WO1986004580A1

WO1986004580A1 - Piperidine derivatives

Info

Publication number: WO1986004580A1
Application number: PCT/JP1985/000052
Authority: WO
Inventors: Hirosada Sugihara; Kohei Nishikawa; Katsumi Ito
Original assignee: Takeda Chemical Industries, Ltd.
Priority date: 1985-02-08
Filing date: 1985-02-08
Publication date: 1986-08-14

Abstract

Novel compounds by general formula (I), wherein A represents an alpha-amino acid residue, B represents formula (II) (wherein R4 represents hydrogen, lower alkyl, aralkyl or amino lower alkyl), the A-B bond represents a peptide bond, with R4 in B optionally being bound to A, R1 represents hydrogen, lower alkyl or aralkyl, R2 represents hydrogen, lower alkyl, aralkyl or acyl, and X represents alkylene, and salts thereof are effective in inhibiting angiotensin-converting enzyme, and are useful for diagnosis, prophylaxis, and treatment of circulatory organ diseases such as hypertension, heart disease, apoplexy, etc.

Description

Specification

Plastic insulator

Technical field '

The present invention relates to a novel piperidine derivative useful as a medicine. Background art

Although various compounds having an inhibitory action on angiotensin converting enzyme are known, no compound having ω- (4-piperidyl) -amino acid as a partial structure is known at all.

The present inventors have angiotensin converting enzyme inhibitory action,

10 As a result of intensive search for a compound useful as a therapeutic agent for cardiovascular diseases such as heart disease and stroke, the production of a piperidine derivative having an excellent action was successfully completed, and the present invention was completed.

Disclosure of the invention

The present invention uses the formula

C00R ¹

A -B-NH -CH

X one ⁽¹⁾

[Wherein A represents one amino acid residue and B represents the formula

20 R ⁺

One C one C H-0

(Wherein R ⁺ represents hydrogen, lower alkyl. Aralkyl or amino-lower alkyl), the bond between A and B represents a peptide bond, and the group R ^{+ in} B R may be hydrogen, lower alkyl or aralkyl, and R ² may be hydrogen, lower alkyl, aralkyl or X represents alkylene. However, international applications PCT / JP84 / 00172, PCT / JP84 00221, PCT / JP84 / 00362 and PCT / JP84 /

[Excluding a portion overlapping the allowable range described in [00363]] and a salt thereof.

In the above formula, as an amino acid residue represented by A for example, Arani Roh, N a - Aruginino, N one Asuparagino, glycidyl Shino, N ^alpha - Hisuchijino, Roishino, New ^alpha - Li Gino, Shisuteino, Application Benefits Butofano, A chain amino acid residue such as σ-sino-ku-lino and the carboxyl group in those groups are esterified.

COOR ⁵ CH ₂ C00R ^£

CH ₂ C00R ^; C00R:

C00R ^J : CH ₂ C00R ^£

One

CH ₂ C00 ³

In the two formulas, R ³ represents a group represented by hydrogen, lower alkyl or aralkyl.

Examples of the group formed by the group R ^{+ in} B linked to A include a compound represented by the formula

Replacement

[Wherein R ³ represents hydrogen, lower alkyl or-or aralkyl] and the like.

Examples of the esterified carboxyl group in the above-mentioned chain-amino residue include lower (C _t − ₊ ) alkoxycarbonyl, phenyl lower (aralkyloxycarbonyl such as C alkoxycarbonyl) and the like.

Regarding the above formula (I), the lower alkyl group represented by R i.RS.R ³ or R ⁺ includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isoptyl, sec-butyl, tert-butyl and the like. About 1 to 4 alkyl groups are exemplified. Examples of the aralkyl group represented by R ¹ , !! ² ,! ^ ³ or R include benzyl, phenethyl, 3-phenylpropyl, α-methylbenzyl, α-ethylbenzyl, α-methylphenethyl, -methylphenethyl, and S-ethylphenyl; And lower phenyl (C ₊ ) alkyl groups. Replacement Examples of the acyl group represented by R ² include lower (C ₅ ) alkanols (eg, acetyl, propionyl), benzoyl, phenyl lower (C _t -J alkoxycarbonyl) (eg, benzyloxycarbonyl) ), Lower (C- ₊ ) alkoxycarbonyl (eg, tert-butoxycarbonyl) groups.

Examples of the amino lower alkyl group represented by R ⁴ include amino lower alkyl groups having about 1 to 4 carbon atoms, such as aminoethyl, aminopropyl, and aminobutyl. .

The alkylene chain represented by X is, for example, a straight chain or branched chain.

R

Examples thereof include alkylene chains having about 1 to 7 carbon atoms, such as divalent groups such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, propylene, ethylmethylene, and dimethyltetra'methylene. It is. The alkylene may have an unsaturated bond (eg, double bond, triple bond) in the chain.

When the compound of the present invention is specifically disclosed, for example, the compounds shown in Tables 1 to 4 and the like can be mentioned.

table 1

C00R '

A -B -M -CHC

, One '

Replacement ABXR ¹ R You cc—

o ... o o

ccl

-C-CH-

! 1 i-(CH ₂ ) ₄ -H

0 (CH ₂ ) * NH _!

C00H

-(CH ₂ ) ₊ -C ₂ H ₅ C00CH ₂ Ph

CH ₂ C00H

! -C-CH- 1 1 ί-(CH ₂ ) ₊ -H

, 0 CH _£

ノ上-

C-CH ₂ C00H

-C-CH- -N--(CH ₂ ) ₊ -C ₂ H ₅ C00CH ₂ P

,,--:., 0 CH ₃

Replacement ABXRR

2P

-C-CH--(CH,),-C ₂ H ₅ H

—COOH

0 CH ₃

Οΐ c-one

s H3)-

H- ^ε K)>

Ή X a V

8-

08SW) / 98 O HOOD

HOOO

06

H003- OT • e

HONO,

HOOO

s

HOOO ^z HO

00

0 cho

HOOO

'T: V

HK

H3-HX-H3-0-V

Stroke ^ε Η3 0

z

One by one

lDd 08SW) / 98 OM

0 00, Table 3

A-B--

_ (CH ₂ ) ₊ -

1—— ί

! 0

CH ₂ C00H

1—— “;

¹ b

CH ₂ C00H-C ₂ H ₅ C00CH ₂ Ph

CH ₂ C00H

Replacement Table 4

COOH

2 -D A-B-NH-CH '., \

(CH ₂ ) ₊

\ /

s ,. 0

Ichi-COOH

[In the above table, Ph represents phenyl:

Replacement R ¹ is preferably hydrogen or lower alkyl, R ² is preferably hydrogen, R ³ is preferably hydrogen, and R ⁺ is lower alkyl or amino lower alkyl. , Or A is preferable, and R ⁺ is more preferably lower alkyl. X is preferably trimethylene, tetramethylene or bentamethylene. X is more preferably ': the case of tetramethylene.

A— B—

(i)

(iii)

Ma / ■, Ma ,,,-

(v)

"" ——.

