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WO1986007064A1 - Derives de piperidine - Google Patents

Derives de piperidine Download PDF

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Publication number
WO1986007064A1
WO1986007064A1 PCT/JP1985/000280 JP8500280W WO8607064A1 WO 1986007064 A1 WO1986007064 A1 WO 1986007064A1 JP 8500280 W JP8500280 W JP 8500280W WO 8607064 A1 WO8607064 A1 WO 8607064A1
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WO
WIPO (PCT)
Prior art keywords
acid
reaction
compound
tert
lower alkyl
Prior art date
Application number
PCT/JP1985/000280
Other languages
English (en)
Japanese (ja)
Inventor
Hirosada Sugihara
Kohei Nishikawa
Katsumi Ito
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/JP1985/000280 priority Critical patent/WO1986007064A1/fr
Priority to EP85309393A priority patent/EP0187037A3/fr
Publication of WO1986007064A1 publication Critical patent/WO1986007064A1/fr
Priority to US07/180,836 priority patent/US4816466A/en
Priority to US07/218,951 priority patent/US4871842A/en
Priority to US07/400,680 priority patent/US4954625A/en

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Classifications

    • 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 novel piperidine derivatives useful as medicaments.
  • the present inventors have intensively searched for a compound having angiotensin converting enzyme inhibitory activity and useful as a therapeutic agent for cardiovascular diseases such as hypertension, heart disease, and stroke. Gin derivatives were successfully produced, and the present invention was completed.
  • the present invention uses the formula
  • ⁇ represents an amino acid residue
  • B represents the formula
  • PI * represents hydrogen, lower alkyl, aralkyl or amino-lower alkyl
  • the bond between A and B represents a peptide bond
  • the group in B represents A They may be connected.
  • R 1 represents hydrogen, lower alkyl or aralkyl
  • R 2 represents hydrogen, lower alkyl, aralkyl or substitution X represents alkylene.
  • R 3 represents hydrogen, lower alkyl or aralkyl
  • R 3 represents hydrogen. It represents lower alkyl or aralkyl.
  • esterified carboxyl group in the above-mentioned chain ⁇ -amino acid residue examples include lower (C alkoxycarbonyl) and phenyl lower (C alkoxycarbonyl, such as aralkyloxycarbonyl).
  • Arui 1 4 lower as the Arukiru groups such as methyl represented by, Echiru, propyl, isopropyl, heptyl, I Sopuchiru, sec- heptyl, tert- butyl And an alkyl group having about 1 to 4 carbon atoms.
  • 11 1, 11 2, 11 3 or 1 4 shown is Ararukiru groups and to, for example base Njiru, phenethyl .3- phenylpropyl, alpha-methylbenzyl, One Echirubenjiru, alpha-Mechirufuenechiru, / 3-Mechirufue Nechiru; Phenyl lower (C- 4 ) alkyl groups such as 8-ethylphenyl;
  • acyl group represented by R 2 for example, a lower group (C alkanol) -1
  • amino lower alkyl group represented by R 4 examples include amino lower alkyl groups having about 14 carbon atoms, such as aminominyl, aminopropyl, and aminobutyl.
  • the alkylene chain represented by X is, for example, a linear or branched alkylene having about 1 to 7 carbon atoms, such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene,
  • Divalent groups such as heptamethylene, propylene, ethylmethylene and dimethyltetramethylene.
  • the alkylene bridge may have an unsaturated bond (eg, double bond, triple bond) in the chain.
  • R 1 is preferably hydrogen or lower alkyl
  • R 2 is preferably hydrogen
  • R 3 is preferably hydrogen
  • R 4 is lower alkyl or amino lower alkyl, or The case where it is linked to A is preferable, and the case of lower alkyl is more preferable.
  • X is preferably trimethylene, tetramethylene or pentamethylene. X is more preferably tetramethylene.
  • R 4 ′ is preferably a group represented by lower (indicating CiJ alkyl), and more preferably a group represented by formula (i) or ( ⁇ ).
  • the compound (I) of the present invention has an asymmetric carbon in the molecule, any of the R configuration, the S configuration, and a mixture thereof are included in the present invention.
