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WO1993018007A1 - Nouveau derive de carbostyrile - Google Patents

Nouveau derive de carbostyrile Download PDF

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Publication number
WO1993018007A1
WO1993018007A1 PCT/JP1993/000303 JP9300303W WO9318007A1 WO 1993018007 A1 WO1993018007 A1 WO 1993018007A1 JP 9300303 W JP9300303 W JP 9300303W WO 9318007 A1 WO9318007 A1 WO 9318007A1
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WO
WIPO (PCT)
Prior art keywords
hydroxy
naphthyl
aminoethyl
tetrahydro
group
Prior art date
Application number
PCT/JP1993/000303
Other languages
English (en)
Japanese (ja)
Inventor
Susumu Tsuchiya
Hiroaki Mori
Kouzou Hiratsuka
Noriko TAKENAWA
Kazuya OSAKA
Original Assignee
Tokyo Tanabe Company Limited
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 Tokyo Tanabe Company Limited filed Critical Tokyo Tanabe Company Limited
Priority to AU36487/93A priority Critical patent/AU3648793A/en
Publication of WO1993018007A1 publication Critical patent/WO1993018007A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/24—Oxygen atoms attached in position 8
    • C07D215/26—Alcohols; Ethers thereof

Definitions

  • the present invention is 3 2 - has a ⁇ Dorenari emissions receptor stimulating effect, and relates to weak novel carbostyril derivative action on the heart.
  • Propoterol having a carbostyril skeleton has been reported as a compound with a high ⁇ 2-adrenergic receptor stimulating activity and selectivity (Gianlob Ob Medicinal Chemistry, 19, 9 No., 1138-111, pp. 197).
  • an object of the present invention is to provide a compound having excellent selectivity for ⁇ 2 -drainine receptor (particularly, having a weak effect on the heart). Disclosure of the invention
  • OY is a lower alkoxy group optionally protected by a hydroxyl group or a phenyl group or a protected hydroxyl group
  • ⁇ is a hydrogen atom, or a hydroxyl group as a substituent, or an alkoxy group having 1 to 5 carbon atoms.
  • the dashed lines at positions 3 and 4 represent saturated or double bonds at positions 3 and 4.
  • the compound (I) of the present invention has two asymmetric carbons, there are four kinds of optical isomers.
  • the present invention includes all of these four optical isomers and mixtures thereof in its scope.
  • ⁇ (RR) isomer J and “(RS) isomer” are described before the coordination of the asymmetric carbon at the 5-position substituent of CH 2 (OH) of carbostyril.
  • the coordination of the asymmetric carbon at the 2-position of the tetrahydronaphthyl group is shown below.
  • the configuration of the asymmetric carbon at one CH (OH) position is the (R) configuration
  • the configuration of the asymmetric carbon at the 2-position of the tetrahydronaphthyl group is (S ) Indicates coordination.
  • the compound (I) having a double bond at the 3- and 4-positions can take two types of tautomers which can be interconverted as shown in the following formula. It includes any of these tautomers.
  • the salt of the compound (I) of the present invention is not particularly limited as long as it is a pharmacologically acceptable salt.
  • the present invention also includes hydrates of the compound (I) of the present invention and a pharmacologically acceptable salt thereof. It is.
  • the compound (I) of the present invention can be produced according to the following steps 1 to 9.
  • the adduct (IV) is produced by subjecting the epoxy compound (II) and the amino compound (III) to a reaction without a solvent or using an appropriate solvent.
  • the reaction solvent include alcohols such as methanol, ethanol, and isopropanol, chloroform, dimethyl sulfoxide, and the like, but are not particularly limited.
  • the reaction temperature is from 110 to 120, preferably from 20 to 90. Good to do in C. Eight
  • OY is a lower group which may be substituted with a hydroxyl group or a phenyl group.
  • Alkoxy is a group or a protected hydroxyl group
  • Z is represents a hydroxyl group, containing 1-5 alkoxy group having a carbon or an O CH 2 one A group, as a hydrogen atom or, or a substituent