: 0

CH ₂ C00H

In the two formulas, R ⁺ ′ represents a lower (C n :) alkyl group, preferably a group represented by the following formula, more preferably a group represented by the formula (i) or ()). - 14 -

1 The compound (I) of the present invention has an asymmetric carbon in the molecule, but 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 and hydrobromides; inorganic acid salts such as sulfates, nitrates and phosphates, for example, acetates, tartrates, citrates, and delta-malic acid Organic salts such as salts, maleates, toluenesulfonates, and methanesulfonates; metal salts such as sodium salts, potassium salts, calcium salts, and aluminum salts; such as triethylamine salts, guanidine salts, and ammonium salts. And pharmacologically acceptable salts such as salts with bases such as hydrazine salt, quinine salt and cinchonine salt.

10 The compound (I) of the present invention has, for example, the formula

Α-Η (II)

In the above formula, the symbol has the same meaning as described above:

N-chlorophenol, pentafluorophenol, 2-nitrophenol Or phenols such as 412-trophenol or Ν-hydroxy compounds such as N-hydr σ succinimide, 1-hydroxybenztriazole, Ν-hydroxy piperidine and the like. The compound (III) can be condensed in the presence of a catalyst such as, for example, to convert the compound (III) into an active ester form, and then dehydrated and condensed with the compound (III). The dehydration-condensation reaction N is carried out by using the compound (DI) as it is or

R

Two

Any conversion to the activated ester can be facilitated, preferably by the addition of an organic base, such as a quaternary ammonium salt or tertiary amines (eg, triethylamine, -methylpiberidine). . The reaction temperature is usually from 120 to 150, preferably around room temperature, and usually used solvents include, for example, dioxane, tetrahydrofuran, acetate nitrile, pyridine,>:,: \ '- Examples thereof include dimethylformamide, Ν, -dimethylacetamide, dimethylsulphoxide, Ν—'methylpyridinone, σ mouth form, and methylene chloride, which may be used alone or as a mixed solvent.

Compound (I) of the present invention:

A-Β-Ν Η ₂ )

Wherein the symbols are as defined above]

C00R ¹ '

¾ ' ^a -CH: (V)

In the two formulas, R ¹ ′ and X are as defined above. W ^a represents a halogen or a group represented by the formula: R ^a S〇 ₂ — 0— (where R ^a represents lower (C ₊ ) alkyl, trifluoromethyl, phenyl or P-tolyl); Is also produced by reacting a compound of the formula -16-

1 can The reaction is usually carried out in a single or mixed solvent of water or another organic solvent (eg, acetonitrile, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, benzene, toluene), or under solvent-free conditions. It can proceed by maintaining the temperature range of ~ +150 ° C.

5 At this time, a base such as potassium carbonate, sodium hydroxide, sodium hydrogencarbonate, pyridine, triethylamine and the like can be coexistent in the reaction system for the purpose of accelerating the reaction rate.

The compound (I) of the present invention is, for example, a compound represented by the formula

10 C00R ¹

0 = C: (VI)

[Wherein each symbol can be produced by subjecting a compound represented by the same meaning as above to a condensation reaction under reducing conditions.

The reducing conditions include, for example, metals such as platinum, palladium, rhodium, and Raney nickel, and mixtures thereof with any carrier (eg, carbon, barium sulfate, calcium sulfate, potassium carbonate, calcium carbonate). Catalytic reduction as a catalyst, for example, reduction with metal hydride compounds such as lithium aluminum hydride, lithium borohydride, lithium cyanoborohydride, sodium borohydride, sodium cyanoborohydride, sodium metal magnesium Reaction conditions such as reduction with alcohols and the like, reduction with metals such as 铁 and zinc and acids such as hydrochloric acid and acetic acid, electrolytic reduction, and reduction with reductase can be given. The self-reaction usually takes place in water or an organic solvent (eg methanol, ethanol, ethyl ether, dioxane, methylene glycol).

The reaction is carried out in the presence of σ-lid, quenched form, benzene, toluene, acetic acid, dimethylformamide, dimethylacetamide). -, 2 I

— 17—

1 different but generally — 20 ° C to ÷ 100. C is preferred. This reaction can sufficiently achieve the purpose at normal pressure, but the reaction may be carried out under pressure or under reduced pressure depending on circumstances.

Further, the compound (I) of the present invention is represented by, for example, the formula

¹ C00R ¹

A -B--CH;. ~ 'S

Λ. —

[In the formula, Ζ represents a protecting group that can be removed 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 direct reduction reaction. In the formula (VI), all kinds of protecting groups which can be removed by hydrolysis represented by Ζ include, for example, allyl groups and ゃ trityl groups, among which benzoyloxycarbonyl, tert-butoxycarbonyl are particularly preferred. , Trifluoroacetyl, trityl and the like are advantageous when the reaction is carried out under relatively mild reaction conditions. As a protecting group that can be eliminated by catalytic reduction represented by Z: for example, benzyl, diphenylmethyl, benzyloquinone, and the hydrolysis reaction in the _three methods: water or, for example, methanol, ethanol, Organic solvents such as dioxane, pyridine J, acid, acetate, methylene chloride, etc.

20 The reaction is carried out in a mixture of these solvents. 'Acids (eg, hydrogen chloride, hydrogen bromide, hydrogen iodide, hydrogen fluoride, sulfuric acid, methanesulfonic acid, ρ-toluenesulfonic acid, trifluoroacetic acid) ) Or ': Add a base (eg, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium bicarbonate, sodium acetate, triethylamine). You can also. The above reaction is usually carried out in a range of about −20 to −1 δ0. In addition, the catalytic reduction reaction in this method is carried out using water or, for example, methanol, ethanol, dioxane, tetrahydro. Organic solvent or a mixed solvent thereof and the like furan, for example platinum, the pressure of the _s present reaction Tsune圧Ma other carried out in the presence of a suitable catalyst, such as path Rajiumu one-carbon to 1 5 0 Kg / cm ² of about The reaction is carried out at room temperature or at a temperature of about 150 ° C below, but the reaction generally proceeds sufficiently at room temperature and normal pressure.

The compound (I) of the present invention has the formula

A-B -NH-CH ^ ί ~ \ (VI)

To (（-R ² ′ [wherein each symbol: is also as defined above.]: Can also be produced by solvolysis of a cyano group.

The above solvolysis reaction is carried out in water or an organic solvent such as methanol, ethanol, dioxane, pyridicy, acetic acid, acetone, methylene chloride or a mixture thereof, and an acid (eg, , Hydrogen chloride, hydrogen bromide, hydrogen iodide, hydrogen fluoride, sulfuric acid, methanesulfonic acid, ρ-toluenesulfonic acid, trifluoroacetic acid, acidic resin) or base (eg, sodium hydroxide, water) Oxidizing lime, carbonated lime, sodium bicarbonate (sodium acid, triethylamine) can be added. Anti-K is usually — 20 ~ + 150. (: Performed within a range.

