WO1994015908A1

WO1994015908A1 - Propionamide derivative and medicinal use thereof

Info

Publication number: WO1994015908A1
Application number: PCT/JP1993/000051
Authority: WO
Inventors: Yoichi Naka; Yoshitaka Fukumasu; Kunitomo Adachi; Ikuko Kishi; Hiroki Tamakawa
Original assignee: Yoshitomi Pharmaceutical Industries, Ltd.
Priority date: 1993-01-14
Filing date: 1993-01-14
Publication date: 1994-07-21

Abstract

A propionamide derivative represented by general formula (I) and a salt thereof, wherein R?1 and R2¿ represent each hydrogen, etc.; R?3 and R4¿ are combined together to represent optionally substituted C¿2?-C7 alkylene, etc.; R?5¿ represents hydrogen, etc.; and R6 represents -X-CO-O-R7, etc. These compounds inhibit a neutral endopeptidase activity, have an improved oral absorbability, and can potentiate the biological effects of an atrial natriuretic peptide which is a potent natriuretic, diuretic and hypotensive hormone. Therefore, they are useful for treating various diseases of the circulatory organs, including hypertension, cardiac insufficiency, angina pectoris, renal insufficiency, premenstrual syndrome, cyclic edema, Ménière disease, aldosteronism (primary and secondary), pulmonary edema, hypereninemia, ascites and hypercalciuria, and for treating glaucoma. They are useful also for treating gastrointestinal diseases, particularly diarrhea and irritable colon syndrome, and pains.

Description

Specification

Propionic acid amide derivatives and their pharmaceutical uses

"Technical field"

The present invention relates to a propionic acid amide derivative having a neutral endopeptidase inhibitory activity and a pharmaceutical use thereof.

"Background technology"

Atrial natriuretic peptide (AN P) is an endogenous substance mainly having a vasodilatory action and a sodium diuretic action secreted from the heart, and its blood concentration is known to increase in the pathology of hypertension and heart failure. It is considered to be a defense mechanism of the living body. ANP has vasodilator and diuretic effects, suppresses hormone secretion (aldosterone, renin, vasopressin, catecholamine, etc.), increases production of erythrocyte poetin, suppresses hypertrophy and proliferation of vascular smooth muscle, and glomerular mesangium. It has been reported that it inhibits cell proliferation and cardiac hypertrophy. In view of the above, ANP has an excellent effect as a therapeutic agent for high blood pressure and heart failure and is expected to be clinically useful, but has the drawback that it cannot be administered orally because of its peptide. ANP, on the other hand, is metabolized and inactivated in vivo by neutral endopeptidase (NEP) and clearance receptors. Elevated blood levels of ANP in pathology result in down regulation of the clearance receptor, and NEP plays an important role in ANP metabolism. Therefore, drugs that inhibit NEP increase blood ANP levels, resulting in diuretic 'hypertensive action, renin-angiotensin' suppression of the aldosterone (R-A-A) system, and the like.

Therefore, NEP inhibitors are known to include hypertension, heart failure, angina, renal failure, premenstrual syndrome, peripheral edema, Meniere's disease, hyperaldosteronism (primary and secondary), pulmonary edema, hyperreninemia, ascites and It is thought to be useful in the treatment of many cardiovascular diseases, including hypercalciuria, or glaucoma.

For example, JP-A-63-165533, JP-A-2-42047, JP-A-2-124682 and JP-T-2-504 No. 799 describes that a series of cycloalkyl-substituted or spiro-substituted glutaramide derivatives having a neutral endopeptidase inhibitory action are used in various heart diseases such as hypertension, heart failure and renal failure. It is described that it is useful for treatment of vascular diseases and the like.

On the other hand, neutral endopeptidase is also known as enkephalinase, and is known as an enzyme that inactivates opioid peptides in the central nervous system. Therefore, studies have been conducted to utilize this enkephalinase inhibitor as an analgesic, and it has been reported that Keratorphan having hydroxamic acid [Life Sciences, Vol. 35, No. 1023-1 030 (19984)] and thiolphan and acetorphan having an mercapto group are known.

Furthermore, Japanese Patent Application Laid-Open No. 2-161 discloses the R (+) form (retorphan) and the S (-) form (cinorphan) of acetorphan (racemic), an enkephalinase inhibitor described above, respectively. Have a therapeutic effect on gastrointestinal disorders such as diarrhea and irritable bowel syndrome.

"Disclosure of the invention"

An object of the present invention is to find a compound having a neutral endopeptidase inhibitory activity and useful as a medicament.

As a result of intensive studies, the present inventors have found that a propionic acid amide derivative having a hydroxycarbamoyl group at the 3-position and di-substitution at the 2-position has a potent neutral endopeptidase inhibitory action. However, they have found that they are effective in treating various diseases caused by the present enzyme, and have completed the present invention.

That is, the present invention provides (1) a general formula

Wherein R ¹ and R ² are the same or different and represent hydrogen, lower alkyl, substituted lower alkyl, alkanol, substituted alkanol, aralkyl, substituted aralkyl, benzoyl, substituted benzoyl,

R ³ and R ⁴ are the same or different and are lower alkyl, substituted lower alkyl, aralkyl A substituted aralkyl or an alkylene having 2 to 7 carbon atoms which may have a substituent together with R ³ and R ⁴ , an alkylene having 2 to 7 carbon atoms which may have a substituent, Arke shows Nylene,

R ⁵ represents hydrogen, lower alkyl, substituted lower alkyl, aralkyl, substituted aralkyl,

