JPS61194097A - Novel peptide and peptide derivative, manufacture and medicinal composition - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION [Technical Field] The present invention relates to novel peptides and peptide derivatives, their production methods and uses, and pharmaceutical compositions containing them.

DESCRIPTION OF THE INVENTION This invention provides an optional isostere in which the methylene groups of the backbone chain are di-substituted and one or both substituents are fluorine and/or chlorine.
The compounds of this invention are enzyme inhibitors.Due to the nature of the peptides or peptide analogs, they can be used to inhibit various enzymes. , for example esterases, in particular lipases such as phospholipase A2, or proteases such as aspartyl proteases, in particular chymosin, renin, catebusin D and pepsin, zinc-proteases, in particular angiotennase converting enzyme, aminopeptidases,
In particular, it can be used as an inhibitor of leucine aminopeptidase, thiol proteases, especially papain, serine proteases, especially elastase, carboxypeptidases, especially carboxypeptidase A and B, juvenile hormone esterase and acetylcholinesterase.

Clearly, therefore, the peptides and peptide analogs of this invention have a general structure that varies depending on the particular enzyme that is to be inhibited. Generally these structures are similar to those of known inhibitors and/or substrates for the particular enzyme. It is generally most advantageous when the fluorinated and/or chlorinated methylene group is located at or near the part of the inhibitory peptide or peptide analog that corresponds to or reacts with the active site of the enzyme to be inhibited.

For example, as inhibitors of renin, the compounds of this invention have an overall structure that is advantageously related to the structure of a particular determinant that binds to the active site of renin of the renin substrate angiotensinogen.

The methylene groups of the backbone chain are preferably substituted by fluorine.

In particular, the invention provides compounds as described above, wherein the fluorinated and/or chlorinated methylene group is part of an amino acid residue of a statine or a statone or an isostere of a statine or a statone. .

A preferred group of compounds of the invention is of the formula A is hydrogen or a substituent, and B is hydroxy or another substituent, with the proviso that
at least one of A and B is a peptide residue, R1 is fluorine or chlorine, R1 is fluorine, chlorine or another substituent, R4 is hydroxy, alkoxy or acyloxy,
Either R6 is hydrogen, or R3 and R4 taken together are oxo, and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl or an aryl or heteroaryl moiety as desired. is a substituted aryl, aralkyl, heteroaryl or heteroarylalkyl moiety, or an isostere form thereof.
R1 is preferably fluorine. R2 is preferably fluorine. R5 preferably constitutes hydroxo or together with R4 oxo, and the specific peptide residue is composed of one or more amino acids. 1 on the peptide residue
When more than 1 amino acid residues are present, these are usually peptide carbamoyl groups, i.e. -〇 〇 N H-
It is connected by

Isosteric forms of the compounds of this invention are defined, for example, when one or more peptide carbamoyl groups are in isosteric form, or when a natural Cedar counterpart is present, one or more amino acid residues are non-naturally The compound of this invention has the following configuration.

The isosteric form of the peptide carbamoyl group is, for example, −
CH, NH- (reduction), -COCHl- ('7), -
CH(OH)CHt (hydroxy), -CH(N
H*) CH* - (7 mino), CHt CHt-
or -CJ(t CHt CH* - (hydrocarbon). Preferably, the compound of this invention does not contain a peptide carbamoyl group in the entire isostere form. When it contains a peptide carbamoyl group in the isostere form, it is preferably It has one or two, preferably one, peptide carbamoyl group in the star shape.

Preferably the peptide residues are composed of natural amino acid residues in their natural configuration. If amino acid residues in a non-natural configuration are present, preferably one or two amino acid residues in a non-natural configuration are present.
There is only one, especially one. Amino acid residues as used herein include amino acid residues such as prolone and hydroxyproline.

Peptide residues preferably consist of 1 to 7 amino acid residues.

