JPS61275258A - Dipeptide or the like - Google Patents

Abstract

NEW MATERIAL:A dipeptide expressed by formula I [R<1> and R<2> represent the formula -B-R<6> (B represents straight chain or branched lower alkylene which may have a single or double bond; R<6> represents aryl or heteroaryl), 1-10C alkyl, etc.; R<3> represents optionally substituted ethylene, trimethylene, etc.; R<4> represents OH, 1-10C alkoxyl, etc.; R represents H, 1-5C aliphatic acyl, etc.; A represents single bond, O or S] or its salt. EXAMPLE:(3S,4S)-4-[2(R2)-[2-( 1-Naphthyl )methyl-3-( 1-naphthyl )propionylamino]nonanoylamino-3-hydroxy-6-methylheptan-oyl-L-isoleucinol. USE:A diagnostic or remedy for hypertension based on renin-angiotensin system. PREPARATION:A compound expressed by formula II is reacted with a compound exprssed by formula III according to the peptide synthesis method (example; azide process) to obtain the compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION (Objectives) The present invention relates to novel dipeptides having renin inhibitory activity and pharmacologically acceptable salts thereof.

As peptide derivatives having a renin inhibitory effect, tetrapeptides, tripeptide derivatives, and the like are conventionally known (Japanese Patent Application Laid-open No. 151166/1983, etc.).

The inventors of the present application have conducted intensive research over many years on the synthesis of peptide derivatives and their renin inhibitory activity, and have found that dipeptides with novel structures previously unknown have excellent renin inhibitory activity. Todoroki discovered that scales were an important intermediate for synthesizing this compound.
The invention of the present application has been completed.

(Structure) The dipeptide derivative according to the present invention is a compound having formula (I).

In the above formula, R1 and R2 are the same or different, and represent a -C6 group (in the formula,
B represents a linear or branched lower alkylene group which may have a single bond or a double bond in the chain, and R represents an aryl group or a heteroaryl group. ), C1-C4゜alkyl group or formula -R4 group (wherein E is 1
R represents a lower alkylene group which may be interrupted by two oxygen atoms, and R represents a lower alkoxy group, an aryloxy group, an arylthio group, an aralkyloxy group, or a nitrogen atom-containing heterocyclyl group. ), R3 is an optionally substituted ethylene, trimethylene or tetramethylene group (the substituent represents a lower alkyl, phenyl or hydroxyl group), a group having the λ formula -qH- (in the formula, R represents a nitrogen atom a heterocyclyl-substituted lower alkyl group, a C5-C18 alkyl group, a group having a halogen-substituted group (wherein R9 and R10 are the same or different and represent a lower alkyl group; ), R4 represents an isopropyl group, a 5'8 cycloalkyl group or a phenyl group, and R5 represents a hydroxyl group, a cl-c1o alkoxy group. , aryloxy group, amino group, mono- or di(C1-C1o
Alkyl) amine group [The alkyl group may have one or two substituents, which are the same or different, such as a hydroxyl group, a lower alkoxy group, a halogen atom, an optionally substituted phenyl group, Pyridyl group, C3-08 cycloalkyl group, di(lower alkyl)amino group, di(indicates a hydroxy lower acylamino group or a heterocyclyl group containing a nitrogen atom), mono- or di(C3-c4 alkenyl)amino group, C -c cycloalkylamino group,
aryl amino group, a heterocyclylamino group containing a nitrogen atom (the amino and heterocyclyl of the group are bonded with N-C), a heterocyclyl group containing a nitrogen atom (the heterocyclyl group is a nitrogen atom contained in the group) ) or a group having the formula -NHR (wherein R
is an amine group, an optionally substituted C1-C1o aliphatic acylamino group (the substituent is a halogen atom, a lower alkoxy group, an aryloxy group, an arylacyl group, an aryl group, or a C3-C8 cycloalkyl group) - Show.

), arylacylamino group, cinnamoylamino group,
Heteroarylacyloxy amino group, optionally substituted lower alkylamino group (the substituent represents a hydroxyl group, lower alkoxy group, C1-05 aliphatic acyloxy group, arylacyloxy group, or aryl group), arylamino group or a heterocyclyl group containing a nitrogen atom (the heterocyclyl group is bonded to an -NH- group through a nitrogen atom)
, R represents a hydrogen atom, a C1-C5 aliphatic acyl group, or an arylacyl group, and A represents a single bond, an oxygen atom, or a sulfur atom.

The groups defined in compound (I) have the following meanings.

A straight chain or branched lower alkylene group which may have a double bond in the chain represents a C1-04 alkylene group,
For example, methylene, ethylene, methylmethylene, trimethylene, propylene, tetramethylene, n-propylmethylene, 2-ethylethylene, 3-methyltrimethylene, 2-methyltrimethylene, arylev (-CH2CH
-CH-), 2-butynire 7 (-CHCH-CH-C
H2-) or 3-butenylene (-cH2ca2ca-C
I can give H-).

