WO1985004658A1 - Derives de 1,5 benzoxathiepine et leur preparation - Google Patents

Derives de 1,5 benzoxathiepine et leur preparation Download PDF

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Publication number
WO1985004658A1
WO1985004658A1 PCT/JP1984/000168 JP8400168W WO8504658A1 WO 1985004658 A1 WO1985004658 A1 WO 1985004658A1 JP 8400168 W JP8400168 W JP 8400168W WO 8504658 A1 WO8504658 A1 WO 8504658A1
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WIPO (PCT)
Prior art keywords
reaction
compound
formula
hydrogen
acid
Prior art date
Application number
PCT/JP1984/000168
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English (en)
Japanese (ja)
Inventor
Hirosada Sugihara
Minoru Hirata
Original Assignee
Takeda Chemical Industries, Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Takeda Chemical Industries, Ltd. filed Critical Takeda Chemical Industries, Ltd.
Priority to PCT/JP1984/000168 priority Critical patent/WO1985004658A1/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 EP87116048A priority patent/EP0300088A3/fr
Priority to FI844940A priority patent/FI80029C/fi
Priority to DE8484308691T priority patent/DE3480397D1/de
Priority to PT79666A priority patent/PT79666B/pt
Priority to EP84308691A priority patent/EP0145494B1/fr
Priority to IE320684A priority patent/IE58159B1/en
Priority to HU844657A priority patent/HU201922B/hu
Priority to AT84308691T priority patent/ATE47851T1/de
Priority to CA000469996A priority patent/CA1247613A/fr
Priority to PH31583A priority patent/PH21851A/en
Priority to KR1019840007941A priority patent/KR910009288B1/ko
Priority to PH32900A priority patent/PH23423A/en
Publication of WO1985004658A1 publication Critical patent/WO1985004658A1/fr
Priority to US06/806,809 priority patent/US4672064A/en
Priority to ES551262A priority patent/ES8705417A1/es
Priority to PH34714A priority patent/PH23651A/en
Priority to US07/038,787 priority patent/US4751316A/en
Priority to CA000575739A priority patent/CA1258462A/fr
Priority to CA000575740A priority patent/CA1258463A/fr
Priority to JP1032376A priority patent/JPH02191272A/ja
Priority to JP1032375A priority patent/JPH02191271A/ja

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    • 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, 5-pentazoxachevin 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, the present inventors have found not only an excellent serotonin s 2 receptor blocking action, but also a calcium antagonism action and a diuretic action. It also has antithrombotic effects, and is useful as a prophylactic or therapeutic agent for ischemic heart diseases such as angina pectoris and myocardial infarction, and thrombosis and hypertension. Successful production of novel and 5-benzoxoxathipinepine derivatives Thus, the present invention has been completed.
  • the present invention uses the formula
  • B 2 each represent hydrogen, halogen, hydroxy, lower alkynole or lower alkoxy
  • E 3 and R 4 represent hydrogen, lower alkyl or optionally substituted cycloalkyl or alkenyl, respectively.
  • X is hydrogen, substituted or low-alkyl, substituted or aryl- or esterified or amidated, carboxyl
  • Y is> C - 0 or ⁇ rCH- 0E 5 (wherein, E 5 is hydrogen, ⁇ sheet or indicates the goodness amide substituted) indicates an integer of m Wahi 1-2 , II represents an integer from t to 6], a salt thereof, and a method for producing them.
  • Examples of the lower aki group represented by R L or E 2 include aki groups having about 1 to 4 carbon atoms, such as meth, eth, propyl, isoprop; w, butyl, sec-butyl; u, tert-butyl.
  • Examples of the lower alkoxy group represented by, R i or include methoxy, ethoxy, broboxy, isopropoxyg, butoki, isobutoxy, sec-butoxy, ert butoxy, and any alkoxy group having about 1 to 4 carbon atoms. .
  • Examples of the lower alkyl group represented by E 3 or E 4 include an alkyl group having about 1 to 4 carbon atoms, such as meth, ethyl, pro-H, isobrobi, buty, isobuti, sec-buty, ter-71-buty.
  • Examples of the cycloalkyl group represented by R 3 or R 4 include, but are not limited to, a cycloalkyl group having about 3 to 8 carbon atoms, such as cyclo nbutyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohepty, cyclooctyl.
  • Agerare, the cycloalkyl group for example ( ⁇ _ 4 A key group (e.g., main switch, E Ji, Turks, butyl etc.), ( ⁇ one 4 A Koki ⁇ groups (e.g., main butoxy, ethoxy, Purobokishi, iso Propoxy, butoxy, etc.),
  • ⁇ la key group represented by R 4 example Penjiru, phenethyl, 3 Ichipuko - Help pills, lambda Mechi Penji, a one E Ji 1 / Penzi, a-methyl buenetyl, ⁇ -methi funeti; U, ⁇ - eth A bueneti
  • halogens e.g., fluorine,
  • Examples of such substituted pheno-lower alkyl groups include 2- (4-chloro). Mouth)) ethyl, 2-(4-hydroxyphenyl) eth, 2-(4-methoxyphenyl) eth 2 ⁇ 2 (3, 4 dimethyl phenyl) eth, 2 3 (3, 4, 5 ⁇ 1) Trim Toki Shifue), 21- (3,4-methylenedioxy) ⁇ ), 21- (p-1tri), 3,4,1-dimethoxyphene, 34-methylenedixybenzy, 3,4,5 -Trimethoxybenzyl, 41-pentyl, 41-cloth pen, etc.
