WO1999009001A1 - Derives de phenylethanolaminotetraline et bronchodilatateurs - Google Patents

Derives de phenylethanolaminotetraline et bronchodilatateurs Download PDF

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Publication number
WO1999009001A1
WO1999009001A1 PCT/JP1998/003545 JP9803545W WO9909001A1 WO 1999009001 A1 WO1999009001 A1 WO 1999009001A1 JP 9803545 W JP9803545 W JP 9803545W WO 9909001 A1 WO9909001 A1 WO 9909001A1
Authority
WO
WIPO (PCT)
Prior art keywords
hydroxy
carbon atom
acid
acceptable salt
phenylethanolaminotetralin
Prior art date
Application number
PCT/JP1998/003545
Other languages
English (en)
Japanese (ja)
Inventor
Tetsuro Tamai
Nobuyuki Tanaka
Hideyuki Muranaka
Ken Kikuchi
Naoyuki Tsutsumi
Masuo Akahane
Original Assignee
Kissei Pharmaceutical Co., Ltd.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Kissei Pharmaceutical Co., Ltd. filed Critical Kissei Pharmaceutical Co., Ltd.
Priority to AU85620/98A priority Critical patent/AU8562098A/en
Publication of WO1999009001A1 publication Critical patent/WO1999009001A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/18—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides
    • C07C235/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • the present invention relates to phenylethanolaminotetralin derivatives useful as pharmaceuticals and pharmacologically acceptable salts thereof.
  • substituted phenylethanolaminotetralin derivative for example, a compound having an intestinal-selective sympathomimetic action and an anti- pollakiuria action,
  • the (S) -powered carbon atom in the formula represents a carbon atom in the S configuration, and the carbon atom to which (R) is attached has the same meaning as described above.)
  • Japanese Patent Publication No. 6-506666, No. 6-5006955 Japanese Patent Publication No. 6-506666, No. 6-5006955. But force s et al., These compounds are marked / 3 3 - having adrenergic activity /? 3—A is a drenerin receptor stimulant.
  • the present inventors have conducted intensive studies to find compounds useful as bronchodilators.
  • certain phenylethanolaminotetralin derivatives in which the 3- and 4-positions of the phenyl moiety have been substituted and the 7-position of the tetralin moiety has been substituted with a carbamoylalkoxy group have potent and selective bronchodilator effects.
  • the present invention provides a compound represented by the general formula
  • A is a lower alkylene group
  • B is an amino group, a di-lower alkylamino group or a 3- to 7-membered alicyclic amino group which may contain an oxygen atom
  • n is 1 or 2
  • R indicates the carbon atom in the R configuration.
  • a pharmaceutically acceptable salt thereof .
  • the present invention relates to a medicament comprising a phenylethanolaminotetralin derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof.
  • the present invention relates to a bronchodilator comprising, as an active ingredient, a phenylethanolaminotetralin derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof.
  • the present invention provides an airway obstruction disorder or a bronchial stenosis disorder caused by administering a phenylethanolaminotetralin derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof. It relates to a method for preventing or treating a disease caused by the disease.
  • the present invention relates to a phenyletano represented by the general formula (I) for the manufacture of a medicament for preventing or treating a disease caused by an airway obstructive disorder or a bronchial stenosis disorder.
  • the present invention relates to the use of a phenylethanolaminotetralin derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof as a bronchodilator.
  • the present invention provides an airway obstructive agent comprising using a phenylethanolaminotetralin derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient of a drug.
  • the present invention relates to a method for producing a medicament for preventing or treating a disease caused by a disorder or a bronchial stenosis disorder.
  • the di-lower alkylamino group means a linear or linear alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group and an isopropyl group.
  • the lower alkylene group includes a methylene group, an ethylene group and Refers to a linear alkylene group having 1 to 3 carbon atoms in the trimethylene group.
  • Examples of the 3- to 7-membered alicyclic amino group which may contain an oxygen atom include a 1-pyrrolidinyl group, a piperidino group, and a morpholino group.
  • the compound represented by the general formula (I) of the present invention can be produced as follows.
  • the compound represented by the general formula (I) of the present invention has the general formula
  • R 1 is a hydroxyl-protecting group, and n and (R) the carbon atom to which the force is applied have the same meaning as described above);
  • R 1 n and the (R) -enforced carbon atoms have the same meanings as described above, and, if desired, alcoholic reaction with a reagent such as trifluoroacetic anhydride. After protecting the hydroxyl group and the amino group, the obtained phenol compound is represented by the general formula
  • optically active mandelic acid derivative represented by the general formula (II) used as a starting material in the production method can be obtained by producing according to a method described in a literature or a method similar thereto.
  • R 1 and n in the formula have the same meanings as described above, and then obtained optically according to a conventional method using a resolving reagent such as optically active 1- (1-naphthyl) ethylamine. It can be manufactured by dividing.
  • the amine compound represented by the formula (III) used as a starting material in the production method can be produced by a method described in a literature or a method similar thereto (for example, Eur. J. Med. C. hem., No. 29, 259-2
