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WO1992016497A1 - Derive d'acide amine ayant une activite inhibant la renine - Google Patents

Derive d'acide amine ayant une activite inhibant la renine Download PDF

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Publication number
WO1992016497A1
WO1992016497A1 PCT/JP1992/000329 JP9200329W WO9216497A1 WO 1992016497 A1 WO1992016497 A1 WO 1992016497A1 JP 9200329 W JP9200329 W JP 9200329W WO 9216497 A1 WO9216497 A1 WO 9216497A1
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Prior art keywords
group
compound
same
reaction
acid
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PCT/JP1992/000329
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English (en)
Japanese (ja)
Inventor
Saizo Shibata
Yasuki Yamada
Hiroki Tada
Hiroyuki Tsuji
Itsuo Uchida
Ikuro Nakamura
Yoshiharu Hayashi
Kiyoteru Ikegami
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Japan Tobacco Inc.
Yoshitomi Pharmaceutical Industries, Ltd.
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Publication of WO1992016497A1 publication Critical patent/WO1992016497A1/fr

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
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    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
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    • C07D209/04—Indoles; Hydrogenated indoles
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    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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    • C07D263/06—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • 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
    • C07D417/12—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 linked by a chain containing hetero atoms as chain links
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to a novel amino acid derivative compound having renin inhibitory activity, and is used in the medical field.
  • Renin is an amino acid that specifically decomposes plasma angiotensinogen
  • AI angiotensin I
  • AII angiotensin II
  • AII's physiological activity is not only the above-mentioned pressor action, but also aldosterone, a type of corticosteroid (Na + and C 1-storage in the body, and K + and H + Therefore, renin inhibitors are useful as therapeutics for hypertension due to excessive renin and as diagnostics for identifying hypertensive patients due to excessive renin, and various studies have been conducted in recent years.
  • peptide compounds having renin inhibitory activity Japanese Patent Application Laid-Open Nos. Sho 63-146658 / 1985, W090 / 075211 / EP03
  • Many publications such as Japanese Patent Publication No. 966 065 and Japanese Patent Application No. 2-1111 / 13 have been reported. There. Recently, it has been reported that a compound having renin inhibitory activity is effective as a therapeutic drug for HIV infection (Japanese Patent Application Laid-Open No. 3-471196).
  • a conventionally known peptide derivative having a renin inhibitory action has a large molecular weight and is difficult to be absorbed, and therefore its pharmacological effect cannot be sufficiently exerted by oral administration.
  • An object of the present invention is to provide a compound which has an excellent renin inhibitory action, is easily absorbed due to its low molecular weight, and can be orally administered.
  • the present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have excellent renin-inhibiting activity, and because of the low molecular weight, have good absorbability, and have a reduced blood pressure lowering caused by oral administration.
  • the present inventors have found a novel amino acid derivative having the action represented by the general formula [I], and have completed the present invention.
  • ⁇ R 1 , R 2 , R 2 are the same or different and are a hydrogen atom, a hydroxyl group, a lower alkoxy group, a halogen atom or a phenyl group which may be substituted;
  • X] is — 0—, 1 S— or 1 NR 4 — (R 4 represents a hydrogen atom or an N-protecting group);
  • ⁇ (A is a hydrogen atom or a lower alkyl group and Y, means a lower alkyl group)
  • X,, X 3 and 1 are the same as described above; m represents an integer of 1 to 2; D represents an optionally substituted phenyl group;
  • ⁇ Z and Z 2 are the same or different and are each a hydrogen atom or
  • R 6 is a lower alkanoyl group, an amino acid-derived acyl group or
  • R 7 and R 8 are the same or different and are each a hydrogen atom, a lower alkyl Or R 7 and R 8 together with an adjacent nitrogen atom represent a 5- or 6-membered saturated heterocyclic group, and n represents an integer of 1 to 10))), Or Z, and Z 2 together with two adjacent oxygen atoms form a cyclic acetal, a cyclic ketal, or a cyclic carbonate;
  • Z 3 is a lower alkyl group ⁇ ], a pharmaceutically acceptable acid addition salt and a base addition salt thereof, and the present invention relates to these amino acid derivatives.
  • the present invention provides a novel intermediate useful for producing the amino acid derivative [I] and a salt thereof.
  • Another aspect of the present invention comprises the above-mentioned amino acid derivative [I] or a salt thereof as an active ingredient. It is intended to provide a pharmaceutical composition useful as an antihypertensive or the like.
  • the target compound [I] or a salt thereof and intermediates [II] and [III] for producing the target compound [I] can be produced by the production method described below,
  • the production of the target compound [I] or its intermediates [II] and [III] is not limited to the following production methods.
