WO1985004402A1 - Fused 7-membered ring compounds and process for their preparation - Google Patents

Fused 7-membered ring compounds and process for their preparation Download PDF

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Publication number
WO1985004402A1
WO1985004402A1 PCT/JP1984/000119 JP8400119W WO8504402A1 WO 1985004402 A1 WO1985004402 A1 WO 1985004402A1 JP 8400119 W JP8400119 W JP 8400119W WO 8504402 A1 WO8504402 A1 WO 8504402A1
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WO
WIPO (PCT)
Prior art keywords
compound
amino
formula
reaction
benzothiazepine
Prior art date
Application number
PCT/JP1984/000119
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English (en)
French (fr)
Japanese (ja)
Inventor
Hirosada Sugihara
Kohei Nishikawa
Katsumi Ito
Original Assignee
Takeda Chemical Industries, Ltd.
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Publication date
Application filed by Takeda Chemical Industries, Ltd. filed Critical Takeda Chemical Industries, Ltd.
Priority to PCT/JP1984/000119 priority Critical patent/WO1985004402A1/ja
Priority to US06/599,187 priority patent/US4564612A/en
Priority to EP84302564A priority patent/EP0125056B1/en
Priority to AT84302564T priority patent/ATE60061T1/de
Priority to IE927/84A priority patent/IE57599B1/en
Priority to DE8484302564T priority patent/DE3483920D1/de
Priority to DK196884A priority patent/DK196884A/da
Priority to NO841555A priority patent/NO162235C/no
Priority to GR74460A priority patent/GR79905B/el
Priority to AR84296356A priority patent/AR244217A1/es
Priority to ES531740A priority patent/ES531740A0/es
Priority to PH30584A priority patent/PH21294A/en
Priority to CA000452446A priority patent/CA1209993A/en
Priority to AU27092/84A priority patent/AU565188B2/en
Priority to PT78454A priority patent/PT78454B/pt
Priority to NZ207915A priority patent/NZ207915A/en
Priority to FI841590A priority patent/FI82455C/fi
Priority to HU841550A priority patent/HU193008B/hu
Priority to KR1019840002110A priority patent/KR910007965B1/ko
Priority to IL71617A priority patent/IL71617A/xx
Priority to IL74004A priority patent/IL74004A/xx
Priority to NO850045A priority patent/NO160712C/no
Priority to CA000471650A priority patent/CA1281718C/en
Priority to HU8560A priority patent/HUT38631A/hu
Priority to NZ210781A priority patent/NZ210781A/en
Priority to NZ220233A priority patent/NZ220233A/en
Priority to US06/691,005 priority patent/US4638000A/en
Priority to EP85300271A priority patent/EP0156455A3/en
Priority to IE850148A priority patent/IE850148L/xx
Priority to JP60012053A priority patent/JPS60231668A/ja
Priority to DK33385A priority patent/DK33385A/da
Priority to PH31789A priority patent/PH23261A/en
Priority to PT79931A priority patent/PT79931B/pt
Priority to ES540548A priority patent/ES8702389A1/es
Priority to ZA851293A priority patent/ZA851293B/xx
Priority to AR299618A priority patent/AR241113A1/es
Priority to GR850705A priority patent/GR850705B/el
Priority to KR1019850001864A priority patent/KR910009201B1/ko
Priority to FI851154A priority patent/FI82465C/fi
Priority to ES544748A priority patent/ES8609290A1/es
Publication of WO1985004402A1 publication Critical patent/WO1985004402A1/ja
Priority to ES554039A priority patent/ES8801635A1/es
Priority to ES554040A priority patent/ES8701722A1/es
Priority to US06/900,816 priority patent/US4739066A/en
Priority to PH34615A priority patent/PH24015A/en
Priority to NO871049A priority patent/NO871049D0/no
Priority to ES557636A priority patent/ES8801653A1/es
Priority to FI882956A priority patent/FI81089C/fi
Priority to AR312003A priority patent/AR241112A1/es
Priority to PH37629A priority patent/PH25131A/en
Priority to JP1118070A priority patent/JPH0215060A/ja

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/022—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2
    • C07K5/0222—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2 with the first amino acid being heterocyclic, e.g. Pro, Trp
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to a novel condensed seven-membered ring compound useful as a medicine and a method for producing the same.
  • the present inventors have enthusiastically searched for a compound having an inhibitory action on angiotensin-converting enzyme and useful as a therapeutic agent for antihypertensive.As a result, the present inventors have succeeded in producing a fused 7-membered ring compound having an excellent action, completed. Disclosure of the invention
  • the present invention relates to the formula COOR 3
  • R 1 and R 2 each represent hydrogen, halogen, trifluoromethyl, lower alkyl or lower alkoxy, or both are connected to each other to form tri or tetramethylene
  • R 3 is hydrogen, lower Alkyl or aralkyl
  • R 4 is hydrogen or optionally substituted alkyl, aralkyl or cycloalkylalkyl
  • X is S (0) n (where ⁇ represents an integer of 0 to 2).
  • Y represents a carboxyl group which may be esterified or amidated, and m represents 1 or 2.
  • Examples of the lower alkyl group represented by R 1 , R 2 or R 3 include alkyl groups having about 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. Is raised.
