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WO1986002644A1 - Derives de 1,5-benzoxathiepines et leur procede de preparation - Google Patents

Derives de 1,5-benzoxathiepines et leur procede de preparation Download PDF

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Publication number
WO1986002644A1
WO1986002644A1 PCT/JP1984/000526 JP8400526W WO8602644A1 WO 1986002644 A1 WO1986002644 A1 WO 1986002644A1 JP 8400526 W JP8400526 W JP 8400526W WO 8602644 A1 WO8602644 A1 WO 8602644A1
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WIPO (PCT)
Prior art keywords
compound
reaction
methyl
group
lower alkyl
Prior art date
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Application number
PCT/JP1984/000526
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English (en)
Japanese (ja)
Inventor
Hirosada Sugihara
Minoru Hirata
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Takeda Pharmaceutical Co Ltd
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Takeda Chemical Industries Ltd
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Priority to PCT/JP1984/000526 priority Critical patent/WO1986002644A1/fr
Priority to DK584184A priority patent/DK166779B1/da
Priority to AU36468/84A priority patent/AU570753B2/en
Priority to ES538517A priority patent/ES8702399A1/es
Priority to GR81240A priority patent/GR81240B/el
Priority to NO844993A priority patent/NO169773C/no
Priority to HU844657A priority patent/HU201922B/hu
Priority to EP84308691A priority patent/EP0145494B1/fr
Priority to FI844940A priority patent/FI80029C/fi
Priority to PT79666A priority patent/PT79666B/pt
Priority to AT84308691T priority patent/ATE47851T1/de
Priority to IE320684A priority patent/IE58159B1/en
Priority to EP87116048A priority patent/EP0300088A3/fr
Priority to CA000469996A priority patent/CA1247613A/fr
Priority to DE8484308691T priority patent/DE3480397D1/de
Priority to KR1019840007941A priority patent/KR910009288B1/ko
Priority to PH31583A priority patent/PH21851A/en
Priority to CN85104426.3A priority patent/CN1008737B/zh
Priority to PH32900A priority patent/PH23423A/en
Priority to US06/806,809 priority patent/US4672064A/en
Priority to ES551262A priority patent/ES8705417A1/es
Publication of WO1986002644A1 publication Critical patent/WO1986002644A1/fr
Priority to PH34714A priority patent/PH23651A/en
Priority to US07/038,787 priority patent/US4751316A/en
Anticipated expiration legal-status Critical
Priority to CA000575740A priority patent/CA1258463A/fr
Priority to CA000575739A priority patent/CA1258462A/fr
Priority to JP1032376A priority patent/JPH02191272A/ja
Priority to JP1032375A priority patent/JPH02191271A/ja
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D411/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D411/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D327/00—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D327/02—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms one oxygen atom and one sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D411/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D411/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a novel 1,5-benzozochepine derivative useful as a medicine and a method for producing the same.
  • the present inventors have conducted intensive studies to create a compound having a specific serotonin S 2 receptor blocking action. As a result, not only an excellent serotonin S 2 receptor blocking action, but also calcium antagonism and cerebral vasospasm relaxation were achieved. It also has a renal circulation-improving effect, diuretic effect, and antihemolytic effect, such as ischemic heart disease such as angina and myocardial infarction, blood hypertension, cerebral vasospasm, and transient cerebral ischemic attack.
  • the present inventors have succeeded in producing a 1,5-benzoxaxin: pin derivative useful as an agent for preventing or treating cerebral circulatory disorders, and completed the present invention.
  • the present invention uses the formula
  • R t and R 2 are each hydrogen; halogen, hydroxy, lower alkyl or lower alkoxy, and R 3 and R + are each hydrogen or optionally substituted lower alkyl, cycloalkyl or X represents an aralkyl group or forms a ring together with an adjacent nitrogen atom, and X is hydrogen, an optionally substituted lower alkyl group, an optionally substituted aryl group, or an esterified or amidated group.
  • examples of the halogen represented by R 2 include fluorine, chlorine, bromine, iodine and the like.
  • Examples of the lower alkyl group represented by R t or R 2 include alkyl groups having about 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.
  • Examples of the lower alkoxy group represented by R 2 include alkoxy groups having about 1 to 4 carbon atoms, such as methoxy, ethoxyquin, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy. It is more preferable that one of R and R 2 is hydrogen and the other is lower alkoxy, and it is more preferable that the lower alkoxy group is bonded to the 7-position of the benzoxacepine skeleton.
  • Examples of the lower alkyl group represented by R 3 or R + include an alkyl group having about 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopyl butyl, butyl, isobutyl, sec-butyl and tert-butyl.
  • the alkyl group example C 3 - 8 cycloalkyl (e.g., cyclopropyl, cyclobutyl, Shikurobe pentyl, cyclohexyl, the cycloalkyl heptyl, Shikurookuchiru), halogen (e.g., off, Seo-containing, chlorine, bromine), human Droxy, lower (C t-J alkoxy (eg, methoxy, ethoxy, propoxy, butokin), lower (C t - 5 ) alkanoyloxy (eg, acetoxy, propionyloxy, butyryloxy, bivaloyloxy), mono- or di- lower (C) Arukiruami Bruno (eg, Mechiruamino, dimethyl Amino, Mechiruechiruami Roh), C 3 - 8 consequent opening Arukirua Roh (e.g., cycloalkyl Penchiruamino, Kishiruamino to sik
  • Replacement Mino eg, acetamido, propionamide
  • benzamide lower (d- 4 ) alkylthio (eg, methylthio, ethylthio, propylthio, butylthio), carbamoyl, ⁇ —lower (C 4 ) alkyl rubamoyl ( For example, it may be substituted with methylcarbamoyl, ethylcarbamoyl), ⁇ , ⁇ -di-lower (C! ⁇ + ) Alkyl rubamoyl (eg, dimethylcarbamoyl, getylcarbamoyl, methylethylcarbamoyl).
  • Examples of the cycloalkyl group represented by R 3 or R 4 include a cycloalkyl group having about 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Cycloalkyl groups include, for example, lower (C + ) alkyl groups (eg, methyl, ethyl, propyl, butyl, etc.), lower (C 4 ) alkoxy groups (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc.), 5 It may be replaced by a alkanoylamino group (eg, acetoamide), a hydroxy group, or the like.
