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WO1992012973A1 - Derive de chromane - Google Patents

Derive de chromane Download PDF

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Publication number
WO1992012973A1
WO1992012973A1 PCT/JP1992/000046 JP9200046W WO9212973A1 WO 1992012973 A1 WO1992012973 A1 WO 1992012973A1 JP 9200046 W JP9200046 W JP 9200046W WO 9212973 A1 WO9212973 A1 WO 9212973A1
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WO
WIPO (PCT)
Prior art keywords
group
lower alkyl
substituted
alkyl group
groups
Prior art date
Application number
PCT/JP1992/000046
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English (en)
Japanese (ja)
Inventor
Akira Shiozawa
Yukihiro Sagawa
Makoto Hosono
Atsuro Inubushi
Kazuhisa Narita
Masashi Iida
Original Assignee
Nippon Kayaku Kabushiki Kaisha
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 Nippon Kayaku Kabushiki Kaisha filed Critical Nippon Kayaku Kabushiki Kaisha
Publication of WO1992012973A1 publication Critical patent/WO1992012973A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to antihypertensive agents, therapeutic agents for angina pectoris, circulatory agents such as cerebral circulation improving agents, antiasthmatic agents, therapeutic agents for disorders associated with smooth muscle contraction of the uterus or urinary tract, and anticonvulsants for epilepsy.
  • circulatory agents such as cerebral circulation improving agents, antiasthmatic agents, therapeutic agents for disorders associated with smooth muscle contraction of the uterus or urinary tract, and anticonvulsants for epilepsy.
  • New chromane derivatives that are expected to grow.
  • the present invention has the general formula (1):
  • R 5 is a hydrogen atom, a lower alkyl group, 1 to 10 A lower alkyl group, a phenyl group, a substituted phenyl group, a pyridyl group, or a pyrimidinyl group substituted with one halogen), n is an integer of 0 or 1, and R 4 is a lower alkyl group, a cycloalkyl group having 1 to 10 carbon atoms, a phenyl group, a substituted phenyl group, a furyl group, a phenyl group, a pyridyl group, a pyrimidyl group, Lower alkyl groups substituted with 1 to 10 halogen groups, lower alkyl groups substituted with 1 to 10 halogen atoms, amino groups, lower alkyl groups
  • a lower alkyl group, —C ( X) 1 ( ⁇ ) friendship1 R (where X, n, and R 4 are the same as above) or a protecting group]. And a physiologically acceptable acid addition salt thereof.
  • a lower alkyl group is a straight-chain or branched alkyl group having 1 to 5 carbon atoms
  • a substituted phenyl group is, for example, each independently a lower alkyl group having 1 to 3 carbon atoms such as a methyl group.
  • Halogens such as chloro, methoxy, etc., alkoxy substituted with 1 to 3 carbon atoms, amino, or mono-substituted with nitro, etc .
  • Di-, tri-substituted phenyl groups, and -A phenyl group and a phenyl lower alkyl group substituted by 0CH2CH (0N02) are a lower alkyl group having 1 to 5 carbon atoms substituted by a phenyl group.
  • the substituted phenyl lower alkyl group means a lower alkyl group having 1 to 5 carbon atoms, which is substituted with the substituted phenyl group.
  • the lower alkylamino group refers to an amino group substituted with a lower alkyl having 15 to 15 carbon atoms.
  • the protecting group include general protecting groups such as an alkoxybenzyl group such as a tetrahydropyranyl group, a benzyl group, and a methoxybenzyl group; a benzyl group; Kid
  • Examples of the compound of the present invention include the following compounds.
  • Trans 1-6 (3—2-Tropoxypropylpyrusulfo 2) -3,4-Dihydro 2,2 —Dimethyl 1 4 — (2—Oxo 1 1 1 Pyrrolidinyl ) 1 2 H — benzo [b] pyran 1 3 — all 22.
  • the compound of the present invention has an asymmetric carbon atom at the 3- and 4-positions of the chroman ring (and, in some cases, in the substituents of the chroman ring), The body exists.
  • the target compound of the present invention includes each of the purely isolated optically active substances and their racemic substances. It also includes cis or trans isomers based on the 3rd and 4th configuration, but preferred coordination Is a trans isomer.
  • the compound of the present invention can be produced by the following production method.
  • the compound [I] of the present invention or a salt thereof is a 6-cyano form
  • C 6 H 5 C 0 NCH 3 group 2-oxo-11-pyrrolidinyl group, 2-oxo-11-piperidinyl group, 1,2—dihydro-2-oxo-1-1-pyridyl
  • A is a hydrogen atom, a nitro group, a lower alkyl group, a lower alkyl group substituted with 1 to 3 nitroxyl groups,
  • T i C l 0 Louis scan acids such as 4, 5-1 0 times moles, and preferred rather about 1-3 fold molar is used.
