JPH02157276A - New (-)2-pyrazoline compound and remedy for cerebral angiopathy containing the same as active ingredient - Google Patents
New (-)2-pyrazoline compound and remedy for cerebral angiopathy containing the same as active ingredientInfo
- Publication number
- JPH02157276A JPH02157276A JP63311868A JP31186888A JPH02157276A JP H02157276 A JPH02157276 A JP H02157276A JP 63311868 A JP63311868 A JP 63311868A JP 31186888 A JP31186888 A JP 31186888A JP H02157276 A JPH02157276 A JP H02157276A
- Authority
- JP
- Japan
- Prior art keywords
- pyrazoline
- nicotinoyl
- methyl
- cerebral
- remedy
- 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.)
- Granted
Links
- 239000004480 active ingredient Substances 0.000 title claims description 7
- 206010059245 Angiopathy Diseases 0.000 title abstract description 4
- 230000002490 cerebral effect Effects 0.000 title abstract description 4
- -1 (-)2-pyrazoline compound Chemical class 0.000 title description 6
- KKMMIKKVFRCZBO-UHFFFAOYSA-N (3-methyl-3,4-dihydropyrazol-2-yl)-pyridin-3-ylmethanone Chemical compound CC1CC=NN1C(=O)C1=CC=CN=C1 KKMMIKKVFRCZBO-UHFFFAOYSA-N 0.000 claims abstract description 16
- 208000026106 cerebrovascular disease Diseases 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 11
- 229940124597 therapeutic agent Drugs 0.000 claims description 4
- 230000000694 effects Effects 0.000 abstract description 17
- 206010048962 Brain oedema Diseases 0.000 abstract description 13
- 208000006752 brain edema Diseases 0.000 abstract description 13
- 230000001154 acute effect Effects 0.000 abstract description 10
- 206010061216 Infarction Diseases 0.000 abstract description 6
- 230000007574 infarction Effects 0.000 abstract description 6
- 230000003287 optical effect Effects 0.000 abstract description 6
- 230000007654 ischemic lesion Effects 0.000 abstract description 5
- MCGBIXXDQFWVDW-UHFFFAOYSA-N 4,5-dihydro-1h-pyrazole Chemical compound C1CC=NN1 MCGBIXXDQFWVDW-UHFFFAOYSA-N 0.000 abstract description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 abstract description 4
- 238000002360 preparation method Methods 0.000 abstract description 4
- MLUCVPSAIODCQM-NSCUHMNNSA-N crotonaldehyde Chemical compound C\C=C\C=O MLUCVPSAIODCQM-NSCUHMNNSA-N 0.000 abstract description 3
- MLUCVPSAIODCQM-UHFFFAOYSA-N crotonaldehyde Natural products CC=CC=O MLUCVPSAIODCQM-UHFFFAOYSA-N 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 abstract description 2
- ATBIAJXSKNPHEI-UHFFFAOYSA-N pyridine-3-carbonyl chloride Chemical compound ClC(=O)C1=CC=CN=C1 ATBIAJXSKNPHEI-UHFFFAOYSA-N 0.000 abstract description 2
- 238000000926 separation method Methods 0.000 abstract description 2
- 230000003902 lesion Effects 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 230000004048 modification Effects 0.000 abstract 1
- 238000012986 modification Methods 0.000 abstract 1
- 241000700159 Rattus Species 0.000 description 14
- 150000003839 salts Chemical class 0.000 description 10
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- 210000004556 brain Anatomy 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 239000012071 phase Substances 0.000 description 8
- 206010008118 cerebral infarction Diseases 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 206010008089 Cerebral artery occlusion Diseases 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 210000003657 middle cerebral artery Anatomy 0.000 description 6
- 201000007309 middle cerebral artery infarction Diseases 0.000 description 6
- 201000006474 Brain Ischemia Diseases 0.000 description 4
- 206010008120 Cerebral ischaemia Diseases 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000002504 physiological saline solution Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 206010060860 Neurological symptom Diseases 0.000 description 3
- 208000006011 Stroke Diseases 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- FNOKJRGVMILSFT-UHFFFAOYSA-N 2-methyl-3,4-dihydropyrazole Chemical compound CN1CCC=N1 FNOKJRGVMILSFT-UHFFFAOYSA-N 0.000 description 2
- KDTSAMBCRXSULF-UHFFFAOYSA-N 5-methyl-4,5-dihydro-1h-pyrazole Chemical compound CC1CC=NN1 KDTSAMBCRXSULF-UHFFFAOYSA-N 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 231100000111 LD50 Toxicity 0.000 description 2