  • Examples of the ring formed by R 3 and H 4 together with the adjacent nitrogen atom include, in addition to the nitrogen atom, a cyclic amino group which may have any heteroatom such as nitrogen, oxygen, and sulfur. It contains 5 amino acids, such as molyyl, biberyl, vibezyl, and homobiperazyl, and five cyclic amino groups.
  • the amino amino group may have a substituent at a substitutable 3 ⁇ 4 position. Examples of such a substituent include low ⁇ (c x _ 4 )
  • aryl group examples include a phenyl group.
  • halogen eg,
  • the phenyl group in the aralkyl group and the aromatic organic acid residue may have 1 to 3 groups such as a halogen (eg, pulp, nitrogen, bromine, iodine), a Ci-4 anolex group (eg, a methyl group).
  • Heterocycles as substituents include, for example, pyrrolyl, pyrazolyl, imidazolyl, pyridyl; 1 /, pyrimidyl-, pi! A 5- to 7-membered ring containing 1 to 3 nitrogen atoms, such as dazini, triazini and azepi.
  • the lower alkyl group represented by X is, for example, an alkyl group having about 1 to 4 carbon atoms, such as meth, eth, bromo, isoprop, buty, isobut, sec-buty, tert-buty. May be substituted with, for example, y, hydroxy, acyl, or aryl.
  • Examples of the lower parent group substituted with oxo include aceti, buchibi-, and butyryl. Is raised.
  • Examples of the lower alkyl group substituted with hydroxy include a hydroxymethyl group.
  • Examples of the acyl group as an acyl group include an acyl group derived from a lower fatty acid such as acetyl, propyl, and butyryl.
  • Examples of the lower alkyl group substituted with a phenyl include quaternary (Ci-4) alkyl substituted with a phenyl group, and the phenyl group has one to three groups, for example, halogen (eg, halogen). , Azulium, chlorine, bromine, iodine), c ⁇ — 4
  • alkoxy group eg, methoxy, ethoxy, propoxy, isobutoxy, n, butoxy
  • methylenedioxy amino, nitro, hydroxy, etc. May be replaced by
  • the aryl group represented by X includes, for example, a phenyl group, and the phenyl group has 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine), c, _ ⁇ alkyl group (e.g., methylcarbamoyl, E Ji, Turks, blanking chill), Ci one 4 A Kokishi group (e.g., main butoxy, ethoxy, propoxy, Isopuropoki ⁇ , butoxy), Mechirenjiokishi group, Amino groups, two Toro group, human It may be substituted by a droxy group or the like.
  • halogen atoms eg, fluorine, chlorine, bromine, iodine
  • c e.g., methylcarbamoyl, E Ji, Turks, blanking chill
  • Ci one 4 A Kokishi group e.g., main butoxy, ethoxy, propoxy, Is
  • (Ci-) Fe-lower alkoxycarbols such as acoxica balls and benzyl-based xycarbols.
  • the amidated carboxyl group represented by 2: is, for example, a norebamoy group, and the amino group of the canolebamoy group is one or two quaternary (( ⁇ -4) aki, fu- , Hue-may be replaced by lower alkynoleds.
  • Examples of the acyl group represented by E g include acetinol, propio-M butylyl, parelli, and vivaloy, such as an anorecanol group having about 1 to ⁇ carbon atoms, penzol, fenacet, fu- / V 7 *
  • An aromatic group derived from boric acid for example, a group in which the aromatic group is a phenyl group in the aromatic group, and the phenyl group is composed of three or more halogen atoms, for example. ..
  • alkyl group eg, meth, eth, propyl, buty A, CJ ⁇ oxy group (eg, methoxy, ethoxy, propoxy, y) y-propoxy, butoxy), a methylenedioxy group, an amino group, a nitro group or a hydroxy group.
  • force Bamoi can be mentioned, amino group ⁇ Anoreki of ⁇ Ka Bamoi group (e.g., methylcarbamoyl, E Ji, flop port pills, butyl), Hue -, phenylene over low Suialki (It may be substituted by Italy, benzyl, phenethyl / etc.)
  • the phenyl group of the phenyl group and the phenyl-lower quinole group may be one to three, for example, halogen.
  • Ci-4 alkyl group eg, meth, eth, propyl, butyl
  • ⁇ —4 alkoxy group eg, methoxy, ethoxy, propoxy, ibupropho
  • methylenedioxy amino, nitro, hydroxy, etc.