R ⁶ is phenyl, substituted phenyl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, formula X—CO—〇—R ⁷ (where X is a linear or branched chain having 1 to 20 carbon atoms) Alkylene, cycloalkylene, lower alkyl-substituted cycloalkylene, phenylene, substituted phenylene, formula 1 CH (R ⁸ ) 1 (where R ⁸ is aralkyl, substituted aralkyl, heteroaryl lower alkyl, formula 1 Q—Z—R ⁹ (Where Q represents lower alkylene, Z represents —〇—, one S-, -N (R ¹⁰ ) —, and R ⁹ represents hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, Arukanoiru, substituted Arukanoiru, Ariru, substitution Ariru, Ararukiru, a substituted Ararukiru, R ^{1 (1} is hydrogen, lower alkyl, substituted lower alkyl, § La Kill, or indicate a.) Indicating a substituent Ararukiru, R ⁸ represents a group forming a heterocycle connexion such together with R ^5.) Indicates, R ⁷ is hydrogen, an ester Le forming residues.) , Formula—X—CO—N (R ^I) ) R ¹² (where R ¹¹ represents hydrogen, lower alkyl, substituted lower alkyl, aralkyl, substituted aralkyl, R ¹² represents aralkyl, substituted aralkyl, formula—Y — CO— 0— R ⁷ (where Y is a straight or branched chain alkylene, cycloalkylene, lower alkyl-substituted cycloalkylene, phenylene, substituted phenylene, substituted alkylene having 1 to 20 carbon atoms, formula CH (R ^{] S} )-(where R ¹³ represents aralkyl, substituted aralkyl, heteroaryl lower alkyl, formula-QZR ⁹ (where Q, Z and R ⁹ are as defined above), or R ¹³ represents R ¹¹ to together such connexion show a group forming a hetero ring.) indicates, X, R ⁷ The same meanings as defined above.) Shows a.]

A propionic acid amide derivative represented by

(2) R ¹ and R ² are hydrogen, R ³ and R ⁴ are alkylene having 2 to 7 carbon atoms which may have a substituent together, R ⁵ is hydrogen, R ⁶ is — X— C 0-0-R ⁷ or one X—C〇N (R ⁿ ) one R ¹² (where R ⁷ , R ¹ ′, R ¹² Is as defined in claim 1. The propionamide derivative and the salt thereof according to the above (1), wherein

(3) R ¹ and R ² are hydrogen, R ³ and R ⁴ are alkylene having 5 to 6 carbon atoms which may have a substituent together, R ⁵ is hydrogen, The propionic acid amide derivative and the salt thereof according to the above (1) to (2), wherein R ⁶ is —X—C 0-0-R ⁷ ,

(4) A neutral endopeptidase inhibitor comprising the propionic acid amide derivative and the salt thereof according to (1) to (3) as an active ingredient,

(5) a pharmaceutical composition comprising the propionic acid amide derivative and the salt thereof according to (1) to (3) as an active ingredient;

(6) a diuretic comprising the propionic acid amide derivative and the salt thereof according to (1) to (3) as an active ingredient,

(7) A drug for treating hypertension, comprising the propionic acid amide derivative and the salt thereof according to (1) to (3) as an active ingredient or

(8) A therapeutic agent for heart failure comprising the propionic acid amide derivative and the salt thereof according to (1) to (3) as an active ingredient.

Among the propionic acid amide derivatives of the present invention, preferred are:

◎ N— [1— (N-hydroxycarbamoylmethyl) -cyclohexanic acid luponyl] glycine

◎ N— [1- (N-hydroxycarbamoylmethyl) 1-cyclohexanyl rubonyl] glycine 2-phenylethyl ester

◎ N— [11- (N-hydroxycarbamoylmethyl) 1-cyclohexane power rubonyl] glycine ethyl ester

◎ N-C 1-(N-hydroxycarbamoylmethyl) -1-cyclopentane luponyl] glycine

◎ 3 -— [11- (N-hydroxycarbamoylmethyl) -1-cyclohexane power lipoxamide] Propionic acid

◎ N- [1— (N-hydroxycarbamoylmethyl) -1-cyclopentane power ponyl] 1-11-phenylalanine ◎ N— [11- (N-hydroxycarbamoylmethyl) -1-cyclopentane-powered luponyl] 1-L-isoleucine

◎ N— [1- (N-Hydroxycarbamoylmethyl) -1-cyclopentane-Rubonyl] -1-L-valine ethyl ester

◎ N— [1- (N-hydroxycarbamoylmethyl) -1-cyclohexanyl rubonyl] glycine 2-phenylethyl ester

◎ N- [11- (N-hydroxycarbamoylmethyl) -1-cyclohexane power rubonyl] glycine n-butyl ester

◎ N-C 1-(N-hydroxycarbamoylmethyl) -1-cyclohexane power ponyl] glycine 2-indanyl ester

◎ N— [11- (N-hydroxycarbamoylmethyl) -1-cyclohexanyl rubonyl] glycine cyclohexyl ester

◎ N— [11- (N-hydroxycarbamoylmethyl) —1-cyclohexane power rubonyl] 1-L-phenylalanine cyclohexyl ester

◎ N— [1— (N-hydroxycarbamoylmethyl) -1-cyclopentane carbonyl] Glycine N— (2-phenylethyl) amide

◎ N— [1— (N-hydroxycarbamoylmethyl) -1-cyclohexane power ponyl] glycine N-methyl-N— (2-phenylethyl) amide

◎ N— [11- (N-hydroxycarbamoylmethyl) -1-cyclohexane power ponyl] Glycine 1-L-phenylalanine

◎ N— [1- (N-Hydroxycarbamoylmethyl) -1-cyclohexanyl rubonyl] glycine—L-aspartic acid

And the like.

