JPS5825678B2 - Oxazole powder - Google Patents
Oxazole powderInfo
- Publication number
- JPS5825678B2 JPS5825678B2 JP48016407A JP1640773A JPS5825678B2 JP S5825678 B2 JPS5825678 B2 JP S5825678B2 JP 48016407 A JP48016407 A JP 48016407A JP 1640773 A JP1640773 A JP 1640773A JP S5825678 B2 JPS5825678 B2 JP S5825678B2
- Authority
- JP
- Japan
- Prior art keywords
- azepinone
- degrees
- melting point
- general formula
- acid
- 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
-
- 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
- A61P11/14—Antitussive agents
Description
【発明の詳細な説明】
本発明は一般式Ｉ
〔式中、Ｒは炭素原子１ないし６個の飽和または不飽和
の脂肪族アシル基；メチルまたはメトキシ基またはハロ
ゲン原子によって置換されていてもよいベンゾイル基；
ピリジンカルボニル基またはフェニルアシル基を示す〕
の新規オキサゾール類また無機および有機酸とのそれら
の生理的に許容されうる酸付加塩、およびそれらの製造
法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compounds of the general formula I [wherein R is a saturated or unsaturated aliphatic acyl group having 1 to 6 carbon atoms; optionally substituted with a methyl or methoxy group or a halogen atom] Benzoyl group;
Indicates a pyridine carbonyl group or a phenyl acyl group]
oxazoles and their physiologically acceptable acid addition salts with inorganic and organic acids, and processes for their preparation.
Ｒの適当な意味は、＝た仁えばホルミル、アセチル、ブ
タノイル、イソブタノイル、ヘキサノイル、クロトノイ
ル、ベンソイル、４−クロロベンソイル、２−メトキシ
−５−クロロ−ベンソイル、３−メチル−ベンゾイル、
ニコチノイル、イソニコチンイルまたはフェニルアセチ
ル基を包含する。Suitable meanings of R include, for example, formyl, acetyl, butanoyl, isobutanoyl, hexanoyl, crotonoyl, benzoyl, 4-chlorobenzoyl, 2-methoxy-5-chloro-benzoyl, 3-methyl-benzoyl,
Includes nicotinoyl, isonicotinyl or phenylacetyl groups.
上記一般式■の新規化合物は価値ある薬理活性を所有し
、特にそれらは低い急性毒性で非常に強力な鎮咳活性を
示し、そして次の方法に従って製造できるニ
一般式■
〔式中、Ｒは上記と同じ意味を有し、そしてＨａｌは塩
素、臭素またはヨウ素原子を示す〕の５−・・ロゲンー
アゼピノン−（４）−誘導体またはその酸付加塩を尿素
と反応させることによる。The new compounds of the above general formula ■ possess valuable pharmacological activities, in particular they exhibit very strong antitussive activity with low acute toxicity, and can be prepared according to the following method. and Hal represents a chlorine, bromine or iodine atom] or an acid addition salt thereof, by reacting with urea.
反応は熔融状態において有利に行なわれ、そして所望な
らば触媒量の酸たとえば氷酢酸の存在において行なうこ
とができるが、反応はまたエタノール、インプロパツー
ル、ｔ−ブタノール、氷酢酸、ジオキサン、ジメチルホ
ルムアミド、ジメチルアセトアミドのような溶媒中また
は上記溶媒の混合物中、都合よくは使用した溶媒の沸騰
温度までの温度において行なうことができる。Although the reaction is advantageously carried out in the molten state and can be carried out if desired in the presence of catalytic amounts of acids such as glacial acetic acid, the reaction can also be carried out in the presence of ethanol, impropatol, t-butanol, glacial acetic acid, dioxane, dimethylformamide. , dimethylacetamide, or in a mixture of the abovementioned solvents, conveniently at temperatures up to the boiling temperature of the solvent used.
反応はまた一般式■の化合物が対応のアゼピノン−（４
）と当量の塩素、臭素またはヨウ素との反応によってそ
の場所で製造されるような方法で行なうことができる。The reaction also shows that the compound of general formula
) with an equivalent amount of chlorine, bromine or iodine.
かく得られた化合物は所望ならば公知の方法によって無
機または有機酸とでそれらの生理的に許容されうる酸付
加塩に変換できる。The compounds thus obtained can be converted, if desired, into their physiologically acceptable acid addition salts with inorganic or organic acids by known methods.
適当な酸はたとえば塩酸、臭化水素酸、硫酸、リン酸、
酒石酸、コハク酸、クエン酸、アジピン酸、エンボン酸
（ｅｍｂｏｎｉｃ ａｃｉｄ）、フマール酸またはマレ
イン酸を包含する。Suitable acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,
Includes tartaric acid, succinic acid, citric acid, adipic acid, embonic acid, fumaric acid or maleic acid.
出発物質として使用される一般式■の化合物は対応のへ
キサヒドロ−アゼピノン−（４）を当モル量の塩素、臭
素またはヨウ素でハロゲン化することによって得られる
。The compound of general formula (1) used as a starting material can be obtained by halogenating the corresponding hexahydro-azepinone (4) with an equimolar amount of chlorine, bromine or iodine.
かく得られた一般式Ｈの化合物は精製されなくてもよい
。The compound of general formula H thus obtained does not need to be purified.