  • Salts of compound (I) include, for example, hydrochlorides; inorganic acid salts such as hydrobromide, sulfate, nitrate, and phosphate, such as acetate, tartrate, citrate, fumarate, and the like.
  • Maleic acid salts, toluenesulfonic acid salts organic acid salts such as methanesulfonic acid salt, for example, sodium salts, potassium salts
  • metal salts such as calcium salts, aluminum salts, etc., for example, triethylamine salts, guanidine salts, ammonium salts, Bases such as drazine salt, quinine salt and cinchonine salt
  • the compound (I) of the present invention has, for example, the formula
  • R represents a lower alkyl or aralkyl group corresponding to R 1
  • R 2 ′ represents an acyl group corresponding to R 2 , and other symbols are as defined above
  • the dehydration condensation reaction can be performed, for example, by an amide bond forming reaction in a normal peptide. That is, dicyclohexylcarbodiimide.
  • a peptide-forming reagent such as ⁇ , ⁇ '—carbonyldiimidazole, diphenylphosphoric acid azide, cyanophosphate getyl phosphate is used alone, or the compound (m) is, for example, 2, Phenyls such as 4,5-trichlorophenol, pentachlorophenol, pentaphenylolenophenol, 212-trophenol or 4-nitrophenol, or N-hydroxysuccinimide.
  • 1-hydroxy ⁇ -Hydroxy compounds such as benzotriazole and ⁇ -hydroxypiperidine are condensed in the presence of a catalyst such as dicyclohexylcarbodiimide to convert the compound ( ⁇ ) into an active ester, and then the compound ( ⁇ ) And dehydration condensation.
  • the dehydration-condensation reaction is preferably an organic base, for example, a quaternary ammonium salt or a tertiary amine, in any case of converting the compound (III) as it is or an activated ester of the compound (III). (Eg, Trietilami) , N-methylbiperidine).
  • the reaction temperature is usually from 120 to 150 ° C., preferably around room temperature, and usually used solvents include, for example, dioxane, tetrahydrofuran.aceto nitrile, pyridine, N, N-dimethylformamide , N, N-dimethylacetamide. Dimethylsulfoxide, N-methylpyrrolidone, chloroform, methylene chloride, etc., and may be used alone or as a mixed solvent.
  • the compound (I) of the present invention is, for example, a compound represented by the formula
  • W a is a halogen or the formula R a S 0 2 - 0- (wherein, R a represents a group represented by lower (C represents an alkyl, triflumizole Ruo Russia methyl, Fuweniru or p- tolyl), and other symbols
  • R a represents a group represented by lower (C represents an alkyl, triflumizole Ruo Russia methyl, Fuweniru or p- tolyl)
  • the reaction is usually carried out with water or another organic solvent (eg, acetonitrile, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, etc.). (Benzene, toluene) alone or in a mixed solvent, or under solvent-free conditions by keeping the temperature in the range of about ⁇ 20 to + 150 ° C.
  • a base such as potassium carbonate, sodium hydroxide, sodium hydrogen carbonate, pyridine, and triethylamine can be coexisted in the reaction system.
  • the compound (I) of the present invention is, for example, a compound represented by the formula (R 2)
  • the reducing conditions include, for example, metals such as platinum, palladium, rhodium, Raney nickel and mixtures thereof with any carrier (eg, carbon, sulfuric acid, calcium sulfate, calcium carbonate, calcium carbonate).
  • Catalytic reduction as a catalyst for example, reduction with metal hydrides such as lithium aluminum hydride, lithium borohydride, lithium cyanoborohydride, sodium borohydride, sodium cyanoborohydride, metal sodium, metal Reaction conditions such as reduction with magnesium and alcohols, reduction with metals such as iron and zinc and acids such as hydrochloric acid and sulfuric acid, electrolytic reduction, and reduction with reductase can be given.
  • the above reaction is usually carried out with water or an organic solvent (eg, methanol, ethanol, ethyl ether, dioxane, methylene chloride, dimethylformaldehyde, benzene, toluene, acid, dimethylformamide, dimethylacetamide). ), And the reaction temperature varies depending on the reducing means, but is generally preferably about ⁇ 20 ° C. to + 100 ° C. This reaction can sufficiently achieve its purpose at normal pressure, but the reaction may be carried out under increased or reduced pressure as necessary.