In the formula (I), a compound in which R ¹ is hydrogen and / or R ³ is hydrogen is obtained by hydrolyzing or removing a compound in which R ¹ is lower alkyl or R ³ is lower alkyl. The compound can also be produced by subjecting a compound of the formula (I) in which R ^{1 is} benzyl or / and R ^{3 is} benzyl to a direct contact reduction reaction. can do. In the present method, the hydrolysis or elimination reaction is carried out with water or, for example, methanol, ethanol, ethyl sulphate, cholesterol form, tetrahydrofuran, The reaction is carried out in an organic solvent such as dioxane, pyridine, acetic acid, acetone, methylene chloride or a mixture thereof, and the acid (eg, hydrogen chloride, hydrogen bromide, hydrogen fluoride, hydrogen iodide, sulfuric acid, methanesulfone) Addition of acid, toluene-sulfonic acid, trifluoroacetic acid) or base (eg, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate, sodium carbonate J) Can also. The above reaction is usually carried out in a range of about −210. Catalytic reduction reaction in the present method; water or an organic solvent such as methanol, ethanol, ethyl ester, dioxane, tetrahydrofuran or a mixed solvent thereof, for example, an appropriate solvent such as palladium-carbon. It is performed in the presence of a catalyst. This reaction is carried out at normal temperature or a pressure of up to about 150 Kg / cm ² at a temperature ranging from normal temperature to +1 δ 0 ° C. In formula (I), R ¹ is lower alkyl or § la; Rekiru or Roh and R ³ is lower alkyl or Ararukiru Certain compounds of formula (I), R ¹ is hydrogen L ,: or / and R ^[delta] is A compound that is hydrogen is represented by the formula

R ¹ '-OH (IX)

Or expression

R ³ '-0 Η (X)

Wherein R ^L ′ and R ³ ′ represent lower alkyl or aralkyl, and can be produced by a condensation reaction with a compound represented by the formula: As the condensation reaction conditions, for example, reaction conditions using a condensation reagent (eg, dicyclohexylcarbodiimide, carbonyldiimidazole, getyl cyanophosphate, azide diphenylphosphate), or an acid catalyst (eg, hydrogen chloride) , Hydrogen bromide, Ρ-toluenesulfonic acid). Reaction: Also in a suitable solvent (eg, dimethylformamide, acetonitrile, tetrahydrofuran, methylene chloride) or in a mixed solvent or without solvent, in the temperature range of -20-1 δ 0 ° C. ₃ replacements going on In the formula (I), R ¹ is lower alkyl or aralkyl or / and

The compound wherein R ³ is lower alkyl or aralkyl is a compound represented by the formula (I) wherein R ¹ is hydrogen or a compound wherein Z and R ³ are hydrogen.

R ¹ "— W ^b (XI)

Or expression

R ³ "-W ^b (XK)

[Wherein, R ¹ "and R ³ " represent lower alkyl or aralkyl, W ^b is halogen or a formula R ^b SO 2 — 0— (where R ^b is lower (C n) alkyl, trifluoro) Which represents a group represented by methyl, phenyl or p-tolyl)]. Reaction: In a suitable solvent (eg, dimethylformamide, acetonitrile, dimethylsulfoxide, tetrahydrofuran), a base (eg, carbonate) in a temperature range of about 20 to ÷ 15 ° C. It proceeds in the presence of potassium, sodium carbonate, sodium bicarbonate, and bicarbonate.

When the group R ² is hydrogen in the compound (I) of the present invention, the group represented by the formula (I)

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 the presence of water or an organic solvent such as methanol, ethyl acetate, ethanol, dioxane, tetrahydrofuran or the like; 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 of up to about 150 KgZcm ^{2 at} a temperature from normal temperature to −150 ° C.

In this method, solvolysis or elimination reaction: water or an organic solvent such as methanol, ethanol, ethyl acetate, chloroform, tetrahydrofuran dioxane, pyridine, acetic acid, acetate, or methylene chloride. Alternatively, the reaction is carried out in a mixed solvent thereof, and the acid (eg, hydrogen chloride, hydrogen bromide, hydrogen fluoride) is used. Hydrogen hydride, hydrogen iodide, sulfuric acid, methanesulfonic acid, toluene sulfonic acid, trifluoroacetic acid) or base (eg, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, sodium carbonate, g (Sodium acid) can also be added. The above reaction is usually carried out in a range of about 120 to + 150 ° C.

The compound in which the group R ² in the formula (I) is lower alkyl, aralkyl or acyl is the same as the compound in which the group R ² in the formula (I) is hydrogen.

R ² "-w ^c (xm)

Wherein, R ² ': or a lower alkyl, Ararukiru or Ashiru, W ^c is halogen or wherein R ^c S 0 ₂ - 0- (wherein, R ^c is a lower (C one ₊₎ alkyl, Torifuruoro Represents methyl, phenyl or p-tolyl). Can be obtained by reacting a compound represented by the formula Reaction ': The reaction proceeds by keeping both in a suitable solvent (eg, dimethylformamide, acetonitrile, dimethylsulfoxide, tetrahydrofuran) at a temperature in the range of about 120 to 150 ° C. . At this time, for the purpose of accelerating the reaction rate, 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.

In addition, a compound in which the group R ² in the formula (I) is a lower alkyl or an aralkyl is a compound in which the group R ² in the formula (I) is a hydrogen and a lower (C alkyl aldehyde or ': It can also be obtained by condensing a alkyl aldehyde [eg, phenyl lower (C alkyl aldehyde :) under reducing conditions.

The reducing conditions include, for example, metals such as platinum, palladium, rhodium, and Rane-12 'sogel, and those with any carrier (single row, carbon, barium sulfate, sulfuric acid calcium, barium carbonate, carbonic acid calcium). Combined catalysis with mixture Reduction, for example, reduction with metal hydrides such as lithium aluminum hydride, lithium borohydride, lithium cyanoborohydride, sodium borohydride, sodium borohydride, metal alcohol, and metal sodium, etc. The reaction conditions include reduction, reduction with metals such as iron and zinc and acids such as hydrochloric acid and acetic acid, electrolytic reduction, and reduction with reductase. The above reaction usually involves the presence of water or an organic solvent (eg, methanol, ethanol, ethyl ether, dioxane, methylene chloride, chloroform, benzene, toluene, diacid, dimethylformamide, dimethylacetamide). The reaction is carried out at a lower temperature, and the reaction temperature varies depending on the reducing means, but is generally preferably about 120 ° C to 100 ° C. This reaction may be carried out in response to connexion pressurizing or under reduced pressure by the mosquito ^ convenient that can achieve the charging and partial objects at normal pressure ₃

The compound in which the group R ² in the formula (I) is acyl is the same as the compound in which the group R ^{2 in the} formula (I) is hydrogen.

(R v) ₂ 0 '(X IY)-

[In the formula, RV ′: also represents an acyl corresponding to R ² ].