The moiety represented by formula (I) is a statin or a statone or a statin derivative or an amino acid residue of a statin derivative. It preferably has the same configuration as the natural statin at the carbon atom to which R is attached when asymmetrically substituted. The carbon atoms to which R3 and R4 are attached preferably have the R configuration when asymmetrically substituted.

Another preferred group of the invention is the formula (I a) [
In the formula, R and R4-R4 have the above meanings, X is hydrogen or a peptide amino terminal blocking group, Y is a hydroxy or peptide carboxy terminal blocking group, and one of A and B is a peptide residue; , the other is a bond or a peptide residue] or its isostere form.

X is preferably a peptide amino end blocking group.

Y is preferably a peptide carboxy end blocking group.

The peptide amino end-blocking groups may be, for example, 2 to 1 in total.
alkoxycarbonyl with O carbon atoms, alkanoyl with a total of 2 to 10 carbon atoms, a total of 4
cycloalkylcarbonyl having ~8 carbon atoms,
aroyl, or alkylsulfonyl having a total of 1 to 10 carbon atoms, especially alkoxycarbonyl having a total of 4 to 6 carbon atoms, especially t-butoxycarbonyl (BOC), or alkylsulfonyl having a total of 4 to 6 carbon atoms; Alkanoyl having carbon atoms, especially isovaleroyl (Iva). Cycloalkylcarbonyl preferably has a total of 4.
Consists of 6 or 7 carbon atoms.

Aroyl is preferably benzoyl. Alkylsulfonyl preferably consists of 3 to 6 carbon atoms and is preferably branched.

Peptide carboxy end blocking groups include, for example, alkoxy having 1 to 5 carbon atoms, amino, 1 to 5 carbon atoms,
alkylamino having 1 to 1 on the alkyl moiety individually
dialkylamino, (1-benzylpiperidin-4-yl)amino or (pyridine-
2-yl)methylamino, especially alkoxy having 1 to 5 carbon atoms, amino, alkylamino having 1 to 5 carbon atoms, (1-benzylpiperidin-4-yl)amino or (pyridin-2-yl) Methylamino, especially alkoxy having 1 to 3 carbon atoms, especially methoxy or ethoxy.

Alkoxy preferably has 1 to 5 carbon atoms, especially methoxy. Acyloxy preferably has 2 to 6 carbon atoms and is especially acetoxy.

Alkyl preferably has 1 to 5 carbon atoms and is especially branched, especially isobutyl.

Cycloalkyl preferably has 3 to 7 carbon atoms and is especially cyclopendel or cyclohexyl. Cycloalkylalkyl preferably has 3 to 7 carbon atoms, especially 5 (Il!l or 6 carbon atoms) in the cycloalkyl part and 1 to 5 carbon atoms, especially 1 carbon atom, in the alkylene part. Aryl is preferably phenyl. Aralkyl is preferably phenylalkyl having 7 to 12 carbon atoms, especially benzyl. Heteroaryl is preferably pyridinyl,
Especially 4-pyridinyl, chenyl, especially 2-chenyl, or furyl, especially 2-furyl, preferably pyridinyl. Heteroarylalkyl preferably has 1 to 6 carbon atoms, especially 1 carbon atom in its alkylene portion. The heteroaryl part of heteroarylalkyl preferably has the meaning given above as preferred in the case of heteroaryl. The optional substituents on the aryl or aralkyl moiety preferably range from 1 to
1 or 2 alkyl groups of 5 carbon atoms, 1
Alkoxy with ~5 carbon atoms, atomic number 9-3
5 halogens, hydroxy and/or amino, preferably 1 or 2 methyl, methoxy, chlorine, bromine,
A hydroxy or amino group, especially one hydroxy, amino, chlorine or bromine, optionally in protected form in the appropriate position.

A a and Ba may have a reported value in the art, giving high affinity and selectivity to known enzyme inhibitors, such as renin inhibitors.