必要なヘキサヒドロ−アゼピノン−（４）類は一部分は
文献〔ヨコオＡｋ、 Ｙｏｋｏｏ ）等、ブレチン・オ
ブ・ケミカル・ソサエティ・オブ・ジャパン（Ｂｕｌｌ
、Ｃｈｅｍ、 Ｓｏｃ 、 Ｊａｐａｎ） ２９．６３
１（１９５９）参照〕から公知であり、または例Ａない
しＥと同様にして製造できる。The necessary hexahydro-azepinones (4) are partially available in the literature (Yokoo Ak, Yokoo), Bulletin of Chemical Society of Japan (Bull), etc.
, Chem, Soc, Japan) 29.63
1 (1959)] or can be prepared analogously to Examples A to E.
先に述べたように、一般式■の新規オキサゾールおよび
それらの酸付加塩は価値ある薬理性質、特に非常に低毒
性で鎮咳活性を示す。As mentioned above, the novel oxazoles of general formula (1) and their acid addition salts exhibit valuable pharmacological properties, in particular antitussive activity with very low toxicity.
鎮咳活性は、たとえば次の物質で、エンゲルホルン（Ｅ
ｎｇｅｌｈｏｒｎ ）およヒヒュツシュマン（Ｐ ｉｉ
ｓｃｈｍａｎｎ ） Ｃアルツナイミツテルフオルシュ
ンク（Ａｒｚｎｅｉｍｉｔｔｅｌｆｏｒｓｃｈｕｎｇ
） １３ 、４７４−４３０（，１９６３））の方法に
従って試験した：Ａ＝２−アミノー６−アセチルー４・
５・７・８−テトラヒドロ−６Ｈ−オキサゾロ〔５・４
−ｄ〕アゼピノン塩酸塩、
比較として、
Ｂ−アセチルージヒドローコデイノンー塩酸塩。Antitussive activity is demonstrated by the following substances, for example, Angelhorn (E
ngelhorn) and Hütschmann (P ii
schmann) C Arzneimittelforschung
) 13, 474-430 (, 1963): A=2-amino-6-acetyl-4.
5,7,8-tetrahydro-6H-oxazolo[5,4
-d] azepinone hydrochloride, as a comparison, B-acetyl dihydrocodeinone hydrochloride.
問題の物質は目覚めた（ａｗａｋｅ ）白ネズミの６な
いし８匹の各々に対し５１ｎ９／ｋｇの用量において経
口的に投薬した。The substance in question was administered orally to each of 6 to 8 awake white rats at a dose of 51n9/kg.
７．５％水性クエン酸−スプレーの吸入によって反射性
咳漱（ｃｏｕｇｈ ｒｅｆｌｅｘｅｓ ）を作り出した
。Cough reflexes were produced by inhalation of a 7.5% aqueous citric acid-spray.
咳反射の平均百分率変化を問題の物質の投薬後３０分間
測定した。The mean percentage change in the cough reflex was measured for 30 minutes after administration of the substance in question.
更に、物質ＡおよびＢの経口急性毒性（観察期間：１４
日間）を、・・ツカネズミで定位的（ｏｒｉｅｎｔａｔ
ｉｖｅｌｙ）に決定し、一方物質りのＬＤ５゜はリッチ
フィールド（Ｌｉｔｃｈｆｉｅｌｄ）およびウイルコク
メン（Ｗｉ １ｃｏｘｏｎ） （ジャーナル・オブ・フ
ァマコロジー・アンド・エキスペリメンタル・テラピー
（Ｊ 、 Ｐｈａｒｍａｃｏｌ、 Ｅｘｐ 、 Ｔｈｅ
ｒ 、） ９６．９９−１１３（１９４９））の方法に
従い、観察時間内に各種用量の投薬後に死んだ動物の数
から計算した。Furthermore, the oral acute toxicity of substances A and B (observation period: 14
(days),...
ively), while the material's LD5° was determined by Litchfield and Wilcoxon (Journal of Pharmacology and Experimental Therapy, Pharmacol, Exp, The
r,) 96.99-113 (1949)) was calculated from the number of animals that died after administration of various doses within the observation time.
次の表はその結果を含んでいる：
本願化合物に類似する下記の二つの化合物について、同
様の比較試験を行なった。The following table contains the results: A similar comparative test was conducted on the following two compounds that are similar to the compound of the present application.
Ｃ＝２−アミノ−４・５・７・８−テトラヒドロ−６Ｈ
−チアゾロ〔５・４−ｄ〕アゼピノンジ塩酸塩
Ｄ＝２−アミノ−６−（２−ヒドロキシエチル）−４・
５・７・８−テトラヒドロ−６Ｈ−チアゾロ〔５・４−
ｄ〕アゼピノンジ塩酸塩
化合物Ｅはネコにおいて１〜／ｋｇ ｉ 、ｖ 、の投
与量ですでに血圧に対して強力な作用を示すので鎮咳剤
として使用することはできない。C=2-amino-4,5,7,8-tetrahydro-6H
-thiazolo[5.4-d]azepinone dihydrochloride D=2-amino-6-(2-hydroxyethyl)-4.
5,7,8-tetrahydro-6H-thiazolo[5,4-
d] Azepinone dihydrochloride Compound E cannot be used as an antitussive because it already shows a strong effect on blood pressure in cats at doses of 1 to 1 kg i,v .