  • the sulfur atom in the formula (I) depends on the value of E, for example, sulfide, sulfo
  • the group-(C3 ⁇ 4) Q- in the formula (I) forms a ⁇ > according to the value of n, for example, methylene, dimethylene, trimethylene, tetramethylene, pentamethylene, and hexamethylene.
  • Examples of compound (I) include inorganic salts such as hydrochloride, hydrobromide, sulfate, nitrate, and phosphate, such as citrate, tartrate, citrate, fumaric acid, and maleic acid. Acid salts, toluenesulfonic acid, methanesulfonate Salts with any organic acid, and any pharmacologically acceptable salts.
  • inorganic salts such as hydrochloride, hydrobromide, sulfate, nitrate, and phosphate, such as citrate, tartrate, citrate, fumaric acid, and maleic acid.
  • the compound (I) of the present invention is, for example, a compound represented by the formula
  • W is halogen or the formula R-S0 2 -0 - group represented by (E lower A key, flop We - shows a tolyl - le or p ) Is subjected to a condensation reaction, a reduction reaction after the condensation reaction, or a reduction reaction after the condensation reaction, followed by an acylation or carbamoylation reaction. .
  • the condensation reaction is usually carried out in the presence of a ⁇ group
  • examples of the base include, for example, lithium carbonate, lithium hydrogencarbonate, sodium carbonate, sodium methoxide, sodium hydride, lithium diisoprobiamide.
  • Inorganic bases such as triethylamine, pyridine, 1,8-diazabicyclo [5,4, 0] -7-Pindecene and other organic amines.
  • the reaction can be favorably advanced by using, for example, sodium iodide, iridium iodide, or the like as a catalyst.
  • the above reaction is usually carried out in an organic solvent (eg, acetone, 2-butanone, acetate-tri,, Bf-dimethylformamide, methylene chloride, benzene, tonolene, tetrahydrofuran, dioxane),
  • the reaction temperature is -20 e C ⁇ +15 ⁇ " ⁇ , and preferably +20 to ⁇ +120 e C -CtT.
  • the above reaction is usually carried out with water or an organic solvent (eg, methano-noreth, ethano-, ethynolete, dioxane, methylene chloride, octaform, benzene, toluene, acetic acid, dimethylformamide, dimethylacetamide) )), and the reaction temperature varies depending on the reducing means, but is generally preferably about ⁇ 20 to 100 ° C.
  • an organic solvent eg, methano-noreth, ethano-, ethynolete, dioxane, methylene chloride, octaform, benzene, toluene, acetic acid, dimethylformamide, dimethylacetamide
  • acylation or hydropamoylation reaction after the condensation reduction, it is possible to carry out the reaction using an ordinary alcohol-derivative acylation or thermopamoylation reaction.
  • means of such an acylation reaction include, for example, a reactive derivative of an organic acid corresponding to R 5 (an acid anhydride, an acid halide).
  • Product in the presence of an inorganic base such as pyridine, triethylamine, if, U-dimethylaline, an organic base, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, or the like. it can.
  • the above reaction is usually carried out in an organic solvent (eg, methanol, ethanol, ethyl ether, dioxane 'methylene chloride, pentane, dimethylformamide, pyridine), and the reaction temperature is generally -203 ⁇ 4 ⁇ . + ⁇ 00 is preferable.
  • an organic solvent eg, methanol, ethanol, ethyl ether, dioxane 'methylene chloride, pentane, dimethylformamide, pyridine
  • the force Bamoi reaction is the A code derivative obtained in example reduction, Isoshiane preparative acids corresponding to E 5 (eg, methylcarbamoyl Isoshiane - DOO, Echirui Soshiane doo, phenylene Ruisoshiane bets, p - black port Hue
  • -Izosyanet can get ⁇ rr reacted.
  • the above reaction is usually carried out in a suitable organic solvent (eg, methano-, ethanol, acetate-tolyl, dioxane, tetrahydrobran, methylene chloride, chloroform, toluene,, ir-dimethinoleformamide).
  • a suitable organic solvent eg, methano-, ethanol, acetate-tolyl, dioxane, tetrahydrobran, methylene chloride, chloroform, toluene,, ir-dimethinoleformamide.
  • medium "CFT cracks the reaction temperature is generally degree is preferred to +1 50 one 20 for ⁇
  • the compound (I) of the present invention is, for example, a compound of the formula
  • R3 and B4 have the same meanings as defined above.
  • the compound (I) of the present invention has, for example, the formula
  • Examples of the reducing conditions include catalytic reduction using a metal such as platinum, palladium, Raney-Rocke, rhodium, or a mixture thereof with an optional carrier, such as lithium hydride aluminum, lithium borohydride. , Lithium cyanoborohydride, sodium borohydride, sodium cyanoborohydride, reduction by metal hydride ⁇ , sodium metal hydride,
  • OMPI Reaction conditions such as reduction with metal magnets, lumps and alcohols, reduction with metals such as iron and zinc and hydrochloric acid and sulfuric acid, electrolytic reduction, and reduction with reduced sulfur can be used.