  • alkyl group represented by R 4 a linear or branched alkyl group having about 1 to 16 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, butyl, pentyl, isopentyl, hexyl, Heptyl, octyl, nonyl, decyl, pendecyl, dodecyl, tridecyl, tetradecyl, pentadecyl), and these groups may be substituted, for example, hydroxy, lower (Ci-14) alkoxy (eg, methyl Xy, ethoxy, propoxy, butoxy), mercapto, lower (Ci-4) alkylthio (eg, methylthio, ethylthio, propylthio, butylthio) amino, mono or di-lower (Ci-14) alkylamino (Eg, methylamino, dimethylamino,
  • Examples of the aralkyl group represented by R 3 or R 4 include, for example, benzyl, phenethyl, 3-phenylpropyl group, ⁇ -methylbenzyl group, ⁇ -ethylbenzyl group, monomethylphenethyl group, / 3-methylphenethyl group, 3- A phenyl lower (C i-*) alkyl group having about 7 to 10 carbon atoms, such as ethyl phenyl group; and the phenyl group in the phenyl lower alkyl group has 1 to 3 halogen atoms (eg, fluorine). , Chlorine, bromine, iodine), Ci-4
  • halogen atoms eg, fluorine
  • Alkyl group eg, methyl group, ethyl group, propyl group, butyl group, etc.
  • C14 alkoxy group eg, methoxy group, ethoxy group, methoxy group, isopropoxy group, A butoxy group, a methylenedioxy group, etc.
  • the alkyl group in the phenyl lower alkyl group may also have a peripheral substituent.
  • Examples of such substituted phenyl lower alkyl groups include 2- (4-chlorophenyl) ethyl, 2- (4-hydroxyphenyl) ethyl, and 2- (4-methoxyphenyl) ethyl. , 2- (3.4-dimethyloxyphenyl) ethyl group, 2- (3,4,5-trimethyloxyphenyl) ethyl group, 2- (3,4-methylenedioxyxyphenyl) ethyl group, 2- (P-tolyl) ethyl group, 3,4-dimethyloxybenzyl group, 3,4-methylenedioxybenzyl group, 3,4,5-trimethoxybenzyl group, 4-ethylpentyl group, Examples thereof include a benzyl group, a-aminophenyl group, and a / 3-aminophenyl group.
  • Examples of the cycloalkylalkyl group represented by R 4 include cyclopropylethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl, Cs-8 cycloalkyl lower (Ci 14> alkyl group having about 4 to 12 carbon atoms, such as cycloheptylethyl, cyclooctylethyl, etc., such as norpolnyleethyl, bicyclo [2.2.2] octylmethyl) , Bicyclo (3.3.1) nonylpropyl.
  • Bicyclo (3.3.0) bicyclo lower alkyl groups such as octyl butyl, for example, tricyclo lower alkyl groups such as adamantyl ethyl and the like.
  • halogen Ci-4 alkyl, Ci-14 alkoxy, amino Group, a hydroxy group, or a hydroxy group.
  • the group represented by X forms sulfide, sulfoxide, or sulfone depending on its oxidation state.
  • esterified ethoxy group represented by Y examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isopropoxycarbonyl, sec-propyl.
  • Lower (G i —4) alkoxycarbonyl groups such as xycarbonyl, tert-atoxycarbonyl, etc.
  • Phenyl lower (Ci-14) alkoxycarbonyl groups such as benzyloxycarbonyl, ⁇ -phenyloxycarbonyl, & phenyloxycarbonyl, phenylpropyloxycarbonyl, and phenylbutyloxycarbonyl, and amidation is the force Rupokishiru group e.g.
  • alkyl eg, benzyl, phenethyl, phenylpropyl, phenylacetyl.
  • Groups represented by ⁇ include G H2, CHz CH2 and
  • Salts of compound (I) include, for example, hydrochlorides, hydrobromides, sulfates.
  • Inorganic acid salts such as nitrates, phosphates, etc., for example, fossilates, tartrates, citrates, fumaric acid,
  • Organic acid salts such as maleate, toluenesulfonate and methanesulfonate, such as sodium salts, potassium salts, calcium salts and aluminum salts, such as metal salts such as triethylamine salts, guanidine salts, ammonium salts
  • Pharmacologically acceptable salts such as salts with bases such as hydrazine salt, quinine salt and cinchonine salt.
  • the compound (I :) of the present invention is represented by the formula
  • C can be produced by subjecting the compound represented by the formula to a reduction reaction under the reduction conditions c.
  • the conditions for the reduction include, for example, metals such as platinum, palladium, Raney nickel, Reduction using a mixture of benzene and any carrier as catalyst, such as lithium aluminum hydride, lithium borohydride, lithium cyanoborohydride, borohydride
  • metal hydrides such as sodium and sodium borohydride, metal sodium thorium, metal matanesium, etc.
  • Reaction conditions such as reduction with metals, metals such as iron and zinc, and acids such as hydrochloric acid and sulfuric 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 remote means, but it is generally preferably about 20 to about 20. This reaction can sufficiently achieve the purpose at normal pressure, but the reaction may be carried out under increased or reduced pressure by convenience.
  • the compound (I) of the present invention has, for example, the formula
  • each symbol is as defined above.
