimized for reduced thrombosis effect
AU2003275266A1 (en) 2002-10-03 2004-05-04 Smithkline Beecham Corporation Therapeutic compounds based on pyrazolopyridine derivatives
WO2005000194A2 (en) 2002-10-08 2005-01-06 Rinat Neuroscience Corp. Methods for treating post-surgical pain by administering an anti-nerve growth factor antagonist antibody and compositions containing the same
RU2338555C2 (ru) * 2002-10-08 2008-11-20 Ринат Ньюросайенс Корп. Способы лечения послеоперационной боли введением антагониста фактора роста нервов и композиции, содержащие фактор роста нервов
KR100484525B1 (ko) * 2002-10-15 2005-04-20 씨제이 주식회사 이소티아졸 유도체, 그 제조방법 및 약제학적 조성물
US20040082543A1 (en) * 2002-10-29 2004-04-29 Pharmacia Corporation Compositions of cyclooxygenase-2 selective inhibitors and NMDA receptor antagonists for the treatment or prevention of neuropathic pain
EP1558586B1 (en) * 2002-10-30 2011-03-30 Merck Sharp & Dohme Corp. Inhibitors of akt activity
GB0225548D0 (en) * 2002-11-01 2002-12-11 Glaxo Group Ltd Compounds
AU2003283096A1 (en) * 2002-11-05 2004-06-07 Merck Frosst Canada And Co. Nitric oxide releasing prodrugs of diaryl-2-(5h)-furanones as cyclooxygenase-2 inhibitors
AU2003291757A1 (en) * 2002-11-08 2004-06-03 Bristol-Myers Squibb Company Formulations of low solubility bioactive agents and processes for making the same
US20040147581A1 (en) * 2002-11-18 2004-07-29 Pharmacia Corporation Method of using a Cox-2 inhibitor and a 5-HT1A receptor modulator as a combination therapy
KR100470075B1 (ko) 2002-11-21 2005-02-05 씨제이 주식회사 1,2,4-트리아졸 유도체, 그 제조방법 및 약제학적 조성물
GB0227443D0 (en) * 2002-11-25 2002-12-31 Glaxo Group Ltd Pyrimidine derivatives
KR100491317B1 (ko) 2002-11-26 2005-05-24 씨제이 주식회사 1,2,4-트리아졸 유도체, 그 제조방법 및 약제학적 조성물
KR100470076B1 (ko) 2002-11-27 2005-02-05 씨제이 주식회사 1,2,4-트리아졸 유도체, 그 제조방법 및 약제학적 조성물
JP2006511606A (ja) 2002-12-13 2006-04-06 ワーナー−ランバート・カンパニー、リミテッド、ライアビリティ、カンパニー 下部尿路症状を治療するα−２−δリガンド
CA2510445A1 (en) * 2002-12-19 2004-07-08 Pharmacia Corporation Methods and compositions for the treatment of herpes virus infections using cyclooxygenase-2 selective inhibitors or cyclooxygenase-2 inhibitors in combination with antiviral agents
AU2003300264A1 (en) * 2002-12-20 2004-07-22 Pharmacia Corporation Compositions of cyclooxygenase-2 selective inhibitors and selective serotonin reuptake inhibitors for the treatment or prevention of a vaso-occlusive event
US9498530B2 (en) 2002-12-24 2016-11-22 Rinat Neuroscience Corp. Methods for treating osteoarthritis pain by administering a nerve growth factor antagonist and compositions containing the same
EP1575517B1 (en) 2002-12-24 2012-04-11 Rinat Neuroscience Corp. Anti-ngf antibodies and methods using same
ES2215474B1 (es) 2002-12-24 2005-12-16 J. URIACH & CIA S.A. Nuevos derivados de fosforamida.
US7569364B2 (en) * 2002-12-24 2009-08-04 Pfizer Inc. Anti-NGF antibodies and methods using same
US7332183B2 (en) * 2002-12-26 2008-02-19 Pozen Inc. Multilayer dosage forms containing NSAIDs and triptans
US7772188B2 (en) 2003-01-28 2010-08-10 Ironwood Pharmaceuticals, Inc. Methods and compositions for the treatment of gastrointestinal disorders
US20070265606A1 (en) * 2003-02-14 2007-11-15 Reliant Technologies, Inc. Method and Apparatus for Fractional Light-based Treatment of Obstructive Sleep Apnea
EP1594441B1 (en) 2003-02-19 2010-12-15 Rinat Neuroscience Corp. Method for treating pain by administering a nerve growth factor antagonist and an nsaid and composition containing the same
US20040214753A1 (en) * 2003-03-20 2004-10-28 Britten Nancy Jean Dispersible pharmaceutical composition for treatment of mastitis and otic disorders
US20050009931A1 (en) * 2003-03-20 2005-01-13 Britten Nancy Jean Dispersible pharmaceutical composition for treatment of mastitis and otic disorders
MXPA05009978A (es) * 2003-03-20 2005-11-04 Pharmacia Corp Formulacion dispersable de un agente antiinflamatorio.
US20050004098A1 (en) * 2003-03-20 2005-01-06 Britten Nancy Jean Dispersible formulation of an anti-inflammatory agent
US20040220155A1 (en) * 2003-03-28 2004-11-04 Pharmacia Corporation Method of providing a steroid-sparing benefit with a cyclooxygenase-2 inhibitor and compositions therewith
MY135852A (en) 2003-04-21 2008-07-31 Euro Celtique Sa Pharmaceutical products
US20040220187A1 (en) * 2003-04-22 2004-11-04 Pharmacia Corporation Compositions of a cyclooxygenase-2 selective inhibitor and a sodium ion channel blocker for the treatment of pain, inflammation or inflammation mediated disorders
WO2004093816A2 (en) * 2003-04-22 2004-11-04 Pharmacia Corporation Compositions comprising a selective cox-2 inhibitor and a calcium modulating agent
WO2004093813A2 (en) * 2003-04-22 2004-11-04 Pharmacia Corporation Compositions of a cyclooxygenase-2 selective inhibitor and a calcium modulating agent for the treatment of pain, inflammation or inflammation mediated disorders