That is, A: Bond Hls- Phe- Leu- -P he -P he - -β-(l-naphthyl)-Ala- -Val-Vat - -Phe-His- -Pro-Phe-His - -His -P ro -P he -His --H
is -P he -P ro -His -L eu
--Pro-His-Pro-Phe-His -l
1e- Leu- Val- ' -Vat-Phe- -Val-Tyr- -Leu-Phe- -Ile-Phe- -Ile-H1s- -Ala-Phe- -Phe-Phe- -Leu-Tyr- -Leu- Val -Phe - -V at -I le -His -I 1e-H
In the case of is-Lys--Val-11e-His-Lys- and a pepsin inhibitor: A: Bond -Val--Val-Val-B: Bond Ala- Alkoxycarbonyl preferably has a total of 4 to 6 carbon atoms, preferably branched, especially BOC
It is. Alkanoyl preferably has a total of 2 to 6 carbon atoms and is preferably branched, especially Iva. Cycloalkylcarbonyl preferably has a total of 4
．． Has 6 or 7 carbon atoms. Aroyl is preferably benzoyl. Alkylsulfonyl preferably has 3 to 6 carbon atoms and is preferably branched.

Glossary of terms BOC = tertiary butoxycarbonyl His = L-histidine I va = miniisovaleroyl e = L-isoleucine Leu = L-leucine Lys = L-lysine Phe = L-phenylalanine Pro = L-proline stadine * = 4-amino-3-hydroxy-6-methylhebutanoic acid statone* = 4-amino-3-oxo-6-methylhebutanoic acid Tyr = L-tyrosine Val = L-valine *: Absolute configuration is specified in the specification It is described in.

Another preferred group of compounds of the invention is the formula (I
aa) [wherein Rl-R4 has the above-mentioned meaning, Xa is hydrogen, alkoxycarbonyl or alkanoyl having a total of 2 to 10 carbon atoms, cycloalkyl having a total of 4 to 8 carbon atoms; carbonyl, aroyl, or alkylsulfonyl having a total of 1 to 10 carbon atoms, Y is hydroxy, alkoxy having 1 to 5 carbon atoms, amino, alkylamino having 1 to 5 carbon atoms, alkyl dialkylamino, (1-benzylpiperidin-4-yl)amino or (pyridin-2-yl)methylamino having individually 1 to 5 carbon atoms in the moieties and R is hydrogen, 1 to 5 carbon atoms; alkyl having atoms, cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 3 to 7 carbon atoms in the cycloalkyl part and 1 to 5 carbon atoms in the alkylene part, optionally a phenyl ring phenyl mono- or di-substituted by alkyl having 1 to 5 carbon atoms or phenylalkyl having 7 to 12 carbon atoms, 1
Alkoxy with ~5 carbon atoms, atomic number 9-3
5 halogen, hydroxy or amino, pyridinyl,
chenyl or furyl or pyridinylalkyl having 6 to 110+ carbon atoms, chenylalkyl having 5 to to carbon atoms or furylalkyl having 5 to 10 carbon atoms, one of Aaa and B being an amino acid residue; 1 to 15 peptide residues, and the other is a bond or an amino acid residue 1 to 15 peptide residues] or its isostere form.

In a subgroup, Y is (pyridin-2-yl)
Other than methylamino.

Yet another group of compounds of this invention is represented by the formula %) where Xaa is hydrogen, alkoxycarbonyl of 2 to 6 carbon atoms or 2 to 6 carbon atoms; Yaa is hydroxy; Alkoxy having 5 atoms, amino, alkylamino having 1 to 5 carbon atoms, (1-
benzylpiperidin-4-yl)amino or (pyridin-2-yl)methylamino, R is alkyl of 1 to 5 carbon atoms, and one of Aaa8 and B is 1 to 7 in the natural configuration A peptide residue consisting of 1 to 7 natural amino acids, the other being a bond or a peptide residue consisting of 1 to 7 natural amino acids in a natural configuration] or its isostere form.