  • the dehydration ring closure reaction can be performed, for example, by an amide bond formation reaction in a normal peptide. That is, a peptide-forming reagent such as dicyclohexylcar positimide, ⁇ , ⁇ '—capillonyldi, dazole, diphenyl phosphate azide, or cetyl cyanophosphate alone is used alone, or a common inorganic acid (eg, hydrochloric acid, sulfuric acid, Nitric acid, hydrobromic acid) to convert the amino group of compound i: iv ⁇ into protons, and then, for example, 2,4,5-trichlorophenol, pentachlorophenol, pentaflurophenol, 2-pentachlorophenol. Nitrov
  • OMPi N-hydroxy compounds such as phenol II or N-hydroxysuccinimide, 1-hydroxybenztriazole, N-hydroxypiperidine, such as phenol or 4-nitrophenol, can be converted to dicyclohexylcarposimid, etc. It can be carried out by condensing in the presence of a medium, converting to an active ester form, and then cyclizing.
  • an organic base such as a quaternary ammonium salt or a tertiary amine (Eg, triethylamine, N-methylpiperidine).
  • the reaction temperature is usually from ⁇ 20 to 150, preferably around room humidity, and examples of commonly used solvents include dioxane, tetrahydrofuran, acetonitrile, pyrididine, N 2 N, N-dimethylformamide. N, N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, chloroform, methylene chloride and the like, and these may be used alone or as a mixed solvent.
  • the compounds of the present invention can also be any organic compound having the same side chain length.
  • the compounds of the present invention can also be any organic compound having the same side chain length.
  • Z represents a protecting group which can be eliminated by hydrolysis or catalytic reduction, and other symbols have the same meanings as described above.
  • the protecting group which can be eliminated by the hydrolysis represented by Z in (V) any kind of an acyl group or a trityl group can be used, and among them, benzyloxycarbonyl, tert-butoxycarbonyl, trifluryl, It is advantageous when the reaction is carried out under relatively mild reaction conditions such as tert-yl, trityl, etc.
  • Examples of protecting groups that can be removed by catalytic reduction represented by Z include benzyl, diphenylmethyl, and benzyl.
  • the hydrolysis reaction in this method is water or, for example, methanol, ethanol, dioxane, pyridine, or the like. Emissions, acetic acid, acetone, carried out in organic solvent or a mixed solvent thereof and the like methylene chloride, acid (e.g. for reaction rate enhancing, hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric o one
  • the above reaction is usually carried out in a range of about 120 to about 150.
  • the catalytic reaction in the present method is carried out in water or an organic solvent such as methanol, ethanol, dioxane, tetrahydrofuran or a mixed solvent thereof in the presence of a suitable catalyst such as platinum, palladium-carbon. Done.
  • This reaction is carried out at normal pressure or a pressure of up to about 15 O kgZcnf at normal temperature to +150, but the reaction generally proceeds sufficiently at normal temperature and normal pressure.
  • the compound (I) of the present invention may also be, for example, a compound of the formula
  • each symbol is as defined above.
  • it can also be produced by solvolysis of a cyano group.
  • the above-mentioned solvolysis reaction is carried out with water or methanol,
  • the reaction is carried out in an organic solvent such as toluene, dioxane, pyridine, sulfuric acid, acetone, methylene chloride or a mixture thereof, and the acid is used to promote the reaction rate (eg, hydrochloric acid, hydrobromic acid, hydrogen iodide Acid, hydrofluoric acid, sulfuric acid, methanesulfonic acid, ⁇ -toluenesulfonic acid, trifluoroacetic acid, or base (eg, sodium hydroxide, potassium hydroxide,
  • Potassium carbonate, sodium bicarbonate, sodium acetate, triethylamine can also be added.
  • the reaction is usually carried out in the range of about 120 to +150.
  • R 3 and have the same meanings as described above, and W represents a halogen or a T3 ⁇ 4 group represented by the formula R 5 S 0 2 0-(R s represents lower alkyl, phenyl or p-tolyl.) .
  • W represents a halogen or a T3 ⁇ 4 group represented by the formula R 5 S 0 2 0-(R s represents lower alkyl, phenyl or p-tolyl.
  • a base such as potassium carbonate, sodium hydroxide, sodium hydrogen carbonate, pyridine, triethylamine and the like can be coexisted in the reaction system as a deoxidizing agent for the purpose of accelerating the reaction rate.
  • the compound of the present invention (I) also has the formula
  • W is a halogen or the formula Rs 'S 02 one 0- group represented by (R 5' is lower alkyl, phenyl or ⁇ - Bok Lil the shown to.), Upsilon are as defined above.
  • a base such as charcoal potassium, sodium hydroxide, hydrogenated sodium and the like
  • R 3 is hydrogen or ⁇ ⁇ ⁇ is carboxyl, and R 3 is lower (Ci-4) alkyl, or Z and Y are lower (Ci-4) alkoxycarbonyl
  • Producing the compound (I) by subjecting the ester compound to hydrolysis or elimination reaction, or by corrosion reduction of a benzyl ester compound in which R 3 is benzyl or Z and Y are benzyl xycarbonyl.
  • R 3 is hydrogen or ⁇ ⁇ ⁇ is carboxyl
  • R 3 is lower (Ci-4) alkyl
  • Z and Y are lower (Ci-4) alkoxycarbonyl
  • R 3 is a lower (Ci one 4) alkyl, or Z and Y is a lower (Ci - if a 4 "alkoxy force Ruponiru is, R 3 is hydrogen, or and Y is a force Rupokishiru
  • the compound can also be produced by subjecting the compound to an esterification reaction.
  • R e -H (XI) (wherein, R 6 represents a lower alcohol residue, a phenyl lower alcohol residue, or an ⁇ -amino acid residue whose carboxyl group may be protected with lower alkyl or phenyl lower alkyl.