- 230000007059 acute toxicity Effects 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000001647 drug administration Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- BCQZXOMGPXTTIC-UHFFFAOYSA-N halothane Chemical compound FC(F)(F)C(Cl)Br BCQZXOMGPXTTIC-UHFFFAOYSA-N 0.000 description 2
- 229960003132 halothane Drugs 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000000004 hemodynamic effect Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 238000007917 intracranial administration Methods 0.000 description 2
- 230000000302 ischemic effect Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000001766 physiological effect Effects 0.000 description 2
- 238000004393 prognosis Methods 0.000 description 2
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 101100428830 Caenorhabditis elegans mml-1 gene Proteins 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 206010013509 Disturbances in consciousness Diseases 0.000 description 1
- 208000012671 Gastrointestinal haemorrhages Diseases 0.000 description 1
- 206010019670 Hepatic function abnormal Diseases 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 101100166829 Mus musculus Cenpk gene Proteins 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 206010062237 Renal impairment Diseases 0.000 description 1
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
- 206010038678 Respiratory depression Diseases 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 210000001627 cerebral artery Anatomy 0.000 description 1
- 230000003727 cerebral blood flow Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 208000030304 gastrointestinal bleeding Diseases 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000008447 perception Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 150000003219 pyrazolines Chemical class 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は、虚血病巣を保護することにより脳血管障害急
性期の脳浮腫の生成を抑制し、梗塞巣を縮小する作用を
持ち、脳血管障害急性期の治療に有用な新規（−）２−
ピラゾリン化合物、及びそれを有効成分とする脳血管障
害治療剤に関するものである。[Detailed Description of the Invention] [Field of Industrial Application] The present invention has the effect of suppressing the production of cerebral edema in the acute phase of cerebrovascular accident by protecting the ischemic focus, and reducing the size of the infarct focus. Novel (-)2- useful for treatment of acute phase of vascular disorder
The present invention relates to a pyrazoline compound and a therapeutic agent for cerebrovascular disorders containing the same as an active ingredient.
わが国の脳血管障害による死亡率は年々低下し病因別死
亡率では、ガン、心臓病に続いて３位になっているが、
それでも脳血管障害の患者の３０〜６０％が急性期に死
亡していると言われている。また生命を取り留めた人で
も多くが意識障害、運動障害或は知覚障害に苦しめられ
ている。ちなみにわが国における老人性痴呆の５０％は
脳血管障害由来であると言われている。The mortality rate due to cerebrovascular disorders in Japan has been decreasing year by year, and in terms of mortality rate by cause, it ranks third after cancer and heart disease.
Even so, it is said that 30-60% of patients with cerebrovascular disorders die during the acute stage. Furthermore, even among those who survive, many suffer from disturbances in consciousness, movement, or perception. Incidentally, it is said that 50% of senile dementia cases in Japan are caused by cerebrovascular disorders.
生命予後の神経障害の多くは急性期の脳虚血に起因して
いるが、これらの神経症状の治療は症状が固定した慢性
器では極めて困難である。Many of the neurological disorders that have a negative prognosis are caused by acute cerebral ischemia, but treatment of these neurological symptoms is extremely difficult in chronic cases where the symptoms are fixed.
脳血管障害急性期の治療は脳浮腫対策と全身及び頭蓋内
の血行動態を調節することにより虚血病巣を保護し、障
害の範囲を極力小さくすることに主眼が置かれている。Treatment for the acute phase of cerebrovascular accidents focuses on protecting ischemic lesions and minimizing the extent of damage by countering cerebral edema and regulating systemic and intracranial hemodynamics.
脳浮腫対策としては現在グリセロールの様な高張液やス
テロイド剤の静脈内投与がなされているが、高張液の輸
液は体液の電解質のバランスを崩し易く、またステロイ
ド剤は消化管出血等の副作用が強い。一方ベントバルビ
タールの様なパルピッレートには脳虚血に対して脳保護
作用があることが知られており（Ａｎｅｓｔｈｅｓｉｏ
ｌｏｇｙ、 ４７．２８５゜１９７７）、また臨床にも
応用されている（日本臨床、４３、１８５．１９８５）
。しかしながらパルピッレートは有効投与量と意識低下
、呼吸抑制作用等の副作用のでる投与量とが極めて近く
、完全な全身管理が可能な施設でしか使用できない、ま
た肝機能、腎機能障害等の副作用がある。Hypertonic fluids such as glycerol and steroids are currently administered intravenously as a countermeasure against cerebral edema, but hypertonic fluids tend to disrupt the electrolyte balance of body fluids, and steroids have side effects such as gastrointestinal bleeding. strong. On the other hand, palpyrates such as bentobarbital are known to have a brain protective effect against cerebral ischemia (Anesthesio
(Japan Clinical, 43, 185.1985).