An aryl group or an aryl moiety such as an aryloxy group or an arylthio group represents an optionally substituted phenyl, indya, or char, and examples of the substituent include a lower alkyl group, fluorine, chlorine, bromine, It represents a halogen atom such as iodine, a lower alkoxy group, a lower alkoxycarbonyl group, a trifluoromethyl group, an amino group, a cyano group, or a nitro group. Furthermore, examples of the low-kill moiety include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, S-butyl, or t-butyl (the same applies hereinafter).

The heteroaryl group may be fused with a phenyl/I/ring and represents a 5- to 6-membered cyclic aromatic group containing oxygen, sulfur or/and nitrogen atoms, such as furyl, chenyl, oxasilyl, thiazolyl, imidazolyl. , pyridyl, benzofuryl, benzothiophenyl, indolyl, benzthiazolyl, benzimidazolyl, quinolyl, or isoquinolyl, and may have a substituent on the ring, such as a lower alkyl group, halogen, etc. An atom or a lower alkoxy group can be mentioned.

The C4-C4° alkyl group is, for example, the above-mentioned 01-0
In addition to 4 alkyl groups, n-pentyl, 2-ethylpropyl, 1,2-dimethylpropyl, 1-methylbutyl, 2
-methylbutyl, isopentyl, 1-methylpentyl,
S-hexyl, 1,3-dimethylbutyl, 3,3-dimethylbutyl, n-heptyl, 1-methylhexyl, n-
Octyl, 1. s-dimethylhexyl, n-nonyl, n
-Can give deciles.

The lower alkylene group which may be interrupted by one oxygen atom indicates a C4-C4 alkylene group, for example, C4-C4 alkylene having no double bond in B,
Formula -0M2-0-CH2-.

-CHCH-G-CH2-, -CH2-0<H2CH2
−.

-CH2CH2-0-CH2CH2- group can be mentioned.

The aralkyl group is, for example, a benzyl or phenethyl group, and the phenyl moiety may have a substituent, and the substituent is the same as the substituent for the aryl group described above.

A heterocyclyl group containing a nitrogen atom contains 1 or 2 nitrogen atoms and may contain 5 to 6 oxygen or sulfur atoms.
Indicates a membered cyclic group, such as piperidyl, piperidino, pyrrolidyl, pyrrolidino, morpholinyl, morpholino, oxazolidinyl, oxacyridino, thiazolidinyl, thiasiridino, imidazolidino, piperazinyl, piperazino, and has a substituent on the ring. Examples of the substituent include lower alkyl, hydroxy lower alkyl group, lower alkoxy, optionally substituted phenyl (the substituent is the same as the substituent for the aryl group described above), and heteroaryl. group, aralkyl, carboxy, lower alkoxycarbonyl, or cinnamoyl (the substituent on the phenyl ring is the same as the substituent on the aryl group).

The C-C alkyl group in R8 is, for example, the above-mentioned C-
Among the alkyl groups of C, in addition to the alkyl group of 05-C1°, n-dodecyl, n-hexadecyl, n-oc! Examples include decyl, but preferred is a C5-C1o alkyl group.

Examples of the C-C alkenyl group optionally substituted with halogen in R8 include vinyl, allyl, 2-7
'Lopenyl, metaallyl, medium temperature ≠ 2-butenyl, 3-(tenyl, 2-methyl-2-butenyl, 3-methyl-2-
7"vinyl, 2-methyl-3-butenyl, 4-pentenyl, 2-chloroallyl-"2.2--)chlorovinyl.

Examples of the alkynyl group of C2Cs include ethynyl,
Propargyl, 2-1 thynyl, 3-butynyl, and 4-pentynyl can be mentioned.

The C3-C8 cycloalkyl group is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl group.

Examples of the alkenyl moiety of the C3-C4 alkenylamino group in R5 include allyl, metaallysl, 2-butenyl, and 3-butenyl.

C4-〇. Examples of the aliphatic acyl group include formyl, acetyl, propionyl, n-butyryl, imbutyryl, n-valeryl, isovaleryl, pivaloyl, n-
Examples include hexanoyl, n-heptanoyl, n-octanoyl, and n-nonanoyl. Also, C, Cs
As the aliphatic acyl group, among the above groups, C4-C5
Indicates the group of

The substituents on the aryl moiety of the arylacylamino group or cinnamoylamino group in R11 may be the same or different, and 1 to 3 substituents may be present, but preferably lower alkyl groups, halogen [-1 lower alkyl A trifluoromethyl group, a C, Cs aliphatic acyl group, a nitro group or a cyano group can be mentioned.

The heteroarylacyl moiety of the heteroarylacylamide 7 group of R is preferably 2-4L<, which may be substituted with a halogen atom, methyl or methoxy, 3-furoylcarbonyl, 2-chenylcarbonyl, 2 +j3-4L
lt, 4-pyridinecarbonyl or indolyl-2-carbonyl.