  • R 6 represents a lower alcohol residue, a phenyl lower alcohol residue, or an ⁇ -amino acid residue whose carboxyl group may be protected with lower alkyl or phenyl lower alkyl.
  • R 6 represents a lower alcohol residue, a phenyl lower alcohol residue, or an ⁇ -amino acid residue whose carboxyl group may be protected with lower alkyl or phenyl lower alkyl.
  • R e is a lower Arupiru or indicates ⁇ - amino acid residues force Rupokishiru group is protected by Fuemiru lower Arupiru, and the other symbols are as defined above.
  • R e ′ represents an ⁇ -amino acid residue, and other symbols have the same meanings as described above.
  • the compound can also be produced by oxidizing the corresponding sulfide compound.
  • the oxidation reaction is carried out, for example, by the action of an organic peracid (eg, methyl peroxybenzoic acid, peroxide acid) 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), and is usually carried out in a temperature range of 120 to 100.
  • reaction of compound (fl) with (H) or (: I;) a protecting group known per se [eg, benzyloxycarbonyl, tert-butoxycarbonyl, cycloacetyl, phthalimid,
  • the target compound can be obtained by protecting the group with an imido and subjecting the reaction to a reaction, followed by a deprotection reaction known per se.
  • A represents a linear or branched alkylene having about 1 to 16 carbon atoms, and Ra and Rb each represent hydrogen, lower (C i- 4 ) alkyl, aryl, or cycloalkyl; The other symbols are as defined above) can be produced, for example, as follows: Compound ((; and formula CHCOOR 3
  • Wa is halogen or wherein R e S 0 2 - (wherein, R e is a lower alkyl, phenyl or p - shows the Application Benefits Le) groups represented by 0 and one of R c and R d Represents hydrogen and the other represents a protecting group (eg, benzoyl, acetyl), or both represent fluorimidide and succinimide with adjacent nitrogen atoms, and other symbols are as defined above.
  • R e S 0 2 - wherein, R e is a lower alkyl, phenyl or p - shows the Application Benefits Le
  • R c and R d Represents hydrogen and the other represents a protecting group (eg, benzoyl, acetyl), or both represent fluorimidide and succinimide with adjacent nitrogen atoms, and other symbols are as defined above.
  • R e S 0 2 - wherein, R e is a lower alkyl, phenyl or p -
  • a compound in which Ra or / and Rb is lower alkyl or cycloalkyl can be prepared, for example, by compounding the corresponding aldehyde or ketone with the compound (lb) usually using water or an organic solvent (eg, alcohol, Reaction under ethereal, tetrahydrofuran, methylformamide, and acetonitrile) or in a mixed solvent thereof under a reducing condition at a temperature range of about 120 to + 100 ° C. It can be manufactured by making it.
  • an organic solvent eg, alcohol, Reaction under ethereal, tetrahydrofuran, methylformamide, and acetonitrile
  • Examples of the reducing conditions include catalytic reduction using a catalyst such as a metal such as platinum or palladium or a mixture thereof with an optional carrier, for example, lithium aluminum hydride, lithium borohydride, lithium cyanoborohydride, hydrogen hydride.
  • a catalyst such as a metal such as platinum or palladium or a mixture thereof with an optional carrier, for example, lithium aluminum hydride, lithium borohydride, lithium cyanoborohydride, hydrogen hydride.
  • Reduction with metal hydrides such as sodium borohydride and sodium borohydride
  • reduction with alcohols such as sodium and magnesium
  • reduction with metals such as iron and zinc and acids
  • hydrochloric acid and acetic acid Reaction conditions such as electrolytic reduction, reduction with a reductase, etc. can be raised.
  • a compound in which Ra, Z and Rb are acyl is a compound obtained by reacting an activated organic acid derivative such as an acid anhydride or an acid halide with a compound (lb), usually with water or an organic solvent [ Eg, ethyl acetate, methylene chloride, ether. Benzene, toluene, triethylamine, dimethylformamide) or a mixture thereof It can be produced by reacting in a solvent in a temperature range of about 20 to 150 ° C. At this time, an organic base (eg, triethylamine, picolin, pyridine) or an inorganic base (eg, sodium hydrogen carbonate) may be added to promote the reaction rate.
  • an organic base eg, triethylamine, picolin, pyridine
  • an inorganic base eg, sodium hydrogen carbonate
  • the target compound (I) of the present invention thus obtained can be separated and purified from the reaction mixture by a conventional means such as extraction, concentration, neutralization, filtration, recrystallization, column chromatography, thin layer chromatography, etc. It can be isolated by using it.
  • the conjugate (IJ may have at least two stereoisomers depending on the type of the substituent represented by R 4 , etc.) Each of these isomers and these mixtures is naturally within the scope of the present invention. And, if desired, these isomers can be produced individually. For example, each of the single isomers of the starting compounds . ⁇ ⁇ .IV), CV.CW; and (W) can be used. By carrying out the above reaction, a single optical isomer of compound (I :) can be obtained, and when the product is a mixture of two or more isomers, this can be separated by ordinary separation.
  • an optically active acid eg, camphorsulfonic acid, tartaric acid, dibenzoyltartaric acid, etc.
  • an optically active base salt eg, cinchonine, nconidine, quinine, quinidine, monomethylbenzinoleamine, dehydroabiethylamide
  • a method for generating a salt with :) such, various chroma Togurafi over, by separation means such as fractional recrystallization, can be separated into its its isomers.