In the subgroup, the compounds are not in isosteric form. In yet another subgroup, Yaa is other than (pyridin-2-yl)methylamino.

Yet another group of compounds of this invention has the formula % formula %) (Iaaaa) [wherein R8-R4, X, Y and R are as defined above, Aaaaa, bond, -Val-1 -His-Pro
-Phe-His-1-Phe-Phe- or -Ph
e-His-, Baaaa, bond, -Ala-1-Leu-1-V
al-1-11e-1-11e-Phe-1-Yal-
Phe-1-11e-His- or -Leu-P
he-, but at least one of A and B is a bond] or its isostere form.

In one subgroup, the compound is not in isosteric form.In another subgroup, Aaaaa is a bond, -
Phe -Phe- or -Phe-His.

In yet another subgroup, B is -VBr-
Phe-1-11e-His- or -Leu-Phe
− is.

The compounds of this invention may be in free form, for example amphoteric form, or in salt form, for example acid addition salts, or anionic salts.

The free form of the compound can be converted into the salt form and vice versa by known methods. Examples of salt forms include, for example, trifluoroacetate, hydrochloride, sodium, potassium and ammonium salts.

The compounds of the invention are obtained by a process consisting of linking two corresponding peptide residues or their precursors, optionally in isosteric form, and, if necessary, suitably transforming the product compounds in precursor form. .

This method is carried out in a similar manner to known methods.

Precursors of peptide residues include, for example, the peptide amino and/or carboxy terminal groups which are desired to be eliminated or substituted in the compound of the invention to be obtained;
2 f= is a compound, for example in protected form, with another functional group such as hydroxy which is desired to be converted to another functional group such as oxo. Peptide residues can be single amino acid residues that vary depending on the length of the resulting peptide, for example. The foregoing applies mutatis mutandis to the isoster form.

The coupling step is carried out by general methods known in peptide synthesis. For example, it is carried out in an inert solvent such as dimethylformamide. Preferably it is carried out at a temperature of about 0° to about 25°. The presence of a base, such as N-methylmorpholine, is preferred.

The optional conversion steps are also carried out analogously to known methods. The oxidation of hydroxy to keto groups is carried out in an inert solvent such as methylene chloride. Examples of the oxidizing agent include chromium cypyridinium trioxide complex. The reaction temperature is about 0° to about 50°C, preferably room temperature.

In particular, the compound of formula (Ia) is a compound of formula (IIa) (IIa) [wherein R, R, and R2 have the meanings given above, X' is a peptide amino terminal protecting group, and a' A is , a bond or a peptide residue] or its appropriate isostere form and the corresponding compound of the formula (IIIa) a'2 H-B-Y (Illa) [wherein Y' is the peptide carboxy terminus a protecting group and a' B is a peptide residue] or its appropriate isostere form, or -Z (Ilb) [ to X'- of formula (IIb) where X′ has the above-mentioned meaning, Aa″ is a peptide residue, and Z is a leaving group] or its appropriate isosteric form and formula ( IIlb) Represented by the formula (Illb) (Illb) [wherein R, Rt, Rt and Y' are as defined above, A is an anion, and Ba'' is a bond or a peptide residue] the corresponding compound or its appropriate isostere form, if necessary suitably converting the hydroxy moiety of the resulting compound to the corresponding oxo moiety and/or removing any protecting groups and/or removing any protecting groups. Obtained by a method consisting of replacing a protecting group with another group.

Peptide amino-terminal or carboxy-terminal blocking groups are, for example, groups selected from the aforementioned peptide amino-terminal or carboxy-terminal blocking groups, within appropriate ranges.

X' is preferably alkoxycarbonyl having a total of 2 to 6 carbon atoms, especially BOC. Y' is preferably alkoxy having 1 to 5 carbon atoms, especially methoxy. Z is preferably -N3. A is preferably an anion of a strong mineral acid such as trifluoroacetic acid.

