JPH0526775B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to substituted peptide compounds, and more particularly to novel substituted peptide compounds and salts thereof having pharmacological activity and the use of these compounds as antihypertensives or analgesics. The present invention can provide substituted peptide compounds and salts thereof represented by the following formula; [In the formula, X is or

[Formula] R ₇ is hydrogen, lower alkyl, halogen, keto,
Hydroxy,

【formula】 azide, amino,

【formula】

【formula】

【formula】

【formula】

【formula】

【formula】

1- or 2-naphthyl, -(CH ₂ ) _n -(cycloalkyl) represented by [Formula],

[Formula] -O- (lower a Lukiru),

【formula】

1- or 2-naphthyloxy, -S- (lower alkyl) represented by [Formula],

[Formula] Also teeth

1- or 2-naphthylthio represented by the formula; R ₈ is keto, halogen,

【formula】

[Formula] -O- (lower a Lukiru),

1- or 2-naphthyloxy represented by [Formula], -
S- (lower alkyl),

[expression] or

1- or 2-naphthylthio represented by the formula; R ₉ is keto or

[Formula] R ₁₀ is halogen or -Y-R ₁₆ ; R ₁₁ , R' ₁₁ , R ₁₂ and R' ₁₂ are each individually hydrogen or lower alkyl, or R' ₁₁ , R ₁₂ and R' ₁₂ are each hydrogen ,

[Formula] R ₁₃ is hydrogen, lower alkyl having 1 to 4 carbon atoms, lower alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, chloro, bromo, fluoro, trifluoromethyl, hydroxy, phenyl, phenoxy, phenylthio or phenylmethyl; _R14 is hydrogen, lower alkyl having 1 to 4 carbon atoms, lower alkoxy having 1 to 4 carbon atoms, lower alkylthio having 1 to 4 carbon atoms, chloro, bromo, fluoro, trifluoromethyl or hydroxy; m is 0, 1, 2, 3 or 4; p is 1, 2 or 3 (provided that if either R ₁₃ and R ₁₄ is hydrogen, methyl, methoxy, chloro or fluoro, p is an integer greater than 1); R ₁₅ is hydrogen or lower alkyl having 1 to 4 carbon atoms; Y is oxygen or sulfur; R ₁₆ is lower alkyl having 1 to 4 carbon atoms or

[Formula] or an unsubstituted 5- to 6-membered cyclic group formed by combining two R _16s , or a lower alkyl substituent having 1 to 4 carbon atoms, or a di( Substituted 5- to 6-membered cyclic group having a lower (alkyl having 1 to 4 carbon atoms) substituent; R ₄ is hydrogen, lower alkyl

[Formula] −(CH ₂ ) _n −(cycloalkyl),

【formula】

【formula】

【formula】

[Formula] Also teeth

[Formula] R ₅ is hydrogen, lower alkyl,

【formula】

[Formula] −(CH ₂ ) _r −OH,

【formula】

【formula】

[Formula] -(CH ₂ ) _r -NH ₂ , - (CH ₂ ) _r -SH, -(CH ₂ ) _r -S- (lower alkyl),

[expression] or

[Formula] r is an integer from 1 to 4; R ₁₉ is lower alkyl, benzyl, or phenethyl; R ₂₀ is hydrogen, lower alkyl, benzyl, or phenethyl; R is hydrogen, lower alkyl, cycloalkyl,

[Formula] −(CH ₂ ) ₂ −NH ₂ , − (CH ₂ ) ₃ −NH ₂ , −(CH ₂ ) ₄ −NH ₂ , −(CH ₂ ) ₂ −
OH, −(CH ₂ ) ₃ −OH, −(CH ₂ ) ₄ −OH, −(CH ₂ ) ₂
−SH, −(CH ₂ ) ₃ −SH or −(CH ₂ ) ₄ −SH; R ₁ is hydrogen, lower alkyl, halo substitution (lower)
alkyl,

【formula】

【formula】

【formula】

【formula】

[Formula] −(CH ₂ ) _r −NH ₂ , − (CH ₂ ) _r −SH, −(CH ₂ ) _r −OH, −(CH ₂ ) _r −S−
(lower alkyl),

[Formula] Ma Taha

[Formula] (However, when R is a group other than hydrogen, R ₁ is hydrogen); R ₂ is

【formula】

[expression] or

[Formula] R ₃ is hydrogen, lower alkyl,

【formula】

【formula】

【formula】

[Formula] Halo-substituted (lower) alkyl, -(CH ₂ ) _n -(cycloalkyl),

【formula】

[Formula] −(CH ₂ ) _r −OH, −(CH ₂ ) _r −NH ₂ , −(CH ₂ ) _r −SH, −(CH ₂ ) _r −S
-(lower alkyl),

[Formula] Ma Taha

[Formula] (m, R ₁₄ , p and r have the same meanings as above); R ₆ is hydrogen, lower alkyl, benzyl, benzhydryl,

【formula】

[Formula] −CH (CH ₂ −OH) ₂ or

[Formula] R ₁₇ is hydrogen, lower alkyl, cycloalkyl or phenyl, R ₁₈ is hydrogen, lower alkyl, lower alkoxy or phenyl, or R ₁₇ and R ₁₈
together, −(CH ₂ ) ₂ −, −(CH ₂ ) ₃ −, −CH=CH−
or

[Formula] is formed; R ₂₁ and R ₂₂ each independently represent hydrogen or lower alkyl; R ₂₃ represents lower alkyl]. The invention relates in its broadest aspects to the substituted peptide compounds, pharmaceutical compositions and methods of using the compounds as pharmaceutical ingredients. In formula [], the terms used to define various symbols have the following meanings. Lower alkyl includes straight chain or branched groups not exceeding 7 carbon atoms;
In particular, lower alkyl having not more than 4 carbon atoms is preferred, and methyl and ethyl are most preferred. Similarly, lower alkoxy and lower alkylthio include lower alkyl as defined above attached to oxygen or sulfur. Cycloalkyl includes saturated cyclic groups having 3 to 7 carbon atoms, of which cyclopentyl and cyclohexyl are most preferred. Halogen includes chloro, bromo and fluoro. Halo-substituted (lower) alkyl refers to a lower alkyl group as defined above in which one or more hydrogens are replaced with chloro, bromo or fluoro, such as trifluoromethyl (preferred), pentafluoroethyl, 2,2, Includes 2-trichloroethyl, chloromethyl, bromomethyl and the like.

【formula】

[expression] and

[Formula] represents that each alkylene bridge can be bonded to all ring-forming carbon atoms that can be bonded. Next, the method for producing the compound of the present invention [] will be described in detail. The compound of the present invention [] in which R is hydrogen can be produced by the following method. formula: [In the formula, R ₄₀ and R ₆ in the X group represent a protecting group (for example, R ₄₀ is a protecting group such as benzyloxycarbonyl and R ₆ is benzyl). R ₁ and [In the formula, R ₂ and R ₃ have the same meanings as above] The oxazolone represented by the following is reacted, and R ₄₀ and
By removing the R ₆ protecting group, for example, by hydrogenation, a compound [] in which R and R ₆ are hydrogen can be obtained. The carboxymethyl peptide ester intermediate [] has the formula: [In the formula, X and R ₁ have the same meanings as above] A peptide ester represented by the following formula is reacted with tert-butyl bromoacetate, and then an R ₄₀ protecting group is introduced (for example, by treatment with benzyl chloroformate). be able to. The compound of the present invention [] has the formula: [In the formula, halo represents halogen (preferably chloro or bromo). R ₂ and R ₃ have the same meanings as above] A ketone represented by the formula: [In the formula, X, R and R ₁ have the same meanings as above] React the peptide ester represented by the following in the presence of a base such as sodium hydrogen carbonate, and remove the R ₆ ester group as necessary. It can also be obtained by The above ketone intermediate [] has the formula: [In the formula, R ₄₀ represents a protecting group such as benzyloxycarbonyl, and halo represents a halogen. R ₃ has the same meaning as above] The ketone represented by the formula is treated with hydrogen bromide and acetic acid, and then combined with the formula: [In the formula, R ₂ and halo have the same meanings as above] It can be obtained by reacting an acid halide represented by the following in the presence of a base such as sodium hydrogen carbonate. Moreover, the compound of the present invention [] has the formula: [In the formula, R, R ₂ and R ₃ have the same meanings as above] An aminoketone represented by the formula, especially its hydrochloride, and [In the formula, R ₆ in the X group represents a protecting group that can be easily removed, and halo represents a halogen (preferably chloro or bromo). R ₁ has the same meaning as above] It can also be obtained by reacting a haloacetylamino acid (or imino acid) ester shown below. Furthermore, the compound of the present invention [] has the formula: [In the formula, R, R ₁ , R ₂ and R ₃ have the same meanings as above] and an aminoketone carboxylic acid represented by the formula: HX [] [In the formula, R ₆ in X can be easily eliminated. It can also be obtained by coupling an amino acid (or imino acid) ester represented by the following formula in the presence of a coupling agent such as dicyclohexylcarbodiimide. Compounds where R ₆ is hydrogen by removing the R ₆ protecting group []
can be obtained. The above aminoketone intermediate [] can be produced as follows. formula: [In the formula, R ₄₀ represents a protecting group such as benzyloxycarbonyl. R has the same meaning as above] A carboxyalkylamine such as the above is converted to its acid chloride, and then this is reacted with oxazolone [ ] to form the formula: [In the formula, R, R ₂ , R ₃ and R ₄₀ have the same meanings as above] A compound represented by the formula is obtained. The aminoketone intermediate [ ] can be obtained by removing the R ₄₀ protecting group of this compound by a reduction method such as hydrogenation. In addition, an aminoketone intermediate [] in which R is a group other than hydrogen can be prepared by reacting a ketone [] with a substituted amine represented by the formula: R-NH ₂ [] [wherein R has the same meaning as above].
Obtainable. Aminoketone carboxylic acid intermediate [] is an aminoketone [] and the formula: [Wherein, prot represents an easily removable ester protecting group such as t-butyl. halo and
R ₁ has the same meaning as above] By reacting a haloacetic ester represented by the formula: [In the formula, R ₁ , R ₂ , R ₃ and prot have the same meanings as above] It can be obtained by preparing an ester represented by the following formula and removing the ester protecting group. In the various reactions described above, R, R ₁ ,
Any or all of R ₃ and R ₅

【formula】

[Formula] −(CH ₂ ) _r −NH ₂ ,

[Formula] −(CH ₂ ) _r −SH, − (CH ₂ ) _r −OH or , the hydroxy, amino, imidazolyl, mercapto or guanidinyl functions in these groups should be protected during the reaction. Suitable protecting groups include benzyloxycarbonyl, t-butoxycarbonyl, benzyl, benzhydryl, trityl, etc., and nitro (for guanidinyl)
includes. Protecting groups can be used, for example, by hydrogenation,
Desorption is achieved by treatment with acid or other known methods of achieving completion of the reaction. The ester products of the present invention, wherein R ₆ is lower alkyl, benzyl or benzhydryl, are:
Treatment with sodium hydroxide in aqueous dioxane,
Alternatively, chemical treatments such as treatment with trimethylsilyl bromide can yield products in which R ₆ is hydrogen. A benzyl or benzhydryl ester group can also be reduced by treatment with hydrogen, for example in the presence of a palladium/carbon catalyst, to give a product [ ] in which R ₆ is hydrogen. _R6 is

The ester [] of the present invention, which is [Formula], is a peptide [] or [] in the various reactions described above, or a compound that already has the ester group in the structure of the haloacetylamino acid (or imino acid) ester []. can be obtained by using Such ester compounds can be used to protect the N-atom of a peptide [ ] or [ ] in which R ₆ is hydrogen, or a haloacetylamino acid (or imino acid) ester [ ].

[expression] or

Treat an acid halide like [formula] to form this protected compound and the formula: [In the formula, L represents a group capable of being eliminated, such as chloro, bromo, tolylsulfonyl, etc. R ₁₇ and R ₁₈ have the same meanings as above] A compound represented by the following is reacted in the presence of a base,
The N is then removed by a method such as treatment with an acid or hydrogenation.
- can be obtained by removing the protecting group. Also R ₆

The ester of the present invention [] having the formula can also be obtained by treating the product [] in which R ₆ is hydrogen with a molar excess of the compound []. _R6 is

The ester [] of the present invention, which is [Formula], is a product [] in which R ₆ is hydrogen,
formula: [In the formula, R ₂₁ , R ₂₂ and R ₂₃ have the same meanings as above] It can be obtained by treating with a molar excess of the compound represented by the following formula. R ₆ is −CH(CH ₂ −OH) ₂ or

The ester product of the present invention [] having the formula [] is a product [] in which R ₆ is hydrogen;
formula: or expression: [In the formula, Prot has the same meaning as defined above] It can be obtained by coupling a molar excess of the compound represented by the formula in the presence of a coupling agent such as dicyclohexylcarbodiimide to remove the hydroxy protecting group. The ester products of the present invention [ ] in which R ₆ is lower alkyl can be obtained by subjecting the carboxylic acid compound, i.e., the compound [] in which R ₆ is hydrogen, to a conventional esterification treatment such as an alkyl halide of the formula R ₆ -halo or It can be obtained from the carboxylic acid compound by treatment with an alcohol represented by the formula: R ₆ -OH. The peptide ester intermediates [] and [] can be produced as follows. R ₆
is, for example, benzyl, the hydrochloride of an amino acid (or imino acid) ester [XII] and the formula: [In the formula, Prot is

Represents a protecting group such as [Formula]. R and R ₁ have the same meanings as above]
The N-protected amino acid represented by is coupled. This reaction is preferably carried out in the presence of a coupling agent such as dicyclohexylcarbodiimide. The peptide ester intermediates [] and [] can be obtained by removing the N-protecting group of the product, for example by treatment with trifluoroacetic acid. Haloacetylamino acid (or imino acid) ester intermediate [] is an amino acid (or imino acid) ester [] with the formula: [In the formula, halo has the same meaning as above] It can be obtained by reacting a haloacetyl halide represented by the following. The compound of the present invention [] in which R ₇ is amino can be obtained by reducing the corresponding compound [] in which R ₇ is azide. In the structure of formula [], preferred compounds [] regarding the peptide moiety are as follows. R is hydrogen, straight chain or branched (lower) alkyl having 1 to 4 carbon atoms, or phenyl; R ₁ is hydrogen, straight chain or branched (lower) alkyl having 1 to 4 carbon atoms, CF ₃ , -( CH ₂ ) _r −NH ₂ (r
is an integer from 1 to 4),

【formula】

【formula】

【formula】

【formula】

[Formula] -CH ₂ -SH, -(CH ₂ ) ₂ -S -CH ₃ ,

[Formula] −CH ₂ − OH,

[expression] or

[Formula] (However, when R is a group other than hydrogen, R ₁ is hydrogen); R ₄ is hydrogen, cyclohexyl or phenyl; R ₅ is hydrogen, a straight chain or branched chain having 1 to 4 carbon atoms ( (lower) alkyl, −CH ₂ −OH,

【formula】

【formula】

【formula】

【formula】

[Formula] −(CH ₂ ) ₄ −NH ₂ , −CH ₂ − SH, −(CH ₂ ) ₂ −S−CH ₃ ,

【formula】

【formula】 or

[Formula] R ₆ is hydrogen, a straight chain or branched (lower) alkyl having 1 to 4 carbon atoms, an alkali metal salt,

【formula】

[Formula] −CH (CH ₂ −OH) ₂ or

[Formula] R ₂₃ is a straight chain or branched (lower) alkyl having 1 to 4 carbon atoms, especially -C(CH ₃ ) ₃ ; R ₁₇ is hydrogen, a straight chain or branched (lower) alkyl having 1 to 4 carbon atoms, (lower) alkyl or cyclohexyl; R ₁₈ is straight-chain or branched (lower) alkyl having 1 to 4 carbon atoms or phenyl; R is straight-chain or branched (lower) alkyl having 1 to 4 carbon atoms, especially -C (CH ₃ ) ₃ ; R ₇ is hydrogen; R ₇ is hydroxy; R ₇ is linear or branched (lower) alkyl having 1 to 4 carbon atoms or cyclohexyl; R ₇ is amino; R ₇ is -O-( (lower alkyl is a straight chain or branched group having 1 to 4 carbon atoms); R ₇ is

[Formula] (m is 0, 1 or 2, R ₁₃ is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro or hydroxy); R ₇ is

[Formula] 1-naphthyloxy or 2-naphthyloxy (m is 0,
1 or 2, R ₁₃ is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro or hydroxy); R ₇ is -S- (lower alkyl) (lower alkyl is a straight chain or branched chain having 1 to 4 carbon atoms) group); R ₇ is

[Formula] 1-naphthylthio or 2-naphthylthio (m is 0, 1 or 2, R ₁₃ is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro or hydroxy); R ₈ is -O- (lower alkyl) ( Lower alkyl is a straight chain or branched group having 1 to 4 carbon atoms); R ₈ is

[Formula] (m is 0, 1 or 2, R ₁₃ is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro or hydroxy); R ₈ is -S- (lower alkyl) (lower alkyl has 1 to 1 carbon atoms) 4 straight chain or branched group); R ₈ is

[Formula] (m is 0, 1 or 2, R ₁₃ is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro or hydroxy); R ₉ is phenyl, 2-hydroxyphenyl or 4-hydroxyphenyl; R ₁₀ are both fluoro or chloro; R ₁₀ are both -Y-R ₁₆ (Y is oxygen or sulfur, R ₁₆ is a straight chain or branched (lower) alkyl having 1 to 4 carbon atoms, or two R _{R 11 ,} R ' ₁₁ , R ₁₂ and R' ₁₂ are all hydrogen, or R ₁₁ is phenyl, 2-hydroxyphenyl or 4-hydroxyphenyl, R' ₁₁ , R ₁₂ and
A compound [] in which R′ ₁₂ is hydrogen; In the structure of formula [], the most preferred compounds [] regarding the peptide moiety are listed below. X is

【formula】

[expression] or

[Formula] R is hydrogen or methyl; R ₁ is hydrogen, methyl or -(CH ₂ ) ₄ NH ₂ , especially methyl (provided that when R is a group other than hydrogen, R ₁
is hydrogen); R ₆ is hydrogen, a linear or branched (lower) alkyl having 1 to 4 carbon atoms, or an alkali metal salt; R ₄ is cyclohexyl or phenyl; R ₇ is hydrogen, cyclohexyl, or an alkali metal salt having 1 to 4 carbon atoms; lower alkoxy,

【formula】

[expression] or

Compounds of the formula: (m is 0, 1 or 2, R ₁₃ is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro or hydroxy), especially R ₇ is hydrogen; t is 2 or 3, especially 2; []. Preferred compounds [] regarding the keto moiety in the structure of the formula [] are listed below. R ₂ is

[Formula] (m is 0, 1 or 2, R ₁₄ is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro or hydroxy), especially phenyl; R ₃ is linear or branched with 1 to 4 carbon atoms (lower) alkyl, -( _CH2 ) _r - _NH2 ,

[expression] or

[Formula] (m is 0, 1 or 2, R ₁₄ is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro or hydroxy, r is an integer from 1 to 4), especially benzyl; The compounds of the present invention [] in which R ₆ is hydrogen form salts with various inorganic or organic acids. Although non-toxic, pharmacologically acceptable salts are preferred, other salts are also useful in isolating or purifying the product. Such pharmacologically acceptable salts are derived from salts of metals such as sodium, potassium or lithium, salts of alkaline earth metals such as calcium or magnesium, amino acids such as arginine, lysine, etc. Includes salts. Such salts can be obtained by reacting an acid form compound of the invention with a feed base equivalent of the desired ion in a salt-precipitating medium or by reacting in an aqueous medium and lyophilizing. Similarly, the compounds of the present invention, especially the compounds in which R ₆ is an ester group, form salts with various inorganic or organic acids. Such salts are preferably non-toxic and pharmacologically acceptable salts as above, but
Other salts are also useful in isolating or purifying the product. Such pharmacologically acceptable salts include salts with hydrochloric acid, methanesulfonic acid, sulfuric acid, maleic acid, and the like. This salt can be obtained by reacting the product with an equivalent amount of acid in a salt-precipitating medium. As mentioned above, in the molecule of the compound [] of the present invention,