In the definition of each of the above symbols, lower alkyl is a straight or branched chain having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyl. Alkyl is alkanol, alkenyl having 2 to 22 carbon atoms such as acetyl, propionyl, butyryl, 2-methylpropionyl, bivaloyl, hexanoyl, octanoyl, dodecanoyl, octadecanoyl, and aralkyl is benzyl, Phenylethyl, phenylpropyl, pheny And alkylene having 2 to 7 carbon atoms which may have a substituent by combining R ³ and R ⁴ with ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene and the like. , R ³ and R ⁴ may be taken together, and the alkenylene having 2 to 7 carbon atoms which may have a substituent is vinylene, 1-propenylene, 2-propenylene, 1-butenylene, 2 —Butenylene, 1,3—butenenylene, 1—pentenylene, 2-pentenylene, 1,3-pentenenylene, etc., even if these alkylene, alkenylene, and alkynylene have Good substituents include chlorine, bromine, iodine, fluorine halogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, etc. Ethoxy, propoxy, isopropoxy, isobutoxy, butoxy, isobutoxy, tertiary butoxy, etc. having 1 to 4 carbon atoms, such as alkoxy, hydroxyl, nitro, amino, etc .; heteroaryl is pyrrolyl, imidazolyl, pyridyl, pyrazinyl, Pyrimidinyl, pyrazodin pyrimidinyl, imidazopyrimidinyl, pyridazinyl, indolyl, indazolyl, chenyl, furyl, thiazolyl, oxazolyl, etc. are defined as straight-chain or branched-chain alkylene having 1 to 20 carbon atoms. Dimethylene, trimethylene, tetramethylene, pentamethylene, hexmethylene, methylmethylene, dimethylmethylene, ethylmethylene, isopropylmethylene, isobutylmethylene, secondary butylmethylene, octylmethylene, decylmethylene, Lower alkylene is a straight or branched chain alkylene having 1 to 6 carbon atoms, such as methylene, dimethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene and cycloalkylene. Is cycloalkylene having 3 to 7 carbon atoms such as cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene and cycloheptylene; and heteroaryl lower alkyl is pyrrolylmethyl, imidazolylmethyl, pyridylmethyl, pyrazinylmethyl. , Pyrimidinylmethyl, pyrazodin pyrimidinylmethyl, imidazopyrimidinylmethyl, pyridazinylmethyl, indolylmethyl, indazolylmethyl, chenylmethyl, furylmethyl, thiazolylmethyl, oxazolylmethyl, etc. , Aryl is phenyl, naphthyl, etc., alkenyl is vinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, etc., and alkynyl are ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, etc., and R ⁸ is formed together with R ⁵ A hetero ring may have a hetero atom such as sulfur, oxygen, nitrogen, etc. in the ring, and the hetero ring has 1 to 3 halogen, lower alkyl, lower alkoxy, hydroxyl group as a substituent. Which may be condensed with a benzene ring which may have nitro, nitro, amino or the like, and include pyrrolidine, piperidine, homopiperidine, thiazolidine, oxazolidine, indoline, isoindoline, 1,2, 3, 4-tetrahydroisoquinoline, etc., R ^{1 3} is the heterocyclic ring is connexion formed such together with R ^{1 1} has a fart terrorist atoms such as addition of sulfur, oxygen, nitrogen in the ring And the hetero ring may be condensed with a benzene ring which may have 1 to 3 halogen, lower alkyl, lower alkoxy, hydroxyl, nitro, amino, etc. as a substituent. And represents pyrrolidine, piberidine, homopiperidine, thiazolidine, oxazolidine, indoline, isoindoline, 1,2,3,4-tetrahydroisoquinoline, respectively.

Substituents of the substituted lower alkyl include halogens such as chlorine, bromine, iodine and fluorine, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy and other alkoxy having 1 to 4 carbon atoms, hydroxyl groups, Substituted alkanoyl, substituted aralkyl, substituted benzoyl, substituted phenyl, substituted phenylene, substituted alkenyl, substituted alkynyl, substituted aryl, and substituted heteroaryl with nitro, amino, carboxyl, etc. are chlorine, bromine, iodine, Halogens such as fluorine, alkyl having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary Carbon number, such as butoxy 1 4 alkoxy, hydroxyl, nitro, Amino and shown.

When R ⁷ represents an ester-forming residue, examples of the ester include alkyl esters (methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, tertiary butyl ester, hexyl ester, octyl ester, decyl ester, dodecyl ester) , Tetradecyl ester, hexadecyl, octadecyl ester, etc.), cycloalkyl ester (cyclopropyl ester) , Cyclobutyl ester, cyclopentyl ester, cyclohexyl ester, cycloheptyl ester), aralkyl ester (benzyl ester, phenylethyl ester, phenylpropyl ester, benzhydryl ester, tritylester, p-nitrobenzyl ester, p-methylbenzyl ester, p-methoxyphenylethyl ester, etc.), 2-indanyl ester or an ester compound which can be hydrolyzed in vivo. Ester residues that form ester compounds that can be hydrolyzed in vivo are those that can be easily decomposed in vivo to form free carboxylic acid or salts thereof, such as dimethylaminoethyl, dimethylaminopropyl, and benzyl. Aminoalkyl esters such as methylaminoethyl, etc., alkoxycarbonyloxyalkyl esters such as acetoxymethyl, bivaloyloxymethyl, 1-acetoxityl, 1-pipa'-mouth niloxymethyl, 1-ethoxycarbonyloxyshethyl, Esters such as phthalidyl, dimethoxyphthalidyl, etc., rubamoylmethyl, rubamoylethyl, N-methylcarbamoylmethyl, N, N-dimethylcarbamoylmethyl, N, N-dimethylcarbamoylethyl, N, N-getylcarbamoylmethyl, N , N—Jetilkar Can be exemplified Jiokisoren one-2-one one 4-I methyl ester - force Luba moil alkyl esters such as Moiruechi Le, main Tokishimechiru, alkoxyalkyl esters or 5, such as main Tokishechiru - methyl-1, 3.

When the compound of the general formula (I) of the present invention has a carboxyl group, the carboxyl group may be reacted with the corresponding amine to form an amide. The amide-forming residue may be amino or methylamino, Mono- or dialkylamino such as ethylamino, propylamino, butylamino, benzylamino, phenylethylamino, phenylpropylamino, dimethylamino, ethylamino, dipyramino, dibutylamino and the like can be mentioned.

When the compound of the general formula (I) of the present invention has a carboxyl group, the salt may be a metal salt such as a lithium salt, a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a zinc salt, an aluminum salt, and the like, triethylamine, Salts with organic bases such as dicyclohexylamine, N-methylmorpholine, and pyridine; lysine; Examples include salts with amino acids such as stidine, ordinine, and arginine, and ammonium salts.

When the compound (I) of the present invention has an asymmetric carbon atom, racemic forms, diastereoisomers and individual optical isomers may exist, but the present invention includes all of them. In addition, cis- and trans-isomers or a mixture thereof are also included.

The present invention also covers all such cases where the compound of the present invention exists as its corresponding hydrate or other solvate.

According to the present invention, the compound of the general formula (I) can be produced by the following method:

R ³

R ¹ 0 — N (R ² ) -CO-CH ₂ -C-COOH (I)

R ⁴

(In the formula, each symbol is as defined above.)

