JPS6126996B2 - - Google Patents
Info
- Publication number
- JPS6126996B2 JPS6126996B2 JP55029312A JP2931280A JPS6126996B2 JP S6126996 B2 JPS6126996 B2 JP S6126996B2 JP 55029312 A JP55029312 A JP 55029312A JP 2931280 A JP2931280 A JP 2931280A JP S6126996 B2 JPS6126996 B2 JP S6126996B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- hydroxyl group
- isopropylaminopyrimidine
- following
- hydrogen atom
- 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
Links
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- 210000005036 nerve Anatomy 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 230000001172 regenerating effect Effects 0.000 claims description 4
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims description 3
- FOEMIZSFFWGXHX-UHFFFAOYSA-N 2-methylsulfanylpyrimidine Chemical compound CSC1=NC=CC=N1 FOEMIZSFFWGXHX-UHFFFAOYSA-N 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000012454 non-polar solvent Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 16
- 241000700159 Rattus Species 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 230000000144 pharmacologic effect Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 210000003497 sciatic nerve Anatomy 0.000 description 3
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 230000003902 lesion 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
- 239000000203 mixture Substances 0.000 description 2
- 230000008929 regeneration Effects 0.000 description 2
- 238000011069 regeneration method Methods 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- RBCOYOYDYNXAFA-UHFFFAOYSA-L (5-hydroxy-4,6-dimethylpyridin-3-yl)methyl phosphate Chemical compound CC1=NC=C(COP([O-])([O-])=O)C(C)=C1O RBCOYOYDYNXAFA-UHFFFAOYSA-L 0.000 description 1
- UBGRSKXBCVWAOV-UHFFFAOYSA-N 2-(propan-2-ylamino)pyrimidin-5-ol Chemical compound CC(C)NC1=NC=C(O)C=N1 UBGRSKXBCVWAOV-UHFFFAOYSA-N 0.000 description 1
- VVTBLRLLKIDVKB-UHFFFAOYSA-N 2-methylsulfanylpyrimidin-5-ol Chemical compound CSC1=NC=C(O)C=N1 VVTBLRLLKIDVKB-UHFFFAOYSA-N 0.000 description 1
- -1 4-Hydroxy-2-isopropylaminopyrimidine Methyl thiouracil Chemical compound 0.000 description 1
- BKDYEBFKDKOMQE-UHFFFAOYSA-N 4-hydroxy-2-(propan-2-ylamino)-1h-pyrimidin-6-one Chemical compound CC(C)NC1=NC(O)=CC(=O)N1 BKDYEBFKDKOMQE-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 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
- HWGBHCRJGXAGEU-UHFFFAOYSA-N Methylthiouracil Chemical class CC1=CC(=O)NC(=S)N1 HWGBHCRJGXAGEU-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- FDJOLVPMNUYSCM-UVKKECPRSA-L cobalt(3+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2,7, Chemical compound [Co+3].N#[C-].C1([C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP([O-])(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)[N-]\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O FDJOLVPMNUYSCM-UVKKECPRSA-L 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 229940120124 dichloroacetate Drugs 0.000 description 1
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- FTCYIGBVOHNHCD-UHFFFAOYSA-N isaxonine Chemical compound CC(C)NC1=NC=CC=N1 FTCYIGBVOHNHCD-UHFFFAOYSA-N 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229960002545 methylthiouracil Drugs 0.000 description 1
- 201000006938 muscular dystrophy Diseases 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical class OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- JZRWCGZRTZMZEH-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N JZRWCGZRTZMZEH-UHFFFAOYSA-N 0.000 description 1