  • A is lower alkoxy as substituent It represents a carbonyl group, an N-substituted or unsubstituted rubamoyl group or a lower alkoxycarbonyl group, or a linear alkylene chain having 1 to 4 carbon atoms and having a hydroxyl group.
  • the protecting group Y various protecting groups usually used for protecting a hydroxyl group can be used, and a benzyl group is particularly preferable.
  • Removal of the protecting group at the 8-position hydroxyl group of the adduct (IV) can be carried out by a conventional method.
  • Y is a benzyl group
  • catalytic reduction or CTH catalytic transfer nodrogenesis
  • (V) is produced by de-benzylation by the transfer hydrogenation method.
  • reaction solvent for example, alcohols such as methanol, ethanol, and isopropanol, tetrahydrofuran, water, and a mixed solvent thereof are used, but are not particularly limited.
  • the reaction is preferably carried out under normal pressure at 0 to 100 ° C, especially at 20 to 40.
  • an excess of ammonium formate preferably 50 to 300 times, is used in the presence of a catalyst such as palladium-carbon (Pd-C) using alcohols such as methanol and ethanol as a reaction solvent.
  • a catalyst such as palladium-carbon (Pd-C) using alcohols such as methanol and ethanol as a reaction solvent.
  • the reaction is carried out at normal temperature and normal pressure by adding molar ammonium formate.
  • OY represents a protected hydroxyl group, preferably a benzyl group
  • Z represents a hydrogen atom, or a hydroxyl group, an alkoxy group having 1 to 5 carbon atoms, or one OCH 2 —A group as a substituent.
  • A has the same meaning as described above.
  • the dashed lines at positions 3 and 4 indicate that positions 3 and 4 are saturated or double bonds.
  • (VII) can be produced.
  • the reaction solvent include, but are not particularly limited to, methylene chloride, chloroform and the like.
  • the reaction is preferably carried out at 170 to 30 ° C, especially at 130 to 20 ° C.
  • the alkylation of the adduct (VII) (where the dotted lines at positions 3 and 4 indicate that the positions 3 and 4 are saturated or double bonds) is carried out at room temperature in an alcohol solution such as methanol as a reaction solvent.
  • VIII can be produced by methylation using diazomethane in the above.
  • Step 5 (XI) (where the dotted lines at positions 3 and 4 are saturated or double bonds at positions 3 and 4, R 2 is a hydrogen atom or a lower alkyl group, and n represents an integer of 1 to 5) Is prepared by reacting the ester group in the side chain of (IX) with an excess of amide (X).
  • the reaction solvent alcohol such as methanol or ethanol is used, and the reaction is preferably carried out at 50 to 150 ° C, particularly 70 to 100 ° C, in a sealed tube.
  • the compound of the general formula (I) is a mixture of four different optical isomers. Each optical isomer can be produced by the method shown below (Steps 6 to 9).
  • Epoxy (II) and optically active amine (XII) (Y is benzyl group) Wherein z has the same meaning as described above) under the same conditions as in Step 1 to produce the adduct (XIII).
  • the (XIII) is an optically active (2R) -amino form (XII)
  • a diastereomer mixture of the (RR) form and the (SR) form is obtained
  • the optically active (2S) -amino form (XIII) is obtained.
  • XII) is used, a diastereomer mixture of (RS) form and (SS) form can be produced.
  • optically active acylating agent (XIV) which is a mixture of two diastereomers of the (RR) form and the (SR) form, is converted to an optically active acylating agent (XIV) to form a diacyl form (XV) (Y is a benzyl group, and Z is Having the same meaning) It can be separated by gel column chromatography.
  • the optically active acylating agent (XIV) include L-proline derivatives and camphorsulfonic acid chloride.
  • L-proline derivatives (S)-(-1) -N- (trifluoroacetyl) prolyl chloride Is particularly preferred.
  • the reaction solvent methylene chloride, chloroform, or the like is used, but is not particularly limited.
  • the reaction is preferably carried out at a temperature of from 170 to 30 ° C, especially from 0 to 10 ° C.
  • the optically active acylating agent (XIV) is required to be twice as much as (XIII
  • An alcohol such as methanol or ethanol is used as a reaction solvent, but is not particularly limited.