The peptide moiety represented by the formula is in the L-configuration. Furthermore, when R ₃ is a group other than hydrogen, an asymmetric center exists in the keto portion of the molecule. Thus, the compound of the present invention [] can exist as a diastereomer or a mixture thereof. Racemates, enantiomers or diastereomers can be used as starting materials in the production process. When diastereomeric compounds are prepared, the products can be separated by conventional chromatography or fractional crystallization methods. The compound of the present invention [] in which the imino acid ring is monosubstituted exhibits cis-trans isomerism. The configuration of the final product is R ₇ , R ₈ and
Depends on the configuration of the R ₉ substituents. The compound of the present invention [ ] and its pharmacologically acceptable salts are antihypertensive agents. These compounds inhibit the conversion of the decapeptide angiotensin to angiotensin and are therefore useful in reducing or alleviating angiotensin-related hypertension. Angiotensinogen produces angiotensin through the action of the enzyme renin on blood pseudoglobulin. Angiotensin is angiotensin converting enzyme (ACE)
Converts to angiotensin. Angiotensin is an antihypertensive active substance that has been implicated as a causative agent of various types of hypertension in various mammals (eg, humans). The compounds of the present invention mediate the angiotensinogen→(renin)→angiotensin→angiotensin system by suppressing angiotensin-converting enzyme and reducing or blocking the production of angiotensin, an active substance that increases blood pressure. By administering a composition containing one type of compound (or mixture) of the present invention in this manner, mammals (e.g., humans) with hypertension can be treated.
can reduce angiotensin-dependent hypertension. Approximately 0.1-100 to lower blood pressure
Based on the dosage of mg (preferably about 1 to 50 mg)/Kg (body weight)/day, it is appropriate to administer this once a day, preferably in 2 to 4 divided doses. The active substance is preferably administered orally, but also subcutaneously,
Administration may also be parenteral, such as intramuscularly, intravenously or intraperitoneally. The compound of the present invention can also be formulated in combination with a diuretic for the treatment of hypertension. A medicament comprising a combination of a compound of the present invention and a diuretic is administered to a mammal in need of the drug at a dose of about 30 to 600 mg, preferably about 30 to 330 mg, of the compound of the present invention and about a diuretic per day.
It can be administered in an effective amount consisting of 15-300 mg, preferably about 15-200 mg. Examples of diuretics contemplated for use in combination with the compounds of the invention include thiazide diuretics such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methyclothiazide, trichloromethiazide, polythiazide or benzene thiazide, and ethacrynic acid,
Chiclinafuene, Chlorthalidone, Furosemide,
Mention may be made of musolimine, bumetanide, triamterene, amiloride, spironolactone and salts of these compounds. For use in lowering blood pressure, the compounds of the invention can be formulated in compositions such as tablets, capsules or elixirs for oral administration, or as sterile solutions or suspensions for parenteral administration. Approximately 10 to 500 mg of a compound of the invention can be contained in a unit dosage form compatible with accepted pharmaceutical practice in a physiologically acceptable vehicle, carrier, excipient, binder,
Contains preservatives, stabilizers, flavoring agents, etc. The amount of active substance in these compositions or medicaments should be such that the required dosage as described above will be administered. Also, X of the present invention

The compound [ ] of the formula has enkephalinase inhibitory activity and is useful as an analgesic. Therefore, by administering a composition containing one or more mixtures of such compounds or their pharmacologically acceptable salts, suffering in mammals can be alleviated. About 0.1 to 100 mg of active compound (preferably about 1 to 100 mg)
The desired analgesic activity is achieved by administering the drug once per day, preferably in 2 to 4 divided doses, based on the dosage of 50 mg)/Kg (body weight)/day. Although the compositions are preferably administered orally, they may also be administered parenterally, such as subcutaneously. Next, a method for producing a preferred compound of the present invention will be specifically explained with reference to Examples. LH−20 is phar−
Sephadex Chromatography Egel, commercially available from Macia Fine Chemicals. In addition, in Examples, temperature (°C) may be simply expressed as "°". Example 1 1-[N-[3-(benzoylamino)-2-oxo-4-phenylbutyl]-L-alanyl]-L
-Production of proline monohydrochloride:- (a) Production of L-alanyl-L-proline phenylmethyl ester/p-toluenesulfonate:-N-[(1,1-dimethylethoxy)carbonyl]- 310.7 g of L-alanine, 396.2 g of L-proline phenylmethyl ester hydrochloride, 338.6 g of dicyclohexylcarbodiimide, 251.5 g of hydroxybenzotriazole hydrate, 285.7 ml of diisopropylethylamine, and tetrahydrofuran.
Combine 5000 ml at 0°C (add dicyclohexylcarbodiimide last) and stir overnight at room temperature.
The reaction mixture is filtered and concentrated. Dissolve the residue in 4000 ml of ethyl acetate, add 5% sodium hydrogen carbonate (2000 ml x 2) and 5% potassium hydrogen sulfate (2000 ml).
x 2 times) and water. The ethyl acetate layer is dried (magnesium sulfate) and concentrated. The residue was dissolved in 3000 ml of diethyl ether and left overnight at 0°C.
The mixture was filtered and the liquid was concentrated to give crude N-[(1,1
-dimethylethoxy)carbonyl]-L-alanyl-L-proline phenylmethyl ester 620
get g. 275 g of N-[(1,1-dimethylethoxy)carbonyl]-L-alanyl-L-proline phenyl methyl ester were cooled on an ice bath and treated with 500 ml of cold trifluoroacetic acid (freshly distilled) under an argon atmosphere. Treat and stir at room temperature for 1 hour.
The mixture is concentrated under reduced pressure and azeotroped twice with toluene. Crude trifluoroacetate (oil) in ether
Dissolve in 500 ml and slowly treat with stirring with a 6000 ml solution of p-toluenesulfonic acid hydrate (1 equivalent) in ether. Collect the formed precipitate. Dissolve the solid in 1000ml methanol and 4000ml ether.
Process and cool. The generated precipitate is collected and dried to obtain 300 g of L-alanyl-L-proline phenylmethyl ester p-toluenesulfonate. mp156-158℃. (b) 1-[N-[2-(1,1-dimethylethoxy)
-2-Oxoethyl]-N-[(phenylmethoxy)carbonyl]-L-alanyl]-L-proline phenylmethyl ester production: -L-alanyl-L-proline phenylmethyl ester/p-toluene Sulfonate 32.16g
(72 mmol), tert-butyl bromoacetate 14.2 g
(72 mmol), 20.1 ml (144 mmol) of triethylamine and 290 ml of tetrahydrofuran are stirred at room temperature for 72 hours. Benzyl chloroformate
12.4 ml (87.8 mmol) and triethylamine 12.5
ml (87.8 mmol) and stir the mixture overnight. The reaction product is evaporated and partitioned between water and ethyl acetate. The ethyl acetate solution was washed with dilute hydrochloric acid and then water, and the ethyl acetate solution was evaporated and chromatographed on silica gel (230-400 mesh) using an ethyl acetate/hexane (1:1) solvent system (10 psi pressure). attached, 1-[N-[2-(1,
1-dimethylethoxy)-2-oxoethyl]-N
-[(phenylmethoxy)carbonyl]-L-alanyl]-L-proline phenylmethyl ester
Obtain 19.5g. (c) 1-[N-(carboxymethyl)-N[(phenylmethoxy)carbonyl]-L-alanyl]-L
-Production of proline phenyl methyl ester:
- 1-[N-[2-(1,1-dimethylethoxy)-
2-oxoethyl]-N-[(phenylmethoxy)
18 g (34.3 mmol) of carbonyl]-L-alanyl]-L-proline phenyl methyl ester is dissolved in 50 ml of trifluoroacetic acid and left at room temperature for 1.5 hours. The mixture was evaporated and filtered through a small column of 200 g of silica gel using a chloroform/methanol/acetic acid (9.6:0.2:0.2) solvent mixture.
11.4 g of 1-[N-(carboxymethyl)-N[(phenylmethoxy)carbonyl]-L-alanyl]-L-proline phenylmethyl ester are obtained. (d) 1-[N-[3-benzoylamino)-2-oxo-4-phenylbutyl]-N-[(phenylmethoxy)carbonyl]-L-alanyl]-L-
Production of proline phenylmethyl ester: - 1-[N-(carboxymethyl)-N-[(phenylmethoxy)carbonyl]-L-alanyl]-L-
Proline phenyl methyl ester 7.0g (15.0
mmol) in 50 ml of dry tetrahydrofuran, cooled on an ice bath, and dissolved in 1.57 ml of oxalyl chloride.
(18 mmol), then 4 drops of dimethylformamide are added. (After 5 minutes, the mixture is stirred for a further 1 hour at room temperature. The mixture is evaporated, redissolved in 30 ml of tetrahydrofuran and the solution is cooled on an ice bath.
It is added dropwise over 5 minutes to a solution of 3.96 g (15.75 mmol) of (4H)-oxazolone in 24 ml of ice-cold tetrahydrofuran. 2.5 ml (17.1 mmol) of triethylamine are added and the mixture is stirred at room temperature overnight.
The mixture is filtered to remove triethylamine hydrochloride, the tetrahydrofuran solution is evaporated and redissolved in 16 ml of pyridine. 0.050 ml of 4-dimethylaminopyridine is added and the solution is stirred at room temperature for 3 hours.
Add 16 ml of glacial acetic acid and heat the mixture at 100° C. for 45 minutes. The reaction mixture was cooled and evaporated under reduced pressure.
Dissolve in ethyl acetate and extract with aqueous sodium bicarbonate and dilute hydrochloric acid. After evaporation of the ethyl acetate extract, it was chromatographed on silica gel (230-400 mesh) with an ethyl acetate/benzene (4:6) solvent system to give 1-[N-[3-benzoylamino)-2- Oxo-4-phenylbutyl]-N
4.9 g of -[(phenylmethoxy)carbonyl]-L-alanyl]-L-proline phenylmethyl ester is obtained. Elemental analysis, _C40H41N3O7・_0.42H2O Calculated values: C, 70.31%; _N , 6.15%; _H , _6.17
%, Actual value: C, 70.31%; N, 6.13%; H, 6.08
%. (e) 1-[N-[3-benzoylamino)-2-oxo-4-phenylbutyl]-L-alanyl]-
Production of L-proline monohydrochloride: - 1-[N-[3-benzoylamino)-2-oxo-4-phenylbutyl]-N-[(phenylmethoxy)carbonyl]-L-alanyl]-L- Dissolve 1.0 g of proline phenyl methyl ester in 30 ml of absolute ethanol and 2.25 ml of 1N hydrochloric acid. 0.200 g of palladium/carbon catalyst (10%) is added and the solution is stirred under an atmosphere of hydrogen overnight. Remove the catalyst and evaporate the solution. 0.700 g of crude product is combined with 0.300 g of crude product obtained from a previous small-scale reaction and passed through an LH-20 column (1 inch x 15 inches) in methanol. The fractions containing the desired product are combined, evaporated, dissolved in water and filtered. Freeze-dry the clear aqueous solution to obtain 1-[N-[3-benzoylamino]
0.800 g of -2-oxo-4-phenylbutyl]-L-alanyl]-L-proline monohydrochloride was obtained.
[α] ²⁵ _D = -59.6 (in methanol, C = 1.4), mp98
~130℃ (decomposition). TLC (silica gel, n-butanol/acetic acid/water (4:1:1)) R _f =0.44. Elemental analysis, _C25H30N3O5Cl・_{0.75H2O ,} calculated values: C, 59.88%; H, 6.33 _% ; _N , 8.38
%; Cl, 7.07%; Actual value: C, 59.82%; H, 6.30%; N, 8.42
%: Cl, 6.85%. Example 2 1-[N-[7-amino-3-(benzoylamino)-2-oxoheptyl]-L-alanyl]-
Production of L-proline dihydrochloride: - (a) N ² -benzoyl-N ⁶ - [(phenylmethoxy)carbonyl]- Production of L-lysine: - N ⁶ - [(phenylmethoxy)carbonyl] - L-
10.09 g (36 mmol) of lysine in 26 ml of ice-cold aqueous 1N sodium hydroxide solution with 5 ml of benzoyl chloride.
ml (43.2 mmol) of aqueous 4N sodium hydroxide
Add 10.8 ml simultaneously in 5 portions over 30 minutes. Remove the ice bath and continue stirring at room temperature for an additional 1.5 hours. The reaction mixture is extracted with ethyl acetate (extracts are discarded), the aqueous mother liquor is acidified with dilute hydrochloric acid and extracted with ethyl acetate. Concentrate the ethyl acetate extract,
The residue was crystallized from ethyl acetate/hexane with ^N2
12.9 g of -benzoyl-N ⁶ -[(phenylmethoxy)carbonyl]-L-lysine are obtained. mp110～
112℃ (109℃). (b) 2-phenyl-4-[4-[[(phenylmethoxy)carbonyl]amino]butyl]-5(4H)-
Production of oxazolone: ^-N2 -benzoyl- ^N6 -[(phenylmethoxy)
Carbonyl]-L-lysine 11.53g (30 mmol)
Dissolve in 55 ml of tetrahydrofuran and stir on an ice bath. A solution of 6.8 g (33 mmol) of dicyclohexylcarbodiimide in tetrahydrofuran is added dropwise to this mixture over 15 minutes. After 1 hour, remove the ice bath and continue stirring at room temperature for an additional 18 hours. Separate the dicyclohexylurea and concentrate the tetrahydrofuran solution under reduced pressure. The residue was crystallized from ethyl acetate-hexane to give 2-phenyl-4-[4-
9.4 g of [[(phenylmethoxy)carbonyl]amino]butyl]-5(4H)-oxazolone are obtained. m.
p.72-73℃ (68℃). (c) 1-[N-[3-(benzoylamino)-7-
[[(phenylmethoxy)carbonyl]amino]-
Production of 2-oxoheptyl]-N-[(phenylmethoxy)carbonyl]-L-alanyl]-L-proline phenylmethyl ester:- 1-[N-(carboxymethyl)-N-[(phenyl methoxy)carbonyl]-L-alanyl]-L-
2.82 g (6 mmol) of proline phenyl methyl ester (product of Example 1c) are dissolved in 20 ml of tetrahydrofuran and the solution is stirred on an ice bath. Add 0.63 ml (7.2 mmol) of oxalyl chloride and then 4 drops of dimethylformamide. The mixture is stirred on the ice bath for 20 minutes and then at ambient temperature for an additional hour. The solvent is removed under reduced pressure and the residue is redissolved in 10 ml of tetrahydrofuran and cooled on an ice bath. 2-Phenyl-
4-[4-[[(phenylmethoxy)carbonyl]amino]butyl]-5(4H)-oxazolone 2.2g
(6 mmol) in 14 ml cold solution of tetrahydrofuran,
Then 0.85 ml (6 mmol) of triethylamine is added. Remove the ice bath and stir the mixture at ambient temperature overnight. The precipitated triethylamine hydrochloride is removed and the mother liquor is concentrated under reduced pressure. Redissolve this in 6 ml of pyridine and add 4-dimethylaminopyridine.
Add 0.030 g and stir the solution for 3 hours at room temperature. 6 ml of acetic acid are added and the mixture is heated to 105° C. for 45 minutes. This was evaporated and dissolved in ethyl acetate,
Wash with water, dilute hydrochloric acid and aqueous sodium bicarbonate solution. After evaporating the solvent, 3.8 g of the crude product was transferred to silica gel.
230 g was chromatographed with ethyl acetate-hexane (4:3) and then ethyl acetate-hexane (2:1) eluent to give 1-[N-[3-(benzoylamino)-7-[[ (Phenylmethoxy)carbonyl]amino]-2-oxoheptyl]-N-
[(phenylmethoxy)carbonyl]-L-alanyl]-L-proline phenylmethyl ester 1.8
get g. (d) 1-[N-[7-amino-3-(benzoylamino)-2-oxoheptyl]-L-alanyl]
-Production of L-proline dihydrochloride:-1-[N-[3-(benzoylamino)-7-
[[(phenylmethoxy)carbonyl]amino]2
-oxoheptyl]-N-[(phenylmethoxy)
1.3 g (1.6 mmol) of carbonyl]-L-alanyl]-L-proline phenyl methyl ester,
Dissolve in 75 ml of ethanol and 5 ml of aqueous 1N hydrochloric acid.
0.450 g of 10% palladium/carbon catalyst is added and the mixture is hydrogenated at normal pressure overnight. The catalyst is removed and the solution is evaporated to reduced pressure. The residue is dissolved in water and lyophilized. The lyophilizate was treated with ether and 1-
[N-[7-amino-3-(benzoylamino)-2
0.6 g of -oxoheptyl]-L-alanyl]-L-proline hydrochloride was obtained. mp80~155℃; [α] ²² _D =
-50°C (in methanol, c=1.1); R _f 0.09 (on silica gel, n-butanol/acetic acid/water (4:1:
1). Elemental analysis, _C22H32N4O5・_2HCl・_1.5H2O Calculated values: C, _49.63 %; H, 7.00%; _N , 10.52
%; Cl, 13.55%, actual value: C, 49.63%; H, 68.2%; N, 10.48
%; Cl, 13.36%. Example 3 1-[N-[3-(benzoylamino)-2-oxoheptyl]-L-alanyl]-L-proline.
Production of monohydrochloride: - (a) Production of N-benzoyl-D,L-norleucine: - 39.3g (300 mmol) of D,L-norleucine
is dissolved in 150 ml of 2N sodium hydroxide, and while stirring on an ice bath, 150 ml of 2N sodium hydroxide and 38.3 ml (330 mmol) of benzoyl chloride are added over 30 minutes. The ice bath is removed and after 1.5 hours the mixture is extracted with ether. The aqueous part was made acidic with 2N hydrochloric acid, the crystals were collected and N-benzoyl-D,L
- Obtain 68.9 g of norleucine. mp131~133℃
(125℃). (b) Preparation of 4-butyl-2-phenyl-5(4H)-oxazolone: - 40 g (170 mmol) of N-benzoyl-D,L-norleucine in 300 ml of tetrahydrofuran on an ice bath.
Dissolve while stirring. A solution of 38.52 g (187 mmol) of dicyclohexylcarbodiimide in 195 ml of tetrahydrofuran is added dropwise to this mixture over 15 minutes. Remove the ice bath and continue stirring at room temperature for an additional 18 hours. The dicyclohexylurea is removed and the tetrahydrofuran solution is concentrated under reduced pressure. 31.7 g of the residue is purified on silica gel with hexane:ether (2:1) to obtain 32.1 g of 4-butyl-2-phenyl-5(4H)-oxazolone. (c) Production of 1-[N-[3-(benzoylamino)-2-oxoheptyl]-N-[(phenylmethoxy)carbonyl]-L-alanyl]-L-proline phenylmethyl ester:- 1-[N-(carboxymethyl)-N-[(phenylmethoxy)carbonyl]-L-alanyl]-L-
A solution of 1.41 g (3 mmol) of proline phenyl methyl ester (product of Example 1c) in 10 ml of tetrahydrofuran is cooled on an ice bath. While stirring, add 0.32 ml (3.7 mmol) of oxalyl chloride and then 4 drops of dimethylformamide. The mixture is stirred on the ice bath for 20 minutes and then at room temperature for 1 hour. This was evaporated under reduced pressure and 5ml of tetrahydrofuran was added.
Re-dissolve and cool on an ice bath. 4-butyl-2-
A cold solution of 0.65 g (3 mmol) of phenyl-5(4H)-oxazolone in 5 ml of tetrahydrofuran is added dropwise, followed by 0.43 ml (3.1 mmol) of triethylamine. The mixture is stirred at ambient temperature overnight. After removing the triethylamine hydrochloride, the tetrahydrofuran solution is concentrated under reduced pressure. The residue is redissolved in 3 ml of pyridine, 0.015 g of 4-dimethylaminopyridine is added and the mixture is stirred at room temperature for 3 hours. 3 ml of acetic acid are added and the mixture is heated at 100° C. for 40 minutes. This is evaporated, redissolved in ethyl acetate and washed with water, saturated sodium bicarbonate solution, dilute hydrochloric acid and water. After evaporation, the residue was transferred onto silica gel,
Chromatography with ethyl acetate:benzene (4:6) solvent system yielded 1-[N-[3-(benzoylamino)-2-oxoheptyl]-N-[(phenylmethoxy)carbonyl]-L -alanyl]-
0.8 g of L-proline phenyl methyl ester is obtained. (d) Production of 1-[N-[3-(benzoylamino)-2-oxoheptyl]-L-alanyl]-L-proline monohydrochloride: - 1-[N-[3-(benzoylamino) 0.96 g (1.5 mmol) of -2-oxoheptyl]-N-[(phenylmethoxy)carbonyl]-L-alanyl]-L-proline phenylmethyl ester is dissolved in 75 ml of ethanol. 2ml of 1N hydrochloric acid, then 10%
Add 0.200 g of palladium/carbon catalyst. The solution is stirred under an atmosphere of hydrogen overnight. The catalyst was removed, the ethanol solution was evaporated, the residue was dissolved in water and lyophilized to give 1-[N-[3-(benzoylamino)-2-oxoheptyl]-L-alanyl]-
0.62 g of L-proline monohydrochloride was obtained. mp86～
123℃; [α] ²³ _D = -62.9° (in methanol, c=
1.05); R _f 0.57 (on silica gel, n-butanol/
Acetic acid/water (4:1:1)). Elemental analysis, calculated as C ₂₂ H ₃₁ N ₃ O ₅・HCl・2H ₂ O: C, 53.85%; H, 7.40%; N, 8.57
%; Cl, 7.23%; Actual value: C, 53.85%; H, 7.20%; N, 8.73
%; Cl, 7.29%. Example 4 Production of 1-N-[3-(benzoylamino)-2-oxo-4-(3-pyridinyl)butyl]-L-alanyl]-L-proline dihydrochloride: - (a) 2- Production of (benzoylamino)-3-(3-pyridinyl)-2-propenoic acid: -2-phenyl-4-(3-pyridinylmethylene)
-5(4H)-oxazolone 3 g (12 mmol) [Griffith et al.: The Journal of Organic Chemistry (J.Org.
Chem.) Vol. 29, p. 2659] with 24 ml of acetic acid and an aqueous solution.
Dissolve in 150ml of 0.5N hydrochloric acid. This mixture is stirred at room temperature overnight. This is evaporated and re-evaporated from absolute ethanol. This is treated with tetrahydrofuran, filtered and the solid is treated again with absolute ethanol to give 2.8 g of 2-(benzoylamino)-3-(3-pyridinyl)-2-propenoic acid. mp215
~216℃ (203℃). (b) Production of 2-(benzoylamino)-3-(3-pyridinyl)-2-propanoic acid: - 14 g (46 mmol) of 2-(benzoylamino)-3-(3-pyridinyl)-2-propenoic acid. water 500
ml and hydrogenated overnight using 1.8 g of 10% palladium/carbon catalyst. The catalyst is removed and the reaction mixture is evaporated to a small volume (100 ml) and lyophilized to give 13.1 g of product. This lyophilized material is treated with an anhydrous ethanol-ether mixture;
12 g of 2-(benzoylamino)-3-(3-pyridinyl)-2-propanoic acid are obtained by filtration. mp99～
115℃. (c) 1-[N-[3-(benzoylamino)-2-oxo-4-(3-pyridinyl)butyl]-N-
Production of [(phenylmethoxy)carbonyl]-L-alanyl]-L-proline phenylmethyl ester: - 1-[N-(carboxymethyl)-N-[(phenylmethoxy)carbonyl]-L-alanyl ]-L-
6.2 g (13.1 mmol) of proline phenyl methyl ester (product of Example 1c) are dissolved in 20 ml of tetrahydrofuran and the solution is stirred on an ice bath. To this are added oxalyl chloride and then 4 drops of dimethylformamide. Place mixture on ice bath, 20
After stirring for a minute, the mixture is stirred for an additional hour at ambient temperature.
The solvent was removed under reduced pressure and the residue was dissolved in tetrahydrofuran.
Re-dissolve in 20ml. 4 g (13 mmol) of 2-(benzoylamino)-3-(3-pyridinyl)-2-propanoic acid was suspended in 45 ml of tetrahydrofuran, and while stirring on an ice bath, 1.96 ml (14 mmol) of triethylamine and 2.96 g of dicyclohexylcarbodiimide were added. (14 mmol). The mixture is stirred at room temperature overnight, filtered and the liquid is evaporated to dryness. The residue is dissolved in 30 ml of tetrahydrofuran and stirred on an ice bath. Add the above 1-[N-(carboxymethyl)-N-
[(phenylmethoxy)carbonyl]-L-alanyl]-L-proline phenylmethyl ester
Add a 20 ml solution of acid chloride in tetrahydrofuran. 1.9 ml (13.6 mmol) of triethylamine are added and the mixture is stirred at room temperature overnight. Through this process, triethylamine hydrochloride is removed. The liquid is evaporated under reduced pressure, redissolved in 15 ml of pyridine, 0.065 g of 4-dimethylaminopyridine is added and the mixture is stirred at room temperature for 3 hours. Add 16 ml of acetic acid and heat the mixture at 100° C. for 45 minutes. This is evaporated, redissolved in ethyl acetate and washed with aqueous sodium bicarbonate and water. After evaporation, the ethyl acetate extract was chromatographed on silica gel with ethyl acetate eluent to give 1-[N-[3-(benzoylamino)-2-oxo-4-(3-pyridinyl)butyl]- N-[(phenylmethoxy)carbonyl]-L
-Alanyl]-L-proline phenylmethyl ester (3.3 g) is obtained. (d) Production of 1-[N-[3-(benzoylamino)-2-oxo-4-(3-pyridinyl)butyl]-L-alanyl]-L-proline dihydrochloride: - as described in item c above phenyl methyl ester product of
2.6 g (3.84 mmol) was dissolved in 75 ml of ethanol, 8 ml of aqueous 1N hydrochloric acid, then 10% palladium/
Add 0.6g of carbon catalyst. After hydrogenation for 16 hours, the catalyst
Add 0.5 and continue hydrogenation for another 6 hours. The mixture is filtered, evaporated and combined with a similar reaction product obtained by hydrogenating 0.8 g of the ester product described in section c above. Hydrogenation products in water
Chromatography on LH-20 gives a homogeneous product. An aqueous solution of this material was treated with 3 ml of aqueous 1N hydrochloric acid and the solution was lyophilized to give 1-[N-[3
-(Benzoylamino)-2-oxo-4-(3-
1.0 g of pyridinyl)butyl]-L-alanyl]-L-proline dihydrochloride was obtained. mp120~135℃;
[α] ²² _D = -55.5° (in methanol, c = 11); R _f 0.1
1
(On silica gel, n-butanol/acetic acid/water (4:1:1)). Elemental _analysis , calculated as _C24H28N4O5・2HCl・_2H2O : C, _51.35 %; H, 5.75%; _N , 9.98
%; Cl, 12.63%, actual value: C, 51.35%; H, 5.84%; N, 9.96
%; Cl, 12.84%. Example 5 1-[N-[3-(benzoylamino)-4-(4
-Hydroxyphenyl)-2-oxobutyl]-
Production of L-alanyl]-L-proline monohydrochloride: - (a) Production of 2-phenyl-4-[[4-(phenylmethoxy)phenyl]methyl]-5-(4H)-oxazolone: - 81 ml of 0.5N sodium hydroxide and 81 ml of water on an ice bath
Into the solution, 11.0 g (40.5 mmol) of O-benzyl-L-tyrosine is dissolved with vigorous stirring. To this mixture (5 equal portions) add 52 lbs. of benzoyl chloride.
ml, 45 ml of 1N sodium hydroxide and further 400 ml of water
Add the entire amount over 25 minutes. Remove the ice bath and allow to react at room temperature for 2 hours. The mixture was diluted with ethyl acetate.
Extract times. The aqueous portion was filtered and acidified with 1N hydrochloric acid, and the crystals were separated to obtain 12.9 g of N-benzoyl-O-benzyl-L-tyrosine. mp166~168
℃ (162℃). 12.76 g (35 mmol) of this N-benzoyl-O-benzyl-L-tyrosine are dissolved in 50 ml of dry tetrahydrofuran with stirring on an ice bath. Add to this 7.7g of dicyclohexylcarbodiimide.
Add dropwise a mixture of (37.4 mmol) and 18 ml of tetrahydrofuran. After 20 minutes, remove the ice bath and allow the reaction to proceed at room temperature overnight. Dicyclohexyl urea is removed and the liquid is concentrated to dryness. The crude product was crystallized from ether/hexane to give 2-phenyl-4-
[[4-(phenylmethoxy)phenyl]methyl]-
10.26 g of 5(4H)-oxazolone are obtained. mp85～
87℃ (83℃). (b) 1-[N-[3-(benzoylamino)-2-oxo-4-[4-phenylmethoxy)phenyl]
Production of butyl]-N-[(phenylmethoxy)carbonyl]-L-alanyl]-L-proline phenylmethyl ester:- 1-[N-(carboxymethyl-N-[(phenylmethoxy)carbonyl]) 2.82 g (6 mmol) of -L-alanyl]-L-proline phenyl methyl ester (product of Example 1c) are dissolved in 20 ml of tetrahydrofuran and the solution is stirred on an ice bath. 0.63 ml of oxalyl chloride ( 7.2 mmol) and then 4 drops of dimethylformamide are added. The mixture is stirred for 20 minutes on an ice bath and then for a further hour at ambient temperature. The solvent is removed under reduced pressure and the residue is redissolved in 10 ml of tetrahydrofuran. Cool on an ice bath.
To this stirred cold solution is added a cold solution of 2.14 g (6 mmol) of 2-phenyl-4-[[4-(phenylmethoxy)phenyl]methyl]-5(4H)-oxazolone in 40 ml of tetrahydrofuran.
Add 0.84 ml (6 mmol) of triethylamine,
A basic environment is maintained throughout the entire reaction by adding additional amounts of triethylamine. The mixture is stirred once at ambient temperature. The liquid was evaporated and redissolved in 7 ml of pyridine. 4-
0.030 g of dimethylaminopyridine is added and the mixture is stirred at room temperature for 3 hours. 7 ml of acetic acid are added and the mixture is heated to 100° C. for 45 minutes. This is evaporated and the residue is redissolved in ethyl acetate and washed with saturated sodium bicarbonate and dilute hydrochloric acid. The neutral ethyl acetate extract was evaporated and chromatographed on 300 g of silica gel using an ethyl acetate:benzene (6.5:3.5) solvent system to give 1-[N-[3-(benzoylamino)-2- 2.7 g of oxo-4-[4-(phenylmethoxy)phenyl]butyl]-N-[(phenylmethoxy)carbonyl]-L-alanyl]-L-proline phenylmethyl ester is obtained. (c) 1-[N-[3-(benzoylamino)-4-
(4-Hydroxyphenyl)-2-oxobutyl]-L-alanyl]-L-proline monohydrochloride production: - 1.8 g (2.26 mmol) of the ester product described in item b above was mixed with 150 ml of ethanol (aqueous 1N hydrochloric acid). 3.5ml
(contains). 10% palladium/carbon catalyst
0.500 g is added and the solution is stirred under hydrogen atmosphere overnight. This was evaporated, dissolved in water and lyophilized to 1-[N-[3-(benzoylamino)-4-(4
-Hydroxyphenyl-2-oxobutyl]-L
-Alanyl]-L-proline monohydrochloride was obtained.
mp118~150℃; [α] ²² _D = -63.1° (in methanol,
c=1.07); R _f 0.47 (on silica gel, n-butanol/acetic acid/water (4:1:1:)). Elemental _analysis , calculated as _C25H29N3O6・HCl・_2H2O : C, 57.42%; _H , 6.16%; _N , 8.04
%; Cl, 6.78%, Actual value: C, 57.42%; H, 6.03%; N, 8.04
%; Cl, 7.11%. Examples 6 to 62 The peptide esters shown in the columns below are treated according to the procedures of Examples 1 to 3 and 5 above to obtain the carboxymethyl peptide esters shown in the columns.
This is converted to its acid chloride and further reacted with the oxazolone shown in the column to give the N-protected ester product shown in the column. The N-protecting group and ester group were then removed to give the final products shown in the column where R ₆ is hydrogen (substituents for each product are shown in Table 1). R ₁ protecting group of Examples 20, 36-39 and 41, Example 43 and
_R3 protecting group of 44 and _R5 of Examples 49, 50 and 52-55
The protecting group is removed during the final step of the synthesis. The R ₆ ester group shown in Examples 57-62 is not eliminated.