  • 0 represents the X- Y-
  • A, X, Y and Z 3 are as defined above Zeta ,, are the same the Z, a, Zeta 12 is the same as the Zeta 2 (where, Zeta Eta and Zeta 12 are not hydrogen atoms at the same time).
  • Zeta Eta and Zeta 12 are not hydrogen atoms at the same time.
  • “Lower alkyl” refers to a straight or branched chain alkyl group containing from 1 to 7 carbon atoms and includes, for example, methyl, ethyl, ⁇ -propyl, isopropyl, ⁇ -butyl, isobutyl. sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylpropyl, 2,2-dimethylbutyl, 2 —Methylpentyl, n-hexyl, 2-methylhexyl and the like.
  • those having 1 to 5 carbon atoms are preferable, and those having 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, tert-butyl and the like are preferable.
  • the “optionally substituted phenyl group” is a lower alkyl group, a hydroxyl group, a lower alkyloxy group, or a phenyl group optionally substituted with a halogen atom.
  • “Lower alkoxy” refers to straight or branched chain alkoxy containing 1 to 7 carbon atoms and includes, for example, methoxy, ethoxy, II-propoxy, isopropoxy, n-butoxy. Si, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, 1-methylbutoxy, 2,2-dimethylpropoxy, 2,2-dimethylbutoxy, 2-methylpentoxy, n-hexyl Xy, 2-methylhexyloxy and the like.
  • ⁇ ⁇ —protecting group is a protecting group used in the ordinary field of amino acid chemistry, and any protecting group may be employed as long as it protects the amino group or imino group from various reactions. I can do it.
  • a substituted or unsubstituted lower alkanol group such as formyl, acetyl, propionyl, and trifluoroacetyl
  • a phthaloyl group such as tert-butoxycarbonyl (Boc) and tert-amyloxycarbonyl
  • Group benzyloxycarbonyl ( Cbz), substituted or unsubstituted aryloxycarbonyl groups such as p-nitrobenzoyloxycarbonyl; substituted or unsubstituted arylsulfonyl groups such as benzenesulfonyl and tosyl; trityl, benzyl and the like
  • an aralkyl group such as formyl, acety
  • Halogen atom refers to fluorine, chlorine, bromine, and iodine.
  • lower alkanol refers to a straight chain of C 8 to C 8 such as acetyl, propionyl, butyryl, isoptyryl, valeryl, isovaleryl, bivaloyl, hexanoyl, heptanyl, and octanol groups. O or alkanol group
  • the acyl group J derived from an amino acid is an amino acid (for example,
  • H 2 N- CHR- C OOH from substituents other than a hydroxyl group portion content of the carboxy group (i.e., a H 2 N- CHR- CO-), either natural or unnatural ⁇ Mi Amino Acids You may.
  • a 5- or 6-membered saturated heterocyclic group joined with a nitrogen atom Is a 5- or 6-membered saturated heterocyclic group containing at least one nitrogen atom, such as 1-pyrrolidinyl, 1-virazolidinyl, 1-imidazolidinyl, 1,2,4— Triazolidin — 1 — yl, 1,2 — oxabridin — 2 — yl, 1, 3 — oxazolidin-1 3 — yl, 1, 2 — thiazolidin 1 — 2, 1, 3 — Thiazolidin-1 3-yl, piperidino, perhydro 1, 2-oxazine 1-2 yl, perhidro 1, 3-oxaxin 1-3-yl, morpholino, perchidro 2-diazin-1 And 1-pyrrolidinyl, particularly preferably 1-pyrrolidinyl, morpholino, piberidino and piperazinyl.
  • ⁇ Cyclic acetal j means methylene acetal (-0-CH 2 -0-), ethylidene acetal (10-CH (CH 3 ) -0), butylidene acetate, benzylidenease 1, 2, 2, 2-trichloroethylidene acetal and the like, particularly preferably methylene acetal.
  • ⁇ Cyclic ketal J means isopropylidene ketal
  • a “carboxy protecting group” is an ester that forms an ester with a carboxy group, for example, a methyl group, an ethyl group, a tert-butyl group, a benzyl group, a phenacyl group, a tricycloethyl group, and a p-nitrobenzene group.
  • a carboxy group for example, a methyl group, an ethyl group, a tert-butyl group, a benzyl group, a phenacyl group, a tricycloethyl group, and a p-nitrobenzene group.
  • Group, difluoromethyl group, etc. which can be used as long as they are usually used in this field, and are not particularly limited thereto.
  • N—Elimination reaction of protecting group refers to a reaction in which an amino group or an imino group is generated by removing the protecting group from a protected amino group or an imino group.
