JPS597706B2 - Calbostyril Yudou Tainoseizohou - Google Patents
Calbostyril Yudou TainoseizohouInfo
- Publication number
- JPS597706B2 JPS597706B2 JP50072171A JP7217175A JPS597706B2 JP S597706 B2 JPS597706 B2 JP S597706B2 JP 50072171 A JP50072171 A JP 50072171A JP 7217175 A JP7217175 A JP 7217175A JP S597706 B2 JPS597706 B2 JP S597706B2
- Authority
- JP
- Japan
- Prior art keywords
- formulas
- formula
- general formula
- tables
- chemical
- 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
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- Quinoline Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】
本発明は新規なるカルボスチリル誘導体の製造法に関す
る。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing carbostyryl derivatives.
本発明で得られるカルボスチリル誘導体は一般式〔式中
Ｒ１、Ｒ２及びＲ３は水素原子又は炭素数１〜４個の低
級アルキル基を示す。The carbostyril derivative obtained in the present invention has the general formula [wherein R1, R2 and R3 represent a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms].
またＲ４及びＲ５は水素原子、炭素数１〜４個の低級ア
ルキル基又は一般式一（ＣＨ２）ｎ−《 》 （式中ｎ
は０〜４の整数を示す）で表わされる基を示すか、或い
は互いに結合してシクロアルキル基を示す。更に３・４
位の点線で示される結合は一重結合又は二重結合を示す
。〕で表わされる化合物である。In addition, R4 and R5 are a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, or the general formula 1(CH2)n-《》 (in the formula n
is an integer of 0 to 4), or bonded to each other to represent a cycloalkyl group. 3.4 more
A bond indicated by a dotted line indicates a single bond or a double bond. ] This is a compound represented by
本発明に於いては更に上記化合物の酸付加塩を包含する
。本発明の上記化合物は新規化合物であつて、β−アド
レナリン作働薬として有用なものである。本発明に係る
カルボスチリル誘導体は一般式〔式中Ｒ１、Ｒ２、Ｒ３
及び３・４位の点線で示される結合は夫々上記と同様の
意味を表わす。The present invention further includes acid addition salts of the above compounds. The above compounds of the present invention are novel compounds and are useful as β-adrenergic agonists. The carbostyril derivative according to the present invention has the general formula [wherein R1, R2, R3
and the bonds shown by dotted lines at the 3rd and 4th positions have the same meanings as above.
〕で表わされる化合物と一般式〔式中Ｒ４及びＲ５は夫
々上記と同様の意味を示す。] and the general formula [wherein R4 and R5 each have the same meaning as above.
で表わされるカルボニル化合物とを還元アミノ化条件下
に反応させることにより得られる。上記に於いてＲ１、
Ｒ２、Ｒ３、Ｒ４及びＲ５で表わされる炭素数１〜４個
の低級アルキル基としては例えばメチル、エチル、プロ
ピル、イソプロピル、ブチル、Ｓｅｃ−ブチル及びＴｅ
ｒｔ−ブチル基等が挙げられる。It is obtained by reacting a carbonyl compound represented by the following under reductive amination conditions. In the above, R1,
Examples of lower alkyl groups having 1 to 4 carbon atoms represented by R2, R3, R4 and R5 include methyl, ethyl, propyl, isopropyl, butyl, Sec-butyl and Te.
Examples include rt-butyl group.
またＲ４及びＲ５で表わされる基−（ＣＨ２）ｎ−《−
一》 （式中ｎはＯ〜４の整数）としては例えばフエニ
ル、ベンジル、フエネチルしてシクロアルキル基を示す
ものとしては例えばシクロヘキシル及びシクロペンチル
基等が挙げられる。本発明の出発物質として用いられる
一般式（１）で表わされる化合物は新規化合物である。Also, the group represented by R4 and R5 -(CH2)n-<<-
(1) (wherein n is an integer of O to 4) includes, for example, phenyl, benzyl, phenethyl, and examples of cycloalkyl groups include cyclohexyl and cyclopentyl groups. The compound represented by general formula (1) used as a starting material in the present invention is a new compound.
