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WO1986000618A1 - Composes cycliques condenses a 7 membres et leur procede de preparation - Google Patents

Composes cycliques condenses a 7 membres et leur procede de preparation Download PDF

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Publication number
WO1986000618A1
WO1986000618A1 PCT/JP1984/000363 JP8400363W WO8600618A1 WO 1986000618 A1 WO1986000618 A1 WO 1986000618A1 JP 8400363 W JP8400363 W JP 8400363W WO 8600618 A1 WO8600618 A1 WO 8600618A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
hydrogen
group
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Prior art date
Legal status (The legal status 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 status listed.)
Ceased
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PCT/JP1984/000363
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English (en)
Japanese (ja)
Inventor
Hirosada Sugihara
Kohei Nishikawa
Katsumi Ito
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
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/JP1984/000363 priority Critical patent/WO1986000618A1/fr
Priority to IL84625A priority patent/IL84625A/xx
Priority to IL74004A priority patent/IL74004A/xx
Priority to NO850045A priority patent/NO160712C/no
Priority to CA000471650A priority patent/CA1281718C/fr
Priority to NZ220233A priority patent/NZ220233A/en
Priority to NZ210781A priority patent/NZ210781A/en
Priority to AU37602/85A priority patent/AU573679B2/en
Priority to US06/691,005 priority patent/US4638000A/en
Priority to EP85300271A priority patent/EP0156455A3/fr
Priority to IE850148A priority patent/IE850148L/xx
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 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
Publication of WO1986000618A1 publication Critical patent/WO1986000618A1/fr
Priority to ES554040A priority patent/ES8701722A1/es
Priority to ES554039A priority patent/ES8801635A1/es
Priority to US06/900,816 priority patent/US4739066A/en
Anticipated expiration legal-status Critical
Priority to NO871049A priority patent/NO871049D0/no
Priority to ES557636A priority patent/ES8801653A1/es
Priority to AU12362/88A priority patent/AU598105B2/en
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
Ceased legal-status Critical Current