Further, in compound (I), suitable groups for R, R, R and R5 are, for example, as follows.

R+ R2: CH3-, CHCH-, CHΔcH2-.

CH30CH2CH,, CH3CH20CH2CH2-
, CH30-(-CH2+20+CH2+2゜CH3C
H2-0(CH2+2,0(CH2+2゜mino栖)-,
, to c) oe-ca2chi2. eNcH2).

G H2-o-(cH2)-2o-6C [(2q).

072 Ya・C-Kuniko・I2°9"・CH3 11 oN-cH, p-CH2CH,-, Od 2
#J2 R3: CH- 1: n″::10H21-・”-12H25□ n”J'
ss-・-CH2￥12. Be=cH, luster H2-=CH.

-CH-5-CH3 (R':) "%/"H3CH3/cLHs ('>,
('')--c-, b-b-a5.

BeCH3, PeC2H5, ÷@.

-NH2, -NHCH,, -NHC2H5, -NH-n
-C,H,.

-NH-1-C,)I, , →H-n-C'H, -NH
-i-C4H9゜-NH-s-C4H9, -MH-n-
C5H11, -NH-1-C5H1,.

N(02H5)2 -N(" 3H7)
2.

-N(i-C5H7)2 -N(n-04H
9)2.

-N(i 04H9)2 N(n 0
6H15)2.

-N (n-08H17) 2 #N
(n-09H19)2 +-NH~0H→MH -w8v0H to OH5 -N(cH2cH2oH)2゜-NH/A-10CH5, -NHNOC2H5-NH(
CH2CH20C2H5)2゜-NH~0'1-NHN
Br NHNF - Nagihashi\C4.

-NH/’-”Br NH%　　　NH△σ1 -NHA@f-NHbeγ003゜ -WXr　　　　To NH.

-Ehe @ -NH Bust 0j-NH Ta9
-NHgo■N.

-NH Pe -NH Small 0 -NHA/N(CH3)2-N)(NN(C2H5)2
-Bookha ψ\N(n 04H9)2.

H3 -NH/'V'C>-NH/''vAN N-CH3 Mxin11 几11 NiNH2, -NHCOOH3NHCOC2
H5, MHCOn-C5H7-NHCO-i-C5H7
, -NHCiO-n-C4HyNHCO/'S-/CJ
, NHC! Q ha! to CINHOOOH20
C2H5.

To NHCO 100be ◇ NHO nnn father 0 heat To NHCo 02NHCObe rOH5 1,. nnfigF Nl. , 8-Oton-coc
i-i5NHCH2, NHO2H5 N) (/\10H, Nruhe10C2H5 In compound (1), when optical isomers based on asymmetric carbon exist, optically active forms and racemic forms are included, but preferably the formula The compound having the general formula (1) of the present invention can be made into a pharmacologically acceptable salt. Examples of such salts include mineral salts such as hydrochloride, sulfate, and phosphate; acid additions such as acid salts, organic acid salts such as maleate, succinate, citrate, methanesulfonate, benzenesulfonate, P-)luenesulfonate f) J: 5 Nasulfonate, etc. Salts or alkali metal salts or alkaline earth metal salts such as sodium salts, potassium salts, calcium salts, magnesium salts, and organic base salts such as dicyclohexylamine salts can be mentioned.

Further, in the compound (+), preferably 1) a compound in which at least one of R1 and R2 is a group of the formula -B-R6, a methyl group substituted with a heterocyclyl group containing a C5
'11B alkyl group, halogen compound, 3) Compound where R4 is inpropyl 4) R5 is amino group, mono- or di-(C4-C4゜alkyl) amino group, mono- or di-(hydroxyC
1-C1o alkyl) amino group, mono- or di-(substituted C1-C4 alkyl) amino group [the substituent of the alkyl group is a lower alkoxy group, an optionally substituted phenyl group, a pyridyl group, a di-(lower alkyl) amino group or a heterocyclyl group containing a nitrogen atom.],]C3-C8
Cycloalkylamino group heterocyclylamino group i1&
Formula-N) (Group having R11 [wherein R11 is an amino group, a C1-C1° aliphatic acylamino group, a substituted C
2-05 aliphatic acylamino group (the substituent is a halogen atom, lower alkoxy group, optionally substituted phenyl or C3-C8 cycloalkyl group), benzoylamino group, cinnamoylamino group (the The phenyl portion of the group may be substituted with a lower alkyl group, a), a lower alkoxy group, a trifluoromethyl group, a C1-05 aliphatic acyl group, a nitro group, or a cyan group. ) or an optionally substituted lower alkylamino group 5
) a compound in which R is a hydrogen atom, 6) a compound in which A is a single bond, 7) an ethylene in which at least one of R1 and R2 is a group of the formula -B-R6, and R3 is optionally substituted with methyl; trimethylene M (wherein R8 is a methyl group substituted with a heterocyclyl group containing a nitrogen atom, an alkyl group at C5018, R5 which may be substituted with a halogen is an amino group, mono- or di(
C1-010 alkyl) amino group, mono or di(
Hydroxy c, -〇iG alkyl) amino group, mono- or di-(substituted c1-c4 alkyl) amino group [the substituent of the alkyl group is a lower alkoxy group, an optionally substituted phenyl group, a pyridyl group, a di(lower alkyl ) A heterocyclyl group containing an amino group or a nitrogen atom. ],
C5 (+E cycloalkylamino group, heterocyclylamino group, group having the formula -m 11 [wherein, B11 is an amino group, 01-C, aliphatic acylamino group, substituted C2-05 aliphatic acylamino group (The substituent is a halogen atom, a lower alkoxy group, an optionally substituted phenyl or a C3C8 cycloalkyl group.)
, benzoylamino group, cinnamoylamino group (the phenyl part of the group is substituted with a lower alkyl group, a halogen atom, a lower alkoxy group, a trifluoromethyl group, an aliphatic acyl group of 01-05, a nitro group or a cyano group) ) or optionally substituted lower aryl, a compound in which B is a hydrogen atom and A is a single bond, 8) a compound in which R1 and R2 are the same or different and have the formula -B-R6 group , is a C501B alkyl group, a C2-05 alkenyl group, or a C2-05 alkynyl group. ), 10) A compound in which R5 is a mono-(C1″10 alkyl) amino group, a mono-(hydroxy C4-C4° alkyl) amino group, a mono-(substituted C1-04 alkyl) amino group [alkyl group substitution Components are lower alkoxy group, optionally substituted phenyl group, pyridyl group, di(lower alkyl)
It is an amino group or a heterocyclyl group containing a nitrogen atom.