  • the compound of the present invention obtained by the above production method can be easily isolated and purified by a conventional separation means such as a fractional recrystallization method, a purification method using column chromatography, and a solvent extraction method.
  • the phenylethanolaminotetralin derivative represented by the general formula (I) of the present invention can be converted into a pharmacologically acceptable salt by a conventional method.
  • salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, menthoxyacetic acid, methanesulfonic acid, benzenesulfonic acid, p-Toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, lingic acid, carbonic acid, glutamic acid, aspartic acid, etc.
  • Salts with inorganic bases such as acid addition salts, sodium salts and potassium salts can be mentioned.
  • the compound represented by the general formula (I) of the present invention also includes a solvate with a pharmaceutically acceptable solvent such as hydrated ethanol.
  • the bronchodilator effect (? 2 -adrenergic receptor stimulating effect) of the compound represented by the general formula (I) of the present invention can be measured by an in vitro test using an isolated trachea of a guinea pig described below,
  • Compound 1 described in Example 1 is 2.
  • 5 X 10 _10 molarity indicates histamine 1.
  • Example 2 compound described 2 the EC 50 of value was 5.
  • the compound of the present invention is an excellent compound having a very strong bronchodilator effect.
  • the effect of the compound represented by the above general formula (I) of the present invention on the heart is measured by an in vitro test using an isolated atria of a guinea pig described below.
  • the EC ⁇ 20 value of Compound 2 was 6.6 ⁇ 10— ° molar.
  • the compound of the present invention is a compound having a very weak cardiac action (adrenergic receptor stimulating action) as compared with the above bronchodilator action (/? 2— adrenergic receptor stimulating action).
  • the compound of the present invention has a very strong bronchodilator effect, has a weak side effect on the heart such as tachycardia, reduces the burden on the heart, and is useful as a powerful and selective bronchodilator. . Therefore, the compounds of the present invention are very useful for prevention or treatment of diseases caused by airway obstructive disorders such as bronchial asthma or bronchial stenosis disorders.
  • the compound represented by the general formula (I) of the present invention is a very stable compound and has excellent storage stability.
  • an appropriate pharmaceutical composition for example, a tablet or powder It is orally or parenterally administered as fine granules, granules, capsules, inhalants, injections and the like.
  • These pharmaceutical compositions can be prepared by a pharmaceutical method performed in a general preparation, by using carriers, excipients and other additives commonly used for pharmaceuticals.
  • the dosage is determined appropriately according to the gender, age, weight, degree of symptoms, etc. of the target patient.In the case of oral administration, it is generally 1 to 1000 mg per adult per day. In the case of parenteral administration (injection, etc.), the dosage is generally in the range of 0.01 to 100 mg per adult per day, in single or divided doses. In the case of inhalation, the dose is generally in the range of 0.05 to 50 mg / adult. [Industrial applicability]
  • the compound of the present invention has a strong and selective bronchodilator effect, and is very suitable for preventing or treating diseases caused by airway obstructive disorders such as bronchial asthma or bronchial stenosis disorders.
  • the reaction mixture was added to a solution of 21.6 g of getyl oxalate in 200 ml of tetrahydrofuran under stirring at 80 ° C under an argon atmosphere and allowed to react for 1 hour.Then, 100 ml of ethanol and 1.40 g of sodium borohydride in 100 ml of ethanol were successively added. added. The mixture was stirred at ⁇ 30 ° C. for 30 minutes, 8.26 ml of acetic acid was added, and after stirring for 5 minutes, a solution of 14.8 g of hydrogen bicarbonate in 50 ml of water was added to the reaction mixture, and the mixture was concentrated under reduced pressure.
  • Acetamide (7.4 g) is dissolved in tetrahydrofuran (100 ml), and a 10 molar borane dimethyl sulfide complex (4.2 ml) is added at room temperature. The mixture was stirred under reflux for 4 hours.
  • the reaction solution was added to a solution of 10.8 g of getyl oxalate in 300 ml of tetrahydrofuran under stirring at 195 ° C under an argon atmosphere, and reacted for 1 hour. Then, 200 ml of ethanol and 755 mg of sodium borohydride were sequentially added. After stirring the reaction solution at -35 ° C for 45 minutes, 4.70 ml of acetic acid was added, and after stirring for 15 minutes, a solution of 6.9 g of sodium hydrogen carbonate in 300 ml of water was added, and the reaction solution was concentrated under reduced pressure. The residue was extracted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate.
  • reaction mixture was neutralized by adding 50 ml of a 1N aqueous sodium hydroxide solution under ice-cooling and stirring, concentrated to dryness under reduced pressure, methylene chloride was added to the residue, and the insoluble matter was removed by filtration.
  • Atria of male H art 1 ey guinea pigs (body weight 450-600 g) were excised and subjected to experiments according to the Magnus method. Specimens were suspended in a 37 ° C K rebs-Hense 1 eit solution aerated with a mixed gas containing 95% oxygen and 5% carbon dioxide and loaded with 0.5 g. Automatic pulsations were recorded on the rectogram via a tension transducer. The drug concentration at which the test drug was added and the heart rate was increased 20 times per minute was evaluated as ⁇ 2 () value.