. However, the effective dose of palpyrate is extremely close to the dose at which it causes side effects such as decreased consciousness and respiratory depression, so it can only be used in facilities where complete systemic control is possible, and it also has side effects such as impaired liver function and renal function. .
最近になって脳虚血に対する脳保護作用を有する薬物と
してＮ１ｚｏｆｅｎｏｎｅが報告されたが、この薬物に
は意、？ｆａ障害の改善作用はあるものの脳浮腫を抑制
する作用はない（日本臨床、４３．１８５．１９８５）
。Recently, N1zofenone has been reported as a drug that has a brain-protective effect against cerebral ischemia, but is there anything wrong with this drug? Although it has the effect of improving FA disorder, it does not have the effect of suppressing brain edema (Japan Clinical, 43.185.1985)
.
脳血管障害急性期の脳７７腫の生成を抑制し、虚血病巣
を保護し生命予後の神経症状を改善しつる薬物の開発が
望まれている。There is a desire for the development of a drug that suppresses the formation of brain tumors during the acute phase of cerebrovascular accidents, protects ischemic lesions, and improves neurological symptoms that affect life's prognosis.
本発明は（−）２−ピラゾリン化合物を用いて脳浮腫の
抑制、虚血病巣の保護作用及び神経症状の改善作用を持
つ薬剤を提供することを目的としている。An object of the present invention is to provide a drug that uses a (-)2-pyrazoline compound to suppress cerebral edema, protect ischemic lesions, and improve neurological symptoms.
発明者は種々のピラゾリン化合物を合成してその生理活
性を調べ、新規な２−ピラゾリン誘導体が脳虚血急性期
の脳浮腫を抑制し、梗塞巣を縮小する作用があることを
見いだし特許を出願している（出願番号６３−１４６８
５０）。The inventor synthesized various pyrazoline compounds and investigated their physiological activities, and found that a new 2-pyrazoline derivative had the effect of suppressing cerebral edema during the acute phase of cerebral ischemia and reducing the size of the infarct, and filed a patent application. (Application number 63-1468
50).
発明者は上記出願の２−ピラゾリン誘導体の光学異性体
について検討し、新規な（−）１−ニコチノイル−５−
メチル−２〜ピラゾリンがそのラセミ体より生理活性が
強く、副作用が弱いことを見いだし本発明を完成させる
に到った。The inventor studied the optical isomers of the 2-pyrazoline derivative of the above application, and obtained a novel (-)1-nicotinoyl-5-
The present invention was completed by discovering that methyl-2-pyrazoline has stronger physiological activity and less side effects than its racemic form.
ラセミ体の１−ニコチノイル−５−メチル−２−ピラゾ
リンはクロトンアルデヒドとヒドラジンを反応させて２
−ピラゾリンとし、これにニコチン酸クロライドを反応
させて得ることができる。（−）体の１−ニコチノイル
−５−メチル−２−ピラゾリンはラセミ体を市販の光学
分離カラムを用いて分割分取することができる。Racemic 1-nicotinoyl-5-methyl-2-pyrazoline is produced by reacting crotonaldehyde with hydrazine.
- It can be obtained by reacting pyrazoline with nicotinic acid chloride. The (-) form of 1-nicotinoyl-5-methyl-2-pyrazoline can be separated into a racemic form using a commercially available optical separation column.
また本発明は、上記新規（−）ｌ−ニコチノイル−５メ
チル−２−ピラゾリン及びその製薬上許容し得る塩を有
効成分とする脳血管障害治療剤に関するものである。The present invention also relates to a therapeutic agent for cerebrovascular disorders containing the novel (-)l-nicotinoyl-5methyl-2-pyrazoline and its pharmaceutically acceptable salt as an active ingredient.
本発明の脳血管障害治療剤の投与によって、脳血管障害
急性期の脳浮腫対策と全身及び頭蓋内の血行動態を調節
することにより虚血病巣を保護し、障害の範囲を極力小
さくすることができる。By administering the therapeutic agent for cerebrovascular disorders of the present invention, it is possible to protect ischemic lesions and minimize the extent of damage by countering cerebral edema during the acute phase of cerebrovascular disorders and regulating systemic and intracranial hemodynamics. can.