  • reaction of a carboxy-protecting group refers to a reaction in which a carboxy group is generated by removing the protecting group from a protected carboxyl group.
  • the pharmacologically acceptable salts of the target compound [I] are conventional non-toxic salts, for example, formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzene
  • Organic acid addition salts such as sulfonates and toluenesulfonates
  • inorganic acid addition salts such as hydrochlorides, hydrobromides, sulfates, phosphates
  • salts such as aspartate and glutamate. Examples include, but are not limited to, salts with amino acids.
  • Compound [VI] or a salt thereof is compound [IV] or carbohydrate. It can be produced by reacting the reactive derivative at the xy group or a salt thereof with the compound [V] or the reactive derivative at the amino group or a salt thereof. This reaction is a so-called peptide synthesis reaction, and a method known per se can be employed.
  • W 1 in the compound [V] means a propyloxy protecting group.
  • the reactive derivative means a derivative obtained by activating a group participating in the reaction, such as a carboxy group or a amino group, by an arbitrary method.
  • Suitable salts of the compound [VI] may be referred to those exemplified for the compound [I].
  • Suitable reactive derivatives at the carboxy group of compound [IV] include acid halides, acid anhydrides, activated amides, activated esters, and the like. More specifically, acid chlorides; acids Azide; substituted phosphoric acid such as dialkylcarboxylic acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc., sulfonic acid such as thiosulfuric acid, sulfuric acid, methanesulfonic acid, etc.
  • Suitable salts of the compound [IV] and its reactive derivative include, for example, alkali metal salts such as sodium salt and potassium salt, and alkaline earth salts such as calcium salt and magnesium salt.
  • alkali metal salts such as sodium salt and potassium salt
  • alkaline earth salts such as calcium salt and magnesium salt.
  • Metal salts, ammonium salts such as trimethylamine salt, triethylamine salt, pyridine salt, picolinate salt, dicyclohexylamine salt, N, N'dibenzylethylenediamine salt
  • base salts such as organic base salts.
  • Suitable reactive derivatives in the amino group of compound [V] include a Schiff base imino group formed by the reaction of compound [V] with a carbonyl compound such as aldehyde or ketone. Or its enamine tautomer; compound [V] and bis (trimethylsilyl) acetamide, mono (trimethylsilyl) acetate Silyl derivatives formed by the reaction with silyl compounds such as mid, bis (trimethylsilyl) urea; and derivatives formed by the reaction of compound [V] with phosphorus trichloride, phosgene, and the like.
  • a Schiff base imino group formed by the reaction of compound [V] with a carbonyl compound such as aldehyde or ketone. Or its enamine tautomer; compound [V] and bis (trimethylsilyl) acetamide, mono (trimethylsilyl) acetate Silyl derivatives formed by the reaction with silyl compounds such as mid, bis (trimethylsilyl
  • Suitable salts of the compound [V] and its reactive derivative may be referred to the salts exemplified for the compound ⁇ [I].
  • the reaction is usually carried out with water, for example, alcohols such as methanol and ethanol, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl nitrate, N, N —
  • water for example, alcohols such as methanol and ethanol, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl nitrate, N, N —
  • a common solvent such as dimethylformamide or pyridine
  • these conventional solvents may be used as a mixture with water.
  • N N'-dicyclohexylcarboimide;N-cyclohexylN'-morpholinoethylcarbodiimidN; Cyclohexyl N '— (4-Jetylaminocyclohexyl) carbodiimide; N, N' — Getyl carbodiimide; N, N '— Diisopropyl propyl carbodiimide; N-ethyl L-N '-(3-dimethylaminopropyl) carbodiimide; N, N'-carbonylbis- (2-methylimidabour); pentamethyleneketene-1 N-cyclohexylimin; diphenylketene-1 N-cyclo Xylimine; Ethoxydiacetylene; 1-alkoxy-1-1-chloroethylene; Trialkyl phosphite; E
  • the reaction can also be carried out with alkali metal bicarbonates, tri (lower) alkylamines, pyridines, N- (lower) alkylmorpholines, N, N-di (lower) alkylbenzylamines, etc.
  • the reaction may be carried out in the presence of an inorganic or organic base.
  • the reaction temperature is not particularly limited, but the reaction is usually performed under cooling or heating.
  • Compound [VI I] or a salt thereof can you to prepared by subjecting the compound [VI] or a salt thereof to elimination reaction of the carboxy protective group W 1.
  • Suitable salts of the compound [VI I] include the base salts as exemplified for the compound [IV], and the acid addition salts as exemplified for the compound [1].
  • This reaction is performed according to a conventional method such as hydrolysis, reduction and the like.
  • the hydrolysis is preferably performed in the presence of a base or an acid.