  • the compound of the present invention ie, the fused 7-membered ring compound represented by the formula (III) and a salt thereof can be used for angiotensin against animals, particularly mammals (eg, human dog, cat, rabbit, guinea pig, rat) Inhibition of converting enzyme, Bradycun degrading enzyme (kininase, etc.) It is useful as an agent for diagnosing, preventing or treating. Since 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 as such or an appropriate pharmaceutically acceptable carrier, excipient, and diluent.
  • the oral dose when administered to an adult patient for the treatment of hypertension, for example, is usually about 0.02 to 20 or about 0.2 to 2;
  • a dose of about 0.02 to 0.2 / hill is about 0.02 to 0.2 ⁇ ⁇ , and these doses are about 1 to 5 times a day depending on the symptoms. It is desirable to administer. .
  • the starting compounds ( ⁇ ), ( ⁇ ), [ ⁇ ), (7 ⁇ and ⁇ ['..] of the present invention can be easily produced, for example, by a method represented by the following reaction formula.
  • R 7 is halogen or Jiazo two ⁇ beam group
  • Q is C androgenic or formula R 8 S 02 groups represented in one 0- (R 3 represents lower alkyl, phenyl or p- Bok Lil.) , And the other symbols are m sd;
  • the reaction of (XVI) ⁇ (XW) is a reduction reaction of a nitro group to an amino group, and any of the known reduction methods can be used. —Catalyst reduction using palladium, sulfide palladium, platinum, etc. as a carrier with carbon or palladium sulfate as a carrier, or reduction reaction with metals such as zinc, tin, stannous chloride, iron, etc. with acid or alkali.
  • the dehydration ring-closure reaction of the compound thus obtained to the compound (XIX) can be advantageously carried out usually in the presence of a known dehydration condensing agent.
  • Examples of such a dehydrating condensing agent include dicyclohexylcarpoimide, carbonyldiimidazole, and getyl cyanophosphate, etc.
  • Examples of the solvent include dioxane, methylene chloride, acetonitrile, N, N-dimethylformamide, tetrahydrofuran, etc. are used, and the reaction is usually carried out in a temperature range of about 110 to 100. At this time, triethylamine, pyridine, etc.
  • the addition of the compound (XXI) by the condensation reaction of the compound (XXI) with the compound (XX) can be carried out usually using a base such as sodium hydride or potassium carbonate. In the presence of N, N-dimethylformamide,
  • OMPI It can be produced by condensing in a solvent such as methylsulfoxide, acetate and the like in a temperature range of about 110 to about 10100.
  • a solvent such as methylsulfoxide, acetate and the like
  • hydrazine hydrate is treated in a solvent such as methanol, ethanol, dioxane or the like at a temperature of about 10 ° to +100, and the compound (I ′) ) Can be manufactured.
  • the compound (IT) when X is a sulfoxide or a sulfone, the compound (IT) can be produced by oxidizing the compound (IT). Acid, peracetic acid) or an inorganic oxidizing agent (eg, 'hydrogen peroxide, periodic acid) The above reaction is usually carried out with water or an organic solvent (eg, methanol, ethanol, dioxane). , Dichloromethane) in the presence of the compound (XV), (XVI), (XH), (XIX) or (XXI). ) To convert each sulfide group to sulfoxide or sulfone.
  • Acid peracetic acid
  • an inorganic oxidizing agent eg, 'hydrogen peroxide, periodic acid
  • the above reaction is usually carried out with water or an organic solvent (eg, methanol, ethanol, dioxane). , Dichloromethane) in the presence of the compound (XV), (XVI), (XH), (
  • Compound (I) can also be produced by subjecting (I ′) to a reaction for producing compound (I) using compound (n).
  • the reaction of (XXII) ⁇ (XXffl) can be carried out by a similar reaction to the reaction of (XU) ⁇ (XV).
  • the compound (IV ′) can be produced by subjecting the nitro group to a reduction reaction to an amino group and then to an alkylation reaction, and in the case where X in the compound (IV) is sulfoxide or sulfone, (I ′
  • the compound can be produced by subjecting the reaction to a reaction similar to the reaction of) ⁇ (n).
  • compound (IV ′) can be subjected to a reaction as compound (IV) to produce compound (I), and the oxidation reaction can be carried out with compound (XX EI ) To convert the sulfido group into sulfoxide or sulfone, and then subject to a reaction for producing compound (IV) to produce compound (IV).
  • compound (XXIV) is compound ⁇ It can be produced by subjecting (I) to a per se known amino acid amino group protection reaction.
  • the reaction of (X XIV) ⁇ (V) proceeds by keeping both in a suitable solvent at a temperature in the range of about 20 to 150 ° G.
  • a deoxidizing agent is used to accelerate the reaction rate.
  • bases such as potassium carbonate, sodium hydroxide, sodium bicarbonate, pyridine, and triethylamine are coexistent in the reaction system.
  • compound (VI) in the production method of compound (VI), compound (VI) can be obtained according to a known Strecker (Strecker) reaction using compounds (I), (XXV) and hydrogen cyanide as starting compounds.
  • the reaction of (XIX) ⁇ (XXVI) can proceed by the same reaction as the reaction of (XXI) ⁇ (II ′).
  • Compound (W) can be produced by condensing compound (XXVI) and compound (M) in the presence of a metal hydride such as sodium cyanoborohydride.