  • an organic solvent eg, methanol, ethanol, ethyl ether, dioxane, methylene chloride, dimethylformaldehyde, benzene, toluene, acid, dimethylformamide, dimethylacetamide.
  • the compound (I) of the present invention is, for example, a compound represented by the formula
  • Z represents a protecting group which can be eliminated by hydrolysis or catalytic reduction, and other symbols are as defined above. Can be produced by subjecting the compound represented by the formula [1] to hydrolysis or catalytic reduction.
  • the protecting group which can be eliminated by hydrolysis represented by Z in the formula (VI) any kind of an acyl group or a trityl group can be used. Among them, benzyloxycarbonyl, tert-butoxycarbonyl, trifluoroacetyl and trityl And the like are advantageous in the case of a reaction under relatively mild reaction conditions.
  • Protecting groups which can be eliminated by catalytic reduction represented by Z include, for example, benzyl, diphenylmethyl, benzyloxycarbonyl and the like.
  • the hydrolysis reaction in this method is carried out in water or an organic solvent such as methanol, ethanol, dioxane, pyridine, acetic acid, acetate, methylene chloride or a mixture thereof, and an acid (eg, chloride) to promote the reaction rate.
  • Hydrogen iodide Hydrogen fluoride, sulfuric acid, methanesulfonic acid.
  • P-toluenesulfonic acid, trifluoroacetic acid) or base eg, sodium hydroxide, hydroxylated lime, carbonic acid lime, carbonic acid
  • Hydrogen sodium, sodium acetate, and triethylamine can be added.
  • the above reaction is usually carried out in a range of about 120 to + 150 ° C.
  • the catalytic reduction 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 monocarbon or the like.
  • the reaction is carried out at normal temperature or at a pressure of up to about 150 KgZcm 2 at room temperature to + 150 ° C. In general, the reaction proceeds sufficiently at room temperature and normal pressure.
  • the compound (I) of the present invention has the formula
  • the solvolysis reaction is carried out in water or an organic solvent such as methanol, ethanol, dioxane, pyridine, sulfuric acid, acetone, methylene chloride or a mixed solvent thereof.
  • Hydrogen chloride Hydrogen bromide, hydrogen iodide, hydrogen fluoride, sulfuric acid, methanesulfonic acid, ⁇ -toluenesulfonic acid, trifluoroacetic acid, acidic resins
  • bases eg, sodium hydroxide, hydroxylic power, carbonic acid
  • Potassium sodium bicarbonate, sodium acetate, and triethylamine.
  • the reaction is usually carried out in a temperature range of about 20 to 115 ° C.
  • the compound in which R 1 is hydrogen or and R 3 is hydrogen is obtained by hydrolyzing a compound in which R 1 is lower alkyl or / and R 3 is lower alkyl in the formula (I :). or can be prepared by subjecting the elimination reaction, also, in formula (I), even cowpea to be subjected to catalytic reduction to R 1 Gabe Njiru or Z and R 3 Gabe is Nji le compound Can be manufactured.
  • the hydrolysis or elimination reaction in this method is carried out with water or an organic solvent such as methanol, ethanol, ethyl acetate, chloroform, tetrahydrofuran, dioxane, pyridine, acetic acid, acetate, methylene chloride, or a mixed solvent thereof.
  • the reaction is carried out in an acid (eg, hydrogen chloride, hydrogen bromide; hydrogen fluoride, hydrogen iodide, sulfuric acid, methanesulfonic acid, ⁇ ⁇ -toluenesulfonic acid, trifluoroacetic acid) or a base (eg, sodium hydroxide, water (Potassium oxide, carbon dioxide, sodium bicarbonate, sodium carbonate, sodium acetate)
  • the above reaction is usually carried out at a temperature in the range of about 120 to 115 ° C.
  • the catalytic reduction reaction in this method is carried out in water or an organic solvent such as methanol / ethanol, ethyl acetate, dioxane, tetrahydrofuran or a mixed solvent thereof in the presence of a suitable catalyst such as palladium-carbon. Done.
  • This reaction is carried out under normal pressure or a pressure up to about 150 KgZcm 2 at a temperature from normal temperature to + 150 ° C.