The reaction may be carried out in water or a suitable organic solvent (eg, ethyl ether, ethyl ether, tetrahydrofuran, methylene chloride, chloroform-form, benzene), or a mixture thereof in a temperature range of −20 to +1 δ 0 °. The process proceeds by maintaining the temperature in the C range. At this time, for the purpose of accelerating the reaction rate, a base such as carbon dioxide, sodium hydroxide, sodium hydrogencarbonate, pyridine or triethylamine can 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. Can be separated by using

Compound (I) may have at least two stereoisomers. Both of these individual isomers and mixtures thereof are, of course, included in the scope of the present invention, and these isomers can be produced individually if desired. For example, by performing the above-mentioned reaction using each single isomer of the starting compounds (1 [), (111), (1 ^), 0), and (\ '1) at least 01), A single optical isomer of compound (I) can be obtained, and when the product is a mixture of two or more isomers, it can be obtained by a conventional separation method such as an optically active acid (eg, Sulphonic acid, tartaric acid, dibenzoyltartaric acid, etc.), optically active bases (row, cinchonine, cinchonidine, quinine, quinidine, α-methylbenzylamine, dehydroabiethylamine, etc.) The respective isomers can also be separated by separation means such as chromatography and fractional recrystallization.

The compound of the present invention, that is, the compound represented by the formula (I) and a salt thereof are useful for the treatment of mammals (eg, humans, dogs, cats, egrets, monkeys, rats). Shows angiotensin exchange enzyme inhibitory action and bradykinin degrading enzyme (kininase) inhibitory action. For example, it is useful as a diagnostic, preventive or therapeutic agent for cardiovascular diseases such as hypertension, hypertension-induced heart disease, and side stroke. is there. The compound of the present invention is dazzling, has good absorption even when administered by mouth, has excellent sustainability, and is also excellent in stability. Therefore, when used as the above-mentioned medicament, it is per se or appropriate pharmacologically acceptable. It can be safely orally or non-orally administered as a pharmaceutical composition such as powder, granules, tablets, capsules and injections by mixing with carriers, excipients and diluents. Dosage is subject

： Hyuan The strength varies depending on the disease state and the route of administration.For example, when administered to adult patients for the treatment of renal or essential hypertension, a single dose for oral administration is usually about 0.02 to 1 Omg / Kg, especially 0. 0 to 2 mg / kg, especially about 0.04 to 0.8 mg / kg, intravenous dose is about 0.002 to 1 mg / kg, especially about 0.02 to 1 mg / kg, especially about The dose is preferably about 0.02 to 0.2 mg ZKg, and it is desirable to administer these doses at about 0.1 to 3 times a day, especially about 1 to 2 times, depending on the symptoms.

The starting compounds (DI), (V), (YO, TI) and (VI) of the present invention can be easily produced, for example, by a method represented by the following reaction formula.

--1

(VI)

(CH ₃ ) ₃ C0-B- H _{2 v} „„

Five

HC1

(I)

(VI)

C00R ¹ ', small

R ₂ '-N ^r -X-C00R ⁵ > R ₂ '-'-X- C-COORi

R ₂ '-, -X-CH-C00R ¹ '

10 OH (XIX)

R-N-X- CH- C00R ^:

Ψ (V)

¹ (v) 'οοβ

A-B- H> A-B-N-CH

X- X- ² '

(XXI)

(VI)

20 ₂ '-^-X-CHO.HCN

, _n - _TT — (XM)

AB-. \ H ₂ AB-NH-CH

, ゝ

(iv) (vi) ^X_R5

Five In the above reaction formula, R ⁵ represents lower (C i-) alkyl or aralkyl [eg, phenyl lower (C i-) alkyl], and the other symbols are as defined above. The process for producing the compound (1E) represented by the above reaction formula will be described in more detail. The reaction is carried out by reacting tert-butylamino acid (XV) with the compound) under reducing conditions. Compound (XVI) is produced. Subsequent treatment of (XVI) with an acid (eg, hydrogen chloride) gives compound (m).

In the process for producing Compounds (V) and (YI), Compound (XW) and Compound (XVI) are condensed in the presence of a base such as sodium ethoxide, and then lithium chloride is added in aqueous dimethyl sulfoxide. By heating in the presence of, for example, the compound (γτ) is obtained. Compound (¾) can be easily obtained from compound (vr) by hydrolysis, transesterification and the like. Compound (V) can be produced by subjecting compound (ΥΓ) to a reduction reaction known per se and then subjecting (XIX) to a halogenation reaction or a sulfonylation reaction known per se.

Compound (¾) is a compound having a protected amino group derivative (XX)

After reacting (V) to lead to compound (x), it can be converted to (YD. In the process for producing compound (W), compound (R and (XXtt) and hydrogen cyanide are used as starting compounds. The compound () can be obtained according to a known Strecker reaction.

Compounds (Π), (IV) and (XX) are described in the literature [eg, Biochemical and Biophysical Research Communications, 117, 108 (1983):

Federation of European Biochemical Societies, 165, 201 (1984): Journal of Medicinal Chemistry, 26, 1267 (1983): Tetrahedron

Letters, 24, 5339 (1983): Tetrahedron Letters, 25, 4479 (1984): Tetrahedron Letters, 25, 4483 (1984): Japanese Unexamined Patent Publication No. 57-19 Japanese Patent Publication No. 2395/95: Japanese Patent Application Laid-Open No. 55-59 / 175: Japanese Patent Application Laid-Open No. 59-130 / 268 / Japanese Patent Application Laid-Open No. 59-172 / 365 : Japanese Unexamined Patent Publication No. 59-296686: Japanese Unexamined Patent Publication No. 59-118866: Japanese Unexamined Patent Publication No. 59-134765: Japanese Unexamined Patent Publication No. 58 JP-A-177977-JP: JP-A-58-177977-JP Publication: JP-A-55-δ-515155: JP-A-55-2719 Publication No. 9: Japanese Patent Publication No. 59-101 4 63 Publication: European Patent Publication 6 8 17 3 Publication: British Patent Publication 2 0 9 5 6 8 2 Publication: European Patent Publication 5 1 3 9 Publication No. 1: European Patent Publication No. 57997/98: South African Patent No. 8366736] or a method analogous thereto.

Compounds (V), (VO, (XVH) and (ΧΜ) are described, for example, in International Applications PCT / JP84 / 00172, PCT / JP84 / 00221, PCT / JP84 / 00362 and PCT / JP84 / 00363. It can be produced by a method or a method analogous thereto.

BEST MODE FOR CARRYING OUT THE INVENTION

Example 1

— (L-alanil) -1-N— (2-indanyl) glycine tert-butyl ester 'oxalate 2 g, sodium nitrate 0.788, sodium acid 0.58 g, Sieve 3 A 10 g, ethyl 6— (1 benzyloxycarbo-2-ru 4-piperidyl) 1-2—oxohexanoate 3.6 g and ethanol 50 mi Sodium borohydride 0.

A solution of 6 g of ethanol in 50 ml was added dropwise at room temperature over 3 hours! After standing overnight, the reaction solution is filtered, and the filtrate is distilled off under reduced pressure. The residue was extracted with 200 ml of ethyl acetate and 50 ml of water. The oily product was dried and evaporated under reduced pressure. The obtained oil was separated and purified by silica gel gel chromatography (hexane: ethyl acetate = 1 _: 1 to 2: 3). From the first fraction: \ 'one [N—: (R) — 5 1 (1 Benzyloxycarbonyl 4-piperidyl) 1 1

Difference

D-5

0.35 g of 1-28-l-pentylpentyl] -L-araranyl] -N- (indan-1-yl) glycine tert-butyl ester is obtained as a colorless oil.

