TW200914455A - Uses of 2-[piperidinyl]methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-one for providing an analgesic effect, anti-allergic effect and histamine H1 receptor antagonism effect - Google Patents
Uses of 2-[piperidinyl]methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-one for providing an analgesic effect, anti-allergic effect and histamine H1 receptor antagonism effect Download PDFInfo
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- TW200914455A TW200914455A TW097107568A TW97107568A TW200914455A TW 200914455 A TW200914455 A TW 200914455A TW 097107568 A TW097107568 A TW 097107568A TW 97107568 A TW97107568 A TW 97107568A TW 200914455 A TW200914455 A TW 200914455A
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- 230000000202 analgesic effect Effects 0.000 title claims abstract description 11
- 230000008485 antagonism Effects 0.000 title abstract description 7
- 230000000694 effects Effects 0.000 title abstract description 4
- 102000003834 Histamine H1 Receptors Human genes 0.000 title abstract description 3
- 108090000110 Histamine H1 Receptors Proteins 0.000 title abstract description 3
- FGRWXMRRCSCNDK-UHFFFAOYSA-N 2-(piperidin-1-ylmethyl)-3,6-dihydro-2h-imidazo[1,2-c]quinazolin-5-one Chemical compound C1N2C(=O)NC3=CC=CC=C3C2=NC1CN1CCCCC1 FGRWXMRRCSCNDK-UHFFFAOYSA-N 0.000 title abstract 2
- 230000003266 anti-allergic effect Effects 0.000 title description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 5
- 201000010099 disease Diseases 0.000 claims abstract description 4
- 239000004480 active ingredient Substances 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- -1 hexamethylene thiol Chemical class 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 206010070835 Skin sensitisation Diseases 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 231100000370 skin sensitisation Toxicity 0.000 claims description 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 2
- PGCRDIRKSWIOPB-UHFFFAOYSA-N 2-methyl-2,3-dihydro-1h-imidazole Chemical compound CC1NC=CN1 PGCRDIRKSWIOPB-UHFFFAOYSA-N 0.000 claims description 2
- 206010039085 Rhinitis allergic Diseases 0.000 claims description 2
- 201000009961 allergic asthma Diseases 0.000 claims description 2
- 201000010105 allergic rhinitis Diseases 0.000 claims description 2
- 208000006673 asthma Diseases 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims description 2