  • the above reaction is usually carried out with water or an organic solvent (eg, methanol, ethanol ⁇ , ethiate, dioxane, methylene chloride, clofenhomone, zenzen, benzene, drenchic acid, dimethylformamide, dimethyla).
  • the reaction is carried out in the presence of (cetoamide), and the reaction temperature is different depending on the reducing means, but is preferably about ⁇ 20′C to + ⁇ 00. This reaction can sufficiently achieve its purpose at normal pressure, but 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 is carried out by using a reducing means such as lithium aluminum hydride, sodium hydride, dimethyxmethy 1 year old xialuminum, sodium acetoborohydride, aluminum hydride, diborane, or alkylborane.
  • a reducing means such as lithium aluminum hydride, sodium hydride, dimethyxmethy 1 year old xialuminum, sodium acetoborohydride, aluminum hydride, diborane, or alkylborane.
  • the above reaction is usually carried out in the presence of an organic solvent (eg, ethyl ether, tetrahydro: 7 run, dioxane, toluene, benzene), and the reaction temperature varies depending on the reduction means, but is generally ⁇ 20 e C ⁇ . Approximately +120 e C is preferable.
  • the reduction reaction in the formula (W): when ⁇ is, for example, an esterified or amidated carboxyl, and
  • a compound which is a sulphoxide or a sulphone in which a melon is i or 2 can also be produced by oxidizing a corresponding sulfide compound.
  • the oxidation reaction is carried out, for example, by reacting an organic peracid (eg, perbenzoic acid, peracetic acid, peracetic acid) and 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 in a temperature range of ⁇ 20 ° C. to +10 O′C.
  • the objective compound (I) of the present invention thus obtained can be obtained by using ordinary separation and purification means from the reaction mixture, for example, extraction, concentration, neutralization, bacteria, recrystallization, column chromatography, thin-layer chromatography, and the like. Can be isolated.
  • Bakai example IT is CE-OE 5, it may exist stereoisomers of small 3 ⁇ 4 Kutomo 2 ⁇ . The difference between these individual isomers and their mixtures is, of course, included in the box of the present invention. D, if desired].
  • These isomers can also be produced individually. For example, the above reaction is carried out using a single isomer of each of the raw compounds (W) and (I)], and a single optical isomer of the compound (I) can be obtained. If the product is a mixture of two or more isomers, it can be separated by the usual separation method, for example, using an optically active acid (eg, camphorsphonic acid tartarjo, dibenzoyltartaric acid, malic acid, etc.). Can be separated into the respective isomers by various methods such as chromatographic chromatography, fractional recrystallization, etc.
  • an optically active acid eg, camphorsphonic acid tartarjo, dibenzoyltartaric acid, malic acid, etc.
  • OMPI Pin derivatives are specific to animals and mammals (eg, humans, pigs, dogs, cats, egrets, guinea pigs, and ragts), and have specific blockade of tontone S 2 receptors. It has an antagonistic effect on calcium, a diuretic effect and an antithrombotic effect, and is useful as a preventive or therapeutic agent for ischemic heart diseases such as angina pectoris and myocardial infarction, thrombosis and hypertension.
  • the compound of the present invention has low toxicity, is well absorbed even by oral administration, and has excellent stability.
  • the compound itself or an appropriate pharmacologically acceptable carrier, excipient it can be safely orally or parenterally administered as a pharmaceutical composition such as powders, granules, powders, syrups, injections, etc. by mixing with diluents.
  • a pharmaceutical composition such as powders, granules, powders, syrups, injections, etc. by mixing with diluents.
  • a single dose of oral administration is usually about 0.1-1 G ⁇ Z. 0.3 to 3 ⁇ ⁇ ? Is preferred, and the dose is about 0.003 to 0.1 k9 for intravenous administration.
  • the dose is preferably about 0.01 to 1 ⁇ Z ⁇ , and it is desirable to administer these doses about 1 to 3 times a day depending on the symptoms.
  • the starting compounds ( ⁇ ), ( ⁇ ), (VI) and (VI) can be produced, for example, by the method shown in the following reaction formula.
  • ⁇ X may be substituted aryl or carboxyl field A which may be esterified or amidated
  • Hal represents a halogen (eg, bromine, nitrogen), and the other symbols are as defined above.
  • a compound that is a carboxyl that may be amidated first, the compound (3 ⁇ 4) is used as a starting compound in a suitable organic solvent (eg,
  • the compound (an) can be obtained by reacting with (S).
  • (S) in the reaction, it is usually preferable to coexist, for example, potassium charcoal, hydrogen bicarbonate !; ,
  • the reaction rate is usually 0
  • the compound in which the squash is 1 or 2 in the formula OOD can be produced by oxidizing the compound (M).