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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
    • 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 is useful as a medicament.
  • various compounds having angiotensin-converting enzyme inhibitory activity are known, a compound having a condensed 7-membered ⁇ as a basic skeleton is a 3-port pupa Patent Publication No. 723552 * C Only what was done *
  • the present invention uses the formula
  • R 1 and R 2 each represent hydrogen, halogen, trifluoromethyl, lower aki or lower oxy, or rain or swiftly form tri or tetramethylene, and ⁇ "tit, hydrogen, lower aki or araki, R 4 is hydrogen or lower aki, S 6 is a condensed or non-fused complex containing at least 1, 0 or S as a ring atom A represents an acetylene chain, n represents 1 or 2) and its method of producing K and K.
  • the halogen represented by H 1 or E 2 includes, for example, fluorine, nitrogen, bromine, and tertiary oxygen, and lower alkoxy represented by R 1 or ttR 2.
  • the group include methoxy, ethoxy, buta-poxy, y-broxy, butoxy, isobutoxy, ⁇ — butoxy, ter-butoxy * Akoxy group having about 1 to 4 carbon atoms.
  • R 1 spare S 2 is, rather it may also form a A Killen Lou and the rain's, trimethylene, A Killen Bridge, and the like, such as tetramethylene, H 1, R 2, R 3, there is R 4 methyl example is a lower a key group represented by R 5, Chi, Burobi, isopropoxy bi, Petit, I, knobs Ji, «- butyl, ter - the a kill group Buchi * which number 1 to 4 ⁇ of carbon can give.
  • C may be the same kind of atom or two or more kinds of atoms may coexist as a ring-constituting atom, for example, oxeta -, Thieta, azetzi, tethydrov 9, tetrat droche, biloli zini, oxa-(3, 4, 5, 6-tedrhidraw 2 H-villa-), cheat, bilidil, and kissiba -, Ceva, Perhi droazebiru, O Small Kisoriki, Chiokaji, Perhydroazo ⁇ -/ w, Dioxur, Zixa, Biperazini, Hori-, Ba
  • C l-5 akanoy (, acechi, brobi), benzoy, fu ⁇ ⁇ (3 ⁇ 41 -4) ⁇ ⁇ ⁇ ⁇ ⁇ (eg, ⁇ ⁇ ⁇ ⁇ ,), low-grade C Ci-4)
  • E group further fluorine, 3 ⁇ 4 arsenide, bromine any halogen, methoxy, E butoxy, Puroboki ⁇ , butoxy how low ⁇ (C 1 - 4)
  • interspersed condensed or non-condensed heteroalicyclic groups include, for example, 1-ferviperidi, 1-pendiviperidi, 1-furbiperidyl, 1-pendibiperidi, 1-acetibiperidyl, 1 One Penzo Biradil, One Ferni Schmaj; V, 4-Ace Biperaziru, One Penzo Biperaj, One Chile Dorinyl, 1,3 dioxoisoindori-, 1,2,3,4-tetratetra-dose 1-year-old xoisoquinolyl, 1,2,3,4-tetrahidroxy 3-oxoisoquinolyl 4 groups Is raised.
  • the A Quillen chain represented by A for example linear or branched A Killen chain of 1 to 1 about 6 carbon atoms can be mentioned, Kisamechi such as methylene, E styrene, preparative Rimechiren, tetramethylene s pentamethylene, to Ren, hebutamethylene, octamethylene, nonamethylene, decamethylene, pendecamethylene, dodecamethylene, tridecamethylene, tetradecamethylene, pentadecamethylene, hexadecamethylene, provylene, ethylmethylene, 4-butyhexamethylene, 3,3-dimethyl Hexamethylene, 5,5—diethylhexamethylene, 3,5-dimethylnonadiethylene and other two superior groups.
  • the alkylene chain may have an uncomplexed bond (eg, a double bond or a triple bond) in the chain.
  • Cn ⁇ n The two dominant groups denoted by Cn ⁇ n are methylene, ethylene or ethylidene, depending on the ⁇ of n.
  • the present invention has an asymmetric carbon in the molecule, but the present invention includes the deviation of the R configuration and the S configuration. * However, it is preferable that the absolute position of the carbon in the £ (* 1) is R and the absolute position of the carbon in the £ (* 2) is S ⁇ .
  • Examples of itMs (I) include: * Mongolia, hydrobromic acid,
  • potassium, aluminum such as tritamine, guadin, danzium, hydrazine, kyune, cynco
  • the compound (I) of the present invention has, for example, the formula
  • a dehydration-closure reaction ⁇ by applying a dehydration-closure reaction ⁇ :
  • the closing of the crotch can be performed, for example, by an amide bond formation in a normal peptide.
  • a peptide-forming reagent such as dicyclohexica posimidide,, 1 ⁇ , -force / V pozimidazo, diphenophosphate azide, or ⁇ thiophosphoric acid alone, or
  • a normal nucleic acid-free eg, hydrogen chloride,, acid, bromine
  • 2,4,5-trichlorophenol / w Pentachlorophenol, bentaf phenol, 2-Etropheno or 4-1-trophenol * Which phenols or If hydride Lokisk ⁇ imid, 1-t-droquin ⁇ benzotriazole, ir-hydroxy y biveridine 3 ⁇ 4 which] ⁇ ⁇
  • SJSfi degree usually - 2 0 + 5 0 Dea, preferably room location near der, as usually for Ru »medium e.g. Jiokisan, Tet, Dorofuran, Aseto - tri 9 Pyridine, N, 1I- dimethylcarbamoyl ho Muamido, ⁇ , »—Dimethylacetamide, Dimethisoxide, ir-Methylpyrrolidone Chloroform, Idimethylene *, etc., which may be used alone or as a mixture.
  • the present compound (I) has the formula (summer)-
  • TT a halogen or the formula R a S0 3 - 0 - (wherein, R a is a lower A key, preparative riffs Oromechi, Hue - Le or p - shows a bird)
  • R a is a lower A key, preparative riffs Oromechi, Hue - Le or p - shows a bird
  • J3 ⁇ 4s is usually water or other fiber (eg, acetate-tolyl, dimethiformamide, dimethiformide)