  • a metal hydride such as sodium cyanoborohydride.
  • Compound (I) can also be produced by subjecting the reaction to (VI).
  • the compound used in the reaction is selected so as not to interfere with the reaction, for example, an inorganic acid salt such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc.
  • organic acid salts such as acetate, tartrate, citrate, fumarate, maleate, toluenesulfonate, and methanesulfonate, for example, sodium, potassium, calcium, and aluminum salts
  • Metal salts such as triethylamine salts, guanidine salts, ammonium salts, hydrazine salts, quinine salts, and salts with bases such as cinchonine salts.
  • the compound ⁇ ia ′) has angiotensin converting enzyme inhibitory activity and is useful as a compound for diagnosing, preventing and treating hypertension, like Compound (I). Best form to do
  • Table 2 shows the results obtained by reacting the S- (2-dimethoxyphenyl) -l-cysteine derivative obtained in Reference Example 6-9 with N-ethoxycarbonylphthalimid in the same manner as in Reference Example 1. The compound shown is obtained.
  • Reference Example 10 (2-Nitroguchi-1-4-Trifluoromethylphenyl) -cis-cysteine 5.39 was added to 2.5 N sodium hydroxide solution 6 7 «6 obtained in 10 and stirred at room temperature for 30 minutes. After that, under ice-cooling, benzyl 2-carbonylcarbonyl 2.7 »6 and a 1N aqueous solution of sodium hydroxide are simultaneously added dropwise over 30 minutes. After stirring at room temperature for 2.5 hours, the reaction mixture is extracted with ethyl ether, and the aqueous solution is made weakly acidic with 1N hydrochloric acid.
  • Cicarboni-5-phthalimidopentyl) amino-4-oxo-1,2,3,4,5-tetrahydro1,5-benzothiazepine-15-ethyl acetate 0.99 is obtained as a colorless oil.
  • the reaction solution is extracted by adding water 10 and ethyl acetate 300, and the extract is washed with water and distilled off under reduced pressure.
  • Add 5 parts of oxalic acid and 3 parts of ethyl acetate to the obtained oil dissolve it, add 120 W of petroleum ether and shake well. After standing, the supernatant was decanted, and the residue was subjected to the same treatment four times.Then, saturated aqueous sodium bicarbonate solution and ethyl acetate (300 W) were added for extraction, followed by extraction.
  • the solution is dried over anhydrous magnesium sulfate and evaporated under reduced pressure.
  • IRV cw-i 3 3 3 0 (NH), 1 7 8 0, 1 7 4 0, 1720,
  • Example 14 The methoxycarbonyl-3-phenylpropylaminobenzothiazepine derivative obtained in 41-17 was treated with hydrogen chloride as in Example 5 to give the compounds shown in Table 12 as colorless powders. .
  • the extract is washed with 0.1 ⁇ hydrochloric acid and water,
  • Elemental analysis value c is H is I 20 s S ⁇ H C i
  • Example 5 3 (5-benzyloxycarnylamino-11-carboquinpentyl :) obtained in 2— (2): amino-4, oxo-1,2,3,4,5— Dissolve tetrahydro-1,5 -benzothiazepine-15-acetic acid 40 ⁇ in acetic acid 1, add 30% hydrogen bromide acetic acid solution 1 and release at room temperature for 1 hour. Place.
  • Example 56 Example of using 1,5-benzothiazepine 5-na-methyl monoacetic acid tert-butyl ester derivative obtained in Example 55 Treatment with hydrogen hydride as in 5 gives the compounds shown in Table 15. Table 15
  • Example 60 Dissolve 0.15 of this product in 2 ⁇ ⁇ water, add 0.5 ⁇ ⁇ sodium hydroxide aqueous solution followed by 0.5 ⁇ ⁇ acetic acid, and purify with Amberley XAD- 2 in the same manner as in Example 60. 0.096 of the same educt as obtained in Example 60 are obtained.
  • Example 6 5.. Reference Example 4 3 (H) — [1 (S) ethoxycarbonyl-15-phthalimidopentyl] amino obtained from 2 or 47—amino-4,1-oxo-2,3 , - 4, 5-te us arsenide draw 1, 5-Benzochiaze etc.
  • Example 1 6 7 4 1 (ester), 1 660 (amide)
  • Example 5 9 3 (3 ⁇ 4) —C 5 —Amino 1 (S) —Ethoxycanolepone Lpentinole] amino 1 4-oxo 1 2,3,4,5—Tetrahydrodraw 1 , 5-benzothiazepine mono 5-acetic acid dihydrochloride 0.2 ⁇ ethanol 1 ⁇ ⁇ And add cyclohexanone 2 ⁇ and sodium cyanoborohydride 0.3 ⁇ , and leave at room temperature overnight. After distilling off ethanol under reduced pressure, add 1N aqueous sodium hydroxide solution 4 to the residue and stir at room temperature for 1 hour. Water 2 is added to the reaction mixture, and the mixture is extracted three times with 20 ml of ethyl acetate.
  • Angiotensin I-converting enzyme of the compound of the present invention ⁇ ACE angiotensin I-converting enzyme of the compound of the present invention ⁇ ACE
  • the experiments were performed by a modified method of Cushman et al. (Biochemical Ph.a., maco Iogy, 20, 637, 197 "!). That is, the inhibitory effect on ACE was determined from the rate of inhibition of hippuric acid production when the compound of the present invention was added to the amount of hippuric acid produced by ACE using hypol-L-histidyl-l-leucine (() as a substrate.