化合物Ｆはラットに５〜／ｋｙ経口投与すると、２９％
の反射性咳漱の減少を示した。When compound F was orally administered to rats at 5~/ky, 29%
showed a decrease in reflex cough cough.
本願発明の化合物の効果は以上の比較化合物のそれより
顕著に高いことが判る。It can be seen that the effects of the compounds of the present invention are significantly higher than those of the above-mentioned comparative compounds.
以下の実施例で本発明を説明する。The following examples illustrate the invention.
例Ａ
１−ベンジル−へキサヒドロ−アゼピノン−（４）一塩
酸塩
トルエン３１０ｍ１中のカリウム−ｔ−ブトキサイド４
２．０Ｐ（３７５ミリモル）の沸騰溶液に、トルエン１
２ｏｍ＃ｃ溶かしたＮ−エトキシ−カルボニルエチル−
Ｎ−ベンジル−４−アミノーエチルーブチレー）８５．
０ｆ（２６４ミリモル）を攪拌しつつ３．５時間内に滴
下し、そして形成したエタノールを同時に留去した。Example A 1-Benzyl-hexahydro-azepinone-(4) monohydrochloride Potassium-tert-butoxide 4 in 310 ml toluene
To a boiling solution of 2.0P (375 mmol), add 1 part of toluene.
2om#c dissolved N-ethoxy-carbonylethyl-
N-benzyl-4-aminoethyl butylene)85.
Of (264 mmol) was added dropwise with stirring within 3.5 hours and the ethanol formed was distilled off at the same time.
その後、２５％塩酸１００ｒＩＬｌを混合物に冷却しつ
つ滴下し、そして有機層を塩酸５０ｍ１で３回抽出した
。Thereafter, 100 rILl of 25% hydrochloric acid was added dropwise to the mixture while cooling, and the organic layer was extracted three times with 50 ml of hydrochloric acid.
合せた酸抽出液を４時間１００度Ｃまで加熱した。The combined acid extracts were heated to 100 degrees C for 4 hours.
冷却した後、反応物を水酸化ナトリウム溶液でｐＨ１０
ないし１１に調節し、そしてシクロヘキサンで抽出した
。After cooling, the reaction was adjusted to pH 10 with sodium hydroxide solution.
and extracted with cyclohexane.
有機層を硫酸ナトリウムで乾燥した後、溶媒を真空中で
除去し、得られた塩基をイソプロパツール８０ｍ１に溶
かし、そしてインプロパツール性塩酸で塩酸塩を沈澱さ
せた。After drying the organic layer over sodium sulfate, the solvent was removed in vacuo, the resulting base was dissolved in 80 ml of isopropanol, and the hydrochloride salt was precipitated with inpropanol hydrochloric acid.
収量：４０？（理論量の６３％）、融点：１９４度Ｃ（
エタノールから）。Yield: 40? (63% of theoretical amount), melting point: 194 degrees C (
from ethanol).
例Ｂ
ヘキサヒドロ−アゼピノン−（４）一塩酸塩１−ベンジ
ン−ヘキサヒドロ−アゼピノン−（４）一塩酸塩８０ｆ
（３３４ミリモル）を、メタノール７２０ｍ１および水
８０７７１１中、酸化パラジウム（８グ）の存在におい
て、室温および５ないし６気圧の水素圧で水素化した。Example B Hexahydro-azepinone-(4) monohydrochloride 1-benzine-hexahydro-azepinone-(4) monohydrochloride 80f
(334 mmol) was hydrogenated in 720 ml of methanol and 807,711 ml of water in the presence of palladium oxide (8 g) at room temperature and 5 to 6 atmospheres of hydrogen pressure.
必要量の水素の吸収後、水素化触媒を吸引瀝過し、溶媒
を真空中で除去し、得られた塩基をイソプロパツールに
溶かし、そしてインプロパツール性塩酸で塩酸塩を沈澱
させた。After absorption of the required amount of hydrogen, the hydrogenation catalyst was filtered off with suction, the solvent was removed in vacuo, the base obtained was dissolved in isopropanol and the hydrochloride salt was precipitated with inpropanol hydrochloric acid.
収量４５グ（理論量の９０％）、融点：１９５度Ｃ（イ
ンプロパツールから）。Yield 45 g (90% of theory), melting point: 195 degrees C (from Improper Tools).
例Ｃ
■−アセチルーへキサヒドロ−アゼピノン−（４）へキ
サヒドロ−アゼピノン−（４）一塩酸塩１８グ（１２０
ミリモル）を水９ｍｌ、炭酸カリウム２２Ｐ（６１ミリ
モル）およびクロロホルム１５０７７１１と混合した。Example C ■-acetyl-hexahydro-azepinone-(4) hexahydro-azepinone-(4) monohydrochloride 18 g (120
mmol) was mixed with 9 ml of water, potassium carbonate 22P (61 mmol) and chloroform 1507711.
攪拌しそして沸騰温度まで加熱しつつ、クロロホルムｌ
ＱｍＡ’に溶かしたアセチルクロライド１１？（１４０
ミリモル）を混合物にゆつ（り滴下し、そして還流を４
ないし５時間続けた。While stirring and heating to boiling temperature, add chloroform l
Acetyl chloride 11 dissolved in QmA'? (140
dropwise into the mixture and refluxed for 4
It lasted about 5 hours.