  • the oxidation reaction may be, for example, an organic acid (eg, metabenzo-perbenzoic acid, overwork), an inorganic oxidizing agent (eg, aqueous 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 in a temperature range of about ⁇ 20 ° C. to about + 100 ° C. .
  • an organic solvent eg, methanol, ethanol, dioxane, dichloromethane
  • the compound in which m is 0 can be used for the next reaction after the oxidation reaction.
  • the closure reaction for obtaining the compound (xiy) from the compound ( ⁇ ) is usually performed in an organic solvent (eg, ⁇ , w-dimethylformamide, acetonitrile, methanol dimethyl sulfoxide). It proceeds favorably in the presence of a group (eg, sodium methoxide, sodium ethoxide, potassium tertiary butoxide, sodium hydride).
  • organic solvent eg, ⁇ , w-dimethylformamide, acetonitrile, methanol dimethyl sulfoxide
  • a group eg, sodium methoxide, sodium ethoxide, potassium tertiary butoxide, sodium hydride.
  • the reaction temperature is usually-20 to +
  • the compound () when X is a lower alkyl which may be substituted, the compound () is reacted with the compound (a) to obtain a compound (XV).
  • the compound (XX) can be obtained by introducing the compound (XVI), subjecting it to a ring-closure reaction, oxidizing, and then subjecting it to an ester group removal reaction.
  • the reaction between compounds (() and () can be carried out in the same manner as the reaction between compound #r () and ( ⁇ ).
  • the compound (XV) is converted to the compound (XVI)
  • the compound (sn can be converted in the same manner as the method for converting the sn to the compound (xa).
  • XI) (The reaction can be carried out in the same manner as in the reaction (2).
  • reaction between compound (XW) and (XV8D is performed using a suitable organic solvent (eg, acetone, 2-butanone, acetonitrile, 2T, S-dimethylformamide, dimethyl
  • a suitable organic solvent eg, acetone, 2-butanone, acetonitrile, 2T, S-dimethylformamide, dimethyl
  • reaction can be smoothly carried out by adding, for example, potassium iodide, sodium iodide or other iodinated compound as ⁇ 3 ⁇ 4.
  • the reaction is usually preferably about ⁇ 20 ° C . ⁇ + 15 O′C.
  • XDO in a suitable organic solvent eg, dimethyl sulfoxide, if, IT-dimethylformamide, ⁇ , -dimethyl / wacetoamide
  • a suitable organic solvent eg, dimethyl sulfoxide, if, IT-dimethylformamide, ⁇ , -dimethyl / wacetoamide
  • sodium chloride, lithium chloride, potassium chloride, sodium bromide eg, sodium chloride, lithium chloride, potassium chloride, sodium bromide
  • compound (xa) when X is hydrogen, compound (xa) can be obtained by subjecting compound (XVI) to a reaction similar to the reaction of (X3X) ⁇ CXX).
  • the compound (XVI) is prepared by reacting the compound () with the compound (xa) using the compound () as a parent compound and then oxidizing a sulfur atom as necessary to obtain a compound. Furthermore, it is possible to produce even cowpea to subjecting the compound obtained by (XXV) to the normal 3 ⁇ 4 hydrolysis reaction ⁇
  • the reaction between compounds cm) and (x3 ⁇ 4) can be carried out in the same manner as the reaction between compounds Q vi) and (: m).
  • Compound ( ⁇ ) can be obtained by subjecting compound () to a reduction reaction.
  • the reduction reaction for example, lithium hydride, lithium borohydride, lithium borohydride, sodium borohydride, sodium cyanoborohydride, tritert-butoxylithium hydride ⁇ Reduction of metal hydrides, sodium metal, metal magnesium 3 ⁇ 4 -Reducing with platinums, palladium, rhodium and other metals and their
  • the reaction is carried out in the presence of methanol, ethanol, ethiate, dioxane, methylene chloride, chloromethane, benzene, to! / Ene, drusic acid, dimethyl I-formamide, and dimethinoleacetamide.
  • methanol ethanol, ethiate, dioxane, methylene chloride, chloromethane, benzene, to! / Ene, drusic acid, dimethyl I-formamide, and dimethinoleacetamide.
  • the reaction of (XXK) ⁇ (XXX) can be carried out by using the usual means of acylation or alkamoylation of alcohol derivatives.
  • the means of the ⁇ shea reaction for example, a reactive derivative (e.g., acid anhydride, acid halide) an organic group (examples of the organic acid corresponding to Y 5, viridin, triethylene Ji Amin,: tr, an if - Dimethylamine) or a compound in the presence of an inorganic base (eg, sodium carbonate, sodium carbonate, sodium hydrogencarbonate)
  • a reactive derivative e.g., acid anhydride, acid halide
  • an organic group examples of the organic acid corresponding to Y 5, viridin, triethylene Ji Amin,: tr, an if - Dimethylamine
  • an inorganic base eg, sodium carbonate, sodium carbonate, sodium hydrogencarbonate
  • the above reaction is usually carried out in an organic solvent (eg, methano-, ethanol, ethyl-ether, dioxane, methylene chloride, toluene, dimethylformamide, viridin), and the reaction temperature is generally -20. About C ⁇ + 100'C is preferable.