Compounds of this invention can be isolated and purified from reaction mixtures in analogy to known methods. Racemic and/or diastereomeric mixtures may be separated by known methods.

The compounds used as starting materials can also be obtained by methods analogous to known methods.

If the fluorinated and/or chlorinated methylene group is part of the statin-based amino acid unit, the basic starting materials for obtaining the compounds of this invention are fluorine and/or
or the corresponding statin substituted by chlorine.

A compound of formula (I[a) may be, for example, a compound of formula (I[[)(III
) [wherein X', Aa' and R have the above meanings]
The corresponding compound represented by formula (■) (IV) [wherein R, and R, are as defined above, and Alk is alkyl having 1 to 4 carbon atoms, preferably ethyl] It can be obtained by reacting with the corresponding compound, and hydrolyzing the alkoxy group from the resulting ester.

Unless otherwise stated regarding the preparation of a particular starting material, the preparation is carried out by conventional methods or methods analogous to those described herein.

In the following examples, all temperatures are in degrees Celsius and uncorrected.

[Example] Example I N-BOC-(4S,3R)-2,2-difluorostatin-Val-PheOCHs (bond) N-BOC-(
4S,3R)-2,2-difluorostatin 727a+
800 mg of gSH-Val-PheOMe hydrochloride and 630 mg of N-hydroxybenzotriazole are dissolved in dimethylformamide 5a+I and 0.41 of N-methylmorpholine is added. A solution of 480a+g of dicyclohexylcarbodiimide in dimethylformamide is added at 0°.

The reaction mixture was taken up in ethyl acetate at room temperature for 24 hours,
Wash with water, dry with potassium carbonate, and concentrate to dryness. The residue is chromatographed on silica gel using ether/hexane as eluent.

The title compound is obtained (MP 105-108°).

The starting material is obtained as follows: a) 1.45 g of zinc dust are suspended in 30 ml of tetrahydrofuran and heated to reflux temperature. Immediately 4.4 g of ethyl bromodifluoroacetate are added and as soon as a vigorous reaction begins, 2 g of N-BOC-L-leucinal dissolved in 5o+1 tetrahydrofuran are added dropwise. After 30 minutes the reaction mixture was allowed to cool, then taken up in ethyl acetate and diluted with 2
Wash with N-tartaric acid.

The organic phase is dried over magnesium sulphate, concentrated to dryness and chromatographed on silica gel using ether/hexane (2:8) as eluent. N-BOC-(4S
, 3R)-2,2-difluorostatin ethyl ester is obtained ([α]"=-12,2", c=0.29,
in ethanol).

b) N-BOC~(4S,3R)-2,2-difluorostatin ethyl ester tg is dissolved in methanol/water and reacted with 0.25 g of concentrated sodium hydroxide solution. 2
After a period of time, the mixture is acidified with 2N tartaric acid and extracted with ethyl acetate. The organic phase is dried over magnesium sulphate and concentrated to dryness. (crude) N-BQC-(4S,3R)-2,2
- Difluorostatin is obtained.

Example 2 N-BOC-(45)-2,2-difluorostatin-Val PheOCHs (precursor conversion by oxidation) 30 mg of the title compound of Example 1 are added to a solution of chromium cypyridinium trioxide complex 90B and methylene chloride 20 ml. . After 30 minutes at room temperature, the reaction mixture is filtered over silica gel and the filtrate is concentrated to dryness.

The residue is chromatographed on silica gel using ether/hexane as eluent. The title compound is obtained.

Example 3 (4S,3R)-2,2-difluorostatin 7-Val
P heo CHs ) Refluoroacetate (precursor conversion by removing the protecting group) 1 g of the title compound of Example 1 is dissolved in 5 ml of methylene chloride and reacted with 5 ml of trifluoroacetic acid at 0°. After 30 minutes, the mixture is concentrated to dryness under reduced pressure. Any remaining traces of trifluoroacetic acid are removed by repeated azeotropic condensation with benzene.