冷却後、沈澱した塩を瀝過し、クロロホルム層を５％塩
酸および水で２回抽出した。After cooling, the precipitated salt was filtered off, and the chloroform layer was extracted twice with 5% hydrochloric acid and water.
有機層を硫酸ナトリウムで乾燥した後、溶媒を真空中で
除去して、■−アセチルーへキサヒドロ−アゼピノン−
（４）１’ ３．９ Ｐ （理論量の７６％）が淡黄色
の油として生成した。After drying the organic layer over sodium sulfate, the solvent was removed in vacuo to give ■-acetyl-hexahydro-azepinone-
(4) 1' 3.9 P (76% of theory) was produced as a pale yellow oil.
すべての１−アシル−へキサヒドロ−アゼピノン−（４
）は、対応のアシルクロライドを使用し、同様にして製
造された。All 1-acyl-hexahydro-azepinone-(4
) was prepared in a similar manner using the corresponding acyl chloride.
例１
２−アミノ−６−アセチル−４・５・７・８−テトラヒ
ドロ−６Ｈ−オキサゾロ〔４・５−ｄ〕アゼピノン塩酸
塩
■−アセチルー５−プロモーへキサヒドロ−アゼピノン
−（４１１４，３Ｐ （６１ミリモル）〔１−アセチル
−へキサヒドロ−アゼピノン−（４）をクロロホルム中
臭素でブロム化することによって製造した〕を尿素１８
．５ｆ（３０８ミリモル）とよく混合し、そして６０な
いし７０度Ｃまで６時間加熱した。Example 1 2-Amino-6-acetyl-4,5,7,8-tetrahydro-6H-oxazolo[4,5-d]azepinone hydrochloride -acetyl-5-promohexahydro-azepinone-(4114,3P (61 18 mmol) [prepared by bromination of 1-acetyl-hexahydro-azepinone-(4) with bromine in chloroform]
．． 5f (308 mmol) and heated to 60-70 degrees C for 6 hours.
冷却された熔融物を水に溶かし、炭酸カリウムでアルカ
リ性に調節し、そしてクロロホルムで抽出した。The cooled melt was dissolved in water, made alkaline with potassium carbonate, and extracted with chloroform.
乾燥しそして抽出剤を留去した後、粗塩基を塩酸塩に変
換し、それを活性炭の添加によりインプロパツールから
再結晶した。After drying and distilling off the extractant, the crude base was converted into the hydrochloride salt, which was recrystallized from Impropateur by addition of activated carbon.
収量：８１（理論量の６７．２％）、融点：１７８度Ｃ
６
ＣＧＩＨＩ３Ｎ３０２ （１９５，２２）計算値：Ｃ５
５，３８Ｈ６，７１Ｎ２１．５３測定値： ５５．４
０ ６．７１ ２１．４０塩酸塩の融点：２２２度
Ｃ（分解）。Yield: 81 (67.2% of theory), melting point: 178 degrees C
6 CGIHI3N302 (195,22) Calculated value: C5
5,38H6,71N21.53 Measured value: 55.4
0 6.71 21.40 Melting point of hydrochloride: 222 degrees C (decomposition).
例２
２−アミノ−６−アセチル−４・５・７・８−テトラヒ
ドロ−６Ｈ−オキサゾロ〔４・５−ｄ〕アゼピン
１−アセチル−５−プロモーへキサヒドロ−アゼピノン
−（４）１４．３ ｆ （６１ミリモル）および尿素１
８．５Ｐ（３０８ミリモル）をインプロパノール６０Ｔ
ｆＬｌ中で２ないし３時間還流した。Example 2 2-amino-6-acetyl-4,5,7,8-tetrahydro-6H-oxazolo[4,5-d]azepine 1-acetyl-5-promohexahydro-azepinone-(4) 14.3 f (61 mmol) and urea 1
8.5P (308 mmol) in propanol 60T
Refluxed in fLl for 2-3 hours.
溶媒を留去した後、得られた残渣を水に溶かし、混合物
を水酸化ナトリウム溶液でｐＨ１０に調節し、そしてク
ロロホルムで抽出した。After evaporation of the solvent, the residue obtained was dissolved in water, the mixture was adjusted to pH 10 with sodium hydroxide solution and extracted with chloroform.
乾燥したクロロホルム抽出液から得られた粗塩基をイソ
プロパツールから再結晶した。The crude base obtained from the dried chloroform extract was recrystallized from isopropanol.
収量：４１（理論量の３３％）、融点：１７８度０
塩酸塩は塩基のアルコール溶液をインプロパツール性塩
酸と反応させることによって得られた。Yield: 41 (33% of theory), melting point: 178°0 The hydrochloride salt was obtained by reacting an alcoholic solution of the base with impropateric hydrochloric acid.
融点：２２２度Ｃ（分解）。Melting point: 222 degrees C (decomposed).
例３
２−アミノ−６−ブチリル−４・５・７・８−テトラヒ
ドロ−６Ｈ−オキサゾロ〔４・５−ｄ〕−アゼピン−塩
酸塩
ｔ−ブチリル−５−プロモーへキサヒドロ−アゼピノン
−（４）および尿素から例１に従って製造した。Example 3 2-Amino-6-butyryl-4,5,7,8-tetrahydro-6H-oxazolo[4,5-d]-azepine-hydrochloride t-butyryl-5-promohexahydro-azepinone-(4) and urea according to Example 1.