本発明の化合物の塩の例としては塩酸塩、燐酸塩、フマ
ール酸塩、マレイン酸塩等がある。Examples of salts of the compounds of the invention include hydrochlorides, phosphates, fumarates, maleates, and the like.
上記の（−）ｌ−ニコチノイル−５−メチル−２−ピラ
ゾリン及びその塩は注射剤、座剤、または経口剤として
使用に供すことができる。また脳浮腫対策として通常用
いられている２０％グリセロール液に溶かして輸液して
もよい。The above (-)l-nicotinoyl-5-methyl-2-pyrazoline and its salts can be used as injections, suppositories, or oral preparations. Alternatively, it may be dissolved in a 20% glycerol solution, which is commonly used as a countermeasure against cerebral edema, and then infused.
脳血管障害の急性期における上記（−）■−ニコチノイ
ルー５−メチルー２−ピラゾリン及びその塩の望ましい
投与量は日ｆｆ１０．１〜２．０ｇである。The preferred dosage of the above (-)■-nicotinoyl-5-methyl-2-pyrazoline and its salts in the acute phase of cerebrovascular disorder is ff 10.1 to 2.0 g per day.
注射剤として使用する場合は、例えば上記（−）ｌニコ
チノイル−５−メチル−２−ピラゾリンまたはその塩を
３％含む注射液１０＋ｎＱを一日数回静脈内投与するか
、 または１０％グルコースの様な栄養液５００ｍＱに
（−）ｌ−ニコチノイル−５−メチル−２−ピラゾリン
またはその塩を３％含む注射液を溶かして１時間から８
時間かけて輸液してもよい。When used as an injection, for example, the injection solution 10+nQ containing 3% of the above (-)l nicotinoyl-5-methyl-2-pyrazoline or its salt may be administered intravenously several times a day, or a drug containing 10% glucose or the like may be administered intravenously several times a day. Dissolve an injection solution containing 3% (-)l-nicotinoyl-5-methyl-2-pyrazoline or its salt in 500 mQ of nutrient solution for 1 to 8 hours.
Infusion may be given over time.
座剤は上記（−）■−ニコチノイルー５−メチルー２−
ピラゾリンまたはその塩を微粉末にしてウイテブゾール
（登録商標）の様な基剤に分散溶解して製造することが
できる。Suppositories are the above (-)■-nicotinoyl-5-methyl-2-
It can be produced by pulverizing pyrazoline or its salt and dispersing and dissolving it in a base such as Uitebuzol (registered trademark).
上記（−）■−ニコチノイルー５−メチルー２−ピラゾ
リンまたはその塩は望ましくは基剤中に１〜１０％含ま
れ、実際に使用する場合は上記（−）ｌ−ニコチノイル
−５−メチル−２−ピラゾリンまたはその塩を５〜１０
％含む座剤３ｇを一日数回用いることができる。The above (-)■-nicotinoyl-5-methyl-2-pyrazoline or its salt is preferably contained in the base at 1 to 10%, and when actually used, the above (-)l-nicotinoyl-5-methyl-2- Pyrazoline or its salt 5-10
3 g of suppositories containing % can be used several times a day.
経口剤として使用する場合、上記（−）１−ニコチノイ
ル−５−メチル−２−ピラゾリンまたはその塩０．１〜
２．０ｇを製薬上許容し得るベシクル、担体、賦形剤、
結合剤、安定剤と共に一般に認められた方法に従って混
和して錠剤、カプセル剤をつくることができる。これら
の経口剤は症状に応じて一日数回投与される。When used as an oral agent, the above (-)1-nicotinoyl-5-methyl-2-pyrazoline or a salt thereof from 0.1 to
2.0 g of pharmaceutically acceptable vesicles, carriers, excipients,
Tablets and capsules can be prepared by mixing with binders and stabilizers according to generally accepted methods. These oral preparations are administered several times a day depending on the symptoms.
以下実施例によって本発明を説明する。The present invention will be explained below with reference to Examples.
実施例１
■−ニコチノイルー５−メチルー２−ピラゾリンの合成
１）５−メチル−２−ピラゾリン
ヒドラジンモノハイドレート２．３ｇをエタノール５ｍ
Ｑに溶解し、水冷下に酢酸２．７ｇを滴下した。この混
合物を加熱還流しながらクロトンアルデヒド２．７ｇを
滴下、更に３時間加熱還流した。濃アンモニア水３ 、
５ｍＱを滴下した後、クロロホルム２０ｍＱで２回抽出
したゆ有機相を無水硫酸マグネシウムで乾燥後、減圧蒸
留（１４４℃１０．３ｍｍｌ１ｇ） シて５−メチル−
２−ピラゾリン１．９ｇ（収率６０％）を得た。Example 1 ■-Synthesis of Nicotinoyl-5-methyl-2-pyrazoline 1) 2.3 g of 5-methyl-2-pyrazoline hydrazine monohydrate was mixed with 5 m of ethanol.