  • the compound (I) of the present invention is, for example, a compound of the formula (V)
  • lT b is halogen or wherein R b S0 2 - 0- (wherein, R 3 ⁇ 4 lower A key, triflumizole Ruo Russia methyl, Hue - or p- tri showing a) at approval a group I Table However, other 3 ⁇ 4 symbols have the same meanings as in the above.).
  • the reaction is carried out in a single or mixed state with water or other exchangeable solvents (eg, acetate, dimethylformamide, dimethylphosphoxide, tetrahydrofuran, benzene, toene). This can be achieved by maintaining the humidity in a moderate range.
  • This K for example, sodium radicals such as sodium charcoal, sodium hydroxide and sodium hydride can coexist in the ⁇ system.
  • the reducing conditions include, for example, catalytic reduction using platinum, palladium, -dimethyl or a mixture of these and any carrier.
  • lithitamaminium hydride, lithium borohydride, ⁇ a Gold hydrides such as lithium borohydride, sodium borohydride, sodium borohydride ⁇ : reduction by gold, sodium sodium, metal magnesium, carrier by doco and alcohols J, iron by iron With metals: 3 ⁇ 4 ⁇ conditions such as reduction with acid, acid, electrolytic reduction, and reduction with reductase t can be mentioned.
  • the upper £ ® ⁇ is usually measured in the presence of water or an organic solvent (eg, methanol, ethanol, ethyl ether, dioxane, methylene chloride, chlohom, penzentoluene, acetic acid, dimethylformamide, dimethylacetamide).
  • an organic solvent eg, methanol, ethanol, ethyl ether, dioxane, methylene chloride, chlohom, penzentoluene, acetic acid, dimethylformamide, dimethylacetamide.
  • a compound in which R 4 is hydrogen is, for example, a compound represented by the formula
  • Z represents a protecting group which can be eliminated by hydrolysis or bonding, and other symbols are as defined above.
  • Has the hydrolysis of the compound represented by One IS-i can also be manufactured by the contactor ⁇ iSic ⁇ .
  • protecting group which can be converted to K by the hydrolysis represented by z all kinds of ⁇ - and trithi groups can be used, but, in particular, benzyloxyboel, tert-butoxycarpo-, trifoacetyl, tri- ⁇ Chi is relatively relaxed.
  • protecting groups which can be separated from JK such as benzyl, diphenylmethy, and benzyloxy, are given below.
  • This method ic * hydrolysis is carried out in water or an organic solvent such as methanol, ethanol, dioxane, pyridine, vinegar, acetate, methylene dichloride, etc.
  • an organic solvent such as methanol, ethanol, dioxane, pyridine, vinegar, acetate, methylene dichloride, etc.
  • Cyanide, bromine, hydrogen iodide, hydrogen fluoride, diatom, methanesulfonate, p-toluenesulfonate, trifluoroacetic acid) or a group (eg, sodium hydroxide, sodium hydroxide, carbonic acid) Potassium, sodium bicarbonate, sodium nitrate, and triethamine) can be added.
  • the above reaction is usually carried out in the range of about ⁇ 20 to +150.
  • the contact reduction reaction in this method can be carried out with water or, for example, methano-, ethanol, dioxane, tetrahydrofuran.
  • R * is hydrogen, for example,
  • JJB solvolysis is carried out in water or, for example, in methano-, ethanol, dioxane, viridine, drunk test, acetone, methylene dichloride, or a mixture thereof.
  • Acids eg, hydrogen iodide, hydrogen bromide, hydrogen iodide, fluorine, «S, methanesulfonate, p-toensulfonate, trifluoro, acidic resin
  • Acids eg, hydrogen iodide, hydrogen bromide, hydrogen iodide, fluorine, «S, methanesulfonate, p-toensulfonate, trifluoro, acidic resin
  • the essential conditions include platinum, palladium, and platinum, which are a mixture of any metal and any carrier as a carrier, for example, lithium aluminum hydride, lithium borohydride, cyanohydrogen. Lithium borohydride, sodium borohydride, sodium anodium borohydride, etc. Gold-shung hydride 4C carrier, gold-sodium sodium, metallic magnesium * Reduction by irons, iron, etc.
  • the reaction conditions can be raised, such as the reduction of any metal and acid or acid such as persulfate, reduction of acid, reduction with the source enzyme t, ordinarily water or organic (eg, methanol,
  • the reaction is carried out in the presence of ethano pendant, ethiate / W, virgin oxane, methylene chloride, glume hom, benzene, toene, rich acid, dimethylformamide, dimethylacetamide.
  • I go-between Ru different to one in 3 ⁇ 4 -! 2 0 Te ⁇ + 1 0 0 is preferably about.
  • This reaction can sufficiently achieve its purpose 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 when the atom in the group which associates with the group A is a nitrogen atom, for example, the compound (I) may be a compound represented by the formula (X Xia) wherein W c is halogen or Represents a group represented by the formula R c S0 2 -0-(where R c represents lower aki, trifluoromethy, hu- or p-tri); Represents a constituent atomic group, and represents a group R e as a formula-: ⁇ ) .
  • the reaction can be carried out using a suitable solvent or a mixed solvent.
  • potassium groups such as potassium carbonate, sodium hydroxide, sodium hydrogencarbonate, viridine and triethyamine can be coexisted in the reaction system.