  • C + alkyl groups eg, methyl, ethyl, propyl, butyl, etc.
  • lower (C 4 ) alkoxy groups eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc.
  • 5 It may be replaced by a alkanoylamino group (eg, acetoamide), a hydroxy group, or the like.
  • Examples of the aralkyl group represented by R 3 or R + include, for example, a phenyl-lower (C + ) alkyl group such as benzyl, phenethyl, 3-phenylpropyl, 1-methylbenzyl, 1-methylbenzyl, 1-methylphenyl, 1-methylphenethyl, and ethylphenyl.
  • the phenyl group in the mono-lower alkyl group may be 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) and lower (d-J alkyl groups (eg, methyl, ethyl).
  • phenyl-lower alkyl group examples include, for example, 2- (4 -Chlorophenyl) ethyl, 2- (4-hydroxyphenyl) ethyl, 2- (4-methoxyphenyl) ethyl, 2- (3,4-dimethoxyphene)
  • Examples of the ring formed by R 3 and R 4 together with the adjacent nitrogen atom include a cyclic amino group which may have a hetero atom such as nitrogen, oxygen or sulfur in addition to the nitrogen atom.
  • a cyclic amino group which may have a hetero atom such as nitrogen, oxygen or sulfur in addition to the nitrogen atom.
  • Includes 5- to 7-membered cyclic amino groups such as lysinyl, morpholinyl, piperidyl, piperazinyl, and hopiperazinyl.
  • Cyclic amino group may have a substituent at a substitutable position, as such substituent include lower (C i - 4) alkyl (e.g., methylcarbamoyl _ Le, Echiru, propyl, heptyl), Ariru, Examples include aralkyl, acyl, and heterocycle.
  • aryl group as a substituent examples include a phenyl group, and the phenyl group has 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine).
  • Lower (C t ⁇ + ) alkyl Groups eg, methyl, ethyl, propyl, butyl
  • lower (d- 4 ) alkoxy groups eg, methoxy, ethoxy, propoxy, isop- ⁇ -oxy, butoxy
  • aralkyl as a substituent may be, for example, a phenyl, lower (C)
  • acyl as a substituent include lower (CJ alkanol (eg, acetyl) (C i- + ) fatty acid residues such as benzoyl, phenyl-lower (C 4 ) alkanol, and phenyl-lower (CJ alkenoyl (eg, cinnamoyl)).
  • the aralkyl group and the phenyl group in the aromatic organic acid residue may have 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine), lower (C
  • Alkyl groups eg, methyl, ethyl, propyl, butyl
  • C t -J alkoxy groups eg, methoxy. Ethoxy, propoxy, isopropoxy, butoxy
  • the hetero ring as a substituent include a nitrogen atom such as pipalyl, virazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, triazinyl, azepinyl and the like. 5- to 7-membered rings containing 1 to 3 atoms.
  • the Oyopi 1 more preferably when they form a ring in which R 3 and R + are substituted with ⁇ reel together with the adjacent nitrogen atom, further preferably be a piperazinyl substituted with Ariru.
  • Examples of the lower alkyl group represented by X include alkyl groups having about 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. May be replaced by, for example, oxo, hydroxy, acyloxy, aryl.
  • Examples of the lower alkyl group substituted by oxo include lower (C 1- + ) alkyl groups such as acetyl, propionyl, and butyryl.
  • Examples of the lower alkyl group substituted with hydroxy include groups such as hydroxymethyl.
  • Examples of the acyl group as the acyloxy group include an acyl group derived from a lower fatty acid such as a lower (C 5 ) alkanol (eg, acetyl, propionyl, butyryl).
  • Examples of the lower alkyl group substituted with the acyloxy group include: Examples include acetyloxymethyl, propionyloxymethyl, and butyryloxymethyl.
  • Examples of the lower alkyl group substituted with aryl include lower (C t ⁇ + ) alkyl substituted with a phenyl group such as benzyl.
  • the group can be one to three halogens (eg, fluorine, chlorine, bromine, iodine), lower (C t- + ) alkyl groups (eg, methyl, ethyl, propyl, butyl), lower (C
  • alkoxy group eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy
  • a methylenedioxy group an amino group, a ditro group, a hydroxy group, and the like.
  • Examples of the aryl group represented by X include a phenyl group, and the phenyl group is one to three halogens (eg, fluorine, chlorine, bromine, iodine), lower (C t-J alkyl groups (eg, , Methyl, ethyl, propyl, butyl,), lower (C t- + ) alkoxy groups (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy), methylenedioxy group, amino group, nitro group, hydroxy It may be substituted by a group or the like.
  • halogens eg, fluorine, chlorine, bromine, iodine
  • C t-J alkyl groups eg, Methyl, ethyl, propyl, butyl
  • C t- + ) alkoxy groups eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy
  • esterified carboxyl group represented by X examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl and the like. Low (CJ
  • Examples of the amidated carboxyl group represented by X include a carbamoyl group, and the carbamino group has one or two amino groups.
  • X is preferably an esterified carboxyl group, and more preferably a lower alkoxycarbonyl.
  • the Ashiru group represented by R 5 for example, Asechiru, propionyl, Puchiriru, valeryl, lower alk force Roh I le group number 1 to about 6 carbon atoms, such as pivaloyl, Benzoiru, full We two Ruasechiru, Fang incense such phenylpropionyl Fuweniru lower from family carboxylic acid (C: - 6) and spoon a such as Al force Noiru
  • the aromatic ring in the aromatic carboxylic acid is a phenyl group
  • the phenyl group may be one to three halogens (eg, fluorine, chlorine, bromine, iodine), Lower (d- + ) alkyl groups (eg, methyl, ethyl, propyl, butyl), lower (d-J alkoxy groups (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy), methylenedioxy, amino It may be substituted by a group, nitro group, hydroxy group and the like.
  • halogens eg, fluorine, chlorine, bromine, iodine
  • Lower (d- + ) alkyl groups eg, methyl, ethyl, propyl, butyl
  • lower (d-J alkoxy groups eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy
  • methylenedioxy amino It may be substituted by
  • Examples of the optionally substituted carbamoyl group represented by R 5 include carbamoyl, and the amino group of the carbazyl group is a lower (C i + ) alkyl (eg, methyl, ethyl, propyl, heptyl), Fuweniru, phenylene Lou lower (C t - 4) alkyl (e.g., benzyl, Fuwenechiru) may be substituted or the like.