US20040229803A1 (en) * 2003-04-22 2004-11-18 Pharmacia Corporation Compositions of a cyclooxygenase-2 selective inhibitor and a potassium ion channel modulator for the treatment of pain, inflammation or inflammation mediated disorders
US20050107387A1 (en) * 2003-05-13 2005-05-19 Pharmacia Corporation Compositions of a cyclooxygenase-2 selective inhibitor and a peroxisome proliferator activated receptor agonist for the treatment of ischemic mediated central nervous system disorders
US20060160776A1 (en) * 2003-05-28 2006-07-20 Pharmacia Corporation Compositions of a cyclooxygenase-2 selective inhibitor and a cannabinoid agent for the treatment of central nervous system damage
KR20110117731A (ko) 2003-05-30 2011-10-27 랜박시 래보러터리스 리미티드 치환된 피롤 유도체와 ｈｍｇ―ｃｏ 억제제로서의 이의 용도
CN1309717C (zh) * 2003-06-03 2007-04-11 李小虎 4－芳基－5h－噻吩－2－酮衍生物、其制法和用途
WO2004110492A2 (en) * 2003-06-06 2004-12-23 Glaxo Group Limited Composition comprising triptans and nsaids
WO2005000238A2 (en) * 2003-06-20 2005-01-06 Merck & Co., Inc. Use of selective cyclooxygenase-2 inhibitors for the treatment of endometriosis
US20050065154A1 (en) * 2003-06-24 2005-03-24 Pharmacia Corporation Treatment of migraine accompanied by nausea with a combination of cyclooxygenase-2 selective inhibitors and anti-nausea agents
WO2005007106A2 (en) * 2003-07-10 2005-01-27 Pharmacia Corporation Compositions of a cyclooxygenase-2 selective inhibitor and a non-nmda glutamate modulator for the treatment of central nervous system damage
WO2005009342A2 (en) * 2003-07-16 2005-02-03 Pharmacia Corporation Method for the treatment or prevention of dermatological disorders with a cyclooxygenase-2 inhibitor alone and in combination with a dermatological treatment agent and compositions therewith
WO2005009354A2 (en) * 2003-07-17 2005-02-03 Pharmacia Corporation Compositions of a cyclooxygenase-2 selective inhibitor and an ikk inhibitor for the treatment of ischemic-mediated central nervous system disorders or injury
US20070010571A1 (en) * 2003-08-20 2007-01-11 Nitromed, Inc. Nitrosated and nitrosylated cardiovascular compounds, compositions and methods of use
US20050119262A1 (en) * 2003-08-21 2005-06-02 Pharmacia Corporation Method for preventing or treating an optic neuropathy with a cox-2 inhibitor and an intraocular pressure reducing agent
US20050107350A1 (en) * 2003-08-22 2005-05-19 Pharmacia Corporation Method for the treatment or prevention of bone disorders with a cyclooxygenase-2 inhibitor alone and in combination with a bone disorder treatment agent and compositions therewith
US20050187278A1 (en) * 2003-08-28 2005-08-25 Pharmacia Corporation Treatment or prevention of vascular disorders with Cox-2 inhibitors in combination with cyclic AMP-specific phosphodiesterase inhibitors
AU2004270162B2 (en) * 2003-08-28 2010-05-13 Nicox S.A. Nitrosated ad nitrosylated diuretic compouds, compositions and methods of use
AU2004315596B2 (en) 2003-08-29 2011-11-24 President And Fellows Of Harvard College Inhibitors of cellular necrosis
WO2005023189A2 (en) * 2003-09-03 2005-03-17 Pharmacia Corporation Method of cox-2 selective inhibitor and nitric oxide-donating agent
US20050131028A1 (en) * 2003-09-11 2005-06-16 Pharmacia Corporation Methods and compositions for the extended duration treatment of pain, inflammation and inflammation-related disorders
EP1663229B1 (en) 2003-09-25 2010-04-14 Euro-Celtique S.A. Pharmaceutical combinations of hydrocodone and naltrexone
GB0323585D0 (en) * 2003-10-08 2003-11-12 Glaxo Group Ltd Compounds
GB0323584D0 (en) * 2003-10-08 2003-11-12 Glaxo Group Ltd Compounds
GB0323581D0 (en) * 2003-10-08 2003-11-12 Glaxo Group Ltd Novel compounds
FR2860792B1 (fr) * 2003-10-10 2006-02-24 Sanofi Synthelabo Derives de thiophene-2-carboxamide, leur preparation et leur application en therapeutique
WO2005044227A1 (en) * 2003-11-05 2005-05-19 Glenmark Pharmaceuticals Limited Topical pharmaceutical compositions
US20050100594A1 (en) * 2003-11-12 2005-05-12 Nilendu Sen Pharmaceutical formulation containing muscle relaxant and COX-II inhibitor
WO2005051919A1 (en) * 2003-11-26 2005-06-09 Pfizer Products Inc. Aminopyrazole derivatives as gsk-3 inhibitors
US7067159B2 (en) * 2003-12-05 2006-06-27 New Chapter, Inc. Methods for treating prostate cancer with herbal compositions
ATE546734T1 (de) 2003-12-05 2012-03-15 Cleveland Clinic Foundation Risikomarker für eine herzkreislaufkrankheit
US7070816B2 (en) * 2003-12-05 2006-07-04 New Chapter, Inc. Methods for treating prostatic intraepithelial neoplasia with herbal compositions
BRPI0506994A (pt) 2004-01-22 2007-07-03 Pfizer derivados de triazol que inibem a atividade antagonista da vasopressina
US20090131342A1 (en) * 2004-01-22 2009-05-21 Nitromed, Inc. Nitrosated and/or nitrosylated compounds, compositions and methods of use
US20050203081A1 (en) * 2004-02-25 2005-09-15 Jinbo Lee Inhibitors of protein tyrosine phosphatase 1B