収率：理論量の４１％、融点：１３２ないし１３８度Ｃ
０
塩酸塩の融点：１８２ないし１８４度Ｃ３ＣＩＩＨＩ□
Ｎ３０□（２２３，２８）、ＨＣＩ （２５９，７４）
計算値：Ｃ５９，１７Ｈ７，６７Ｎ１８．８２測定値：
５９．２０ ７．６６ １８．９２例４
２−アミノ−６−インブチリルー４・５・７・８−テト
ラヒドロ−６Ｈ−オキサゾロ〔４・５−ｄ）アゼピン
１−インブチリル−５−プロモーへキサヒドロ−アゼピ
ノン−（４）および尿素から例１に従って製造した。Yield: 41% of theory, melting point: 132-138 degrees C
0 Melting point of hydrochloride: 182 to 184 degrees C3CIIHI□
N30□ (223,28), HCI (259,74)
Calculated value: C59,17H7,67N18.82 Measured value:
59.20 7.66 18.92 Example 4 2-Amino-6-inbutyryl-4,5,7,8-tetrahydro-6H-oxazolo[4,5-d)Azepine 1-inbutyryl-5-promohexahydro-azepinone - (4) and urea according to Example 1.
塩基の融点：１８０度ＣＯ
Ｃｌ１Ｈ１７Ｎ３０２ （２２３，２８）計算値：Ｃ５
９，１７Ｈ７，６７Ｎ１８．８２測定値： ５９．４
０ ７．６８ １８．６２例５
２−アミノ−６−クロロホルム４・５・７・８−テトラ
ヒドロ−６Ｈ−オキサゾロ〔４・５−ｄ〕アゼピノ
ンークロトノイルー５−プロモーへキサヒドロ−アゼピ
ノン−（４）および尿素から例１に従い製造した。Melting point of base: 180 degrees CO Cl1H17N302 (223,28) Calculated value: C5
9,17H7,67N18.82 Measured value: 59.4
0 7.68 18.62 Example 5 2-amino-6-chloroform 4,5,7,8-tetrahydro-6H-oxazolo[4,5-d]azepinone-crotonoyl-5-promohexahydro-azepinone- (4) and urea according to Example 1.
塩基の融点：１６８度ＣＯ
Ｃｌ１ ＨＩ３Ｎ３０２ （２２１，２６）計算値：Ｃ
５９，７１Ｈ６，８３Ｎ１８．９９測定値： ６０．
００ ６．６８ １９．００例６
２−アミノ−６−フェニルアセチル−４・５・７・８−
テトラヒドロ−６Ｈ−オキサゾロ〔４・５−ｄ〕アゼピ
ノ
ン−フェニルアセチル−５−プロモーへキサヒドロ−ア
ゼピノン−（４）および尿素から例１に従い製造した。Melting point of base: 168 degrees CO Cl1 HI3N302 (221,26) Calculated value: C
59,71H6,83N18.99 Measured value: 60.
00 6.68 19.00 Example 6 2-Amino-6-phenylacetyl-4, 5, 7, 8-
Prepared according to Example 1 from tetrahydro-6H-oxazolo[4.5-d]azepinone-phenylacetyl-5-promohexahydro-azepinone- (4) and urea.
塩基の融点：２１４度ＣＯ
Ｃｌ５Ｈ１７Ｎ３０２ （２７１，３２）計算値：Ｃ６
６，４０Ｈ６，３１Ｎ１５．４９測定値： ６５．９
０ ６．３０ １５．４０例７
２−アミノ−６−ベンゾイル−４・５・７・８−テトラ
ヒドロ−６Ｈ−オキサゾロ〔４・５−ｄ〕アゼピノン塩
酸塩
■−ベンゾイルー５−プロモーへキサヒドロ−アゼピノ
ン−（４）および尿素から例１に従い製造した。Melting point of base: 214 degrees CO Cl5H17N302 (271,32) Calculated value: C6
6,40H6,31N15.49 Measured value: 65.9
0 6.30 15.40 Example 7 2-Amino-6-benzoyl-4,5,7,8-tetrahydro-6H-oxazolo[4,5-d]azepinone hydrochloride -benzoyl-5-promohexahydro-azepinone - (4) and urea according to Example 1.
塩酸塩の融点：２１０度Ｃ０
Ｃ，４Ｈ１５Ｎ３０２．ＨＣｌ （２９３，７５）計算
値：Ｃ５７，２０Ｈ５，５０Ｎ１４．３２測定値：
５７．２０ ５．６１ １４．０６例８
２−アミノ−６−（４−クロロベンゾイル）−４・５・
７・８−テトラヒドロ−６Ｈ−オキサゾロ−〔４・５−
ｄ〕アゼピノン塩酸塩
１−（４−クロロベンソイル）−５−プロモーヘキサヒ
ドロ−アゼピノン−（４）および尿素から例１に従い製
造した。Melting point of hydrochloride: 210 degrees C0 C, 4H15N302. HCl (293,75) Calculated value: C57,20H5,50N14.32 Measured value:
57.20 5.61 14.06 Example 8 2-amino-6-(4-chlorobenzoyl)-4.5.
7,8-tetrahydro-6H-oxazolo-[4,5-
d] Azepinone hydrochloride Prepared according to Example 1 from 1-(4-chlorobenzoyl)-5-promohexahydro-azepinone-(4) and urea.