  • the amino group of the carbazyl group is a lower (C i + ) alkyl (eg, methyl, ethyl, propyl, heptyl), Fuweniru, phenylene Lou lower (C t - 4) alkyl (e.g., benzyl, Fuwenechiru) may be substituted or the like.
  • the phenyl group of the phenyl group and the phenyl lower alkyl group may have 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine), lower (C t ⁇ + ) alkyl groups (eg, methyl, ethyl). , Propyl, butyl), lower (C 1-) alkoxy groups (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy), methylenedioxy, amino, nitro, hydroxy, etc. Is also good.
  • Y is preferably hydroxymethylene.
  • the sulfur atom in the formula (I) forms, for example, sulfide, sulfoxide and sulfone depending on the value of m. In particular, it is preferable that m is 0.
  • the group (CH 2 ) n— in the formula (I) forms, for example, methylene, dimethylene, trimethylene, tetramethylene, pentamethylene, and hexamethylene depending on the value of n. Of these, trimethylene is preferred.
  • salt of compound (I) examples include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, nitrate and phosphate, such as acetate, tartrate, citrate, fumarate, and the like.
  • Pharmaceutically acceptable salts such as salts with organic acids such as maleate, toluenesulfonate and methanesulfonate are mentioned.
  • the compound (I) of the present invention is, for example, a compound represented by the formula
  • n, R 3 and R 4 are as defined above, W is halogen or a formula R—
  • a compound (IE) represented by a group represented by S 0 2 -0— (R represents lower (C 1 -J alkyl, phenyl or P-tolyl)) is subjected to a condensation reaction, a reduction reaction after the condensation reaction, It can be produced by subjecting it to a reduction reaction after condensation reaction followed by acylation or carbamoylation reaction .
  • the condensation reaction is usually carried out in the presence of a base.
  • Inorganic bases such as hydrogen carbonate, sodium carbonate, sodium methoxide, sodium hydride, lithium diisopropylamide, triethylamine, pyridine, 1.8-diazabicyclo [5,4,0] -7-decene Organic amines, etc.
  • the reaction can be favorably advanced by using sodium iodide, lithium iodide, or the like as a catalyst.
  • the above reaction is usually carried out in an organic solvent (eg, acetone, -2-butanone, acetonitrile, N, N-dimethylformamide, methylene chloride, benzene, toluene, tetrahydrofuran, dioxane).
  • the temperature can be about 20 to +150, preferably about -20 to + 120 ° C.
  • Reduction with lithium metal hydride such as lithium borohydride, lithium cyanoborohydride, sodium borohydride, sodium cyanoborohydride, tri-tert-butoxydium aluminum hydride, metal sodium, metal magnesium, etc.
  • Reduction with alcohols catalytic reduction using a mixture of metals such as platinum, palladium, and potassium or their mixtures with any carrier, reduction with metals such as iron and zinc and acids such as hydrochloric acid and sulfuric acid, electrolytic reduction Reaction conditions such as reduction with a reducing enzyme, reduction with a complex of a borohydride compound such as diborane or a borohydride compound such as borane-trimethylamine and an amine can be given.
  • the above reaction is usually carried out in the presence of water or an organic solvent (eg, methanol, ethanol, ethyl ether, dioxane, methylene chloride, chloroform, benzene, toluene, acetic acid, dimethylformamide, dimethylacetamide).
  • the reaction temperature varies depending on the reducing means, but is generally: about 20 ° (: to 100. (: degree is preferable.)
  • the acylation or rubamoylation reaction after the condensation reduction can be carried out by using the usual means of acylation or rubamoylation of alcoholic conductors.
  • a reactive derivative of an organic acid corresponding to R 5 an acid anhydride, an acid halide, or the like
  • R 5 an acid anhydride, an acid halide, or the like
  • pyridine triethylamine, N, -dimethylaniline, or the like. It can be obtained by reacting in the presence of an inorganic base such as organic base, sodium carbonate, carbonated carbonate, sodium hydrogencarbonate and the like.
  • the above reaction is usually carried out in an organic solvent (eg, methanol, ethanol, ethyl ether, dioxane, methylene chloride, toluene, dimethylformamide, pyridine), and the reaction temperature is generally 120 ° C. It is preferably about + 100 ° C.
  • the force Rubamoiru reaction is the alcohol derivative obtained in example reduction, Isoshianeto acids that corresponds to R 5 (e.g., methyl isobutyl Xia Natick DOO, Echiruisoshiane over preparative, phenylisoserine Xia Natick DOO, .rho. Kurorofuwe two the Ruisoshiane g) in a counter-:: two ⁇
  • reaction temperature is generally between 20 ° C and 150 ° C. C is good
  • the compound (I) of the present invention has, for example, the formula n-W
  • W ′ is halogen or R′— S 0 2 — 0— (where R ′ is lower (d
  • alkyl a group represented by showing a Fuweniru or p- tolyl) compound and the other symbols represented by as defined] and expression '
  • reaction between the compound (RO and the amines (V) can be carried out in a suitable organic solvent (eg, methanol, ethanol, dioxane, acetonitrile, tetrahydrofuran, N, N-dimethylformamide, methylene chloride, dimethyl sulfoxide and In any mixed solvent of a suitable organic solvent (eg, methanol, ethanol, dioxane, acetonitrile, tetrahydrofuran, N, N-dimethylformamide, methylene chloride, dimethyl sulfoxide and In any mixed solvent of a suitable organic solvent (eg, methanol, ethanol, dioxane, acetonitrile, tetrahydrofuran, N, N-dimethylformamide, methylene chloride, dimethyl sulfoxide and In any mixed solvent of a suitable organic solvent (eg, methanol, ethanol, dioxane, acetonitrile, tetrahydr
  • the reaction temperature is preferably about 0 ° C. to + 150 ° C.
  • an organic base such as triethylamine, pyridine, N, N-dimethylaniline, for example, carbon dioxide or sodium carbonate ,Carbonated water
  • An inorganic base such as sodium phosphate may be used as a catalyst.