  • ACE 100 Protein concentration 20mgZ
  • a solution of the invention compound was added.
  • a boric acid monohydrochloric acid buffer solution containing dimethyl sulfoxide having the same degree as that of the sample solution was used. After heating this solution at 37 ° C for 1 hour, the reaction was stopped by adding 1N hydrochloric acid 150 ⁇ , centrifugation was performed at 5000 rpm for 2 minutes after adding ethyl acetate (0.1). The ethyl ethyl drunk layer was removed, dried under nitrogen gas at 4 CTC or less, and distilled water was added to the residue (4), mixed well, and colorimetrically determined at a wavelength of 228 nm.
  • mice Male rats (Sp “ague-Daw I ey”) weighing 250-350 g and bred under free access to food and water were used. The day before the experiment, pentoparbital sodium (50 mgZkg) was used. After injection into the abdominal cavity, the rat was crushed, and a polyethylene tractor was inserted and fixed in the hip artery for blood pressure measurement and in the hip vein for injection of angiotensin I and I, respectively.
  • the average blood pressure of the control period on the day of the experiment was measured using an electric sphygmomanometer (Nihon Kohden, MP-4T or NEC-San-ei, MPU-0.5-290-0-) After recording, 300 ngZkg of angiotensin I and then 100 ngZkg of angiotensin E were injected into the crotch vein to examine the blood pressure effect. Next, 3 and ⁇ Omg Zkg of the compound of the present invention were orally administered as an aqueous solution or a gum arabic suspension, and angiotensin I and II were repeatedly injected at 20.60 and 120 minutes after the administration, and the pressor response was monitored. . In calculating the suppression rate of the pressure-boosting action of Anji Taishin I, Anji Taishin! [The suppression rate was corrected based on the time variation of the pressure increase reaction.
  • the compound (I) of the present invention when used, for example, as a therapeutic agent for hypertension, it can be used, for example, according to the following formulation. 1.1) Tablets
  • the condensed 7-membered ring compound (I) provided by the present invention has excellent pharmacological action and is useful as a pharmaceutical.

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PCT/JP1984/000119 1983-04-22 1984-03-24 Fused 7-membered ring compounds and process for their preparation WO1985004402A1 (en)

Priority Applications (50)

Application Number Priority Date Filing Date Title
PCT/JP1984/000119 WO1985004402A1 (en) 1984-03-24 1984-03-24 Fused 7-membered ring compounds and process for their preparation
US06/599,187 US4564612A (en) 1983-04-22 1984-04-11 Condensed, seven-membered ring compounds and their use
EP84302564A EP0125056B1 (en) 1983-04-22 1984-04-13 Condensed, seven-membered ring compounds, their production and use
AT84302564T ATE60061T1 (de) 1983-04-22 1984-04-13 Ankondensierte siebengliedrige ringverbindungen, ihre herstellung und ihre verwendung.
IE927/84A IE57599B1 (en) 1983-04-22 1984-04-13 Condensed,seven-membered ring compounds,their production and use
DE8484302564T DE3483920D1 (de) 1983-04-22 1984-04-13 Ankondensierte siebengliedrige ringverbindungen, ihre herstellung und ihre verwendung.
DK196884A DK196884A (da) 1983-04-22 1984-04-17 Forbindelser med kondenserede syvleddede ringe
NO841555A NO162235C (no) 1983-04-22 1984-04-17 Analogifremgangsmaate for fremstilling av terapeutisk aktive benzotiazepinforbindelser.
GR74460A GR79905B (enrdf_load_html_response) 1983-04-22 1984-04-18
AR84296356A AR244217A1 (es) 1983-04-22 1984-04-18 Procedimiento para preparar derivados de acidos 3-amino-4-oxo-2,3,4,5-tetrahidro-1,5-benzotiazepin-5-alcanoicos(c2-c3)
ES531740A ES531740A0 (es) 1983-04-22 1984-04-18 Procedimiento para preparar cetonas heterociclicas nitrogenadas con anillo de siete miembros y condensadas.
PH30584A PH21294A (en) 1983-04-22 1984-04-18 Derivatives of 1,5-benzothiazepine-5-acetic acid, their pharmaceutical composition and method of using thereof
CA000452446A CA1209993A (en) 1983-04-22 1984-04-19 Condensed, seven-membered ring compounds and their use
AU27092/84A AU565188B2 (en) 1983-04-22 1984-04-19 Tetrahydrobenz-1,5-thiapin-4-ones
PT78454A PT78454B (en) 1983-04-22 1984-04-19 Condensed seven-membered ring compounds and their use
NZ207915A NZ207915A (en) 1983-04-22 1984-04-19 Benzothiazepines and pharmaceutical compositions
FI841590A FI82455C (fi) 1983-04-22 1984-04-19 Foerfarande foer framstaellning av nya, terapeutiskt verksamma bensotiazepinderivat.
HU841550A HU193008B (en) 1983-04-22 1984-04-20 Process for producing benzothiazepines
KR1019840002110A KR910007965B1 (ko) 1983-04-22 1984-04-21 축합 7원 고리 화합물의 제조방법
IL71617A IL71617A (en) 1983-04-22 1984-04-22 3-(amino-1-carboxylalkyl)amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid derivatives,method for producing them and pharmaceutical compositions containing them
IL74004A IL74004A (en) 1984-03-24 1985-01-04 3-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine derivatives,their production and pharmaceutical compositions containing them
NO850045A NO160712C (no) 1984-03-24 1985-01-04 Analogifremgangsmaate for fremstilling av terapeutisk aktive benzotiazepin-forbindelser.