AR047894A1 (es) * 2004-02-25 2006-03-01 Wyeth Corp Derivados de tiofeno como inhibidores de la proteina tirosina fosfatasa 1b (ptpasa 1b); metodos para su preparacion, composiciones farmaceuticas que los contienen y su uso en el tratamiento de enfermedades mediadas por ptpasa 1b
AU2005243247B2 (en) 2004-04-07 2012-03-01 Regents Of The University Of Minnesota Methods for treating bone cancer pain by administering a nerve growth factor antagonist
MXPA06012510A (es) * 2004-04-28 2006-12-15 Pfizer Derivados de 3-heterociclil-4-fenil-triazol como inhibidores del receptor de vasopresina via.
GB0410121D0 (en) * 2004-05-06 2004-06-09 Glaxo Group Ltd Compounds
US7507823B2 (en) * 2004-05-06 2009-03-24 Bristol-Myers Squibb Company Process of making aripiprazole particles
US20080138282A1 (en) * 2004-06-03 2008-06-12 The Trustees Of Columbia University In The City Of New York Radiolabeled Arylsulfonyl Compounds and Uses Thereof
EP1604666A1 (en) 2004-06-08 2005-12-14 Euro-Celtique S.A. Opioids for the treatment of the Chronic Obstructive Pulmonary Disease (COPD)
SI1765292T1 (en) 2004-06-12 2018-04-30 Collegium Pharmaceutical, Inc. Formulations of medicines to discourage abuse
CA2571807A1 (en) 2004-07-01 2006-01-19 Merck & Co., Inc. Mitotic kinesin inhibitors
ES2257929B1 (es) * 2004-07-16 2007-05-01 Laboratorios Del Dr. Esteve, S.A. Derivados de pirazolina, procedimiento para su obtencion y utilizacion de los mismos como agentes terapeuticos.
CA2574627A1 (en) * 2004-07-22 2006-02-02 Pharmacia Corporation Compositions for treatment of inflammation and pain using a combination of a cox-2 selective inhibitor and a ltb4 receptor antagonist
EP1784179A4 (en) 2004-08-24 2010-03-31 Merck Sharp & Dohme COMBINATION THERAPY FOR THE TREATMENT OF CYCLOOXYGENASE-2-MEDIATED DISEASES OR CONDITIONS IN PATIENTS WITH RISK TO THROMBOTIC CARDIOVASCULAR EVENTS
US7622142B2 (en) * 2004-09-14 2009-11-24 New Chapter Inc. Methods for treating glioblastoma with herbal compositions
US20060064133A1 (en) * 2004-09-17 2006-03-23 Cardiac Pacemakers, Inc. System and method for deriving relative physiologic measurements using an external computing device
WO2006041855A2 (en) 2004-10-04 2006-04-20 Nitromed, Inc. Compositions and methods using apocynin compounds and nitric oxide donors
US9164104B2 (en) 2004-10-06 2015-10-20 The Brigham And Women's Hospital, Inc. Relevance of achieved levels of markers of systemic inflammation following treatment
WO2006052899A2 (en) * 2004-11-08 2006-05-18 Nitromed, Inc. Nitrosated and nitrosylated compounds, compositions and methods for the treatment of ophthalmic disorders
JP2008520578A (ja) * 2004-11-15 2008-06-19 ニトロメッド インコーポレーティッド 複素環式の酸化窒素供与体基を含む利尿化合物、組成物および使用方法
ES2321535T3 (es) 2004-12-23 2009-06-08 Glaxo Group Limited Compuestos de piridina para el tratamiento de enfermedades mediadas por prostaglandinas.
AU2005320547B2 (en) 2004-12-27 2009-02-05 Eisai R & D Management Co., Ltd. Method for stabilizing anti-dementia drug
WO2006078995A1 (en) * 2005-01-21 2006-07-27 Nitromed, Inc. Cardiovascular compounds comprising heterocyclic nitric oxide donor group compositions and methods of use
JP2008528626A (ja) * 2005-01-31 2008-07-31 マイラン ラボラトリーズ インク． ヒドロキシル化されたネビボロールを含む薬学的組成物
WO2007086884A2 (en) * 2005-02-16 2007-08-02 Nitromed, Inc. Organic nitric oxide donor salts of antimicrobial compounds, compositions and methods of use
US7521435B2 (en) * 2005-02-18 2009-04-21 Pharma Diagnostics, N.V. Silicon containing compounds having selective COX-2 inhibitory activity and methods of making and using the same
US20090012057A1 (en) * 2005-02-28 2009-01-08 Nitromed, Inc. Cardiovascular Compounds Comprising Nitric Oxide Enhancing Groups, Compositions and Methods of Use
EP1702558A1 (en) 2005-02-28 2006-09-20 Euro-Celtique S.A. Method and device for the assessment of bowel function
WO2006099058A2 (en) * 2005-03-09 2006-09-21 Nitromed, Inc. Organic nitric oxide enhancing salts of angiotensin ii antagonists, compositions and methods of use
WO2006110918A1 (en) * 2005-04-13 2006-10-19 Ambit Biosciences Corporation Pyrrole compounds and uses thereof
AU2006241771B2 (en) * 2005-04-28 2010-09-09 Eisai R & D Management Co., Ltd. Composition containing anti-dementia drug
AU2006244393B2 (en) * 2005-05-05 2012-06-21 Cook Biotech Incorporated Implantable materials and methods for inhibiting tissue adhesion formation
ATE550019T1 (de) 2005-05-17 2012-04-15 Merck Sharp & Dohme Cis-4-ä(4-chlorophenyl)sulfonylü-4-(2,5- difluorophenyl)cyclohexanepropansäure zur behandlug von krebs
WO2006123242A1 (en) * 2005-05-18 2006-11-23 Pfizer Limited 1, 2, 4 -triazole derivatives as vasopressin antagonists
US20090048219A1 (en) * 2005-05-23 2009-02-19 Nitromed Inc. Organic nitric oxide donor salts of nonsteroidal antiinflammatory compounds, compositions and methods of use
EP1982711A1 (en) 2005-05-31 2008-10-22 Mylan Laboratories, Inc Compositions comprsing nebivolol
US20090018091A1 (en) * 2005-08-02 2009-01-15 Nitromed, Inc. Nitric Oxide Enhancing Antimicrobial Compounds, Compositions and Methods of Use