IRV ^ m ^-1 : 3320CNH); 1730, 1690, 1650 (C = O). Mass spectrum (m / e): 677 (M ⁺ )

} NMR spectrum S (in _{CD C1 3): 7. 3 (} 5 H, Fuenirupuro tons of Benjiruokishika Ruponiru group), 7. 2 (4 H, phenyl pro ton Indaniru group), 5. 1 (2 H, Methyleneproton of benzyloxycarbonyl group), 1.4 (methylprotone of 9H, tert-butyl group)

From the second fraction, N— [N — [(S) —5— (1-benzyloxyl 0

0.4 g of bonyl-4-piperidyl) -1-ethoxycarbonyldipentyl] -L-alanyl] -1-N- (indane-1-yl) glycine tert-butyl ester is obtained as a colorless oil.

IR Jax ^tcm " ^1: 3320CNH); 1760, 1690, 1640 (C = O). 'Mass spectrum (mZe): 677 (M ⁺ )

NMR spectrum 5 (in _{CD C1 3):. 7. 3} (5 H, Fuenirupuro tons of Benjiruokishika carbonyl group), 7. 1 (4 Η, phenyl pro tons of Indaniru group), [delta] 1 (Benjiruokishi Methyleneproton of carbonyl group), 1.4 (methylproton of tert-butyl group) 0 Example 2

-[N-[(R) -5- (1-benzyloxycarbonyl 4-piperidyl) -1-1-ethoxycarbonylpentyl] -1 L-aranyl] -1- (indan-1-yl) glycine tert- Dissolve 0.35 g of butyl ester in 2 ml of acid, add 2 ml of a 30% hydrogen bromide acid solution, and leave at room temperature for 1 hour. Add 50 ml of ethyl ether, shake, and decant the supernatant. The colorless precipitate was washed with ethyl ether and dried under reduced pressure. -[N-[(R)-1 -ethoxycarbonyl-2-yl 5-(4-piperidyl) pentyl]-L-aranyl]-N- (indan-1-yl) glycine dihydrobromide 0.3 g of the acid salt is obtained as a colorless powder.

As elemental folding value _{_{_{_{C 27 H 41 N 3 0 5}}}} · 2 HBr · 4 H 2 0

Calculated: C, 44.94; H.7.13; N.5.82

Found: C. 45.33; H. 6.97;, 5.72

a] D-7.9 ° (in methanol)

SI MS spectrum (mZe): 488 (MH ⁺ )

Example 3

N-1 N-1 [(S) —5— (1—benzyloxycarbinyl 4-piperidyl) -1—1-ethoxycarbonylcarbonylpentyl] -1-L-1-aranyl] —N— (indan-1 2- Le) and glycine tert- butyl ester 0. 4 g was dissolved in a 2 ml acetic acid, was added to 3 0% odor匕水containing acetic acid solution 2 ml, adding _c Echirueteru 5 0 ml to stand at room temperature for 1 hour, pretend After mixing, the supernatant is decanted and removed. The colorless precipitate is washed with ethyl ether and distilled off under reduced pressure.

N—: X — [(S) —11-Ethoxycarbonyl-5- (4-piberidyl) pentyl: 1-L-aralanyl] —X— (indan-1-yl) glycine 'hydrogen bromide 0.3 g of the acid salt is obtained as a colorless powder.

As elemental圻値〇 _{_{_{27 Η 41 3 0 5 · 2}}} HBr · 3 H 2 0

Calculated: C, 46.09; H.7.01; N, 5.97

Found: C.46.19; H.6.95;, 5.91

[] D 2.6 ° (in methanol)

SI MS spectrum (m / e): 488 (MH ⁺ )

Example

Dissolve 26.1 g of N-benzyloxycarbonyl L-alanine in 10 ml of tetrahydrofuran, and stir the mixture with the following solution. Chillamine 16.4 ml of tetrahydrofuran 20 tnl solution is added dropwise. Then add a solution of 11.2 mi of tetraethylfuran in 20 ml of tetraethyl carbonate. After stirring for 20 minutes, add a solution of 15.4 g of L-proline tert-butyl ester in 102 ml of chloroform at −10 ° C or lower over a period of 48 minutes. After dropping, stir under cooling for 1 hour, and then stir 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 is 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 is dried over anhydrous magnesium sulfate and then distilled off under reduced pressure to obtain 33.8 g of N- (N-benzyloxycarbonyl-1-L-alanyl) -1-L-proline tert-butyl ester as an oil. . Dissolve this product in 304 ml of methanol, add 8.12 g of oxalic acid and 10% palladium carbon (water content, 3.6 g), and carry out catalytic reduction at room temperature and pressure. U. 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 NL-alanyl-L-proline tert-butyl ester. 20.2 g of the acid salt were obtained as a colorless powder.

[α-84.1 ° (c = l, in methanol) Elemental peak value C ₁₂ H ₂₂ N ₂ 0 ₃ C ₂ H ₂ 0 ₊ 1 / 2H ₂ 0

Calculated: C.49.25; H.7.38; N.8.21

Found: C.48.95; Η, δ.94; .8.05

Example 5

N-CL-araryl)-L-proline tert-butyl ester 'oxalate 2 g, sodium acetate 13,0.7 g of acid, molecular sieve 3 A 10 g, ethyl 6- (1 Benziloxycarboneru 4-1 peryl) 1

Lyse While stirring a mixture of 3.4 g of 2-oxohexanoate and 50 ml of ethanol, a solution of 0.57 g of cyanoborohydride was added dropwise to a solution of 40 ml of ethanol in 40 ml at room temperature for 2 hours. After standing overnight, the reaction solution is filtered, and the filtrate is distilled off under reduced pressure. The obtained oil was purified by silica gel column chromatography (hexane: g, ethyl acetate = 1: 1 to hexane: acetone = 1: 1: 1) to give N — [— [5— (1 —0.66 g of benzyloxycarbonyl-1-piperidyl) -11-ethoxycarbonylpentyl] -l-alanyl] -l-proline tert-butyl ester is obtained as a colorless oily product.

IR level ^ cnT ¹ : 332δ (Η); 1730, 1690, 1650 (C = O). Mass spectrum (m / e): 601 ( ⁺ )

NMR spectrum 5 (in _{CD C1 3): 7. 3 (} 5 H, Fuenirupuro tons of Benjiruokishika Ruponiru group), 5. 1 (2 Eta, methylene pro tons of benzyl O Kin carbonylation Le group), 1. (9 H.tert-Butyl methylprot Example 6

-: x-: 5-(1 -benzyloxycarbonyl- 1 -piperidyl)-1 -ethoxycarbonyldipentyl: -L-alanyl] -l-proline tert-butyl ester 0.668 acetic acid 1.5 ml And add 2 mi of a 30% solution of hydrogen bromide in acetic acid, and leave at room temperature for 1 hour. After adding 50 ml of ethyl ether to the reaction mixture and shaking, the precipitate is washed twice with 50 ml of ethyl ether. The obtained yellow syrup is dissolved in δ ml of water and extracted with 10 ml of ethyl acetate. Lyophilization of the aqueous layer yields 0.4 g of N- [N-1-ethoxycarboyl 5- (4-piperidyl) pentyl] -L-aranyl-L-proline • 2-hydrobromide.