  • a compound in which R 1 is lower alkyl or aralkyl or R and R 3 is lower alkyl or aralkyl is a compound represented by the formula (I) in which R 1 is hydrogen or / and R 3 is hydrogen.
  • the condensation reaction conditions include, for example, reaction conditions using a condensation reagent (eg, dicyclohexylcarbodiimide, carbonyldiimidazole, getyl cyanophosphate, azide diphenylphosphate), or an acid catalyst (eg, hydrogen chloride). , Hydrogen bromide, toluenesulfonic acid).
  • a condensation reagent eg, dicyclohexylcarbodiimide, carbonyldiimidazole, getyl cyanophosphate, azide diphenylphosphate
  • an acid catalyst eg, hydrogen chloride
  • Hydrogen bromide, toluenesulfonic acid Hydrogen bromide, toluenesulfonic acid.
  • the anti-ft proceeds in a suitable solvent (eg, dimethylformamide, acetonitrile, tetrahydrofuran, methylene chloride) or a mixed solvent, or in the absence of a solvent in a
  • a compound wherein R 1 is lower alkyl or aralkyl or and R 3 is lower alkyl or aralkyl is a compound represented by the formula (I) wherein R 1 is hydrogen or Z and R 3 are hydrogen.
  • R 1 "and R 3 " represent lower alkyl or aralkyl
  • W b is halogen or a formula R b S 0 2—0— (where R b is lower (d- *) alkyl, Which represents a group represented by orthomethyl, phenyl or p-tolyl).
  • a suitable solvent eg, dimethylformamide.acetonitrile, dimethylsulfoxide, tetrahydrofuran
  • a base eg, potassium carbonate, sodium carbonate, sodium bicarbonate, hydrogen bicarbonate
  • a base eg, potassium carbonate, sodium carbonate, sodium bicarbonate, hydrogen bicarbonate
  • the compound can be produced by subjecting a compound in which R 2 is benzyl or acyl to a catalytic reduction reaction, an elimination reaction or a solvolysis reaction.
  • the catalytic reduction reaction in this method is carried out in water or an organic solvent such as methanol, ethyl acetate, ethanol, dioxane, tetrahydrofuran or a mixed solvent thereof in the presence of a suitable catalyst such as palladium-carbon. .
  • This reaction is carried out under normal pressure or a pressure of up to about 150 K gZcm 2 at a temperature from normal temperature to + 150 ° C.
  • the solvolysis or elimination reaction is carried out by using water or an organic solvent such as methanol, ethanol, ethyl acetate, chloroform, tetrahydrofuran, dioxane, pyridine, sulphonic acid, acetone, methylene chloride or the like.
  • the reaction is carried out in a mixed solvent, and is carried out in an acid (eg, hydrogen chloride, hydrogen bromide, hydrogen fluoride, hydrogen iodide, sulfuric acid, methanesulfonic acid.
  • P-toluenesulfonic acid, trifluoroacetic acid) or a base eg, hydroxylated
  • a base eg, hydroxylated
  • the above reaction is usually carried out in the range of about ⁇ 20 to about 150 ° C.
  • Replacement The compound in which the group R 2 in the formula (I) is lower alkyl, aralkyl or acyl is a compound of the formula (I) in which the group R 2 is hydrogen.
  • W c is halogen or the formula R c 3 0 2 -! In 0 (wherein R c is a lower (C) alkyl, triflates Ruo Russia methyl, phenyl or p —Indicating tolyl).
  • a suitable solvent eg, dimethylformamide, acetonitrile, dimethylsulfokind, tetrahydrofuran
  • a base such as carbon dioxide, sodium hydroxide, sodium hydrogen carbonate, pyridine and triethylamine can be coexisted in the reaction system as a deoxidizing agent.
  • the compound in which the group R 2 in the formula (I) is lower alkyl or aralkyl is the same as the compound in which the group R 2 in the formula (I) is hydrogen than the lower (C ⁇ ) alkyl aldehyde or aralkyl.
  • aldehydes e.g., Fuweniru lower (C t one 4) alkyl Ruarudehi de] can also be obtained by condensing the reductive conditions of.