CA000471650A CA1281718C (en) 1984-03-22 1985-01-08 Derivatives of 3-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5- acetic acid
HU8560A HUT38631A (en) 1984-03-24 1985-01-08 Process for preparing new condensed 7-member ring compounds and pharmaceutical compositions comprising such compounds
NZ210781A NZ210781A (en) 1984-03-24 1985-01-08 Benzothiazepine derivatives and pharmaceutical compositions
NZ220233A NZ220233A (en) 1984-03-24 1985-01-08 Piperidine derivatives
US06/691,005 US4638000A (en) 1983-08-12 1985-01-14 Condensed seven-membered ring compounds, their production and use
EP85300271A EP0156455A3 (en) 1984-03-22 1985-01-15 Condensed seven-membered ring compounds, their production and use
IE850148A IE850148L (en) 1984-03-24 1985-01-23 Condensed seven-membered ring compounds their preoduction¹and use
JP60012053A JPS60231668A (ja) 1984-03-22 1985-01-24 縮合７員環化合物およびそれを含有してなる高血圧症予防・治療剤
DK33385A DK33385A (da) 1984-03-24 1985-01-25 Kondenserede syvleddede forbindelser og farmaceutiske praeparater deraf
PH31789A PH23261A (en) 1984-03-24 1985-01-29 Condensed seven-membered ring compounds and pharmaceutical preparation containing said compounds
PT79931A PT79931B (en) 1984-03-24 1985-02-06 Process for the preparation of 3-amino-2,3,4,5-tetra hydro-1,5-benzothiazepine derivatives and pharmaceutical compossitions therewith
ES540548A ES8702389A1 (es) 1984-03-24 1985-02-20 Un procedimiento para preparar nuevos compuestos con anillo condensado de siete miembros.
ZA851293A ZA851293B (en) 1984-03-24 1985-02-20 Condensed seven-membered compounds,their production and use
AR299618A AR241113A1 (es) 1984-03-24 1985-02-27 Procedimiento para preparar derivados de acidos 3-amino-4-oxo-2,3,4,5-tetrahidro-benzotiazepin-5-alcancarboxilicos y sus sales
GR850705A GR850705B (enrdf_load_html_response) 1984-03-24 1985-03-20
KR1019850001864A KR910009201B1 (ko) 1984-03-12 1985-03-21 축합 7원 고리 화합물의 제조방법
FI851154A FI82465C (fi) 1984-03-24 1985-03-22 Foerfarande foer framstaellning av nya bensotiazepinderivat.
ES544748A ES8609290A1 (es) 1983-04-22 1985-07-01 Procedimiento para preparar cetonas heterociclicas nitroge- nadas con anillo de siete miembros y condensadas
ES554039A ES8801635A1 (es) 1984-03-24 1986-04-16 Un procedimiento para preparar derivados de 3-amino-4-oxo-2,3,4,5-tetrahidro-1,5-benzoxazepina.
ES554040A ES8701722A1 (es) 1984-03-24 1986-04-16 Un procedimiento para preparar derivados de acidos carboxilicos
US06/900,816 US4739066A (en) 1984-03-22 1986-08-27 Intermediates for the preparation of condensed seven-membered ring compounds
PH34615A PH24015A (en) 1984-03-24 1986-12-18 A process of preparing 1,5(5h)-benzothiazepine 4-one derivatives
NO871049A NO871049D0 (no) 1984-03-24 1987-03-13 Kondenserte 7-leddete forbindelser og fremgangsmaate for deres fremstilling.
ES557636A ES8801653A1 (es) 1984-03-24 1987-07-29 Un procedimiento para preparar derivados de 3-amino-4-oxo-2,3,4,5-benzoxapina
FI882956A FI81089C (fi) 1984-03-24 1988-06-21 4-piperidyl-substituerade karboxylsyraderivat och foerfarande foer deras framstaellning.
AR312003A AR241112A1 (es) 1984-03-24 1988-09-22 Procedimiento para preparar derivados de acidos-3-amino-4-oxo-2,3,4,5-tetrahidro-benzotaizepin-5-alcancarboxilicos y sus sales.
PH37629A PH25131A (en) 1984-03-24 1988-10-03 A process for preparing benzothiazepine derivatives
JP1118070A JPH0215060A (ja) 1984-03-22 1989-05-10 ４―ピペリジン誘導体

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FR2607004B1 (fr) * 1986-11-20 1990-06-01 Synthelabo Compositions pharmaceutiques contenant du diltiazem et un inhibiteur de l'enzyme de conversion de l'angiotensine
JPH0657707B2 (ja) * 1987-05-25 1994-08-03 吉富製薬株式会社 ピペリジン化合物
DE4322109C2 (de) * 1993-07-02 2001-02-22 Franz Durst Brenner für ein Gas/Luft-Gemisch
JP2002241368A (ja) * 1997-02-18 2002-08-28 Shionogi & Co Ltd 新規ベンゾラクタム誘導体およびそれを含有する医薬組成物
WO1998041510A1 (fr) * 1997-03-14 1998-09-24 Shionogi & Co., Ltd. Nouveaux derives du benzolactame et compositions medicamenteuses les contenant

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