- ZEMGGZBWXRYJHK-UHFFFAOYSA-N thiouracil Chemical compound O=C1C=CNC(=S)N1 ZEMGGZBWXRYJHK-UHFFFAOYSA-N 0.000 description 1
- 229950000329 thiouracil Drugs 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は新規なヒドロキシ ピリミジン誘導
体、その製造法及び神経再生剤としての治療用途
に関する。
すなわち本発明は、次式：
（式中、A4、A5及びA6はそれぞれ水素原子又はヒ
ドロキシル基を表わすが、A4、A5及びA6の少く
とも一つはヒドロキシル基を表わすものとする）
を有する２−イソプロピル アミノ ピリミジン
のヒドロキシ誘導体を提供する。
本発明の化合物は特に神経再生の分野及び筋ジ
ストロフイーの処置に有用である。
したがつて本発明はさらに、上記式を有する２
−イソプロピルアミノピリミジンのヒドロキシ誘
導体を活性成分とする神経再生剤を提供するもの
である。本発明の神経再生剤は後記薬理活性試験
データから明らかなごとく、きわめて低投与量で
所望の効果を示すことが認められる。
本発明の化合物は例えば、下記の反応式に従つ
て２−メチルチオ ピリミジンとイソプロピルア
ミンとを無極性溶剤中で上昇温度、好ましくは
100〜120℃の温度において加圧下に反応させるこ
とによつて製造できる。
次に本発明を実施例により更に説明する。
実施例 １
４−ヒドロキシ−２−イソプロピルアミノピリ
ミジン
沃化メチルとチオウラシルとナトリウム メタ
ノレートの存在下で反応させることによつて原料
としてのメチル チオウラシルを得た。このメチ
ル チオウラシル20ｇ（0.14モル）を乾燥トルエ
ン200ml及びイソプロピルアミン200mlを含む１
の加圧反応器に装入し、反応を110−120℃で加圧
下に24時間行なつた。得られた反応混合物を蒸発
乾固させ、アセトン／ジエチルエーテル（50／
50）で処理し、過し、水洗いしい、イソプロピ
ルアセテートから再結晶させた。かくして融点
140℃の白色結晶性生成物17ｇ（収率84％）を得
た。この化合物の元素分析は式C7H11N3Oと良く
一致した。
標題化合物から常法によりその塩酸塩を融点
233〜234℃の白色結晶性生成物として得た。
紫外吸収スペクトル
The present invention relates to novel hydroxypyrimidine derivatives, their preparation and their therapeutic use as nerve regenerating agents. That is, the present invention is based on the following formula: (In the formula, A 4 , A 5 and A 6 each represent a hydrogen atom or a hydroxyl group, but at least one of A 4 , A 5 and A 6 represents a hydroxyl group)
A hydroxy derivative of 2-isopropylaminopyrimidine is provided. The compounds of the invention are particularly useful in the field of nerve regeneration and in the treatment of muscular dystrophies. Therefore, the present invention further provides 2 having the above formula.
- A nerve regenerating agent containing a hydroxy derivative of isopropylaminopyrimidine as an active ingredient is provided. As is clear from the pharmacological activity test data described below, the nerve regenerating agent of the present invention is recognized to exhibit desired effects at extremely low doses. The compounds of the invention can be prepared, for example, by combining 2-methylthio pyrimidine and isopropylamine in a non-polar solvent at elevated temperatures, preferably according to the reaction scheme below.
It can be produced by reaction under pressure at a temperature of 100 to 120°C. Next, the present invention will be further explained by examples. Example 1 4-Hydroxy-2-isopropylaminopyrimidine Methyl thiouracil as a raw material was obtained by reacting methyl iodide, thiouracil, and sodium methanolate in the presence of sodium methanolate. 20 g (0.14 mol) of this methyl thiouracil was added to a solution containing 200 ml of dry toluene and 200 ml of isopropylamine.
The reaction was carried out at 110-120° C. under pressure for 24 hours. The resulting reaction mixture was evaporated to dryness and diluted with acetone/diethyl ether (50/
50), filtered, washed with water and recrystallized from isopropyl acetate. Thus the melting point
17 g (84% yield) of white crystalline product at 140° C. was obtained. Elemental analysis of this compound was in good agreement with the formula C 7 H 11 N 3 O. From the title compound, its hydrochloride salt was determined by a conventional method at its melting point.