The solution was dissolved in Q and 2.7 g of acetic acid was added dropwise while cooling with water. While heating the mixture under reflux, 2.7 g of crotonaldehyde was added dropwise, and the mixture was further heated under reflux for 3 hours. concentrated ammonia water 3,
After dropping 5 mQ of chloroform, the organic phase was extracted twice with 20 mQ of chloroform, dried over anhydrous magnesium sulfate, and distilled under reduced pressure (144°C, 10.3 mml 1 g) to give 5-methyl-
1.9 g (yield 60%) of 2-pyrazoline was obtained.
２）１−ニコチノイル−５−メチル−２−ピラゾリンニ
コチン酸クロライド塩酸塩４ｇを クロロホルム２０ｎ
＋Ｑに懸濁し、 水冷下に５−メチル−２−ピラゾリン
１．７ｇとトリエチルアミン４ｇの混合物を滴下した後
、水洗濃縮し、シリカゲルカラムクロマトグラフィー（
クロホルム／メタノール＝ １００／ １ ）で生成し
た。収斌３．４ｇ
実施例２
（−）１−ニコチノイル−５−メチル−２−ピラゾリン
ラセミ体の１−ニコチノイル−５−メチル−２−ピラゾ
リン３．０ｇを高速液体クロマトグラフィーを用いて分
割分取し、光学純度９９％の（−）１−ニコチノイル−
５−メチル−２−ピラゾリン１．４ｇを得た。2) 4 g of 1-nicotinoyl-5-methyl-2-pyrazoline nicotinic acid chloride hydrochloride and 20 n of chloroform
+Q, and a mixture of 1.7 g of 5-methyl-2-pyrazoline and 4 g of triethylamine was added dropwise under water cooling, washed with water, concentrated, and subjected to silica gel column chromatography (
chloroform/methanol = 100/1). Yield: 3.4 g Example 2 3.0 g of racemic 1-nicotinoyl-5-methyl-2-pyrazoline (-)1-nicotinoyl-5-methyl-2-pyrazoline was fractionated using high performance liquid chromatography. , (-)1-nicotinoyl- with optical purity of 99%
1.4 g of 5-methyl-2-pyrazoline was obtained.
ｌｌ１ｐ、 ６７−６９℃
Ｃα）ｏ” ３４５℃（０，００５ｇ／＋ｎＱ、 Ｅ
ｔｏｌｌ、 ２５℃）分取条件は以下の通りである。ll1p, 67-69℃ Cα)o” 345℃ (0,005g/+nQ, E
toll, 25°C) The preparative conditions are as follows.
高速液クロ ＬＣ−８Ａシステム（島津製作所）カラム
キラルセルＯＤ（ダイセル、２０ｍ Ｘ ２５ｃ
ｍ）
流ｆ！に２５＋＋＋Ｑ／＋＋＋ｉｎ
移動相 ヘキサン／エタノール／メタノール＝１０
０／ ２ ／ ２
実施例３
（−）１−ニコチノイル−５−メチル−２−ピラゾリン
を有効成分とする注射剤
（−）ｌ−ニコチノイル−５−メチル−２−ピラゾリン
０．３ｇを取り、０．９％生理食塩水１０ｍΩに溶かし
、 １０ｍＱアンプルに封入して水性注射剤とする。High performance liquid chromatography LC-8A system (Shimadzu) Column Chiralcel OD (Daicel, 20m x 25c
m) Flow f! to 25+++Q/+++in Mobile phase Hexane/ethanol/methanol=10
0/2/2 Example 3 Injection containing (-)1-nicotinoyl-5-methyl-2-pyrazoline as an active ingredient (-) Take 0.3 g of l-nicotinoyl-5-methyl-2-pyrazoline, .Dissolve in 10 mΩ of 9% physiological saline and seal in a 10 mQ ampoule to prepare an aqueous injection.
輸液用注射剤としては上述の溶液を１０％グリセリン溶
液（グリセオール、中外） ２００ｍＱや１０％グルコ
ース溶液５００＋Ｊに溶解して用いることが出来る。As an injection for infusion, the above-mentioned solution can be used by dissolving it in 200 mQ of a 10% glycerin solution (Glyceol, Chugai) or 500+J of a 10% glucose solution.