  • the reducing conditions include, for example, contact with a metal such as platinum, palladium. Rhodium, Raney Nigel or a mixture thereof with an optional carrier (eg, carbon, barium sulfate, sulfuric acid, calcium carbonate, calcium carbonate).
  • a metal such as platinum, palladium. Rhodium, Raney Nigel or a mixture thereof with an optional carrier (eg, carbon, barium sulfate, sulfuric acid, calcium carbonate, calcium carbonate).
  • Reduction for example, reduction with metal hydrides such as lithium aluminum hydride, lithium borohydride, lithium cyanoborohydride, sodium borohydride, sodium borohydride, metal sodium, metal magnesium, etc.
  • Reduction by alcohols, reduction by metals such as iron and zinc and acid such as hydrochloric acid, acid, electrolytic reduction, reduction by reductase, etc.
  • the conditions can be raised.
  • the above reaction is usually carried out in the presence of water or an organic solvent (eg, methanol, ethanol, ethyl ether, dioxane, methylene chloride: octamethylform, benzene. Toluene. Acid, dimethylformamide, dimethylacetamide).
  • the reaction is carried out, and the reaction temperature varies depending on the reducing means, but is generally preferably about ⁇ 20 ° C. to + 100 ° C. This reaction can achieve the purpose of filling at normal pressure, but may be carried out under increased or reduced pressure as appropriate.
  • the compound in which the group R 2 in the formula (I) is acryl is the same as the compound in which the group R 2 in the formula (I) is hydrogen.
  • R 2 ' ⁇ shows the Ashiru corresponding to R 2] can also be prepared by reaction of a compound represented by.
  • the reaction is carried out in water or a suitable organic solvent (eg, ethyl ethyl ether, tetrahydrofuran, methylene chloride, chloroform, benzene), or a mixture thereof in a temperature range of ⁇ 20 to 150 ° C. This is achieved by maintaining the temperature in the appropriate temperature range.
  • a base such as carbon dioxide lime, sodium hydroxide, sodium hydrogen carbonate, pyridine and triethylamine may be coexisted in the reaction system as a deoxidizing agent.
  • the salt of compound (I) can be obtained by the reaction itself for producing compound (I), but if necessary, an acid, alkali, or base can be added to produce a salt of compound (I).
  • 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 and the like. It can be isolated by using
  • Compound (I) may have at least two stereoisomers. These individual
  • the compound of the present invention that is, the compound represented by the formula (I) and a salt thereof can be used for angiotensin exchange enzyme in animals, especially mammals (eg, human, dog, cat, egret, malt, rat). It has an inhibitory action and an inhibitory action on bradykinin-decomposed semen (kininase), and is useful as a diagnostic, preventive or therapeutic agent for cardiovascular diseases such as hypertension, heart disease and stroke caused by hypertension. Since the compound of the present invention has low toxicity, is well absorbed even by oral administration, has excellent sustainability, and is excellent in stability, it can be used as such or a suitable pharmacologically acceptable carrier when used as the above-mentioned medicament.
  • mammals eg, human, dog, cat, egret, malt, rat
  • kininase bradykinin-decomposed semen
  • cardiovascular diseases such as hypertension, heart disease and stroke caused by hypertension.
  • the compound of the present invention has low toxicity, is
  • a single dose for oral administration is usually 0.02 to 10 mg ZKg. Especially about 0.02 to 2 mg / Kg, especially about 0.04 to 0.8 mg ZKg, for intravenous administration, a single dose of about 0.02 to 1 mgZKg, especially about 0.02 to 1 mgZKg, especially about 0.02 ⁇
  • the dose is preferably about 0.2 mg / Kg, and these doses are preferably administered about 1 to 3 times a day, particularly about 1 to 2 times, depending on the symptoms.
  • the starting compounds ( ⁇ ), (V), (YI), (VI) and () of the present invention can be easily produced, for example, by a method represented by the following reaction formula.
  • R 5 represents lower (C alkyl or aralkyl [eg, phenyl lower (C alkyl)], and other symbols are as defined above.
  • Production of compound (m) represented by the above reaction formula The method will be described in more detail.
  • Compound (XVI) is produced by using tert-butyl ester of aminoamino acid (XV) as a starting compound and reacting with compound (vr) under reducing conditions.