Carboxylic acid compound or its reactive derivative with the general formula ZR ⁵ is represented by

HN <(I)

\ R ⁶

(In the formula, each symbol is as defined above.)

And reacting the compound represented by

When compound (II) is a free carboxylic acid, the reaction is carried out using a usual amide coupling method. That is, N, N'-dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -1-ethylcarboimide is used as a condensing agent, and more preferably, 1-hydroxybenzotriazodiamide is used. And N-methylmol The reaction is performed under cooling to room temperature or under heating in the presence of an organic base such as holin. When compound (II) is a reactive derivative of a carboxylic acid (acid halide, thiol ester, acid anhydride, mixed acid anhydride, ester, acid azide, acid amide, etc.), the reaction is usually inert. The reaction is carried out in a solvent, in the presence of a tertiary base such as triethylamine, pyridine, disopiropyruethylamine or the like, from a temperature of cooling to room temperature. As the inert solvent used in the condensation reaction, it is possible to appropriately select and use methylene chloride, chloroform, tetrahydrofuran, benzene, ether, dioxane, toluene, acetone, methanol, ethanol, or a mixture thereof. Monkey

When R ⁷ of the compound (I) represents an ester-forming residue, the compound represented by the general formula is obtained by subjecting a compound in which R ⁷ is hydrogen to an esterification reaction widely used in the field of organic chemistry.

R ⁷ '-OH

(In the formula, R ⁷ ′ represents an ester-forming residue.)

Can also be synthesized by reacting

In addition, as a method for removing the substituents of R ′ and R ⁷ , hydrogenation such as hydrolysis with a normal acid or alkali or catalytic reduction (for example, a method using palladium carbon under a stream of hydrogen) is used. It can be done easily.

The synthetic intermediate of the general formula (II) as a raw material can be produced by the following synthesis method.

The compound of the general formula (II) has the general formula

(Wherein each symbol is as defined above, and the compound of the general formula (IV) is synthesized by the method described in E. Rothstein et al., J. Chem. Soc., Page 211, 1926). And the general formula

R ¹ one hundred and one ^{N (R 2) - Η (} V)

(In the formula, each symbol is as defined above.)

In a solvent such as tetrahydrofuran, dioxane, chloroform, methylene chloride, in the presence or absence of a base catalyst (potassium carbonate, sodium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, triethylamine, pyridine, etc.) It can be obtained by reacting at room temperature or under cooling for several hours.

The compound of the general formula (I) thus obtained can be separated and purified from the reaction mixture by a method known per se such as recrystallization, column chromatography and the like.

Further, when the compound of the general formula (I) of the present invention has a carboxyl group, an inorganic base (lithium hydroxide, sodium hydroxide, potassium hydroxide, hydroxylamine, magnesium hydroxide, hydroxide) may be used in a conventional manner. Treatment with zinc, aluminum hydroxide, etc., organic bases (triethylamine, dicyclohexylamine, dimethylmorpholine, pyridine, etc.) or amino acids (lysine, histidine, ordinine, arginine, etc.) and ammonia It can be a salt.

When the compound (I) of the present invention has a chiral carbon atom, it is usually obtained as a racemate or a mixture of diastereoisomers. Racemic form It can be separated into optical isomers. Such optical isomers can also be produced by using optically active starting materials. Further, diastereoisomers can be purified by fractional crystallization or chromatography. In addition, enantiomers can be synthesized and separated by conventional methods. Also, stereoisomers can be produced according to a method known per se.

Preferred compounds of the invention are illustrated in the table below.

In the table, the following abbreviations are used to simplify the description.

A s n asparagine

Asp Aspartic acid

G 1 n Guru Yu Min

G 1 υ glucumic acid

G 1 y Glycine

I 1 e isoleucine

Leu Leucine

Me t Methionin

Phe feniralanin

Pr o proline

S e r serine

Thr threonine

Tyr tyrosine

R ³

j

R type N (R ² ) -CO- CH ₂ -C -CON

'R'

R '

Compound No. R ¹ R ² R ³ R ⁴ R ⁵ R ⁶

1 HH-(CH ₂ ) 5-H -CH2-C00H

2 H CD H CH3-CH2 "" CH3-CH2— H-CHz-COOH

3 O-CH2- H-(CH ₂ ) 4-H -CH ₂ -C00-CH ₂ -¾

4 HH _ (CH ₂ ) 4-H -CH2-COOH

5 CH ₃ -CO--(CH ₂ ) 5-H -CH ₂ -C00-CH _2-

6 'Q CH ₂ -lI-(CH ₂ ) 5-H -CH ₂ -CH ₂ -C00-CH _2- ^ n nu ヽ

I Π n-!! ^ 5-Π -CH2-CH2-COOH

CH

8 © -CH2- H-(CH ₂ ) 4-H 1-1CH-C00CH2- ©

CH _2- ©

-(CH ₂ ) 4-H -CH-C00H

X

_{11 HH - (CH 2) 4} - H

12 H-(CH ₂ ) 5-H -CH2-C00H

13 HH-(CH ₂ ) 2-H -CHa-cooH

14 HH-(CH ₂ ) 3-H

τ

l

^{^{© - z HQ003- <H - 5}} (Ζ Η0) - Η 6ΐ

H003- ^Z H3- U Ο

Π one nJ η η 0Τ ι

H- ^ε Η0- ^ε Η0 Η 11

^{^{- 9 (Ζ Η3) - -03-}} ε Η3 Η 9ΐ

₉ H • ON ψ \

, Η

Ν〇〇one- ³ Η〇 one 0 — ( ₃ Η) N-0-, Η

: Η

000 / C6df / IDd 80651 / ^ 6 ΟΛΥ rf ^ .ccoc oo CO CO

_n rf ^ c to OO C n

id in ad

R'-ON (R ² ) -C〇CH ₂ -C 一 CON

R '