実施例４
（−）■−ニコチノイルー５−メチルー２−ピラゾリン
を有効成分とする原剤
（−）１−ニコチノイル−５−メチル−２−ピラゾリン
１０ｇを取り、ウィテップゾルト３５（デイナミルノー
ベルケミカルズ、西ドイツ国）９ｇに６０℃で加熱溶解
し、よく混合する。これを鋳型に一個当り１．５ｇまた
は３ｇになるように流し込み、冷却して固まらせ、原剤
とする。Example 4 10 g of (-) 1-nicotinoyl-5-methyl-2-pyrazoline was taken as a raw material containing (-)■-nicotinoyl-5-methyl-2-pyrazoline as an active ingredient, and Witep Solt 35 (Dinamil Nobel Chemicals, West Germany) was added. ) in 9 g by heating at 60°C and mix well. This is poured into a mold at a weight of 1.5g or 3g per piece, cooled and solidified, and used as a raw material.
実施例５
（−）１−ニコチノイル−５−メチル−２−ピラゾリン
を有効成分とする経口剤
（−）ｌ−ニコチノイル−５−メチル−２−ピラゾリン
を４５ｇ、乳糖４２ｇ、トウモロコシデンプン４５ｇ
及び結晶セルロース２５ｇをよく混合した。これにヒド
ロキシプロピルセルロース５ｇを水に溶解した液で練合
造粒し、５０℃で４時間乾燥した。これにステアリン酸
マグネシウム３ｇを加えてよく混合し、打錠機を用いて
一錠当り２００ｍｇの重量を打錠し、錠剤を得た。Example 5 Oral preparation containing (-)1-nicotinoyl-5-methyl-2-pyrazoline as an active ingredient (-) 45 g of l-nicotinoyl-5-methyl-2-pyrazoline, 42 g of lactose, 45 g of corn starch
and 25 g of crystalline cellulose were thoroughly mixed. This was kneaded and granulated with a solution in which 5 g of hydroxypropyl cellulose was dissolved in water, and dried at 50° C. for 4 hours. 3 g of magnesium stearate was added thereto, mixed well, and tableted using a tablet machine to give a weight of 200 mg per tablet.
実施例６
ラットの中太脳動脈閉塞による虚血性脳浮腫に対する（
−）■−ニコチノイルー５−メチルー２−ピラゾリンの
作用
ラットの中太脳動脈閉塞は用材等の方法（Ｊ。Example 6 Against ischemic cerebral edema caused by middle cerebral artery occlusion in rats (
-)■- Effect of Nicotinoyl-5-methyl-2-pyrazoline Occlusion of the middle cerebral artery in rats was performed by the method of Materials et al. (J.
Ｃｅｒｅｂｒａｌ １３１ｏｏｄ Ｆｌｏｗ ａｎｄ
Ｍｅｔａｂｏｌｉｓ＋＋、 １９８１．５３−６０）に
従って実施した。即ち、８〜１０週令の雄性Ｗｉｓｔａ
ｒラットを用い、２％ハロセン麻酔下に布中大脳動脈を
閉塞した。 （−）Ｉ−ニコチノイル−５−メチル−２
−ピラゾリンを０．９％生理食塩水に溶解し、３または
１０ｍｇ／ ｋｇ／ ｈｒの速度でラットの尾静脈に２
４時間点滴静注した。中太脳動脈閉塞２４時間後にラッ
トを屠殺、脳を摘出し、左右両半球の脳水分含量を湿乾
重量法で求めた。対照群のラットも同様に中太脳動脈の
閉塞を行い、薬物投与群と同様に０．９％生理食塩水を
２４時間点滴静注した。脳浮腫抑制率は下記の式に従っ
て求めた。結果を表１に示す。Cerebral 131ood Flow and
Metabolis++, 1981.53-60). That is, 8-10 week old male Wista
Using rats, the middle cerebral artery was occluded under 2% halothane anesthesia. (-)I-nicotinoyl-5-methyl-2
- Pyrazoline was dissolved in 0.9% saline and administered into the tail vein of rats at a rate of 3 or 10 mg/kg/hr.
The drug was infused intravenously for 4 hours. Twenty-four hours after the middle cerebral artery occlusion, the rats were sacrificed, the brains were removed, and the brain water content in both the left and right hemispheres was determined by the wet-dry weight method. The middle cerebral artery of rats in the control group was similarly occluded, and 0.9% physiological saline was intravenously infused for 24 hours in the same manner as in the drug administration group. The cerebral edema suppression rate was calculated according to the following formula. The results are shown in Table 1.