  • the reaction is usually performed in a mixed solvent of water and an acid. Examples of the acid include acetic acid and propionic acid.
  • the reaction temperature is not particularly limited, and the reaction is usually performed under cooling, at room temperature, or under heating. Specifically, the reaction is carried out for 1 to 48 hours from room temperature to around the boiling point of the solvent, but a reaction around the boiling point of the solvent gives good results.
  • An acid such as H 2 SO 4 or HCl is used in an amount of about 0.5 to 10 times, preferably about 1 to 3 times, of [II].
  • the reaction temperature is not particularly limited, and the reaction is usually performed under cooling, at room temperature, or under heating. Specifically, the reaction is carried out from room temperature to the boiling point of the solvent for 1 to 48 hours, but a reaction near the boiling point of the solvent gives good results.
  • the amount of an acid such as HC 1 gas or a Lewis acid such as BF 3 or Et 20 is about 0.5 to 10 moles, preferably about 1 to 3 moles relative to C III].
  • the reaction is usually performed in an alcohol solvent such as ethanol. Better results are obtained when the reaction temperature is near the boiling point of the solvent or when the temperature is higher than the boiling point of the solvent in a sealed tube.
  • the corresponding 6-ester [IV] is formed. [IV] is isolated by a conventional isolation method such as extraction, recrystallization, or chromatography.
  • An acid such as hydrochloric acid or hydrogen bromide or a base such as sodium hydroxide or potassium hydroxide is used in a large excess, preferably about 1 to 3 moles, based on the catalyst amount with respect to [IV]. Is done.
  • the reaction is usually carried out in an alcohol solvent such as ethanol or diethyl glycol or in water.
  • the reaction temperature is not particularly limited, and may range from room temperature to the vicinity of the boiling point of the solvent for 1 to 48 hours; (depends. [V] is used for the conventional isolation method such as extraction, recrystallization, or chromatography, etc.) Thus, it is isolated.
  • an amine such as nitroxylamin is added 1 to 10 times the obtained 6-chloroformyl compound. About 1 mole, preferably about 1 to 3 moles, is used.
  • the reaction is carried out in an organic solvent such as methylene chloride or chloroform and the reaction temperature is not particularly limited. The reaction is carried out at a temperature from room temperature to the boiling point of the solvent for 0.1 to 48 hours.
  • [I] is isolated by a conventional isolation method such as extraction, recrystallization, or chromatography.
  • an alcohol such as ethoxyethyl alcohol is preferably used in an amount of about 1 to 10 times the molar amount of the 6-chloroformyl compound. and rather the c reaction about 1-3 fold molar is used the reaction temperature around the boiling point of the chamber warm et solvent in an organic solvent menu Chi les emissions chloride, such as click throat Holm not particularly limited, at room temperature ⁇ 1 to 48 hours near the boiling point of the solvent.
  • Chi les emissions chloride such as click throat Holm not particularly limited, at room temperature ⁇ 1 to 48 hours near the boiling point of the solvent.
  • [I] can be isolated by a conventional isolation method such as extraction, recrystallization, or chromatography. [Root. 1 1 2]
  • This method utilizes the Grignard reaction, for example, the R 1 force in the compound [I] in the following scheme.
  • One CO (CH 2) a 0 N 02, etc. wherein the group represented by the above-mentioned partial structural formula (a) is 2-oxo-111-pyrrolidinyl group, 2 -oxo- 1 —piperidinyl group, 1 , 2 — Jihiro
  • This method includes the following methods.
  • the Grignard reagent can react with the cyano form [II].
  • the imino body is immediately hydrolyzed with an acid.
  • R 6 MgBr (here, R 6 ) represents a lower alkyl group, a cycloalkyl group having 11 to 10 carbon atoms, a phenyl group, a substituted phenyl group, or a substituted phenyl group. It is a aryl group, a phenyl group, a pyridyl group, a pyrimidyl group, or a lower alkyl group substituted with one to three protected hydroxyl groups.
  • the Grignard reagent represented by the formula (1) is used in an amount of about 0.5 to 5 times, preferably about 1 to 3 times by mole.
  • the reaction is carried out in an organic solvent such as anhydrous ether, anhydrous tetrahydrofuran, or anhydrous benzene or anhydrous toluene at room temperature to near the boiling point of the solvent for 1 to 48 hours.
  • a ketone form is obtained by hydrolyzing an imine form obtained as a reaction intermediate with an acid such as hydrochloric acid by an ordinary method. For example, as R 6 M g B r
