WO1987005020A1 - Derives de 3,4-dihydro-2h-benzopyranne et leur usage medicinal - Google Patents

Derives de 3,4-dihydro-2h-benzopyranne et leur usage medicinal Download PDF

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Publication number
WO1987005020A1
WO1987005020A1 PCT/JP1987/000106 JP8700106W WO8705020A1 WO 1987005020 A1 WO1987005020 A1 WO 1987005020A1 JP 8700106 W JP8700106 W JP 8700106W WO 8705020 A1 WO8705020 A1 WO 8705020A1
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Prior art keywords
hydroxy
tetramethyl
dihydro
benzopyran
ethyl
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PCT/JP1987/000106
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English (en)
Japanese (ja)
Inventor
Katsushi Eziri
Koichi Kanehira
Manzo Shiono
Yoshiji Fujita
Jhoji Yamahara
Yutaka Maruyama
Michio Terasawa
Hiroshi Ochi
Tetsuya Tahara
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Kuraray Co., Ltd.
Yoshitomi Pharmaceutical Industries, Ltd.
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Application filed by Kuraray Co., Ltd., Yoshitomi Pharmaceutical Industries, Ltd. filed Critical Kuraray Co., Ltd.
Publication of WO1987005020A1 publication Critical patent/WO1987005020A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • 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
    • C07D405/06—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 linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to a novel compound having a chroman skeleton useful as a medicament and a medicinal use thereof.
  • an object of the present invention is to provide a novel compound having an excellent inhibitory activity on 5-boxoxygenase action and having a highly safe chroman skeleton, and an action of 5-lipoxygenase. in addition to the inhibitory activity anti ⁇ les.! the regulation first working is to provide Kohi static Mi down action, lipid peroxidation said chemical preventing action, a novel compound that Yusuke also pharmacological actions such as inhibition of platelet aggregation.
  • Another object of the present invention is to provide a pharmaceutical composition containing the novel compound and a method for treating various diseases by administering the novel compound. Disclosure of the invention
  • n represents an integer of 1, 2 or 3
  • R is R 2 ⁇ - ⁇
  • And represents a nitrogen heterocyclic group selected from the group consisting of N, ", and, wherein R 1 and R 2 are each a hydrogen atom or an aralkyl group which may have a substituent, an aralkyl group, or an aralkyl group.
  • R 1 and R 2 are each a hydrogen atom or an aralkyl group which may have a substituent, an aralkyl group, or an aralkyl group.
  • R 3 represents a hydrogen atom or an alkyl group.
  • 3,4—Dihydro-2H—benzopyrane derivatives and their pharmacologically acceptable salts [hereinafter, these compounds are referred to as 3,4-dihydro 2H—benzopyrane derivatives (I )), 2 consisting of at least one therapeutically effective amount of 3,4-dihydro-2H-benzoviran derivative (I) and a pharmaceutically acceptable excipient.
  • 5—Riboxygenase action This is achieved by providing a method for treating a disease caused by at least one of lugi action, histamine action, lipid peroxidation action, and platelet aggregation action.
  • R 1 and R 2 each represent a hydrogen atom or an optionally substituted alkyl group, an aralkyl group, an arylalkenyl group, an aryl group or an acyl group.
  • the alkyl group has 1 to 18 carbon atoms, preferably 1 to 6 carbon atoms, and may be straight-chain or branched, for example, methyl, ethynole, fu-bil, isof pill, and butyl. ⁇ , isobutyl, t-butylinole, pen_tinole, isole-pentinole, t- ⁇ -inchile, hexisole, heptyl, octyl, nonyl, desizole, ⁇ decyl, Dodecyl, tetradecyl, hexadecyl, octadecyl and the like, and a typical example of a substituent of these alkyl groups is a hydroxyl group.
  • the aryl part of the aralkyl group may be monocyclic or condensed cyclic (eg, phenyl group, naphthyl group, etc.).
  • the alkyl part may have 1 to 6, particularly 1 or 2, carbon atoms.
  • representative examples of such an aralkyl group include a benzyl group, a phenethyl group, and a naphthylmethyl group.
  • the benzyl group which may have a substituent is particularly classified into two types represented by the following formulas.