ＣＬ：対照群の左半球の脳水分含量
ＣＲ：対照群の右半球の脳水分含量
ＳＬ：薬物投与群の左半球の脳水分含量ＳＲ：薬物投与
群の右半球の脳水分含量また急性毒性の５０％致死量Ｌ
Ｄ５０はマウスに薬物を静脈内投与し、投与後７２時間
までの死亡率から常法により算出した。結果を表１に示
す。CL: Brain water content in the left hemisphere of the control group CR: Brain water content in the right hemisphere of the control group SL: Brain water content in the left hemisphere of the drug-administered group SR: Brain water content in the right hemisphere of the drug-administered group 50% lethal dose L
D50 was calculated by a conventional method from the mortality rate up to 72 hours after administering the drug to mice intravenously. The results are shown in Table 1.
表１から明らかな様に、 ■−ニコチノイルー５−メチ
ルー２−ピラゾリンの（−）体はラットの中太脳動脈閉
塞による脳浮腫を有意に抑制し、その作用はラセミ体や
（＋）体よりも強かった。また急性毒性は（−）体がラ
セミ体や（＋）体よりも弱かった。As is clear from Table 1, the (-) form of -nicotinoyl-5-methyl-2-pyrazoline significantly suppresses brain edema caused by middle cerebral artery occlusion in rats, and its effect is greater than that of the racemic form or the (+) form. It was also strong. In addition, the acute toxicity of the (-) form was weaker than that of the racemic form and the (+) form.
実施例７
ラットの中太脳動脈閉塞による脳梗塞巣に対する（−）
１−ニコチノイル−５−メチル−２−ピラゾリンの作用
ラットの中太脳動脈閉塞は用材等の方法（Ｊ。Example 7 Against cerebral infarction caused by middle cerebral artery occlusion in rats (-)
Effect of 1-Nicotinoyl-5-methyl-2-pyrazoline Occlusion of the middle cerebral artery in rats was performed by the method of J. et al. (J.
Ｃｅｒｅｂｒａｌ Ｂｌｏｏｄ Ｆｌｏｗ ａｎｄ Ｍ
ｅｔａｂｏｌｉｓｍ、 １９８１．５３−６０）に従っ
て実施した。即ち、８〜１０週令の雄性Ｗｉｓｔａｒラ
ットを用い、２％ハロセン麻酔下に人中大脳動脈を閉塞
した。（−Ｈ−ニコチノイル−５−メチル−２−ピラゾ
リンを０．９％生理食塩水に溶解し、１０ｍｇ／ｋｇ／
ｈｒの速度でラットの尾静脈に２４時間点滴静注した。Cerebral Blood Flow and M
etabolism, 1981.53-60). That is, using male Wistar rats aged 8 to 10 weeks, the philtral cerebral artery was occluded under 2% halothane anesthesia. (-H-nicotinoyl-5-methyl-2-pyrazoline was dissolved in 0.9% physiological saline, 10 mg/kg/
It was injected intravenously into the tail vein of rats at a rate of hr for 24 hours.
対照群も同様に０．９％生理食塩水を２４時間静脈内投
与した。中大脳動脈閉ｒｌ！、２４時間後にラットを屠
殺、脳を摘出した。摘出した脳をＴＴＣで染色し、頭頂
から６等分に切断した。断面を写真撮影し、プラニメー
ターで梗塞巣の全層に対する割合を測定し、対照群の梗
塞巣を１００％ として薬物投与による梗塞巣の縮小率
を計算した。結果を表２に示す。表２から明らかな様に
１−ニコチノイル−５−メチル−２−ピラゾリンの（−
）体はラットの中太脳動脈閉塞による脳梗塞巣を有ｙｉ
：に縮小し、その作用はラセミ体よりも強かった。Similarly, 0.9% physiological saline was intravenously administered to the control group for 24 hours. Middle cerebral artery closure RL! After 24 hours, the rats were sacrificed and the brains were removed. The removed brain was stained with TTC and cut into 6 equal parts from the top of the head. The cross section was photographed, the ratio of the infarct to the total thickness was measured using a planimeter, and the reduction rate of the infarct due to drug administration was calculated, taking the infarct in the control group as 100%. The results are shown in Table 2. As is clear from Table 2, 1-nicotinoyl-5-methyl-2-pyrazoline (-
) The body of a rat with a cerebral infarction caused by occlusion of the middle cerebral artery.
: and its effect was stronger than that of the racemate.