  • Suitable bases include, for example, alkali metals such as sodium and potassium, hydroxides and carbonates of these metals, etc.
  • Suitable acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, hydrogen fluoride and the like.
  • the hydrolysis is usually carried out in water, an alcohol such as methanol or ethanol, an inert solvent such as methylene chloride, chloroform, tetrachloromethane or tetrahydrofuran, or a mixture thereof. Any other solvent that does not adversely affect can be used. Liquid bases or acids can also be used as solvents.
  • the hydrolysis temperature is not particularly limited, but the reaction is usually carried out under cooling or heating. Reduction methods applicable to the elimination reaction include a chemical reduction method and a catalytic reduction method.
  • Suitable reducing agents used in the chemical reduction method are, for example, a combination of a metal such as tin, zinc, iron and the like, and an acid such as formic acid, acetic acid, propionic acid, trifluoroacetic acid and the like.
  • Suitable catalysts used for the catalytic reduction include, for example, platinum catalysts such as platinum oxide and platinum oxide; palladium catalysts such as palladium black, palladium oxide and palladium monocarbon; nickel catalysts such as reduced nickel and Raney nickel. It is a common one such as a medium, for example, an iron catalyst such as reduced iron or ferrous iron.
  • Reduction usually involves water, methanol, ethanol, propanol,
  • N, N-dimethylformamide The reaction is carried out in a conventional solvent or a mixture thereof. Further, when the acids used for chemical reduction are liquid, they can be used as a solvent. Suitable solvents to be used for the catalytic reduction include the above-mentioned solvents and dimethyl ether, dioxane, tetrahydrofuran, and the like, and any other solvent that does not adversely affect the reaction can be used. The use of is also possible.
  • the reaction temperature for this reduction is not particularly limited, and the reaction is usually carried out under cooling or heating.
  • the reactive derivative or a salt thereof at the carboxy group of the compound [VII] which can be used in the next step can be produced not only from the compound [VII] but also from the compound [VI] or a salt thereof.
  • the compound ( ⁇ ) may be used instead of the compound (VI) or a salt thereof via the compound (VII).
  • An acid azide derivative which is a reactive derivative at the carboxy group of the compound [ ⁇ ] can be produced via the acid hydrazide derivative of the above.
  • the reactive derivative as exemplified for the compound [IV] may be referred to.
  • Suitable salts of the reactive derivative of the compound [VI I] may be referred to the salts as exemplified for the compound [VI I].
  • the target compound [I] ([I-a]) or a salt thereof is a compound [VI! Or its reactive derivative at the carboxy group or Reacts their salts with the compound [ViIi] or its reactive derivative at the amino group or a salt thereof to form a peptide bond and, if necessary, remove the ⁇ -protecting group. It can be manufactured by enclosing.
  • This reaction is a peptide synthesis reaction and can be performed in substantially the same manner as in the first step.
  • the description of the first step may be referred to.
  • the compound [VII] is reacted with the compound [VIII], and then the ⁇ -protecting group of the reaction product is removed. By separation, the target compound [I] ([I-a]) can be produced.
  • This elimination reaction is carried out by a conventional method such as hydrolysis, reduction and the like.
  • the hydrolysis is preferably performed in the presence of a base or an acid including a Lewis acid.
  • Suitable bases include, for example, alkali metals such as sodium and potassium, alkaline earth metals such as magnesium and calcium, hydroxides or carbonates or bicarbonates of these metals, hydrazine, for example tritium.
  • Trialkylamines such as methylamine and triethylamine, picolin, 1,5-diazabicyclo [4.3.0] nona-5-ene, 1,4 diazabicyclo [2.2.2] octane, 1,8 —Diazabicyclo [5.4.0]
  • Inorganic bases and organic bases such as 7-ene are exemplified.
  • Suitable acids include organic acids such as, for example, formic acid, diacid, propionic acid, trichloroacetic acid, trichloroacetic acid, 1-hydroxybenzotriazole, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, and the like.
  • organic acids such as hydrogen chloride, hydrogen bromide, hydrogen fluoride and the like, and acid addition salt compounds such as pyridine hydrochloride can be mentioned.
  • Desorption using a Lewis acid such as trichloroacetic acid such as trichloroacetic acid or trifluoric acid is preferably performed in the presence of a cation scavenger such as anisol or phenol. I like it.
  • hydrolysis can be performed using an alcohol such as methanol.
  • the reaction is usually performed in water, an alcohol such as methanol or ethanol, a solvent such as methylene chloride, chloroform, tetrachloromethane, or tetrahydrofuran, or a mixture thereof. Any other solvent can be used as long as it does not adversely affect the reaction. Liquid bases or acids can also be used as solvents.