  • the aryl portion of the arylalkenyl group may be monocyclic or condensed cyclic (eg, a phenyl group, a naphthyl group, etc.), and the alkenyl portion has 1 to 6, particularly 3 carbon atoms. Is preferred.
  • a typical example of an arylalkenyl group is a cinnamyl group.
  • the aryl group may be either monocyclic or condensed cyclic, and typical examples thereof include a phenyl group and a naphthyl group, and an aryl group which may have a substituted lysine group.
  • a phenyl group which may have a substituent is represented by the following formula.
  • acyl group examples include aromatic acyl groups such as a benzoyl group, a phenylacetyl group, a cinnamyl group, and a naphthyl group; a pyridylcarbonyl group, Examples include heterocarbonyl groups such as a carbocarbonyl group and a thiophenylcarbonyl group.
  • aromatic acyl groups such as a benzoyl group, a phenylacetyl group, a cinnamyl group, and a naphthyl group
  • a pyridylcarbonyl group examples include heterocarbonyl groups such as a carbocarbonyl group and a thiophenylcarbonyl group.
  • benzoyl which may have a substituent The group is represented by the following formula.
  • Q 1 , Q z , Q 3 , Q 4, and Q 5 are each a hydrogen atom; a halogen atom such as fluorine, chlorine, or bromine; methyl, ethyl, ethyl pinole, isopropyl, butyl, Isobutynole, t-butyl, pentinole, isopentinole, t-pentinole, hexinole, -hexinole, -octyl, nonyl, decyl, pendesi / 'le, dodecyl, tetradecyl, hexadecyl, octadecyl, octadecyl Alkyl groups (particularly, having 1 to carbon atoms; L8, especially 1 to 6 carbon atoms); trifluoromethyl groups; methoxy, ethoxy, methoxy, ethoxy, butoxy, butoxy
  • Q 6 is a hydrogen atom; a fluorine atom such as fluorine, chlorine, or bromine; or a lower alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, and t-butoxy. Group (especially 1 to 6 carbon atoms, especially 1 to 4 carbon atoms).
  • a pyridyl or S represents a phenyl group which may have a substituent, wherein the substituent is the same or different as a halogen atom or a lower alkoxyl group.
  • Q 1 ′ are each a hydrogen atom; a halogen atom such as fluorine, chlorine, and bromine; and methyl, ethyl, and phenyl. Mouth pill, isopul pill, butyl, isobutyl, t-butyl, ⁇ .
  • Q 1 4 Q 1 5 and Q 1 6 are each a hydrogen atom; off Tsu-containing, chlorine, c ⁇ Gen atom such as bromine; methylation, Echiru, propyl, i Sopuro pin le, heptyl, I Sobuchiru, t - Pentyl, pentinole, isopentylene, t-pentyl, hexyl, heptinole, octinole, noninole, desinole, pendesinole, dodesinole, tetradesinole, hexadesinole, ok Alkyl groups such as tadecyl (especially 1 to 18 carbon atoms, especially 1 to 6 carbon atoms); trifluoromethyl group; methoxy, ethoxy, terephthaloxy, isopropoxy, Lower alkoxy group (particularly 1 to 6 carbon atoms) such as butoxy, butoxy, etc .; amino, methylamin
  • Lower alkyl radicals (especially charcoal R 3 represents a hydrogen atom; or an amino group which may be substituted with a prime number 1 to 6); a ditoro group; a cyano group; Methyl, ethyl, propyle, fucinole, pentinole, hexineole, hefe. It represents an alkyl group such as chizore, octinole, nonyl, decyl, pendecyl, dodecyl, heptadecyl, etc. (in particular, having 1 to 1 carbon atoms, especially 1 to 11 carbon atoms).
  • salts of the 3,4-dihydro-2H-benzovirane derivative represented by the general formula (I) include salts of mineral acids such as hydrochloric acid and sulfuric acid; methanesulfonic acid, p— Salts of organic sulfonic acids such as toluenesulfonic acid; organic carboxylic acids such as acetic acid, ⁇ -bioionic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, lingic acid, and citric acid And the like.