  • H 3 is of Group wherein Z and E S is hydrogen is hydrogen, the formula (I) in, E 3 is lower A key or Z and H 5 is a lower A key
  • I? Can also be produced by contacting with a penge or z and R s are penges.
  • the hydrolysis or ⁇ -elimination reaction in this method is water or tobacco, such as methanol, ethanol, brewery, clomethone, tetrahydro: orchid, dioxane, viridin, acetic acid, acetate, and methylene dichloride.
  • the reaction is carried out in any organic solvent or a mixture thereof, and the acid (eg, hydrogen hydride, hydrogen bromide, fluorinated fc *, hydrogen iodide, «, methanesulfonate, P-toenphone, trifon)
  • Acetic acid or base eg, sodium hydrate, potassium hydride, potassium carbonate, sodium bicarbonate, carbonate
  • the above reaction is usually performed in a range of about 120 to about 150.
  • the reduction reaction may be carried out with water or a solvent such as methanol, ethanol, ethyl acetate, dioxane, tetrahydrofuran or any other solvent or a mixture thereof. It is done in the presence. Under a pressure of the reaction until atmospheric pressure or 1 5 O iv Ot 2 about, room temperature
  • the compound can be produced by condensing SJS with a compound represented by H 5 ′ -OH (XV) [wherein 'and H 5 ' represent lower aki or araki].
  • the condensation conditions include, for example, reaction conditions using a condensation reagent (eg, dicyclohexacapide, capodiimidazo, cyanophosphate jet, difluorophosphate azide), or acid transfer arrowhead ( For example, it is possible to increase the conditions under which hydrogen peroxide, t * bromine, and p-toluenesulfonic acid) are used.
  • a condensation reagent eg, dicyclohexacapide, capodiimidazo, cyanophosphate jet, difluorophosphate azide
  • acid transfer arrowhead For example, it is possible to increase the conditions under which hydrogen peroxide, t * bromine, and p-toluenesulfonic acid.
  • Anti-appropriate * In a solvent or mixed solvent, or
  • Eta 3 is lower alkyl or ⁇ la kill or / and is a lower A key or ⁇ la key compounds In formula (I), but in Bruno and R 5 are hydrogen is hydrogen Certain compounds have the formula
  • R 3 ′′ and R 5 ′′ represent a lower aki or alkenyl, and ⁇ represents a halogen or a formula R d S 02-0-(where R d is a lower aki, a trimethylmethacrylate, a phenol) Or a group represented by p-tolyl)] can be produced.
  • the reaction proceeds in a suitable solvent in a fi degree range of about ⁇ 20 to +150 in the presence of a base (eg, potassium potassium, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate).
  • a base eg, potassium potassium, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate.
  • the reduction reaction is performed in water or, for example, methanol, ethyl acetate, ethanol, dioxane, tetrahydrofuran * which is attached in R purple or a mixed solvent thereof, for example, palladium-carbon. Performed in the presence of a medium. This reaction is carried out at normal pressure or at a pressure up to about 150 at a humidity of +150.
  • reaction is carried out in water or, for example, in water or, for example, methano-, ethanol, thiocyanate, chloroform, tetradro7-lane, dioxane, pyridine, acetic acid, acetate, methylene hydride.
  • organic solvent eg, hydrogen peroxide, hydrogen bromide, hydrogen fluoride, iodine, acid, methanesulfonate, p-transferonic acid, trifluorene.
  • Vinegar, or sodium hydroxide eg, sodium hydroxide, sodium hydroxide, potassium carbonate, sodium hydrogen carbonate, sodium carbonate, sodium acetate
  • the above is usually performed in the range of about 120 to about 150.
  • S 7 is lower A key indicates ⁇ La / w key or ⁇ Shi, halogen or the formula E ⁇ S0 2 -0 - (In the formula, H e is lower A key, preparative riffs Oromechi, Hue - Or P-tri)) «Replacement OMPI
  • J Can be obtained by S) S.
  • the reaction proceeds by maintaining the temperature in the appropriate four solvents at a temperature in the range of about 120 to about 150.
  • the compound having a substituted imino group by the formula (I group E in 6 4C in :) lower (an alkylene or ⁇ la key has the formula (I) of Group compound having a group iC unsubstituted Imino groups in It can also be obtained by condensing a lower (C 1-4 ) aldehyde or a carboxylic acid under reducing conditions.
  • Examples of the reducing conditions include contact reduction using a catalyst such as platinum, palladium, rhodium or the like or a mixture thereof with an optional carrier, such as lithium hydride, lithium borohydride, cyano hydride.
  • a catalyst such as platinum, palladium, rhodium or the like or a mixture thereof with an optional carrier, such as lithium hydride, lithium borohydride, cyano hydride.
  • Lithium borohydride, sodium borohydride, sodium cyanoborohydride Spectroscopy due to metal hydrides, reduction with sodium metal, gold magnesium and other alcohols, iron, sub-dust It is possible to raise the reaction conditions such as which metal is used, and the reaction conditions are homogeneous by acid such as acetic acid and enzymatic acid;
  • the above reaction is usually carried out with water or an organic solvent (eg, methanol, ethanol, ethetate, dioxane, methylene chloride, chloro-T3 hom,