  • the carbamoylation reaction is carried out, for example, by adding an alcohol derivative (XXK) obtained by a reduction reaction to an isocyanate corresponding to ⁇ ⁇ (eg, methyl ⁇ iso3 / ane, ethyl isocyanate). , Pheny y sinate, and p-cloth phen-isophenate).
  • the above reaction is usually carried out in a suitable organic solvent (eg, methanol, ethanol, acetate, dioxane, tetrahydrofuran, methylene chloride, chlorofoam, tween, N, if —dimethyl / 1 Homamido)
  • a suitable organic solvent eg, methanol, ethanol, acetate, dioxane, tetrahydrofuran, methylene chloride, chlorofoam, tween, N, if —dimethyl / 1 Homamido
  • the reaction temperature is preferably about 20 'C to +150' C to eliminate the reaction.
  • the reaction between compound ( ⁇ and (XS) can be carried out in the same manner as the reaction between compound (VI) and (xa).
  • Compound (XXX2) is converted from compound C5d to a dilute mineral acid.
  • Compound ( ⁇ ) can be obtained by subjecting compound ( ⁇ ) to the reduction reaction of) ⁇ (XXK), and the reaction of (XXW) ⁇ (XXXV) is the same as the reaction of (XK) ⁇ (xxx). The same can be done.
  • Compound (XXXVI) is compound (XXXV)
  • the reaction between the compound (XO and (XXXW) can be carried out in the same manner as the reaction with the compound (XVI).
  • the reaction of (XXW) ⁇ (XK) is the same as the reaction of CXXW) ⁇ ( ⁇ )
  • the reaction of (00 ⁇ ) ⁇ 1 ») can be performed in the same manner as the reaction of (: 503 ⁇ 4) ⁇ (XXX).
  • the chemical name used in the reaction is as long as it does not interfere with the reaction, such as hydrochloric acid, hydrobromic acid, sulfate, nitric acid, and nitric acid.
  • Acids Inorganic acids such as hydrostatic, tartaric, citrate, Bumar, maleate, toluenesulfonate, methanol sulphonate Any organic acid, such as sodium salt, potassium lime, calcium Salt, aluminum-palladium Any metal contact, such as triethiamin, guanidine, ann: pium, hydrazine, quinine salt, cinchonine salt.
  • Cis isomer Recrystallized from ethyl sulphate to give colorless needles. Melting point
  • Trans isomer hydrochloride ⁇ : Recrystallized from methanol and ether to obtain colorless needles. Melting point 1 70— 1 80 'C (decomposition)
  • Reference Example 25 Methyl 7-methoxy 3 1-year-old xo 3 and 4-dihydro 2H-1 and 5 and 1-pentazoxaxevibin 14- and 4-boxylate 30 and 1 and 1- and 3-broken mouth broban 50 f, anhydrous carbon dioxide 46 Heat a mixture of calcium fluoride 10 f, tetrabutylammonium iodide 1.0 f, and acetate tri 30 under reflux for 4 hours. After cooling, the inorganic substance is removed by filtration, the filtrate is concentrated under reduced pressure, the obtained residue is dissolved in ethyl acetate, washed with water and dried, and the solvent is distilled off under reduced pressure.
  • Ethyl xanyl monoacetate-3 1) Purified with meth 7-method ⁇ 3-oxo-l 4- [3- (4-f-biperazine-l-l-l) brop] -3,4-dihydro-2E — 1,5,1 Benzoxachachevin 1-41 carboxylate is obtained, recrystallized from methanoate and white Crystal and Ruru. Mp, 1 0- 1 1 2 e C. Yield 2.1.
  • Methyl 7-Methoxy 3-oxo 4- obtained in Example 1 [3- (4-Fu-bizin-1-1)) -3,4-dihedro 2H-1, 51 Dissolve benzoxachebin-14-carboxylate 38 in a mixed solvent of tetrahydrofuran 4 and methanol 20 and stir under ice-cooling, and add sodium borohydride 3.7 little by little. After completion of the reaction, the solvent is distilled off under reduced pressure, water is added and the mixture is extracted with ethyl acetate.
  • Example 2-1 ⁇ The compound obtained in Example 2-1 ⁇ was reduced with sodium borohydride in the same manner as in Example 12 to obtain the compounds shown in Table 4.