収率：理論量の１４％、塩基の融点：２３２ないし２３
３度Ｃ０
塩酸塩の融点：２３８ないし２４０度Ｃ０Ｃ，４Ｈ，、
ＣｌＮ３０□ （２９１，７４）計算値：Ｃ５７，６４
Ｈ４，８４Ｎ１４．４０測定値： ５７．６０ ４
．７９ １４．３８例９
２−アミノ−６−（２−メトキシ−５−クロロ−ベンゾ
イル）−４・５・７・８−テトラヒドロ−６Ｈ−オキサ
ゾロ〔４・５−ｄ〕−アゼピン
１−（２−メトキシ−５−クロロ−ベンゾイル）−５−
プロモーへキサヒドロ−アゼピノン−（４）および尿素
から例１に従い製造した。Yield: 14% of theory, melting point of base: 232-23
3 degrees C0 Melting point of hydrochloride: 238 to 240 degrees C0C, 4H,
ClN30□ (291,74) Calculated value: C57,64
H4,84N14.40 measurement value: 57.60 4
．． 79 14.38 Example 9 2-Amino-6-(2-methoxy-5-chloro-benzoyl)-4,5,7,8-tetrahydro-6H-oxazolo[4,5-d]-azepine 1-(2 -methoxy-5-chloro-benzoyl)-5-
Prepared according to Example 1 from promoter hexahydro-azepinone-(4) and urea.
収率：理論量の３１％；塩基の融点＝２３５度Ｃ６Ｃ１
５Ｈ１６ＣＩＮ３Ｃ３（３２１，７３）計算値：Ｃ５５
，９９Ｈ５，０２Ｎ１３．０５測定値： ５５８０
５．２７ １２．８８例１０
２−アミノ−６−ニコチノイルー４・５・７・８−テト
ラヒドロ−６Ｈ−オキサゾロ〔４・５−ｄ）アゼピン−
ジ塩酸塩
１−ニコチノイル−５−プロモーへキサヒドロ−アゼピ
ノン−（４）−臭化水素酸塩および尿素から例に従い製
造した。Yield: 31% of theory; melting point of base = 235 degrees C6C1
5H16CIN3C3 (321,73) Calculated value: C55
,99H5,02N13.05 Measured value: 5580
5.27 12.88 Example 10 2-Amino-6-nicotinoyl-4,5,7,8-tetrahydro-6H-oxazolo[4,5-d)Azepine-
Prepared according to the example from dihydrochloride 1-nicotinoyl-5-promohexahydro-azepinone-(4)-hydrobromide and urea.
ジ塩酸塩の融点：２３４ないし２３５度Ｃ８Ｃ，３Ｈ，
、Ｎ４０２．２ＨＣ１（３３１，２０）計算値：Ｃ４７
，１４Ｈ４，８７Ｎ１６．９１測定値 ４７，２０
４．９９ １６．９８例１１
２−アミノ−６−インニコチツイルー４・５・７・８−
テトラヒドロ−６Ｈ−オキサゾロ〔４・５−ｄ〕アゼピ
ノンオキサレート
■−インニコチノイルー５−プロモーへキサヒドロ−ア
ゼピノン−（４）−臭化水素酸塩および尿素から例１に
従い製造した。Melting point of dihydrochloride: 234 to 235 degrees C8C, 3H,
, N402.2HC1 (331,20) Calculated value: C47
,14H4,87N16.91 Measured value 47,20
4.99 16.98 Example 11 2-amino-6-inicotitwiru 4, 5, 7, 8-
Tetrahydro-6H-oxazolo[4.5-d]azepinone oxalate -innicotinoyl-5-promohexahydro-azepinone-(4)-hydrobromide and urea prepared according to Example 1.
オキサレートの融点：２３８度ＣＯ
Ｃｌ３Ｈ１４Ｎ４０２（３４８，３）、ＨＯＯＣ−ＣＯ
ＯＨ言慎値 ：Ｃ５１，７２Ｈ４，６３Ｎ１６．０８測
定値： ５１．５５ ４．６２ １６．１６例１
２
２−アミノ−６−ホルミル−４・５・７・８−テトラヒ
ドロ−６Ｈ−オキサゾロ〔４・５−ｄ〕アゼピノ
ンーホルミルー５−プロモーヘキサヒドロ−アゼピノン
−（４）および尿素から例１に従い製造した。Oxalate melting point: 238 degrees CO Cl3H14N402 (348,3), HOOC-CO
OH standard value: C51,72H4,63N16.08 Measured value: 51.55 4.62 16.16 Example 1
2 Example 1 from 2-amino-6-formyl-4,5,7,8-tetrahydro-6H-oxazolo[4,5-d]azepinone-formyl-5-promohexahydro-azepinone-(4) and urea Manufactured according to.
塩基の融点：１７８度Ｃ０
Ｃ３Ｈ５，Ｎ３０□ （１８１，２０）
計算値：Ｃ５３，０３Ｈ６，１２
測定値： ５２．０７ ６．１３
例１３
２−アミノ−６−ヘキサノイル−４・５・７・８−テト
ラヒドロ−６Ｈ−オキサゾロ〔４・５−ｄ）アゼピン
■−ヘキサノイルー５−プロモーヘキサヒドロ−７ゼピ
ノンー（４）および尿素から例１に従い製造した。Melting point of base: 178 degrees C0 C3H5,N30□ (181,20) Calculated value: C53,03H6,12 Measured value: 52.07 6.13 Example 13 2-Amino-6-hexanoyl-4, 5, 7, 8 -Tetrahydro-6H-oxazolo[4.5-d)Azepine ■-Hexanoyl-5-promohexahydro-7 Zepinone--Prepared according to Example 1 from (4) and urea.