  • the compound (I) of the present invention has, for example, the formula
  • Examples of the reducing conditions include catalytic reduction using a catalyst such as a metal such as platinum, palladium, Raney-nickel, and potassium or a mixture thereof with an optional carrier, for example, lithium aluminum hydride, lithium borohydride, shear Reduction with metal hydride compounds such as lithium borohydride, sodium borohydride, sodium cyanoborohydride, 'metal sodium, metal
  • a catalyst such as a metal such as platinum, palladium, Raney-nickel, and potassium or a mixture thereof with an optional carrier
  • lithium aluminum hydride, lithium borohydride, shear Reduction with metal hydride compounds such as lithium borohydride, sodium borohydride, sodium cyanoborohydride, 'metal sodium, metal
  • reaction conditions include reduction with magnesium and other alcohols, reduction with metals such as iron and zinc and acids such as hydrochloric acid and acetic acid, electrolytic reduction, and reduction with reductase.
  • the above reaction is usually carried out in the presence of water or an organic solvent (eg, methanol, ethanol, ethyl ether, dioxane, methylene chloride, chloroform, benzene, toluene, acetic acid, dimethylformamide, dimethylacetamide).
  • the reaction temperature is different depending on the reducing means, but is generally preferably about 120 to +100. This reaction can achieve the purpose of filling at normal pressure, but the reaction may be carried out under increased or reduced pressure depending on circumstances.
  • the compound (I) of the present invention can also be prepared, for example, by a compound of the formula
  • the reduction reaction For example, lithium aluminum hydride, Natoriumu, dimethyl Tokishimechiru Okishiarumi two ⁇ beam, hydrogenated Asetokishihou containing Natoriumu, hydrogenated aluminum two ⁇ beam, diborane.
  • Compounds of sulfoxide and sulfone in which m is 1 or 2 in formula (I) can also be produced by oxidizing the corresponding sulfide compound.
  • the oxidation reaction is carried out, for example, by reacting an organic peracid (eg, metabenzo-perbenzoic acid, peracetic acid) and an inorganic oxidizing agent (eg, hydrogen peroxide, periodic acid).
  • an organic peracid eg, metabenzo-perbenzoic acid, peracetic acid
  • an inorganic oxidizing agent eg, hydrogen peroxide, periodic acid.
  • the above reaction is usually carried out in the presence of water or an organic solvent (eg, methanol, ethanol, dioxane, dichloromethane), and is usually carried out at a temperature in the range of 20 ° C to + 100 ° C.
  • the target compound (I) of the present invention thus obtained is separated from the reaction mixture by a conventional method.
  • difference Isolation can be achieved by using separation and purification means such as oil extraction, concentration, neutralization, filtration, recrystallization, column chromatography, and thin layer chromatography.
  • separation and purification means such as oil extraction, concentration, neutralization, filtration, recrystallization, column chromatography, and thin layer chromatography.
  • ⁇ is> ⁇ ⁇ 1 when one is OR 5, there may be two stereoisomers least. Both of these individual isomers and mixtures thereof are, of course, included in the scope of the present invention, and these isomers can be produced individually if desired.
  • a single optical isomer of the compound (I) can be obtained.
  • the product is a mixture of two or more isomers, this is separated by a conventional separation method, for example, by forming a salt with an optically active acid (eg, camphorsulfonic acid, tartaric acid, dibenzoyltartaric acid, malic acid, etc.). Or by means of various separation methods such as chromatography and fractional crystallization.
  • an optically active acid eg, camphorsulfonic acid, tartaric acid, dibenzoyltartaric acid, malic acid, etc.
  • the compound of the present invention ie, the 1,5-benzozochepine derivative represented by the formula (I), is useful for animals, particularly mammals (eg, human, pig, dog, cat, egret, guinea pig, rat).
  • mammals eg, human, pig, dog, cat, egret, guinea pig, rat
  • specific cell opening phosphatonin S 2 receptor blocking action, a force Runumu antagonism, cerebral vasospasm remission action, renal circulation improving action indicates a diuretic and Kochi ⁇ , for example angina pectoris and the like myocardial infarction
  • It is useful as a prophylactic or therapeutic agent for cerebral circulatory disorders such as ischemic heart disease, blood ⁇ ⁇ hypertension, cerebral vasospasm ⁇ transient cerebral ⁇ blood attacks.
  • the compound of the present invention has low toxicity, is well absorbed even when administered orally, and has excellent stability, when it is used as the above-mentioned medicament, it may be used by itself or an appropriate pharmacologically acceptable carrier, excipient, and diluent. It can be safely orally or parenterally administered as a pharmaceutical composition such as powder, granules, tablets, capsules, injections, etc. by mixing with a medicament. The dose varies depending on the target disease state and the route of administration.
  • ischemic heart disease When administered to adult patients for the treatment of illness or hypertension, a single dose is usually about 0.1 to 1 OmgZKg, preferably about 0.3 to 3 mg / Kg for oral administration, and a single dose for intravenous administration. 0.0 3-0.img / Kg, especially 0.1-0.1 mg ZKg is preferable, and these dosages should be administered about 1-3 times a day depending on the symptoms. desirable.
  • Hal represents a halogen (eg, bromine, chlorine), and the other symbols are as defined above.
  • compound 01 is first used as a starting compound. Reacting with compound (IX) in an organic solvent (eg, acetone, acetonitrile, benzene, toluene, methylene chloride, N, N-dimethylformamide) and then reacting with compound (XI) Thus, compound (3 ⁇ 4) can be obtained.
  • an organic solvent eg, acetone, acetonitrile, benzene, toluene, methylene chloride, N, N-dimethylformamide
  • compound (3 ⁇ 4) can be obtained.
  • a base such as carbon dioxide and sodium bicarbonate coexist in order to promote the anti-IS rate.
  • the reaction rate is usually about 0 to + 120 ° C. preferable.
  • the compound wherein m is 1 or 2 can be produced by oxidizing the compound (XI).
  • the oxidation reaction is carried out, for example, by the action of an organic peracid (eg, peroxybenzoic acid, peroxyacid) or an inorganic oxidizing agent (eg, hydrogen peroxide, periodic acid).
  • the above reaction is usually carried out in the presence of water or an organic solvent (eg, methanol, ethanol, dioxane, dichloromethane), usually 120. C-10. It is performed in a temperature range of about C.
  • the compound in which m is 0 can be used for the next reaction without subjecting to the oxidation reaction.