Abstract

L'invention concerne des dérivés de phényléthanolaminotétraline représentés par la formule générale (I) ainsi que leurs sels acceptables sur le plan pharmacologique, lesquels présentent des effets bronchodilatateurs puissants et sélectifs et sont hautement utiles en tant que bronchodilatateurs, formule dans laquelle A représente alkylène inférieur; B représente amino, di(alkyle inférieur)amino ou amino alicyclique à 3 à 7 éléments, contenant facultativement de l'oxygène; n représente un nombre entier égal à 1 ou 2; et les atomes de carbone fournis avec (R) ont chacun la configuration R.
PCT/JP1998/003545 1997-08-19 1998-08-10 Derives de phenylethanolaminotetraline et bronchodilatateurs WO1999009001A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU85620/98A AU8562098A (en) 1997-08-19 1998-08-10 Phenylethanolaminotetralin derivatives and bronchodilators

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP9/259233 1997-08-19
JP25923397 1997-08-19

Publications (1)

Publication Number Publication Date
WO1999009001A1 true WO1999009001A1 (fr) 1999-02-25

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1998/003545 WO1999009001A1 (fr) 1997-08-19 1998-08-10 Derives de phenylethanolaminotetraline et bronchodilatateurs

Country Status (4)

Country Link
AU (1) AU8562098A (fr)
CO (1) CO4960653A1 (fr)
WO (1) WO1999009001A1 (fr)
ZA (1) ZA987425B (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6046192A (en) * 1996-04-12 2000-04-04 Kissei Pharmaceutical Co., Ltd. Phenylethanolaminotetralincarboxamide derivatives
WO2000075114A1 (fr) * 1999-06-04 2000-12-14 Novartis Ag Agonistes du recepteur beta 2-adrenergique

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0770013A (ja) * 1993-05-28 1995-03-14 Sanofi Sa β３ −アドレナリン作動薬として作用する｛（７Ｓ）−７−［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチルアミノ］−５，６，７，８−テトラヒドロナフタレン−２−イルオキシ）酢酸及びその薬学的に許容されうる塩、並びにそれらが存在する薬学的組成物及び研究室用試薬
WO1997030023A1 (fr) * 1996-02-19 1997-08-21 Kissei Pharmaceutical Co., Ltd. Derives de phenylethanolaminotetralinecarboxamide 3,4-disubstitue
JPH09255637A (ja) * 1996-03-27 1997-09-30 Kissei Pharmaceut Co Ltd ３，４−ジ置換フェニルエタノールアミノテトラリンカルボン酸誘導体

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0770013A (ja) * 1993-05-28 1995-03-14 Sanofi Sa β３ −アドレナリン作動薬として作用する｛（７Ｓ）−７−［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチルアミノ］−５，６，７，８−テトラヒドロナフタレン−２−イルオキシ）酢酸及びその薬学的に許容されうる塩、並びにそれらが存在する薬学的組成物及び研究室用試薬
WO1997030023A1 (fr) * 1996-02-19 1997-08-21 Kissei Pharmaceutical Co., Ltd. Derives de phenylethanolaminotetralinecarboxamide 3,4-disubstitue
JPH09255637A (ja) * 1996-03-27 1997-09-30 Kissei Pharmaceut Co Ltd ３，４−ジ置換フェニルエタノールアミノテトラリンカルボン酸誘導体

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6046192A (en) * 1996-04-12 2000-04-04 Kissei Pharmaceutical Co., Ltd. Phenylethanolaminotetralincarboxamide derivatives
US9040559B2 (en) 1999-04-06 2015-05-26 Novartis Ag BETA2-adrenoceptor agonists
WO2000075114A1 (fr) * 1999-06-04 2000-12-14 Novartis Ag Agonistes du recepteur beta 2-adrenergique
US6878721B1 (en) 1999-06-04 2005-04-12 Novartis Ag Beta2-adrenoceptor agonists
KR100718615B1 (ko) * 1999-06-04 2007-05-16 노파르티스 아게 베타２-아드레날린성 촉진제
US7622483B2 (en) 1999-06-04 2009-11-24 Novartis Ag β2-adrenoceptor agonists
US7820694B2 (en) 1999-06-04 2010-10-26 Novartis Ag Beta-2-adrenoreceptor agonists
CZ302403B6 (cs) * 1999-06-04 2011-05-04 Novartis Ag Agonisté beta-2-adrenoceptoru
EP2332915A1 (fr) 1999-06-04 2011-06-15 Novartis AG Agonistes du beta-2-adrenorecepteur

Also Published As

Publication number Publication date
AU8562098A (en) 1999-03-08
CO4960653A1 (es) 2000-09-25
ZA987425B (en) 1999-02-22

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