  • a compound in which R 4 is a lower radical can also be produced by subjecting a compound in which R 4 is hydrogen in formula (I) to hydrogen. .
  • the reaction is usually with water or an organic solvent (eg, methanol, ethano-, ethiate, dioxane, methylene chloride, chlorinated hom, benzene, toluene, drunkic acid, dimethylformamide, dimethyl acetate).
  • an organic solvent eg, methanol, ethano-, ethiate, dioxane, methylene chloride, chlorinated hom, benzene, toluene, drunkic acid, dimethylformamide, dimethyl acetate.
  • Toamide Toamide
  • Acquis fcSiS reaction conditions are appropriate: H is mixed.
  • groups such as potassium carbonate, sodium hydroxide, sodium bicarbonate, pyridine and thiamine are coexistent in the reaction system to promote the reaction rate. You can do that too.
  • the compound (I) can be obtained by the reaction for producing the compound (I) itself, but it is also possible to add an acid, an alkali, and a 3 ⁇ 4 group as needed to produce the compound (I). .
  • the object I) of the present invention thus obtained can be obtained by using conventional separation and purification means from the reaction mixture, such as extraction, concentration, neutralization, ⁇ ⁇ , recrystallization, column chromatography, and thin layer chromatography. Can be separated
  • Compound (I) may exist in at least the stereoisomers of 4 Rev. Naturally, these individual isomers and the difference between these compounds are also included in the scope of the present invention. If desired, these isomers can also be produced by a process. For example, starting compounds (I), (summer), (w), (v), (3 ⁇ 4),
  • optically active acid ⁇ , camphorsphonic acid, Meng Tartar, Meng Teng, dipenzo liquor
  • Optically active groups eg, cinchonine, synchidine, chi & n, chidin, amethypendiamine, dehydroavidiamine *, etc.
  • Each isomer can also be separated by separation means such as chromatography, separation and recrystallization.
  • the compound of the present invention ie, the condensed 7-membered compound represented by the formula (I) and the compound thereof are referred to as animals]), sputum animals ( ⁇ , humans, dogs, cats, egrets, momots, Butto) and its inhibitory action on amphoterin converting enzyme, butadiene-decomposing enzyme (quinase).
  • the compound of the present invention has low toxicity, absorbs well even when administered orally, has excellent kneading properties, and is also excellent in stability, it can be used by itself or as appropriate pharmacologically when used as a medicament for medical treatment. It can be mixed with an acceptable carrier, pharmaceutical preparation and diluent, and administered as an oral or parenteral pharmaceutical preparation such as powder, granules, pharmaceutical preparations, cabose preparations, and injections.
  • the dosage varies depending on the condition of the target disease and the administration route.For example, when administered to adult breathing subjects for the treatment of Xus or genuine hypertension, one dose is usually 0.02- About 10
  • Raw material compounds of the present invention (), (a), (V), (W), ( ⁇ ), (x) — 2 ⁇ — and (21) can be easily manufactured, for example, by a method represented by the following J3 ⁇ 4S equation.
  • the compound (2) can be formed by adding the compound (2) to the compound-fe (xv) by applying the following reaction to the normal -toro group to the amino group. You can get it.
  • the amino group of the compound () is protected with an appropriate amino-protecting group (eg, a phthaloy group) to obtain the compound (II) first.
  • an appropriate amino-protecting group eg, a phthaloy group
  • the compound (XXVI) is converted to a compound (CXXVI) in an aqueous solution in the presence of a compound (XXVI) and a base (eg, sodium carbonate, carbon monoxide, potassium hydrogen carbonate), usually at about 0 to about 100. Easily progresses at a temperature of a
  • the reaction of (XXM) ⁇ (XXK) is a transfer reaction of a -toro group to an amino group, H, and a usual well-known method can be used.
  • the reduction can be performed by, for example, paradigm-single-carbon, varium-supported palladium, sulfide-palladium ⁇ - platinum *, or sensitized reduction using sensitized medium, or lotus powder, tin, ⁇ -tin, iron, etc. Reduction with metals and acids or iron * is used.
  • the water ring-closure reaction of the compound (XXK) thus obtained to the compound ⁇ * (XXX) is usually performed in the presence of a known condensing agent.
  • I can.
  • hydrocondensation examples include dicyclohexica pomidide, power poimidimidazo, and ⁇ anoline dijet.
  • the solvent for example, dioxane, methylene dichloride, acetate-tri, ⁇ , dimethyiformamide, tetra-t ⁇ »furan, and the like are used, and the reaction is usually performed at a fi degree range of about 110 to about 100. Be performed.
  • ⁇ (3 ⁇ 4) is a normal radical reaction, for example, a method in which a low-acid aldehyde corresponding to the group R * is reacted under reducing conditions, or a compound (XX) is appropriately And the like.
  • Compound (V) is obtained by converting compound (XXV) to an amino group
  • % S can be produced by subjecting to K water ring closure ⁇ .