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims 2
- 150000002576 ketones Chemical class 0.000 claims 2
- LWTIGYSPAXKMDG-UHFFFAOYSA-N 2,3-dihydro-1h-imidazole Chemical compound C1NC=CN1 LWTIGYSPAXKMDG-UHFFFAOYSA-N 0.000 claims 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical group O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- 229910052731 fluorine Inorganic materials 0.000 claims 1
- 239000011737 fluorine Substances 0.000 claims 1
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 125000004076 pyridyl group Chemical group 0.000 claims 1
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- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
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- 235000002639 sodium chloride Nutrition 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 3
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 3
- 229960001138 acetylsalicylic acid Drugs 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- JJCFRYNCJDLXIK-UHFFFAOYSA-N cyproheptadine Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2C=CC2=CC=CC=C21 JJCFRYNCJDLXIK-UHFFFAOYSA-N 0.000 description 3
- 229960001140 cyproheptadine Drugs 0.000 description 3
- 206010013990 dysuria Diseases 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- DVOJQKBCYXOZLZ-UHFFFAOYSA-N 1-(2,3-dihydro-1H-imidazol-2-ylmethyl)piperidine Chemical class C1CCN(CC1)CC2NC=CN2 DVOJQKBCYXOZLZ-UHFFFAOYSA-N 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
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- 208000024780 Urticaria Diseases 0.000 description 2
- 229940035676 analgesics Drugs 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
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- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
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- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
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- 238000012360 testing method Methods 0.000 description 2
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 description 1
- VQZRVPWIZFFSQD-UHFFFAOYSA-N 6h-quinazolin-5-one Chemical compound C1=NC=C2C(=O)CC=CC2=N1 VQZRVPWIZFFSQD-UHFFFAOYSA-N 0.000 description 1
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 1