], 03-C8 cycloalkylamino group, or formula
-NHK'l group [wherein, B11 is an amino group, C
1-C4o aliphatic acylamino group, substituted. C2
-C5 aliphatic acylamino group (the substituent is a halogen atom, a lower alkoxy group, phenyl or an 05-c cycloalkyl group) or a lower alkylamino group which may be substituted with a hydroxyl group. ], 11) R' and R2 are the same or different and have the formula -B-
R6L8 is a group, R3 is a group having the formula -crystal- (wherein R8 is an alkyl group of 05-018, an alkenyl group of C2-05 or an alkynyl group of C2-C5), R4
is an isopropyl group, R5 is mono-(C4-01o
alkyl)amino group, mono-(hydroxyC1-01o
alkyl)amino group, 7-(substituted C1-04 alkyl)amino group [The substituent of the alkyl group is a lower alkoxy group, an optionally substituted phenyl group, a pyridyl group, a di(lower alkyl)amino group, or a nitrogen atom. It is a heterocyclyl group containing. ], 05-08 cycloalkylamino group or group having the formula -N)IR" [wherein Bil is an amino group, a C1-C1o aliphatic acylamino group, a substituted c2o5 aliphatic acylamino group (the substituents are Halogen atom, lower alkoxy group, phenyl or C5-08
is a cycloalkyl group. ) or a lower alkylamino group which may be substituted with a hydroxyl group. ] Adashi, R
is a hydrogen atom, and A is a single bond; 12) A compound in which R1 or R2 are the same or different and are naphthylmethyl, quinolylmethyl, benzyl, pyridylmethyl, or chenylmethyl group; 14) R'' is Mono-(C4O1゜alkyl)amino group, mono-(hydroxyc1'10alkyl)amino group, mono-(substituted C4-04alkyl)amino group [the substituents of the alkyl group are lower alkoxy groups, optionally substituted phenyl ] or a C3-08 cycloalkylamino group.

Furthermore, in compound (1), the compounds illustrated below can be mentioned suitably.

Number R1-A-R2R5R' R5375NH
-0 378NH-○ Furthermore, in the above table, compound numbers 74°79, 1
79. Regarding 183 and 205, compounds in which R is an acetyl group instead of a hydrogen atom can be mentioned.

The compound of the present invention having the general formula (1) can be easily produced according to the following method.

Method A Method B (+) (V) Method D (io) Method D (l,) In the above formula, R1, R2, R6, R4, R'', R and A
has the same meaning as described above, R11a is the same group as B11 except for the acylamino group, and B12 is a lower alkyl group or an aryl group.

Method A is a method for producing compound (()).

The first step of this method is to use compound (II) or a reactive derivative thereof and compound (1) to synthesize a peptide using a conventional method for peptide synthesis, such as an azide method, an active ester method, a mixed acid anhydride method, a carbodiimide method, or an oxidation method. It is carried out by a condensation method using a reducing system.

In the above peptide synthesis, the azide method involves combining an amino acid or its ester with hydrazine in an inert solvent (e.g. dimethylformamide).
This is carried out by reacting an amino acid hydrazide produced by reacting it at around room temperature with a nitrous acid compound to convert it into an azide compound, and then treating it with an amine compound.