塩基の融点：１４２度Ｃ０
Ｃ，３Ｈ２，Ｎ３０２（２５１，３３）
計算値：Ｃ６２，１３Ｈ８，４１Ｎ１６．７３測定値：
６１．５０ ８．１７ １６．９８本発明は特
許請求の範囲記載の製法であるが、なお以下の態様をも
包含するものである。Melting point of base: 142 degrees C0 C,3H2,N302(251,33) Calculated value: C62,13H8,41N16.73 Measured value:
61.50 8.17 16.98 The present invention is a manufacturing method described in the claims, but it also includes the following embodiments.
（１）反応を触媒量の酸の存在において行なう、特許請
求の範囲に従う方法。(1) A process according to the claims, wherein the reaction is carried out in the presence of a catalytic amount of acid.
（２）一般式■の５−ハロゲン−アゼピノン−（４）−
誘導体をその場で製造する、特許請求の範囲または上記
（１）に従う方法。(2) 5-halogen-azepinone-(4)- of general formula ■
A method according to claim 1 or (1) above for producing the derivative in situ.
（３）反応を使用した溶媒の沸点までの温度で行なう、
特許請求の範囲、上記（１）または（２）に従う方法。(3) carrying out the reaction at a temperature up to the boiling point of the solvent used;
A method according to claim (1) or (2) above.
Claims (1)
の脂肪族アシル基；メチルまたはメトキシ基またはハロ
ゲン原子によって置換されていてもよいベンゾイル基；
ピリジンカルボニルまたはフェニルアシル基を示す〕の
新規オキサゾールおよび無機および有機酸によるそれら
の生理的に許容されうる酸付加塩の製造法において、一
般式■〔式中、Ｒは上記と同じ意味を有し、Ｈａｌは塩
素、臭素またはヨウ素原子を示す〕の５−・・ロゲンー
アゼピノンー（４）−誘導体またはその酸付加塩を熔融
状態または溶媒中において尿素と反応させ、所望ならば
ついで、かく得られた一般式■の化合物を無機または有
機酸でそれらの生理的に許容されうる酸付加塩に変換す
ることからなる方法。[Claims] 1 General formula ■ [In the formula, R is a saturated or unsaturated aliphatic acyl group having 1 to 6 carbon atoms; a methyl or methoxy group, or a benzoyl group optionally substituted with a halogen atom;
pyridinecarbonyl or phenylacyl group] and their physiologically acceptable acid addition salts with inorganic and organic acids, the general formula , Hal represents a chlorine, bromine or iodine atom] or its acid addition salt is reacted with urea in the melt or in a solvent, and if desired, then A process consisting of converting the obtained compounds of general formula (1) into their physiologically acceptable acid addition salts with inorganic or organic acids.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2206385A DE2206385C2 (en) | 1972-02-10 | 1972-02-10 | 2-Amino-4,5,7,8-tetrahydro-6H-oxazolo- [4,5-d] azepine derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS4886885A JPS4886885A (en) | 1973-11-15 |
| JPS5825678B2 true JPS5825678B2 (en) | 1983-05-28 |
Family
ID=5835665
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP48016407A Expired JPS5825678B2 (en) | 1972-02-10 | 1973-02-09 | Oxazole powder |
Country Status (24)
| Country | Link |
|---|---|
| JP (1) | JPS5825678B2 (en) |
| KR (1) | KR780000196B1 (en) |
| AT (1) | AT321296B (en) |
| BE (1) | BE795257A (en) |
| BG (1) | BG22826A3 (en) |
| CA (1) | CA997342A (en) |
| CH (1) | CH576476A5 (en) |
| CS (1) | CS181231B2 (en) |
| DD (1) | DD104083A5 (en) |
| DE (1) | DE2206385C2 (en) |
| DK (1) | DK137011C (en) |
| FI (1) | FI54126C (en) |
| FR (1) | FR2181718B1 (en) |
| GB (1) | GB1412377A (en) |
| HU (1) | HU165459B (en) |
| IE (1) | IE37347B1 (en) |
| IL (1) | IL41512A (en) |
| NL (1) | NL173525C (en) |
| NO (1) | NO131599C (en) |
| PL (1) | PL84740B1 (en) |
| RO (1) | RO61191A (en) |
| SE (1) | SE380805B (en) |
| SU (1) | SU474990A3 (en) |
| ZA (1) | ZA73924B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3820775A1 (en) * | 1988-06-20 | 1989-12-21 | Thomae Gmbh Dr K | NEW 4,5,7,8-TETRAHYDRO-6H-THIAZOLO (5,4, -D) AZEPINES, THEIR PREPARATION AND THEIR USE AS DRUGS |
| DE4345224C2 (en) * | 1993-12-18 | 1999-07-01 | Asta Medica Ag | Process for the preparation of acid addition salts of azelastine and flezelastin |
| CL2004000553A1 (en) | 2003-03-20 | 2005-02-04 | Actelion Pharmaceuticals Ltd | USE OF GUANIDINE DERIVATIVE COMPOUNDS AS ANTAGONISTS OF THE FF NEUROPEPTIDE RECEIVER; COMPOUNDS DERIVED FROM GUANIDINA; PREPARATION PROCEDURES; AND PHARMACEUTICAL COMPOSITION THAT UNDERSTANDS THEM. |