表１ ラットの中太脳動脈閉塞による脳浮腫に対する１
−二コチノイル−５−メチル−２−ピラゾリンのラセミ
体及び光学異性体の作用及び急性毒性（ＬＤ５０）
木：対照群に対してＰ ＜０．０５で有意＊＊：対照群
に対してｐ ＜ｏ、ｏｏｔで有意表２ ラットの中太脳
動脈閉塞による脳梗塞に対する１−ニコチノイル−５−
メチル−２−ピラゾリンのラセミ体及び光学異性体の作
用
＊：対照群に対してｐ ＜ｏ、ｏｓで有意＊＊：対照群
に対してＰ ＜０．００１で有意代理人 弁理士 戸
１）親 男Table 1 1 against cerebral edema caused by middle cerebral artery occlusion in rats
- Effect and acute toxicity (LD50) of racemic and optical isomers of nicotinoyl-5-methyl-2-pyrazoline Wood: Significant at P < 0.05 vs. control group **: P < vs. control group Significant for o, oot Table 2 1-Nicotinoyl-5- against cerebral infarction caused by middle cerebral artery occlusion in rats
Effects of racemic and optical isomers of methyl-2-pyrazoline *: Significant at p < o, os vs. control group **: Significant at p < 0.001 vs. control group Representative Patent Attorney Door
1) Parent male
Claims (1)
リン。 ２、（−）１−ニコチノイル−５−メチル−２−ピラゾ
リンを有効成分とする脳血管障害治療剤。[Claims] 1,(-)1-nicotinoyl-5-methyl-2-pyrazoline. A therapeutic agent for cerebrovascular disorders containing 2,(-)1-nicotinoyl-5-methyl-2-pyrazoline as an active ingredient.
Priority Applications (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63311868A JPH0662609B2 (en) | 1988-12-12 | 1988-12-12 | Novel (-) 2-pyrazoline compound and cerebrovascular disorder therapeutic agent containing the same |
| US07/443,577 US5089622A (en) | 1988-12-12 | 1989-11-30 | (-)-2-pyrazoline compounds and therapeutic agent for cerebrovascular disorders containing the same as effective ingredient |
| CA002004554A CA2004554C (en) | 1988-12-12 | 1989-12-04 | Novel(-)-2-pyrazoline compound, optical resolution of the same, and therapeutic agent for cerebrovascular disorders containing the same as effective ingredient |
| EP89122591A EP0373512B1 (en) | 1988-12-12 | 1989-12-07 | (-)-2-pyrazoline compound, optical resolution of the same, and therapeutic agent for cerebrovascular disorders containing the same as effective ingredient |
| DE8989122591T DE68901172D1 (en) | 1988-12-12 | 1989-12-07 | (-) - 2-PYRAZOLINE COMPOUND, THEIR OPTICAL UNLOCKING AND THERAPEUTIC AGENT FOR THE TREATMENT OF CEREBRAL VEGETABLE DISEASES, CONTAINING THIS COMPOUND AS AN ACTIVE INGREDIENT. |
| KR1019890018417A KR920001778B1 (en) | 1988-12-12 | 1989-12-11 | Novel-2-pyrazoline compound and its optical resolution method |
| US07/480,852 US5075449A (en) | 1988-12-12 | 1990-02-16 | Method of optically resolving (±)-1-(3-pyridylcarbonyl)-5-methyl-2-pyrazoline |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63311868A JPH0662609B2 (en) | 1988-12-12 | 1988-12-12 | Novel (-) 2-pyrazoline compound and cerebrovascular disorder therapeutic agent containing the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH02157276A true JPH02157276A (en) | 1990-06-18 |
| JPH0662609B2 JPH0662609B2 (en) | 1994-08-17 |
Family
ID=18022383
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63311868A Expired - Fee Related JPH0662609B2 (en) | 1988-12-12 | 1988-12-12 | Novel (-) 2-pyrazoline compound and cerebrovascular disorder therapeutic agent containing the same |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0662609B2 (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6479157A (en) * | 1987-06-17 | 1989-03-24 | Mitsui Toatsu Chemicals | Novel 2-pyrazolines and remedy for cerebrovascular disorder containing said compound as active component |
-
1988
- 1988-12-12 JP JP63311868A patent/JPH0662609B2/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6479157A (en) * | 1987-06-17 | 1989-03-24 | Mitsui Toatsu Chemicals | Novel 2-pyrazolines and remedy for cerebrovascular disorder containing said compound as active component |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0662609B2 (en) | 1994-08-17 |
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