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[Table] Example 63 1-[N-[(S)-3-(benzoylamino)-2
-Production of -oxo-4-phenylbutyl]-L-alanyl]-L-proline monohydrochloride: - (a) (S)-3-amino-1-chloro-4-phenyl-2-butanone hydrogen bromide Preparation of acid acid: - 51.4 g of (S)-[3-chloro-2-oxo-1-(phenylmethyl)propyl]carbamic acid phenylmethyl ester in 252 ml of acetic acid and acetic acid.
Dissolve in a mixture of 348 ml of 3.45N hydrogen bromide at room temperature.
Hold for 1.5 hours. The reaction mixture was concentrated under reduced pressure;
Precipitation with ether yields 36.6 g of (S)-3-amino-1-chloro-4-phenyl-2-butanone hydrobromide. mp (175℃) 177-179℃. (b) (S)-N-[3-chloro-2-oxo-1-
Production of (phenylmethyl)propyl]benzamide: - (S)-3-Amino-1-chloro-4-phenyl-2-butanone hydrobromide 36.3g (130.3
mmol) into 520 ml of dry tetrahydrofuran and 18.2 ml (130.3 mmol) of triethylamine,
Suspend with stirring for 10 minutes. Place the mixture on an ice bath and add 15.2 ml of benzoyl chloride followed by 10.95 g of sodium bicarbonate. 5 minutes later,
Remove the ice bath and keep the mixture at room temperature for 1.5 hours.
The reaction mixture is concentrated under reduced pressure and the residue is taken up in 1000 ml of aqueous methanol (10% water). The precipitate was collected, washed with methanol, and (S)-N-[3-chloro-2-oxo-1-(phenylmethyl)propyl]
25.3 g of benzamide is obtained. mp (160℃) 170~
[α] ²³ _D = −129° (c = 1.7 in dimethylformamide). (c) 1-[N-[(S)-3-(benzoylamino)
−
Preparation of 2-oxo-4-phenylbutyl]-L-alanyl]-L-proline 1,1-dimethylethyl ester: - 50 ml of dimethylformamide under argon atmosphere
, 2.42 g (10 mmol) of L-alanyl-L-proline 1,1-dimethylethyl ester, 0.840 g of sodium hydrogen carbonate, and (S)-N-[3-
3.01 g of chloro-2-oxo-1-(phenylmethyl)propyl]benzamide was mixed and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to about half of its original volume, the residue was taken up in ethyl acetate and washed with saturated sodium bicarbonate to give the crude product.
Obtain 2.25g. This material was absorbed in ethyl acetate:methanol (95:5) and silica gel column 135
Ethyl acetate:methanol (95:5) applied to g
and eluted with 1-[N-[(S)-3-(benzoylamino)-2-oxo-4-phenylbutyl]-L-
0.860 g of alanyl]-L-proline 1,1-dimethylethyl ester is obtained. (d) 1-[N-[(S)-3-(benzoylamino)
−
Preparation of 2-oxo-4-phenylbutyl]-L-alanyl]-L-proline monohydrochloride:- 1-[N-[(S)
-3-(Benzoylamino)-2-oxo-4-phenylbutyl]-L-alanyl]-L-proline.
1,1-dimethylethyl ester 0.740g (1.46
(mmol) and keep at room temperature for 30 min. This was concentrated, dissolved in water, filtered, and lyophilized to 1-[N-[(S)-3-(benzoylamino)-2-
Oxo-4-phenylbutyl]-L-alanyl]-
0.600 g of L-proline monohydrochloride was obtained. mp83
~163℃; [α] ²⁵ _D = −109° (in methanol, c=
1.04); R _f 0.6 (on silica gel, butanol/acetic acid/water (4:1:1)). Elemental analysis, _{C25H29N3O5 ・}HCl・_1.65H2O , calculated values: C, 57.99%; _H , 6.48%; _N , 8.12
%; Cl, 6.85%; Actual value: C, 57.99%; H, 6.39%; N, 8.09
%; Cl, 6.95%. Example 64 (S)-1-[N ² -[3-(benzoylamino)-
Production of 2-oxo-4-phenylbutyl]-L-lysyl]-L-proline dihydrochloride: - (a) 1-[ ^N6 -[(1,1-dimethylethoxy)carbonyl] ^-N2- [ (Phenylmethoxy)carbonyl]-L-lysyl]-L-proline 1,1-
Preparation of dimethyl ethyl ester: - In 25 ml of dimethylformamide on an ice bath under an argon atmosphere, N ⁶ -[(1,1-dimethylethoxy)
^{9.51 g} of carbonyl]-N2-[(phenylmethoxy)carbonyl]-L-lysine and 3.825 g of hydroxybenzotriazole are dissolved with stirring.
To this were added 4.49 g of L-proline 1,1-dimethylethyl ester, then 2.2 ml of N,N'-diisopropylethylamine and 5.15 g of dicyclohexylcarbodiimide. After 15 minutes, remove the ice bath and allow the reaction to proceed at room temperature for 6.5 hours. Remove dimethylformamide under reduced pressure. The residue is taken up in ethyl acetate and the dicyclohexylurea is separated off. liquid
Wash to neutralize with 10% potassium bisulfate and saturated sodium bicarbonate. 13.26 g of the crude product was placed on a silica gel column in ethyl acetate:hexane (2:1).
1-[ ^N6 -[(1,1-dimethylethoxy)carbonyl] ^-N2 -[(phenylmethoxy)carbonyl]-L-lysyl]-L-proline.1,1- 13.0 g of dimethyl ethyl ester is obtained. (b) (S)-1-[N ² -[3-(benzoylamino)
-2-oxo-4-phenylbutyl]-N ⁶ -
[(1,1-dimethylethoxy)carbonyl]-
Production of L-lysyl]-L-proline 1,1-dimethylethyl ester:- The ester product of item (a) above was dissolved in ethanol for 10
% palladium/carbon catalyst to reduce 1-[N ⁶ −
[1,1-dimethylethoxy)carbonyl]-L-
3.99 g of [lysyl]-L-proline 1,1-dimethylethyl ester were obtained. This material was dissolved in 40 ml of dimethylformamide and 3.01 g of (S)-N-[3-chloro-2-oxo-1-(phenylmethyl)propyl]benzamide (product of Example 63b)
and 0.840 g of sodium bicarbonate.
After stirring for 18 hours at room temperature, the reaction mixture is concentrated under reduced pressure, taken up in ethyl acetate and washed with saturated sodium bicarbonate. 7.0g of the crude product was placed on a silica gel column,
Purified by elution with ethyl acetate: 1% methanol,
(S)-1-[N ² -[3-(benzoylamino)-2
-oxo-4-phenylbutyl]-N ⁶ -[(1,1
-dimethylethoxy)carbonyl]-L-lysyl]
1.7 g of -L-proline 1,1-dimethylethyl ester is obtained. (c) (S)-1-[N ² -[3-(benzoylamino)
- Production of 2-oxo-4-phenylbutyl]-L-lysyl]-L-proline dihydrochloride: - 1.6 g of the ester product of item (b) above and 1.5N hydrochloric acid:
20 ml of acetic acid was treated at room temperature for 30 minutes, concentrated to dryness,
The crude product was treated with ether to form a solid.
Obtain 1.37g. This material is added to water, filtered through Millipore and lyophilized to give 1.28 g of product. The product was further purified on a LH-20 column in water to give (S)-1-[ ^N2- [3-(benzoylamino)-2
-Oxo-4-phenylbutyl]-L-lysyl]-
0.740 g of L-proline dihydrochloride was obtained. mp120
〜180℃; [α] ²⁵ _D = −84.8° (in methanol, c=
1.05); R _f 0.61 (trace at 0.9) (on silica gel,
Chloroform/methanol/acetic acid (38%) (60:
40:20)). Elemental analysis, calculated as _C28H36N4O5・_2HCl・_3H2O : C, 52.98%; H, 6.98%; _N , _8.83
%; Cl, 11.17%; Actual value: C, 52.98%; H, 6.93%; N, 8.66
%; Cl, 11.31%. Example 65 N-[N-[[(s)-3-(benzoylamino)-2
-Production of oxo-4-phenylbutyl]-L-alanyl]-N-cyclohexylglycine monohydrochloride: - (a) Production of N-cyclohexylglycine 1,1-dimethylethyl ester: - Cyclohexylamine (70.35ml) and sodium bicarbonate (12.9 g) are suspended in 200 ml of absolute ethanol with stirring in an ice bath. Bromoacetic acid/1,1-dimethylethyl ester (20.78 ml) was added dropwise to this. Remove ice bath. 24 at room temperature
After an hour, the reaction mixture is concentrated to dryness, taken up in chloroform and washed with water. The crude product (42 g) is chromatographed on silica gel eluting with ethyl acetate/hexane (2:1) to give 27.4 g of N-cyclohexylglycine 1,1-dimethylethyl ester. (b) Production of N-cyclohexyl-N-[N-[(phenylmethoxy)carbonyl]-L-alanyl]glycine 1,1-dimethylethyl ester: -N-[(phenylmethoxy)carbonyl]-L −
Alanine (4.46g), N-cyclohexylglycine 1,1-dimethylethyl ester (4.26g),
Hydroxybenzotriazole (3.06 g), dicyclohexylcarbodiimide (4.12 g) and triethylamine (2.8 ml) are stirred in 40 ml of dimethylformamide at room temperature for 20 hours. The reaction mixture is then concentrated in vacuo and taken up in ethyl acetate to remove the dicyclohexylurea, and the liquid is neutralized and washed with 10% potassium bisulfate and saturated sodium bicarbonate to yield 5.9 g of crude product. Crystallized from ether/hexane to give 3.97 g of N-cyclohexyl
N-[N-[(phenylmethoxy)carbonyl]-L
-Alanyl]glycine 1,1-dimethylethyl ester is obtained. mp104~105°. (c) Production of N-(L-alanyl)-N-cyclohexylglycine 1,1-dimethylethyl ester:- The ester product (3.9 g) of (b) above was treated with a palladium/carbon catalyst (10%, 700 mg). of methanol and stirred under hydrogen atmosphere for 4 hours. The reaction mixture was filtered and concentrated to dryness to give 2.65 g of crude N-
(L-alanyl)-N-cyclohexylglycine
1,1-dimethylethyl ester is obtained. (d) N-[N-[[(s)-3-(benzoylamino)-
2-oxo-4-phenylbutyl]-L-alanyl]-N-cyclohexylglycine 1,1
- Preparation of dimethyl ethyl ester: - Crude ester product of (c) above (2.6 g), sodium bicarbonate (764 mg) and (s)-N- of Example 63(b)
[3-chloro-2-oxo-1-(phenylmethyl)propyl]benzamide (2.75 g) is stirred in 25 ml of dimethylformamide for 20 hours. The reaction mixture is concentrated to dryness, taken up in ethyl acetate and washed with saturated sodium bicarbonate to give 4.7 g of crude product.
Purification was performed on a silica gel column eluting with ethyl acetate/methanol (99:1), and 1.5 g of N-
[N-[[(s)-3-(benzoylamino)-2-oxo-4-phenylbutyl]-L-alanyl]-N-
Cyclohexylglycine 1,1-dimethylethyl ester is obtained. (e) N-[N-[[(s)-3-(benzoylamino)-
Production of 2-oxo-4-phenylbutyl]-L-alanyl]-N-cyclohexylglycine monohydrochloride:- 5 ml of the ester product (500 mg) of (d) above was added.
Treat with 1.5N hydrochloric acid/acetic acid for 30 minutes and then concentrate to dryness at room temperature. Take the crude product in methanol,
Purify with LH-20 column to obtain 413 mg of product. This was made semicrystalline in acetonitrile/ether, and N-[N-[[(s)-3-(benzoylamino)-2-oxo-4-phenylbutyl]-L-alanyl]-N-cyclohexylglycine mono Obtain the hydrochloride. mp154−157° (132°), [α] ²³ _D = −
67.4° (c=1.35, methanol). Rf = 0.60 (minor impurities 0.92) (silica gel, chloroform/methanol/concentrated ammonia = 30:10:2). Elemental analysis (as C ₂₈ H ₃₅ N ₃ O ₅・HCl・2H ₂ O) Calculated values: C61.35, H6.99, N7.67, Cl, 6.47 Actual values: C61.08, H6.79, N7. 65, Cl6.46 Example 66 N-[N-[[(s)-3-(benzoylamino)-2
-Production of oxo-4-phenylbutyl]-L-alanyl]-N-phenylglycine monohydrochloride: - (a) Production of N-phenylglycine 1,1-dimethylethyl ester: - Ether (in 100 ml) of triethylamine (11.25
g, 0.11 mol) and aniline (9.3 g, 0.10 mol) are cooled to 0° in an ice bath under an argon atmosphere. To this is added bromoacetic acid 1,1-dimethylethyl ester (18 g, 0.093 mol) over 30 minutes. The resulting mixture is stirred at 0° for 1 hour, then warmed to room temperature and stirred overnight. Filter the solution, rinse with ether, and concentrate the solution.
6.9 g of yellow oil are obtained. Rf = 0.6, 0.7 (silica gel, ethyl acetate). Chromatography was performed on LPS-1 using hexane/ethyl acetate (7:3) as the eluent to obtain 2.3 g of N-phenylglycine 1,1-dimethylethyl ester as a pale yellow liquid. Rf = 0.7 (silica gel, ethyl acetate). (b) N-phenyl-N-[N-[(phenylmethoxy)carbonyl]-L-alanyl]glycine.
Preparation of 1,1-dimethylethyl ester:- A solution of N-(phenylmethoxy)carbonyl]-L-alanine (2.8 g, 12.7 mmol) in dry tetrahydrofuran (50 ml) was placed in a dry ice-ethanol bath under argon. Cool inside. N to this
- Methylmorpholine (1.28g, 12.7mmol) and isobutylchloroformate (1.73g, 12.7mmol)
mol). After 20 minutes, N-phenylglycine 1,1-dimethylethyl ester (3.7g,
12.7 mmol). The resulting mixture is stirred at -20° for 1 hour and then at room temperature overnight. The mixture is partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer is washed successively with 1N hydrochloric acid and 10% sodium bicarbonate, dried (MgSO ₄ ), and concentrated. LPS
-1 ethyl acetate/hexane (3:1→1:
4.0 g of N-phenyl-N-[N-[(phenylmethoxy)carbonyl]-L-alanyl]glycine 1,1-dimethylethyl ester was purified by chromatography using a gradient of 1). Obtained as an oil. Rf = 0.4 (silica gel, ethyl acetate). (c) Production of N-(L-alanyl)-N-phenylglycine 1,1-dimethylethyl ester:
- the ester product of (b) above (4.0 g, 9.7 mmol)
A solution of 10% in ethanol (125 ml) and a 10% palladium/carbon catalyst is stirred under a stream of hydrogen for 18 hours. The solution was filtered, concentrated, dissolved in ethyl acetate and diluted with 1N
Extract with hydrochloric acid. Treat the aqueous layer with sodium bicarbonate until basic and extract with ethyl acetate.
The collected ethyl acetate extracts were dried (MgSO ₄ ) and
Concentration yields 1.3 g of N-(L-alanyl)-N-phenylglycine 1,1-dimethylethyl ester as a white solid. Rf=0.52 (small amount spot 0.64)
(Silica gel, ethyl acetate/methanol = 1:
1). (d) N-[N-[[(s)-3-(benzoylamino)-
Preparation of 2-oxo-4-phenylbutyl]-L-alanyl]-N-phenylglycine 1,1-dimethylethyl ester: - Preparation of Example 63(b) in dry dimethylformamide
(s)-N-[3-chloro-2-oxo-1-(phenylmethyl)propyl]benzamide (1.4g, 4.7m
To a stirred solution of N-(L-alanyl)-N-phenylglycine 1,1-dimethylethyl ester (1.3 g, 4.7 mmol) was added sodium bicarbonate (0.38 g, 4.7 mmol) and iodine. Add sodium chloride (0.7 g, 4.7 mmol). After stirring overnight at room temperature, the mixture is concentrated, dissolved in ethyl acetate and filtered. Wash the solution with 10% sodium bicarbonate, dry (MgSO ₄ ), and concentrate to a yellow oil. LPS
Chromatography was performed using a gradient of ethyl acetate/hexane (1:1) → ethyl acetate at 1.8
g of N-[N-[[(s)-3-(benzoylamino)-
2-oxo-4-phenylbutyl]-L-alanyl]-N-phenylglycine 1,1-dimethylethyl ester is obtained. Rf=0.34 (silica gel,
Ethyl acetate). (e) N-[N-[[(s)-3-(benzoylamino)-
Preparation of 2-oxo-4-phenylbutyl]-L-alanyl]-N-phenylglycine monohydrochloride: - Ester product of (d) above (1.6 g in hydrochloric acid/acetic acid (1.77 N, 17.0 ml) , 2.9 mmol) is stirred for 30 minutes at room temperature. The solution is concentrated and the residue is triturated with ether to give a pale yellow solid. Recrystallized from methanol/ether to yield 0.84 g of N.
-[N-[[(s)-3-(benzoylamino)-2-oxo-4-phenylbutyl]-L-alanyl]-N
- Phenylglycine monohydrochloride is obtained as a white crystalline solid. mp147~159° (decomposed). Rf = 0.8 (silica gel, butanol/hydrochloric acid/water = 1:1:1).
[α] _D = −12.7° (c = 1.5, methanol). Elemental analysis (as C ₂₈ H ₂₉ N ₃ O ₅・HCl・0.65H ₂ O) Calculated value: C62.77, H5.89, N7.84, Cl, 6.62 Actual value: C62.77, H5.70, N7 .84, Cl6.12 Example 67 (s)-1-[N-[[3-(benzoylamino)-2
-Oxo-4-phenylbutyl]-N-methyl-L-alanyl]-L-proline monohydrochloride production: - (a) N-[(phenylmethoxy)carbonyl]-L
- Preparation of alanine: - Dissolve L-alanine (89.1 g, 1 mol) in 2N sodium hydroxide (500 ml) and cool to 0°.
Add benzyl chloroformate (204.5g, 12
mol) and 4N sodium hydroxide (250 ml) are added dropwise simultaneously over the course of 1 hour. The reaction mixture is stirred overnight (0° to room temperature) and washed with ethyl acetate (2×500 ml). The aqueous part is PH2.0 with 6N-hydrochloric acid.
Acidify and extract with ethyl acetate (600 ml x 3). Dry the collected ethyl acetate extracts (Na ₂ SO ₄ )
was concentrated on a rotary evaporator and the solid residue was tritiated with petroleum ether to give 194.0 g of N-
[(Phenylmethoxy)carbonyl]-L-alanine is obtained as a white solid. (b) Preparation of N-methyl-N-[(phenylmethoxy)carbonyl]-L-alanine: - N-[(phenylmethoxy)carbonyl]-L-alanine (22.3 g. 0.1 in tetrahydrofuran (250 ml) mol) and methyl iodide (50 ml, 0.8
To a cold (0°) solution of mol) is carefully added with mild stirring a sodium hydride suspension (14.25 g, 0.3 mol). The suspension was stirred overnight under a nitrogen atmosphere (0°→room temperature), poured slowly into saturated sodium bicarbonate (200 ml), and ethyl acetate (300 ml).
dilute with water and separate each layer. The organic layer is extracted again with saturated sodium bicarbonate. The combined aqueous layer is acidified to pH 2.0 with 10% potassium bisulfate and extracted with ethyl acetate. The collected ethyl acetate extracts were dried ( _Na2
SO ₄ ) and concentrated under reduced pressure to a dark oily residue (23.0g).
shall be. This crude acid is treated with dicyclohexylamine (20ml) in ether (150ml). The resulting crude dicyclohexylamine salt was collected (37.0 g) and recrystallized from chloroform/ether (35.0 g).
Conversion back to the acid by partitioning between 1N hydrochloric acid/ethyl acetate gave a pale yellow oil which crystallized on standing (17.4 g). Recrystallized from ethyl acetate/petroleum ether (11.2
g) to obtain 4.0 g of N-methyl-N-[(phenylmethoxy)carbonyl]-L-alanine as a white crystalline product. mp65~66.5°, [α] ²⁵ _D = −31.1
°
(c=2, acetic acid). (c) 1-[N-methyl-N-[(phenylmethoxy)
Carbonyl]-L-alanyl]-L-proline
Preparation of 1,1-dimethylethyl ester: - N-methyl-N-[(phenylmethoxy)carbonyl]-L in distilled tetrahydrofuran (50 ml)
- In a solution of alanine (4.74 g, 20 mmol), L-
Add proline 1,1-dimethylethyl ester (3.42 g, 20 mmol), hydroxybenzotriazole hydrate (3.06 g, 20 mmol) and dicyclohexylcarbodiimide (4.12 g, 20 mmol). The reaction mixture is stirred overnight to remove the precipitated dicyclohexylurea and the liquid is concentrated. The residue was dissolved in ethyl acetate (50 ml), saturated sodium bicarbonate (2 times), 10% potassium bisulfate (2 times)
and water (twice), dried (Na ₂ SO ₄ ),
Concentrate to give 6.4 g of 1-[N-methyl-N-[(phenylmethoxy)carbonyl]-L-alanyl]-L-
Proline 1,1-dimethylethyl ester is obtained as an oily residue. (d) Preparation of 1-(N-methyl-L-alanyl)-L-proline 1,1-dimethylethyl ester: - 6.4 g of the ester product of (c) above in ethanol (95%, 150 ml). , 16.4 mmol) and 0.8 g
The 10% palladium/carbon catalyst mixture is hydrogenated at atmospheric pressure overnight. The catalyst is filtered off and the liquid is evaporated. The resulting oily residue was dried under high vacuum to solidify to give an oily solid residue (3.8 g).
1.5 g of 1-(N
-Methyl-L-alanyl)-L-proline 1,
1-dimethylethyl ester monohydrochloride is obtained as a white solid. Rf = 0.44 (silica gel, 20% methanol/chloroform). [α] ²⁵ _D = -102.1° (c = 2
,
acetic acid). 2.3g of 1-(N-methyl-L) was extracted from the ether solution.
-alanyl)-L-proline 1,1-dimethylethyl ester is obtained as an oil. Rf = 0.44 (silica gel, 20% methanol/chloroform). [α]
²⁵ _D = -101.6° (c = 2, acetic acid). (e) (s)-1-[N-[[3-(benzoylamino)-
2-oxo-4-phenylbutyl]-N-methyl-L-alanyl]-L-proline 1,1-
Preparation of dimethyl ethyl ester: - 1-(N
-Methyl-L-alanyl)-L-proline 1,
1-dimethylethyl ester (2.1 g, 8.19 mmol), (s)-N-[3-chloro-2-oxo-1-(phenylmethoxy)propyl]benzamide (2.46 g, 8.19 mmol), excess sodium bicarbonate and sodium iodide (1.22 g, 8.10 mmol) is stirred at room temperature under nitrogen atmosphere overnight. The reaction mixture is concentrated, the residue is partitioned between water/ethyl acetate, the layers are separated and the aqueous layer is extracted again with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate and water, dried ( _Na2
SO ₄ ) and concentrated to an oily residue (3.5 g).
Flat chromatography (silica gel 200
g, 1% methanol/ethyl acetate), 2.8 g
(s)-1-[N-[[3-(benzoylamino)-2
-Oxo-4-phenylbutyl]-N-methyl-
L-alanyl]-L-proline 1,1-dimethylethyl ester is obtained as a yellow oil. (f) (s)-1-[N-[[3-(benzoylamino)-
Preparation of 2-oxo-4-phenylbutyl]-N-methyl-L-alanyl]-L-proline monohydrochloride: - Ester product of (e) above (1.4 g, 2.7 mmol)
is treated with 2N hydrochloric acid/acetic acid (20 ml). After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure and the resulting oily residue was tritiated with ether (4
1.05 g of (s)-1-[N-[[3-(benzoylamino)-2-oxo-4-phenylbutyl]
-N-methyl-L-alanyl]-L-proline.
The monohydrochloride salt is obtained as an off-white solid. mp125
~135°, Rf = 0.24 (silica gel, n-butanol/acetic acid/water = 4:1:1). [α] ²⁵ _D = -87° (c
= 1, methanol). Elemental analysis (as C ₂₆ H ₃₁ N ₃ O ₅・HCl・0.7H ₂ O) Calculated values: C60.68, H6.41, N8.16, Cl, 6.88 Actual values: C60.68, H6.36, N7 .95, Cl6.48 Example 68 (s)-1-[N-[3-(benzoylamino)-2-
Oxo-4-phenylbutyl]-4-phenylglycyl]-L-proline hydrochloride (20:3)
Production of: - (a) 1-(bromoacetyl)-L-proline 1,
Preparation of 1-dimethylethyl ester:- L-proline 1, in methylene chloride (250 ml)
1-dimethylethyl ester (34.2g, 0.2mol)
To a cooled (−10°) solution of diisopropylethylamine (38.3 ml, 0.22 mol) and bromoacetyl chloride (16.5 ml, 0.2 mol) were added dropwise over 20 minutes while the temperature was between −10° and −5°. Hold. The dark reaction mixture was stirred overnight (from −10° to room temperature) and
Concentrate under reduced pressure. The oily residue was redissolved in ethyl acetate, washed with saturated sodium bicarbonate (twice), 10% potassium bisulfate (twice), and water (twice), dried (Na ₂ SO ₄ ), and concentrated to a dark color. Oily residue (28.0
g). By flash chromatography (LPS-1 silica gel, 10% ethyl acetate/methylene chloride), 11.0 g of 1-(bromoacetyl)-
L-proline 1,1-dimethylethyl ester is obtained as a pale yellow oil. (b) Production of 1-(N-phenylglycyl)-L-proline 1,1-dimethylethyl ester:
- A solution of 1-(bromoacetyl)-L-proline 1,1-dimethylethyl ester (2.1 g, 7.5 mmol) in distilled tetrahydrofuran (40 ml),
Aniline (1.5 g, 15 mmol) is added and the reaction mixture is stirred under nitrogen overnight. The reaction mixture was diluted with ethyl acetate (200 ml), washed with saturated sodium bicarbonate (2 x 50 ml) and water (2x), dried (Na ₂ SO ₄ ) and concentrated in vacuo to a dark oily residue (4.0
g). By flash chromatography (LPS-1 silica gel, 10% ethyl acetate/methylene chloride), 2.2 g of 1-(N-phenylglycyl)-L-proline 1,1-dimethylethyl ester was obtained as a dark oil. This is dried under high vacuum to solidify. (c) (s)-1-[N-[3-(benzoylamino)-2
- Preparation of oxo-4-phenylbutyl]-4-phenylglycyl]-L-proline 1,1-dimethylethyl ester: - 1-(N
-Phenylglycyl)-L-proline 1,1-
dimethyl ethyl ester (1.06 g, 3.5 mmol),
Example 63(b) of (s)-N-[3-chloro-2-oxo-1-(phenylmethyl)propyl]benzamide (1.06 g, 3.5 mmol), excess sodium bicarbonate and sodium iodide (0.52 g, 3.5 mmol) is stirred overnight at room temperature under nitrogen atmosphere. The reaction mixture was poured into water (50ml) and ethyl acetate (50ml).
×3) Extract. The combined ethyl acetate extracts are washed with saturated sodium bicarbonate (2x) and water (3x), dried (Na ₂ SO ₄ ), and concentrated under reduced pressure to give a dark oily residue (2.0 g). By flash chromatography (LPS-1 silica gel, 5% ethyl acetate/methylene chloride → 15% ethyl acetate/methylene chloride), 0.3 g of (s)-1-[N-[3-(benzoylamino)- 2-oxo-4-phenylbutyl]
-N-phenylglycyl]-L-proline 1,
1-dimethylethyl ester is obtained as a pale yellow foam. (d) (s)-1-[N-[3-(benzoylamino)-2
-Oxo-4-phenylbutyl]-N-phenylglycyl]-L-proline hydrochloride (20:3)
Preparation of: - Ester product of (c) above (0.28 g, 0.49 mmol)
is treated with 2N hydrochloric acid/acetic acid. After stirring for 1 hour at room temperature, the reaction mixture was concentrated under reduced pressure and the resulting oily residue was tritylated (4 times) with ether to give 0.14 g of (s)-1-[N-[3-(benzoylamino)]. -2-oxo-4-phenylbutyl]-N-
Phenylglycyl]-L-proline hydrochloride (20:3) was obtained as an off-white solid. mp110～
140°, Rf=0.76 (small spot 0.53) (silica gel,
n-butanol/acetic acid/water = 3:1:1). Elemental analysis (as C ₃₀ H ₃₁ N ₃ O ₅・0.15HCl・0.5H ₂ O) Calculated value: C68.22, H6.13, N7.95, Cl1.00 Actual value: C68.22, H6.00, N8.25, Cl0.99 Examples 69-90 The ester products in the columns are obtained as in Examples 63-68, except that the ketones in the columns below, the acid chlorides in the columns and the peptides in the columns are used. By removing the R ₆ ester group and other protecting groups,
The corresponding final product in acid form is obtained.