  • XVI) can be treated with an acid (eg, hydrogen chloride) to give compound ( ⁇ ⁇ ).
  • compound (XVI) and compound (XVI) are condensed in the presence of a base such as sodium ethoxide, and then the presence of lithium chloride or the like in aqueous dimethyl sulfoxide.
  • the compound ( ⁇ ) is obtained by heating under the following conditions.
  • Compound ( ⁇ ) can be easily obtained from compound ( ⁇ ) by hydrolysis, transesterification, or the like.
  • Compound (V) can be produced by subjecting compound CVT) to a reduction reaction known per se (XDO is subjected to a halogenation reaction or sulfonylation reaction known per se) to S. .
  • Compound (W) can be converted to (VE) after reacting derivative (XX) with a protected amino group with, for example, compound (V) to give compound (XXI).
  • compounds () and (XXI) and hydrogen cyanide are used as starting compounds to obtain compound ( ⁇ ) according to a known Strecker reaction.
  • Japanese Patent Application Laid-Open No. 58-55451 Japanese Patent Application Laid-Open No. 59-231510: Japanese Patent Application Laid-Open No. 55-15369: Japanese Unexamined Patent Publication No. Sho 58-188,857: Japanese Unexamined Patent Publication No. 57-203,050: Japanese Unexamined Patent Publication No. 57-81865, Japanese Unexamined Patent Publication No. 55- No. 1 4 7 2 5 7 Publication: Japanese Unexamined Patent Publication No. 59-206 687 No. Publication: Japanese Unexamined Patent Publication No. 55-59 1775 No. 8: Japanese Unexamined Patent Publication No.
  • NMR spectrum S (in CD C1 3):. 7. 3 (5 H, Fuenirupuro tons Benjiruokishika carbonyl group), 7. 2 (4 H, phenyl pro ton Indaniru group), 5. 1 (2 H Benjiruo Methyleneproton of oxycarbonyl group), 1.4 (9H, methylproton of tert-butyl group)
  • N— [N — [(S) —5 -— (1 benzyloxycarbonyl) —1—ethoxycarbylpentyl] —L-aralanyl] —N— (indan 0.4 g of 12-yl) glycine tert-butyl ester is obtained as a colorless oil.
  • the mixture is stirred under cooling for 1 hour, and then stirred at room temperature for 1.5 hours.
  • the reaction solution is added to 600 ml of ice water, the pore-form layer is separated and distilled off under reduced pressure.
  • the residue was dissolved in 304 ml of ethyl acetate, and washed with 1N aqueous sodium hydroxide, saturated saline, a 20% aqueous phosphoric acid solution, and saturated saline.
  • the ethyl acetate layer was dried over anhydrous magnesium sulfate and then distilled under reduced pressure.
  • N- (N-benzyloxycarbonyl-L-araryl) -L-proline tert-butyl ester 33.8 g was oily Obtained as a product. Dissolve the product in 304 ml of methanol, add 8.12 g of oxalic acid and 10% palladium-carbon (hydrous, 3.6 g), and carry out catalytic reduction at room temperature and pressure. The catalyst was removed by filtration, the filtrate was distilled off under reduced pressure, 400 ml of ethyl ether was added to the residue, and the precipitated crystals were collected by filtration to give N-L-aralanyl-L-proline tert-butyl ester. 20.2 g of the acid salt are obtained as a colorless powder.
  • N- [N-C (S) -5- (4-piperidyl) -1- 1-ethoxycarbonylpentyl] -L-alanyl] -N- (indan-1-yl) glycine tert-butyl ester 0.3g Is dissolved in 2 ml of deacidified acid, add 1 ml of 30% hydrogen bromide deacidified solution, and leave at room temperature for 30 minutes. Add 50 ml of ethyl ether to the reaction mixture, shake and remove the supernatant by decanting.
  • N- [NC (S) -5- (1-benzyloxycarbonyl-2-piperidyl) -1-carboxylpentyl] -L-alanyl] -1-N- (indane-2-yl) glycine tert- 0.5 g of butyl ester is dissolved in 20 ml of methanol, and catalytic reduction is carried out at room temperature and pressure using 10% palladium on carbon (50% water, 0.5 g) as a catalyst.