- COXVTLYNGOIATD-HVMBLDELSA-N CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O Chemical compound CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O COXVTLYNGOIATD-HVMBLDELSA-N 0.000 description 1
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- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000000043 antiallergic agent Substances 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 229940067131 aspirin 100 mg Drugs 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
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- 125000005708 carbonyloxy group Chemical group [*:2]OC([*:1])=O 0.000 description 1
- 229960000265 cromoglicic acid Drugs 0.000 description 1
- VLARUOGDXDTHEH-UHFFFAOYSA-L disodium cromoglycate Chemical compound [Na+].[Na+].O1C(C([O-])=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C([O-])=O)O2 VLARUOGDXDTHEH-UHFFFAOYSA-L 0.000 description 1
- 206010013663 drug dependence Diseases 0.000 description 1
- 235000013601 eggs Nutrition 0.000 description 1
- XFBVBWWRPKNWHW-UHFFFAOYSA-N etodolac Chemical compound C1COC(CC)(CC(O)=O)C2=N[C]3C(CC)=CC=CC3=C21 XFBVBWWRPKNWHW-UHFFFAOYSA-N 0.000 description 1
- 229960005293 etodolac Drugs 0.000 description 1
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- YLQWCDOCJODRMT-UHFFFAOYSA-N fluoren-9-one Chemical compound C1=CC=C2C(=O)C3=CC=CC=C3C2=C1 YLQWCDOCJODRMT-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
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- 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
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
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- 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]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
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- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Heart & Thoracic Surgery (AREA)
- Immunology (AREA)
- Cardiology (AREA)
- Toxicology (AREA)
- Rheumatology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Otolaryngology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
200914455 九、發明說明： 【發明所屬之技術領域】 本發明係有關使用2-[六氫吡啶基]曱基_2,3_二氫咪唾 [1,2-幻。f唾啉_5(6H)-酮來提供病人止痛效果、抗過敏欵 果、及組織胺Η1受體拮抗作用的用途發明。 【先前技術】 美國專利第5，158,953號揭示一系列2-取代甲基_2,3_二 氫咪唑[1，2-幻喹唑啉_5(6Η)_酮化合物的合成，及其在預防 及治療高血壓的用途。 美國專利第5,340,814及5,512,677號揭示一系列3_取代 甲基-2,3-二氫咪唑以，、幻喹唑啉_5(611)_酮化合物的合成， 及其在治療高血壓及排尿困難的用途。 美國專利第5,932,584號揭示光學活性的3_取代甲基 -2,3-—氫咪唑喹唑啉_5(6Η)-酮化合物的合成，及其 在治療向血壓及排尿困難的用途。 