  • the compound (x 'm) is usually subjected to a ring closure reaction to obtain a compound (XE) from an organic solvent (eg, M, N-dimethylformamide, acetonitrile, methanol, dimethyl sulfoxide).
  • an organic solvent eg, M, N-dimethylformamide, acetonitrile, methanol, dimethyl sulfoxide.
  • a base eg, sodium methoxide, It proceeds favorably in the presence of sodium ethoxide, tertiary butoxide, and sodium hydride.
  • the reaction temperature is usually preferably from about 120 ° C to about 100 ° C.
  • the compound (XIV ′) is obtained as an alkali metal salt in the above reaction
  • the compound (XB) can be isolated by a conventional method after neutralization with, for example, lauric acid, hydrochloric acid, sulfuric acid, or the like. .
  • the compound (VI) when X is a lower alkyl which may be substituted, the compound (VI) is reacted with the compound (XI) to obtain a compound (XV), and if necessary, the compound (XV) Is converted to a compound (XYI), subjected to a ring closure reaction, alkylated, and then subjected to a removal reaction of an ester group to obtain a compound (XX).
  • the reaction between compound (VI) and (a) can be carried out in the same manner as the reaction between compound (VI) and (IX).
  • the compound (XV) When the compound (XV) is converted to the compound (XVI), the compound (XV) can be converted to the compound ( ⁇ ) in the same manner as described above.
  • the ring closure reaction of (X vo ⁇ (xvi) can be performed in the same manner as the reaction of (xno ⁇ (x) y).
  • the reaction between compound (XVI) and (X) can be carried out using a suitable organic solvent (eg, acetone, 2-butanone, acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, benzene, toluene,
  • a suitable organic solvent eg, acetone, 2-butanone, acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, benzene, toluene
  • the reaction can be performed in the presence of a base (eg, sodium carbonate, carbonated carbonate, sodium hydrogencarbonate, sodium hydride, sodium methoxide, tritylamine, pyridine) in tetrahydrofuran.
  • a base eg, sodium carbonate, carbonated carbonate, sodium hydrogencarbonate, sodium hydride, sodium methoxide, tritylamine, pyridine
  • an iodine compound such as potassium iodide or sodium io
  • reaction of XDO ⁇ (XX) follows the usual ester group removal reaction, and the compound (XE) is converted to a suitable organic solvent (eg, dimethyl sulfoxide, N, N-dimethylformamide, ⁇ , ⁇ -dimethylacetamide) )
  • a suitable organic solvent eg, dimethyl sulfoxide, N, N-dimethylformamide, ⁇ , ⁇ -dimethylacetamide
  • salt eg, sodium chloride
  • the process proceeds by heating at about + 50 ° C to + 160 ° C in the presence of lithium chloride, calcium chloride, and sodium bromide.
  • compound (XXI) when X is hydrogen, compound (XXI) can be obtained by subjecting compound (XW) to a reaction similar to the reaction of ( ⁇ ) ⁇ ( ⁇ ).
  • Compound (XVI) is obtained by reacting compound 01) as a starting compound with compound ( ⁇ ), and then oxidizing a sulfur atom if necessary to obtain compound (XX1Y), which is subjected to the same ring closure reaction as described above. Further, it can also be produced by subjecting the obtained compound (XXV) to a usual hydrolysis reaction.
  • the reaction between compound (III) and (XXVII) can be carried out in the same manner as the reaction between compound (XW) and (XW).
  • Compound (III) can be obtained by subjecting compound (XXVI) to a reduction reaction.
  • a reduction reaction for example, lithium aluminum hydride, lithium borohydride, lithium cyanoborohydride, sodium borohydride, sodium 'n'anoborohydride, sodium tert-butoxide Reduction with metal hydrides such as lithium aluminum, reduction with metal sodium, metal magnesium, etc. and alcohols, catalytic reduction using a mixture of platinum, palladium, rhodium, etc.
  • reaction conditions such as reduction with a complex of a borohydride such as borane-trimethylamine and amines, etc.
  • the above reaction is usually carried out with water or an organic solvent (eg, methanol / ethanol).
  • an organic solvent eg, methanol / ethanol.
  • the reaction can be carried out by using a means of a rubamoylation reaction.
  • the means of the Ashiru reaction for example, a reactive derivative of an organic acid corresponding to R 5 (e.g., acid anhydride, acid halide) of an organic base (e.g., pyridinium Jin, Toryechiruami down, New, Nyu- Jimechiruaniri down ) Or an inorganic base (eg, sodium carbonate, calcium carbonate, sodium hydrogen carbonate) in the presence of compound (XXIX).
  • an organic base e.g., pyridinium Jin, Toryechiruami down, New, Nyu- Jimechiruaniri down
  • an inorganic base eg, sodium carbonate, calcium carbonate, sodium hydrogen carbonate
  • the above reaction is usually performed in an organic solvent (eg, methanol, ethanol, ethyl ether, dioxane, methylene chloride, toluene, dimethylformamide, pyridine), and the reaction temperature is generally 120 ° C. It is preferably about + 100 ° C.
  • the catalyzed molybmoylation reaction is carried out, for example, by adding an isocyanate (eg, methyl isocyanate, ethyl isocyanate, phenyl isocyanate) corresponding to R 5 to an alcohol derivative (XXIX) obtained by a reduction reaction. , P-chlorophenylisocyanate).
  • reaction temperature is preferably about 120 ° C. to about 110 ° C.
  • reaction between compound (XB and (XX XI) can be carried out in the same manner as the reaction between compound (XVI) and (XVI).
  • Compound (XXX ffi) is obtained by converting compound (XXX n) to a dilute mineral acid (column ⁇ ). , Hydrochloric acid, sulfuric acid).
  • the compound (XXVI) can be obtained by subjecting the compound ( ⁇ ) to a reaction similar to the reaction of () (3 ⁇ 40 ⁇ (1 [[)).
  • the compound used in the reaction may be any one of inorganic salts such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc., as long as the reaction is not hindered.
  • organic acid salts such as acetate, tartrate, citrate, fumarate, maleate, toluenesulfonate and methanesulfonate
  • metal salts such as sodium, potassium, calcium, and aluminum salts
  • a salt such as a salt with a base such as a triethylamine salt, a guanidine salt, an ammonium salt, a hydrazine salt, a quinine salt or a cinchonine salt.