  • P is a suitable protecting group, for example, a tetrahydrovinylyl group, a methoxybenzyl group, a t-butyldimethylsilyl group or the like. These protecting groups are deprotected by a conventional method, and the resulting alcohol is ditoxylated by a conventional method to obtain the compound [I] of the present invention.
  • the Grignard reagent may be reacted with the 6-chloroformyl form obtained in (4) in the presence of cuprous chloride in the same manner as in (a) above.
  • Examples of the compound obtained by the production method 2 include the compounds N 0.11, 26, and 41.
  • the compound [I] of the present invention or a salt thereof can also be produced by the following two methods.
  • This method involves acylating an amidine derivative [] obtained by reacting, for example, nitroxyshetilamine with an imidite [VIII] derived from the 6-cyano derivative [II].
  • an amidine derivative [] obtained by reacting, for example, nitroxyshetilamine with an imidite [VIII] derived from the 6-cyano derivative [II].
  • compound (II) is dissolved in anhydrous alcohol such as anhydrous methanol or anhydrous ethanol, hydrochloric acid gas is introduced under ice-cooling, and left in a refrigerator for 1 hour to 1 week.
  • the corresponding alcohol hydrochloride [VIII] used as a solvent is obtained.
  • This product is neutralized with sodium hydrogencarbonate, ammonia water, etc., and then the imidite [VIII] is reacted with, for example, 2-2-troxicetilamine.
  • the resulting amidine [IX] is converted to a normal acylation reaction condition, for example, with acetyl chloride or the like, in the presence of triethylamine, in an inert solvent such as black form. By doing so, the desired compound [I] of the present invention is obtained.
  • This method is based on N-cyanoimidate [ ⁇ ] obtained by reacting an orthoester [X] derived from 6-cyano isomer [II] with cyanamide or the like.
  • This product is reacted with cyanamide in the presence of about 1 to 5.0 moles of acetic anhydride at about 0.1 to 5.0 moles at 130 to 140 ° C to give N-cyanoimide. (XI) with good yield.
  • this [XI] with, for example, about 0.1 to 5.0 moles of nitroxyshetilamine, the desired compound [I] of the present invention can be obtained at a high yield.
  • the compound of the present invention has a potent vasoconstrictor ameliorating effect and is expected as a vasodilator.
  • test drug (1 0 one 8 ⁇ 3 X 1 0 - M ) were applied cumulatively in bus common ratio 3. Each specimen was finally confirmed for maximum relaxation by papaverine.
  • the content of the compound of the present invention in the preparation varies depending on the preparation, but is usually 0.1 to 100% by weight.
  • the dose is determined according to the age, weight, condition, purpose of treatment, etc. of the patient, but the therapeutic dose is generally 0.000 ⁇ ; 0.003 mg / day, 0.003 to 3000 mg / day by oral administration.
  • the phosphate buffer solution and the aqueous layer of saturated saline are combined, concentrated under reduced pressure, and methylene chloride is added to the concentrated residue for extraction.
  • Step 2 Transform obtained in step 1 3 — (4 — methoxybenziloxy) 1 6 — (1 — methinole 2 — nitroxy shecilo kisica rubonil) 1 4 — (2 — oxy So — 1 — pyrrolidinyl) 2H-benzo [b] pyran (449.5 mg, 0.85 mmo 1), 2, 3-dichloromethane 5, 6- Di-cyanone 4-benzoquinone (289.9 rag, 1.28 mmol) was reacted in the same manner as in Example 5 and worked up, followed by silica gel chromatography (development).
  • reaction solution is concentrated under reduced pressure, anhydrous tetrahydrofuran (5 ml) is added to the concentrated residue, and cuprous chloride (7.5 nig, 0.08 mmol) is added.
  • cuprous chloride 7.5 nig, 0.08 mmol
  • the solution was cooled on ice, and a solution of 3-methoxybenziloxypropirma gnecimubutate in tetrahydrofuran (3-methoxybenziloxypropizolebromide 0.96 g, magne 99.4 rag. (Prepared with 7.5 ml of anhydrous tetrahydrofuran) and stirred under ice-cooling for 1 hour. The reaction is stopped with water, and the reaction mixture is extracted with ethyl acetate.
  • the concentrated residue was purified by silica gel chromatography (developing solvent, ethyl acetate: hexane 2: 1), and trans- 3 — (4-methoxybenziloxy) — 6 — ⁇ 1-ase 1- (4-methoxybenzyl) butyl ⁇ 1- (2-oxo-111-pyrrolidinyl) -12H-benzo [b] pyran (962.4 mg) Get.
  • reaction mixture is cooled on ice, 0.1 N hydrochloric acid (5 ml) is added, and the methanol of the reaction mixture is distilled off under reduced pressure, followed by extraction with ethyl acetate. The organic layer is washed with a saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.