  • the reaction is preferably carried out at 130 to 50 ° C, especially at 10 to 30 ° C.
  • the debenzylation of the pure optical isomer (XVI) [(13 ⁇ 413 ⁇ 4) -isomer and (51-isomer) can be performed by the CTH method used in step 2. From the (RR) -isomer to the (RR) -isomer (XV II ) And (SR) form to (SR) form (XV II).
  • optically active (RS) form and (SS) form (XVII) can be produced.
  • the compound of the present invention has an excellent and selective 2- adrenergic receptor stimulating action.
  • the pharmacological actions of representative compounds of the present invention are shown below.
  • a guinea pig tracheal muscle was excised by a conventional method to prepare a specimen. Preparation This mixed gas (95% 0 2, 5% C0 2) under aeration, Sakae kept at 37 e C nutrient solution (Tyrode's solution, 0. 03MM Asukorubin acid, 0. 03mM EDTA, IOM Fuwentorami down) the filled And suspended in an organbath with a load of 1 g. The test compound was cumulatively added to the feeding tank at 10 minute intervals, and the change in tracheal muscle relaxation due to the addition of the test compound was recorded on a recorder. The tracheal muscle dilation was expressed as the molar concentration (EC 5 ) of the test compound at which 50% relaxation relative to the maximum relaxation by isoproterenol occurred.
  • EC 5 molar concentration
  • Example 2 By a conventional method, were excised right atrium of the guinea pig, a mixed gas (95% 0 2, 5% C0 2) under aeration, Krebs solution kept at at 37, 0. 03mM Asuko Rubin acid, 0. 0 3 mM EDTA, The patient was suspended in a nutrient tank (organbath) filled with 10 M pentamine, loaded with 0.5 g, and the systolic force and the number of beats were recorded on a recorder. The test drug was cumulatively added to the nutrient tank at 2.5 minute intervals, and the EC 25 (25% enhancement value) was determined from the pulse rate before and after administration.
  • organbath a nutrient tank
  • Ratio is a value obtained by dividing the value of the right atrium (EC 25 ) by the value of the tracheal muscle (EC S ), relative to the value of pro-power terol.
  • Example 5 8-benzyloxy-5- [1-hydroxy-2- (7-ethoxy-1,2,3,4-tetrahydro-1-naphthyl) aminoethyl] carbostyryl (0.36 g) methanol (20 ml) Add ammonium formate (1.0 g) to the solution and stir at room temperature for 10 minutes. 10% Pd-C (0.10 g) is added to the reaction solution, and the mixture is stirred at room temperature for a while. After confirming the disappearance of the raw materials, the catalyst is filtered off, water is added to the residue, and the mixture is purified by ODS short column chromatography (0DS: octadecylsilyl, reverse-phase silica gel column chromatography).
  • the target substance is adsorbed to ODS by flowing only with ion-exchanged water as an eluent.
  • the column was washed with a sufficient amount of ion-exchanged water, and the desired product was eluted with methanol to give 8-hydroxy-5- [1-hydroxy2- (7-ethoxy-1,2,3,3) as an oil. 4-tetrahydro-2-naphthyl) aminoethyl] carbostyryl was obtained in an amount of 0.10 g (yield: 34%).
  • hydrochloride was prepared in accordance with the method of Example 5, and 8-hydroxy-5- [1-hydroxy-2- (7-hydroxy-1,2,3,4-tetrahydro-12-naphthyl) aminoethyl] carboethyl was used. 6 Omg (yield: 85%) of styryl hydrochloride is obtained as a light tan powder.
  • hydrochloride was prepared according to the method of Example 5 to give 8-methoxy-5- [1-hydroxy-2- (7-methoxy-1,2,3,4-tetrahydro-2-naphthyl) aminoethyl] carbostyryl. 53 mg (yield: 82%) of hydrochloride is obtained as a pale yellow powder.
  • hydrochloride was prepared according to the method of Example 5, and 8-hydroxy-5- [1-hydroxy-2— (1,2,3,4-tetrahydro-2-naphthyl) aminoethyl] carbostyril hydrochloride was used. Get.
  • hydrochloride was prepared according to the method of Example 5, and 8-hydroxy-5- [1—hydroxy-2- (7-ethoxycarbonylmethoxy-1,2,3,4-tetrahydroxy-2-naphthyl) aminoethyl ] Carbostyril hydrochloride is obtained.
  • hydrochloride was prepared according to the method of Example 5, and 8-hydroxy-5- [1-hydroxy-2- (7-potassium rubamoyl methoxy-1,2,3,4-tetrahydro-2-naphthyl) aminoethyl ] Carbostyril.