The (crude) title compound is obtained.

Example 4 N-BOC-Phe-Summer-1is-(4S,3R)-
2,2-cyfluorostatin-Val-PheOCHs
(Binding) 500 mg of the title compound of Example 3 and N-BOC-P
320 g of he-His-Na in dimethylformamide 3
ml, reacted with 0.1-1 of N-methylmorpholine and left at 0-5°C for 24 hours. The reaction mixture is taken up in ethyl acetate, washed with water, dried over potassium carbonate and concentrated to dryness. The residue is recrystallized from methanol/methylene chloride/ether. The title compound is obtained (
MP133-136°). [(!]”=-41,1@(
c = 1.0 in methanol).

■) Starting from the compound of Example 4, as in Example 2.

2) Starting from the compound of Example 7, as in Example 2.

3) Starting from the compound of Example I8, as in Example 4,
By reaction with Iva-Val-OH (MP 196-198°). This compound is prepared by reacting isovaleric acid with L-valine ethyl ester hydrochloride in dimethylformamide in the presence of 4-methylmorpholine and isobutyl chloroformate.

4) Starting from the compound of Example 19, as in Example 3.

5) Starting from the compound of Example 19, as in Example 2.

6) Starting from the compound of Example 1a), as in Example 1,
By reaction with alanylisoamylamide acetate (MP 102-104°) in chloroform. This compound was synthesized from N-(benzyloxycarbonyl)-L-alanylisoamylamide (MP1) in acetic acid and methanol.
07-108°) with hydrogen over 10% Pd-C.

The compounds of this invention have pharmacological activity.

In particular, they exhibit typical enzyme inhibitory effects.

The inhibitory effect on a particular enzyme will of course vary depending on the overall peptide structure. That is, the above-mentioned compounds that are particularly suitable as renin activity inhibitors are tested using the test method of Murakami et al.
[Analytical] (Iochemistry)
t, Biochem, ) Jl l O (1981).
232-239 (with the modification that the concentration of the synthetic substrate was lowered from 20 μM to 7 μM)] and the method of Kobol et al.
Actor (B iochem, B 1opbys, A
cta) 4523 (197B) 485-493) shows 50% inhibition of mouse submandibular gland renin activity against synthetic octapeptide substrates at concentrations of 10'M-10''M.

Bolsen and Jorgensen's antibody trapping method [Journal of Clinical Endocrinology and Metabolism (J.

Cl1n, Endocrin, Metab, )J
39 (1974) 816-825), these compounds suppress human plasma renin activity at concentrations ranging from 10'M to 10''M.

Therefore: - The compounds of the invention are indicated for the prevention and treatment of conditions characterized by diseases associated with enzyme dysfunction and in which inhibition of enzyme activity is required.

For example, as renin inhibitors, these compounds are suitable for use in the prevention and treatment of hypertension and congestive heart failure.

As elastase inhibitors these compounds are suitable for use in the prevention and treatment of general inflammation, emphysema, arthritis and deterioration of elastic tissues, for example due to infections.

Compounds of Examples 6 and 7 inhibit veptin with values of 6 x IO''M and 5 x 1 O10M, respectively.

Among the compounds of the invention in which the fluorinated and/or chlorinated methylene group is part of an amino acid unit of a statin or statone or isostere form of a statin or statone, compounds based on statones are preferred. Further, compounds in which the methylene group is fluorinated, particularly difluorinated, are preferred.

Examples 4 and 5, especially the title compound of Example 5, are suitable for the prevention and treatment of hypertension and congestive heart failure.

Directions - The daily dose is from about IQ to about 500B, preferably administered orally in divided doses or in sustained release form of 0.25xy to about 2501 g of compound.