  • mineral acids such as hydrochloric acid and sulfuric acid
  • methanesulfonic acid p— Salts of organic sulfonic acids such as toluenesulfonic acid
  • organic carboxylic acids such as acetic acid, ⁇ -bioionic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, lingic acid, and citric acid
  • the 3,4-dihydro-2 2-benzopyran derivative represented by the general formula (I) can be produced, for example, by the following methods (i) to (iv).
  • n is as defined above, and — NI,--1 ⁇ R2,,, — -N 3 ⁇ 4
  • Or - represents a nitrogen-containing heterocyclic group represented by S, R 'in here, R 2 and R 3 are as defined above, Z is labile atom or group, such as chlorine, halogen such as bromine Atoms; lower alkylsulfonyloxy groups such as methanesulfonyloxy; benzenes-norefoninoleoxy, p—arenes such as leno-nizoleoxy Represents a sulfonyloxy group, etc.
  • the compound represented by the general formula ( ⁇ -1) and the nitrogen-containing complex ring compound represented by the general formula ( ⁇ ) in an amount of about 1 to 20 mol per 1 mol of the compound are dissolved in toluene, xylene, and dimethyl.
  • an inert solvent such as formamide
  • R 5 represents a hydroxyl-protecting group such as benzyl, acetyl, benzoyl, etc.
  • R 6 represents a hydrogen atom or the same hydroxyl group as R 5.
  • a protecting group That is, a compound represented by the general formula ((-2) and a nitrogen-containing compound represented by the general formula (m) in an amount of about 1 to 20 mol per mol of the compound.
  • reaction is carried out at a temperature in the range of about 50 to 250, preferably about 80 to 200, or the nitrogen-containing heterocyclic compound represented by the general formula ( ⁇ ) is reacted with the nitrogen-containing heterocyclic compound.
  • a base such as n-butyllithium or sodium hydride per mole of compound in an inert solvent such as toluene, tetrahydrofuran or dimethylformamide , — 78 at ⁇ about 100 'c, preferably about -2 () ⁇ (: ⁇ +
  • the compound represented by the general formula ( ⁇ -2) and the halide represented by the general formula (IV) are treated in an inert solvent such as toluene, benzene, methylene chloride, 1,2-dichloroethane, and the like.
  • Gin Tri After reacting at a temperature of about 120'c to +150, preferably about 0 to 80'c in the presence or absence of a base such as ethylamine or calcium carbonate, If necessary, a hydroxyl-protecting group is eliminated from the product according to a conventional method to produce a 3,4-dihydro 2 H-benzoviran derivative represented by the general formula (I-2). it can.
  • n is as defined above, and Y represents a group represented by —0— or 1 N H —
  • the nitrile represented by the general formula (III-3) and the substituted ethylamine represented by the general formula (V) in an amount of about 1 to 3 molar equivalents relative to the nitrile are combined with the nitrile.
  • nitric acid such as zinc chloride, stannic chloride, and ferric chloride
  • the product is further heated to reflux with about equimolar amount of boron trifluoride in an inert solvent such as dioxane or ethylene glycol dimethyl ether to obtain a compound represented by the general formula (1).
  • an inert solvent such as dioxane or ethylene glycol dimethyl ether
  • the 3,4-dihydro-2H-benzoviran derivative represented by the general formula (1) from the reaction mixture obtained by the above methods (i> to (iv) is separated and purified by a general organic synthesis reaction. The same can be done by the method used for separating and purifying the obtained product from the reaction mixture.
  • the 3,4-dihydro-2H-benzoviran derivative represented by the general formula (I) has an asymmetric carbon atom at the 2-position of the chroman skeleton, and two kinds of asymmetric carbon atoms based on the asymmetric carbon atom are provided. : Has optical isomers (enantiomers). When the 3,4-dihydro-2H-benzopyrane derivative has two or more asymmetric carbon atoms, it has a diastereomer derived from these asymmetric carbon atoms. Each of these isomers uses the corresponding optically active compound represented by the general formula (IV-1) known in the literature as a raw material, via a compound represented by the general formula (IV-2) by a conventional method.
  • Test Compound column for example, the compound means the compound of the number 'shown at the beginning of each of the compound groups of 71 listed above as an eclectic example. The numbers follow this. Test example 1
  • guinea pig peritoneal polymorphonuclear nuclei The leukocyte 105: 0000 X g supernatant fraction was prepared, and the ability to produce arachidon and other 5-hydroxyhydroxysate trinate (5—HETE) was measured. .
