JP2019537627A - 低胃毒性のナプロキセン系非ステロイド性抗炎症薬 - Google Patents
低胃毒性のナプロキセン系非ステロイド性抗炎症薬 Download PDFInfo
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- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 229940127293 prostanoid Drugs 0.000 description 1
- 150000003814 prostanoids Chemical class 0.000 description 1
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 description 1
- 229960004172 pyridoxine hydrochloride Drugs 0.000 description 1
- 235000019171 pyridoxine hydrochloride Nutrition 0.000 description 1
- 239000011764 pyridoxine hydrochloride Substances 0.000 description 1
- 150000003227 pyridoxines Chemical class 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- HSSLDCABUXLXKM-UHFFFAOYSA-N resorufin Chemical compound C1=CC(=O)C=C2OC3=CC(O)=CC=C3N=C21 HSSLDCABUXLXKM-UHFFFAOYSA-N 0.000 description 1
- 210000004706 scrotum Anatomy 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 210000001626 skin fibroblast Anatomy 0.000 description 1
- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical compound [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
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- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4415—Pyridoxine, i.e. Vitamin B6
-
- 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]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/65—One oxygen atom attached in position 3 or 5
- C07D213/66—One oxygen atom attached in position 3 or 5 having in position 3 an oxygen atom and in each of the positions 4 and 5 a carbon atom bound to an oxygen, sulphur, or nitrogen atom, e.g. pyridoxal
- C07D213/67—2-Methyl-3-hydroxy-4,5-bis(hydroxy-methyl)pyridine, i.e. pyridoxine
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Rheumatology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pain & Pain Management (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pyridine Compounds (AREA)
Abstract
Description
R2+R3=−C(CH3)2−またはCH(CH3)−の場合、R1=
スキーム−式Iの化合物の合成の化学的スキーム;
表1−分析用HPLCの勾配溶出モードパラメーター;
表2−胃内投与における式Iの化合物の急性毒性;
表3−式Iの化合物およびいくつかの既知のNSAIDの特性比較;
表4−2000mg/kgの用量での単剤投与による式Iの化合物の胃毒性;
表5−胃内投与における式Iの化合物の急性滲出性炎症に対する効果;
表6−ラットに対する式Iの化合物の鎮痛作用;
表7−ラットに対する式Iの化合物の解熱作用;
ピリドキシン(ビタミンB6)およびナプロキセンのフラグメントを含む請求された式Iの化合物の調製は、市販の基質、試薬および溶媒を用いて、以下のスキームに従って、2段階で実施した。
丸底フラスコに、5lのアセトン中の、28.35gのピリドキシン塩酸塩II、95.23gのナプロキセンIII、50.52gの4−N,N−ジメチルアミノピリジンならびに123.73gのジシクロヘキシルカルボジイミドを装填する。ジシクロヘキシル尿素の沈殿物の形成が停止するまで、反応混合物を攪拌した後、沈殿物を濾過し、200mlのアセトンで洗浄し、濾液を真空中で蒸発させた。生成物をシリカゲルによるカラムクロマトグラフィー(酢酸エチル−石油エーテル=1:1の溶出液)で精製する。生成物IVが白色結晶質物質として得られる(収量82.0g、74%)。より詳細には、この化合物の調製物およびその性質は、特許文献3による発明に記載されている。
82.0gの化合物IVを丸底フラスコに入れ、1lのアセトンを加えて、10分間撹拌する。得られた溶液に、18.22gの(S)−2−(6−メトキシ−2−ナフチル)プロピオン酸(ナプロキセン)IIIを加え、沈殿物が完全に無くなるまで撹拌する。ロータリーエバポレーター(90rpm、残圧10ミリバール、温度40℃)を用いて真空中でアセトンを除去する。沈殿物を収集し、ロータリーエバポレーター(90rpm、残圧10ミリバール、温度80℃)を用いて真空下で乾燥する。請求された化合物Iの収率は100.1g(99.9%)である。
実験は、両方の性のWistarラット、6匹/群に対し、固定用量法に従って実施した。初期胃内投与量は、5000mg/kgとした。使用溶媒は0.5%ツイーン80溶液(ツイーン80−ポリオキシエチレンのソルビタンおよびオレイン酸誘導体;市販ポリマー)で、これは、0.5gのツイーン80を100mlの蒸留水中に溶解することにより調製した。
胃毒性の調査では、6〜7週齡の、180〜220gの体重の雌および雄Wistarラットを採用した。各群の動物の数は10匹とした。
式Iの化合物を、調査前の16時間にわたり断食させたラットの胃内に1回投与した。2000mg/kgの量の試験物質の懸濁液(ツイーン80の0.5%水溶液中)の投与の3時間後に、動物を安楽死させた;それらの胃を取り出し、小弯に沿って切開し、生理的溶液で洗浄して内容物を取りだした。
0−損傷なし;
0.5−充血;
1−単一微量損傷(1または2箇所の出血);
2−複数の損傷(びらん、スポット出血);
3−粘膜の顕著な複数の損傷(びらん、出血);
4−粘膜の全表面にわたる全体損傷(広範囲の出血、びらん、穿孔)。
立体構造的酵素シクロオキシゲナーゼ1(COX1)は、種々の細胞型で発現し、それらの正常な(生理学的)機能活性の確保に関与している。シクロオキシゲナーゼ2(COX2)は、重度炎症状態においてプロスタグランジンの合成に関与している。
・COXプローブ−2μl;
・溶解した補助因子−4μl(1時間安定);
・細胞ライセート−20μl;
・COX緩衝液を用いて、体積を172μlにする。
ナプロキセンストック溶液およびジメチルスルホキシド(DMSO)中の1000μMの濃度の式Iの物質を使用して、2倍希釈により予備的希釈液を調製する。それぞれ、62.5〜1000μMの5つの希釈液を調製する。
平均正味RFU=平均RFU−平均ブランクRFU
COX阻害のパーセンテージは、次式に従って計算される:
この実験は、6〜7週齡の、180〜220gの体重の雌および雄Wistarラットを使って実施した。各群の動物の数は10匹とした。
式Iの化合物の鎮痛特性の調査では、6〜7週齡の、180〜220gの体重の雌および雄Wistarラットを採用した。各群の動物の数は10匹とした。
実験の結果を表6に示す。
式Iの化合物の解熱特性の調査では、6〜7週齡の、180〜220gの体重の雌および雄Wistarラットを採用した。各群の動物の数は10匹とした。
Claims (1)
- 式(I):
である、抗炎症、鎮痛および解熱作用、ならびに低減した急性毒性および胃毒性を有するナプロキセン系非ステロイド性抗炎症薬。
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RU2016143071 | 2016-11-02 | ||
PCT/RU2017/000808 WO2018084748A1 (ru) | 2016-11-02 | 2017-10-31 | Нестероидное противовоспалительное средство на основе напроксена, обладающее низкой гастротоксичностью |
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US20200147067A1 (en) | 2020-05-14 |
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