【table】

【table】

【table】

【table】

【table】

【table】

[Table] R ₁ protecting groups of Examples 74, 76 and 77, Example 78
and the R ₃ protecting group of 80, and Examples 81 and 83
The ˜85 R ₅ protecting group is removed as the final step of the synthesis. The R ₆ ester group of Examples 87-90 was not removed. Example 91 (±)-1-[N-[3-(benzoylamino)-
Production of 2-oxo-4-phenylbutyl]-N-methylglycine]-L-proline monohydrochloride: - (a) [3-(benzoylamino)-2-oxo-4
-Phenylbutyl]methylcarbamic acid phenylmethyl ester preparation: -N-Methyl-N-[(phenylmethoxy)carbonyl]glycine (2.23 g, 10 mmol) is dissolved in 30 ml of tetrahydrofuran and cooled in an ice bath.
Add oxalyl chloride (1 ml, 11.5 mmol) followed by 2 drops of dimethylformamide. 30 in ice bath
After stirring for a minute, the mixture is stirred at room temperature for 1 hour. Add 0.25 ml of oxalyl chloride to this. The mixture is evaporated, redissolved in 15 ml of tetrahydrofuran and stirred in an ice bath. 2-phenyl-4-(phenylmethyl)-5(4H)-oxazolone (3.1 g,
A solution of 12.4 mmol) dissolved in 15 ml of tetrahydrofuran is added to the above solution and stirred in an ice bath.
Add triethylamine (1.4 ml, 10 mmol),
Stir the solution overnight at room temperature. The precipitated triethylamine hydrochloride is removed. Tetrahydrofuran was removed from the residue, then redissolved in pyridine (5 ml), and p-dimethylaminopyridine (20 ml) was added. After stirring for 3 hours at room temperature, acetic acid (5 ml) is added and the reaction mixture is kept at 105° for 30 minutes. The reaction mixture is then evaporated and the residue is dissolved in ethyl acetate and washed with aqueous sodium bicarbonate and water. After trituration with ethyl acetate/hexane, 2.2 g
A homogeneous [3-(benzoylamino)-2-oxo-4-phenylbutyl]mecarbamic acid phenylmethyl ester is obtained. mp140~141°. (b) Preparation of (±)-N-[3-(methylamino)-2-oxo-1-(phenylmethyl)propyl]benzamide hydrochloride: - Ethanol (50 ml) containing 1N-hydrochloric acid (2 ml)
, [3-(benzoylamino)-2-oxo-4
-Phenylbutyl] Methylcarbamic acid phenylmethyl ester (0.5 g) was dissolved. Add palladium/carbon catalyst (10%, 100 mg) and continue hydrogenation overnight. The reaction mixture was then filtered, evaporated, dissolved in water and lyophilized to give 300 mg (±)
-N-[3-(methylamino)-2-oxo-1-
(Phenylmethyl)propyl]benzamide hydrochloride is obtained as a homogeneous white powder. (c) (±)-1-[N-[3-(benzoylamino)
- Preparation of 2-oxo-4-phenylbutyl]-N-methylglycine]-L-proline 1,1-dimethylethyl ester: - (±)-N in dimethylformamide (20 ml)
-[3-(Methylamino)-2-oxo-1-(phenylmethyl)propyl]benzamide hydrochloride (1.65 g, 5 mmol), 1-(bromoacetyl)-L-proline of Example 68(a) The reaction mixture of 1,1-dimethylethyl ester (2.9 g, 10 mmol) and diisopropylethylamine (1.74 ml, 10 mmol) is stirred at room temperature under nitrogen overnight. The reaction mixture is partitioned between water/ethyl acetate and the aqueous layer is extracted again with ethyl acetate. The ethyl acetate extract was dried (Na ₂ SO ₄ ) and concentrated to a yellow oily residue (4.0 g).
shall be. Flash chromatography (150g
of Merck silica gel 60), 0.7g of (±)-1
-[N-[3-(benzoylamino)-2-oxo-
4-phenylbutyl]-N-methylglycine]-L
-Proline 1,1-dimethylethyl ester is obtained as a yellow foam. (d) (±)-1-[N-[3-(benzoylamino)
- Preparation of 2-oxo-4-phenylbutyl]-N-methylglycyl]-L-proline monohydrochloride: - Ester product of (c) above (0.4 g, 0.79 mmol)
was treated with 2N hydrochloric acid/acetic acid (5 ml). at room temperature
After stirring for 45 minutes, the reaction mixture was concentrated under reduced pressure and the resulting oily residue was tritiated with ether (3
0.28 g of (±)-1-[N-[3-(benzoylamino)-2-oxo-4-phenylbutyl]
-N-methylglycine]-L-proline monohydrochloride is obtained as a white solid. mp125~130°. Rf＝
0.73 (silica gel, n-butanol/acetic acid/water =
3:1=1). Elemental analysis (as C ₂₅ H ₂₉ N ₃ O ₅・HCl・0.23H ₂ O) Calculated values: C61.01, H6.24, N8.54 Actual values: C61.01, H6.10, N8.36 Example 92 (S)-7-[[[3-(benzoylamino)-2-
Oxo-4-phenylbutyl]methylamino]
Production of acetyl]1,4-dithia-7-azaspiro[4,4]nonane-8-carboxylic acid trifluoroacetate salt (1:1): - (a) (S)-7-(bromoacetyl)- Preparation of 1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid: 1N sodium hydroxide (25 ml) cooled to -0°
(S)-1,4-dithia-7-azaspiro[4,4]nonane-8-carboxylic acid hydrochloride (2.1
g, 8.7 mmol) and bromoacetyl bromide (2.1 g, 0.91 ml, 10.4 mmol) was added dropwise over 10 minutes. The reaction mixture was stirred for 2 hours (from 0° to room temperature), washed with ethyl acetate (2 times), and the aqueous layer was adjusted to PH
Acidify to 2 and extract with ethyl acetate (3 times).
The combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated to yield 2.25 g of (S)-7-(bromoacetyl)-1,
4-dithia-7-azaspiro[4.4]nonane-8
- Obtain carboxylic acid. (b) Production of (S)-7-(bromoacetyl)-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid diphenylmethyl ester:
- (S)-7-(bromoacetyl)-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid (2.25 g, 6.9 mmol) was added to ethyl acetate (159
ml). Diphenyldiazomethane (1.3
g, 6.9 mmol) and the reaction mixture is stirred at room temperature overnight. The decolorized reaction mixture was diluted with saturated sodium bicarbonate (2 times) and 10% potassium bisulfate (2 times).
and washed with water, dried (Na ₂ SO ₄ ) and concentrated.
2.5 g of (S)-7-(bromoacetyl)-1,4-
Dithia-7-azaspiro[4.4]nonane-8-carboxylic acid diphenylmethyl ester is obtained as a white solid residue. The remaining compounds in Table I above are formulated similarly. Descriptions of the compositions or substances represented by the various trade names and trade names mentioned above are provided below. Luprole L: A condensate of nonylphenol (1 mol) and ethylene oxide (13 mol) Aromazole H: A solvent mixture of alkylbenzenes Dispersol T&AC: A mixture of sodium sulfate and a condensate of formaldehyde and sodium naphthalene sulfonate Luprole APN5 : Nonylphenol (1 mol)
and naphthalene oxide (5.5 mol) Cellophas B600: Sodium carboxymethylcellulose thickener Rizapol NX: Condensate of nonylphenol (1 mol) and ethylene oxide (8 mol) Aerosol OT/B: Dioctyl sodium sulfosuccinate Perminal BX] Sodium alkylnaphthalene sulfonate. Example 18 The compounds of the present invention are tested against diseases caused by various fungi that mainly parasitize the leaves of plants. The technique used is as follows. For all tests except those for Botrytia cinerea, plants were grown in 4 cm diameter
The plants were grown in John Innes potting compost (No. 1 or 2) in small pots. A layer of fine sand is provided at the bottom of the pot containing the dicots to facilitate uptake of the test compound by the roots of the plants. The test compound can be formulated by bead milling with an aqueous Dispersol T solution or as a solution by dissolving the test compound in acetone or acetone/ethanol and diluting it to the desired concentration immediately before use. was prescribed.
For foliar diseases, solutions and suspensions with an active ingredient content of 100 ppm are sprayed on the foliage and applied to the roots of the plants via the soil. For tests against botrytis cinerea of grapes, grape berries are sprayed with the test compound. The spray is applied to maximum foliage retention and the roots are soaked so that the final concentration of active ingredient is equivalent to approximately 40 ppm per dry soil. When applying spray liquid to grains,
Tween 20 was added to give a final concentration of 0.05%. Most tests are preventive protection tests in which the test compound is applied to the soil and roots and leaves one or two days before inoculating the plants with the disease. However, in the case of tests against barley powdery mildew (Erysiphe graminis hordei) and gray mold (Botrytis cinerea), the treatment was an eradication test, and the test compound was applied one day after inoculation. Inoculation of grape berries in the Botrytis cinerea test is carried out by incising the fruit twice and then immersing the fruit in a suspension of disease spores.
To treat the remaining leaves, the spore suspension was applied by spraying onto the leaves of the test plants. After being inoculated with the disease, the plants were placed in an appropriate environment to allow infection and disease until the disease could be evaluated. The period from inoculation to disease evaluation was varied between 4 and 14 days depending on the type of disease and environment. Disease control rates were recorded using the following grading: 4 = No disease 3 = Contain-5% disease on untreated plants 2 = 6-25% disease on untreated plants 1 = Untreated 26-59% disease on plants 0 = 60-100% disease on untreated plants The results obtained are shown in the table below.

Table: Example 19 This example reveals the plant growth regulating properties of the compounds of the invention. The test compound is applied as a total spray of emulsion diluted to give the concentrations indicated in the table. Plants are grown in 7.62 cm pots with peat compost and sprayed at the two-leaf stage. The plant growth regulating effect is evaluated 13 or 19 days after application of the test compound. The growth inhibition rate is recorded by a grade of 1 to 3: 1 = 0 to 30% inhibition rate 2 = 31 to 75% inhibition rate 3 = 75% inhibition rate or higher No grade of 1 to 3 indicates no effect. . The associated plant growth regulating effects are shown as follows: G = Darker green color of leaves A = Tip growth effect T = Tillering effect The results are shown in the table. If no numerical value is given, the test compound is substantially inactive as an inhibitor.

【table】

[Table] Example 20 This example demonstrates the plant growth regulating properties of Compound No. 6 in barley. Compound No. 6 is 95% water and 95% cyclohexanone and "Simperonik" NPE1800
5% mixture of 3.3% and "Tween" 85 1.7%
and applied to barley plants at a field equivalent rate of 4 Kg per hectare (at a volume equivalent of 1000 per hectare). Barley was grown in 10.16 cm pots of John Innes No. 1 Potting Compost at a ratio of 3 barley plants per pot, with 1 to 1.5 barley plants per pot.
Ten consecutive pots are treated at the leaf stage (13 days after sowing). On the 14th day, the plant growth regulating effect is recorded on untreated plants according to a grade of 1 to 3: 1 = 1 to 30% plant growth regulating effect 2 = 31 to 75% 〃 〃 3 = >75% 〃 〃 Absence of grades 1 to 3 indicates no effect. Plant toxicity (phytotoxicity) is recorded on a scale of 0 to 5. Repeated record drug damage 1 Y2D2L/
2 However: Y = Decrease in overall plant size 2 Y2D2B/G/L/ 2 3 Y2D2B/L/ 2 4 Y/D/ 1 D = Decrease in leaf size or area 5 Y/D/L2 2 6 Y/ D/L/ 2 L = shorter internodes 7 Y/E/B/L2G/ 2 8 Y2D2L2 2 B = reduced number of leaves 9 Y2D2B/L2 3 10 Y2D2B/L/ 2 G = darker green color of leaves Compound All barley plants treated with No. 6 were observed to have strong erect stems and erect leaves. Plants that were not treated fell over when not supported. On day 36, plants were evaluated for height from the soil surface to the apical lamina. Average height (mm) Plants treated with compound No. 6 69.9 Untreated control 132.4 This represents a 47% reduction in height. On the 84th day, 3 pots of treated plants and 3 pots of untreated plants are extracted and the height to the apical leaf lamina, leaf area, new weight, dry weight, and number of spikelets are measured. . The results are shown below for average data.

Table 1 The compounds therefore retard the growth of plants without adversely affecting their growth. Example 21 This example illustrates the synergistic effect exhibited by a mixture of compound No. 6 of Table I and a substance having the internationally recognized common name chlormequat chloride (CCC). Spring wheat (cv. Timmo) and spring barley (cv.
Sundance) is grown in John Innes No. 1 potting compost in 10 cm diameter pots at a rate of 4 wheat plants per pot. At the 2-3 leaf stage, the test compound (Compound No. 6 in Table I) and CCC ('Allotecus'
5C) in multiple combinations and at multiple application rates. A complete processing list is given below.
The term "Allotex" is the trade name for a commercial preparation containing chlormequat chloride.

【table】

[Table] Compound No. 6 is 95% water and cyclohexane
It is formulated as an emulsion consisting of 5% of a preparation containing 95%, "Sinperonik" NPE 1800 3.33% and "Tween" 85 1.65%. "Allotex" 5C
and by adding a solution containing “Aglar” 90.
Make a final concentration of 0.1%. As is clear from the table of results below, not all application rates shown were used in all tests.

[Table] The numbers in parentheses are the suppression rate of plant height growth.
(%).

[Table] The numbers in parentheses are the suppression rate of plant height growth.
(%).
The following table lists the compounds of Table I only for height inhibition.
This clearly demonstrates the synergy between No. 6 and chlormequat chloride. The data on tillering (algae development) is shown below.

【table】

[Table] The results shown in the table and in the table show that the tillering effect produced by using a mixture of the test compound and curmecoat chloride is greater than the tillering effect achieved when the test compound is used by itself. There is clear evidence of augmentation (and synergy). Example 22 This example illustrates the ability of Compound No. 6 of Table I to inhibit the growth of rice plants. Rice plants were grown in pots with two high ridges (i.e. small clumps) placed in each pot and grown at two times: 14 days after transplanting ( _T1 ) and 39 days after transplanting. After a day (T ₂ ), it is treated with compound No. 6 of Table I. The test compound was 0.1, 0.4, 1.0, 4.0Kg/ha at 1000/ha using a 5% preparation* system of the test solution.
Apply with. The final height measurement will be made after transplantation.
Do this after 103 days. The results are shown in the table below.

[Table] Compound No. 6 is formulated as an aqueous emulsion consisting of 95% water and 5% of a mixture containing 95% cyclohexane, 3.33% "Simperonik" NPE 1800 and 1.67% "Tween" 85. The above results show that the height of the rice plants is Compound No. in Table I.
6; and that application early in the rice growth stage produces the greatest suppressive effect. Example 23 This example illustrates the plant growth regulating properties of Compound No. 6 of Table I in dicotyledonous plants. At a pressure of 30 p.si on young apple and grape trees with approximately 4 to 5 leaves,
The test compound formulated as an emulsion was applied at three application rates.
Spray to a volume equivalent of 1000/ha. The plant is a Jion Innes No. 1 pot with a diameter of 10 to accommodate compost.
cm pots and maintained in a warm greenhouse with 14 hours of sunlight per day at a temperature of 25°C during the day and 20°C at night, where the natural sunlight was extended by high-pressure mercury vapor lamps (model MBFR). let Three weeks after treatment, the height of the young plants from the soil surface to the apical bud is evaluated. The results are given in Table X below. Particularly strong control was observed for both apples and grapes at application rates of 0.4 and 1.0 Kg/ha.

[Table] The apple and grape saplings used in this experiment were grown from small seeds of Retsudo delicias (apple) and small seeds of Ohanezu (grape). Example 24 This example illustrates the plant growth regulating properties of compounds of the invention in cereals. John Innes Potted Compost No.
Wheat (Amada species) in a 10cm diameter pot containing 2.
and seeds of barley (Sonya variety) that have undergone vernalization and have germinated. The compound is formulated as an emulsion*, which is applied to 1 leaf at the 2-leaf stage using a track sprayer.
Spray at 30 p.si to a volume equivalent of 1000/ha on barley and wheat quintuple pots containing 3 plants per pot. The plants were then arranged in a heterogeneous pattern and maintained with a minimum nighttime temperature of 11°C and a minimum daytime temperature of 14°C during a 14-h daylight period, with natural light supplemented by high-pressure mercury vapor lamps (model MBFR). extend it. Irrigate the plants underground. The height of the apical tongue is measured 5 weeks after treatment. The results are shown in the table below
Shown in XI. These results indicate that the tested compounds are capable of producing inhibition and therefore controlling grain lodging. *Test compound 5% Dispensing aid ⁺ 95% + Mixture of cyclohexanone 95%, "Simperonik" NPE1800 3.33% and "Tween" 85 1.67%.