PE20070427A1 (es) * 2005-08-30 2007-04-21 Novartis Ag Compuestos derivados de benzimidazoles sustituidos como inhibidores de tirosina quinasas
CA2624933A1 (en) * 2005-10-04 2007-04-12 Nitromed, Inc. Methods for treating respiratory disorders
US8119358B2 (en) 2005-10-11 2012-02-21 Tethys Bioscience, Inc. Diabetes-related biomarkers and methods of use thereof
AU2006313430B2 (en) 2005-11-08 2012-09-06 Ranbaxy Laboratories Limited Process for (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- [(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-1-yl]-3, 5-dihydroxy-heptanoic acid hemi calcium salt
EP1954685A4 (en) * 2005-11-16 2009-11-11 Nitromed Inc FUROXANE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
TW200735866A (en) 2005-11-18 2007-10-01 Synta Pharmaceuticals Corp Compounds for the treatment of proliferative disorders
WO2007075541A2 (en) * 2005-12-20 2007-07-05 Nitromed, Inc. Nitric oxide enhancing glutamic acid compounds, compositions and methods of use
US20080293702A1 (en) * 2005-12-22 2008-11-27 Nitromed, Inc. Nitric Oxide Enhancing Pyruvate Compounds, Compositions and Methods of Use
EP1978964A4 (en) 2006-01-24 2009-12-09 Merck & Co Inc JAK2 tyrosine kinase Inhibition
GB0603041D0 (en) 2006-02-15 2006-03-29 Angeletti P Ist Richerche Bio Therapeutic compounds
DK3279663T3 (da) 2006-03-15 2021-10-18 Brigham & Womens Hospital Inc Anvendelse af gelsolin til diagnosticering og behandling af inflammationssygdomme
WO2007126609A1 (en) 2006-03-29 2007-11-08 Nitromed, Inc. Nitric oxide enhancing prostaglandin compounds, compositions and methods of use
TW200813039A (en) 2006-04-19 2008-03-16 Novartis Ag 6-O-substituted benzoxazole and benzothiazole compounds and methods of inhibiting CSF-1R signaling
US20080057590A1 (en) 2006-06-07 2008-03-06 Mickey Urdea Markers associated with arteriovascular events and methods of use thereof
KR101486228B1 (ko) 2006-06-19 2015-01-26 알파마 파머슈티컬스 엘엘씨 약제학적 조성물
US8128460B2 (en) * 2006-09-14 2012-03-06 The Material Works, Ltd. Method of producing rust inhibitive sheet metal through scale removal with a slurry blasting descaling cell
CA2664113C (en) 2006-09-22 2013-05-28 Merck & Co., Inc. Use of platencin and platensimycin as fatty acid synthesis inhibitors to treat obesity, diabetes and cancer
US20080208179A1 (en) * 2006-10-26 2008-08-28 Reliant Technologies, Inc. Methods of increasing skin permeability by treatment with electromagnetic radiation
US8513329B2 (en) 2006-10-31 2013-08-20 Bio-Tec Environmental, Llc Chemical additives to make polymeric materials biodegradable
AU2007313630B2 (en) 2006-10-31 2013-07-04 Bio-Tec Environmental, Llc Chemical additives to make polymeric materials biodegradable
US20110218176A1 (en) 2006-11-01 2011-09-08 Barbara Brooke Jennings-Spring Compounds, methods, and treatments for abnormal signaling pathways for prenatal and postnatal development
RS51940B (en) 2006-12-22 2012-02-29 Recordati Ireland Limited Combined TH2δ LIGANAD THERAPY AND NSAID FOR LOWER URINARY TRACT DISORDERS
PL2109608T3 (pl) 2007-01-10 2011-08-31 Msd Italia Srl Indazole podstawione grupą amidową jako inhibitory polimerazy poli(ADP-rybozy)-(PARP)
US20100111858A1 (en) * 2007-01-19 2010-05-06 Howard Carol P Diangostic and Therapeutic Cyclooxygenase-2 Binding Ligands
WO2008106692A1 (en) 2007-03-01 2008-09-04 Novartis Vaccines And Diagnostics, Inc. Pim kinase inhibitors and methods of their use
GB0704407D0 (en) 2007-03-07 2007-04-18 Glaxo Group Ltd Compounds
WO2008131224A2 (en) 2007-04-18 2008-10-30 Tethys Bioscience, Inc. Diabetes-related biomarkers and methods of use thereof
KR20100017866A (ko) 2007-05-21 2010-02-16 노파르티스 아게 Ｃｓｆ－１ｒ 억제제, 조성물 및 사용 방법
CA2690191C (en) 2007-06-27 2015-07-28 Merck Sharp & Dohme Corp. 4-carboxybenzylamino derivatives as histone deacetylase inhibitors
EP2170062A4 (en) 2007-07-12 2010-12-29 Tragara Pharmaceuticals Inc METHOD AND COMPOSITIONS FOR THE TREATMENT OF CANCER DISORDERS, TUMORS AND TUMOR-DISORDED DISEASES
US7943658B2 (en) * 2007-07-23 2011-05-17 Bristol-Myers Squibb Company Indole indane amide compounds useful as CB2 agonists and method
US8263641B2 (en) 2007-09-10 2012-09-11 Calcimedica, Inc. Compounds that modulate intracellular calcium
US8623418B2 (en) 2007-12-17 2014-01-07 Alpharma Pharmaceuticals Llc Pharmaceutical composition
KR20100126467A (ko) 2008-03-03 2010-12-01 타이거 파마테크 티로신 키나아제 억제제
GB2460915B (en) 2008-06-16 2011-05-25 Biovascular Inc Controlled release compositions of agents that reduce circulating levels of platelets and methods therefor
GB0813142D0 (en) 2008-07-17 2008-08-27 Glaxo Group Ltd Novel compounds
GB0813144D0 (en) 2008-07-17 2008-08-27 Glaxo Group Ltd Novel compounds
CN102256969A (zh) 2008-08-27 2011-11-23 钙医学公司 调节胞内钙的化合物
EP2177215A1 (en) 2008-10-17 2010-04-21 Laboratorios Del. Dr. Esteve, S.A. Co-crystals of tramadol and NSAIDs
CN101429181A (zh) * 2008-12-18 2009-05-13 毛近隆 对羟基苯丙烯酸衍生物及其应用