  • Methyl 7-methoxy-1,3-oxo-3,4-dihydro 2H-1,5-benzobenzoxepin 4-carboxylate 2.0 g, l-chloroacetyl, 4-phenylbiperazine 1.
  • Table 1 shows the results obtained by condensing methyl 3-oxo-1,3,4-dihydro 2H-1,5-benzobenzoxepin-14-carboxylate with halides in the same manner as in Reference Example 9. A compound is obtained.
  • Cis isomer Recrystallized from ethyl acetate to obtain colorless needles. Melting point 2 13-2 15 ° C. Mass vector tn / e: 4 7 2 (M +)
  • Trans isomer hydrochloride Recrystallized from methanol and ether to obtain colorless needles. Melting point 170-180 ° C (decomposition)
  • a mixture of 46 g of potassium chloride, 10 g of potassium iodide, 1.0 g of tetrabutylammonium iodide and 300 ml of acetonitrile is heated to reflux for 4 hours. After cooling, the inorganic substance was removed by filtration, the filtrate was concentrated under reduced pressure, the resulting residue was dissolved in ethyl ethyl ether, washed with water and dried, and the solvent was removed under reduced pressure.
  • Reference Example 3 4- (3-chloropropyl) -1 7-methoxy 3,4 dihydro 2H-1,5 obtained in 5-5-Benzoxacepine 13-one 0.8 g of tetrahydrofuran Dissolve in a solution of 2 ml and 10 mi of methanol, add 0.1 g of sodium borohydride under ice-cooling, and stir for ⁇ hour. The reaction mixture is concentrated under reduced pressure, and water and ethyl acetate are added to the residue and shaken. The organic layer is separated, washed with water and dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure.
  • a mixture of 9.8 g of chloride, 6.2 g of anhydrous potassium carbonate, 3.0 g of potassium iodide and 150 ml of methyl ethyl ketone is stirred for 25 hours while heating under reflux. After cooling, the inorganic substance is removed by filtration, the filtrate is concentrated under reduced pressure, and the residue is dissolved in ethyl ethyl eluate, washed with water and dried.
  • Example 2-11 The compound obtained in Example 2-11 was reduced with sodium borohydride in the same manner as in Example 12 to obtain the compound shown in Table 4.
  • Reference Example 22 4- (1,3-dioxolan-1-yl) ethyl-7-methoxy-3,4-dihydro-2H-1, 5-benzobenzoxepin-3-one 0.8 obtained in Reference Example 2 0.8 g) in 20 ml of methanol, and add sodium borohydride little by little while stirring. When spots of the raw material disappear on thin layer chromatography, add 1N sodium hydroxide solution and extract with ethyl acetate. The organic layers are combined, washed with water and dried, and the solvent is distilled off under reduced pressure. Dioxane 5 nil, water 2 ml and p-toluenesulfo
  • Cis-1- (2-Jetylaminoethyl) -14-hydroxymethyl-7-methoxy-3,4-dihidro 2H-1, 5-benzobenzoxepin 1-3 obtained in Example 25 Dissolve 0.7 g of all in 10 ml of pyridine, add 6 ml of acetic anhydride, and leave at room temperature for 3 hours. Pour the reaction mixture into ice water and extract with ethyl acetate.
  • Example 27 The compound obtained in Example 12 was acetylated in the same manner as in Example 7 to give methyl cis-3-acetoxy 7-methoxy 41- [3- (4-phenylbiperazine-11-yl)] ⁇ Pill] 1,3,4 dihdro 2 ⁇ — 1,5—Benzoxaxepin 14 1-strength lipoxylate is obtained. Recrystallized from ethyl acetate- ⁇ -hexane to form colorless prism crystals. Melting point: 168—170 ° C The structure of this product can be determined by X-ray crystallography.
  • Example 12 The compound obtained in Example 12 was reduced with lithium aluminum hydride in the same manner as in Example 24 to give cis-14 hydroxymethyl-7-methoxy4-1- [3- (4-phenylpyrazine-1-yl). ) Propyl] —3,4-Dihydro 2H—1,5—Benzoxachebishy 3-ol. Recrystallization from ethyl acetate gives colorless needles. Melting point 1 6 3— 1 6 5 ° C Elemental value C 24 H 32 N 20 + S
  • Example 3 Methyl 3-oxo-1- [3 (4-phenylpiperazin-1-yl) propizole] -1,3,4-dihydro-2H-1,5-benzobenzosapepin-1-carboxylate hydrochloride obtained in Example 2
  • the cis form is obtained from the fraction that elutes after the trans form from the fraction that elutes in the form (1).
  • Methyl 7-chloro-1,3-oxo-1,3,4-dihydro 2H-1, 5-benzobenzoxachepine-4 carboxylate was prepared in the same manner as in Example 1 to give 3- (4-pheno).
  • Nylbiperazine—1—yl) propyl chloride is reacted with methyl 7—chloro-1,3-oxo-1,4- [3- (4-phenylpyrazine-1—yl) propyl] 1,3, 4-dihydro-2H-1,5-benzoxacepine 14-carboxylate is obtained.
  • a white powder is obtained as the hydrochloride.
  • Methyl 7-chloro-1-3-oxo-4-1- [3- (4-phenylbiperazin-1-yl) propyl] -1,3,4-dihydro2H-1, 5-benzobenzosachepin-4-carboxyle was reduced with sodium borohydride in the same manner as in Example 12, and methyl 7-chloro-3-hydroxy-4- [3- (4-phenylpyrazine-1 1-yl) -pulp] -3, The cis and trans isomers of 4-dihydro-1 2 H-1,5 and 5-benzoxacepin 4-carboxylate are obtained.
  • the mixture was reacted with 4-phenylpyrazine and treated with methyl cis-3-hydroxy-7-methyl-4-.
  • Methyl cis-1 7-Chloro 4- (3-Clo-propyl) -1 3-Hydroxy-3,4-Dihydro-2H-1,5-Benzoxachepin-14 4-Ripoxylate 0.15g was reacted with N-methyl-2- (3,4-dimethoxyphenyl) ethylamine in the same manner as in Example 39 to give methyl cis-17-chloro-13-hydroquinine 4- ⁇ 3- [N —Methyl-2- (3,4-dimethoxyphenyl) ethylamino] propyl ⁇ —3,4-Dihydro-2H—1,5-benzobenzoxepin—4-carboxylate oil 0.08g
  • the melting point in Reference Examples and Examples is a value measured by a Yanagimoto Micro Melting Point Measuring Device unless otherwise specified.