[Table] (c) (4S)-1-[N-[3-(benzoylamino)
- Preparation of 2-oxo-4-phenylbutyl]-N-methylglycyl]-4-(4-fluorophenoxy)-L-proline monohydrochloride: - Ester product of (b) above (1.2 g, 1.95 mmol)
is treated with 2N hydrochloric acid/acetic acid (20 ml). After stirring for 2 hours at room temperature, the reaction mixture was concentrated under reduced pressure and the oily residue was triturated with ether overnight to give 0.92 g.
(4S)-1-[N-[3-(benzoylamino)-
2-oxo-4-phenylbutyl]-N-methylglycyl]-4-(4-fluorophenoxy)-L
-Proline monohydrochloride is obtained as an off-white solid. mp131~140°, R _f =0.54 (silica gel, n-
Butanol/acetic acid/water = 3:1:1). Elemental analysis (as C ₃₁ H ₃₂ N ₃ FO ₆・HCl・0.55H ₂ O) Calculated values: C61.24, H5.65, N6.91, Cl5.83 Actual values: C61.24, H5.66, N7 .09, Cl5.70 Similarly, Example 1 using the procedure of Examples 91-95
~90 compounds can be produced. Example 96 Production of N-[N-[3-(benzoylamino)-2-oxo-4-phenylbutyl)-N-methylglycyl]-N-cyclohexylglycine monohydrochloride: - (a) (±) -N -[3-(benzoylamino)-2-
Preparation of oxo-4-phenylbutyl]-N-methylglycine 1,1-dimethylethyl ester: Example 91(b) in dimethylformamide (20 ml)
To a solution of (±)-N-[3-(methylamino)-2-oxo-1-(phenylmethyl)propyl]benzamide (5.0 g, 15 mmol) prepared as described in Dimethylethyl ester (13.8g, 3.15ml, 19.5mmol) and diisopropylethylamine (2.5g, 3.4ml, 19.5mmol)
mol). After stirring overnight at room temperature, the reaction mixture is poured into water (100 ml) and extracted with ethyl acetate (3 times). The collected ethyl acetate extracts were dissolved in saturated sodium bicarbonate (twice), 10% potassium bisulfate (twice),
and water (twice), dried (Na ₂ SO ₄ ),
Concentration to a yellow oil, which was dried under high vacuum to give a dry foam, which yielded 5.4 g of (±)-
N-[3-(benzoylamino)-2-oxo-4
-Phenylbutyl]-N-methylglycine 1,
1-dimethylethyl ester is obtained. (b) (±)-N-[3-(benzoylamino)-2-
Production of oxo-4-phenylbutyl]-N-methylglycine monohydrochloride: - Ester product of (a) above (4.51 g, 11 mmol)
is treated with 2N hydrochloric acid/acetic acid (20 ml). at room temperature
After stirring for 2.5 hours, the reaction mixture was concentrated under reduced pressure and the oily residue was tritiated with ether to give 3.3 g of (±)-N-[3-(benzoylamino)-2-oxo-4-phenylbutyl]-N-methyl. Glycine monohydrochloride is obtained as an off-white solid. (c) N-[N-[3-(benzoylamino)-2-oxo-4-phenylbutyl)-N-methylglycyl]-N-cyclohexylglycine 1,1
- Preparation of dimethyl ethyl ester: - (±) in distilled tetrahydrofuran (50 ml) -
N-[3-(benzoylamino)-2-oxo-4
-Phenylbutyl]-N-Cyclohexylglycine 1,1-dimethylethyl ester (0.55 g, prepared as described in Example 65(a)) was added to a solution of N-methylglycine hydrochloride (1.0 g, 2.6 mmol). ,
2.6 mmol), hydroxybenzotriazole hydrate (0.39 g, 2.6 mmol) and dicyclohexylcarbodiimide (0.55 g, 2.6 mmol). The reaction mixture is stirred overnight to remove the precipitated dicyclohexylurea and the liquid is concentrated. The residue was dissolved in ethyl acetate (50 ml) and washed with saturated sodium bicarbonate (2 times), 10% potassium bisulfate (2 times), and water (2 times), dried (Na ₂ SO ₄ ) and left an oily residue. (1.5g). By flash chromatography (100 g of Merck silica gel 60), 0.49 g of N-[N-[3-(benzoylamino)]
-2-oxo-4-phenylbutyl)-N-methylglycyl]-N-cyclohexylglycine 1,
1-dimethylethyl ester is obtained as a foam. (d) Production of N-[N-[3-(benzoylamino)-2-oxo-4-phenylbutyl]-N-methylglycyl]-N-cyclohexylglycine monohydrochloride: - Ester product of (c) above (0.48 g, 0.87 mmol is treated with 2N hydrochloric acid/acetic acid (10 ml). After stirring for 2 hours at room temperature, the reaction mixture is concentrated under reduced pressure and the oily residue is triturated with ether overnight to give a
g of N-[N-[3-(benzoylamino)-2-oxo-4-phenylbutyl)-N-methylglycyl]-N-cyclohexylglycine monohydrochloride is obtained as an off-white solid. mp131~145°, R _f
= 0.36 (silica gel, n-butanol/acetic acid/water = 4:1:1). Elemental analysis ( _{as C28H35N3O5}・HCl・_0.7H2O ) Calculated values: _C61.95 , H6.95, _N7.74 , Cl6.53 Actual values: C61.95, H6.74, N7 .71, Cl6.23 Example 97 (S)-7-[[[(±)-3-(benzoylamino)
- Preparation of 2-oxo-4-phenylbutyl]methylamino]acetyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid methyl ester: - Example in distilled tetrahydrofuran (50 ml)
(±)-N-[3-(benzoylamino)-2-oxo-4-phenylbutyl]-N-methylglycine monohydrochloride (1.0
(S)-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid methyl ester monoacetate (0.66 g, 2.5 mmol)
mmol), dicyclohexylcarbodiimide (0.54 g, 2.5 mmol), hydroxybenzotriazole hydrate (0.39 g, 2.5 mmol) and diisopropylethylamine (0.9 ml, 5 mmol). The reaction mixture is stirred overnight to remove the precipitated dicyclohexylurea and the liquid is concentrated. The residue is dissolved in ethyl acetate (100ml), washed with saturated sodium bicarbonate (2x) and water ( _2x ), dried ( _Na2SO4 ) and concentrated to a yellow oily residue (1.3g). Flash chromatography (Merck silica gel, 25% ethyl acetate/methylene chloride, 1%
methanol/methylene chloride) to produce 0.53 g of (S)-7-[[[(±)-3-(benzoylamino)]
−
2-oxo-4-phenylbutyl]methylamino]acetyl]1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid methyl ester is obtained as a white foam. mp60-62°, R _f =0.52 (silica gel, 5% methanol/methylene chloride). Elemental analysis (as C ₂₈ H ₃₃ N ₃ O ₅ S ₂・0.33H ₂ O) Calculated values: C59.87, H6.04, N7.48, S11.42 Actual values: C59.87, H5.94, N7 .56, S11.36 Example 98 (S)-7-[[[(±)-3-(benzoylamino)
-Production of 2-oxo-4-phenylbutyl[methylamino]acetyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid methyl ester monohydrochloride: - Production of methyl ester of Example 97 material (0.26g,
0.46 mmol) was treated with 2N hydrochloric acid/acetic acid until homogeneous (2 min), concentrated under reduced pressure, and the oily residue was tritylated with ether (twice) to give 0.26 g of (S)-7-[[ [(±)-3-(benzoylamino)
−
2-oxo-4-phenylbutyl]methylamino]acetyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid methyl ester monohydrochloride is obtained as a white solid. mp79~85°,
R _f =0.53 (silica gel, 5% methanol/methylene chloride). Elemental analysis (as C ₂₈ H ₃₃ N ₃ O ₅ S ₂・HCl・0.56H ₂ O) Calculated values: C55.84, H5.88, N6.98, S10.64,
Cl5.88 Actual value: C55.84, H5.95, N6.78, S10.43,
C15.66 Example 99 (4S)-1-[N-[3-(benzoylamino)-
2-oxo-4-phenylbutyl]-N-methylglycyl]-4-(4-fluorophenoxy)
-Production of L-proline methyl ester monohydrochloride: - (a) Production of (4S)-4-(fluorophenoxy)-L-proline methyl ester monohydrochloride:
- A suspension of (4S)-4-(fluorophenoxy)-L-proline (2.5 g, 11 mmol) in methanol was treated with thionyl chloride (8.09 ml, 11 mmol) at -30° under an argon atmosphere. Add. The reaction mixture -
Stir at 20° for 2 hours and then at room temperature for 16 hours. The solvent was removed under reduced pressure, the residue redissolved in methylene chloride (150 ml) and 1N sodium carbonate (2
Wash with water (twice) and water (twice). Drying ( _NgSO4 )
Afterwards, excess hydrochloric acid/methanol is added and the solvent is removed under reduced pressure. Add ether to light brown solid (2.6g)
get. Recrystallize from methanol/ether,
1.49g of (4S)-4-(fluorophenoxy)-L
- Proline methyl ester monohydrochloride is obtained as a light brown solid. mp147~148°, [α] ²⁰ _D = +6.96°
(C=1.55, methanol). (b) (4S)-1-[N-[3-(benzoylamino)
Production of -2-oxo-4-phenylbutyl]-N-methylglycyl]-4-(4-fluorophenoxy)-L-proline methyl ester:
- Example 96 in distilled tetrahydrofuran (20 ml)
(±)-N-[3-(benzoylamino)-2-oxo-4-phenylbutyl]-N-methylglycine monohydrochloride (1.17 g,
(4S)-4-(fluorophenoxy)-L-proline methyl ester monohydrochloride (0.82 g, 3 mmol), hydroxybenzotriazole hydrate (0.46 g, 3 mmol) ) and dicyclohexylcarbodiimide (0.62g, 3m
mol). The reaction mixture is stirred overnight to remove the precipitated dicyclohexylurea and the liquid is concentrated. The residue is dissolved in ethyl acetate (50 ml), washed with saturated sodium bicarbonate (2 times) and water (2 times), dried (Na ₂ SO ₄ ) and concentrated to an oily residue (1.1 g). Flash chromatography (200g
0.15 g of (4S)-1-[N-[3
-(Benzoylamino)-2-oxo-4-phenylbutyl]-N-methylglycyl]-4-(4-fluorophenoxy)-L-proline methyl ester is obtained as a foam. (c) (4S)-1-[N-[3-(benzoylamino)
- Production of 2-oxo-4-phenylbutyl]-N-methylglycyl]-4-(4-fluorophenoxy)-2-proline methyl ester monohydrochloride: - The methyl ester product of (b) above ( 0.15g, 0.26
mmol) was treated with 2N hydrochloric acid/acetic acid until homogeneous (2 min), concentrated in vacuo, and the oily residue was tritylated (twice) with ether to give 0.14 g of (4S).
-1-[N-[3-(benzoylamino)-2-oxo-4-phenylbutyl]-N-methylglycyl]
-4-(4-fluorophenoxy)-L-proline methyl ester monohydrochloride is obtained as an off-white solid. mp105-125°, Rf=0.27 (silica gel, 5% methanol/chloroform). Elemental analysis (as C ₃₂ H ₃₄ FO ₆・HCl) Calculated values: C62.79, H5.76, N6.86, F3.10,
Cl5.79 Actual value: C62.78, H5.73, N6.87, S2.83,
Cl5.33 Example 100 (4S)-1-[N-[(S)-3-(benzoylamino)-2-oxo-4-phenylbutyl]-L
-alanyl]-4-(4-fluorophenoxy)
-Production of L-broline monohydrochloride: - (a) (S)-N-[3-benzoylamino)-2-
Production of oxo-4-phenylbutyl]-L-alanine 1,1-dimethylethyl ester:
- (S)-N in dimethylformamide (80 ml)
- To a stirred solution of [3-chloro-2-oxo-1-(phenylmethyl)propyl]benzamide (10.0 g, 33.1 mmol) was added L-alanine 1,1-dimethylethyl ester hydrochloride (6.0 g, 33 ,1m
mol), sodium bicarbonate (6.1 g, 72 mmol) and sodium iodide (4.9 g, 33·1 mmol). The resulting solution is stirred overnight at room temperature, poured into ether and washed with water (twice) and 10% sodium bicarbonate. Add ether solution to 1N hydrochloric acid (3 times)
The combined extracts are made basic with solid sodium bicarbonate and extracted with ethyl acetate (4 times). The organic extracts were collected, dried (NgSO ₄ ) and
Concentrate to obtain 8.9 g of pale yellow solid. A part of this substance was recrystallized from ethyl acetate to give (S)-N-
[3-(Benzoylamino)-2-oxo-4-phenylbutyl]-L-alanine 1,1-dimethylethyl ester is obtained as a white solid. mp−
106.5~110°. (b) (S)-N-[3-(benzoylamino)-2-
Preparation of oxo-4-phenylbutyl]-L-alanine monoacetate: - A solution of the above ester product (a) (2.95 g, 5.4 mmol) in 1.4 N hydrochloric acid/acetic acid (39 ml) at room temperature. Stir for 2 hours. Collect the resulting white precipitate,
Rinse with ether and dry to give 2.27 g of (S)-
N-[3-(benzoylamino)-2-oxo-4
-Phenylbutyl]-L-alanine monohydrochloride is obtained. mp208~209° (decomposition), [α] _D = −71° (
C
= 0.38%, methanol). R _f =0.51 (silica gel,
Chloroform/methanol/acetic acid = 4:1:1). Elemental analysis (as C ₂₀ H ₂₂ N ₂ O ₄・HCl) Calculated values: C61.64, H5.93, N7.17, Cl9.07 Actual values: C61.33, H5.97, N7.17, Cl8. 79 (c) (S)-N-[N-(benzoylamino)-2-
Production of oxo-4-phenylbutyl]-N-[(phenylmethoxy)carbonyl]-L-alanine: - (S)-N-[3-(benzoylamino)-2-oxo-4-phenylbutyl]-L- To a mixture of alanine monoacetate (2.0 g, 5.1 mmol), benzyl chloroformate (730 μl, 5.1 mmol), water (7 ml) and dioxane (7 ml) was added triethylamine (2.1 ml, 15 mmol) at 25°. Add. The resulting mixture is stirred at 25° for 3 hours, then poured into 5% aqueous sodium bicarbonate and washed with ether. The aqueous layer was acidified (HCl) and extracted into ethyl acetate (3x).
do. The extract is dried (NgSO ₄ ) and concentrated to give a colorless oil. Trituration with ether gives a white granular solid, which is collected and discarded. The mother liquor was concentrated under reduced pressure to give 1.75 g of (S)-N-[N-(benzoylamino)-2-oxo-4-phenylbutyl]-N-[(phenylmethoxy)carbonyl]-L.
-Alanine is obtained as a white glass. (d) (4S)-1-[N-[(S)-3-(benzoylamino)-2-oxo-4-phenylbutyl]-
N-[(phenylmethoxy)carbonyl]-L-
Alanyl]-4-(4-fluorophenoxy)-
Preparation of L-proline phenyl methyl ester: -(S)-N- in tetrahydrofuran (7 ml)
[N-benzoylamino)-2-oxo-4-phenylbutyl]-N-[(phenylmethoxy)carbonyl]-L-alanine (300 mg, 0.62 mmol),
(4S)-4-(4-fluorophenoxy)-L-proline phenylmethyl ester p-trienesulfonate (300 mg, 0.62 mmol), triethylamine (90 μl, 0.62 mmol), dicyclohexylcarbodiimide ( 130 mg, 0.62 mmol) and hydroxybenzotriazole hydrate (90 mg, 0.62
mmol) The mixture is stirred at 25° for 20 hours. Then,
Filter the mixture and dilute with ethyl acetate. The resulting solution was washed successively with 1N hydrochloric acid and 10% aqueous sodium bicarbonate, dried (NgSO ₄ ),
Filter and concentrate to obtain 500 mg of (4S)-1-[N-[(S)
-3-(Benzoylamino)-2-oxo-4-phenylbutyl]-N-[(phenylmethoxy)carbonyl]-L-alanyl]-4-(4-fluorophenoxy)-L-proline phenyl The methyl ester is obtained as a pale yellow oil. (e) (4S)-1-[N-[(S)-3-(benzoylamino)-2-oxo-4-phenylbutyl]-
Preparation of L-alanyl]-4-(4-fluorophenoxy)-L-proline monohydrochloride: - ester product of (d) above (500 mg, 0.6 mmol),
Palladium/carbon catalyst (10%, 100mg), absolute ethanol (15ml) and 1.0N aqueous hydrochloric acid (800μ,
A mixture of 0.8 mmol) is hydrogenated at 1 atm and 25° for 17 hours, then filtered and concentrated. The residue was chromatographed on HP-20 with a linear gradient from [0.01N aqueous hydrochloric acid/methanol = 9:1] to [0.01N aqueous hydrochloric acid/methanol = 1:1]. Collect each fraction containing the desired product (TLC),
Concentrate. Dissolve the residue in a minimum amount of methanol. Addition of ether produced a white precipitate, which was collected and dried under reduced pressure to yield 200 mg of (4S)-1-[N-
[(S)-3-(benzoylamino)-2-oxo-
4-phenylbutyl]-L-alanyl]-4-(4
-Fluorophenoxy)-L-proline monohydrochloride is obtained. mp152~153° (decomposition), [α] ²⁵ _D = -
50° (C=0.5, methanol). R _f =0.75 (silica gel, chloroform/methanol/acetic acid = 4:1:
1). Elemental analysis (as C ₃₁ H ₃₂ FN ₃ O ₆・HCl・1.5H ₂ O) Calculated values: C59.57, H5.80, N6.72, Cl5.67 Actual values: C59.68, H5.56, N6 .67, Cl5.99 Example 101 [1(S),4R]-1-[N-[3-(benzoylamino)-2-oxo-4-phenylbutyl]-
Production of L-alanyl]-4-phenyl-L-proline monohydrochloride: - (a) (S)-N-[N-(benzoylamino)-2-
Preparation of oxo-4-phenylbutyl]-N-[(phenylmethoxy)carbonyl]-L-alanine succinimide ester: Example 100 in tetrahydrofuran (5 ml)
(S)-N-[N-(benzoylamino)-2-oxo-4-phenylbutyl]-N-[(phenylmethoxy)carbonyl]-L prepared as described in (c)
- A mixture of alanine (800 mg, 1.6 mmol), dicyclohexylcarbodiimide (340 mg, 1.6 mmol) and N-hydroxysuccinimide (190 mg, 1.6 mmol) is stirred at 25° for 18 hours. After this,
filtered and concentrated to give 950 mg of (S)-N-[N-(benzoylamino)-2-oxo-4-phenylbutyl]-N-[(phenylmethoxy)carbonyl]-
L-alanine succinimide ester is obtained. (b) [1(S),4R]-1-[N-[3-(benzoylamino)-2-oxo-4-phenylbutyl]
-N-[(phenylmethoxy)carbonyl]-L
Preparation of -alanyl]-4-phenyl-L-proline: -(S)-N in dimethylformamide (5 ml)
-[N-(benzoylamino)-2-oxo-4-
(4R)-4 was added to a solution of phenylbutyl]-N-[(phenylmethoxy)carbonyl]-L-alanine succinimide ester (950 mg, 1.6 mmol).
-Phenyl-L-proline hydrochloride (375 mg, 1.7
mmol) and triethylamine (40 μl, 3.2 mmol)
mol). The resulting mixture is stirred at 25° for 24 hours, then poured into excess 1N hydrochloric acid and extracted with ethyl acetate (3 times). The extracts were combined, dried (NgSO ₄ ), filtered, and concentrated to 1.1 g [1
(S),4R]-1-[N-[3-(benzoylamino)
-2-oxo-4-phenylbutyl]-N-[(phenylmethoxy)carbonyl]-L-alanyl]-
4-phenyl-L-proline is obtained. (c) (1(S),4R]-1-[N-[3-(benzoylamino)-2-oxo-4-phenylbutyl]
-L-Alanyl]-4-phenyl-L-proline monohydrochloride production: -Product of (b) above (1.0g, 1.5mmol), ethanol (20ml), water (5ml), 1.0N- Hydrochloric acid (1.5ml,
1.5 mmol) and palladium/carbon catalyst (10%,
100 mg) at 1 atm and 25° for 18 hours, then filtered and concentrated. Residue HP-20
The mixture was subjected to chromatography using a linear gradient of [0.01N-aqueous hydrochloric acid:methanol=4:60 to 10:90]. Each fraction containing the desired product (TLC) is collected and concentrated. Dissolve the residue in a minimum amount of methanol. Ether was added and the resulting white precipitate was collected and dried to give 300 mg of [1(S),4R]-1-[N
-[3-(benzoylamino)-2-oxo-4-
Phenylbutyl]-L-alanyl]-4-phenyl-L-proline monohydrochloride is obtained. mp160～
162° (decomposition), [α] ²⁵ _D = -57° (C = 1.5, methanol), R _f = 0.8 (silica gel, chloroform/methanol/acetic acid = 4:1:1). Elemental analysis (as C ₃₁ H ₃₃ N ₃ O ₅・HCl・1.35H ₂ O) Calculated values: C63.27, H6.29, N7.14, Cl6.02 Actual values: C63.27, H6.17, N7 .19, C15.97 Example 102 [1(s),4s]-1-[N-[3-(benzoylamino)-2-oxo-4-phenylbutyl]-L-
Preparation of alanyl]-4-phenyl-L-proline monohydrochloride:- In Example 101(b), (4s)-4-phenyl-
Example 101 except for using L-proline hydrochloride
In the same manner as [1(s),4s]-1-[N-[3-(benzoylamino)-2-oxo-4-phenylbutyl]-L-alanyl-4-phenyl-L-proline monohydrochloride get. mp138~143°, [α] _D =
−61° (c=0.3%, methanol). R _f =0.84 (silica gel, chloroform/methanol/acetic acid 4:1:
1). Elemental analysis (as C ₃₁ H ₃₃ N ₃ O ₅・HCl・2.13H ₂ O) Calculated values: C61.80, H6.35, N6.98, Cl5.88 Actual values: C61.80, H6.06, N7 .05, Cl5.65 Example 103 [1(s),4R]-1-[N-[3-(benzoylamino)-2-oxo-4-phenylbutyl]-L
-Alanyl]-4-Cyclohexyl-L-proline monohydrochloride production: - In Example 101(b), the same as Example 101 except that (4R)-4-cyclohexyl-L-proline hydrochloride was used. Then [1(s), 4R]-1-[N-[3