美國專利第6,946,470 Β2號揭示2-[六氫吡啶基]曱基 -2,3-_虱咪唑π，2_幻喹唑啉_5(611)_酮在治療精神病的用 途。 至目前為止對於2_[六氫吼啶基]甲基_2,3_二氫咪唑 [1，2-£]喹唑啉_5(6Η)_酮並未發現除了治療高血壓、排尿困 難及精神病以外的用途。 【發明内容】 200914455 本案發明之—個目的即在提出_種使用定 基]甲基_2,3_二氫咪唑[丨，2-幻喹唑啉-5(6H)-酮化合物來提 供病人止痛效果的新用途。 本案發明之另—個目的即在提出一種使用2_[六氫吡 <基]曱基-2’3-二氣^坐π，2_幻喧n坐咐_5(叫晒化合物來 治療病人的被動性皮膚過敏的新用途。 一本案發明之又一個目的即在提出一種使用2_[六氫吡 啶基]甲基-2,3-二氫咪唑喹唑啉_5(6Η)酮化合物於 病人體内引起組織胺Ηι受體拮抗作用以治療疾病或不適 的新用途。 為了達成上述目的，本發明提供了一種醫藥組合物用 於提供病人止痛效果，該組合物包含一止痛治療有效量作 為有效成分之具有以下化學式⑴的2_[六氫„比啶基]曱基 2’3、二氫咪唑喹唑啉_5(6H)_酮或其醫藥容許鹽，及 與該有效成分共同使用之醫藥容許載體或稀釋劑··
⑴ 其中R1為C1-C6伸烷基、羰基、C1-C6伸烷基羰基、或羰基 氧；R2為氫、C1-C6烷基、C1-C6烷氧基、或鹵素。 本發明亦提供了一種於病人體内引起組織胺Η!受體拮 200914455 抗作用以治療疾病或不適（例如過敏性鼻炎或氣喘）的醫藥 、、且5物，包含一治療有效量作為有效成分的具有上述化學 式（I)的2-[六氫％啶基]曱基_2,3·二氫咪唑喹唑啉 -5(6H:)-酮或其醫藥容許鹽，及與該有效成分共同使用之醫 藥容許載體或稀釋劑。 ’ 本發明亦提供了一種用於治療病人的被動性皮膚過敏 的醫藥組合物，包含一治療有效量作為有效成分的具有前 述化學式⑴的2-[六氫t定基]甲基_2,3_二氣味叩叫哇 哇淋ΜΗ)，或其醫藥容許鹽，及與該有效成分共同使用 之醫藥容許載體或稀釋劑。 較佳的，為伸甲基或羰基，又以羰基為更佳。 較佳的，為氫或齒素’而以齒素為更佳，又以氣為 最佳。 、 較佳的，該2-[六氫。比啶基]甲基_2,3_二氫咪唾 啥唾啉酮為2-Π-(4ϋ苯甲醯基）六氫吡淀基]甲基 -2,3-二氫咪唑[1，2-幻喹唑啉_5(6Η)_酮。 較佳的’前述組合物為口服。 【實施方式】 一系列2-[六氫吡啶基]甲基_2,3_二氫咪唑[124]喹唑 琳-5(6Η)-酮化合物依照美國專利第5,l5M53號所揭示的 方法被合成’該發明的内容在此藉由參考方式被合併於本 案說明書。苯《發的扭體的實驗及醋酸誘發的扭體的實 驗被進行以評估這些化合物作為止痛藥物的潛力。 200914455 被動性皮膚過敏的實驗被進行以評估這些化合物作為 抗過敏藥物的潛力。 組織胺Η,拮抗作用的實驗被進行以評估這些化合物作 為組織胺Η】括抗劑的潛力。 本發明將藉以下實施例被進一步瞭解’該等實施例僅 為說明之用而非用於限制本發明範圍。 本說明書所提及的百分比及份量除非另外指明否則皆 以重量為基準。而各百分比範圍的總合為i 〇〇〇/。。 苯醌誘發的扭體 根據 Siegmund 等人的方法[Siegmund, E，Cadmus，r and Lu, G. A method for evaluating both non-narcotic and narcotic analgesics. Proc. Soc. Exp. Biol. Med. 952: 729-73 1, 195 7_] ’每組實驗使用8隻體重24 土 2克的公CD_i (Cr/ ) 小鼠。將溶媒（2% Tween 80，10 ml/kg)、PDC-130 或 aspirin 以口服方式投予1小時後，以腹腔注射的方式將苯醌（2 mg/kg)打入小鼠腹腔中，在笨醌被注射後的第5分至1〇分 鐘觀察並記錄小鼠扭體的次數並與溶媒處理組比較，以評 估藥物可能的止痛作用。 200914455 表1 PDC-1 3 0對苯醌誘發的扭體的抑制 處理方式 劑量 扭體的次數 溶媒處理組 10 ml/kg 15.1 ± 1.4 PDC-130* 1 mg/kg 2·8 ± 1.2* * * 0.3 mg/kg 5.3 ± 1.7* * * 0.1 mg/kg 6.4 ± 1.6*** 0.03 mg/kg 12.1 士 i. 6 Aspirin 1 00 mg/kg 5.5 士 1.5*** 氫味嗤[1，2-£]喹唑啉_5(6Η)_酮（美國專利第5,1 58,953號的 實施例1 5) 與溶媒處理組比較ρ<0.001 從表1可以看出以PDC-1 30治療的動物與溶媒處理組 比較顯現出明顯降低的扭體次數，此顯示出一可能的止痛 效果。 醋酸誘發的扭體 母組貝驗使用8隻體重24 士 2克的公d 1 (〇 / ·)小 鼠。將溶媒（2% Tween 80, 10 ml/kg)、pDc_13〇 或 aspirin