US20100160351A1 (en) * 2008-12-19 2010-06-24 Nuon Therapeutics, Inc. Pharmaceutical compositions and methods for treating hyperuricemia and related disorders
WO2010071865A1 (en) 2008-12-19 2010-06-24 Nuon Therapeutics, Inc. Pharmaceutical compositions and methods for treating hyperuricemia and related disorders
GB0903493D0 (en) 2009-02-27 2009-04-08 Vantia Ltd New compounds
WO2010103039A1 (en) 2009-03-10 2010-09-16 Euro-Celtique S.A. Immediate release pharmaceutical compositions comprising oxycodone and naloxone
WO2011012622A1 (en) 2009-07-30 2011-02-03 Glaxo Group Limited Benzoxazinone derivatives for the treatment of glytl mediated disorders
WO2011023753A1 (en) 2009-08-27 2011-03-03 Glaxo Group Limited Benzoxazine derivatives as glycine transport inhibitors
WO2011032175A1 (en) 2009-09-14 2011-03-17 Nuon Therapeutics, Inc. Combination formulations of tranilast and allopurinol and methods related thereto
BR112012008849A2 (pt) 2009-10-14 2015-09-22 Schering Corp composto, composição farmacêutica, e, uso de um composto
US10668060B2 (en) 2009-12-10 2020-06-02 Collegium Pharmaceutical, Inc. Tamper-resistant pharmaceutical compositions of opioids and other drugs
WO2011075478A1 (en) 2009-12-16 2011-06-23 N30 Pharmaceuticals, Llc Novel thiophene inhibitors of s-nitrosoglutathione reductase
GB201000685D0 (en) 2010-01-15 2010-03-03 Glaxo Group Ltd Novel compounds
EP2531163A1 (en) 2010-02-01 2012-12-12 The Hospital For Sick Children Remote ischemic conditioning for treatment and preventon of restenosis
CA2795053A1 (en) 2010-03-31 2011-10-06 The Hospital For Sick Children Use of remote ischemic conditioning to improve outcome after myocardial infarction
ES2591004T3 (es) 2010-04-27 2016-11-24 Calcimedica, Inc. Compuestos moduladores del calcio intracelular
US8754219B2 (en) 2010-04-27 2014-06-17 Calcimedica, Inc. Compounds that modulate intracellular calcium
GB201007789D0 (en) 2010-05-10 2010-06-23 Glaxo Group Ltd Novel Compound
GB201007791D0 (en) 2010-05-10 2010-06-23 Glaxo Group Ltd Novel compounds
EP2584903B1 (en) 2010-06-24 2018-10-24 Merck Sharp & Dohme Corp. Novel heterocyclic compounds as erk inhibitors
JP5815029B2 (ja) 2010-07-09 2015-11-17 クオンベルゲンセ プハルマセウトイカルス リミテッド カルシウムチャネル遮断薬としてのテトラゾール化合物
CN103068980B (zh) 2010-08-02 2017-04-05 瑟纳治疗公司 使用短干扰核酸（siNA）的RNA干扰介导的联蛋白（钙粘蛋白关联蛋白质），β1（CTNNB1）基因表达的抑制
SI2606134T1 (sl) 2010-08-17 2019-08-30 Sirna Therapeutics, Inc. RNA-INTERFERENČNO POSREDOVANO ZAVIRANJE IZRAŽANJA GENA VIRUSA HEPATITISA B (HBV) Z UPORABO KRATKE INTERFERENČNE NUKLEINSKE KISLINE (siNA)
RS63063B1 (sr) 2010-08-19 2022-04-29 Zoetis Belgium S A Anti-ngf antitela i njihova upotreba
US8883801B2 (en) 2010-08-23 2014-11-11 Merck Sharp & Dohme Corp. Substituted pyrazolo[1,5-a]pyrimidines as mTOR inhibitors
CA2809830C (en) 2010-08-27 2019-09-10 Calcimedica, Inc. Compounds comprising n-acyl-2-amino-1,3-thiazole for modulating intracellular calcium
WO2012030685A2 (en) 2010-09-01 2012-03-08 Schering Corporation Indazole derivatives useful as erk inhibitors
EP2615916B1 (en) 2010-09-16 2017-01-04 Merck Sharp & Dohme Corp. Fused pyrazole derivatives as novel erk inhibitors
DK2632472T3 (en) 2010-10-29 2018-03-19 Sirna Therapeutics Inc RNA INTERFERENCE-MEDIATED INHIBITION OF GENE EXPRESSION USING SHORT INTERFERRING NUCLEIC ACIDS (SINA)
WO2012087772A1 (en) 2010-12-21 2012-06-28 Schering Corporation Indazole derivatives useful as erk inhibitors
SG191288A1 (en) 2010-12-22 2013-07-31 Purdue Pharma Lp Encased tamper resistant controlled release dosage forms
JP5638151B2 (ja) 2010-12-23 2014-12-10 パーデュー、ファーマ、リミテッド、パートナーシップ 不正加工抵抗性の（ｔａｍｐｅｒｒｅｓｉｓｔａｎｔ）固形経口剤形
EP2665729B1 (en) 2011-01-19 2015-04-01 Convergence Pharmaceuticals Limited Piperazine derivatives as cav2.2 calcium channel blockers
IN2013MN02170A (zh) 2011-04-21 2015-06-12 Piramal Entpr Ltd
TWI646111B (zh) 2011-05-20 2019-01-01 艾爾德生物控股有限責任公司 抗降血鈣素基因相關胜肽（ａｎｔｉ－ｃｇｒｐ）組成物及其用途
EP2770987B1 (en) 2011-10-27 2018-04-04 Merck Sharp & Dohme Corp. Novel compounds that are erk inhibitors
EP2773207B1 (en) 2011-10-31 2018-03-07 Merck Sharp & Dohme Corp. Aminopyrimidinones as interleukin receptor-associated kinase inhibitors
GB201122113D0 (en) 2011-12-22 2012-02-01 Convergence Pharmaceuticals Novel compounds
EP3919620A1 (en) 2012-05-02 2021-12-08 Sirna Therapeutics, Inc. Short interfering nucleic acid (sina) compositions
EP2855458B1 (en) 2012-05-11 2018-08-08 Reset Therapeutics, Inc. Carbazole-containing sulfonamides as cryptochrome modulators
WO2013184871A1 (en) 2012-06-06 2013-12-12 Zoetis Llc Caninized anti-ngf antibodies and methods thereof
JP6280554B2 (ja) 2012-09-28 2018-02-14 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． Ｅｒｋ阻害剤である新規化合物
US9512116B2 (en) 2012-10-12 2016-12-06 Calcimedica, Inc. Compounds that modulate intracellular calcium
PL2925888T3 (pl) 2012-11-28 2018-03-30 Merck Sharp & Dohme Corp. Kompozycje i sposoby do stosowania w leczeniu nowotworów