-(Benzoylamino)-2-oxo-4-phenylbutyl]-L-alanyl]-4-cyclohexyl-L-proline monohydrochloride is obtained. mp140~
154° (decomposed), [α] _D = -83° (c = 0.36%, methanol). R _f =0.84 (silica gel, chloroform/methanol/acetic acid 4:1:1). Elemental analysis (as C ₃₁ H ₃₉ N ₃ O ₅・HCl・0.79H ₂ O) Calculated values: C63.71, H7.17, N7.19, Cl6.06 Actual values: C63.71, H7.21, N7 .05, Cl5.82 Example 104 [1(s),4s]-1-[N-[3-(benzoylamino)-2-oxo-4-phenylbutyl]-L-
Production of [alanyl]-4-cyclohexyl-L-proline monohydrochloride: - In Example 101(b), follow the same procedure as Example 101 except that (4s)-4-cyclohexyl-L-proline hydrochloride is used. Te[1(s),4s]-1-[N-[3-
(Benzoylamino)-2-oxo-4-phenylbutyl]-L-alanyl]-4-cyclohexyl-
L-proline monohydrochloride is obtained. mp139~
141° (decomposed), [α] _D = -80° (c = 0.2%, methanol). R _f =0.83 (silica gel, chloroform/methanol/acetic acid 4:1:1). Elemental analysis (as C ₃₁ H ₃₉ N ₃ O ₅・HCl・1.54H ₂ O) Calculated values: C62.28, H7.26, N7.03, Cl5.93 Actual values: C62.28, H7.01, N7 .02, Cl6.16 Example 105 (s)-7-[((s)-2-[[3-(benzoylamino)
-2-oxo-4-phenylbutyl]amino]
-1-oxopropyl]-1,4-dithia-7
- Preparation of azaspiro[4,4]nonane-8-carboxylic acid monohydrochloride: - In Example 101(b), instead of the L-proline reactant, (s)-1,4-dithia-7-azaspiro [4,4] (s)-7-[(s)-
2-[[3-(benzoylamino)-2-oxo-4
-phenylbutyl]amino]-1-oxopropyl]-1,4-dithia-7-azaspiro[4,4]
Nonane-8-carboxylic acid monohydrochloride is obtained.
mp170-172°, [α] ²⁵ _D = −26° (c = 1.4%, methanol). R _f =0.78 (silica gel, chloroform/
methanol/acetic acid 6:1:1). Elemental analysis (as C ₂₇ H ₃₁ N ₃ O ₅ S ₂・HCl・0.77H ₂ O) Calculated values: C54.77, H5.71, N7.10, S10.83,
Cl5.99 Actual value: C54.77, H5.70, N6.94, S10.82,
Cl6.07 Example 106 [1(s),5s]-1-[N-[3-(benzoylamino)-2-oxo-4-phenylbutyl]-L-
Preparation of [alanyl]-4,5-dihydro-3-phenyl-1H-pyrazole-5-carboxylic acid monohydrochloride: - In Example 101(b), in place of the L-proline reactant, (s)-4 ,5-dihydro-3-phenyl-
The title compound is obtained in the same manner as in Example 101 except that 1H-pyrazole-5-carboxylic acid is used. Example 107 (s)-2-[N-[(s)-3-(benzoylamino)-
2-oxo-4-phenylbutyl]-L-alanyl]-1,2,3,4-tetrahydro-3-
Production of isoquinolinecarboxylic acid monohydrochloride:
- (s) as in Example 101, except that in Example 101(b), the proline reactant is replaced by (s)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic hydrochloride. -2-[N-[(s)-3-(benzoylamino)-2-oxo-4-phenylbutyl]-L-alanyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid/monohydrochloric acid Get salt. Example 108 1-[N-[(s)-3-(benzoylamino)-2-
Oxo-4-phenylbutyl]-L-alanyl]
- Preparation of 2-(2-hydroxyphenyl)-4(R)-thiazolidinecarboxylic acid monohydrochloride: - In Example 101(b), 2-[(2-phenylmethoxy ) phenyl] −
1-[N-[(s)-3-(benzoylamino)-2-oxo- 4-phenylbutyl]-L-
Alanyl]-2-(2-hydroxyphenyl)-4
(R)-thiazolidinecarboxylic acid monohydrochloride is obtained. Similarly, the methods of Examples 96, 97, 99 and 100-108 can be used to prepare the compounds of Examples 1-95. Example 109 (±)-1-[N-[3-(benzoylamino)-
Production of 2-oxo-4-phenylbutyl]-L-alanyl]-L-proline methyl ester monohydrochloride: - (a) 1-[N-(2-ethoxy-2-oxoethyl)-N-[( phenylmethoxy)carbonyl]-
Production of L-alanyl]-L-proline 1,1-dimethylethyl ester:- L-alanyl-L-proline 1,1-dimethylethyl ester (25.44 g, 105 mmol) was added to tetrahydrofuran (400 ml) with stirring. put in. This was added to bromoethyl acetate (11.64ml, 105mmol) and diisopropylethylamine (18.3ml, 105mmol).
mol). After 6 hours, the reaction mixture was cooled in an ice bath and treated with benzyl chloroformate (16.5 ml, 115.5 mmol) and dipropylethylamine (20.1 ml,
115.5 mmol). After 1 hour, remove the ice bath and
The reaction mixture is kept at room temperature overnight. It is then concentrated to dryness, taken up in ethyl acetate and neutralized with 10% potassium bisulfate and saturated sodium bicarbonate. The crude product (52.3 g) was purified on a silica gel column eluting with ethyl acetate/hexane (1:1) to give 42.4 g of 1-[N-(2-ethoxy-2-oxoethyl)-N-[( Phenylmethoxy)carbonyl]-L-alanyl]-L-proline 1,1-dimethylethyl ester is obtained. (b) 1-[N-(carboxymethyl)-N-[(phenylmethoxy)carbonyl]-L-alanyl]-
Production of L-proline 1,1-dimethylethyl ester: - Ester product of (a) above (21 g, 45.4 mmol)
methanol (150 ml) and 1N at room temperature under stirring.
- Place in sodium hydroxide (50 ml, 50 mmol). After 5.5 hours, methanol was removed under reduced pressure and the aqueous portion was extracted with ethyl acetate. The aqueous portion was acidified with concentrated hydrochloric acid and extracted into ethyl acetate to obtain 16.95 g of 1-[N-
carboxymethyl)-N-[(phenylmethoxy)
Carbonyl]-L-alanyl]-L-proline
1,1-dimethylethyl ester is obtained. (c) (±)-1-[N-[N-[3-(benzoylamino)-2-oxo-4-phenylbutyl]-N
- Production of [(phenylmethoxy)carbonyl]-L-alanyl]-L-proline 1,1-dimethylethyl ester: - Ester product of (b) above (10.0 g, 23 mmol)
into tetrahydrofuran (75 ml) in an ice bath with stirring. Add to this oxalyl chloride (2.4 ml,
27.6 mmol), then add 15 drops of dimethylformamide. After 20 minutes, the ice bath is removed and the reaction mixture is kept at room temperature for 1 hour. The mixture is then concentrated to dryness under reduced pressure and stirred into tetrahydrofuran (40 ml) in an ice bath. This was combined with 2-phenyl-4-(phenylmethyl)-5(4H)-oxazolone (6 g, 23.8 m
Triethylamine (3.22 ml,
23 mmol). Triethylamine is added separately to maintain basic conditions. After 20 minutes, remove the ice bath and keep the reaction mixture at room temperature overnight. Triethylamine hydrochloride was removed, and the solution was concentrated to dryness under reduced pressure. The residue is taken up in pyridine (25 ml), 4-dimethylaminepyridine (75 ml) is added and the solution is stirred under argon for 3 hours. Acetic acid (25 ml) is added and the reaction mixture is stirred at 100° for 45 min under a positive flow of argon. The reaction mixture is concentrated to dryness, taken up in ethyl acetate and washed with saturated sodium bicarbonate and dilute hydrochloric acid. The crude product (12.8 g) was chromatographed on silica gel eluting with ethyl acetate/hexane (1:1) to yield 9.05 g of (±)-1-
[N-[N-[3-(benzoylamino)-2-oxo-4-phenylbutyl]-N-[(phenylmethoxy)carbonyl]-L-alanyl]-L-proline 1,1-dimethylethyl ester get. (d) (±)-1-[N-[N-[3-(benzoylamino)-2-oxo-4-phenylbutyl]-N
- Preparation of [(phenylmethoxy)carbonyl]-L-alanyl]-L-proline: - Ester product of (c) above (11.4 g, 17.7 mmol)
in trifluoroacetic acid (50 ml) and kept at room temperature for 45 minutes. It is then concentrated to dryness and tritiated with ether/hexane to obtain 10.3 g of crude product. This substance was mixed with benzene/acetic acid (8:
2) Purified with a medium silica gel column to obtain 9.7 g of (±)-1-[N-[N-[3-(benzoylamino)]
-2-oxo-4-phenylbutyl]-N-[(phenylmethoxy)carbonyl]-L-alanyl]-
Obtain L-proline. mp70~91°, [α] ²³ _D =-
53.0 (c=12.2, methanol). R _f =0.41 (silica gel, benzene/acetic acid = 8:2). Elemental analysis (as C ₃₃ H ₃₅ N ₃ O ₇ ) Calculated values: C67.68, H6.02, N7.17 Actual values: C67.95, H6.02, N6.82 (e) (±) −1− [N-[N-[3-(benzoylamino)-2-oxo-4-phenylbutyl]-N
- Preparation of [(phenylmethoxy)carbonyl]-L-alanyl]-L-proline methyl ester: - Add the acid product of (d) above (3.5 g, 6 mmol) to dimethylformamide (12 ml) under stirring at room temperature. Enter it with
To this are added sodium bicarbonate (630 mg, 7.5 mmol) and methyl iodide (0.47 ml, 7.5 mmol).
After 18 hours, additional methyl iodide (7.4 mmol) and sodium bicarbonate (7.4 mmol) are added. After further stirring for 4 hours, the reaction mixture was concentrated to dryness under reduced pressure.
Take in ethyl acetate and wash with saturated sodium bicarbonate. The crude product (3.7 g) was purified on a silica gel column in ethyl acetate/hexane (2:1) to give 3.5 g.
(±)-1-[N-[N-[3-(benzoylamino)-2-oxo-4-phenylbutyl]-N-
[(phenylmethoxy)carbonyl]-L-alanyl]-L-proline methyl ester is obtained. (f) (±)-1-[N-[3-(benzoylamino)
- Preparation of 2-oxo-4-phenylbutyl]-L-alanyl]-L-proline methyl ester monohydrochloride: - Ester product of (e) above (900 mg, 1.5 mmol)
in ethanol (95%, 100 ml) and 1N hydrochloric acid (1.8 ml). Palladium/carbon catalyst (10
%, 180 mg) and the reaction mixture is stirred under hydrogen overnight. The reaction mixture was filtered to remove the catalyst, concentrated to dryness, and lyophilized twice from water to give 700 mg (±)
-1-[N-[3-(benzoylamino)-2-oxo-4-phenylbutyl]-L-alanyl]-L-
Obtain proline methyl ester monohydrochloride.
mp110~128° (90°), [α] ²³ _D = -69.9° (c = 1
.18,
methanol). R _f =0.63 (silica gel, chloroform/methanol/acetic acid = 9:1:1). Elemental analysis (as C ₂₆ H ₃₁ N ₃ O ₅・HCl・0.92H ₂ O) Calculated values: C60.22, H6.58, N8.11, Cl6.84 Actual values: C60.22, H6.28, N8 .10, Cl7.06 Example 110 (±)-1-[N-[3-(benzoylamino)-
Preparation of 2-oxo-4-phenylbutyl]-L-alanyl]-L-proline methyl ester monomethanesulfonate: - (±)-1- prepared as described in Example 109(e)
[N-[N-[3-(benzoylamino)-2-oxo-4-phenylbutyl]-N-[(phenylmethoxy)carbonyl]-L-alanyl]-L-proline methyl ester (600 mg, 1 mmol) ), methanol (60 ml) and methanesulfonic acid (0.066
ml, 1 mmol). Palladium/carbon catalyst (10%, 120 mg) was added and the reaction mixture was heated under hydrogen for 2.5 min.
Stir for an hour. The reaction mixture is filtered to remove the catalyst and then concentrated under reduced pressure. The crude product is tritiated with ether and filtered. The precipitate was placed in water and lyophilized to give 470 mg of (±)-1-[N-[3-
(Benzoylamino)-2-oxo-4-phenylbutyl]-L-alanyl]-L-proline methyl ester monomethanesulfonate is obtained. m.
p.80-140°, [α] ²³ _D = −61.4° (c = 1.10, methanol). R _f =0.63 (silica gel, chloroform/methanol/acetic acid = 9:1:1). Elemental analysis (as _C26H31N3O5・_CH4O3S ) Calculated values: C56.98, H6.34, N7.30, S5.63 Actual _{values : C56.98} , H6.32, _N7 . 47, S5.63 Example 111 (±)-1-[N-[3-(benzoylamino)-
Preparation of 2-oxo-4-phenylbutyl]-L-alanyl]-L-proline methyl ester hemisulfate: - (±)-1- prepared as described in Example 109(e)
[N-[N-[3-(benzoylamino)-2-oxo-4-phenylbutyl]-N-[(phenylmethoxy)carbonyl]-L-alanyl]-L-proline methyl ester (600 mg, 1 mmol) ) to 1N−
Add to methanol (40 ml) with sulfuric acid (0.9 ml). Palladium/carbon catalyst (10%, 120 mg) is added and the reaction mixture is stirred under hydrogen for 2 hours. The reaction mixture was filtered to remove the catalyst, concentrated to dryness, tritiated with ether, and filtered. The crude product (446 mg) was taken up in water, filtered through Millipore, and lyophilized to give 405 mg of (±)-1-[N-[3-(benzoylamino)-2-oxo-4-phenylbutyl]-L.
-alanyl]-L-proline methyl ester
Obtain hemisulfate.・mp98~112° (85°), [α] ²³ _D
=
−60.3° (c=1.16, methanol). R _f =0.3 (trace)
(Silica gel, chloroform/methanol/acetic acid = 9:1:1). Elemental analysis (C ₂₆ H ₃₁ N ₃ O ₅・0.5H ₂ SO ₄・0.91H ₂ O
) Calculated value: C58.81, H6.42, N7.92, S3.01 Actual value: C58.81, H6.11, N7.91, S3.09 Example 112 (±)-1-[N- [3-(Benzoylamino)-
Production of 2-oxo-4-phenylbutyl]-L-alanyl]-L-proline propyl ester/monomethanesulfonate: - (a) (±)-1-[N-[N-[3-(benzoylamino)] -2-oxo-4-phenylbutyl]-N
- Preparation of [(phenylmethoxy)carbonyl]-L-alanyl]-L-proline propyl ester: - (±)-1- prepared as described in Example 109(d)
[N-[N-[3-(benzoylamino)-2-oxo-4-phenylbutyl]-N-[(phenylmethoxy)carbonyl]-L-alanyl]-L-proline (1.17 g, 2 mmol) and stirred in tetrahydrofuran (2 ml) in an ice bath. After adding n-propanol (3.0 ml, 40 mmol) to this, 4-
Dimethylaminepyridine (122mg, 1mmol) and dicyclohexylcarbodiimide (412mg, 2mmol)
mol). The reaction system was allowed to warm to room temperature and reacted overnight. remove dicyclohexyl urea,
The liquid was concentrated to dryness under reduced pressure. The crude product (1.2 g) was chromatographed on a silica gel column in benzene/acetic acid (9:1) to yield 1.0 g of (±)-1
-[N-[N-[3-(benzoylamino)-2-oxo-4-phenylbutyl]-N-[(phenylmethoxy)carbonyl]-L-alanyl]-L-proline propyl ester is obtained. (b) (±)-1-[N-[3-(benzoylamino)
-2-oxo-4-phenylbutyl]-L-alanyl]-L-proline propyl ester
Preparation of monomethane sulfonate: - Ester product of (a) above (500 mg, 0.8 mmol)
into methanol (50ml). Methanesulfonic acid (0.72 ml, 1N in methanol) and palladium/carbon catalyst (10%, 100 mg) are added and the reaction mixture is stirred under hydrogen overnight. The reaction mixture is filtered to remove the catalyst, concentrated to dryness, tritiated with ether, and filtered to give 406 mg of crude product.
Add this to water, pass through Millipore, and freeze dry.
390 mg of (±)-1-[N-[3-(benzoylamino)-2-oxo-4-phenylbutyl]-L-alanyl]-L-proline propyl ester monomethanesulfonate are obtained. mp82~94°
(69°), [α] ²³ _D = −60.5° (c = 0.95, methanol).
R _f =0.46 (silica gel, _chloroform /methanol _/ acetic _acid = 90:5:5. Elemental analysis ( _C28H35N3O5・_{CH4O3S ・ 0.5H2O}
) Calculated value: C58.15, H6.73, N7.01, S5.34 Actual value: C58.15, H6.63, N7.05, S5.34 Example 113 (±)-1-[N- [3-(Benzoylamino)-
Production of 2-oxo-4-phenylbutyl]-L-alanyl]-L-proline ethyl ester monomethane sulfate: - (a) (±)-1-[N-[N-[3-(benzoyl Amino)-2-oxo-4-phenylbutyl]-N
- Preparation of [(phenylmethoxy)carbonyl]-L-alanyl]-L-proline ethyl ester: - (±)-1- prepared as described in Example 109(d)
[N-[N-[3-(benzoylamino)-2-oxo-4-phenylbutyl]-N-[(phenylmethoxy)carbonyl]-L-alanyl]-L-proline (1.17 g, 2 mmol) and stirred in tetrahydrofuran (2 ml) in an ice bath. To this is added absolute ethanol (2.3 ml, 40 mmol) followed by 4-dimethylaminopyridine (122 mg, 1 mmol) and dicyclohexylcarbodiimide (412 mg, 2 mmol). Allow to react overnight at room temperature. The dicyclohexyl urea is removed, the solution is concentrated to dryness, the residue is taken up in ethyl acetate and washed with 10% potassium bisulfate and saturated sodium carbonate. The crude product (1.2 g) was purified on a silica gel column in benzene/acetic acid (8:2) to yield 1.0 g of (±)-1-[N-
[N-[3-(benzoylamino)-2-oxo-4
-Phenylbutyl]-N-[(phenylmethoxy)
Carbonyl]-L-alanyl]-L-proline ethyl ester is obtained. (b) (±)-1-[N-[3-(benzoylamino)
-Production of 2-oxo-4-phenylbutyl]-L-alanyl]-L-proline ethyl ester monomethane sulfate: - The ester product (500 mg, 0.8147 mmol) of above (a) was added to 500 ml of methanol. - Place in methanolic methanesulfonic acid (1N, 0.733 ml). Palladium/carbon catalyst (10%, 100 mg) is added and the reaction mixture is stirred under positive hydrogen pressure for 3 hours. The reaction mixture was filtered to remove the catalyst, concentrated to dryness, tritiated with ether, and filtered. The precipitate (428 mg) was poured into water, filtered through Millipore, and lyophilized to give 360 mg.
(±)-1-[N-[3-(benzoylamino)-
2-oxo-4-phenylbutyl]-L-alanyl]-L-proline ethyl ester monomethanesulfonate is obtained. mp91~96° (72°), [α]
²³ _D = −57.2° (c = 1.04, methanol). R _f =0.44(
Silica gel, chloroform/methanol/acetic acid =
90:5:5). Elemental analysis ( _{as C27H33N3O5 ・ CH4SO3}・_0.6H2O ) Calculated values: C57.33, H6.56, _N7.17 , _S5.47 Actual values: C57.33, H6. 43, N7.12, S5.47 Example 114 (±)-1-[N-[3-(benzoylamino)-
Production of 2-oxo-4-phenylbutyl]-L-alanyl]-L-proline 1-methylethyl ester monomethanesulfonate: - (a) (±)-1-[N-[N-[3-( benzoylamino)-2-oxo-4-phenylbutyl]-N
- Preparation of [(phenylmethoxy)carbonyl]-L-alanyl]-L-proline 1-ethyl ester: - (±)-1- prepared as described in Example 109(d).
[N-[N-[3-(benzoylamino)-2-oxo-4-phenylbutyl]-N-[(phenylmethoxy)carbonyl]-L-alanyl]-L-proline (1.17 g, 2 mmol), and isopropanol (3.0 ml, 40 mmol) in tetrahydrofuran (2 ml) in an ice bath with stirring. To this is added dicyclohexylcarbodiimide (412 mg, 2 mmol). Allow to react overnight at room temperature. It is then concentrated to dryness and taken up in ethyl acetate to remove the dicyclohexylurea. The solution is neutralized and washed with 10% potassium bisulfate and saturated sodium bicarbonate. The crude product (1.2 g) was purified on a silica gel column with benzene/acetic acid (8:2) to give 1.0 g of (±)-1-[N
-[N-[3-(benzoylamino)-2-oxo-
4-Phenylbutyl]-N-[(phenylmethoxy)
Carbonyl]-L-alanyl]-L-proline 1
- Obtain the ethyl ester. (b) (±)-1-[N-[3-(benzoylamino)
-Production of 2-oxo-4-phenylbutyl]-L-alanyl]-L-proline 1-methylethyl ester monomethanesulfonate: - Ester product of (a) above (815 mg, 1.3 mmol)
in methanol (20 ml) and methanolic methanesulfonic acid (1N, 1.17 ml) under hydrogen in the presence of palladium/carbon catalyst (10%, 160 mg).
Stir for an hour. The reaction mixture was filtered to remove the catalyst and concentrated to dryness under reduced pressure. Trituration of the residue with ether and filtration of the precipitate gives 704 mg of crude product. Add this to 35ml of water (2% solution),
Millipore filtered and lyophilized to 600 mg (±)-1
-[N-[3-(benzoylamino)-2-oxo-
4-phenylbutyl]-L-alanyl]-L-proline 1-methylethyl ester monomethanesulfonate is obtained. mp88~105°, [α] ²³ _D = -
55.2° (c=1.05, methanol). R _f = 0.33 (silica gel, chloroform/methanol/acetic acid = 9:
1:1). _{Elemental analysis} ( _{C28H35N3O5 ・ CH4O3S ・ 0.66H2O}
) Calculated values: C57.89, H6.75, N6.99, S5.33 Actual values: C57.89, H6.62, N6.62, S5.32 Examples 115 to 123 Examples 109, 112, 113 and 114 similarly,
(±)-1-[N-[3-(benzoylamino)-2-
Oxo-4-phenylbutyl]-N-[(phenylmethoxy)carbonyl]-L-alanyl]-L-proline is treated with the reagents listed below. Removal of the alanyl protecting group provides the column ester product.