As the nitrite compounds used, mention may be made, for example, of alkali metal nitrites such as sodium nitrite or alkyl nitrites such as isoamyl nitrite.

The reaction is preferably carried out in an inert solvent, examples of which include amides such as dimethylformamide and dimethylacetamide, sulfoxides such as dimethylsulfoxide, and pyrrolidones such as N-methylpyrrolidone. can be given. Furthermore, the two steps of this method are usually carried out in one reaction solution, and the reaction temperature is
The temperature in the first stage is 150℃ to 0℃, and the temperature in the second stage is 110℃ to 1℃.
The temperature is 0° C., and the time required for the reaction is 5 minutes to 1 hour in the first stage and 10 hours to 15 days in the second stage.

The active ester method is carried out by reacting an amino acid with an active esterifying agent to produce an active ester, which is then reacted with an amine compound.

Both reactions are preferably carried out in an inert solvent; the solvents used include, for example, methylene chloride (IJ)',
Examples include hydrocarbons such as chloroform, ethers, ethers such as tetrahydrofuran, and amides such as dimethylformamide and dimethylacetamide.

Examples of the active esterifying agent used include N-hydroxy compounds such as N-hydroxysuccinimide, hydroxybenzotriazole, and N-hydroxy-5-norbornene-2,3-dicarboximide. The active esterification reaction is preferably carried out in the presence of a condensing agent such as dicyclohexylcarbodiimide or carbonyldiimidazole.

The reaction temperature is -10°C to 1°C in the active esterification reaction.
The reaction between the active ester compound and the amine at 0'C is around room temperature, and the time required for both reactions is 30 minutes to 10 hours.

The mixed acid anhydride method is carried out by producing a mixed acid anhydride of an amino acid and then reacting it with an amine.

The reaction to produce mixed acid anhydrides is carried out using an inert solvent (e.g.
Among the above-mentioned amides and ethers, ethyl chlorocarbonate,
This is accomplished by reacting the amino acid with a lower alkyl carbonate such as isobutyl chlorocarbonate or a di-lower alkyl cyanophosphate such as diethylcyanophosphate.

The reaction is preferably carried out in the presence of an organic amine such as triethylamine or N-methylmorpholine, the reaction temperature is -10°C to 10°C, and the time required for the reaction is 3.
The duration ranges from 0 minutes to 5 hours.

The reaction between the mixed acid anhydride and the amine is preferably carried out in an inert solvent (
For example, the reaction is carried out in the presence of the above-mentioned organic amine in the above-mentioned amides and ethers, the reaction temperature is 0° C. to room temperature, and the reaction time is 1 hour to 24 hours.

The condensation method is carried out by directly reacting an amino acid with an amine in the presence of a condensing agent such as dicyclohexylcarbodiimide or carbonyldiimidazole. This reaction is carried out in the same manner as the reaction for producing the active ester described above.

In this method, when compounds (■), (1), etc. contain an amino group or a carboxy group, and when R11 of one NHR11 group in R5 of compound (1) represents an amine group, each group is protected. It is preferable to remove the relevant protecting group after forming the pevitide bond using the compound.

The protecting group is not particularly limited as long as it is a protecting group used in the field of amino acid chemistry, but examples of protecting groups for amino groups include benzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, t-butyloxycarbonyl group. Examples of the protecting group for the carboxy group include an aralkyl group such as a t-butyl group or a benzyl group. Removal reactions of these protecting groups are carried out according to conventional methods. For example, an acid (e.g.,
by treatment with hydrochloric acid or trifluoroacetic acid),
Other protective groups for amino groups (benzyloxycarbonyl group, etc.) and aralkyl groups that are protective groups for carboxy groups are subjected to catalytic reduction (e.g., reaction in a hydrogen atmosphere at normal pressure to 10 atmospheres using palladium-carbon as a catalyst). By doing so, each can be removed.

Method B is a method in which compound (1) is separately produced, and the second step of this method is to produce A by using compound (ff) and compound (V).
The method is carried out in the same manner as the first step.

In method C, in compound (+), R5 is -NHH11 (
In the formula, R11 has the same meaning as described above. ) is a method for separately producing compound (IC).

The third step is a step of producing a compound having the general formula (Ia), and is achieved by reacting the compound (IT) with the compound (■), and this step is carried out in the same manner as the first step of the human method. be exposed.

The fourth step is to produce a compound having the general formula (1b), in which the compound (Ia) is mixed with the general formula (I) in an inert solvent.
) is achieved by reacting with a hydrazine compound having K.

Examples of the inert solvent used in the reaction include the solvent used in the first step of the human method and alcohols such as methanol and ethanol, and the reaction temperature is 0°C to 100°C.
The reaction time is 10 to 30 hours.

The fifth step is a desired step, and is achieved by reacting the compound (Ib) in which R11a is an amine group with the corresponding carboxylic acid, and this reaction is the same as the first step of the human method. It will be held on.