Compound No. R ¹

61 © -CH2- H-(CH ₂ ) 6 H -CH2-COO-CH2- ©

CH ₂ -CH (CH ₃ ) 2 64-(CH ₂ ) e H -CHCOO-CH3

CH (CH ₃ ) 2

65 © HCH ₂ one _{_{- (CH 2) 4 H -CHCOOC2}} H 5

CH (CH ₃ ) 2

66-(CH ₂ ) 4 H-CHC00C ₂ H 5 67 Q-CH ₂ -H-(CH ₂ ) 5 H CH ₂ J¾

-CH-COOCH2-0

_{_{68 CH 3 - - (CH 2}} ) 5 H -CH2-COO-CH2- 69 © -CH 2 - H - (CH 2) 5 • CH2-COOC (CH 3) 3 70 © -CH 2 - H - (CH ₂ ) 5 -CH2-COOH 71 CHs--(CH ₂ ) 5 H -CH2-COOH

CH ₂ -CH (CH 3) 2 72-(CH ₂ ) ₅ H -CHCOO-CH3

o co

(no mouth)

ψ

,

2 (CcccC:

: R / O CN \ 1 ^ R ⁵

R'-ON (R ² )-CO- CH ₂ --C-CON

1 R ⁶

R ⁴

Compound No. R ¹ R ² R ³ R ⁴ R ⁵ R ⁶

106 -CH ₂ -H-(CH ₂ ) 5-H -CH ₂ COOCH ₂ OCO (CHT)

107 -CH ₂ -H-(CH ₂ ) 4-H — CH ₂ -C00C ₆ H 13

108 H-(CH ₂ ) 4-

109 H-(CH ₂ ) 4-

110 O-CH2- H-(CH ₂ ) 4-H -CH ₂ -C00C ₁₈ H 37

112 HH-(CH ₂ ) 4-H -CH ₂ COOCH ₂ CO (CH3) ₂

113 HH-(CH ₂ ) 4-H -CH ₂ COOCH ₂ CO (C ₂ H ₅ ) ₂

114 HH-(CH ₂ ) 4-H -CH ₂ COOCH ₂ CH ₂ CON (CH ₃ ) ₂

CD

115 HH-(CH ₂ ) 5-H -CH ₂ COOCH ₂ CON (C ₂ H ₅ ) ₂

116 HH-(CH ₂ ) 5-H -CH ₂ COOCH ₂ CH ₂ CO (CH ₃ ) ₂

117 HH-(CH ₂ ) 4-H _CH ₂ COO (CH ₂ ) ₃ N (CH ₃ ) ₂

118 HH-(CH ₂ ) 4-H -CH ₂ COOCH ₂ CONH ₂

119 HH-(CH ₂ ) 5-H _CH ₂ COO (CH ₂ ) ₃ N (CH ₃ ) ₂

120 HH-(CH ₂ ) 5-H -CH ₂ COOCH ₂ CONH ₂

i OM6s -Mi ε £ 3d t.1

O 200KO N 1〇1Ll- 1

n 3C

〇

o

PI: in '* — *

6 ^ 6 ό 6

R ^:

R 5

^{^{R 1 - 0- N (R 2}} ) - CON,ヽR 6

〇

1

R ¹ -0- ■ N (R ² )-CO- C H2-

Compound No. R ¹ R ² R ³ R ⁴ R ⁵ R ⁶

151 HH-(CH 2) 5-H -CH ₂ -C0-L-Met

152 HH-(CH ₂ ) 5 ― H -CH ₂ -CO-L-Pro

153 HH-(CH ₂ ) 5 ― H -CH ₂ -CO-L-Ser

154 HH-(CH ₂ ) 5-H -CHz-CO-L-Thr

155 HH-(CH ₂ ) 5-H -CH ₂ -C0-L-Tyr

156 HH-(CH ₂ ) 5-H

157 HH-(CH ₂ ) 5-H -CH-CO-L-Asn

1

CH

159 HH-(CH ₂ ) 5-H -CH- ₂ -CO-> L-Glu

CH _2- ^

162 H H-(CH 2) 5-H -CH-CO-L-Met

163 H H-(CH 2) 5-H -CH-CO-L-Pro

R -0-N (R ² ) -CO- CH2-

Compound No. R ¹ R ² R ³ R ⁴ R ⁵ R ⁶

166 HH-(CH ₂ ) 5-H -CH-CO-L-Tyr

CH

_{167 HH - (CH 2) 5} - H -CH-CO-L-Asp

CH ₂ -0-CH ₂ -CH _2- © -F

169 H H-(CH 2) 5-H -CH-COOH

CH ₂ -CH _2- © -F

174 HH "(CH2) ₅ -H-CH-COOCH3

When the compound of the general formula (I) and a pharmaceutically acceptable salt thereof are used as a medicament, they may be mixed with a pharmaceutically acceptable carrier, excipient, diluent, or the like, to obtain a powder, granule, powder, tablet ( Orally or parenterally in the form of pharmaceutical compositions such as film-coated tablets, dragees, capsules, injections, suppositories, ointments, cataplasms, transdermal absorbents, nasal drops, eye drops, etc. It can be administered to patients in need of treatment. The dosage may vary depending on the disease to be treated, its symptoms, the age of the patient, or the method of administration. In the case of oral administration, it is usually administered in an amount of 1 to 100 Omg per day for an adult in single or divided doses.

Next, the action of the compound of the present invention will be specifically described by the following test examples.

Test Example 1 Neutral endopeptidase inhibitory activity

The test method was as follows: Ethanol or 10% ethanol solution (2 or 201) of the test compound, rat neutral endopeptidase (NEP) (protein content: 1.1 g) and leucine aminopeptidase were added to Tris buffer (5%). Mix with OmM, pH 8.2) (total 150 11). To this was added 50 μl of a substrate solution (5 mM, succinylalanil-aranyl-aranyl-paranitroanilide), and the enzyme reaction was carried out at room temperature for 15 to 20 minutes, followed by 0.3 N hydrochloric acid. The reaction is stopped by adding 50% of 20% ethanol. The absorbance (A) at 405 nm derived from the released paranitroaniline was measured, and the inhibition rate was determined by the following equation.

Inhibition rate 2 [1 (A-B) Z (T-B)] X 100

(T: absorbance at 405 nm without addition of test solution, B: absorbance at 405 nm without addition of NEP)

Table 1 shows the results.