  • Compound (XXXI) can be produced by attaching a known amino acid-protected amino group to a compound (XXXI) in the production method of compound (1) (K). The reaction of (XXXI) to ⁇ (K) is carried out by keeping the appropriate 43 ⁇ 4 ⁇ neutralization ⁇ ⁇ ) and (W) in the range of -20 to 10150 *. ⁇ Acidic agents such as potassium carbonate, sodium hydroxide, sodium hydrogen hydrogen, bilizine, trieti OMPI (1) A group such as an amine can coexist in SJg: system. In the production method of compound CX), compound (X) can be obtained according to known stripping force-(atrecker) SjSi using compounds (W) and (XXHY) and cyan as raw material ⁇ T. it can.
  • compound c xxxw can be obtained by reacting compound () with (XXXV).
  • Examples include aceturi, methyl I ketone, acetone, and tetrahydrofuran.
  • ⁇ is within a range of about 110 to about 150 in a quantitative range.
  • tretamine, pyridine, potassium carbonate, sodium carbonate, etc., and potassium iodide, etc. to fend off ⁇ jg in an advantageous manner: ftr ⁇
  • R 3 ′ and R 3 ′′ each represent lower aki or araki, and the other symbols are as defined above.
  • the compound (W ') is prepared by combining the compounds (XXXVI) and (XXIX) in the presence of, for example, sodium methoxide or iodine. By doing so, it can be manufactured.
  • the compound (w ′) can be produced by subjecting the compound (ring) to a known halogen ⁇ or sulfo- ⁇ by subjecting the compound (ring ′) to a known reduction. .
  • the starting compound (XXVM) used here is, for example,
  • T 11 represents a halogen
  • A represents A as A, -C ⁇ , and the other symbols have the same meanings as described above.
  • R 6 contains a group that may affect the reaction
  • the group may be, for example, low (C i-5) akanoy (eg, aceti), penzoi, fue lower (Cl-14) akoxy Power ⁇ Po (eg Benji ⁇
  • l in (1), it also includes a compound in which: & 6 is 4-biperidi even when substituted.
  • the compound used for anti-JSi does not hinder the reaction, such as acid, hydrogen bromide, sulfuric acid, sulfuric acid, and sulfuric acid.
  • Clay, dephosphoric acid Which inorganic soils, such as tonacetate, liquor, citric acid, fuma, maleic acid, Tohshong, 3 ⁇ 4, methanance;
  • Sodium ash, potassium, potassium, aluminum, etc. for example, sodium chloride, guadin, ammonium: lime, hydrazine, küne, ⁇ ⁇ 3 ⁇ 4 : : : : 3 ⁇ 4 : : : 3 ⁇ 4 : : : : : : : : : : : : : : : : : : : : : : :
  • Acidic acid 10 f is catalytically reduced in methanol at 5% palladium on carbon at normal fibre and pressure. After absorbing the calculated amount of hydrogen, the solvent is removed and the methanol is depressurized. Add the residue Athe and petroleum Aether: i. Then, remove the bright blue powder & yield 3-(. 1-aminophenothio-2 (H) —phthalimidobionic acid 8.4 f. Dissolve this product 8.4 in dimethylformamide 5 and add 5.5 g of flanolin-monitor ⁇ ⁇ ⁇ ⁇ ⁇ while stirring under ice-cooling.After the performance, stir for 5 minutes and mix.
  • L-cysteine 5.3 f was added to 2.5 sodium hydroxide water 67 W, stirred at room temperature for 30 minutes, and then cooled under ice-cooling. At the same time, the poker, the ⁇ and the 1 ⁇ aqueous sodium hydroxide solution 3 ⁇ 41 are defeated in a JC30 fight. After stirring the field at 2 to 5 o'clock in Murotori, the extract is extracted with ethyl acetate, and the aqueous solution ⁇ is acidified with 1 H3 ⁇ 4 acid.
  • the extract is ft-purified with 0.1% sodium ugly, sodium hydrogen carbonate aqueous solution, dried with anhydrous magnesium, and decompressed. ⁇ r after leaving 3 c R) 1-strength ox-force 4min-year-old oxo- 7-to-IT-format 2,3,4,5-tetradro- 1,5-pentoziazebine ⁇ 5 ⁇ ferment acid tert
  • One butyester 1.4 is obtained as a colorless candy.
  • Example 4 3 (R) -amino-4-oxo-1,2,3,4, ⁇ -tetrahydro-1,5, -pentoziazebine-5-enzyme ter-petester 1f obtained in Example 4 was dissolved in methanol 2 to dissolve it. , Potassium cyanide 0.32 f,-(-fomibuti) lid; imid 1.1 and acetic acid 0.3,
  • Example 40-42 When the benzothiazebine derivative obtained in Example 40-42 was treated with a hydrofluoride solution in the same manner as in Example 35, the compounds shown in Table 7 were obtained. difference -41—
  • Example 40 The benzothiazebine derivative obtained in 40-42 was treated with hydrazine in the same manner as in Example 36. Then, the compound shown in Table 8 is obtained by reacting with di-tert-butydicarbonate.
  • Example 54 (11)-[5-Amino 1 (S) -ethoxy carboxylic acid] Aminnow 4-oxo-1,2,3,4,5—Tetrahydro-1,5-1-: Add 0.2 f of nzothiazebine mono- ⁇ -acetic acid ⁇ 2 acid to 1 IT water solution, add sodium tricum solution 4 WiC and stir in room S for 1.5 hours. The solution is made acidic by adding 1 W of tC acetic acid, and then purified by Amberlite AD-2 Cam Chromatography-(Methanol: water-3: 7). The effluent is concentrated under reduced pressure and freeze-dried.
  • Example 55 Dissolve 0.15 f of this product in water, add 9 H aqueous solution of 1H sodium hydroxide and 0.5 W of acetic acid, and then apply imber Amberlite XAD-2 as in Example 55. To give the same free form 0.99 ⁇ as obtained in Example 55.
  • the benzothiazebine derivatives obtained in the actual examples 68 and 70 were hydrolyzed with 1N hydrous sodium tricum water in the same manner as in the actual travel example 73, and purified by amberite D-2 column chromatography. ⁇ Is obtained as fe-free.