  • a male guinea pig weighing approximately 500 g was intraperitoneally injected with a 10% amount (10 ml / 100 g body weight) of a 2% casein solution. After 16 to 18 hours, the abdomen was opened, and the intraperitoneal exudate was removed. The cells were collected, and then the peritoneal cavity was washed twice with a physiological saline solution containing a phosphate buffer solution (PH 7.4). Profit
  • the obtained leachate and washing solution were collected, centrifuged at 150 X g for 5 minutes, and 0.2% saline was added to the precipitate, and the mixture was subjected to hypotonic treatment to lyse the mixed red blood cells. After adding 1.6% saline to make the solution isotonic, centrifuge similarly, suspend in 50 mM Hepes buffer (pH 8.0), and sonicate (Branson sonifier, model 185). ). Centrifuge at 10,000 for 10 minutes, centrifuge the supernatant at 105,000 X g for 60 minutes, and use the resulting supernatant as the 5-lipoxygenase fraction until use-70 ° C Stored frozen in c.
  • the reaction solution 5 0 m Tris - in hydrochloric acid buffer solution (pH 7. 3), 5 - Li Pokishigena one peptidase fraction (0. 5 mg protein), 3. 4 M ⁇ 1 - 1 C j ⁇ Lucky Don (40 nCimersham International), 1 mM Methanolic chloride, 2 mM ATP and imM glutathione, and the total amount was 0.2 ml.
  • the dimethyl Chirusuruhoki shea test compound was dissolved in de upper ⁇ min at 3 0, 2 minutes the Play Nki Interview base - After cane down, 1 4 C - added ⁇ la key de down 3 ⁇ 4, in 3 0 Incubated for 3 minutes.
  • reaction was stopped by adding 20 mL of 0.4 M citric acid solution, and the reaction product was extracted with 1 ml of ethyl ether.- 0.5 g of sodium sulfate anhydrous was mixed. Transfer the supernatant (0.6 ml) to another test tube and dry to dryness.
  • a guinea pig having a body weight of 350-450 g was dissolved in physiological saline and 1 ml of 0% ovalbumin was intraperitoneally and subcutaneously administered to induce seizure. 2Q to 25 days after the mischief.
  • the sensitized animal was intraperitoneally injected with 5 g / kg i-tan, fixed in a dorsal position, incised, and incised.
  • I purchased Human breathing is performed at a pressure of 50 strokes / min O at a low pressure, and the pressure of air sent to the airway is increased through the pressure sensor in contact with the tracheal force nucleus. It was noted in. After the X-rays stabilized, 2.5 mg of mepyramine, 1 mg of indomethacin, 1 kg of indomethacin and 0.05 mg of probranochol were administered via the common jugular vein, respectively. Three minutes later, the test compound was administered through the common jugular vein. Next, at 2 minutes, 10 mg / kg of ovalbumin was administered via the jugular vein to induce anaphylactic bronchoconstriction 2 minutes later, and the increase in airway resistance was measured for i0 to 15 minutes.
  • the action of the compound of the present invention for preventing lipid hypersurvival was carried out according to the method of Shimada and Yasuda [see Biocim. Biophys. Acta, Vol. 489, p. 1663 (1977)]. That is, using a male rat weighing about 200 g, a liver microsomal suspension was prepared by a conventional method, and the suspension was mixed with 10% QA'M and sulfuric acid. 37 in the presence of iron 20M. After 60 minutes of incubation and incubation at (:), the amount of formed aldehyde was measured by the Ciobarbitic acid method ⁇ ⁇ ⁇ ⁇ ⁇ ⁇
  • S-test compound was 2 3311 added before I Nki i base over emissions ® down.
  • the compound to be administered was orally administered to three puppies. Before and 1 hour after administration, blood was collected and mixed with 10% of a 3.8% sodium citrate solution. The quenched blood was centrifuged at 200 ⁇ g for 10 minutes to obtain platelet-rich plasma. ⁇ La ⁇ The Don the 2. 5 X 1 0 - 4 M (final concentration) was added, platelet aggregation was caused this was measured Ri by the same aggregation measuring apparatus to the one described in the methods. The inhibition rate (%) of the compound before administration of the test compound was determined, and the compound (30) showed an inhibition rate of 41 ⁇ 17 at a dose of 100 mg Zkg ⁇ .