Table 1 Example No. NEP inhibition rate

(I C50, nM)

1 2.7

45.6

7 2. 6

9 1.8

1 1 1. 9

26 20.0

43 20.0

45 8.0

55 2 1.5

59 5. 3

6 1 5.5

62 36. 7

69 48. 0

70 28. 9

72 28. 8

73 18.0 Test example 2 NEP inhibitory activity (bioassay)

The test compound is orally administered to rats, and blood is collected 30 minutes later. After deproteinizing the plasma with acetonitrile, it was concentrated by replacing with nitrogen, and tris buffer containing sodium dimethylsulfate (50 mM, pH 7.7), rat NEP from brush border membrane (30 ug protein amount and substrate solution ( Add 10 zM succinyl-L-alanyl-L mono-alanyl-L-aralanyl-methylcoumalylamide (Suc- (Ala) _3- MCA) / Tris, and perform enzymatic reaction at 37 ° C for 15 minutes. Stop the reaction with 1N hydrochloric acid. The released fluorescence from the MCA is measured with a fluorimeter.

Test Example 3 ANP enhancement in anesthetized dogs

A catheter is inserted into the renal artery and ureter of a dog anesthetized with pentobarbital, and used for intraarterial administration (0.3 to 1 g) of synthetic human ANP and urine collection, respectively. Collect urine before and after ANP administration, and measure urine output (UV) and urinary sodium excretion (UN a V). Drugs are administered intravenously or intraduodenally. The effect of the drug on the UV and UN aV increasing response by ANP is measured to examine the ANP enhancing effect.

Test Example 4 Acute toxicity test

When the compound of Example 1 (30 OmgZkg) was intraperitoneally administered to 5 mice per group, no deaths were observed up to 5 days after the administration. In addition, when the compound of Example 1 (1000 mg Z kg) was orally administered, no deaths were observed up to 5 days after the administration.

From these tests and other experiments, it can be seen that the compound of the general formula (I) and the salt thereof of the present invention have a neutral endopeptidase activity inhibitory activity, an improved oral absorption, and a strong sodium excretion. It can enhance the biological effects of atrial sodium diuretic peptide, a sex, diuretic and hypotensive hormone.

Therefore, the compound is useful for hypertension, heart failure, angina, renal failure, premenstrual syndrome, periodic edema, Meniere's disease, hyperaldosteronism (primary and secondary), pulmonary edema, hyperreninemia, ascites and hypercalciuria It is useful for treating many cardiovascular diseases including glaucoma or glaucoma.

The compounds of the present invention are also useful in the treatment of gastrointestinal disorders (particularly diarrhea and irritable bowel syndrome) and in the treatment of pain.

Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited thereto.

Example 1

N- [11- (N-hydroxycarbamoylmethyl) -1-cyclohexanecarbonyl] glycine (Compound No. 1)

a) Dissolve 6.77 g of benzyloxyamine in 300 ml of tetrahydrofuran Under cooling and stirring at -20 ° C, 2-year-old xaspiro [4.5] decane-1,3-dione was added, and the temperature was raised to room temperature over about 45 minutes. After the reaction solution was poured into ice water and acidified by adding dilute hydrochloric acid, tetrahydrofuran was distilled off to precipitate crystals. This was dissolved in chloroform, washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the crystals were collected by filtration from hexane-ethyl acetate to give 1- (N-benzyloxycarbamoylmethyl). 8.47 g of cyclohexanecarboxylic acid (melting point: 117 to 120 ° C) was obtained. The mother liquor was recrystallized from hexane monoacetate to give the second crystal (2.45 g).

0

b) Dissolve 5.83 g of 1- (N-benzyloxycarbamoylmethyl) -1-cyclohexanecarbonic acid in 140 ml of tetrahydrofuran, and -20. Under cooling and stirring in C, 7.09 g of glycine benzyl ester tosylate, 4.03 g of 1- (3-dimethylaminopropyl) -13-ethylcarbodiimide hydrochloride and 15 ml of disopropylethylamine were successively added. In addition, the temperature was gradually raised to 0 ° C and stirred for about 3 hours. After further stirring at room temperature for 20 minutes, pour into ice water, acidify with dilute hydrochloric acid, extract with ethyl acetate, wash with water, dry with anhydrous sodium sulfate, evaporate the solvent, and crystallize from hexane-ethyl acetate. Was collected by filtration to obtain 6.76 g of N- [11- (N-benzyloxybamoylmethyl) -11-cyclohexanecarbonyl] glycine benzyl ester (melting point: 121 to 122 ° C).

c) Dissolve 6,76 g of N- [11- (N-benzyloxycarbamoylmethyl) -11-cyclohexanecarbonyl] glycine benzyl ester in a mixed solvent of 100 ml of ethanol and 50 ml of ethyl acetate. 0% palladium carbon was added as a catalyst, and the mixture was vigorously stirred under a hydrogen atmosphere at normal temperature and normal pressure for about 6 hours. After the completion of the reaction, the catalyst was filtered, the filtrate was concentrated, and the crystals were collected by filtration from ethanol to obtain the first crystal (3.64 g) and the second crystal (0.39 g). The first crystal was further recrystallized with a mixed solvent of methanol and ethyl acetate, and N- [1- (N-hydroxycarbamoylmethyl) -11-cyclohexanecarbonyl] glycine (melting point 163-167 ° C) 2 .7 g were obtained.