WO2014100065A1 (en) 2012-12-20 2014-06-26 Merck Sharp & Dohme Corp. Substituted imidazopyridines as hdm2 inhibitors
WO2014120748A1 (en) 2013-01-30 2014-08-07 Merck Sharp & Dohme Corp. 2,6,7,8 substituted purines as hdm2 inhibitors
US9149533B2 (en) 2013-02-05 2015-10-06 Purdue Pharma L.P. Tamper resistant pharmaceutical formulations
EP2968276A4 (en) 2013-03-15 2017-02-15 President and Fellows of Harvard College Hybrid necroptosis inhibitors
US10751287B2 (en) 2013-03-15 2020-08-25 Purdue Pharma L.P. Tamper resistant pharmaceutical formulations
TWI634114B (zh) * 2013-05-08 2018-09-01 永恒生物科技公司 作為激酶抑制劑之呋喃酮化合物
US20160166576A1 (en) 2013-07-11 2016-06-16 Merck Sharp & Dohme Corp. Substituted amidopyrazole inhibitors of interleukin receptor-associated kinases (irak-4)
AU2014295042B2 (en) 2013-07-23 2017-03-30 Mundipharma Pty Limited A combination of oxycodone and naloxone for use in treating pain in patients suffering from pain and a disease resulting in intestinal dysbiosis and/or increasing the risk for intestinal bacterial translocation
US20160194368A1 (en) 2013-09-03 2016-07-07 Moderna Therapeutics, Inc. Circular polynucleotides
WO2015054283A1 (en) 2013-10-08 2015-04-16 Calcimedica, Inc. Compounds that modulate intracellular calcium
US10413520B2 (en) 2014-01-29 2019-09-17 Crystalgenomics, Inc. Oral pharmacological composition including 5-{4-(amino sulfonyl)phenyl}-2,2-dimethyl-4-(3-fluorophenyl)-3(2H)-furanone having crystalline structure with excellent stability
KR101446601B1 (ko) * 2014-01-29 2014-10-07 크리스탈지노믹스(주) 5-(4-(아미노설포닐)페닐)-2,2-디메틸-4-(3-플루오로페닐)-3(2h)-퓨라논을 포함하는 약학적 조성물 및 캡슐 제형
TWI690521B (zh) 2014-04-07 2020-04-11 美商同步製藥公司 作為隱花色素調節劑之含有咔唑之醯胺類、胺基甲酸酯類及脲類
JO3589B1 (ar) 2014-08-06 2020-07-05 Novartis Ag مثبطات كيناز البروتين c وطرق استخداماتها
GB201417497D0 (en) 2014-10-03 2014-11-19 Convergence Pharmaceuticals Novel use
GB201417499D0 (en) 2014-10-03 2014-11-19 Convergence Pharmaceuticals Novel use
GB201417500D0 (en) 2014-10-03 2014-11-19 Convergence Pharmaceuticals Novel use
RU2563876C1 (ru) * 2014-11-11 2015-09-27 Федеральное государственное бюджетное образовательное учреждение высшего профессионального образования "Санкт-Петербургский государственный университет" (СПбГУ) Способ получения 2,2-диалкил-4,5-диарилфуран-3(2н)-онов
EP3267996B1 (en) 2015-03-12 2020-11-11 Merck Sharp & Dohme Corp. Pyrazolopyrimidine inhibitors of irak4 activity
US10040802B2 (en) 2015-03-12 2018-08-07 Merck Sharp & Dohme Corp. Thienopyrazine inhibitors of IRAK4 activity
EP3268367B8 (en) 2015-03-12 2022-11-16 Merck Sharp & Dohme LLC Carboxamide inhibitors of irak4 activity
EP3292213A1 (en) 2015-05-04 2018-03-14 Academisch Medisch Centrum Biomarkers for the detection of aspirin insensitivity
TWI770020B (zh) 2016-04-15 2022-07-11 丹麥商Ｈ朗德貝克公司 人類化抗pacap 抗體及其用途
US9737530B1 (en) 2016-06-23 2017-08-22 Collegium Pharmaceutical, Inc. Process of making stable abuse-deterrent oral formulations
BR112019001130A2 (pt) 2016-07-21 2019-04-30 Unilever Nv uso de lactama e composição farmacêutica
CN109475525A (zh) 2016-07-21 2019-03-15 荷兰联合利华有限公司 4-(4-氯苯基)-5-亚甲基-吡咯-2-酮和5-亚甲基-4-(对甲苯基)吡咯-2-酮用于治疗革兰氏阴性细菌感染
US10875830B2 (en) 2016-07-21 2020-12-29 Conopeo, Inc. Method of treatment
US10975084B2 (en) 2016-10-12 2021-04-13 Merck Sharp & Dohme Corp. KDM5 inhibitors
US10947234B2 (en) 2017-11-08 2021-03-16 Merck Sharp & Dohme Corp. PRMT5 inhibitors
WO2019177690A1 (en) 2018-03-12 2019-09-19 Zoetis Services Llc Anti-ngf antibodies and methods thereof
US11993602B2 (en) 2018-08-07 2024-05-28 Merck Sharp & Dohme Llc PRMT5 inhibitors
WO2020033284A1 (en) 2018-08-07 2020-02-13 Merck Sharp & Dohme Corp. Prmt5 inhibitors
EP3852732A1 (en) 2018-09-19 2021-07-28 ModernaTX, Inc. Peg lipids and uses thereof
US20220031631A1 (en) 2018-09-19 2022-02-03 Modernatx, Inc. High-purity peg lipids and uses thereof
EP3883562A4 (en) 2018-11-21 2022-08-03 Tremeau Pharmaceuticals, Inc. PURIFIED FORMS OF ROFECOXIB AND METHODS OF MAKING AND USING
CN110452198B (zh) * 2019-09-03 2021-03-26 山东鲁抗舍里乐药业有限公司 一种非罗考昔的制备方法
CN110452199B (zh) * 2019-09-03 2021-03-30 山东鲁抗舍里乐药业有限公司 一种非罗考昔的制备方法
US10945992B1 (en) 2019-11-13 2021-03-16 Tremeau Pharmaceuticals, Inc. Dosage forms of rofecoxib and related methods
BR112022012032A2 (pt) 2019-12-17 2022-09-06 Merck Sharp & Dohme Llc Inibidores de prmt5
CN114014824B (zh) * 2020-12-09 2023-06-13 上海科技大学 一种杂环化合物的应用
EP4306520A1 (en) * 2021-03-11 2024-01-17 Medshine Discovery Inc. Thiophene compound and application thereof
IL305573A (en) 2021-03-15 2023-10-01 Saul Yedgar Hyaluronic acid conjugated with dipalmitoyl phosphatidyl ethanolamine in combination with non-steroidal anti-inflammatory drugs (NSAIDs) for the treatment or suppression of inflammatory diseases
US11161833B1 (en) 2021-04-09 2021-11-02 Tremeau Pharmaceuticals, Inc. Deuterated etoricoxib, methods of manufacture, and use thereof
IL310885A (en) 2021-08-27 2024-04-01 H Lundbeck As Treatment of cluster headache using anti-CGRP antibodies