  • the method of Bevan & 0 sher (Agents Action, 2, 257, 1972 The experiment was performed using a modified method. That is, the pig heart obtained immediately after slaughter at the slaughterhouse was stored under ice cooling, and the left circumflex coronary artery was separated and collected within 3 hours.
  • a ring-shaped blood vessel sample was prepared by cutting the coronary artery into a slice of about 3 mm in width and suspended in a double-walled organ bath containing 20 ml of Krebs-Henseleit solution using a pair of suspension needles. One of the suspension needles was fixed to the bottom of the organ bath, and the other was connected to a strain transformer user, and the contraction of the porcine coronary artery ring specimen was measured isometrically and recorded on a polygraph recorder.
  • Serotonin S 2 -selector blocking action was measured in the same manner as in Experimental Example 1.
  • the experiments were performed using male beagle dogs weighing 10-14 kg.
  • a polyethylene tube was previously placed in the femoral artery and the femoral vein for measurement of systemic blood pressure and intravenous administration of the drug. That is, surgery was performed aseptically under anesthesia with vent palpitar sodium (intravenous administration of 3QmgZkg), a polyethylene tube was placed in the femoral artery and the femoral vein, and the tube was stoppered. The other end was guided subcutaneously to the back and then out of the body through the skin.
  • the experiment was performed 2-3 days after the operation. That is, the in-arterial indwelling polyethylene tube was connected to a pressure transducer, and the systemic blood pressure was measured and continuously recorded with a polygraph recorder.
  • a transient pressor response was observed in a dose-dependent manner.For example, 30 g / kg was administered for about 30 minutes.
  • a reproducible pressor reaction was observed. Therefore, 30 zg / kg of serotonin was used to examine the effect of the compound of the present invention after oral administration.
  • a Krebs-Henseleit solution is perfused at a rate of about 4 ml / min from the mesenteric artery while heating at 37 ° C.
  • the perfusion pressure was measured (perfusion pressure: about 40 mmHg :).
  • the inhibitory effect on the perfusion pressure increase response when a KC1OmgZ specimen was injected into the mesenteric artery was used. Compounds were injected intra-arterially for 30 minutes prior to KC1 injection.
  • Example 12 cis-dihydrochloride
  • Example 12 ⁇ of (cis) is 10- 7 ⁇ 3 X10 e M a significant KC 1 dose dependency Boost suppression Shown for production.
  • Spontaneously hypertensive rats (13-week-old, male) were used as 5 animals per group.
  • the drug was suspended in a small amount of gum arabic and saline and administered orally at a volume of 25 ml / kg.
  • the control group received only saline containing gum arabic.
  • the rats were placed in a metabolic cage for urine collection, and urine was collected for 5 hours. Urine volume and urinary Na + K + excretion were measured. Na + and K + were measured with a flame photometer (Hitachi 205 DT).
  • Example 12 shows the results.
  • the compound of Example 12 (cis-dihydrochloride) showed a tendency to promote urinary volume, Na + and K + excretion by oral administration of 3 mg / kg, a significant increase in urine volume at iOmg / kg or higher, and a significant increase at 30 mg / kg. There was a significant increase in urine volume, Na + and K +.
  • the test drug was administered intravenously.
  • the compound of Example 12 suppressed the periodic change of coronary blood flow in a dose-dependent manner at a dose of 1 g / kg or more by intravenous administration (Table 13). That is, the compound of Example 12 (cis-form dihydrochloride) suppressed blood formation caused by impaired intravascular blood flow in vivo.
  • Table 13 Effect of periodic changes in coronary blood flow on frequency
  • the numerical value is the number of cyclic changes in the coronary blood flow for 30 minutes, and the numerical value is the mean soil standard error. : P rather than 0.05, ⁇ ;: '*: > 3 ⁇ 4: ⁇ Ku 0,001 Experimental Example 7
  • angiography a polyethylene nucleus was chronically placed in advance in the right vertebral artery under vent valpital anesthesia (30 mg / kg, intravenous administration). Cerebral angiography is performed by injecting 10 ml of the contrast agent, Yodami-Dogglutamine, from a chronic indwelling power source each time under pentobarbital anesthesia. — 50 U). The subarachnoid hemorrhage was caused by injecting 5 ml of fresh autologous blood collected from the inferior venous vein into the cisternal using a spinal needle under pentoparbital anesthesia 2 days after the instillation of the power nutrient. Brain angiography before subarachnoid hemorrhage and on days 3, 6, and 13 The basilar artery was measured.
  • the animals were divided into two groups of three animals, one group was used as a control, and the other group was administered the compound of Example 39 (-hydrochloride).
  • the compound was orally administered at 30 mg / kg on the day of subarachnoid hemorrhage, 1 mgZkg intravenously immediately after subarachnoid hemorrhage, and thereafter, orally at 30 mg / kg daily until 13 days after subarachnoid hemorrhage.
  • Table 14 shows the basilar artery diameter before subarachnoid hemorrhage and the diameter change after subarachnoid hemorrhage.
  • the basilar artery diameter decreased by about 40 and 60% 3 days and 6 days after subarachnoid hemorrhage, respectively, and cerebral vasospasm was observed.
  • the basilar artery diameter decreased slightly in the compound-treated group, and the degree of the decrease was significantly lower than that in the control group.
  • a beagle dog weighing 9-14 kg (normal blood pressure) was used. Pentobarbital Anesthesia was performed along the abdominal midline under anesthesia. In order to measure renal blood flow, the left renal artery was separated, and a probe for electromagnetic blood flow was mounted. In addition, OMPI replaces URt4 A polyethylene tube was inserted retrograde into the abdominal aorta for measurement and fixed. The lead wire of the blood flow meter probe and the other end of the polyethylene tube were exposed subcutaneously to the back of the neck. One week or more after the operation, the animals were subjected to the experiment under anesthesia. Renal blood flow was measured with an electromagnetic flowmeter, and systemic blood pressure was measured with a pressure transducer. The heart rate was measured by driving a pulse rate tachometer with a blood pressure pulse wave.
  • Example 39 (-hydrochloride) was orally administered, but when repeatedly administered to the same individual, an interval of 3 days or more was given.