Example 2

N— [3- (N-hydroxycarbamoyl) —2,2-getylpropionyl] glycine (Compound No.2) a) Dissolve 1.36 g of 3- (N-benzyloxycarbamoyl) -2,2-getylpropionic acid obtained in the same manner as in Example 1 in 12 ml of tetrahydrofuran, and cool to −10 ° C. While stirring, 1.64 g of glycine benzyl ester tosylate,

1- (3-Dimethylaminopropyl) -1-3-ethylcarposimid hydrochloride 0.93 g and diisopropylethylamine 2.7 ml are added sequentially, and the temperature is gradually raised to 0 ° C. Stir for 3 hours. The reaction solution is poured into ice water, acidified with dilute hydrochloric acid, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, the solvent is distilled off, and the residue is purified by silica gel column chromatography (hexane-acetic acid). The resulting mixture was eluted with ethyl acetate) to obtain 1.26 g of N- [1- (N-benzyloxycarbamoyl) -1,2,2-getylpropionyl] glycine benzyl ester (melting point: 100 to 120 ° C.).

b) 1.20 g of N— [3- (N-benzyloxycarbamoyl) —2,2-getylpropionyl] glycine benzyl ester was dissolved in 90 ml of ethanol, and 0.6 g of 10% palladium carbon was added. Under a hydrogen atmosphere, the mixture was vigorously stirred at normal temperature and normal pressure for about 6 hours. After completion of the reaction, the catalyst was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluted with ethyl acetate-methanol), crystallized from ethyl acetate to give N-C3- (N-hydroxycarbamoyl) —2,2-Diethylpropionyl] glycine (mp 174-179 ° C.), 0.71 g, was obtained. The following compounds can be produced by performing the reaction treatment in the same manner as in Examples 1 and 2 above.

Example 3

N- [11- (N-benzyloxycarbamoylmethyl) -11-cyclopentanecarbonyl] glycine benzyl ester (Compound No. 3), melting point 58-59 ° C lH-NMR (CDCl ₃ , ppm) 5: 1.52 -2.22 (8H, m). 2.45 (2H, rs). 3.97 (2H, m), 4.88 (2H, s), 5.18C2H, s), 7.37C10H, s)

Example 4

N- [11- (N-hydroxycarbamoylmethyl) -11-cyclopentanecarbonyl] glycine (compound No.4), oil

lH-NMR (D S0-d, ppm) <5: 1.40-1.80 (6H, brs), 2.00 (2H, s), 2.35 (2H, s), 3.72 (2 H, d-like), 8.05 (lH, br)

Example 5

N- [1- (N-Acetyl-N-benzyloxycarbamoylmethyl) 1-11-cyclohexanecarbonyl] glycine benzyl ester (Compound No.5), oil

lH-N RCCDCls.ppm) 5: 1.30-2.00 (8H, m), 2.32 (3H, s), 3.04 (2H, s), 4.09 (1H, d, J = 6Hz), 4.94 (2H, s), 5.19 (2H, s). 6.48, (1H, t-like, J = 6Hz), 7.35 (5H, s), 7.40 (5H.s)

Example 6

3- [11- (N-benzyloxycarbamoylmethyl) -1-cyclohexanecarboxamide] Propionic acid benzyl ester (Compound No. 6), melting point: 103 ° C

lH-NMRCCDCh.ppm) <5: 1.20-1.80 (1 OH.m), 2.35 (2H, s), 2.56 (2H, t, J = 6 Hz), 3.50 (2H, q, J = 6 Hz), 4.86 ( 2H, s), 5.14 (2H, s), 6.62 (1H, m), 7.36 (10H, s), 8.80 (1H, m)

Example 7

3- [1- (N-hydroxycarbamoylmethyl) -1-cyclohexanecarboxamide] propionic acid (Compound No.7), oil

lH-NMR (CD ₃ OD, ppm) ά: 1.20-2.10 (10H.m), 2.26C2H.s), 2.53 (2H, t-like), 3.46 (2H, m)

Example 8

N-C 1-(N-benzyloxycarbamoylmethyl) -1-cyclopentanecarbonyl] —L-phenylalanine benzyl ester (Compound No. 8)

11- (N-benzyloxycarbamoylmethyl) 1-1-cyclopentanecarbonic acid (3.00 g) was dissolved in tetrahydrofuran (50 ml), and the mixture was cooled under ice-cooling with L-phenylalanine tosylate (5.09 g, 1-ethyl). 2.28 g of 3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 4.1 ml of diisopropylethylamine were sequentially added, and the mixture was gradually raised to room temperature and stirred for about 3 hours. The reaction solution was poured into ice water, acidified with dilute hydrochloric acid, extracted with ethyl acetate, washed with water, and anhydrous sodium sulfate. After drying with, the solvent was distilled off. The obtained residue (0.60 g) was purified by silica gel column chromatography (eluted with hexane-ethyl acetate) and crystallized from hexane-ethyl acetate to give N- [1- (N-benzyloxycarbamoyl). Methyl) 1-cyclopentanecarbonyl] 1-L-phenylalanine benzyl ester (melting point 107-1

(0.8 ° C) 0.43 g was obtained.

lH-NMR (CDCl ₃ , ppm) 5: 1.40-2.00 (6H, m). 2.40 (2H, s), 3.12C2H, d, J = 7Hz), 4.70-4.90C1H, m), 4.87 (2H , s), 5.17 (2H, s), 6.40 (1H, m), 6.95-7.45 (15H, m), 8.85 (lH, m), ia) ²⁵ _D =-25.2 ° (c = 0. 6 3, methanol)

Example 9

N- [11- (N-hydroxycarbamoylmethyl) -11-cyclopentanecarbonyl] L-phenylanilanine (Compound No.9)

N- [11- (N-benzyloxycarbamoylmethyl) -11-cyclopentanecarbonyl] 1-L-phenylalanine benzyl ester was dissolved in 25 ml of ethanol, and 10% palladium carbon was added as a catalyst. Under a hydrogen atmosphere, the mixture was vigorously stirred at normal temperature and normal pressure for about 2.5 hours. After the completion of the reaction, the catalyst was filtered and the filtrate was concentrated to obtain 0.32 g of oily N- [1-1 (N-hydroxycarbamoylmethyl) -11-cyclopentanecarbonyl] -L-phenylalanine.