以口服方式投予後i小時，以腹腔注射的方式將醋酸（〇 5%， 20 ml/kg)打入小鼠腹腔中。在醋酸被注射後的第$至分 鐘觀察並記錄小鼠扭體的次數並與溶媒處理組比較，以評 估藥物可能的止痛作用[參考資料：In〇ue. K , M〇t〇naga，A 200914455 and Nishimura, T. Mechanism of antiinflammatory action of etodolac. Arzneim. .-Forsch. / Drug Res_ 41: 235-239,1991·]。 表2 PDC_ 13〇對醋酸誘發的扭體的抑制 處理方式 劑量 扭體的次數 溶媒處理組 10 ml/kg 12.4 土 1.5 PDC-130* 1 mg/kg 2.1 ± i.i *** 0-3 mg/kg 5·3 ± 1.1 *** 0.1 mg/kg 5.0 ± 1.〇 * * * 0.03 mg/kg 12.1 土 1.6 Aspirin 100 mg/kg 2.4 ± 1.〇 * * * *PDC-130:同表 1 * * .與〉谷媒處理組比較P < 〇 . 〇 〇 1 如表2所示以PDC_13〇治療的動物與溶媒處理組比較 〇顯現出明顯降低的扭體次數，此顯示出—可能的止痛效果。 被動性皮膚過敏 每組實驗使用5隻體重80±2〇克的雄性wistar大鼠。 在實驗前16小時，以皮内注射的方式於大鼠背部兩個點上 打入反應素性抗印白蛋白血清（reaginic anti〇valbumin serum) (0.5 ml)。實驗時將溶媒（2% τ_η 8〇,丨 〇 mi/kg)、 PDC-13G或eyprQheptadine以口服方式投予大鼠。！小時 後，以靜脈注射方式將印白蛋自（lmg)及卜嶋藍色染料 10 200914455 (5 mg)打入大鼠體内，並於30分鐘後將其犧牲。隨後測量 每一隻動物背上條痕（wheal)的直徑並以下列標準評分： 0分：直徑< 〇·〇5公分 1分：直徑〇·〇5 - 〇·2〇公分 2分：直徑0.2 - 〇·4公分 3分：直徑0.4 - 0.6公分 4分：直徑0.6 - 0_8公分 5分：直徑> 0.8公分 每隻動物的最高可能總分為5 X 2 = 1 〇分[參考資料. Goose, J. and Blair, A.M.J.N. Passive cutaneous anaphylaxis in the rat, induced with two homologous reagin-like antibodies and its specific inhibition with disodium cromoglycate. Immunology 16: 749-760, 1969.1 〇 ^ 3 PDC-130對被動性皮膚過敏的抑制效果 處理方式 劑量 總分 ------ 抑制（％): 溶媒處理組 1 0 ml/kg 50 ~—-—- —_ PDC-130* 30 mg/kg 10 80 10 mg/kg 10 80 Cyproheptadine 3 mg/kg 1 mg/kg 16 14 68 79 *PDC-130:同表 1 生的藍色條痕的抑制
百分比 **藥物對被動性皮膚過敏所產 率的依下列公式計算： 11 200914455 總分)χ 100% (溶媒處理組齡·騎轉分媒處理組 從表3可以看出，pDC_13〇 。療，、且的動物顯現出對被 動性皮膚過敏所產生的g色條 一 |巴怿展具有良好抑制百分比，此 顯示出一可能的抗過敏活性。 組織胺H!拮抗作用 每組實驗使用5隻體重80±2〇克的雄性Wistar大鼠。 貝驗時將溶媒（20/0 Tween 8〇，1〇 mI/kg) ' pDc_13〇 或 cyproheptadine以口服方式投予大鼠。！小時後，以靜脈注 射方式將Evans藍色染料（5 mg/o.5 ml/rat)打入大鼠體内， 並立刻以皮肉注射的方式，於大鼠背部兩個點打入組織胺 (每個點30 gg/〇.〇5 mi)。3〇分鐘後，將其犧牲。背部兩個 條痕（wheal)的直徑加以測量並以下列方式加以評分： 〇分：直徑< 0.05公分 1分：直徑0.05 - 0.20公分 2分：直徑0.2-0.4公分 3分：直徑0.4-0.6公分 4分：直徑〇. 6 - 0 _ 8公分 5分：直徑> 0.8公分 每隻動物的最高可能總分為5 X 2 = 1 0分。 12 200914455 胺Η!受體的拮抗作用 劑量 ---— 總分 抑制（％) 1 0 ml/kg 50 -—~~—. 30 mg/kg 10 80 10 mg/kg 14 72 3 mg/kg 20 60 1 mg/kg 18 64 處理方式 溶媒處理組 PDC-130*
Cyproheptadine *PDC-130:同表 * *藥物對組織胺所誘發的該备饮广仏上 色條痕的抑制百分比率的
列公式計算： F (溶媒處理組總分-藥物治療組總分)/_處理組總分)x麵 從表4可以看出，PDC_13〇治療組的動物顯現出對組 織胺所誘發的藍色條痕呈有 民八有良好抑制百分比，此顯示出— 可能的抗組織胺Hl受體的拮抗作用。
L 本發明已參照實施例的特定内容被描述如上，除了下 列申请專利範圍所界定者外， — 、 "亥寺内谷不應視為本發明範 圍的限制。可以理解的是 ^ 了利用以上所描述内容作出多種 修飾和變化。 13
Claims (1)
- 200914455 十、申請專利範圍： 1 · 一種提供病人止痛效果的醫藥組合物，包含一止痛 治療有效量作為有效成分之具有以下化學式⑴的2-[六氳 比疋基]甲基_2,3_二氫咪唑[丨，2-^喹唑啉_1(όΗ卜酮或其醫 市合°午|及與該有效成分共同使用之醫藥容許載體或稀 釋劑： /Η 其中R1為C1-C6伸烷基、羰基、C1_C6伸烷基羰基、或羰基 氧，R2為氫、C1_C6烷基、C1-C6烷氧基、或鹵素。 2.如申請專利範圍第1項的組合物，其中R1為伸甲基 或羰基。 & 3 _如申凊專利範圍第2項的組合物，其中Ri為羰基。 4·如申請專利範圍第1 ' 2或3項的組合物，其中尺2為 氫或鹵素。 14 1 ·如申請專利範圍第4項的組合物，其中R2為鹵素。 200914455 6. 申明專利軏圍第5項的組合物，其中r2為氟 7.