  • the reaction temperature is not particularly limited, and the reaction is usually performed under cooling or heating.
  • Reduction methods applicable to the elimination reaction include chemical reduction and catalytic reduction.
  • the compound [X] or a salt thereof is a compound [IX] or a reactive derivative thereof at a carboxy group or a salt thereof with a compound, [VIII] or a reactive derivative thereof at an amino group or a compound thereof.
  • This reaction is a peptide formation reaction and can be carried out in substantially the same manner as the first step of the above-mentioned production method 1. Therefore, the reaction method and reaction conditions of this reaction are described in the description of the first step of the production method 1. Please refer to the description.
  • Compound [XI] or a salt thereof can be produced by subjecting compound [X] or a salt thereof to a deprotection reaction of ⁇ -protecting group ⁇ ⁇ ⁇ ⁇ .
  • Suitable salts of compound [XI] include compounds [I] Reference may be made to those exemplified in the above. Further, the elimination reaction of the ⁇ -protecting group is the same as the elimination reaction described in the third step of Production Method 1, and the above description may be referred to.
  • the target compound [I] ([Ia]) or a salt thereof is a compound [XI] or a reactive derivative at the amino group or a salt thereof and the compound [IV] or a reactivity thereof at the carboxy group.
  • the derivative can be produced by reacting a derivative or a salt thereof and, if necessary, removing the N-protecting group of the imidazolyl group. Since this reaction is a peptide formation reaction and can be performed in substantially the same manner as the third step of the above-mentioned production method 1, the description of the third step of the production method 1 may be referred to.
  • the elimination of the N-protecting group of the imidazolyl group may be performed after the first step or the second step.
  • Compound [XIV] or a salt thereof can be prepared by converting compound [XII] or a salt thereof with compound [XIII] or a salt thereof by a known method (F. Lane:
  • Suitable salts of the compounds [XII], [XIII] and [XIV] can be referred to the salts as exemplified for the compound [I].
  • the reaction is usually carried out in water, for example, alcohols such as methanol, ethanol, etc., acetone, dioxane, cetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N—Dimethylform
  • alcohols such as methanol, ethanol, etc.
  • chloroform methylene chloride
  • ethylene chloride ethylene chloride
  • tetrahydrofuran ethyl acetate
  • N N—Dimethylform
  • These conventional solvents may be used as a mixture with water.
  • the temperature of the reaction is not particularly limited, the reaction is usually carried out at room temperature or under cooling.
  • Compound [XV] or a salt thereof can you to prepared by subjecting the compound [XIV] or a salt thereof to removal ⁇ reaction of the carboxy protective group W 2.
  • the salts as exemplified for the compound [VII] may be referred to.
  • the decarboxylation reaction of the carboxy protecting group is the same as the elimination reaction in the second step of Production Method 1, and the above description may be referred to.
  • Compound [XIV] has a carboxy-protecting group at two positions of W 1 and W 2, and one of the carboxy groups (W 2 ) is selectively eliminated by a method commonly used by those skilled in the art. It is clear that we can do that.
  • Compound [XVI] or a salt thereof can be produced by subjecting compound [XV] or a salt thereof to a reactive derivative or a salt thereof at the carboxy group by an intramolecular peptide formation reaction. Since this step can be performed in substantially the same manner as the first step of the above-mentioned production method 1, the description of the first step of the production method 1 may be referred to.
  • Compound [XV II] or a salt thereof can be prepared by subjecting the compound [XV I] or a salt thereof to elimination reaction of the carboxy protective group W 1.
  • Compound [I] ([I-b]) or a salt thereof is a compound [XVI] or a reactive derivative thereof at a carboxy group or a salt thereof and a compound [VIII] or a reactive derivative thereof at an amino group. It can be produced by reacting a conductor or a salt thereof and, if necessary, removing the N-protecting group of the imidazolyl group. This reaction is a peptide formation reaction, and can be performed substantially in the same manner as in the third step of the above-mentioned production method 1. Therefore, the description of the third step of the production method 1 may be referred to.
  • the elimination of the N-protecting group of the imidazolyl group may be performed after the first step, the second step, the third step, or the fourth step.
  • Compound [I] ([I-Ic]) or a salt thereof is obtained by subjecting compound [XVI II] or a salt thereof to a condensation reaction with a compound described below at a hydroxyl group. Can be produced.
  • a condensation reaction with a compound described below at a hydroxyl group.
  • Examples of the compound used for the condensation reaction with a hydroxyl group include the following compounds, but are not limited thereto.