  • the 3,4-dihydro-2H-benzopyrane derivative ( ⁇ ) of the present invention is useful for humans and other animals such as horses, horses, pigs, pigs, dogs, mice, rats, and guinea pigs. It has remarkable 5-lipoxygenase-inhibiting activity, antiallergic activity, anti-drug stamin activity, lipid permeation preventing activity, and platelet aggregation inhibiting activity in animals such as animals.
  • the 3,4-dihydro-2H-benzopyrane derivatives (I) of the present invention have low toxicity.
  • the compounds of the present invention) and (30) have acute toxicity values (LD 5 , dd).
  • the male male was> l, 000 mg / kg by oral administration and> 300 mg / kg by intraperitoneal administration.
  • the 3,4-dihydro-2H-benzopyrane derivatives ('1) of the present invention include humans, such as horses, horses, pigs, pigs, dogs, and mice.
  • Bronchial asthma allergic diseases (such as allergic rhinitis), immune diseases (such as autoimmune deficiency and infectious diseases), inflammatory diseases (such as rheumatoid arthritis) in animals such as rats, rats, and guinea pigs. , Ankylosing spondylitis, etc.), psoriasis, cerebrovascular disorders, ischemic heart disease, thrombosis and other various diseases.
  • allergic diseases such as allergic rhinitis
  • immune diseases such as autoimmune deficiency and infectious diseases
  • inflammatory diseases such as rheumatoid arthritis
  • animals such as rats, rats, and guinea pigs.
  • Ankylosing spondylitis, etc. Ankylosing spondylitis, etc.
  • psoriasis cerebrovascular disorders
  • ischemic heart disease thrombosis and other various diseases.
  • the dose of the benzopyrane derivative (I) varies depending on the disease, severity of the patient, tolerability to the drug, etc., but usually 5 per adult per day. 2200 mg, preferably 50-600 mg, which may be administered once or in divided doses. For administration, any form suitable for the administration route can be used.
  • 3,4-Dihydro-2H-benzopyrane derivatives (I) can be prepared for administration using any conventional O formulation method. Accordingly, the present invention also encompasses a pharmaceutical composition having at least one 3,4-dihydro 2 H-benzopyran derivative (I). Such a composition is prepared by conventional means using any desired pharmaceutically acceptable additives such as a pharmaceutical carrier, excipient and the like.
  • the preparation is desirably provided in a form suitable for absorption from the digestive tract.
  • Tablets and capsules for oral administration are in unit dosage form and contain binders, such as syrup, gum arabic, gelatin, sorbit, trakant, polyvinylidone Etc .; ⁇ shaped drugs, such as lactose, corn Powder, calcium phosphate, sorbit, glycine, etc .; lubricants, such as magnesium stearate, talc, polyethylene glycol, silica, etc .; It may contain conventional excipients such as, for example, potato powder, or an acceptable wetting agent, for example, sodium lauryl sulfate! /.,.
  • Oral liquid preparations may be aqueous or oily suspensions, solutions, syrups, elixirs, etc., or reconstituted with water or other suitable vehicle before use. It may be a dry product to be dissolved.
  • Such liquid preparations may contain commonly used excipients, such as suspending agents, such as Solvit Silosov.
  • a pH adjuster When preparing an injection, a pH adjuster, a buffer, a stabilizer, a preservative, a solubilizer, and a 3,4-dihydro--2H-benzopyrane derivative (I) may be used as necessary. Add subcutaneous, intramuscular, or intravenous injections in the usual manner.
  • CDC 13 means CDC £ 3
  • d 6 -DMSO means d 6 -DMSO
  • CD 30 D means CD 3 OD
  • D 20 means D 20 .
  • Example 1 4-benzylpiperidine: I.4 g, 4-(2,3,4-trimethoxybenzene) instead of imidazole 15 g 2.6
  • the reaction and separation operations were carried out in the same manner as in Example 1 except that 3.2 g of g or biazine was used.