  • the compound (I) of the present invention when used, for example, as a therapeutic agent for ischemic heart disease, it can be used, for example, according to the following formulation.
  • Ingredients (1), (2) and 17 g of (3) are mixed and granulated together with 7 g of the paste made from component (3), and 5 g of components (3) and (4) are added to the granules.
  • the mixture is compressed with a compression tablet machine to produce 1000 tablets (7 mm diameter tablets containing 1 Qmg).
  • the 1,5-benzozochepine derivative (I) provided by the present invention has an excellent pharmacological action and is useful as a pharmaceutical.

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Abstract

Des nouveaux dérivés de 1,5-benzoxathiepines représentés par la formule (I), (où R1 et R2 représentent chacun H, un halogène, OH, un alkyle inférieur ou un alkoxy inférieur, R3 et R4 représentent chacun H ou éventuellement un alkyle, cycloalkyle ou aralkyle inférieur de substitution, ou bien, pris ensemble avec l'atome adjacent d'azote, R3 et R4 forment un cycle, X représente H, éventuellement un alkyle inférieur de substitution, éventuellement un aryle de substitution ou éventuellement un carboxy estérifié ou amidé, Y représente >C=O ou CH-OR5 (où R5 représente H, un aryle ou éventuellement un carbamoyle de substitution), m répresente un entier de 0 à 2, et n répresente un entier de 1 à 6) et leurs sels possèdent un effet de blocage du récepteur sérotonine S, une action antagoniste du calcium, une action réductrice de la contraction des vaisseaux sanguins cérébraux, un effet d'amélioration de la circulation rénale, une action diurétique, ainsi qu'une action anti-thrombotique, et sont donc utiles comme médicaments pour la prophylaxie et le traitement des maladies cardiaques, de la thrombose, de l'hypertension et des troubles de la circulation cérébrale.
PCT/JP1984/000526 1983-12-14 1984-11-01 Derives de 1,5-benzoxathiepines et leur procede de preparation Ceased WO1986002644A1 (fr)

Priority Applications (27)

Application Number Priority Date Filing Date Title
PCT/JP1984/000526 WO1986002644A1 (fr) 1984-11-01 1984-11-01 Derives de 1,5-benzoxathiepines et leur procede de preparation
DK584184A DK166779B1 (da) 1983-12-14 1984-12-07 1,5-benzoxatiepinderivater eller farmaceutisk acceptable salte deraf, samt farmaceutisk praeparat indeholdende en saadan forbindelse
AU36468/84A AU570753B2 (en) 1983-12-14 1984-12-10 Benzoxathiepin derivatives
ES538517A ES8702399A1 (es) 1983-12-14 1984-12-12 Un procedimiento para preparar derivdos de 1,5-benzoxatiepina
GR81240A GR81240B (en) 1983-12-14 1984-12-12 1,5-benzoxathiepin derivatives, their production and use
NO844993A NO169773C (no) 1983-12-14 1984-12-12 Analogifremgangsmaate for fremstilling av terapeutisk aktive 1,5-benzoksatiepinderivater
CA000469996A CA1247613A (fr) 1983-12-14 1984-12-13 Derives de la 1,5-benzoxathiepine; preparation et utilisation
EP84308691A EP0145494B1 (fr) 1983-12-14 1984-12-13 Dérivés de 1,5-benzoxathiépine, leur production et usage
FI844940A FI80029C (fi) 1983-12-14 1984-12-13 Foerfarande foer framstaellning av nya, farmaceutiskt aktiva 1,5-bensoxatiepinderivat.
PT79666A PT79666B (en) 1983-12-14 1984-12-13 1,5-benzoxathiepin derivatives their production and use
AT84308691T ATE47851T1 (de) 1983-12-14 1984-12-13 1,5-benzoxathiepin-derivate, deren herstellung und verwendung.
IE320684A IE58159B1 (en) 1983-12-14 1984-12-13 1,5-Benzoxathiepin derivatives, their production and use
EP87116048A EP0300088A3 (fr) 1983-12-14 1984-12-13 Dérivés de 1,5-benzoxathiépine, leur production et usage
HU844657A HU201922B (en) 1983-12-14 1984-12-13 Process for producing 1,5-benzoxathiepin derivatives and pharmaceutical compositions comprising same
DE8484308691T DE3480397D1 (en) 1983-12-14 1984-12-13 1,5-benzoxathiepin derivatives, their production and use
KR1019840007941A KR910009288B1 (ko) 1983-12-14 1984-12-14 1,5-벤족사티에핀 유도체의 제조방법
PH31583A PH21851A (en) 1983-12-14 1984-12-14 1,5-benzoxathiepin derivatives and pharmaceutical compositions containing them
CN85104426.3A CN1008737B (zh) 1984-11-01 1985-06-11 苯并[1]氧[5]硫杂环庚烯衍生物的制备方法
PH32900A PH23423A (en) 1983-12-14 1985-10-08 Process of preparing 1,5-benzoxathiepin derivatives
US06/806,809 US4672064A (en) 1983-12-14 1985-12-10 1,5-benzoxathiepin derivatives, their production and use
ES551262A ES8705417A1 (es) 1983-12-14 1986-01-27 Un procedimiento para preparar derivados de 1,5-benzoxatiepina
PH34714A PH23651A (en) 1983-12-14 1987-01-13 Process for producing 1,5-benzoxathiepin derivatives
US07/038,787 US4751316A (en) 1983-12-14 1987-04-15 1,5-benzoxathiepin derivatives
CA000575740A CA1258463A (fr) 1983-12-14 1988-08-25 Derives de 1,5-benzoxathiepine, production et utilisation
CA000575739A CA1258462A (fr) 1983-12-14 1988-08-25 Derives de 1,5-benzoxathiepine, production et utilisation
JP1032376A JPH02191272A (ja) 1983-12-14 1989-02-10 １，５―ベンゾオキサチエピン誘導体
JP1032375A JPH02191271A (ja) 1983-12-14 1989-02-10 １，５―ベンゾオキサチエピン誘導体

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5625233B2 (fr) * 1977-11-05 1981-06-11

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5625233B2 (fr) * 1977-11-05 1981-06-11

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Phosphorus Sulfur, Vol. 14, No. 2, (1983), C. Savatore et al., p. 151-156 *

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