該化合物は例えば次の様な反応を経て得られる。即ち公
知の一般式
〔式中Ｒ１、Ｒ２及び３・４位の点線で示される結合は
夫々上記と同様の意味を示す。The compound can be obtained, for example, through the following reaction. That is, a known general formula [wherein R1, R2 and the bonds shown by dotted lines at the 3rd and 4th positions respectively have the same meanings as above.
〕で表わされる化合物と〒般式
〔式中Ｒ３は上記に同じであり、Ｘ及びＸ′は同一又は
相異なつてハロゲン原子を示す。] and the compound represented by the general formula [wherein R3 is the same as above, and X and X' are the same or different and represent a halogen atom.
〕で表わされるα−ハロアルカン酸ハライドとをルイス
酸の存在下に反応させて一般式〔式中Ｒ１、Ｒ２、Ｒ３
、Ｘ及び３・４位の点線で示される結合は夫々上記と同
様の意味を表わす。] is reacted with an α-haloalkanoic acid halide represented by the general formula [in the formula R1, R2, R3] in the presence of a Lewis acid.
,
〕で表わされる化合物を得る。次いで該化合物を無溶媒
又は溶媒中でアンモニアと反応させて一般式〔式中Ｒ１
、Ｒ２、Ｒ３及び３・４位の点線で示される場合は夫々
上記と同様の意味を表わす。〕で表わされる化合物を得
た後該化合物の５位のケト基を還元することにより、本
発明に使用される一般式（１）で表わされる化合物を得
ることができる。本発明に於いて一般式（１）で表わさ
れる化合物と一般式（）で表わされるカルボニル化合物
との反応は広く還元アミノ化の条件下に行なうことがで
きる。] is obtained. Next, the compound is reacted with ammonia without a solvent or in a solvent to form a compound of the general formula [in the formula R1
, R2, R3, and the 3rd and 4th positions indicated by dotted lines respectively have the same meanings as above. ] After obtaining the compound represented by the formula (1), the compound represented by the general formula (1) used in the present invention can be obtained by reducing the keto group at the 5-position of the compound. In the present invention, the reaction between the compound represented by general formula (1) and the carbonyl compound represented by general formula () can be carried out under a wide range of reductive amination conditions.
通常は接触還元法により触媒の存在下に行なわれる。こ
の際使用される触媒としては例えば酸化白金、白金黒、
パラジウム黒、パラジウム炭素、ラネーニツケル等が挙
げられる。また水素化剤の存在下に還元アミノ化反応を
行なうこともでき、この際使用される水素化剤としては
例えばナトリウムポロンヒドリド、リチウムァルミニウ
ムヒドリド等が挙げられる。尚一般式（１）で表わされ
る化合物中３・４位が不飽和結合（二重結合）を有する
化合物を原料として用いる場合には、得られる目的化合
物の３・４位が更に還元されることのない比較的還元の
緩和な水素化剤を用いる方が好ましい。本発明に於いて
一般式（１）で表わされる化合物と＝般式（）で表わさ
れるカルボニル化合物との使用割合は適宜選択すればよ
く特に限定されないが、通常前者に対し後者を約２〜３
倍モル用いるのが好ましい。This is usually carried out by a catalytic reduction method in the presence of a catalyst. Catalysts used at this time include, for example, platinum oxide, platinum black,
Examples include palladium black, palladium carbon, and Raney nickel. The reductive amination reaction can also be carried out in the presence of a hydrogenating agent, and examples of hydrogenating agents used in this case include sodium poron hydride and lithium aluminum hydride. In addition, when a compound represented by general formula (1) having an unsaturated bond (double bond) at the 3rd and 4th positions is used as a raw material, the 3rd and 4th positions of the target compound to be obtained may be further reduced. It is preferable to use a hydrogenating agent that has a relatively mild reduction. In the present invention, the ratio of the compound represented by the general formula (1) to the carbonyl compound represented by the general formula () may be appropriately selected and is not particularly limited, but the latter is usually about 2 to 3
It is preferable to use twice the molar amount.