  • Example 1 15 g (0.22 mole) of imidazole was replaced with morpholine, 4-methylbiperidine, pyridin, 4-phenylbiperidine, 4-( The reaction and separation procedures were performed in the same manner except that 0.22 mole of each of 4 — methoxyphenyl) piperidine or 4 — (4 — methoxyphenyl) piperazine was used. 3 and 4 — dihydro 2 H — benzopyran
  • Example 2 substitute for imidazole i 5 g (0.22 mole) In addition to using 0.22 mole of timozoleforin, 4-benzylbenzyl, 4-benzylvinyl or 4- (3,4,5-trimethoxybenzyl) biperazine, respectively In the same manner, by performing the t reaction and the separation operation, the corresponding 3,4—dihydro 2H-benzovirane ⁇ conductor was obtained. Table 6 shows the yield and physical properties of each product.
  • Example 16 (4_ phenyl phenyl) benzyl chloride 4.23 g (17.8 mniole) was replaced with benzhydryl chloride, and Nanaichi (4-methoxy) (Phenyl) benzyl chloride, o— (4—bromophenyl) benzyl chloride, 3, 4, 5—trimethoxybenzyl chloride, 4-methoxybenzenechloride, a
  • the reaction and separation procedures were performed in the same manner except that 17.8 mmole of (4 fluorophenyl) benzyl chloride or 4'-dimethylaminobenzoyl chloride / was used, respectively.
  • Table 8 shows the yields and physical properties of the respective products from which the corresponding 3,4-dihydro-2H-benzopyran derivatives were obtained. Table 8 Products
  • step (a) In step (a) above, instead of 3,4,5—trimethoxybenzoyl chloride, 4.4 g (17.3 mmole) was replaced with 4—chlorobenzyl chloride, 17.3 mmole.
  • the corresponding reaction and separation procedures were carried out in the same manner except for the use, which resulted in the corresponding 2 — [3 — [1 — C 4-(4-cyclohexyl benzoyl) virazine]] 1,3,4-Dihydro 6-hydroxy-1,2,5,7,8-Tetramethyl 2H-benzopyran [Compound (35)] was obtained.
  • Table 9 shows the product yields and physical properties.
  • Kiyoshi 30 1. Benzylpyrazine 10.8 g (61.4 mmole) instead of thiomorpholine, 1-phenylpyridine, p-lysine, 1-methylpipera The reaction and separation procedures should be performed in the same manner except that 61.4 mmole of pyridine, 1- (4-benzyl benzyl) piperazine or 2-indecylimidazole was used, respectively. 3 : 4-dihydro-2H-benzopyra 33 conductors were obtained. Table 10 shows the yield and physical properties of each product.
  • Table 11 shows the physical properties.
  • Example 4 7 Under a nitrogen atmosphere, 3, 4 — dihydro 6 — hydroxy 2 — [2 — (1-dila jule) ethyl] — 2, 5, 7, 8 — tetramethyl 1 2 H—
  • a solution consisting of 5.0 g (15.7 mmole) of nzopyran, 9.6 g of o- (2-pyridyl) benzyl chloride, 100 ml of toluene and 100 ml of dimethylformamide was refluxed for 10 hours. The obtained reaction solution was poured into aqueous sodium hydrogen carbonate and extracted with toluene.
  • Example 30 1-benzylbiverazine was replaced by 10.8 g (61.4 mmo 1 e) in place of 1- (41-trifnoreo lo methinobenzoyl).
  • Table 3 shows the yield and physical properties of each product.
  • the above components are re-oxidized, and are: tin hard o o0-23 capsules, 're: 000 force:'. Having 20 mg of i-cub-filled with cells filled in the cell,
  • the compound (30) was dissolved in acetone, and then: was adsorbed on a microcrystalline cell opening and then dried. This was mixed with corn starch and used as a powder in a conventional manner to prepare a 20-fold powder of compound (30).