  • ITtt E-spectrum (CDCla): 1.00ppm (6H .triplet , 2CH,), 1 .75 (2H sm), 2.45 (6H, m), 3.58 (3 H, singlet, 20 0CH 3), 3.60 ( 2H, double double, CH 2 0H ), 3.90
  • Cis-4-1 (2-ethylaminoethyl) obtained in Example 25-4-hydroxymethyl-7-methoxy-3,4-dihidro2 2--1,5-benzo-year-old Kisachepin-13-year-old Dissolve 0 ⁇ 7 in 1% pyridine, add 6 W of non-hydrous acid, and leave at room temperature for 3 hours. Pour the reaction mixture into ice water and extract with acetic acid. Organic bicarbonate After drying, the solvent was distilled off under reduced pressure, and cis-1,3-acetoxy 4-acetoxy 7-methoxy 4- (2-diaminoamino) 13,4-dihydro 2H- ⁇ , 5-pentoxaxapine To give 0.669 of a colorless oil. Hydrochloric acid is recrystallized from ethanol ether to give white crystals. Melting point ⁇ 77-1 79 ° Ca
  • Example ⁇ 2 The compound obtained in Example ⁇ 2 was acetylated in the same manner as in Example 27, and methinoleth-3-acetoxy 7-methoxy 4-1 [3-1 (4-1 (2-pyperazine-1-11) ) Propyl] -3,4 dihydro 2 2-1,5 benzoxachebin-14 carboxylate is obtained. Recrystallized from n-hexane to form colorless prisms. Melting point 1 68-1 70'C. This product can be determined by X-ray crystallography].
  • OMPI Separation and purification are performed in 1), and cis-isomer is obtained from the fraction that elutes in the trans-isomer from the first-eluting field.
  • Examples 37 to 38 The compounds of Examples 35 and 36 are reduced in the same manner as in Example 12 to obtain the compounds shown in Table 6. 6
  • Reference Example 26 4- (3-chlorobutadiene) -1 3-hydroxy 7-methoxy-3,4-dihydro-2 H—1,5,1-benzoxacevin 14-carboxylate, 4 f is heated under reflux for 20 hours together with 9.0 f of 4-phen-biperazine, 9.0 f of anhydrous potassium carbonate, 0.5 f of potassium iodide and 0.5 f of potassium acetate. After cooling, the inorganic substance is removed by filtration, the filtrate is concentrated under reduced pressure, the residue is dissolved in ethyl acetate, the organic layer is washed with water, dried and the solvent is distilled off under reduced pressure.
  • the product was recrystallized from 50 ⁇ ethazol to give methysis 13-hydroxy 7-methoxy 41-3-(4-fubezin-I-yl) y "nbi-13, 4- Dydro-2H-t, 5-Penzoxachebin-14-carboxylate, a colorless bristol crystal of monoacid salt, melting point 154-155 ⁇ .
  • the experiments were performed using male beagle dogs weighing 10-14. Prior to the experiment, a polyethylene tube was placed in the femoral artery and the femoral vein for measurement of systemic blood pressure and intravenous administration of the drug. In other words, the surgical operation was performed aseptically under anesthesia with Pantobiter's sodium (3O ⁇ Z * ⁇ iv), a polyethylene tube was placed in the femoral artery and femoral vein, and the tube was plugged. . The other end was guided to the back through the skin and out of the body through the skin.
  • the experiment was performed two to three days after the operation. That is, the in-arterial indwelling hollow tube was connected to a pressure transducer, and the systemic blood pressure was measured and continuously recorded with a polygraph recorder. Serotone 3 ⁇ 30 g Z *? it,
  • Example 2 The compound of 2 (cis-form dipyroic acid) continuously suppressed serotonin pressurization at doses of 0 01 1 ⁇ ⁇ 3 ⁇ 4 in a dose-dependent manner.
  • Table 9 Serotonin pressurization suppression in unanesthetized beagle dogs
  • Example 2 the rise of the rinsing pressure by KC1 during the treatment of 2 (ciii-body dihydrochloride) (control) was 73 ⁇ 20 (average of 8 cases) mHg. The value () after the compound treatment when this value was set to I 00 is shown.
  • the compound of Example 12 (c in) was 1 ( ⁇ 7 to 3 X ⁇ ( ⁇ — ⁇ Showed significant KC1 anti-pressor effect.
  • Spontaneously hypertensive rats ( ⁇ ⁇ 3 weeks old, male) 3 ⁇ 4—Group 5E was used.
  • the drug was suspended in a small amount of gum arabic and saline and administered orally in a volume of 25 W.
  • the control group was administered only saline containing arabia gum, and the rats were placed in metabolic cages for urine collection, and urine was collected for 5 hours.
  • Urine volume and urine Ua +, £ + excretion were measured.
  • lfa + and E + were measured using a flame photometer (Hitachi 205 DT).
  • Example 1 A compound of 2 (cis-form, diacid) showed an increase in urine volume, ifa + and urinary excretion by oral administration of 3 3fZ, a significant increase in urine volume at 1 or more, and a urine volume at 30 « ⁇ ⁇ , Na + and K + were significantly increased.