Obtained as a white crystalline product at 233-234°C. ultraviolet absorption spectrum
【表】
遊離塩基は水に不溶であるがクロロホルムに可
溶の白色結晶性生成物（分子量153.18）である。
実施例 ２
５−ヒドロキシ−２−イソプロピルアミノ ピ
リミジン
５−ヒドロキシ−２−メチルチオピリミジンを
用いた以外は実施例１に記載の方法を反復した。
反応温度は105℃にした。かくして融点161℃の標
題化合物が83％の収率で得られた。水／メタノー
ル（60／40）中の紫外吸収スペクトル
λnax：341nｍ Ｅ１％１cm＝205
λnax：241nｍ Ｅ１％１cm＝1210
実施例 ３
４・６−ジヒドロキシ−２−イソプロピルアミ
ノピリミジン
４・６−ジヒドロ−２−メチルチオピリミジン
を用いた以外は実施例１に記載の方法を反復し
た。反応温度は110℃にした。収率67％。式
C7H11N3HClの塩酸塩についての融点215〜220℃
（分解を伴なう）。これは室温で水に不溶の白色結
晶性生成物である。
本発明による化合物の毒性及び薬理活性につい
て以下に示す。
毒 性
本発明の化合物の急性毒性（mg/Kg）をマウス
の腹腔内投与及び経口投与により調べ、その値を
下表に示す。Table: The free base is a white crystalline product (molecular weight 153.18) that is insoluble in water but soluble in chloroform. Example 2 5-Hydroxy-2-isopropylaminopyrimidine The method described in Example 1 was repeated except that 5-hydroxy-2-methylthiopyrimidine was used.
The reaction temperature was 105°C. The title compound with a melting point of 161° C. was thus obtained in 83% yield. Ultraviolet absorption spectrum in water/methanol (60/40) λ nax : 341 nm E 1 % 1 cm = 205 λ nax : 241 nm E 1 % 1 cm = 1210 Example 3 4,6-dihydroxy-2-isopropylaminopyrimidine 4 - The method described in Example 1 was repeated except that 6-dihydro-2-methylthiopyrimidine was used. The reaction temperature was 110°C. Yield 67%. formula
Melting point 215-220 ℃ for hydrochloride of C7H11N3HCl
(with decomposition). It is a white crystalline product that is insoluble in water at room temperature. The toxicity and pharmacological activity of the compounds according to the invention are shown below. Toxicity The acute toxicity (mg/Kg) of the compound of the present invention was investigated by intraperitoneal administration and oral administration to mice, and the values are shown in the table below.
【表】
薬理活性
本発明による化合物の薬理活性をウイスター
（Wistar）系の成長したラツト（雌）の坐骨神経
の再生について行なつた下記の比較試験により調
べた。
ラツトの坐骨神経にサーモサウンドを−20℃で
20分間かけることによりその神経に病変を与え、
ついでラツトに対照薬剤又は本発明の化合物を予
定した継続期間腹腔内投与する。投与終了後にラ
ツトを殺し、坐骨神経を取出して70本の細い平行
白金線（間隔１mm）と接触状態に置き、病変部位
に対し上流方向にかけた電気信号を各白金線上で
調べる。信号を集めることができる最も離れた白
金線により再生された神経長が与えられる。
各供試薬剤及び各投与継続期間について一群８
匹のラツトを用いた。
実施例１、２及び３の化合物は10mg/Kgの割合
で腹腔内投与し、対照薬剤としては当分野で最も
有効な組成物として知られているビタミンB1
（500＝mg/Kg）、ビタミンB6（500mg/Kg）及びビ
タミンB12（５mg/Kg）の混合物を腹腔内投与し
た。薬剤を全く投与しない無処理群の結果と共
に、試験結果を下記の表に示す。再生神経の長さ
は各処理群のすべてのラツトについて測定した長
さの平均値として各継続期間欄にmmの単位で示
す。表中、ダツシユ（−）は再生神経長が採取試
料の長さを超えたことを示す。Table: Pharmacological Activity The pharmacological activity of the compounds according to the invention was investigated in the following comparative test carried out on the regeneration of the sciatic nerve in adult Wistar rats (female). Thermosound was applied to the rat sciatic nerve at -20°C.