  • Compound (30) was dissolved in acetone, which was then adsorbed to the microcrystal cell mouth and dried. To this, corn starch, lactose, and potassium ruboquine methylcellulose were mixed, and then the aqueous solution of poly (vinyl pyridine) was added as a binder and granulated by a conventional method. After adding talc as a lubricant and mixing, the mixture was pressed into 100 tablets. 1 Compound in
  • Glycols were mixed and dissolved by heating at about 80, to which was added a phosphate buffer solution and distilled water in which sodium chloride and propylene glycol had been previously dissolved. Heated and added, with a total volume of 1,000m1 aqueous solution
  • the solution was dispensed into a 2 ml volume of this water ', sealed, and then heated to -M.
  • the compound has a compound (30) 20.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Des dérivés de 3,4-dihydro-2H-benzopyranne représentés par la formule générale (I) (dans laquelle n représente un entier égal à 0, 2 ou 3, R représente un groupe hétérocyclique contenant de l'azote sélectionné parmi les composés (II), R1 et R2 représentent chacun un atome d'hydrogène ou un groupe alkyle, aralkyle, arylalkényle, aryle ou acyle éventuellement substitués, et R3 représente un atome d'hydrogène ou un groupe alkyle) et leurs sels pharmacologiquement acceptables sont décrits. Ces composés ont une activité inhibitrice de la 5-lipoxygénase, un effet anti-allergique, un effet anti-histaminique, un effet préventif de la peroxydation des lipides, un effet inhibiteur de l'agglutination des plaquettes, etc. et sont utiles en tant que médicaments pour traiter l'asthme bronchique, les infections allergiques, les infections à caractère immuno-déficitaire, les infections inflammatoires, le Psoriasis vulgaris, les troubles circulatoires cérébraux, les infections ischémiques, la thrombose, etc. Est également décrit l'emploi des composés comme médicaments.
PCT/JP1987/000106 1986-02-21 1987-02-18 Derives de 3,4-dihydro-2h-benzopyranne et leur usage medicinal WO1987005020A1 (fr)

Applications Claiming Priority (4)

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JP61/38081 1986-02-21
JP3808186 1986-02-21
JP29078286 1986-12-05
JP61/290782 1986-12-05

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WO1987005020A1 true WO1987005020A1 (fr) 1987-08-27

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0354508A2 (fr) * 1988-08-09 1990-02-14 F. Hoffmann-La Roche Ag Dérivés de benzopyranol
EP0364274A1 (fr) * 1988-10-13 1990-04-18 Glaxo Group Limited Dérivés d'imidazole
EP0487510A1 (fr) * 1987-04-27 1992-05-27 The Upjohn Company Amines pharmaceutiquement actives
EP0533579A1 (fr) * 1991-09-18 1993-03-24 Adir Et Compagnie Nouveaux dérivés de la trimétazidine, leur procédé de préparation et les compositions pharmaceutiques les contenant
US5260294A (en) * 1988-08-09 1993-11-09 Hoffman-La Roche Inc. Chromanes and their pharmaceutical compositions and methods
EP0640609A1 (fr) * 1993-08-24 1995-03-01 Ono Pharmaceutical Co., Ltd. Dérivés phénoliques ayant une activité inhibitante de TXA2 synthéthase et 5-lipoxygénase et une activité contre des espèces d'oxygène
WO1995015958A1 (fr) * 1993-12-08 1995-06-15 Alcon Laboratories, Inc. Composes presentant une puissante activite d'antagonistes du calcium et d'antioxydants et leur utilisation en tant qu'agents cytoprotecteurs
US5489593A (en) * 1989-12-28 1996-02-06 The Upjohn Company Anti-aids piperazines
WO2002096362A2 (fr) * 2001-05-30 2002-12-05 Alteon Inc. Methode de traitement de maladies fibreuses ou d'autres indications
WO2005012293A1 (fr) * 2003-08-01 2005-02-10 Nippon Soda Co., Ltd. Composes de phenylazole, leur procede de production et antioxydants