Elemental value C ₂₁ H ₃₇ X ₃ 0 ₅ * 2 HBr · 4 Η ₂₀

Replacement i Calculated: C.39.08; H.7.34; .6.51 '

'' Found: C, 39.43; H, 7.10; Ν, 6.δ0

Example 7

N-[N-[(S)-δ-(1 -benzyloxycarbonyl-4-piperidyl-5-diyl) -1 -ethoxycarbonyldipentyl]-L-alanyl] -1-(indan-2-yl) Glycine tert-butyl ester (0.4 g) is dissolved in methanol (20 ml) and catalytic reduction is carried out at room temperature and pressure using 10% palladium-carbon (50% water, 0.4 g) as a catalyst. After stirring at room temperature for 4 hours, the catalyst was removed by filtration, and the filtrate was distilled off under reduced pressure to give N- [N-[(S) -5- (4-piperidyl 10-zyl) -1-ethoxyethoxycarbonylpentyl] -L 0.3 g of [1-aranyl] -N- (indan-1-yl) glycine tert-butyl ester is obtained as a colorless oil.

Example 8

"N— [N— [(S) — 5— (4-—piperidyl) -1-ethoxycarbonyl ぺ 15-ethyl] -1-L-alanyl] — N— (indan-1-yl) glycine tert— Butyl ester 0.3 g エステル Dissolve in 2 ml of acetic acid, add 1 ml of 30% hydrogen bromide acetic acid solution, leave at room temperature for 30 minutes Add 5 Gml of ethyl ether to the reaction solution, shake, and tilt the supernatant. The precipitate was collected and dried under reduced pressure to give N- [N-[(S) -1ethoxyethoxycarbonyl-5- (4-piperidyl) ben 20 tyl] -1-L-aranyl] -1-N— (indan-1 2 —Yl) Glycine 'dibromide 0 is obtained as a colorless powder.

Example 9

N- [N- (S) -1 monoethoxyquinyl-5- (4-piperidyl) pentyl = —L-alanyl] —N— (indan-1-yl) glycine dihydrobromide 25-hydrogen acid Dissolve 0.25 g of salt in 6 ml of 1 N sodium hydroxide solution and leave at room temperature for 30 minutes. Amberlite X AD— Purify by two-column chromatography (0.1M ammonia water-5% acetonitrile). The concentrate is concentrated under reduced pressure and freeze-dried to give N— [N — [(S) —1—carboxy-5- (4-piperidyl) pentyl] —L—alanyl] —N— ( Indane-2-yl) glycine O.llg is obtained as a colorless powder.

[α] ^ ⁴ + 6.1 ° (c = 0.4 in water) Elemental analysis value C ₂₅ H ₃₇ N ₃ 0 ₅ · 2 H ₂ 0

Calculated value: C 60.59 H8.34 8.48

Obtained value: C 60.37 H7.99 N8.70

S I MS spectrum (m / e): 460 (MH +)

Implementation 咧 10

N— [N _ [(S) —5 -— (1-benzyloxycarbonyl-1-piperidylylyl) -1—11-ethoxycarbylpentyl] —L—araranyl] —N— (indane-2-yl) gly Dissolve 0.55 g of syn tert-butyl ester in 20 ml of methanol and add 5 ml of 1N aqueous sodium hydroxide solution dropwise over 5 minutes. After stirring for 1 hour at room temperature, 2 ml of 1X aqueous sodium hydroxide solution is added dropwise over 5 hours. After 2 ml of water was added dropwise over 2 hours, 10 ml of water was added to the reaction solution, and the mixture was extracted with 10 ml of n-hexane. The aqueous layer is made weakly acidic with 1 N hydrochloric acid and extracted with 50 ml of ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and distilled off under reduced pressure. 0.5 g of L-alanyl] -N- (indane-2-yl) glycine tert-butyl ester are obtained as a colorless oil.

SI MS spectrum (mZe): 650 (MH ⁺ )

Example 11

Replacement N- [N-[(S) -5- (1-benzyloxycarbonyl-1-piperidyl) -1-carboxylpentyl] -1-laranyl] -1-N- (indane-2-yl) glycine — tert —Dissolve 0.5 g of butyl ester in 20 ml of methanol and perform catalytic reduction at room temperature and pressure using 10% palladium-carbon (50% water content, Q.) as a catalyst. After stirring at room temperature for 4 hours, the catalyst was removed by filtration, and the filtrate was evaporated under reduced pressure to give N— [N — [(S) —5— (4-piberidyl) -1-1-carboxypentyl]. 0.28 g of [1-L-aralanyl] -N- (indan-1-yl) glycine tert-butyl ester is obtained as a colorless powder.

Mass vector (mZe): 515 (M ⁺ )

Example

N— [N — [(S) —5- (4-piperidyl) -1-carboxypentyl] —L-alananyl] —N “(indane-1-yl) glycine tert-butyl ester Q.28 g Dissolve in a mixture of 2 ml of acetic acid and 2 ml of ethyl acetate, add 5 ml of 5 N hydrogen chloride aqueous solution of ethyl chloride and leave at room temperature for 1 hour Add 100 ml of ethyl ether to the reaction mixture, and precipitate N— [N — [(S) 1 1—carboxy 1 5— (4—piberidyl) pentyl] —L—araranyl] —N— (indan-2-yl) glycine ♦ 2 hydrochloric acid 0.22 g of salt is protected as a colorless powder.

Example 13

L-alanine tert-butyl ester oxalate 5 g, ethyl 6- (1-benzyloxycarbonyl 4-pyridyl) -2 oxohexanoate llg, sodium acetate A mixture of 1.6 g, 1.2 g of acetic acid and ethanol is stirred at room temperature for 1 hour, and a solution of 1.9 g of sodium cyanoborohydride in ethanol of 100 ml is added dropwise over 4 hours. After stirring overnight at room temperature, add 500 ml of water and extract with 300 ml of ethyl acetate. Wash the extract with water and replace with sulfuric anhydride After drying over magnesium, it is distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography (hexane: acetone = 4: 1). From the first fraction, N-[(R) -5- (1 benzyloxycarbonyl) 1.7 g of piperidyl) -1-ethoxyethoxypentyl] -L-alanine tert-butyl ester is obtained as a colorless oil.