  • Example 3 [1 (S) —ethoxycarbonyl-3-C4-biperidi) obtained in Example 72] amino-1,4-oxo-1,2,3,4,5-tetra, hydro -1,5-Benzothiazepine mono-5-Hydroacetic acid / dihydrobromic acid lump 0.1 is dissolved in ethyl acetate 5 and triethiamine 66 ⁇ 2 W is added, and stirred under ice cooling. Drop 2W3 ⁇ 43 ⁇ 4 in a two-part field. Stir in the fi fi for 50 minutes, add petroleum ether 20 and extract 6 times with sodium bicarbonate water 2. Make the aqueous layer weakly acidic with lomic acid, and extract 3 fractions with dichloromethane methane 3. Extract the solution with magnesium anhydride ' ⁇ One ⁇ 8—
  • Example 3 (R)-[1 (S) -ethoxycarb-3- (C4-vinylidyl) brovir] amino-4-4-oxo-2,3,4,51-teto obtained in Example 72 1,5 -Penzothiazebine-5-vinegar ⁇ '2bromate ⁇ 0.12 f was reacted with acetyl chloride in the same manner as in Example 77 to give 3 (R) — [3- ⁇ 1-acetyl-4-biperidyl. ) 1-1 (S) -ethoxy carbamide] minnow 4 1,2,3,4,5-tetrahydro-1,5-pentoziazebine-5 ⁇ fumigation 7 is obtained as a colorless powder .
  • IRV 1 3320 CHH), 1770, 1 740,
  • Example 8 3 (R) — [1 (S) -ethoxycarbox 10 1-phthalimidode!] Obtained in 5) AMINO 4 1-year-old oxo-1,2,3,4, ⁇ -tetrahydrodraw 1,5 —Penzothiazebin-5-tert-butyster
  • Example 90 3 (R) 1 [4-1 (1-1-benzene-1-(1)-1-benzyl-1-(S)-ethoxyka-butyl] amiso 4 1, no 2, 4, 5-tetrahydrid 1 , 5-Penzothiazebine-1-tert-butyl ester, 0.8-acetic acid, dissolve 0.8-acetic acid, add 30 * hydrogen acetic acid acetic acid solution, and let it stand at room temperature for 1.5 hours. And then remove the supernatant by decanting.
  • the reaction solution After leaving the reaction solution to pass through the room overnight, decompress the mixture, add water sow and ethyl acetate 20 to the residue, and shake. After passing through to remove insoluble matter, the vinegar-containing layer is washed with 0.1N-acid, 0.1-ml aqueous sodium hydroxide solution and water in this order, dried with magnesium anhydride, and then removed.
  • 5-Penzothiazebin-1 5-vinegar mon 0 ⁇ 43- is obtained as a colorless powder.
  • Dissolve 0.3 tert-butylester in 1.5 Wi add 30 * hydrogen bromide acetic acid solution, leave it in the field for 0.5 hours in a room, and add ⁇ SJS solution ⁇ : The supernatant is decanted and removed. Dissolve the sediment in 11 W of 10% sodium hydroxide solution and release in room humidity for 30 minutes. After neutralization by adding 2 W of acetic acid, the product is purified by -2 force, mucography-(water: methano--1: 1).
  • the solution is removed by passing it through an iridium medium and decompressed.
  • Add the mixture of pentacarboxylic acid and chloride to the resulting mixture. After stirring at 1 o'clock, add 20 watts of benji genki potato. Stir in Chamber S 3 ⁇ 4 ⁇ Add sodium charcoal hydrogen hydrogen 30-little by little.
  • Poly-4-biperidi) -Pupano 110 is obtained as a yellow oil.
  • Dissolve the hexanoate 10 in the ethanol 20 by dissolving the hexanoate 10 in the ethanol 20 and permanently using 10% powder carbon (containing 50% water) ⁇ as the sensitizing agent. Perform contact reduction at normal pressure. After the absorption of hydrogen has ceased, the solvent is removed by passing through a sensitizing medium, and the liquid is decompressed and distilled off to obtain ethyl 6- (4-biperidi) hexanoate.
  • This product Add 10 W of water and 200 mL of acetic acid, add 7.2 W of sodium bicarbonate and stir with 7.2 W of penzoxyca-podichloride in the ⁇ chamber moat and stir overnight.
  • the obtained oily substance was purified by silica gel column chromatography (hexane: ethyl acetate ⁇ -3: 1-2: 1) to give 5-(1-pen-year-old sica-po-14-biperidi) pliers; p —Tohens; V phosphate 18- is obtained as an oil.
  • the U layer is separated, washed with water, dried with anhydrous magnesium sulfate, and removed to give 4-thia-capaldehyde 11f as a pale yellow liquid.
  • Ethyl 3- (4-thia-) atalylate 10- is dissolved in ethanol 15 OWi, and 10 ⁇ palladium-carbon (50 * water-containing) 9 f is used as a sensitizing medium to perform contact reduction at normal pressure.
  • Angiotensin I-enzyme (ACE) of the compound of the present invention is angiotensin I-enzyme (ACE) of the compound of the present invention
  • the reaction was stopped by adding ISO ⁇ , and ethyl acetate was added, followed by centrifugation at 11,500 rpm for 2 minutes.
  • the hydrophobic acid layer 0-5W was dried under nitrogen gas under i 40, and the remaining substance was sufficiently added with steam water to be sufficiently diluted, and colorimetrically quantified at a wavelength of 228 nm.
  • the experimental adult crab prepared according to the present invention was shown in Table 15].
  • the compound (I) of the present invention can be used according to a method of treating hypertension, for example, as a method for treating hypertension 8.
  • Ingredients (1), (2) and 17 f of component (3) are mixed and granulated together with a paste made from 7 f of component (3) .
  • the Hakogo 7 kaiyu compound (I) provided by the present invention has excellent action and is useful as a pharmaceutical.