By applying it for 20 minutes, it causes lesions on the nerve,
The rats are then administered a control drug or a compound of the invention intraperitoneally for a predetermined duration. After the administration, the rat is sacrificed, the sciatic nerve is removed and placed in contact with 70 thin parallel platinum wires (1 mm apart), and the electrical signals applied in the upstream direction to the lesion site are examined on each platinum wire. The furthest platinum wire from which signals can be collected gives the regenerated nerve length. Group 8 for each test drug and each administration duration
Two rats were used. The compounds of Examples 1, 2 and 3 were administered intraperitoneally at a rate of 10 mg/Kg, and the control drug was vitamin B 1 , which is the most effective composition known in the art.
(500=mg/Kg), vitamin B 6 (500 mg/Kg) and vitamin B 12 (5 mg/Kg) were administered intraperitoneally. The test results are shown in the table below, along with the results of the untreated group in which no drug was administered. The length of the regenerated nerve is shown in mm in each duration column as the average length measured for all rats in each treatment group. In the table, a dash (-) indicates that the regenerated nerve length exceeded the length of the collected sample.
【表】
上記薬理活性試験において有効な結果を与える
本発明の化合物の投与量（10mg/Kg）がピリミジ
ン環上にヒドロキシル置換基をもたない既知化合
物、２−イソプロピルアミノピリミジン及びその
ジクロロ酢酸塩及び燐酸塩を使用した同様の試験
において有効な結果を与える投与量（遊離塩基換
算で87mg/Kg）と比較して著しく少量である事実
は本出願人自身の特開昭52−100477号公報第２頁
左下欄〜第３頁右上欄（特公昭59−28548号公報
第７〜８欄）を参照すれば明らかである。
投与方法及び有効量
本発明の化合物は薬学的に許容し得る任意既知
の形態、例えば単位投与当り活性化合物５mgを賦
形剤と共に含有する錠剤又はゼラチン カプセル
として投与できる。注射液の場合には活性化合物
を水に溶解した塩酸塩の形で少くとも１mg含む注
射液としして投与できる。人体用には、経口投与
の場合１日当り20mg〜１ｇの投与量を必要とし、
注入投与の場合１日当り１mg〜50mgの量で投与で
きる。
一例として錠剤の組成を下記に示す。
本発明の化合物 ５mg
ラクトース 70mg
タルク 20mg
ステアリン酸マグネシウム ５mg
100mg[Table] The dose (10 mg/Kg) of the compound of the present invention that gives an effective result in the above pharmacological activity test is a known compound that does not have a hydroxyl substituent on the pyrimidine ring, 2-isopropylaminopyrimidine and its dichloroacetate. The fact that the dose is significantly lower than the dose (87 mg/Kg in terms of free base) that gives effective results in a similar test using phosphate is disclosed in the applicant's own Japanese Patent Application Laid-Open No. 100477/1983. This can be clearly seen by referring to the lower left column on page 2 to the upper right column on page 3 (Columns 7 and 8 of Japanese Patent Publication No. 59-28548). Methods of Administration and Effective Amounts The compounds of the invention may be administered in any known pharmaceutically acceptable form, such as tablets or gelatin capsules containing 5 mg of active compound per unit dose with excipients. In the case of injections, they can be administered as injections containing at least 1 mg of the active compound in the form of the hydrochloride salt dissolved in water. For human use, a daily dose of 20 mg to 1 g is required for oral administration.
In the case of injection administration, it can be administered in an amount of 1 mg to 50 mg per day. As an example, the composition of a tablet is shown below. Compound of the invention 5mg Lactose 70mg Talc 20mg Magnesium stearate 5mg 100mg
Claims (1)
ドロキシル基を表わすが、A4、A5及びA6の少く
とも一つはヒドロキシル基を表わすものとする）
を有する２−イソプロピルアミノピリミジンのヒ
ドロキシ誘導体。 ２ 式： （式中、A4、A5及びA6は後記の意義を有する）の
２−メチルチオピリミジンと式： のイソプロピルアミンとを、無極性溶剤中で上昇
温度において加圧下に反応させることからなる、
次式： （式中、A4、A5及びA6はそれぞれ水素原子又はヒ
ドロキシル基を表わすが、A4、A5及びA6の少く
とも一つはヒドロキシル基を表わすものとする）
を有する２−イソプロピルアミノピリミジンのヒ
ドロキシ誘導体の製造法。 ３ 活性成分として次式： （式中、A4、A5及びA6はそれぞれ水素原子又はヒ
ドロキシル基を表わすが、A4、A5及びA6の少く
とも一つはヒドロキシル基を表わすものとする）
を有する２−イソプロピルアミノピリミジンのヒ
ドロキシ誘導体を有効量含有してなる神経再生
剤。[Claims] Primary formula: (In the formula, A 4 , A 5 and A 6 each represent a hydrogen atom or a hydroxyl group, but at least one of A 4 , A 5 and A 6 represents a hydroxyl group)
A hydroxy derivative of 2-isopropylaminopyrimidine having 2 formula: (wherein A 4 , A 5 and A 6 have the meanings given below) and 2-methylthiopyrimidine of the formula: isopropylamine in a non-polar solvent at elevated temperature and under pressure.