| RU2006110738A (en) | 2003-09-05 | 2007-12-10 | Актелион Фармасьютиклз Лтд. (Ch) | GUANIDINE DERIVATIVES |
| EP2327704A4 (en) * | 2008-08-29 | 2012-05-09 | Shionogi & Co | Ring-fused azole derivative having pi3k-inhibiting activity |
| KR20160067959A (en) | 2013-11-11 | 2016-06-14 | 가부시키가이샤 고베 세이코쇼 | Titanium separator material for fuel cells, and method for producing titanium separator material for fuel cells |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5246236A (en) * | 1975-09-23 | 1977-04-12 | Schoeman M J | Carburetor |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BG17786A3 (en) * | 1970-08-14 | 1973-12-25 | ||
| DE2040510C3 (en) * | 1970-08-14 | 1980-03-06 | Dr. Karl Thomae Gmbh, 7950 Biberach | Oxazole and thiazole square brackets on 5,4-d] azepine derivatives |
-
0
- BE BE795257D patent/BE795257A/en not_active IP Right Cessation
-
1972
- 1972-02-10 DE DE2206385A patent/DE2206385C2/en not_active Expired
-
1973
- 1973-01-18 NL NLAANVRAGE7300744,A patent/NL173525C/en not_active IP Right Cessation
- 1973-01-29 DD DD168504A patent/DD104083A5/xx unknown
- 1973-01-29 AT AT73473A patent/AT321296B/en not_active IP Right Cessation
- 1973-01-31 SU SU1878315A patent/SU474990A3/en active
- 1973-02-07 KR KR7300224A patent/KR780000196B1/en active
- 1973-02-08 SE SE7301773A patent/SE380805B/en unknown
- 1973-02-08 CH CH187273A patent/CH576476A5/xx not_active IP Right Cessation
- 1973-02-08 HU HUTO898A patent/HU165459B/hu unknown
- 1973-02-08 BG BG22667A patent/BG22826A3/xx unknown
- 1973-02-09 DK DK74573A patent/DK137011C/en not_active IP Right Cessation
- 1973-02-09 GB GB647673A patent/GB1412377A/en not_active Expired
- 1973-02-09 FR FR7304643A patent/FR2181718B1/fr not_active Expired
- 1973-02-09 FI FI394/73A patent/FI54126C/en active
- 1973-02-09 CA CA163,409A patent/CA997342A/en not_active Expired
- 1973-02-09 JP JP48016407A patent/JPS5825678B2/en not_active Expired
- 1973-02-09 PL PL1973160658A patent/PL84740B1/pl unknown
- 1973-02-09 NO NO533/73A patent/NO131599C/no unknown
- 1973-02-09 IL IL41512A patent/IL41512A/en unknown
- 1973-02-09 CS CS7300000974A patent/CS181231B2/en unknown
- 1973-02-09 ZA ZA730924A patent/ZA73924B/en unknown
- 1973-02-09 IE IE211/73A patent/IE37347B1/en unknown
- 1973-02-10 RO RO73806A patent/RO61191A/ro unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5246236A (en) * | 1975-09-23 | 1977-04-12 | Schoeman M J | Carburetor |
Also Published As
| Publication number | Publication date |
|---|---|
| DE2206385C2 (en) | 1983-04-21 |
| FI54126C (en) | 1978-10-10 |
| AT321296B (en) | 1975-03-25 |
| RO61191A (en) | 1976-10-15 |
| ZA73924B (en) | 1974-11-27 |
| BG22826A3 (en) | 1977-04-20 |
| HU165459B (en) | 1974-08-28 |
| DK137011B (en) | 1978-01-02 |
| IL41512A0 (en) | 1973-04-30 |
| SE380805B (en) | 1975-11-17 |
| NL173525C (en) | 1984-02-01 |
| FR2181718B1 (en) | 1976-12-31 |
| JPS4886885A (en) | 1973-11-15 |
| SU474990A3 (en) | 1975-06-25 |
| NO131599B (en) | 1975-03-17 |
| IE37347L (en) | 1973-08-10 |
| IE37347B1 (en) | 1977-07-06 |
| KR780000196B1 (en) | 1978-05-26 |
| AU5203573A (en) | 1974-08-15 |
| FR2181718A1 (en) | 1973-12-07 |
| IL41512A (en) | 1976-01-30 |
| NL7300744A (en) | 1973-08-14 |
| DK137011C (en) | 1978-06-05 |
| NL173525B (en) | 1983-09-01 |
| GB1412377A (en) | 1975-11-05 |
| FI54126B (en) | 1978-06-30 |
| DD104083A5 (en) | 1974-02-20 |
| CS181231B2 (en) | 1978-03-31 |
| PL84740B1 (en) | 1976-04-30 |
| BE795257A (en) | 1973-08-09 |
| CA997342A (en) | 1976-09-21 |
| CH576476A5 (en) | 1976-06-15 |
| NO131599C (en) | 1975-06-25 |
| DE2206385A1 (en) | 1973-08-16 |
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