IR u III el λ cm ^-1 : 3350 CNH); 1730, 1700 (C = 0) Mass spectrum (m / e): 504 (Μ ⁺ )

N MR spectrum <5 (Rei_0_rei_1 in _3): 7.3 (5 H, Fuwenirupuro tons benzyl O carboxymethyl carbonylation Le group), 5.1 (2 H, s , methylene pro tons of benzyl O alkoxycarbonyl group) , 1.45 (9H, s, methylproton of tert-butyl group) From the second fraction, N-[(S) -5- (1-benzyloxycarbonyl-2-piperidyl) -1-ethoxycarbonylpentyl] 5 g of 1 L-alanine tert-butyl ester is obtained as a colorless oil. ^{^{, IR u H 1 cm -1:}} 3350C H); L730, 1700 (C = 0) Μ RS (CD C1 in _3): 7.2 (5 Eta, Hue Nirupuro tons of benzyl O alkoxycarbonyl group), 5.1 (2 H, s, methylene naptone D-ton of benzyloxycarbonyl group), and 45 (methyl proton of 9H, s, tert-butyl group)

Mass spectrum (mZe): 504 (M +)

Example 14

M — [(R) —5— (1 Benzyl oxycarbonyl-1-4-piperidyl) —1—Ethoxycarbonylpentyl] —L-Aranine tert-Butyl ester 1.7 g dissolved in 2 Nq. And leave at room temperature for 4 hours. 100 ml of ethyl ether is added to the reaction mixture, and the colorless powder that emits light is collected by filtration. N-[((R) _5— (1-benzyloxycarbonyl 4-piperidyl) -1 1-ethoxyquincarbylpentyl] — L-alanineHCl

Replacement 1.2 g of salt are obtained.

As elemental忻値_{_{_{_{C 24 H 38 N 2 O e}}}} ♦ HC1 · H 2 0

Calculated value C57.31 H7.81 N5.57

Found C56J1 H7.85 N5.92 [α] ^ ⁴ -9.9 ° (c = 0.5, in MeOH) Mass spectrum (/ e): 448 (M ⁺ )

Example 15 "'

-[(S)-5— (1 Benzyloxycarbonyl 4-piperidyl) — 1 —Ethoxycarbonylpentyl] —L-alanine tert-butylester 1.5 g of 5 N hydrogen chloride acetic acid solution 3QIR1 And left at room temperature for 5 hours. The reaction mixture was evaporated to dryness under reduced pressure, the residue was washed with ethyl ether, and then dried under reduced pressure to give N-[(S) -5- (1-benzyloxycarbonyl-4-piridyl) 1-1. [Ethoxycarbonylpentyl] -l-alanine ♦ 1.15 g of hydrochloride is obtained as a colorless candy.

As elemental folding value _{_{_{_{C 24 H 38 N 2 0 8}}}} · H C1 · H 2 0

Calculated value C57.31 H7.81 N5.57

Measured value C57.19 H8.06 5.61

[cc] ^ + 12.7 ° (c = 0.5 in MeOH) Mass spectrum (m / e): 448 (M ⁺ )

Example 16

25 g of N- (2-indanyl) glycine tert-butyl ester and N-[(R) -5- (1-benzyloxycarbonyl-1-piperidyl) -1-1ethoxyethoxycarbonylpentyl] -L-alanine · Dissolve 50 mg of hydrochloride in m, Ν-dimethylformamide (2 mU) and add 0.1 ml of getyl cyanophosphate while stirring under ice-cooling. After stirring for 30 minutes, triethylamine 0.1 Add 30 ml under ice-cooling and 30 minutes at room temperature. The reaction mixture is added with 50 mi of water, extracted with 30 ml of ethyl acetate, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give N— [N— (R) —5— (1—benzyloxycarbonyl 4-piperidyl) —1—ethoxyquincarbonyl. 30 mg of ethyl [1-L-alanyl] -N- (indan-1-yl) glycine tert-butyl ester is obtained as a colorless oil.

Example 17

N- (2-Indanyl) glycine tert-butyl ester 25mg and N-[(S) -5- (1 benzyloxycarbonyl-1-piperidyl) -1 1-ethoxycarbylpentyl] -1-L-alanine hydrochloride 50mg Dissolve it in 2 ml of ジ, Ν-dimethylformamide, and add 0.1 ml of getyl cyanophosphate while stirring under ice-cooling. After stirring for 30 minutes, add 0.1 ml of triethylamine and stir under ice-cooling for 30 minutes and at room temperature for 30 minutes. 50 ml of water was added to the reaction solution, extracted with 30 ml of ethyl acetate, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate-1: 1: 1) to give N— [N— (S) —5— (1—benzyloxycarbonyl-14-piperidyl) -1-ethoxy. Carbonylpentyl] -L-alanyl] -1-N- (indane-1-yl) glycine 35 mg is obtained as a colorless oil.

Example 18

tert-butyl (S)-1,2,3.4-tetrahydroisoquinolin-13-carboxylate hydrochloride 0.4 g and N-[(S) -5- (1-benzyloxyl-propionyl-4-piperidyl) -1 Dissolve 0.4 g of [1-ethoxycarbonylpentyl] -L-alanine 'hydrochloride in 20 ml of Ν, Ν-dimethylformamide, and add dropwise J. Qyl cyanophosphate Q.4id while stirring under ice-cooling. in 30 minutes After stirring, add 0.4 ml of trieluminamine dropwise, and stir under ice cooling for 1 hour, then at room temperature for 3Q minutes. The reaction mixture is added with 200 ml of water, extracted with 200 ml of ethyl acetate, and the extract is washed with 5% aqueous phosphoric acid and water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: acetone = 2: 1) to give tert-butyl.

(S) —21- [N — [(S) —51- (1—benzyloxydicarbonyl 4-piperidyl) -1 1—ethoxycarbonylpentyl] —L-araranyl] —1,2, 37 g of 3,4-tetrahydroisoquinoline-3-carboxylate are obtained as a colorless oil.

^{I u cm -1: 1730, 1690} , 1640 (C = 0) MR 5 (CD C1 in _{3): 7.0- 7.3 (9 H} , Fuwenirupuro tons), 5.1 (2 H. s, benzyl O alkoxycarbonyl group Methylene proton), 1.2 (9 Hstert

-Butyl methylproton)

Mass vector (m / e): 663 ( ⁺ )

Example 19

tert-butyl (S) —21- [N — [(S) —δ- (1-benzyloxycalponyl-4-piperidyl) -1—ethoxycarbonylpentyl] —L-aralanyl] 1-1,2,3,4 —Tetrahydroisoquinoline-3-carboxylate Q.37 g is dissolved in 1 ml of citrus acid, 2 ml of a 30% hydrogen bromide acetic acid solution is added, and the mixture is left at room temperature for 1 hour. Add 50 ml of ethyl ether to the reaction mixture, stir and allow the supernatant to decant. The sediment is collected and dried under reduced pressure. (S) 12-[N-[(S)-1-1-ethoxyquincarbonyl-5--(4-piberidyl) pentyl]-L-araranil] , 4-Tetrahydroisoquinoline-l- ^ ronic acid dihydrobromide G.36g is obtained as a colorless powder.

[a] ^ ⁵ ÷ 5.8 ° (c = 0.4, in MeOH) SI MS spectrum (m / e): 474 (MH +), 512 (M + K) +: KI added Example 20

(S) —2— [N — [(S) —1—Ethoxycarbonyl 5 -— (4-piperidyl) pentyl] —L-alanil] -1-1,2,3,4—Tetrahydroisoquinoline—3-Felinerbon Dissolve 0.3 g of acid dihydrobromide in 8 mU of 1 N sodium hydroxide solution and leave at room temperature for 1 hour. After adding 1 ml of acetic acid to the reaction solution, purify by Amberlite XAD-2 column chromatography (0.1 M aqueous ammonia-5% acetonitrile). The effluent was concentrated under reduced pressure and freeze-dried. 0.16 g of 2,3,4-tetrahydroisoquinoline-3-carboxylic acid is obtained as a colorless powder.