如申請專利範圍第i項的 啶基]甲基-2,3_二氫咪唑丨丨2 ，、中"亥2·[六虱吡 '、坐[1，2-幻喹哇啉_5(6Η)__為 :-Π仰敦笨甲醯基)六氯_基]甲基_2,3_二 [1,2-幻喹唑啉 _5(6Ii),。 服 申明專利範圍第1項的組合物，其為 9.種於病人體内弓丨起組織胺H1受體拮抗作A 療疾病或不適的醫藥組合物’包含—治療有效量 成分之如所述中請專利範圍第1項至第8項中任-項所/羞 的具有化學式⑴的2_[六氫°比咬基]甲基-2,3-二氫咪唑 [1，2-£]㈣t5(6H)__或其醫藥容許冑，及與該有效成分 共同使用之醫藥容許載體或稀釋劑。 10.如申請專利範圍第9項的組合物，其中該疾病或不 適為過敏性鼻炎或氣喘。 11' 種用於治療病人的被動性皮膚過敏的醫藥組合 物，包含一治療有效量作為有效成分之如前述申請專利範 圍第1項至第8項t任一項所定義的具有化學式⑴的[六 氫比π疋基J甲基_2,3_二氫咪唾【〗，2_以啥唾啉_5(6Ή)_酮或其 15 200914455 醫藥容許鹽，及與該有效成分共同使用之醫藥容許載體或 稀釋劑。 C C 16 200914455 七、指定代表圖： (一） 本案指定代表圖為：第（ ）圖。 (二） 本代表圖之元件符號簡單說明：八、本案若有化學式時，請揭示最能顯示發明特徵的化學式： 200914455 /7年多月^曰修正減余 七、指定代表圖·· (一） 本案指定代表圖為：第（ ）圖。 (二) 本代表圖之元件符號簡單說明：[無] 八、本案若有化學式時，請揭示最能顯示發明特徵的化學式：
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| TW591029B (en) | 2002-01-04 | 2004-06-11 | Pharmaceutical Ind Tech & Dev | Antipsychotic pharmaceutical composition |
| BRPI0412285A (pt) * | 2003-07-02 | 2006-09-19 | Hoffmann La Roche | os compostos de quinazolinona substituìda por arilamina |
| US20060069124A1 (en) * | 2004-09-07 | 2006-03-30 | Rao P S | Use of MDL-100,907 for treatment of allergic and eosinophil mediated diseases |
-
2007
- 2007-09-25 GB GB0812493A patent/GB2454549B/en active Active
- 2007-09-25 GB GB0718678A patent/GB2453116B/en active Active
- 2007-10-18 US US11/907,853 patent/US20090082373A1/en not_active Abandoned
-
2008
- 2008-01-03 DE DE102008003054A patent/DE102008003054A1/de not_active Withdrawn
- 2008-01-10 JP JP2008002785A patent/JP4845895B2/ja active Active
- 2008-02-20 FR FR0800916A patent/FR2921269B1/fr active Active
- 2008-03-04 TW TW097107568A patent/TWI364280B/zh active
- 2008-03-17 CN CN2008100850725A patent/CN101396365B/zh active Active
-
2010
- 2010-07-26 US US12/843,364 patent/US20100292257A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| GB2454549B (en) | 2009-09-23 |
| US20090082373A1 (en) | 2009-03-26 |
| US20100292257A1 (en) | 2010-11-18 |
| CN101396365B (zh) | 2012-04-18 |
| GB2453116A (en) | 2009-04-01 |
| GB2453116B (en) | 2010-03-17 |
| DE102008003054A1 (de) | 2009-05-07 |
| FR2921269A1 (fr) | 2009-03-27 |
| GB2454549A8 (en) | 2009-09-02 |
| GB2454549A (en) | 2009-05-13 |
| GB0718678D0 (en) | 2007-10-31 |
| JP4845895B2 (ja) | 2011-12-28 |
| CN101396365A (zh) | 2009-04-01 |
| FR2921269B1 (fr) | 2010-05-28 |
| JP2009079029A (ja) | 2009-04-16 |
| GB0812493D0 (en) | 2008-08-13 |
| TWI364280B (en) | 2012-05-21 |
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