  • 1 Z If u and Z 1 2 together form a cyclic ⁇ cell evening Ichiru and cyclic Ke evening Ichiru is formaldehyde, paraformaldehyde, dibromomethane, 2 main Tokishipuropen, 2, 2 - Dimethoxypropane, Acetone, Cyclohexanone, 1,1 Dimethoxycyclohexanone, Acetaldehyde, 1,1 Dimethoxetane, Butylaldehyde, Benzaldehyde, 2,2—Dimethoxy-13 , 3 — dimethylbutane, 1, 1 dimethoxy 1-phenylethane, ZH and Z!
  • This reaction may be performed according to a known method (T.W. Greene, "Protective Groups in Organic Synthesis", 1981, John Wiley & Sons, NY, and “Basic and Experimental Peptide Synthesis", 1987, Maruzen, Tokyo).
  • Compound [XX] or a salt thereof can be produced by subjecting compound [XIX] to a condensation reaction at a hydroxyl group in the same manner as in the first step of production method 4.
  • this condensation reaction is the same as the condensation reaction in the first step of Production Method 4, and the above description may be referred to.
  • Compound [XXI] or a salt thereof can be produced, if necessary, by subjecting compound [XX] or a salt thereof to an elimination reaction of an N-protecting group.
  • Compound [XXIII] or a salt thereof is used in the first step of Production Method 2. Therefore, it can be produced by subjecting the obtained compound [XXII] to a condensation reaction at a hydroxyl group in the same manner as in the first step of production method 4.
  • Compound [XXIV] or a salt thereof can be produced by subjecting compound [XXIII] or a salt thereof to a deprotection reaction of an N-protecting group, if necessary.
  • Suitable salts of the compound [XXIV] and the compound [XXIIII] may be referred to those exemplified for the compound [I].
  • the elimination reaction of the N-protecting group is the same as the elimination reaction described in the third step of Production Method 1, and the above description may be referred to.
  • the compound obtained by the above-mentioned production method can be purified in a simple manner by a conventional method such as pulverization, recrystallization, column chromatography and re-sedimentation.
  • the compound [I] and other compounds of the present invention include one or more stereoisomers based on asymmetric carbon, and all such isomers and mixtures thereof are included in the scope of the present invention. You.
  • the compound [I] of the present invention and salts thereof are suitable for oral administration, parenteral administration or external administration by mixing them as an active ingredient with an organic or inorganic solid or liquid excipient. It can be used in the form of a pharmaceutical preparation. Kabuse as a pharmaceutical preparation Tablets, sugar-coated tablets, granules, solutions, suspensions, emulsions and the like. If desired, these preparations may contain auxiliaries, stabilizers, wetting or emulsifying agents, buffers and other commonly used additives.
  • the dosage varies depending on the age and condition of the patient, but an average daily dosage of 0.1 mgZ individual to about 100 mgZ individual is effective in treating hypertension, heart failure and AIDS.
  • the R ⁇ value of thin-layer chromatography was measured using Merck's pre-coated TLC plate silica gel (Pre-Coated TLC Plates SILI CA GEL) 60 F-2. 5 4 (thickness: 0.25 mm).
  • Preparative thin-layer chromatography was performed using Merck's Pre-Coated TLC Plates SILI CAGE L. Column chromatography of 4 (thickness: 0.25 to 2 marauders) was performed using Merck Kieselgel 60 (70.230 mesh).
  • N-tert-butoxycarbonyl S-methyl-L-cysteine (499 mg) and (2S, 3S, 5S) —2-amino-1—cyclohexyl-6-methyl-3 5-Heptanediol (see EP 396 065, Japanese Patent Application No. 2-111173, Production Example 27) (500 mg) was converted to N, N-dimethylformamide. (10 ml), and added with 1-hydroxybenzotriazole (360 mg) and N, N'-dicyclohexylcarposimid (466 mg) under ice-cooling and stirring. After stirring for 1.5 hours under ice cooling and further for 21 hours at room temperature, the reaction solution was filtered, and the filtrate was evaporated under reduced pressure.
  • the compound (670 mg) obtained in Production Example 1 was dissolved in dichloromethane (15 ml), trifluoroacetic acid (4 ml) was added, and the mixture was stirred at room temperature for 30 minutes. After concentrating the reaction solution under reduced pressure, a saturated aqueous solution of sodium hydrogen carbonate and a tritium aqueous solution are added, and the mixture is extracted with chloroform.
  • (3S) -1,2,3,4-tetratetrahydroquinoline-l-monorubunic acid (J. Med, Chem., 31, 2092 (1988)) was converted to benzyloxycarbonyl according to a conventional method.
  • (3S) 2-benzyloxycarbonyl, 2, 3, 4 — tetrahydroidroquinoline-1 3 — carboxylic acid (934 mg) —Sellin methyl ester 'hydrochloride (700 mg) is dissolved in tetrahydrofuran (40 ml) and stirred under ice-cooling with 1-hydroxybenzotriazole (44 mg).