The following formula: (In the formula, A 4 , A 5 and A 6 each represent a hydrogen atom or a hydroxyl group, but at least one of A 4 , A 5 and A 6 represents a hydroxyl group)
A method for producing a hydroxy derivative of 2-isopropylaminopyrimidine having the following. 3 The following formula as the active ingredient: (In the formula, A 4 , A 5 and A 6 each represent a hydrogen atom or a hydroxyl group, but at least one of A 4 , A 5 and A 6 represents a hydroxyl group)
A nerve regenerating agent comprising an effective amount of a hydroxy derivative of 2-isopropylaminopyrimidine having the following.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB7908494 | 1979-03-10 | ||
| GB7914987 | 1979-04-30 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS55122768A JPS55122768A (en) | 1980-09-20 |
| JPS6126996B2 true JPS6126996B2 (en) | 1986-06-23 |
Family
ID=26270867
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2931280A Granted JPS55122768A (en) | 1979-03-10 | 1980-03-10 | Hydroxypyrimidine derivative*its manufacture and use |
Country Status (24)
| Country | Link |
|---|---|
| JP (1) | JPS55122768A (en) |
| AR (1) | AR222691A1 (en) |
| AU (1) | AU533547B2 (en) |
| BE (1) | BE881752A (en) |
| CA (1) | CA1132561A (en) |
| CH (1) | CH644368A5 (en) |
| DE (3) | DE3009071C2 (en) |
| EG (1) | EG14282A (en) |
| FI (1) | FI66357C (en) |
| FR (2) | FR2451191A1 (en) |
| GB (1) | GB2045756B (en) |
| HK (1) | HK55383A (en) |
| IE (1) | IE49547B1 (en) |
| IN (1) | IN153791B (en) |
| LU (1) | LU82185A1 (en) |
| MX (1) | MX6218E (en) |
| MY (1) | MY8400200A (en) |
| NL (1) | NL184833C (en) |
| NO (1) | NO154054C (en) |
| NZ (1) | NZ192927A (en) |
| OA (1) | OA06484A (en) |
| PT (1) | PT70882A (en) |
| SE (1) | SE435180B (en) |
| SG (1) | SG22683G (en) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE894517A (en) * | 1981-10-16 | 1983-01-17 | Sod Conseils Rech Applic | NEW ISOPROPYLAMINO PYRIMIDINE DERIVATIVE, ITS PREPARATION AND THERAPEUTIC COMPOSITION BASED ON ITS COMPOUNDS |
| US4673677A (en) * | 1983-10-03 | 1987-06-16 | Pfizer Inc. | Method for treatment of gastrointestinal disorders |
| US4554276A (en) * | 1983-10-03 | 1985-11-19 | Pfizer Inc. | 2-Amino-5-hydroxy-4-methylpyrimidine derivatives |
| US4711888A (en) | 1985-07-24 | 1987-12-08 | Pfizer Inc. | Hydroxy and alkoxy pyrimidines |
| WO1989000423A1 (en) * | 1987-07-09 | 1989-01-26 | Pfizer Inc. | 2-amino-5-hydroxy-4-pyrimidones |
| US4910204A (en) * | 1988-06-28 | 1990-03-20 | Pfizer Inc. | 2-amino-5-hydroxy-4-pyrimidones |
| US5264435A (en) * | 1988-12-29 | 1993-11-23 | Mitsui Petrochemical Industries, Ltd. | Pyrimidines and their pharmaceutical acceptable salts, and their use as medicines |
| HU206337B (en) * | 1988-12-29 | 1992-10-28 | Mitsui Petrochemical Ind | Process for producing pyrimidine derivatives and pharmaceutical compositions |