Family Cites Families (53)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH423473A (de) * 1963-01-19 1966-10-31 Ciba Geigy Verfahren zur Herstellung eines photographischen Farbenbildes unter Verwendung neuer Thiophenverbindungen als Farbstoffbildner für Purpurfarbstoffe
DE1938904A1 (de) * 1968-08-02 1970-02-05 Innothera Lab Sa 1-Phenylpyrrole
US3743656A (en) * 1969-05-01 1973-07-03 Wyeth John & Brother Ltd Thiophene and furan lower alkanoic acids and derivatives
GB1381860A (en) * 1971-06-03 1975-01-29 Wyeth John & Brother Ltd Tetrazole derivatives
JPS4891058A (zh) * 1972-03-10 1973-11-27
JPS4891061A (zh) * 1972-03-10 1973-11-27
US3957791A (en) * 1972-09-25 1976-05-18 Sandoz, Inc. Hydroxyalkyl-piperazino-quinoline nitrates
JPS50121261A (zh) * 1974-03-12 1975-09-23
GB1479297A (en) * 1974-07-04 1977-07-13 Beecham Group Ltd 4-substituted butan-2-ones but-3-en-2-ones butan-2-ols and but-3-en-2-ols and pharmaceutical compositions containing them
US4229207A (en) * 1975-08-15 1980-10-21 Ciba-Geigy Corporation Esters of 1,2-diphenyl-cyclohex-1-ene-4-carboxylic acid
GB2000170B (en) * 1977-06-06 1982-02-24 Eastman Kodak Co Electrophoretic migration imaging materials and process
US4318791A (en) * 1977-12-22 1982-03-09 Ciba-Geigy Corporation Use of aromatic-aliphatic ketones as photo sensitizers
US4206220A (en) * 1978-07-13 1980-06-03 Interx Research Corporation Prodrugs for the improved delivery of non-steroidal anti-inflammatory agents
US4302461A (en) * 1979-08-09 1981-11-24 E. I. Du Pont De Nemours And Company Antiinflammatory 5-substituted-2,3-diarylthiophenes
US4427693A (en) * 1981-08-05 1984-01-24 E. I. Du Pont De Nemours And Company Antiinflammatory 4,5-diaryl-α,α-bis (polyhalomethyl)-2-thiophenemethanamines
US4381311A (en) * 1980-12-29 1983-04-26 E. I. Du Pont De Nemours And Company Antiinflammatory 4,5-diaryl-α-(polyhalomethyl)-2-thiophenemethanols
US4820827A (en) * 1982-03-03 1989-04-11 E. I. Du Pont De Nemours And Company 2,3-diaryl-5-bromothiophene compounds of use for the treatment of inflammaton and dysmenorrhea
DE3361812D1 (en) * 1982-03-03 1986-02-27 Du Pont Antiinflammatory and/or analgesic 2,3-diaryl-5-halo thiophenes
US4432974A (en) * 1982-03-04 1984-02-21 E. I. Du Pont De Nemours And Company Antiinflammatory and/or analgesic 2,3-diaryl-5-silyl thiophenes
US4477463A (en) * 1982-05-10 1984-10-16 E. I. Du Pont De Nemours And Company Antiinflammatory and/or analgesic 1-alkyl-4,5-diaryl-2-fluoroalkyl-1H-pyrroles
JPS5916884A (ja) * 1982-07-19 1984-01-28 Fujisawa Pharmaceut Co Ltd 新規フラン化合物
US4543207A (en) * 1982-12-25 1985-09-24 Nippon Petrochemicals Company, Limited Electrical insulating oil and oil-filled electrical appliances
US4539332A (en) * 1983-11-14 1985-09-03 Merck & Co., Inc. 2,5-Diaryl tetrahydrofurans and analogs thereof as PAF-antagonists
US4968817A (en) * 1984-07-27 1990-11-06 National Distillers And Chemical Corporation Manufacture of gamma-crotonolactone by carbonylation of glycidol
US4652582A (en) * 1985-01-09 1987-03-24 E. I. Du Pont De Nemours And Company Antiinflammatory-2-halo-4,5-diarylpyrroles
DE3615157A1 (de) * 1986-05-05 1987-11-12 Schwabe Willmar Gmbh & Co 5-arylalkyl-4-alkoxy-2(5h)-furanone, zwischenprodukte und verfahren zu ihrer herstellung sowie ihre anwendung als therapeutische wirkstoffe
JPS6368581A (ja) * 1986-09-11 1988-03-28 Sekisui Chem Co Ltd α，β−不飽和γ−ブチロラクトンの製造方法
US4851423A (en) * 1986-12-10 1989-07-25 Schering Corporation Pharmaceutically active compounds
DE3718527A1 (de) * 1987-06-03 1988-12-15 Basf Ag Verfahren zur herstellung von 2(5h)-furanonen
EP0300688A1 (en) * 1987-07-21 1989-01-25 FISONS plc Pyrrole derivatives, process for their preparation and pharmaceutical compositions containing them
DE3817808A1 (de) * 1987-07-21 1989-02-02 Bayer Ag Verfahren zur herstellung von 2-substituierten pyrrolen
DE3739882A1 (de) * 1987-11-25 1989-06-08 Bayer Ag Substituierte hydroxylamine
US4929525A (en) * 1987-12-08 1990-05-29 Fuji Electric Co., Ltd. Photoconductor for electrophotography containing azo or disazo compound
US5217971A (en) * 1989-01-05 1993-06-08 Fujisawa Pharmaceutical Co., Ltd. Thiazole compounds and pharmaceutical composition comprising the same
US5145860A (en) * 1989-01-05 1992-09-08 Fujisawa Pharmaceutical Co., Ltd. Thiazole compounds and pharmaceutical composition comprising the same
US5229386A (en) * 1989-01-05 1993-07-20 Fujisawa Pharmaceutical Co., Ltd. Thiazole compounds, processes for the preparation thereof and pharmaceutical composition comprising the same
US5196532A (en) * 1989-02-08 1993-03-23 Basf Aktiengesellschaft Diaryl-substituted heterocyclic compounds, their preparation and drugs and cosmetics obtained therefrom
EP0388909A3 (en) * 1989-03-22 1991-05-08 Fujisawa Pharmaceutical Co., Ltd. Thiazole compounds, processes for the preparation thereof and pharmaceutical composition comprising the same
DE3915450A1 (de) * 1989-05-11 1990-11-15 Gerd Prof Dr Dannhardt Substituierte pyrrolverbindungen und deren anwendung in der pharmazie
KR920701167A (ko) * 1989-07-07 1992-08-11 에릭 에스. 딕커 약제학적 활성 화합물
PH27357A (en) * 1989-09-22 1993-06-21 Fujisawa Pharmaceutical Co Pyrazole derivatives and pharmaceutical compositions comprising the same
US5207817A (en) * 1989-09-23 1993-05-04 Bayer Aktiengesellschaft Herbicidal 5H-furan-2-one derivatives
DE4014420A1 (de) * 1989-09-23 1991-04-04 Bayer Ag 5h-furan-2-on-derivate
JPH05506215A (ja) * 1990-04-17 1993-09-16 アラーガン、インコーポレイテッド 抗炎症剤としての５および／または４位で置換した２（５ｈ）―フラノン
GB9012936D0 (en) * 1990-06-11 1990-08-01 Fujisawa Pharmaceutical Co Thiophene derivatives,processes for preparation thereof and pharmaceutical composition comprising the same
JPH04279672A (ja) * 1991-03-06 1992-10-05 Mita Ind Co Ltd フェニレンジアミン系化合物およびそれを用いた電子写真感光体
JP3014162B2 (ja) * 1991-04-24 2000-02-28 積水化学工業株式会社 α，β−不飽和γ−ブチロラクトンの製造方法
IT1254558B (it) * 1992-03-26 1995-09-25 Mini Ricerca Scient Tecnolog Composti a base di 3,4-diaril-(5h)-furan-2-one ad attivita' fungicida 3
US5274072A (en) * 1992-05-04 1993-12-28 Eastman Kodak Company Polyester composition having copolymerized therein a light absorbing compound
ES2111288T3 (es) * 1993-01-15 1998-03-01 Searle & Co Nuevos 3,4-diaril tiofenos y analogos de los mismos utiles como agentes antiinflamatorios.
US5474995A (en) * 1993-06-24 1995-12-12 Merck Frosst Canada, Inc. Phenyl heterocycles as cox-2 inhibitors
KR960703901A (ko) * 1993-08-19 1996-08-31 로즈 암스트롱 치환된 2(5H)푸라논, 2(5H)티오페논 및 2(5H)피롤론 유도체, 그의 제조 방법 및 엔도텔린 길항제로서의 그의 용도(Substituted 2(5H)Furanone, 2(5H)Thiophenone and 2(5H)Pyrrolone Derivatives, Their Preparation and Their Use as Endothelin antagonists)
EP0739340A1 (en) 1994-01-10 1996-10-30 Merck Frosst Canada Inc. Phenyl heterocycles as cox-2 inhibitors