  • the compound (1.101 g) obtained in Production Example 3 was dissolved in methylene chloride (50 ml), and diisopropylpropylethylamine (1.518 g) was added under ice-cooling and stirring. Chloromethyl methyl ether (846 mg) was added, and the mixture was stirred under ice cooling for 1 hour and at room temperature for 1 day. The solvent was distilled off from the reaction solution, a 10% aqueous solution of citric acid was added, extracted with ethyl acetate (10 O ml), dried over saturated sodium hydrogen carbonate, and evaporated under reduced pressure to remove the residue.
  • the compound (791 rag) obtained in Production Example 6 was dissolved in tetrahydrofuran (18 ml), and 2,2-dimethoxypropane (3.1 ml) and p-toluenesulfonic acid (5 ml) were dissolved. 0 mg) and stirred at room temperature for 1 hour.
  • the reaction solution was added to a saturated aqueous sodium hydrogen carbonate solution (100 ml), and extracted with chloroform (100 ml).
  • the chloroform solution was washed with 0.5 M aqueous solution of citric acid (50 ml), water (50 ml) and saturated saline (5 Oral), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the title compound (100 rig) as a colorless oil was obtained by reacting the compound (205 mg) obtained in Production Example 18 in the same manner as in Production Example 13 (see Table 4).
  • N "-benzyloxycarbonyl- ⁇ -methyl-L-histidine hydrazide (312 mg) was dissolved in N, N-dimethylformamide (5 ml), and the solution was dissolved at 140 ° C. M hydrogen chloride dioxane solution (0.74 m 1), followed by addition of isopentyl nitrite (0.16 m 1) and stirring at 130. After stirring for 30 minutes, the temperature of the reaction mixture was reduced to 30 ° C. — Reduced to 70. C and neutralized with triethylamine. In this solution, the compound obtained in Preparation Example 8 (280 mg) was dissolved in N, N-dimethylformamide (5 ml).
  • the benzoimidabul-2-carboxylic acid used in Examples 2 and 19 was produced according to J. Chem. So Perkin Trans, ⁇ , 2871 (1982).
  • 1-Acetyl-2-indolecarboxylic acid used in Example 6 was obtained by acetylating 2-indolecarboxylic acid using sodium hydride and acetyl chloride.
  • Benzothiabul-2-carboxylic acid used in Example 8 was prepared according to J. Chem. Soc. (C), 71.2328 (1949).
  • the 3-phenylbilogglutamic acid used in Examples 9 to 12 was prepared by Chem. Ber., 100, 1137 (1967).
  • the perimidine-2-carboxylic acid used in Example 13 was obtained by alkaline hydrolysis of perimidine-2-ethyl ribonate (J. Med. Chem., 30, 2081 (1987)). Obtained.
  • the 3-phenyl-2-indolecarboxylic acid used in Example 14 was prepared according to J. Org. Chem .. 37, 3624 (1972) (see Tables 7-10).
  • Example 18 The compounds of Examples 18 and 19 were prepared by reacting an appropriate carboxylic acid with (2S, 3S.5S) 1-2- (S-methyl-L-cystinyl) amino-1-cyclohexyl-6-methyl-1 3,5-Heptanediol (Production Example 2) was produced by reacting in the same manner as in Example 1 (see Table 10).
  • isomer B (112 mg) of the title compound was obtained as a white powder from highly polar isomer B (100 mg) of the ester (see Table 11).
  • Example 25 The compound of Example 25 was produced in the same manner as in Example 2 (see Table 12).
  • the compounds of Examples 31 to 33 were prepared from the compounds obtained in Examples 24 and 27.28 by removing the N-protecting group in the same manner as in Production Example 2 (see Table 13). ).
  • Example 14 The same reaction as in Example 1 was carried out using the compound (20 O mg) obtained in Production Example 11 to obtain the title compound (17 O mg) as a white solid (see Table 14).
  • Example 14 The same reaction as in Example 1 was performed using the compound (200 mg) obtained in Production Example 25 to obtain the title compound (220 mg) as a pale yellow solid (see Table 14). .
  • Example 2 The same reaction as in Example 1 was carried out using the compound (20 O mg) obtained in Production Example 27 to obtain the title compound (16 O mg) as a pale yellow solid (see Table 14). .
  • Example 2 The compound (600 mg) obtained in Example 1 was dissolved in pyridine (6 ml), and acetyl chloride (0.68 ml) was added dropwise under ice-cooling and stirring. After stirring for 0.5 hours under ice-cooling and then at room temperature for 1.5 hours,
  • Example 14 The same reaction as in Example 1 was carried out using 5 -fluorindol -2 -potassic acid (259 mg) to obtain the title compound (570 mg) as a white solid (see Table 14). ).