SI MS spectrum (m / e): 446 (H ⁺ ), 484 (M + K) ⁺ ,

-'522 (Μ + 2> ⁺ I addition example 21 ―

Dissolve 2.4 g of L-proline tert-butyl ester and 5.87 g of N ^α -benzyloxycarbonyl- ^ε -tert-butoxycarbonyl-L-lysine in 30 mU of N, N-dimethylformamide and cool on ice Below, 3 g of cyanophosphate getyl are added dropwise. After stirring for 30 minutes, add a solution of 1.42 g of triethylamine in 5 ml of Ν, Ν-dimethylformamide, and stir under ice-cooling for 1 hour, then at room temperature for 2 hours. Add 500 ml of water to the reaction solution, extract with 300 ml of ethyl acetate, and wash the oil effluent with diluted phosphoric acid solution, Q.IN sodium hydroxide solution, and water. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting oily substance was subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1 to i:

Purification by 1) yields N- (N "-benzyloxycarbonyl-N ^£ -tert-butoxycarponyl-L-lysyl) -L-proline tert-butyl 5.5 g of stell are obtained as a colorless oil.

Mass spectrum (mZe): 533 (M ⁺ )

Dissolve 2.5 g of this product in 50 ml of methanol, and perform catalytic reduction at room temperature and pressure using 10% palladium-carbon (50% water content, lg) as a catalyst. After the absorption of hydrogen has ceased, the catalyst is removed by filtration, and the filtrate is distilled off under reduced pressure. The resulting oil was added Echirueteru 50ml solution of Shiyu cormorants acid 0.5g When ^Ν- (Ν ε one tert- butoxycarbonyl two Lou L- lysyl) Single L- proline tert- Petit glycol ester, sexes salt 1.5 g is obtained as colorless scaly crystals.

Melting point 154-156 ° C

Elemental analysis _{_{_{_{C 20 H 37 N 3 O 5}}}} · (COOH) 2 - as H ₂ 0

Calculated value C52.Q5 H8.14 N8.28

Measured value C51.93 H7.67 N8.10

Example 22:

^N - (N ε -tert - butoxycarbonyl one L over lysyl) - L-proline tert- butyl ester Shiyu Usanshio 0.4 g, Echiru 6- (1 one Benjiruo carboxymethyl one 4- Piperi Jill) Single 2 -Mix 1.5 g of oxohexanoate, 7 g of sodium acetate 0, 5 g of O.Q acetate, and 30 ml of ethanol at room temperature for 30 minutes. A solution of 0.05 g of sodium cyanohydride in ethanol iOml 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. Add 500 ml of water to the reaction mixture, extract with ethyl acetate, wash the extract with water, dry over anhydrous magnesium sulfate, and distill under pressure. The residue was purified by silica gel column chromatography grayed Rafi chromatography (hexane: acetone = 3: 1) to ^{give, N- [N α - [5-} (1 - benzyl O butoxycarbonyl one 4 Piperi Jill) - 1 - Etokishikaru Boniru Bae pentyl] one New ^epsilon - tert-butoxycarbonyl one L- lysyl Ί one 0.43 g of L-proline tert-butyl ester is obtained as a colorless oil.

IR cm " ¹ : 3350 (H); 1730, 1700, 1630 (C = O)

NMR spectrum (5 (in CD Cl ₃ ): 7.25 (5 H, phenyloxycarbonyl group phenylproton), 5.1 (2 H, s, benzyloxycarbonyl group methylene proton), 1.4 8H, s, tert-butyl methyl ester) Mass spectrum (m / e): 758 (M ⁺ )

Example 23

N- [N ^α- [5- (1 -benzyloxycarbonyl-1-piperidyl) -1 1 -ethoxycarbonylpentyl] チル^ε -tert-butoxycarbonyl-L-lysyl] -L-pro Dissolve 0.43 g of phosphorus tert-butyl ester in 1 ra.l of acetic acid, add 2 ml of 30% hydrogen bromide acetic acid solution, and leave at room temperature for 1 hour. Add 50 mi of ethyl ether to the reaction mixture, shake and remove the supernatant by decanting. The precipitate is collected and dried under reduced pressure. Ν— — [1-ethoxyquincarbonyl 5 -— (4-piperidyl) pentyl] —L-lysyl] —proline · 3 hydrobromide 0.3 g Is obtained as a colorless powder.

Element analysis ί C _{2 +} Η 4 _{+ +} 05-3 HBr · 4 H ₂₀

Calculated value C36.79 H7.08 N.15

Measured 值 C 37.27 H7.07 6.72

SIS spectrum (m / e): 469 (MH ⁺ ), 507 (M ÷ K) + KI addition Experimental example 1

Effect of the compound of the present invention on the pressor action of angiotensin I

Two experimental methods]

Male rats (Sprague-Dawley) weighing 300-400 g and bred with free access to food and water were used. The day before the experiment, vent barbita lumnadium (50 mg

Replacement / Kg) was injected intraperitoneally to anesthetize the rat, and then polyethylene tubes were inserted and fixed in the hip artery for blood pressure measurement and in the hip vein for injection of angiotensin I and Π. .

The average blood pressure in the control period on the day of the experiment was measured using an electrosphygmomanometer (NEC-300, MPU-0.5-290-0-0), and a polygraph (NEC-San-ei, 365 type or Nihon Kohden RM-45) was used. After recording with angiotensin I, 300 ng / Kg of angiotensin I and then 100 ng / Kg of angiotensin II were injected into the crotch vein to examine the blood pressure effect. Next, 300 g / Kg 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! Was repeatedly injected to follow the pressor response. In calculating the inhibitory rate of angiotensin I against the pressor action, the inhibitory rate was corrected based on the time variation of the angiotensin I pressor response.

[Actual: experimental results] ...

The experimental results for the compound of the present invention are shown in Table 5. Table 5

Replacement 0-5

1 Industrial applicability

The piperidine derivative (I) provided by the present invention has an excellent pharmacological action and is useful as a pharmaceutical.

0

20

Replacement

Claims

Scope of claim

[Wherein A represents one amino acid residue and B represents the formula

R ⁴

-C-C H- II

0

(Wherein, R ⁺ is hydrogen; represents lower alkyl, aralkyl or amino lower alkyl), and the bond between A and B represents a peptide bond, and the group R ^{+ in} B May be linked to A. R ¹ represents hydrogen, lower alkyl or aralkyl, R ² represents hydrogen, lower alkyl, aralkyl or acyl, and X represents alkylene. However, except for the part which overlaps with the permissible range described in international applications PCT / JP84 / 00172, PCT / JP84 / 00221, PCT / JP84 / 00362 and PCTZJP84 / 00363], or a salt thereof.

"^