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

Abstract

L'invention se rapporte à un dérivé de chromane, représenté par exemple par la formule (I). Ce composé possède une forte activité d'ouverture des vannes à potassium et il est par conséquent susceptible d'être utilisé comme dépresseur des fibres lisses trachéales ou similaire.
PCT/JP1992/000046 1991-01-23 1992-01-22 Derive de chromane WO1992012973A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2142391 1991-01-23
JP3/21423 1991-01-23

Publications (1)

Publication Number Publication Date
WO1992012973A1 true WO1992012973A1 (fr) 1992-08-06

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PCT/JP1992/000046 WO1992012973A1 (fr) 1991-01-23 1992-01-22 Derive de chromane

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WO (1) WO1992012973A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8952009B2 (en) 2012-08-06 2015-02-10 Amgen Inc. Chroman derivatives as TRPM8 inhibitors
US9096527B2 (en) 2011-06-24 2015-08-04 Amgen Inc. TRPM8 antagonists and their use in treatments

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6112685A (ja) * 1984-06-22 1986-01-21 ビーチャム・グループ・ピーエルシー クロマン類及びクロメン類，それらの製法及びそれらを含む医薬組成物
JPS6143113A (ja) * 1984-07-31 1986-03-01 ビーチャム・グループ・ピーエルシー 医薬組成物
JPH02172984A (ja) * 1988-12-23 1990-07-04 Yamanouchi Pharmaceut Co Ltd クロマン誘導体

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6112685A (ja) * 1984-06-22 1986-01-21 ビーチャム・グループ・ピーエルシー クロマン類及びクロメン類，それらの製法及びそれらを含む医薬組成物
JPS6143113A (ja) * 1984-07-31 1986-03-01 ビーチャム・グループ・ピーエルシー 医薬組成物
JPH02172984A (ja) * 1988-12-23 1990-07-04 Yamanouchi Pharmaceut Co Ltd クロマン誘導体

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9096527B2 (en) 2011-06-24 2015-08-04 Amgen Inc. TRPM8 antagonists and their use in treatments
US8952009B2 (en) 2012-08-06 2015-02-10 Amgen Inc. Chroman derivatives as TRPM8 inhibitors

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