Method D is a method for separately producing compound (Ib), which is achieved by reacting compound (ff) with a compound having the general formula (va) and optionally removing the protecting group of the diamino group. The reaction in this step is carried out in the same manner as the reaction in the first step of method A.

Furthermore, when carrying out each of the above methods, protection and deprotection of amino groups of amino acids can be carried out according to conventional methods, if necessary.

After completion of the reactions in each of the above steps, each target compound can be collected from the reaction mixture according to a conventional method. For example, the reaction mixture should be appropriately neutralized, and if insoluble matter is present, r
After removing the residue, the desired product can be obtained by distilling off the solvent. Furthermore, if desired, it can be purified by conventional methods such as recrystallization, reprecipitation, column chromatography, etc.

〔effect〕

The results of an inhibitory effect test on human renin of the peptides having the general formula (1) of the present invention are shown below. The test method is the method of Kokufu et al. [Hypertension
, 5.191-197 (1983)].

Inhibition degree (%) of test compound against human renin (IXlo-6M) Compound of Example 1 99 Compound of Example 7 82 Compound of Example 3 99 Target compound of the present invention (represented in the above test example) As shown above, it exhibits an excellent inhibitory effect on human renin and is useful as a diagnostic and therapeutic agent for hypertension based on the renin-angiotensin system.The dosage forms include tablets, capsules, granules, Examples include oral administration using powders, syrups, etc., and parenteral administration using injections, suppositories, etc. The amount used varies depending on the purpose of use, symptoms, age, etc., but for example, about 0.01 μl per day. The dosage ranges from 100 to 100 kg, and can be administered once or in divided doses.

Next, the present invention will be explained in more detail with reference to Examples.

Example 1°(35,45)-4-t-butyloxycarbonylamino-3-hydroxy-6-methylhebutanoyl L-inleucinol 5B, 6. Q (0,156 mmol)
Add 3 ml of 6N hydrochloric acid/dioxane to the solution and stir at room temperature for 30 minutes.
After stirring for a minute, the mixture was concentrated to dryness under reduced pressure. The residue was dissolved in 2 ml of dimethylformamide and 77.5η of nonanoic acid (0
, 156 mmol) and diethyl cyanophosphate 27.91
1F (0.17 mmol) was added and cooled on ice. Next, 33 wg (0,327 mmol) of triethylamine was added, stirred at room temperature for 3.5 hours, and then concentrated under reduced pressure.

Water was added to the residue, extracted with ethyl acetate, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative silica gel chromatography (developing solvent: chloroform/methanol = 10/'1) to obtain the title compound 21.0119 in the form of a colorless powder.

Melting point 75-78°C Example 2゜2 (R5)-(2-(1-7thyl)methyl-3-(
The reaction and treatment were carried out in the same manner as in Example 1 using 1-naphthyl)propionylamino]hebutanoic acid to obtain the title compound 102η in the form of a colorless powder.

Melting point 95-97°C Example 3゜N-(2-(1-naphthyl)methyl-3-(1-naphthyl)propionyl) -DL-OroriN-(:2-(1-
Naphthyl)methyl-3-(1-naphthyl)propionyl)-DL-allylglycine was reacted and treated in the same manner as in Example 1 to obtain the title compound 59η in the form of a colorless powder.

Melting point: 93-95°C Example 4: 749 mg (2 mmol) of 6N hydrochloric acid/dioxane, After stirring at room temperature for 30 minutes, the mixture was concentrated to dryness under reduced pressure. The residue was dissolved in 20xl of dimethylformamide, and Nt-butyloxycarbonyl-DI, -7' lovargylglycine 42
6 ml (2 mmol) and 270 my (2 mmol) of 1-hydroxybenztriazole were added. Dicyclohexylcarbodiimide 412q (2 mmol) and triethylamine 1- were added under water cooling, and after stirring at 40 to 50°C for 2 hours, the precipitated dicyclohexylurea was filtered off.

Add ethyl acetate to the filtrate, add water, 10% citric acid aqueous solution,
After washing with a 5% aqueous sodium bicarbonate solution and saturated brine, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, ethyl ether was added to the residue, and the precipitate precipitated was collected by filtration. After the oral liquid was distilled off under reduced pressure, 10 x 1 of 6N hydrochloric acid/dioxane was added, and after stirring at room temperature for 30 minutes, it was concentrated to dryness under reduced pressure.

The residue was dissolved in 20Mt of dimethylformamide, and 680tty (2 mmol) of 2-(1-naphthyl)methyl-3-(1-naphthyl)propionic acid and 54311Iy (3 mmol) of diethyl cyanophosphate were added thereto. 1 ml of triethylamine was added to this solution while stirring, and after stirring at 40-50'C for 2 hours, it was poured into ice water and extracted with ethyl acetate. After washing the extracted ethyl acetate with a 10% aqueous citric acid solution, a 5% aqueous sodium carbonate aqueous solution, and saturated brine, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by preparative thin layer chromatography (developing solution: ethyl acetate) to obtain two isomers based on the asymmetric carbon of the propargylglycyl moiety.