  • Example 15 The same reaction as in Example 1 was carried out using pyrrole 2-carboxylic acid (11 O mg) to obtain the title compound (300 mg) as a white solid (see Table 15).
  • Tables 1 to 15 show the structural formulas and physical properties of the compounds according to the above-mentioned Production Examples and Examples. 3 ⁇ 4 1
  • Plasma renin activity was calculated by subtracting the amount of angiotensin I in the reaction solution incubated at 4 from the amount of angiotensin I in the reaction solution incubated at 37.
  • the inhibitory activity () was determined by the following equation.
  • Example 1 Dissolved in 0.1 M citrate in an anaesthetized marmoset (body weight 330-420 g) bred for 1 week on a low-salt diet (containing 0.02% sodium chloride, 1 Z 10 on a normal diet)
  • the compound of Example 1 (1 O rogZlig) was administered at a rate of 2 mlZkg. Blood pressure was measured before and after administration by the Tailcuff method, and the antihypertensive effect was calculated as a percentage of the pre-administration value. The results are shown in Table 19.
  • Table 19 Table 19
  • novel amino acid derivative represented by the general formula (I) and a salt thereof according to the present invention have a strong inhibitory activity against renin, and also have a continuous antihypertensive effect even in oral administration . Therefore, the target compound [I] of the present invention and its salt are expected to be orally administrable and to be used as antihypertensive agents and therapeutic agents for heart failure which are excellent in sustainability.

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Abstract

Composés représentés par les formules générales (I), (II) et (III) dans lesquels un composé (I) est utilisé comme inhibiteur de rénine, tandis que les composés (II) et (III) constituent des intermédiaires pour sa production.
PCT/JP1992/000329 1991-03-22 1992-03-18 Derive d'acide amine ayant une activite inhibant la renine WO1992016497A1 (fr)

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JP3/130769 1991-03-22
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002026705A3 (fr) * 2000-09-29 2002-07-11 Eastman Chem Co Derives d'acide propanoique substitues au lactam tres pur au niveau enantiomere
US6762191B2 (en) 2001-07-05 2004-07-13 Pharmacia & Upjohn Company Therapeutic compounds
US7425556B2 (en) 2005-12-20 2008-09-16 Astrazeneca Ab Compounds and uses thereof
US7465795B2 (en) 2005-12-20 2008-12-16 Astrazeneca Ab Compounds and uses thereof
US8299056B2 (en) 2008-09-08 2012-10-30 Signal Pharmaceuticals, Llc Aminotriazolopyridines, compositions thereof, and methods of treatment therewith

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63275552A (ja) * 1987-05-07 1988-11-14 Kissei Pharmaceut Co Ltd 新規なアミノ酸誘導体
JPS6463559A (en) * 1986-12-19 1989-03-09 Sankyo Co Peptide analog having resin-inhibiting activity

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6463559A (en) * 1986-12-19 1989-03-09 Sankyo Co Peptide analog having resin-inhibiting activity
JPS63275552A (ja) * 1987-05-07 1988-11-14 Kissei Pharmaceut Co Ltd 新規なアミノ酸誘導体

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002026705A3 (fr) * 2000-09-29 2002-07-11 Eastman Chem Co Derives d'acide propanoique substitues au lactam tres pur au niveau enantiomere
US6686477B2 (en) 2000-09-29 2004-02-03 Eastman Chemical Company Highly enantiomerically pure lactam-substituted propanoic acid derivatives and methods of making and using same
US6897323B2 (en) 2000-09-29 2005-05-24 Eastman Chemical Company Highly enantiomerically pure lactam-substituted propanoic acid derivatives and methods of making and using same
US6977303B2 (en) 2000-09-29 2005-12-20 Eastman Chemical Company Highly enantiomerically pure lactam-substituted propanoic acid derivatives and methods of making and using same
US7214803B2 (en) 2000-09-29 2007-05-08 Eastman Chemical Company Highly enantiomerically pure lactam-substituted propanoic acid derivatives and methods of making and using same
US6762191B2 (en) 2001-07-05 2004-07-13 Pharmacia & Upjohn Company Therapeutic compounds
US7425556B2 (en) 2005-12-20 2008-09-16 Astrazeneca Ab Compounds and uses thereof
US7465795B2 (en) 2005-12-20 2008-12-16 Astrazeneca Ab Compounds and uses thereof
US8299056B2 (en) 2008-09-08 2012-10-30 Signal Pharmaceuticals, Llc Aminotriazolopyridines, compositions thereof, and methods of treatment therewith

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