  • Table 1 1 Diuretic effect in hypertensive rats
  • Thrombus formation in the coronary vessels was determined according to the method of Foli; s 3 ⁇ 4 Circulation 54, P. 365 (1 976)], ie, applying force to the circumflex branch of the left coronary artery.
  • the left common carotid artery was inserted and the arterial blood was circulated, and the blood flow was measured using an electromagnetic blood flow meter.
  • the coronary artery circumflex was equipped with a plastic constrictor around the inner stomach 1
  • Thrombus formation was determined from periodic decreases and increases in coronary blood flow, and antithrombotic effects were evaluated based on the effect of drugs on the frequency.
  • the test drug was administered intravenously.
  • the coronary blood flow decreases gradually, decreases from 20 to 3 to several WZmin, and then increases rapidly.
  • the magnitude of the coronary blood flow decreased and increased periodically, with a frequency of 5 to 15/15 minutes.
  • Example 2 The compound of Example 2 (cia body dihydrochloride) dose-dependently controlled the coronary blood flow periodically at a dose of 1 ag intravenously administered (Table 12).
  • the compound of Example 2 cis-body's dihydrochloride
  • Table 1 2 Effect of shadow on the frequency of periodic changes in coronary blood flow
  • 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 prescription.
  • the 1,5-pentazoxaxacevin derivative (I) provided by the present invention has excellent pharmacological action and is useful as a pharmaceutical.

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Abstract

Nouveaux dérivés de 1,5 benzoxathiépines de formule (I) où R1 et R2 représentent chacun un hydrogène, un halogène, un hydroxy, un alkyle inférieur ou un alkoxy inférieur, R3 et R4 représentent chacun un hydrogène, un alkyle inférieur ou un aralkyle ou un cycloalkyle facultativement substitué ou, pris ensemble, R3 et R4 forment un cycle avec l'atome d'azote voisin, X représente un hydrogène, un alkyle inférieur facultativement substitué, un aryle facultativement substitué ou un carboxyle facultativement estérifié ou amidé, Y représente > C=O ou > CH-OR5 (où R5 représente un hydrogène, un acyle ou un amido facultativement substitué), m est un nombre entier de 0 à 2 et n un nombre entier de 1 à 6; ces dérivés et leurs sels ont un effet de blocage du récepteur S de sérotonine, un effet concurrent au calcium, un effet diurétique et un effet antithrombotique et sont utiles pour la prophylaxie et le traitement de l'affection cardiaque ischémique, de la thrombose et de l'hypertension.
PCT/JP1984/000168 1983-12-14 1984-04-04 Derives de 1,5 benzoxathiepine et leur preparation WO1985004658A1 (fr)

Priority Applications (26)

Application Number Priority Date Filing Date Title
PCT/JP1984/000168 WO1985004658A1 (fr) 1984-04-04 1984-04-04 Derives de 1,5 benzoxathiepine et leur 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
AT84308691T ATE47851T1 (de) 1983-12-14 1984-12-13 1,5-benzoxathiepin-derivate, deren herstellung und verwendung.
FI844940A FI80029C (fi) 1983-12-14 1984-12-13 Foerfarande foer framstaellning av nya, farmaceutiskt aktiva 1,5-bensoxatiepinderivat.
DE8484308691T DE3480397D1 (en) 1983-12-14 1984-12-13 1,5-benzoxathiepin derivatives, their production and use
PT79666A PT79666B (en) 1983-12-14 1984-12-13 1,5-benzoxathiepin derivatives their production and use
EP84308691A EP0145494B1 (fr) 1983-12-14 1984-12-13 Dérivés de 1,5-benzoxathiépine, leur production et usage
IE320684A IE58159B1 (en) 1983-12-14 1984-12-13 1,5-Benzoxathiepin derivatives, their production and use
HU844657A HU201922B (en) 1983-12-14 1984-12-13 Process for producing 1,5-benzoxathiepin derivatives and pharmaceutical compositions comprising same
EP87116048A EP0300088A3 (fr) 1983-12-14 1984-12-13 Dérivés de 1,5-benzoxathiépine, leur production et usage
CA000469996A CA1247613A (fr) 1983-12-14 1984-12-13 Derives de la 1,5-benzoxathiepine; preparation et utilisation
PH31583A PH21851A (en) 1983-12-14 1984-12-14 1,5-benzoxathiepin derivatives and pharmaceutical compositions containing them
KR1019840007941A KR910009288B1 (ko) 1983-12-14 1984-12-14 1,5-벤족사티에핀 유도체의 제조방법
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
CA000575739A CA1258462A (fr) 1983-12-14 1988-08-25 Derives de 1,5-benzoxathiepine, production et utilisation
CA000575740A CA1258463A (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

Applications Claiming Priority (1)

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PCT/JP1984/000168 WO1985004658A1 (fr) 1984-04-04 1984-04-04 Derives de 1,5 benzoxathiepine et leur preparation

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Country Link
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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. Salvatore, et al:, p. 151-156 *

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