Melting point 182-188℃ (isomer 1), 92-94℃ (
Isomer 2) Example 5 Innol (38,48) -4-t-butyloxycarbonylamino-3-hydroxy-6-methylhebutanoyl L-
The title compound was synthesized in the same manner as in Example 4 using 312 μm (1 mmol) of inleucinol.

Melting point 55-58°C (isomer 1), 52-55°C (isomer 2) Example 6°Tylamide (a) (38,43)-4-(3(R8)-t-butyloxycarbonylaminocobutyroyl Amino-3-
Hydroxy-6-methylhebutanoic acid morpholinoethylamide DL-β-amino-n-butanoic acid2. asp (20 mmol) was added to 20 w1 of aqueous dioxane (1:1) solution and 2.8 ml of triethylamine, and di-t-
4.8 g (22 mmol) of butyl dicarbonate was added, and the mixture was stirred at room temperature for 4 hours.

After the reaction is complete, add 20rzl of water and add 20ml of ethyl acetate.
After washing the aqueous layer once with water and adjusting the pH to 2 with a citric acid aqueous solution while sufficiently cooling the aqueous layer, 20 ml of ethyl acetate was added.
Extracted twice with /. The ethyl acetate layer was washed with saturated brine, dried over magnesium sulfate, and evaporated under reduced pressure to give Nt-f)oxycarbonyl-DL-β-amino-n.
3.45 g (85%) of -butanoic acid were obtained as white crystals. This N-1-butoxycarbonyl-DL-β-amino-n-butanoic acid 1.0'2 g (s, o.

mmol) and (3s,4s)-4-amino-3-hydroxy-6-methylhebutanoic acid morpholine ethylamide, dihydrochloride 1. a y (s, o.

mmol) in 20 ml of anhydrous tetrahydrofuran and 0.0 mmol of diethyl cyanophosphate was dissolved under cooling under a nitrogen atmosphere.
83xt (5.47 mmol) and 2.30 ml (16.5 mmol) of triethylamine were added and stirred overnight at room temperature.

After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform:methanol = 1:1) to obtain the title compound as a colorless oil with a concentration of 1.36!9 (
58%) was obtained.

Silica gel thin layer chromatography (Rf value): 0.3
0 (Chloroform:methanol=5=1) (b) (3S, 48)-4”-[3(R8)-
1:2-(1-naphthyl)methyl-3-(1-naphthyl)propionylaminobutyroylamino-3-hydroxy-6-methylhebutanoic acid Mo/L/holinoethylamide Example 6 Synthesized in (a) Did (33.48) -4
-C3(R,5)-t-butyloxycarbonylaminobutyroylamino-3-hydroxy-6-methylhebutanoic acid Compound 400m9 obtained by removing the t-butoxycarbonyl group from morpholinoethylamide according to a conventional method
(0.90 miIJ mol) and 3061"I of 2-(1-naphthyl)methyl-3-(1-naphthyl)propionic acid
F (090ml) in 10ml of anhydrous tetrahydrofuran
0.15 g/(0.99 mmol) of diethyl cyanphosphate and 0.41 ml (2.94 mmol) of triethylamine were added under nitrogen atmosphere and cooling with water, and the mixture was stirred overnight at room temperature.

The solvent was distilled off under reduced pressure, and the residue was purified by silica gel thin layer chromatography (chloroform:methanol=1=1) to give the title compound as white crystals, 38011rg (6
1%) obtained.

Melting point: 169-171°C Example 7゜Mide Reacted and treated in the same manner as in Example 6 to obtain the title compound 56ffi.
9 was obtained as colorless powdery crystals.

Melting point 108-111°C Example 8゜Cyl-(38,48)-4-amino-3-hydrocyl/-
IV React and treat in the same manner as in Example 6 to obtain the title compound 86ff
P was obtained as colorless powder crystals.

Melting point: 16γ-170°C Example 9゜Reacted and treated in the same manner as in Example 1 to obtain 200jl of the title compound.
11 was obtained as colorless powdery crystals.

Melting point: 85-88°C Example 10゜Silamide Reacted and treated in the same manner as in Example 1 to obtain 150 rq of the title compound.
was obtained as colorless powder crystals.

Melting point: 78-80°C Example 11° The reaction and treatment were carried out in the same manner as in Example 1 to obtain the title compound 2709 as colorless powdery crystals.

Melting point 71-72°C. “- Example 12 (38,4S)-4-(2(R3)-(2-(1-naphthyl)methyl-3-(1-naphthyl)propionylaminocoheptanoylamino-3-hydroxy-6-methyl Hebutanoic acid hydrazide ethanol-A/3111 to N-(:2-(1-naphthyl)methyl-3-(1-naphthyl)glopionyl]-heptanoylamino(3S,4S)-3-hydroxy-6-
Ethyl methylhebutanoate 284 µ (0,435 mmol) and 80% hydrazine hitlate 275 TIq (4
, 35 mmol) was added, stirred at room temperature for 2 hours, and then incubated overnight. Then, the precipitated crystals are separated, dried, and have a melting point of 1.
A crystal of 45 cm with a temperature of 76-177°C was obtained. The reaction mother liquor was concentrated under reduced pressure, and the target product 185■ (82,8
%)t-obtained.