本反応は溶媒中で行なわれる。This reaction is carried out in a solvent.
この際使用される溶媒としては、通常の還元アミノ化反
応に使用される溶媒が有効に使用され得、例えばメタノ
ール、エタノール等の低級アルコール類、ジオキサン、
テトラヒドロフラン等のエーテル類、ベンゼン、トルエ
ン等の芳香族炭化水素類、酢酸、水等が挙げられる。反
応温度は特に限定されないが、一般に室温乃至還流温度
附近で反応は有利に進行し、該温度範囲内で原料、還元
方法の種類等により適宜選択される。本反応により得ら
れる本発明のカルボスチリル誘導体は必要に応じ、臭酸
、塩酸、硫酸、マレイン酸等の無機酸又は有機酸と反応
させて生理的に許容される酸付加塩とすることができる
。As the solvent used at this time, solvents used in ordinary reductive amination reactions can be effectively used, such as lower alcohols such as methanol and ethanol, dioxane,
Examples include ethers such as tetrahydrofuran, aromatic hydrocarbons such as benzene and toluene, acetic acid, and water. Although the reaction temperature is not particularly limited, the reaction generally proceeds advantageously at room temperature to around reflux temperature, and is appropriately selected within this temperature range depending on the raw materials, the type of reduction method, etc. The carbostyril derivative of the present invention obtained by this reaction can be reacted with an inorganic or organic acid such as hydrochloric acid, hydrochloric acid, sulfuric acid, or maleic acid to form a physiologically acceptable acid addition salt, if necessary. .
本発明を具体的に示すために実施例を掲げる。Examples are given to specifically illustrate the present invention.
実施例 １５−（２−アミノ−１−ヒドロキシ）エチル
−８−ヒドロキシカルボスチリル２．２７にベンツアル
デヒド２．２７、エタノール１００ｍ１及びパラジウム
黒０．５７を加えて水素圧常圧下室温で接触還元する。Example 1 To 2.27 ml of 5-(2-amino-1-hydroxy)ethyl-8-hydroxycarbostyryl, 2.27 ml of benzaldehyde, 100 ml of ethanol, and 0.57 ml of palladium black were added and catalytically reduced at room temperature under hydrogen pressure and normal pressure. .
触媒をＰ去し、Ｐ液に濃塩酸を加えてＰＨｌとした後濃
縮乾固する。残渣をエタノールより再結晶して溶融点１
１９〜１２１℃の無色無定形の５−（２−ベンジルアミ
ノ−１−ヒドロキシ）エチル−８−ヒドロキシカルボス
チリル塩酸塩２水和物２．６ｙを得る。適当な出発物質
を用い上記実施例に準じて得られる本発明の目的化合物
を下記第１表に示す。The catalyst was removed from the P solution, concentrated hydrochloric acid was added to the P solution to obtain PHL, and the mixture was concentrated to dryness. The residue was recrystallized from ethanol to a melting point of 1.
2.6y of colorless amorphous 5-(2-benzylamino-1-hydroxy)ethyl-8-hydroxycarbostyryl hydrochloride dihydrate having a temperature of 19 to 121°C is obtained. The target compounds of the present invention obtained according to the above examples using appropriate starting materials are shown in Table 1 below.