[Table] Example 124 1-[N-[(s)-3-(benzoylamino)-2-
Oxo-4-phenylbutyl]-L-alanyl]
-Production of L-proline sodium salt: -1-[N-[(s)-3-(benzoylamino)-2-
Oxo-4-phenylbutyl]-L-alanyl]-
Dissolve L-proline hydrochloride (424 mg, 1 mmol) in water (50 ml). Aqueous sodium bicarbonate solution (0.1N, 20 ml) is added and the aqueous solution is lyophilized.
Then, it was dissolved in water (10 ml), applied to a Sephadex Chromatography Egel G-10 column (5 cm x 60 cm), and eluted with water. Each fraction containing the desired product was pooled and lyophilized to give 1-
[N-[(s)-3-(benzoylamino)-2-oxo-4-phenylbutyl]-L-alanyl]-L-proline sodium salt is obtained. Example 125 ingredients mg 1-[N-[(s)-3-(benzoylamino)-2-
Oxo-4-phenylbutyl]-L-alanyl]
-L-proline sodium salt...100 Cornstarch...50 Gelatin...7.5 Avicel (microcrystalline cellulose)...25 Magnesium stearate...2.5 Prepare 1000 tablets containing each of the above ingredients from sufficient bulk quantities. do. That is, 1-[N-[(s)-
3-(Benzoylamino)-2-oxo-4-phenylbutyl]-L-alanyl]-L-proline sodium salt and corn starch are mixed with an aqueous solution of gelatin. The mixture is dried and ground to a fine powder. Avicel and then magnesium stearate are mixed while being crushed. This mixture is then compressed into tablets each containing 100 mg of active ingredient.
Form 1000 tablets. Similarly, tablets containing 100 mg of the products of any of Examples 1-123 can be prepared. A similar procedure can also be used to form tablets containing 50 mg of active ingredient. Example 126 50 mg of 1-[N-[(s)-3-(benzoylamino)
Two-piece #1 gelatin capsules, each containing -2-oxo-4-phenylbutyl]-L-alanyl]-L-proline sodium salt, are filled with a mixture of the following ingredients. Ingredient mg 1-[N-[(s)-3-(benzoylamino)-2-
Oxo-4-phenylbutyl]-L-alanyl]
-L-proline sodium salt...50 Magnesium stearate...7 Lactose... 193 250 Capsules containing 50 mg of any of the products of Examples 1 to 123 can be prepared in a similar manner. Example 127 An injection solution is prepared according to the following procedure. Ingredient mg 1-[N-[(s)-3-(benzoylamino)-2-
Oxo-4-phenylbutyl]-L-alanyl]
-L-proline sodium salt...500 Methylparaben...5 Propylparaben...1 Sodium chloride...25 Water for injection...5 The above active substance, retention agent and sodium chloride are dissolved in the water for injection in step 3, and then the volume is reduced. Adjust to 5. The solution is passed through a sterile filter, filled aseptically into a sterile vial, and the vial is sealed with a sterile rubber stopper. Each vial contains active ingredients
Contain 5 ml of injection solution with a concentration of 100 mg/ml. In a similar manner, injection solutions containing 100 mg of active ingredient per ml can be prepared for any of the products of Examples 1-123. Example 128 ingredients mg 1-[N-[(s)-3-(benzoylamino)-2-
Oxo-4-phenylbutyl]-L-alanyl]
-L-proline sodium salt...100 Avicel...100 Hydrochlorothiazide...12.5 Lactose...113 Corn starch...17.5 Stearic acid... 7 350 1000 tablets containing each of the above ingredients are prepared from sufficient bulk quantities. That is, 1-[N-[(s)-3
Slug -(benzoylamino)-2-oxo-4-phenylbutyl]-L-alanyl]-L-proline sodium salt, Avicel and some stearic acid. The slag was ground and passed through a #2 screen and then treated with hydrochlorothiazide,
Mix with lactose, corn starch and remaining stearic acid. Such a mixture is compressed into 350 tablets.
mg capsule-shaped tablet. 1/2 to these tablets
Make notches for division. Similarly, tablets containing 100 mg of the products of any of Examples 1-123 can be prepared.