Also Published As

Publication number Publication date
DE69410092T2 (de) 1998-12-17
EP0822190A1 (en) 1998-02-04
WO1995000501A2 (en) 1995-01-05
CA2163888A1 (en) 1995-01-05
FI956119A (fi) 1995-12-19
HUT74070A (en) 1996-10-28
FI20012510A (fi) 2001-12-19
CY2098B1 (en) 2002-04-05
DE69410092D1 (en) 1998-06-10
TW326042B (en) 1998-02-01
ES2115237T3 (es) 1998-06-16
CN1058008C (zh) 2000-11-01
WO1995000501A3 (en) 1995-04-13
JPH09500372A (ja) 1997-01-14
NO307253B1 (no) 2000-03-06
NO955256L (no) 1996-02-23
BR9406979A (pt) 1996-03-05
YU40394A (sh) 1997-08-22
UA48939C2 (uk) 2002-09-16
PL312196A1 (en) 1996-04-01
EP0705254A1 (en) 1996-04-10
BG100247A (bg) 1996-06-28
SG52703A1 (en) 1998-09-28
US5550142A (en) 1996-08-27
KR100215358B1 (ko) 1999-08-16
AU691119B2 (en) 1998-05-07
AU6197096A (en) 1996-10-31
IL123002A0 (en) 1998-08-16
RU2131423C1 (ru) 1999-06-10
SA94150039B1 (ar) 2005-09-19
CA2176973C (en) 2000-08-22
IL110031A0 (en) 1994-10-07
SI0705254T1 (en) 1998-08-31
FI956119A0 (fi) 1995-12-19
ZA944501B (en) 1995-03-13
PL178203B1 (pl) 2000-03-31
FI112222B (fi) 2003-11-14
US5474995A (en) 1995-12-12
EP0980866A2 (en) 2000-02-23
CA2278241A1 (en) 1994-12-25
MX9404749A (es) 1995-01-31
IL123002A (en) 2001-04-30
YU49053B (sh) 2003-08-29
US5710140A (en) 1998-01-20
CA2364039A1 (en) 1995-01-05
CZ288175B6 (en) 2001-05-16
BG63161B1 (bg) 2001-05-31
CN1295065A (zh) 2001-05-16
US5536752A (en) 1996-07-16
LV12209B (en) 1999-03-20
CA2176973A1 (en) 1994-12-25
FI114913B (fi) 2005-01-31
HU9503319D0 (en) 1996-01-29
EP0980866A3 (en) 2000-03-08
CA2278241C (en) 2006-03-14
HU227913B1 (en) 2012-05-29
SK284114B6 (sk) 2004-09-08
DK0705254T3 (da) 1999-01-25
IL110031A (en) 2000-01-31
CA2176974C (en) 1999-08-24
US6239173B1 (en) 2001-05-29
CA2176974A1 (en) 1994-12-25
AU6967494A (en) 1995-01-17
HK1027474A1 (en) 2001-01-12
NO955256D0 (no) 1995-12-22
EP0754687A1 (en) 1997-01-22
CZ314695A3 (en) 1996-05-15
ATE165825T1 (de) 1998-05-15
HRP940373A2 (en) 1996-12-31
LV12209A (lv) 1999-01-20
SK150295A3 (en) 1997-01-08
RO115354B1 (ro) 2000-01-28
CN1125944A (zh) 1996-07-03
JP2977137B2 (ja) 1999-11-10
NZ267386A (en) 1998-02-26
EP0705254B1 (en) 1998-05-06

Similar Documents

Publication Publication Date Title
CN1129576C (zh) 用作环氧酶－2抑制剂的苯基杂环化合物
CN1143365A (zh) 作为cox-2抑制剂的苯基杂环类化合物
CN1203066C (zh) 作为环加氧酶－2抑制剂的(甲磺酰基)苯基－2－(5h)－呋喃酮
CN1228327C (zh) 羧酸衍生物和包含它们的药物
CN1252057C (zh) 用于治疗与paar有关的疾病的噻唑衍生物
CN100341862C (zh) 噻唑烷衍生物及其医药用途
CN1166658C (zh) 作为环加氧酶-2-抑制剂的4,5二芳基-3(2h)-呋喃酮衍生物
CN1152863C (zh) 作为环氧合酶-2选择性抑制剂的取代的吡啶类化合物及其组合物
CN1260227C (zh) 含氮的五元杂环化合物
CN1277824C (zh) 哌嗪衍生物
CN1578659A (zh) 过氧化物酶体增殖剂激活的受体(ppar)的调节剂
CN1575284A (zh) 作为激酶抑制剂的取代的三唑二胺衍生物
CN1794989A (zh) 用于治疗糖尿病的n－(((((1,3－噻唑－2－基)氨基)羰基)苯基)磺酰基)苯丙氨酸衍生物及相关化合物
CN1170827C (zh) 苯并呋喃基吡喃酮衍生物
CN1507442A (zh) 激活人的过氧化物酶体增殖物激活受体的呋喃和噻吩衍生物
CN1638757A (zh) 组织蛋白酶半胱氨酸蛋白酶抑制剂
CN1658871A (zh) 作为gk活化剂的酰胺衍生物
CN1812979A (zh) 作为蛋白酪氨酸磷酸酶－1b抑制剂的取代氨基羧酸
CN1946666A (zh) 用于治疗代谢性疾病的化合物、药物组合物和方法
CN1356977A (zh) 胰高血糖素拮抗剂/反向激动剂
CN1974596A (zh) 丙型肝炎病毒抑制剂
CN1653047A (zh) 抗炎症药物单环芳酰吡啶酮
CN1946703A (zh) 取代的噻唑和嘧啶衍生物作为黑素细胞皮质激素受体调节剂
CN1894225A (zh) 作为鞘氨醇1－磷酸(内皮分化基因)受体激动剂的(3,4－二取代)丙酸酯
CN1922151A (zh) 取代的吡咯衍生物、组合物和使用方法

Legal Events

Date Code Title Description
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C06 Publication
PB01 Publication
C14 Grant of patent or utility model
GR01 Patent grant
ASS Succession or assignment of patent right

Owner name: MACPHER ROSSITER CO.,LTD.

Free format text: FORMER OWNER: MCFROST (CANADA) CO.

Effective date: 20060113

C41 Transfer of patent application or patent right or utility model
TR01 Transfer of patent right

Effective date of registration: 20060113

Address after: Quebec

Patentee after: Mike Frost Co.

Address before: Quebec

Patentee before: Merck Frosst Canada & Co.

C17 Cessation of patent right
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20031203

Termination date: 20120609