| US4940712A (en) * | 1989-05-26 | 1990-07-10 | Pfizer Inc. | Derivatives of hydroxyprimidines as leukotriene synthesis inhibitors |
| US5270319A (en) * | 1991-09-09 | 1993-12-14 | Warner-Lambert Company | 5-hydroxy-2-pyrimidinylmethylene derivatives useful as antiinflammatory agents |
| US5220025A (en) * | 1992-02-24 | 1993-06-15 | Warner-Lambert Company | 2-substituted amino-4, 6-di-tertiary-butyl-5-hydroxy-1, 3-pyrimidines as antiinflammatory agents |
| US5196431A (en) * | 1992-02-24 | 1993-03-23 | Warner-Lambert Company | 2-substituted amino-4, 6-di-tertiary-buthyl-5-hydroxy-1, 3-pyrimidines as antiinflammatory agents |
| US9133212B1 (en) * | 2005-06-15 | 2015-09-15 | Vanderbilt University | Inhibitors of hemeprotein-catalyzed lipid peroxidation |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB741667A (en) * | 1952-12-05 | 1955-12-07 | Ici Ltd | New pyrimidine derivatives |
| GB756189A (en) * | 1954-02-01 | 1956-08-29 | Ici Ltd | New pyrimidine derivatives |
| ZA711152B (en) * | 1970-03-02 | 1971-11-24 | Ici Ltd | Manufacture of pyrimidines |
| GB1525995A (en) * | 1976-02-18 | 1978-09-27 | Soc D Etudes Prod Chimique | Aminopyrimidine salt |
-
1980
- 1980-02-12 IN IN103/DEL/80A patent/IN153791B/en unknown
- 1980-02-15 BE BE0/199421A patent/BE881752A/en not_active IP Right Cessation
- 1980-02-20 LU LU82185A patent/LU82185A1/en unknown
- 1980-02-20 NZ NZ192927A patent/NZ192927A/en unknown
- 1980-02-26 FI FI800566A patent/FI66357C/en not_active IP Right Cessation
- 1980-02-27 AR AR280106A patent/AR222691A1/en active
- 1980-02-29 PT PT70882A patent/PT70882A/en unknown
- 1980-03-03 CH CH165080A patent/CH644368A5/en not_active IP Right Cessation
- 1980-03-04 NL NLAANVRAGE8001289,A patent/NL184833C/en not_active IP Right Cessation
- 1980-03-04 CA CA346,981A patent/CA1132561A/en not_active Expired
- 1980-03-07 AU AU56248/80A patent/AU533547B2/en not_active Ceased
- 1980-03-07 GB GB8007908A patent/GB2045756B/en not_active Expired
- 1980-03-07 NO NO800664A patent/NO154054C/en unknown
- 1980-03-07 IE IE477/80A patent/IE49547B1/en unknown
- 1980-03-07 SE SE8001812A patent/SE435180B/en not_active IP Right Cessation
- 1980-03-09 EG EG131/80A patent/EG14282A/en active
- 1980-03-10 FR FR8005277A patent/FR2451191A1/en active Granted
- 1980-03-10 MX MX808702U patent/MX6218E/en unknown
- 1980-03-10 FR FR8005278A patent/FR2451370A1/en active Granted
- 1980-03-10 DE DE3009071A patent/DE3009071C2/en not_active Expired
- 1980-03-10 DE DE3050999A patent/DE3050999C2/en not_active Expired
- 1980-03-10 JP JP2931280A patent/JPS55122768A/en active Granted
- 1980-03-10 OA OA57049A patent/OA06484A/en unknown
- 1980-04-30 DE DE19803016752 patent/DE3016752A1/en active Granted
-
1983
- 1983-04-28 SG SG226/83A patent/SG22683G/en unknown
- 1983-11-17 HK HK553/83A patent/HK55383A/en unknown
-
1984
- 1984-12-30 MY MY200/84A patent/MY8400200A/en unknown
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