  • the hydrochloride is obtained as a light tan powder.
  • hydrochloride was prepared according to the method of Example 5 to give 8-hydroxy-5- [1-hydroxy-2- (7-N-ethylcarbamoylmethoxy-1,2,3,4-tetrahydro-2-naphthyl). Amaminoethyl] carbostyryl hydrochloride is obtained as a light tan powder.
  • hydrochloride was prepared according to the method of Example 5 to give 8-hydroxy-5- [1-hydroxy-2- (7-ethoxycarbonylpropoxy-1,2,3,4-tetrahydroxy-2-naphthyl) aminoethyl] Obtain carbostyryl 'hydrochloride.
  • hydrochloride was prepared according to the method of Example 5, and 8-hydroxy-5- [1-hydroxy-2- (7-ethoxyquincarbonylbutoxy-1,2,3,4-tetrahydro-2-naphthyl) amino was prepared. Noethyl] carbostyryl hydrochloride is obtained.
  • 8-Benzyloxy-5-oxylanylcarbostyril (0.46 g) and 2-amino-7-ethoxycarbonylpentyloxytetralin (1.45 g) give 8-benzyloxy-5— [1-hydroxy2 — (7-Ethoxycarbonylpentyloxy-1,2,3,4-tetrahydro-1--2-naphthyl) aminoethyl] carbostyryl is obtained in an amount of 0.52 g (yield: 55%).
  • hydrochloride was prepared according to the method of Example 5, and 8-hydroxy-5- [1-hydroxy-2- (7-ethoxyquincarbonylpentyloxy 1.2,3,4-tetrahydro-2-naphthyl) was used. Aminoethyl] carbostyryl * hydrochloride is obtained.
  • Example 23 8—Benzyloxy 5 — [1 —Hydroxy 2 — (7- (5-Hydroxypentyloxy) 1-1,2,3,4-Tetrahydroxy 2-naphthyl) aminoethyl] carbostyril (Example 2) (Compound 2) (0.25 g) from 8—hydroxy-1 5 — [1 —hydroxy-1 2 — (7- (5-hydroxypentyloxy) 1 1, 2,3,4— There are obtained 148 mg (yield: 72%) of tetrahydro 2-naphthyl) aminoethyl] carbostyril.
  • hydrochloride was prepared in accordance with the method of Example 5, and 8-hydroxy-5- [1-hydroxy-2- (7- (5-hydroxypentyloxy) -11,2,3,4-tetrahydro-2-naphthyl) was used. ) Aminoethyl] carbostyryl. Hydrochloride is obtained.
  • hydrochloride was prepared according to the method of Example 5 to give 8-hydroxy-5-[(1RS) -hydroxy (2R) — (7-methoxy-1,2,3,4-tetrahydro-2-naphthyl) Aminoethyl] carbostyryl (a mixture of two optical isomers) is obtained.
  • Example 2 The debenzylation of the compound of 7 was carried out by the CTH method, and 8-hydroxy-5-[(1RS) -hydroxy (2S)-(7-methoxy-1,2,3,4 —Tetrahydro 2-naphthyl) aminoethyl] carbostyryl hydrochloride (mixture of two optical isomers).
  • the catalyst is filtered off, water is added to the residue, and the mixture is purified by ODS short column chromatography. That is, first, only the ion-exchanged water is flown as an eluent, and the target substance is adsorbed to ODS. Next, the column was washed with a sufficient amount of ion-exchanged water, and the desired product was eluted with methanol to give 8-hydroxy-5-[(1S) -hydroxy (2R)-(7-medium) as an oil. Toxi 1,2,3,4-tetrahydro 2-naphthyl) aminoethyl] carbostyril 59 mg (yield: 74%) is obtained as a yellow powder.
  • Example 3 According to the method of 1, 8-benzyloxy 5-([1R) -hydroxyl (2R)-(7-methoxy-1,2,3,4-tetrahydro-2-naphthyl) Amaminoethyl] carbostyryl (106 mg) from 8-hydroxy-5-[(1R) -hydroquinine-1 (2R) — (7-methoxy1,2,3,4-tetrahydro-2-naphthyl) [Aminoethyl] carbostyryl is obtained as a pale yellow powder (52 mg, yield: 62%).
  • the catalyst After confirming the disappearance of the raw materials on TLC, the catalyst is filtered off, ion-exchanged water is added to the residue, and the mixture is purified by 0 DS short column chromatography. Immediately, the solution is started as a syneresis, and is flushed with only ion-exchanged water to adsorb the target substance to ODS.
  • Example 3 According to the method of 7, from 8-benzyloxy 5-hydroxyxylanicarbarstyryl (0.5 g) and (S) -2-amino 7-ethoxycarbonyl methoxytetralin (1.0 g). 8—Benzyloxy 5 — [(1RS) —Hydroxy (2S) — (7-Ethoxycarbonylmethoxie 1,2,3,4-tetrahydro 2-naphthyl) aminoethyl] Carbostyril as colorless oil 0.53 g (yield: 57%).
  • Example 4 8-Benzyloxy-5- [1-hydroxy-2- (6-methoxy-1,2,3,4-tetrahydro-2-naphthyl) aminoethyl] carbostyril obtained in 1 (0.15 g) Debenzylation was carried out according to the method of Example 10 (CTH method) using 8-hydroxy-5- [1'-hydroxyl 2- (6-methoxy-1,2,3,4-tetrahydro-2-). Naphthyl) aminoethyl] Carbostyril was obtained in an amount of 108 mg (yield: 95%).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Quinoline Compounds (AREA)