Claims (1)

[Claims] 1 Formula: A compound represented by or a pharmacologically acceptable salt thereof [wherein, X is or [Formula] R is hydrogen, lower alkyl, cycloalkyl,
[Formula] −(CH ₂ ) ₂ −NH ₂ , − (CH ₂ ) ₃ −NH ₂ , −(CH ₂ ) ₄ −NH ₂ , −(CH ₂ ) ₂ −
OH, −(CH ₂ ) ₃ −OH, −(CH ₂ ) ₄ −OH, −(CH ₂ ) ₂
−SH, −(CH ₂ ) ₃ −SH, or −(CH ₂ ) ₄ −
SH,; R ₁ is hydrogen, lower alkyl, halo substitution (lower)
Alkyl, [formula] [formula] [Formula] [Formula] −(CH ₂ ) _r −OH, − (CH ₂ ) _r −NH ₂ , −(CH ₂ ) _r −SH, −(CH ₂ ) _r −S−
(lower alkyl), [formula] or [formula] (however, when R is a group other than hydrogen, R ₁ is hydrogen); R ₂ is [formula] [formula] [formula] or [formula] R ₃ is hydrogen, lower alkyl,
[Formula] [Formula] [Formula] [Formula] Halo-substituted (lower) alkyl, -(CH ₂ ) _n -(cycloalkyl),
[Formula] [Formula] −(CH ₂ ) _r −OH, [Formula] −(CH ₂ ) _r −NH ₂ , − (CH ₂ ) _r −SH, −(CH ₂ ) _r −S− (lower alkyl) ,
[expression] or R ₄ is hydrogen, lower alkyl,
[Formula] -(CH ₂ ) _n - (cycloalkyl), [Formula] [Formula] [Formula] [Formula] or [Formula] R ₅ is hydrogen, lower alkyl,
[Formula] [Formula] [Formula] [Formula] [Formula] −(CH ₂ ) _r −OH, − (CH ₂ ) _r −NH ₂ , −(CH ₂ ) _r −SH, −(CH ₂ ) _r − S-
(lower alkyl), [formula] or r is an integer from 1 to 4; _R7 is hydrogen, lower alkyl, halogen, keto,
Hydroxy, [formula] (lower alkyl), azide, amino, [formula] [formula] [formula] [formula] [formula] [formula] [formula] 1- or 2-naphthyl represented by [formula], -(CH ₂ ) _n - (cycloalkyl), [Formula] -O- (Lower alkyl), [Formula] 1- or 2-naphthyloxy represented by [Formula], -S- (Lower alkyl), [Formula] [Formula] 1- or 2-naphthylthio represented by; R ₈ is keto, halogen, [Formula] [Formula] -O- (lower alkyl), 1- or 2-naphthyloxy represented by [Formula], -
S- (lower alkyl),
1- or 2-naphthylthio represented by [Formula] or [Formula]; R ₉ is keto or [Formula] R ₁₀ is halogen or -Y-R ₁₆ ; R ₁₁ , R' ₁₁ , R ₁₂ and R' ₁₂ are Each individually is hydrogen or lower alkyl, or R' ₁₁ , R ₁₂ and R' ₁₂ are hydrogen, R ₁₁ is [Formula] R ₁₃ is hydrogen, lower alkyl having 1 to 4 carbon atoms, lower alkoxy having 1 to 4 carbon atoms , lower alkylthio having 1 to 4 carbon atoms, chloro, bromo, fluoro, trifluoromethyl, hydroxy, phenyl, phenoxy, phenylthio or phenylmethyl; R ₁₄ is hydrogen, lower alkyl having 1 to 4 carbon atoms, lower alkyl having 1 to 4 carbon atoms, Lower alkoxy, lower alkylthio having 1 to 4 carbon atoms, chloro, bromo, fluoro, trifluoromethyl or hydroxy; m is 0, 1, 2, 3 or 4; P is 1, 2 or 3 (provided that R ₁₃ and R ₁₄ is hydrogen, methyl, methoxy, chloro or fluoro, P is a greater integer greater than 1); R ₁₅ is hydrogen or lower alkyl having 1 to 4 carbon atoms; Y is oxygen or sulfur; R ₁₆ is carbon lower alkyl of numbers 1 to 4,
[Formula] or an unsubstituted 5- to 6-membered cyclic group formed by combining two R _16s , or one or more ring-forming carbon atoms is a lower alkyl substituent having 1 to 4 carbon atoms or di- (lower (1 to 4 carbon atoms) alkyl) substituted 5- to 6-membered cyclic group having a substituent; R ₁₉ is lower alkyl, benzyl or phenethyl; R ₂₀ is hydrogen, lower alkyl, benzyl or phenethyl; R ₆ is Hydrogen, lower alkyl, benzyl, benzhydryl, [Formula] [Formula] -CH(CH ₂ -OH) ₂ , [Formula] -(CH ₂ ) ₂ -N(CH ₃ ) ₂ or [Formula] R ₁₇ is hydrogen, lower alkyl, cycloalkyl or phenyl; R ₁₈ is hydrogen, lower alkyl, lower alkoxy,
Phenyl, or R ₁₇ and R ₁₈ together are -(CH ₂ ) ₂ -, -(CH ₂ ) ₃ -, -CH=CH- or [Formula] R ₂₄ is hydrogen, lower alkyl,
[Formula] [Formula] [Formula] or [Formula] R ₂₁ and R ₂₂ each independently represent hydrogen or lower alkyl; R ₂₃ represents lower alkyl]. 2 R is hydrogen, straight chain or branched (lower) alkyl having 1 to 4 carbon atoms, or phenyl; R ₁ is hydrogen, straight chain or branched (lower) alkyl having 1 to 4 carbon atoms, CF ₃ , - ( _CH2 ) _r - _NH2 ,
[Formula] [Formula] [Formula] [Formula] [Formula] -CH ₂ -SH, -(CH ₂ ) ₂ -S -CH ₃ , [Formula] -CH ₂ - OH, [Formula] or [Formula] ( However, when R is a group other than hydrogen, R ₁ is hydrogen); R ₄ is hydrogen, cyclohexyl, or phenyl; R ₅ is hydrogen, linear or branched (lower) alkyl having 1 to 4 carbon atoms, [Formula ] [Formula] [Formula] −CH ₂ −OH, [Formula] [Formula] −(CH ₂ ) ₄ −NH ₂ , −CH ₂ − SH, , −(CH ₂ ) ₂ −S−CH ₃ ,
[Formula] [Formula] or [Formula] R ₆ is hydrogen, a straight chain or branched (lower) alkyl having 1 to 4 carbon atoms, an alkali metal salt ion,
[Formula] [Formula] -CH (CH ₂ -OH) ₂ , [Formula] -(CH ₂ ) ₂ -N(CH ₃ ) ₂ or [Formula] R ₁₇ is hydrogen, a straight chain with 1 to 4 carbon atoms, or Branched (lower) alkyl or cyclohexyl; R ₁₈ is a straight chain or branched (lower) alkyl or phenyl having 1 to 4 carbon atoms; R ₂₃ is straight chain or branched (lower) having 1 to 4 carbon atoms Alkyl; R ₂ is [Formula] R ₃ is linear or branched (lower) alkyl having 1 to 4 carbon atoms, -(CH ₂ ) _r -NH ₂ ,
[Formula] or [Formula] R ₇ is hydrogen, hydroxy, straight chain or branched (lower) alkyl having 1 to 4 carbon atoms, cyclohexyl, amino, -O- (lower alkyl) (lower alkyl has 1 to 4 carbon atoms) straight chain or branched group of 4),
[Formula] [Formula] 1-naphthyloxy, 2-naphthyloxy, -S- (lower alkyl) (lower alkyl is a straight chain or branched group having 1 to 4 carbon atoms), [Formula] 1-naphthylthio or 2 -naphthylthio; R ₈ is -O- (lower alkyl), -S- (lower alkyl), [Formula] or [Formula] (lower alkyl is a straight chain or branched group having 1 to 4 carbon atoms); R ₉ is phenyl, 2-hydroxyphenyl or 4-hydroxyphenyl; R ₁₀ is both fluoro, both chloro or both -Y-R ₁₆ ; Y is oxygen or sulfur; R ₁₆ is C 1-4 Straight-chain or branched (lower) alkyl, or an unsubstituted 5- to 6-membered cyclic group formed by combining two R _16s , or a substituted 5- to 6-membered cyclic group having a methyl or dimethyl substituent on the ring. Cyclic group; R ₁₁ , R' ₁₁ , R ₁₂ and R' ₁₂ are all hydrogen, or R ₁₁ is phenyl, 2-hydroxyphenyl or 4-hydroxyphenyl, R' ₁₁ , R ₁₂ and
R′ ₁₂ is all hydrogen; r is an integer from 1 to 4; m is 0, 1 or 2; R ₁₃ is hydrogen, methyl, methoxy, methylthio,
chloro, bromo, fluoro or hydroxy; R ₁₄ is hydrogen, methyl, methoxy, methylthio,
A compound according to claim 1, wherein chloro, bromo, fluoro or hydroxy; R ₂₄ is phenyl. 3 X is [formula] [Formula] or [Formula] R is hydrogen or methyl; R ₁ is hydrogen, methyl or -(CH ₂ ) ₄ -NH ₂ (However, if R is a group other than hydrogen, R ₁ is hydrogen); R ₄ is Cyclohexyl or phenyl; R ₆ is hydrogen, linear or branched (lower) alkyl having 1 to 4 carbon atoms or alkali metal salt ion; R ₇ is hydrogen, cyclohexyl, lower alkoxy having 1 to 4 carbon atoms, [Formula] [expression] or m is 0, 1 or 2; R ₁₃ is hydrogen, methyl, methoxy, methylthio,
3. A compound according to claim 2, wherein t is 2 or 3; chloro, bromo, fluoro or hydroxy; 4. The compound according to claim 3, wherein X is [Formula]. 5. The compound according to claim 4, wherein R ₂ is phenyl; R ₃ is benzyl. 6. The compound according to claim 5, wherein R is hydrogen; R ₁ is methyl; R ₄ is cyclohexyl; and R ₆ is hydrogen. 7 R is hydrogen; R ₁ is methyl; R ₄ is phenyl; R ₆
6. The compound according to claim 5, wherein is hydrogen. 8. The compound according to claim 5, wherein R is methyl; R ₁ is hydrogen; R ₄ is cyclohexyl; R ₆ is hydrogen. 9. The compound according to claim 3, wherein X is [Formula]. 10. The compound according to claim 9, wherein R ₂ is phenyl; R ₃ is benzyl. 11. The compound according to claim 10, wherein R is methyl; R ₁ is hydrogen; R ₆ is hydrogen. 12. The compound according to claim 10, wherein R is methyl; R ₁ is hydrogen; and R ₆ is methyl. 13. The compound according to claim 10, wherein 13 R is hydrogen; R ₁ is methyl; R ₆ is hydrogen. 14. The compound according to claim 3, wherein X is [Formula]. 15. The compound according to claim 14, wherein R ₂ is phenyl; R ₃ is benzyl. 16. The compound according to claim 15, wherein 16 R is methyl; R ₁ is hydrogen; R ₆ is hydrogen. 17. The compound according to claim 15, wherein R is hydrogen; R ₁ is methyl; R ₆ is hydrogen. 18. The compound according to claim 3, wherein X is [Formula]. 19. The compound according to claim 18, wherein R ₇ is hydrogen. 20 R ₂ is phenyl; R ₃ is -(CH ₂ ) ₄ -NH ₂ ; R
20. The compound according to claim 19, wherein R ₁ is hydrogen; R 1 is methyl; R ₆ is hydrogen. 21 R ₂ is phenyl; R ₃ is -(CH ₂ ) ₃ -CH ₃ ; R
20. The compound according to claim 19, wherein R ₁ is hydrogen; R 1 is methyl; R ₆ is hydrogen. 22. The compound according to claim 19, wherein R ₂ is phenyl; R ₃ is [Formula] R 2 is hydrogen; ₁ is methyl; R ₆ is hydrogen. 23. The compound according to claim 19, wherein R ₂ is phenyl; R ₃ is [Formula] R is hydrogen; R ₁ is methyl; R ₆ is hydrogen. 24. The compound according to claim 19, wherein R ₂ is phenyl; R ₃ is benzyl. 25. The compound according to claim 24, wherein R is hydrogen; R ₁ is methyl; R ₆ is hydrogen. 26 1-[N-[(S)-3-(benzoylamino)
26. The compound according to claim 25, which is -2-oxo-4-phenylbutyl]-L-alanyl]-L-proline monohydrochloride. 27. The compound according to claim 24, wherein R is hydrogen; R ₁ is methyl; R ₆ is methyl. 28. The compound according to claim 24, wherein R is hydrogen; R ₁ is methyl; R ₆ is ethyl. 29. The compound according to claim 24, wherein R is hydrogen; R ₁ is methyl; R ₆ is n-propyl. 25. The compound according to claim 24, wherein 30 R is hydrogen; R ₁ is methyl; R ₆ is isopropyl. 31. The compound according to claim 24, wherein R is methyl; R ₁ is hydrogen; R ₆ is hydrogen. 25. The compound according to claim 24, wherein 32R is hydrogen; _R1 is -( _CH2 ) ₄ - _NH2 ; _R6 is hydrogen. 33. The compound according to claim 18, wherein R ₇ is [Formula]. 34. The compound according to claim 33, wherein R ₂ is phenyl; R ₃ is benzyl. 35. The compound according to claim 34, wherein R is methyl; R ₁ is hydrogen; R ₆ is hydrogen. 36. The compound according to claim 18, wherein R ₇ is [Formula]. 37. The compound according to claim 36, wherein R ₂ is phenyl; R ₃ is benzyl. 38. The compound according to claim 37, wherein R is methyl; R ₁ is hydrogen; R ₆ is hydrogen. 39. The compound according to claim 37, wherein R is methyl; R ₁ is hydrogen; and R ₆ is methyl. 38. The compound of claim 37, wherein R is hydrogen; R ₁ is methyl; R ₆ is hydrogen. 41 Claim 1 in which R ₇ is phenyl
Compound according to item 8. 42. The compound according to claim 41, wherein R ₂ is phenyl; R ₃ is benzyl. 43. The compound according to claim 42, wherein R is hydrogen; R ₁ is methyl; R ₆ is hydrogen. 44. The compound according to claim 18, wherein R ₇ is cyclohexyl. 45. The compound according to claim 44, wherein R ₂ is phenyl; R ₃ is benzyl. 46. The compound according to claim 45, wherein R is hydrogen; R ₁ is methyl; R ₆ is hydrogen. 47 R is lower alkyl, cycloalkyl,
[Formula] −(CH ₂ ) ₂ −NH ₂ , − (CH ₂ ) ₃ −NH ₂ , −(CH ₂ ) ₄ −NH ₂ , −(CH ₂ ) ₂ −
OH, −(CH ₂ ) ₃ −OH, −(CH ₂ ) ₄ −OH, −(CH ₂ ) ₂
-SH, -( _CH2 ) ₃ -SH, -( _CH2 ) ₄ -SH, the compound according to claim 1, wherein m is 0, 1, 2, 3 or 4. 48. The compound according to claim 47, wherein R is methyl. 49 R is hydrogen; [Formula] or [Formula] R ₁ is lower alkyl, halo-substituted (lower) alkyl, [Formula] [Formula] [Formula] [Formula] [Formula] -(CH ₂ ) _r -OH, - (CH ₂ ) _r −NH ₂ , −(CH ₂ ) _r −SH, −(CH ₂ ) _r −S−
(lower alkyl), [formula] or The compound according to claim 1, wherein R ₆ is hydrogen, lower alkyl, benzyl, benzhydryl or [Formula]. 50 formula: A therapeutic agent for hypertension characterized by comprising a compound represented by the formula or a pharmacologically acceptable salt thereof and a pharmacologically acceptable carrier [wherein, X is or [Formula] R is hydrogen, lower alkyl, cycloalkyl [Formula] -(CH ₂ ) ₂ -NH ₂ , - (CH ₂ ) ₃ -NH ₂ , -(CH ₂ ) ₄ -NH ₂ , -(CH ₂ ) ₂ −
OH, −(CH ₂ ) ₃ −OH, −(CH ₂ ) ₄ −OH, −(CH ₂ ) ₂
−SH, −(CH ₂ ) ₃ −SH, or −(CH ₂ ) ₄ −SH; R ₁ is hydrogen, lower alkyl, or halo substituted (lower)
Alkyl, [Formula] [Formula] [Formula] [Formula] [Formula] −(CH ₂ ) _r −OH, − (CH ₂ ) _r −NH ₂ , −(CH ₂ ) _r −SH, −(CH ₂ ) _r -S-
(lower alkyl), [formula] or [formula] (however, when R is a group other than hydrogen, R ₁ is hydrogen); R ₂ is [formula] [formula] [formula] or [formula] R ₃ is hydrogen, lower alkyl,
[Formula] [Formula] [Formula] [Formula] Halo-substituted (lower) alkyl, -(CH ₂ ) _n -(cycloalkyl),
[Formula] [Formula] −(CH ₂ ) _r −OH, [Formula] −(CH ₂ ) _r −NH ₂ , − (CH ₂ ) _r −SH, −(CH ₂ ) _r −S− (lower alkyl) ,
[Formula] or [Formula] R ₄ is hydrogen, lower alkyl,
[Formula] -(CH ₂ ) _n - (cycloalkyl), [Formula] [Formula] [Formula] [Formula] or [Formula] R ₅ is hydrogen, lower alkyl,
[Formula] [Formula] [Formula] [Formula] [Formula] −(CH ₂ ) _r −OH, − (CH ₂ ) _r −NH ₂ , −(CH ₂ ) _r −SH, −(CH ₂ ) _r − S-
(lower alkyl), [Formula] or [Formula] r is an integer of 1 to 4; R ₇ is hydrogen, lower alkyl, halogen, keto,
Hydroxy, [Formula] Azido, Amino, [Formula] [Formula] [Formula] [Formula] [Formula] [Formula] [Formula] 1- or 2-naphthyl --(CH ₂ ) _n -(cycloalkyl ), [Formula] -O- (lower alkyl), [Formula] 1- or 2-naphthyloxy represented by [Formula], -S- (lower alkyl), [Formula] or 1- represented by [Formula] or 2-naphthylthio; R ₈ is keto, halogen, [Formula] [Formula] -O- (lower alkyl), 1- or 2-naphthyloxy represented by [Formula], -
S- (lower alkyl),
1- or 2-naphthylthio represented by [Formula] or [Formula]; R ₉ is keto or [Formula] R ₁₀ is halogen or -Y-R ₁₆ ; R ₁₁ , R' ₁₁ , R ₁₂ and R' ₁₂ are Each individually is hydrogen or lower alkyl, or R' ₁₁ , R ₁₂ and R' ₁₂ are hydrogen, R ₁₁ is [Formula] R ₁₃ is hydrogen, lower alkyl having 1 to 4 carbon atoms, lower alkoxy having 1 to 4 carbon atoms , lower alkylthio having 1 to 4 carbon atoms, chloro, bromo, fluoro, trifluoromethyl, hydroxy, phenyl, phenoxy, phenylthio or phenylmethyl; R ₁₄ is hydrogen, lower alkyl having 1 to 4 carbon atoms, lower alkyl having 1 to 4 carbon atoms, Lower alkoxy, lower alkylthio having 1 to 4 carbon atoms, chloro, bromo, fluoro, trifluoromethyl or hydroxy; m is 0, 1, 2, 3 or 4; p is 1, 2 or 3 (provided that R ₁₃ and R ₁₄ is hydrogen, methyl, methoxy, chloro or fluoro, p is an integer greater than 1); _R15 is hydrogen or lower alkyl having 1 to 4 carbon atoms; Y is oxygen or sulfur; _R16 is carbon lower alkyl of numbers 1 to 4,
[Formula] or an unsubstituted 5- to 6-membered cyclic group formed by combining two R _16s , or one or more ring-forming carbon atoms is a lower alkyl substituent having 1 to 4 carbon atoms or di- (lower (1 to 4 carbon atoms) alkyl) substituted 5- to 6-membered cyclic group having a substituent; R ₁₉ is lower alkyl, benzyl or phenethyl; R ₂₀ is hydrogen, lower alkyl, benzyl or phenethyl; R ₆ is Hydrogen, lower alkyl, benzyl, benzhydryl, [Formula] [Formula] -CH(CH ₂ -OH) ₂ , [Formula] -(CH ₂ ) ₂ -N(CH ₃ ) ₂ or [Formula] R ₁₇ is hydrogen, lower alkyl, cycloalkyl or phenyl; R ₁₈ is hydrogen, lower alkyl, lower alkoxy,
Phenyl, or R ₁₇ and R ₁₈ together are -(CH ₂ ) ₂ -, -(CH ₂ ) ₃ -, -CH=CH- or [Formula] R ₂₄ is hydrogen, lower alkyl,
[Formula] [Formula] [Formula] [Formula] R ₂₁ and R ₂₂ each independently represent hydrogen or lower alkyl; R ₂₃ represents lower alkyl]. 51 Formula: An analgesic agent comprising an enkeparinase inhibitor compound represented by the formula and a pharmacologically acceptable carrier [wherein R is hydrogen, lower alkyl, cycloalkyl [formula] -(CH ₂ ) ₂ - NH ₂ , −(CH ₂ ) ₃ −NH ₂ , −(CH ₂ ) ₄ −NH ₂ , −(CH ₂ ) ₂ −
OH, −(CH ₂ ) ₃ −OH, −(CH ₂ ) ₄ −OH, −(CH ₂ ) ₂
-SH, -(CH ₂ ) ₃ -SH or -(CH ₂ ) ₄ -SH; R ₁ is hydrogen, lower alkyl, halo-substituted (lower alkyl, [formula] [formula] [formula] [formula] [formula] −(CH ₂ ) _r −OH, − (CH ₂ ) _r −NH ₂ , −(CH ₂ ) _r −SH, −(CH ₂ ) _r −S−
(lower alkyl), [formula] or [formula] (however, when R is a group other than hydrogen, R ₁ is hydrogen.); R ₂ is [formula] [formula] [formula] or [formula] R ₃ is hydrogen, lower alkyl,
[Formula] [Formula] [Formula] [Formula] Halo-substituted (lower) alkyl, -(CH ₂ ) _n -(cycloalkyl),
[Formula] [Formula] −(CH ₂ ) _r −OH, [Formula] −(CH ₂ ) _r −NH ₂ , − (CH ₂ ) _r −SH, −(CH ₂ ) _r −S− (lower alkyl) ,
[Formula] or [Formula] R ₅ is hydrogen, lower alkyl,
[Formula] [Formula] [Formula] [Formula] [Formula] −(CH ₂ ) _r −OH, − (CH ₂ ) _r −NH ₂ , −(CH ₂ ) _r −SH, −(CH ₂ ) _r − S-
(lower alkyl), [formula] or [formula] R ₆ is hydrogen, lower alkyl, benzyl, benzhydryl, [formula] [formula] -CH (CH ₂ -OH) ₂ , [formula] - (CH ₂ ) ₂ - N(CH ₃ ) ₂ or [Formula] R ₁₇ is hydrogen, lower alkyl, cycloalkyl or phenyl; R ₁₈ is hydrogen, lower alkyl, lower alkoxy,
Phenyl, or R ₁₇ and R ₁₈ together are -(CH ₂ ) ₂ , -(CH ₂ ) ₃ -, -CH=CH- or [Formula] [Formula] [Formula] or [Formula] R ₂₁ and R ₂₂ are each independently hydrogen or lower alkyl; R ₂₃ is lower alkyl; r is an integer of 1 to 4; m is 0, 1, 2, 3 or 4; p represents 1, 2 or 3].