These compounds may be administered in the same manner as known standard drugs, such as captopril, used for the above-mentioned indications, such as hypertension.

The suitable daily dose of a particular compound will vary depending on a variety of factors, such as the relative potency of action. Accordingly, these compounds may be administered at doses similar to known standard and conventional doses.

The compounds of this invention may be administered in free form or in pharmaceutically acceptable salt form. Such salt forms exhibit the same order of magnitude as the free forms and are easily prepared by conventional methods. This invention also provides pharmaceutical compositions comprising the free form or pharmaceutically acceptable salt form of a compound of this invention in combination with a pharmaceutical carrier. Such compositions may be formulated for enteral, preferably oral administration, eg as a tablet, or for parenteral administration, eg as an injectable solution or suspension.

The compounds of Examples 1-5 and 8-17 are particularly suitable as renin inhibitors. The compounds of Examples 6.7 and 18-20 are particularly suitable as pepsin inhibitors.

Claims (8)

[Claims] (1) Free or salt forms of peptides in which the methylene groups of the backbone chain are di-substituted and one or both substituents are fluorine and/or chlorine, optionally in isosteric form. (2) Formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, A is hydrogen or a substituent, B is hydroxy or another substituent, but,
at least one of A and B is a peptide residue, R_1 is fluorine or chlorine, R_2 is fluorine, chlorine or another substituent, and R_
3 is hydroxy, alkoxy or acyloxy and R_4 is hydrogen or R_3 and R_4
are together oxo, and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl or aryl, aralkyl, heteroaryl or heteroaryl optionally substituted on the aryl or heteroaryl moiety. is an alkyl moiety] or its isosteric free form or salt form. (3) Formula (Ia) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(Ia) [In the formula, R and R_1 to R_4 have the meanings described in claim 2, and X is hydrogen or a peptide amino-terminal blocking group, Y is a hydroxy or peptide carboxy-terminal blocking group, one of A^a and B^a is a peptide residue, and the other is a bond or a peptide residue ] The compound according to claim 2 or its isosteric free form or salt form. (4) Claims consisting of the step of combining two corresponding peptide residues or their precursors in isosteric form, if desired, and, if necessary, appropriately substituting the resulting compound if it is a precursor. A method for producing the compound according to item 1. (5) Formula (IIa) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (IIa) [In the formula, R, R_1 and R_2 have the meanings described in claim 2, and X' is a peptide Amino-terminal protecting group, A^a'
is a bond or a peptide residue] or its appropriate isostere form and the formula (
IIIa) H-B^a'-Y' (IIIa) [wherein, Y' is a peptide carboxy terminal protecting group, and B^a
' is a peptide residue] or a corresponding compound of the formula (IIb) X'-A^a^''-Z(IIb) [wherein, X' has the above meaning, A^a^" is a peptide residue, and Z is a leaving group] or its appropriate isosteric form and formula (IIIb) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (IIIb) [In the formula, R, R_1 and R_2 have the meanings described in claim 2, Y' has the above meanings, B^a ^″ is a bond or a peptide residue, and A^
- is an anion] or its appropriate isostere form, and if necessary, the hydroxyl moiety in the resulting compound is appropriately converted to the corresponding oxo moiety and/or there is a protective group. 4. A process for preparing a compound according to claim 3 or a suitable isostere thereof, which comprises removing the protective group, if any, and/or replacing the protective group, if any, with another group. (6) A pharmaceutical composition comprising a free form or pharmaceutically acceptable salt form of the compound according to claim 1 and a pharmaceutical carrier or diluent. (7) A method for inhibiting enzyme activity, which comprises administering to an animal in need of treatment a therapeutically effective amount of a compound according to claim 1. (8) A method for preventing or treating hypertension or congestive heart failure, which comprises administering to an animal in need of treatment a therapeutically effective amount of the renin-suppressing compound according to claim 1.