Abstract

Dérivé de carbostyrile répondant à la formule (I), et intervenant de manière sélective sur le récepteur de β2-adrénaline, et son sel pharmaceutiquement acceptable. Dans ladite formule (I), -OY représente hydroxy, alcoxy inférieur ou hydroxy protégé; Z représente hydrogène, hydroxy, alcoxy ou -OCH2-A; A représente alcoxycarbonyle inférieur, carbamoyle éventuellement N-substitué ou alkylène linéaire substitué par hydroxy ou alcoxycarbonyle inférieur; et la ligne pointillée entre les positions 3 et 4 indique que la liaison entre celles-ci est simple ou double.
PCT/JP1993/000303 1992-03-13 1993-03-12 Nouveau derive de carbostyrile WO1993018007A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU36487/93A AU3648793A (en) 1992-03-13 1993-03-12 Novel carbostyril derivative

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP4/54733 1992-03-13
JP5473392 1992-03-13

Publications (1)

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WO1993018007A1 true WO1993018007A1 (fr) 1993-09-16

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WO2000075114A1 (fr) * 1999-06-04 2000-12-14 Novartis Ag Agonistes du recepteur beta 2-adrenergique
US6664424B2 (en) 1998-07-01 2003-12-16 Warner-Lambert Company Stereoisomers with high affinity for adrenergic receptors
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JP7676355B2 (ja) 2019-07-01 2025-05-14 キュラセン セラピューティクス インコーポレイテッド βアドレナリンアゴニストおよびその使用方法

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