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Abstract

Nouveaux composés cycliques condensés à 7 membres représentés par la formule (I), où R1 et R2 représentent chacun hydrogène, halogène, trifluorométhyle, alkyle inférieur ou alkoxy inférieur ou, lorsqu'ils sont pris ensemble, ils représentent tri- ou tétraméthylène, R3 et R5 représentent chacun hydrogène, alkyle inférieur ou aralkyle, R4 représente hydrogène ou alkyle inférieur, R6 représente un groupe hétéro-alicyclique condensé ou non condensé contenant au moins un élément parmi N, O ou S en tant qu'atome du cycle, A représente une chaîne alkylène et n représente 1 ou 2, ainsi que leurs sels. Ces composés et leurs sels sont efficaces en tant qu'inhibiteurs de l'enzyme de conversion de l'angiotensine, et sont utiles dans le diagnostic, la prophylaxie et le traitement des maladies du système circulatoire, par exemple de l'hypertension, des maladies cardio-vasculaires ou de l'apoplexie.
PCT/JP1984/000363 1983-08-12 1984-07-13 Composes cycliques condenses a 7 membres et leur procede de preparation Ceased WO1986000618A1 (fr)

Priority Applications (29)

Application Number Priority Date Filing Date Title
PCT/JP1984/000363 WO1986000618A1 (fr) 1984-07-13 1984-07-13 Composes cycliques condenses a 7 membres et leur procede de preparation
IL84625A IL84625A (en) 1984-04-06 1985-01-04 Piperidylalkanoic acid derivatives and a process for their production
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 (fr) 1984-03-22 1985-01-08 Derives de l'acide 3-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5- acetique
NZ220233A NZ220233A (en) 1984-03-24 1985-01-08 Piperidine derivatives
NZ210781A NZ210781A (en) 1984-03-24 1985-01-08 Benzothiazepine derivatives and pharmaceutical compositions
AU37602/85A AU573679B2 (en) 1984-03-22 1985-01-09 2,3,4,5-tetrahydro-1,5- benzothiazepine derivatives
US06/691,005 US4638000A (en) 1983-08-12 1985-01-14 Condensed seven-membered ring compounds, their production and use
EP85300271A EP0156455A3 (fr) 1984-03-22 1985-01-15 Composés contenant des anneaux à 7 membres condensés, leur production et leur emploi
IE850148A IE850148L (en) 1984-03-24 1985-01-23 Condensed seven-membered ring compounds their preoduction¹and use
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.
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 (fr) 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.
ES554040A ES8701722A1 (es) 1984-03-24 1986-04-16 Un procedimiento para preparar derivados de acidos carboxilicos
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.
US06/900,816 US4739066A (en) 1984-03-22 1986-08-27 Intermediates for the preparation of condensed seven-membered ring compounds
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
AU12362/88A AU598105B2 (en) 1984-03-22 1988-02-26 4-piperidyl derivatives
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

Applications Claiming Priority (1)

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PCT/JP1984/000363 WO1986000618A1 (fr) 1984-07-13 1984-07-13 Composes cycliques condenses a 7 membres et leur procede de preparation

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US4512988A (en) * 1984-03-01 1985-04-23 E. R. Squibb & Sons, Inc. Acylamino oxo or hydroxy substituted alkylamino thiazines and thiazepines

Citations (1)

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Publication number Priority date Publication date Assignee Title
JPS58116477A (ja) * 1981-06-05 1983-07-11 メルク・エンド・カムパニ−・インコ−ポレ−テツド 抗高血圧剤としてのパ−ヒドロ−１，４−チアゼピン−５−オンおよびパ−ヒドロ−１，４−チアゾシン−５−オン誘導体

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AU3810972A (en) * 1971-01-22 1973-07-26 Warner-Lambert Company Process forthe preparation of 1, 4 benzothiazepines
US4539150A (en) * 1983-06-29 1985-09-03 Mitsui Toatsu Chemicals, Inc. Benzothiazepine derivatives and their methods of preparation
US4512988A (en) * 1984-03-01 1985-04-23 E. R. Squibb & Sons, Inc. Acylamino oxo or hydroxy substituted alkylamino thiazines and thiazepines

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
JPS58116477A (ja) * 1981-06-05 1983-07-11 メルク・エンド・カムパニ−・インコ−ポレ−テツド 抗高血圧剤としてのパ−ヒドロ−１，４−チアゼピン−５−オンおよびパ−ヒドロ−１，４−チアゾシン−５−オン誘導体

Non-Patent Citations (1)

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Title
Chemical Abstracts, Vol. 94, No. 19, (1981-5-11) (Columbus, Ohio, U.S.A.) Levai, A:, "Oxazepines and thiazepines. Part 10: Sythesis of carboxylic acid derivatives of 2,3-dihydro-2-phenyl-1,5-benzothiazepin-4-(5H)-ones.", Page 657, 2nd step, Abstract No. 94: 156884t; & Pharmazie, 35680 *

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