Claims (1)
１〜４個の低級アルキル基を示す。 また３・４位の点線で示される結合は一重結合又は二重
結合を示す。〕で表わされる化合物と一般式 ▲数式、化学式、表等があります▼ 低級アルキル基又は一般式▲数式、化学式、表等があり
ます▼（式中ｎは０〜４の整数を示す）で表わされる基
を示すか、或いは互いに結合してシクロアルキル基を示
す。 〕で表わされるカルボニル化合物とを還元アミノ化の条
件下に反応させることを特徴とする、一般式▲数式、化
学式、表等があります▼〔式中Ｒ＿１、Ｒ＿２、Ｒ＿３
、Ｒ＿４、Ｒ＿５及び３・４位の点線で示される結合は
夫々上記と同様の意味を表わす。 〕で表わされるカルボスチリル誘導体の製造法。[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R_1, R_2 and R_3 represent a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms. Further, the bonds shown by dotted lines at the 3rd and 4th positions indicate single bonds or double bonds. ] Compounds and general formulas ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Lower alkyl groups or general formulas ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ (where n indicates an integer from 0 to 4) group or combined with each other to represent a cycloalkyl group. ] There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_1, R_2, R_3
, R_4, R_5 and the bonds shown by dotted lines at the 3rd and 4th positions each have the same meaning as above. ] A method for producing a carbostyryl derivative represented by
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP50072171A JPS597706B2 (en) | 1975-06-13 | 1975-06-13 | Calbostyril Yudou Tainoseizohou |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP50072171A JPS597706B2 (en) | 1975-06-13 | 1975-06-13 | Calbostyril Yudou Tainoseizohou |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS51149282A JPS51149282A (en) | 1976-12-22 |
| JPS597706B2 true JPS597706B2 (en) | 1984-02-20 |
Family
ID=13481507
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP50072171A Expired JPS597706B2 (en) | 1975-06-13 | 1975-06-13 | Calbostyril Yudou Tainoseizohou |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS597706B2 (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5776983A (en) * | 1993-12-21 | 1998-07-07 | Bristol-Myers Squibb Company | Catecholamine surrogates useful as β3 agonists |
| US5770615A (en) * | 1996-04-04 | 1998-06-23 | Bristol-Myers Squibb Company | Catecholamine surrogates useful as β3 agonists |
| ATE421322T1 (en) * | 2003-04-04 | 2009-02-15 | Novartis Pharma Gmbh | QUINOLIN-2-ONE DERIVATIVES FOR THE TREATMENT OF RESPIRATORY DISEASES |
| ES2265276B1 (en) | 2005-05-20 | 2008-02-01 | Laboratorios Almirall S.A. | DERIVATIVES OF 4- (2-AMINO-1-HYDROXYETHYL) Phenol as agonists of the BETA2 ADRENERGIC RECEIVER. |
| ES2306595B1 (en) | 2007-02-09 | 2009-09-11 | Laboratorios Almirall S.A. | NAPADISYLATE SALT OF 5- (2 - ((6- (2,2-DIFLUORO-2-PHENYLETOXI) HEXIL) AMINO) -1-HYDROXYETHYL) -8-HYDROXYCHINOLIN-2 (1H) -ONE AS ADRENERGIC RECEIVER AGONIST BETA2 . |
| ES2320961B1 (en) | 2007-11-28 | 2010-03-17 | Laboratorios Almirall, S.A. | DERIVATIVES OF 4- (2-AMINO-1-HYDROXYETHYL) PHENOL AS BETA2 ADRENERGIC RECEIVER AGONISTS. |
| EP2228368A1 (en) | 2009-03-12 | 2010-09-15 | Almirall, S.A. | Process for manufacturing 5-(2-{[6-(2,2-difluoro-2-phenylethoxy) hexyl]amino}-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one |
| EP2578570A1 (en) | 2011-10-07 | 2013-04-10 | Almirall, S.A. | Novel process for preparing 5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1(r)-hydroxyethyl)-8-hydroxyquinolin-2(1h)-one via novel intermediates of synthesis. |
| EP2641900A1 (en) | 2012-03-20 | 2013-09-25 | Almirall, S.A. | Novel polymorphic Crystal forms of 5-(2-{[6-(2,2-difluoro-2-phenylethoxy) hexyl]amino}-1-(R)-hydroxyethyl)-8-hydroxyquinolin-2(1h)-one, heminapadisylate as agonist of the ß2 adrenergic receptor. |
-
1975
- 1975-06-13 JP JP50072171A patent/JPS597706B2/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| JPS51149282A (en) | 1976-12-22 |
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