Elemental analysis: Calculated value as C39H5□N405/R20 c, 71.31:H, 7,98:N, 8.53 Actual value C, 71,80:H, 7,99SN, 8.60 Example 13 (38 ,4S)-4-(3(Rs)-t-butyloxycarbonylamino]butyroylamino-3-hydroxy-6-methylhebutanoic acid morpholinoethylamide 387
．． 5■ (1 mmol) to 6N dioxane hydrochloric acid 3H6f
Add and stir at room temperature for 30 minutes. Dioxane was then distilled off under reduced pressure, 1 omlt of methanol was added, and the process was repeated 3 times to remove dioxane under reduced pressure).
Triethylamine 101.2711i (1
mmol), N-(2-(1-naphthyl)methyl-3-
(1-su7thyl)propionyl)-(R8)-arynulglycine 437.5 μm (1 mmol), diethyl cyanophosphate 179.4 W (1,1 mmol A/), triethylamine 111.1 μm (1 mmol) , 1 mmol) and stirred at room temperature for 3 hours. -After standing overnight, dimethylformamide was distilled off under reduced pressure, a small amount of water was added to the residue, extracted with ethyl acetate, washed with water, dried, ethyl acetate was distilled off, and the entire residue was subjected to silica gel thin layer chromatography (chloroform:
Purified with methanol = 5:1) to produce white powder 251.1'
W (35.5%) was obtained.

Melting point 90-93℃

Claims (1)

[Scope of Claims] Dipeptides having the formula ▲ Numerical formulas, chemical formulas, tables, etc.▼ and pharmacologically acceptable salts thereof. In the above formula, R^1 and R^2 are the same or different, and represent the formula -B-R^6
group (wherein B represents a linear or branched lower alkylene group which may have a single bond or a double bond in the chain, and R^6 represents an aryl group or a heteroaryl group). )
, C_1-C_1_0, alkyl group or formula -E-R^7
group (wherein E represents a lower alkylene group which may be interrupted by one oxygen atom, R^7 is a lower alkoxy group,
It represents an aryloxy group, an arylthio group, an aralkyloxy group, or a heterocyclyl group containing a nitrogen atom. ), R^3 is an optionally substituted ethylene, trimethylene or tetramethylene group (the substituent is lower alkyl,
Indicates phenyl or hydroxyl group. ), a group having the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (wherein R^8 is a heterocyclyl-substituted lower alkyl group containing a nitrogen atom, C_5-C
_1_8 represents an alkyl group, a C_2-C_5 alkenyl group which may be substituted with halogen, or a C_2-C_5 alkynyl group. ) or a group having the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. 0
may form a C_3-C_8 cycloalkyl group together with the bonded carbon atom. ), R^4 represents an isopropyl group, a C_3-C_8 cycloalkyl group, or a phenyl group, and R^5 represents a hydroxyl group, a C_1-C_1_0 alkoxy group, an aryloxy group, an amino group, a mono- or di-(C_1 -C_1_0 alkyl) amino group [The alkyl group may have one or two substituents, which are the same or different and include a hydroxyl group, a lower alkoxy group, a halogen atom, an optionally substituted phenyl group , pyridyl group, C
_3-C_8 represents a cycloalkyl group, di-(lower alkyl) amino group, di-(hydroxy-lower alkyl) amino group, or a heterocyclyl group containing a nitrogen atom. ], mono- or di-(C_3-C_4 alkenyl) amino group,
C_3-C_8 cycloalkylamino group, arylamino group, heterocyclylamino group containing a nitrogen atom (amino and heterocyclyl of the group are bonded with N-C),
A heterocyclyl group containing a nitrogen atom (the heterocyclyl group is bonded to a carbonyl group through the nitrogen atom contained in the group) or a group having the formula -NHR^1^1 (wherein R^1
^1 is an amino group, optionally substituted C_1-C_1
_0 aliphatic acylamino group (the substituent represents a halogen atom, lower alkoxy group, aryloxy group, arylacyl group, aryl group, or C_3-C_8 cycloalkyl group) arylacylamino group, cinnamoylamino group , heteroarylacyloxy group, optionally substituted lower alkylamino group (the substituent represents a hydroxyl group, a lower alkoxy group, a C_1-C_5 aliphatic acyloxy group, an arylacyloxy group, or an aryl group), arylamino or a heterocyclyl group containing a nitrogen atom (the heterocyclyl group is bonded to an -NH- group through a nitrogen atom), R represents a hydrogen atom, a C_1-C_5 aliphatic acyl group or an arylacyl group, and A represents a single bond, an oxygen atom or a sulfur atom.