US7368575B2 (en) * 2004-03-10 2008-05-06 Korea Research Institute Of Chemical Technology 6-alkylamino-2,2′-disubstituted-7,8-disubstituted-2H-1-benzopyran derivatives as 5-lipoxygenase inhibitor
US7470798B2 (en) 2003-09-19 2008-12-30 Edison Pharmaceuticals, Inc. 7,8-bicycloalkyl-chroman derivatives

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS57146767A (en) * 1981-01-29 1982-09-10 Squibb & Sons Inc Substituted chromans

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS57146767A (en) * 1981-01-29 1982-09-10 Squibb & Sons Inc Substituted chromans

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0487510A1 (fr) * 1987-04-27 1992-05-27 The Upjohn Company Amines pharmaceutiquement actives
EP0354508A3 (fr) * 1988-08-09 1991-03-27 F. Hoffmann-La Roche Ag Dérivés de benzopyranol
US5260294A (en) * 1988-08-09 1993-11-09 Hoffman-La Roche Inc. Chromanes and their pharmaceutical compositions and methods
EP0354508A2 (fr) * 1988-08-09 1990-02-14 F. Hoffmann-La Roche Ag Dérivés de benzopyranol
EP0364274A1 (fr) * 1988-10-13 1990-04-18 Glaxo Group Limited Dérivés d'imidazole
US5489593A (en) * 1989-12-28 1996-02-06 The Upjohn Company Anti-aids piperazines
EP0533579A1 (fr) * 1991-09-18 1993-03-24 Adir Et Compagnie Nouveaux dérivés de la trimétazidine, leur procédé de préparation et les compositions pharmaceutiques les contenant
US5750544A (en) * 1993-08-24 1998-05-12 Ono Pharmaceuticals Co., Ltd. Fused phenol derivatives
EP0640609A1 (fr) * 1993-08-24 1995-03-01 Ono Pharmaceutical Co., Ltd. Dérivés phénoliques ayant une activité inhibitante de TXA2 synthéthase et 5-lipoxygénase et une activité contre des espèces d'oxygène
US5534536A (en) * 1993-08-24 1996-07-09 Ono Pharmaceuticals Co. Ltd. Fused phenol derivatives
AU697050B2 (en) * 1993-12-08 1998-09-24 Alcon Laboratories, Inc. Compounds having both potent calcium antagonist and antioxidant activity and use thereof as cytoprotective agents
US5646149A (en) * 1993-12-08 1997-07-08 Alcon Laboratories, Inc. Compounds having both potent calcium antagonist and antioxidant activity and use thereof as cytoprotective agents
WO1995015958A1 (fr) * 1993-12-08 1995-06-15 Alcon Laboratories, Inc. Composes presentant une puissante activite d'antagonistes du calcium et d'antioxydants et leur utilisation en tant qu'agents cytoprotecteurs
CN1100774C (zh) * 1993-12-08 2003-02-05 阿尔康实验室公司 具有高效钙拮抗物和抗氧化剂活性的化合物及其用作细胞保护剂
WO2002096362A2 (fr) * 2001-05-30 2002-12-05 Alteon Inc. Methode de traitement de maladies fibreuses ou d'autres indications
WO2002096362A3 (fr) * 2001-05-30 2003-05-22 Alteon Inc Methode de traitement de maladies fibreuses ou d'autres indications
US6596745B2 (en) 2001-05-30 2003-07-22 Alteon, Inc. Method for treating fibrotic diseases with azolium chroman compounds
WO2005012293A1 (fr) * 2003-08-01 2005-02-10 Nippon Soda Co., Ltd. Composes de phenylazole, leur procede de production et antioxydants
US7553837B2 (en) 2003-08-01 2009-06-30 Nippon Soda Co., Ltd. Phenylazole compounds production process and antioxidants
US7470798B2 (en) 2003-09-19 2008-12-30 Edison Pharmaceuticals, Inc. 7,8-bicycloalkyl-chroman derivatives
US7514461B2 (en) 2003-09-19 2009-04-07 Edison Pharmaceuticals, Inc. Chroman derivatives
US7875607B2 (en) 2003-09-19 2011-01-25 Ampere Life Sciences, Inc. 7,8-bicycloakyl-chroman derivatives
US8044097B2 (en) 2003-09-19 2011-10-25 Ampere Life Sciences, Inc. Chroman derivatives
US7368575B2 (en) * 2004-03-10 2008-05-06 Korea Research Institute Of Chemical Technology 6-alkylamino-2,2′-disubstituted-7,8-disubstituted-2H-1-benzopyran derivatives as 5-lipoxygenase inhibitor

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