  • N — [(S) —5— (1-benzyloxycarbonyl-2-piperidyl) -1 1—ethoxyquinone 1.5 g of alanine tert-butyl ester are obtained as a colorless oil.
  • 3-Hydronic acid dihydrobromide Q.36 g is obtained as a colorless powder.
  • X-I (: ⁇ : ⁇ -tert-butoxycarbonyl_L-lysyl) -di-proline tert-butyl ester.
  • (2) Mix a mixture of 0.07 g of sodium acid, 1.5 g of sodium acid and 0.05 g of acid with 30 ml of ethanol at room temperature for 30 minutes at room temperature. A solution of sodium cyanohydride Q.05g in ethanol (10 ml) is added dropwise to the mixture at room temperature over 4 hours. Further, a solution of 0.2 g of sodium cyanoborohydride in 40 ml of ethanol is added dropwise over 3 hours, and the mixture is stirred overnight.
  • the average blood pressure in the control period on the day of the experiment was measured using an electrosphygmomanometer (NE C-San-Ei, MPU-0.5-290-01-1 ⁇ ), and a polygraph (NE C-San-Ei, 365 type or Nihon Kohden RM-45 type) ), And 300 ng ZKg of angiotensin I and then 100 kg of angiotensin II were injected into the crotch vein to examine the blood pressure effect.
  • 300 gZKg of the compound of the present invention was intravenously administered as a physiological saline solution, and 5, 10, 30, 60, 90 and 120 minutes after the administration, angiotensin I and ⁇ were repeatedly injected, and the pressor response was monitored.
  • the suppression rate was corrected based on the time variation of the angiotensin ⁇ ⁇ pressor response.
  • the piperidine derivative (I) provided by the present invention has an excellent pharmacological action and is useful as a pharmaceutical.

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Nouveaux composés représentés par la formule (I), (dans laquelle A représente un résidu d'acide alpha-aminé, B représente un groupe de formule (II), (dans laquelle R4 représente H, un alkyle inférieur, un aralkyle ou un alkyle inférieur aminé), la liaison entre A et B représente une liaison de peptide, R4 dans B étant éventuellement lié à A, R1 représente H, un alkyle inférieur ou un aralkyle, R2 représente H, un alkyle inférieur, un aralkyle ou un acyle et X représente de l'alkylène) et leurs sels sont efficaces pour inhiber l'enzyme de conversion de l'angiotensine, etc., et utiles dans le diagnostic, la prophylaxie et le traitement de maladies circulatoires telles que l'hypertension, les maladies cardiaques, l'apoplexie, etc.
PCT/JP1985/000280 1984-12-21 1985-05-22 Derives de piperidine WO1986007064A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
PCT/JP1985/000280 WO1986007064A1 (fr) 1985-05-22 1985-05-22 Derives de piperidine
EP85309393A EP0187037A3 (fr) 1984-12-21 1985-12-20 Dérivés de pipéridine, leur production et emploi
US07/180,836 US4816466A (en) 1984-12-21 1988-04-12 Piperidine derivatives
US07/218,951 US4871842A (en) 1984-12-21 1988-07-14 Piperidine derivatives
US07/400,680 US4954625A (en) 1984-12-21 1989-08-30 Piperidine derivatives, their production and use

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PCT/JP1985/000280 WO1986007064A1 (fr) 1985-05-22 1985-05-22 Derives de piperidine

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59134765A (ja) * 1983-01-12 1984-08-02 ヘキスト・アクチエンゲゼルシヤフト 新規なスピロ環式アミノ酸誘導体およびそれらの製造法
JPS6051199A (ja) * 1983-07-06 1985-03-22 ヘキスト・アクチエンゲゼルシヤフト ２‐アザビシクロ〔３．１．０〕ヘキサン‐３‐カルボン酸の誘導体およびそれらの製法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59134765A (ja) * 1983-01-12 1984-08-02 ヘキスト・アクチエンゲゼルシヤフト 新規なスピロ環式アミノ酸誘導体およびそれらの製造法
JPS6051199A (ja) * 1983-07-06 1985-03-22 ヘキスト・アクチエンゲゼルシヤフト ２‐アザビシクロ〔３．１．０〕ヘキサン‐３‐カルボン酸の誘導体およびそれらの製法

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