_{1H-NMR (CD 3 0D,} ppm) ά: 1.30-2.10 (8H, m), 2.38 (2H, s), 3.05-3.30 (. 2H m), 4.7 0 (lH, m), 7.10-7.55 (5H .m)

Example 10

N- [11- (N-benzyloxycarbamoylmethyl) -1-cyclopentane-powered ponyl] 1-L-isoleucine benzyl ester (Compound No.10)

a) Benzoxyamine (12.1 g) was dissolved in tetrahydrofuran (300 ml), and the mixture was cooled and stirred at a temperature of 20 ° C., and the mixture was stirred for 2 years. And gradually raised to room temperature (10 ° C). After concentrating the reaction solution at low temperature, hexane was added and the precipitated crystals were collected by filtration. This was suspended again in a filter form and collected by filtration. 1- (N-benzyloxycarbamoylmethyl) -11-cyclopentanecarboxylic acid (melting point: 105 to 112 ° C) 21.6 g I got

b) 1- (N-benzyloxycarbamoylmethyl) -1-cyclopentanecar Dissolve 3.0 g of boric acid in 50 ml of tetrahydrofuran and cool with ice under ice-cooling. 4.25 g of L-isoisocyantosilate, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 2.28 g of salt and 4.1 ml of diisopropylethylamine were sequentially added, and the mixture was gradually warmed to room temperature and stirred for about 3 hours. The reaction mixture was poured into ice water, acidified with dilute hydrochloric acid, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, the solvent was distilled off, and the crystals were collected by filtration from ethyl hexane monoacetate. Example 11: N- [11- (N-benzyloxycarbamoylmethyl) -11-cyclopentanecarbonyl] -L-isoleucine benzyl ester (melting point 67-68 ° C) 0.29 g was obtained.

N- [1- (N-hydroxycarbamoylmethyl) -1-cyclopentanecarbonyl] L-isoleucine (Compound No.ll)

Dissolve 0.28 g of N- [1- (N-benzyloxycarbamoylmethyl) -1-cyclopentanecarbonyl] 1 L-isoleucine benzyl ester in 15 ml of ethanol, add 10% palladium carbon as a catalyst, Under a hydrogen atmosphere, the mixture was vigorously stirred at normal temperature and normal pressure for about 5 hours. After completion of the reaction, the catalyst was filtered and the filtrate was concentrated to obtain 0.15 g of N- [1-1 (N-hydroxycarbamoylmethyl) _1-cyclopentanecarbonyl] 1 L-isoleucine.

lH-N R (CDCl ₃ , PPm) δ: 0.92 (3H, t, J = 7Hz), 0.96 (3H, d, J = 7Hz), 1.30-2.30 (9H, m), 2.46C2H, s), 4.38 (1H, d, J = 6Hz)

Example 1 2

N- [1- (N-hydroxy-N-methylcarbamoylmethyl) -1-cyclohexanecarbonyl] glycine (compound No.52), oil

_{1H-NMR (CD 3 0D,} ppm) d: 1.30-1.80 (8H, br), 1.80-2.20 (2H, m), 2.78 (2H, s), 3. 20 (3H, s), 3.93 (2H, s)

Example 13

N— [1- (N-methoxycarbamoylmethyl) -1-cyclopentanecarbonyl] glycine benzyl ester (Compound No. 53), melting point 73-77 ° C. Example 14 N— [11- (N-benzyloxycarbamoylmethyl) -11-cyclopentanecarbonyl] 1-L-leucine methyl ester (compound No. 54), melting point 121-124 ° C, ία) ²⁵ D =- 24.9 ° (c = 0.70, methanol)

Example 15

N- 1-(N-hydroxycarbamoylmethyl) -1-cyclopentanecarbonyl] 1 L one-port isine methyl ester (Compound No. 55), melting point 1 19 to 122 ° C, [a] ²⁵ _D = — 34.7 ° (c = 0.51, methanol)

Example 16

N- [11- (N-benzyloxycarbamoylmethyl) -1-cyclopentanecarbonyl] 1-L-one-isine (compound No. 56), melting point 122-123 ° C, ία ²⁵ _D = —14.6 ° ( c = 0.57, methanol)

Example 17

Cis-1-41- (N-benzyloxycarbamoylmethyl) -11-cyclohexanecarboxamide Cyclohexanecarboxylic acid methyl ester (Compound No. 57), mp 98-101 ° C

Example 18

N— [1— (N-Hydroxycarbamoylmethyl) -1-cyclopentanecarbonyl] —L-one-isine (Compound No. 58), melting point 1336 to 1338 ° C

Example 19

N- [1- (N-benzyloxycarbamoylmethyl) -1-cyclohexanecarbonyl] glycine N, N-dimethylcarbamoylmethyl ester (Compound No.59), oil

lH-NMRCCDC .PPm) 5: 1252.10C10H, m), 2.25-2.50 (2H, m), 2.93 (6H, s), 4.09 (2H, d, J = 5Hz), 4.72 (2H, s), 4.96C2H, s), 6.92 (1H, t-like, J = 5Hz), 7.36 (5H, s), 9.60 (1H, m)

Example 20

N- [1- (N-Hydroxycarbamoylmethyl) -1-1-cyclohexanecarbonyl] glycine N, N-dimethylcarbamoylmethyl ester (Compound No. 60), oily oil lH-N RCDMSO-de, ppm) 5: 1.10-1.70 (8H, br), 1.92C2H, m), 2.16 (2H, m), 2.85 (3H, s), 2.95 (3H, s), 3.9K2H, d, J = 5Hz), 4.79 (2H, s), 8.12 (1H, t-like, J = 5Hz), 8.68C1H, m)

Example 2 1

N— [1- (N-benzyloxycarbamoylmethyl) -1-cycloheptanecarbonyl] glycine benzyl ester (Compound No. 61), melting point 90-92 ° C. Example 22

N—C 1-(N-benzyloxycarbamoylmethyl) -1-cycloheptanecarbonyl] 1-L-leucine methyl ester (Compound No. 62), melting point 103-105 ° C, [H] ²⁵ _D = — 22. 9 ° (c = 0.47, methanol)

Example 23

N- [1- (N-Hydroxycarbamoylmethyl) -1-cycloheptanecarbonyl] glycine (Compound No. 63), mp 140-145 ° C

Example 24

N- [11- (N-hydroxycarbamoylmethyl) -11-cycloheptanecarbonyl] -L-isocyanate methyl ester (Compound No.64), oil

lH-NMRCCDCh.ppm) d: 0.93 (6H, d, J = 7 Hz), 1.24 (2H, t, J = 7 Hz), 1.43 (1H, m), 1.46-1.63C12H, m), 2.43 (2H , S), 3.73C3H, s), 4.40-4.63 (1H, br), 6.17-6.40 (1H, br)

Example 25

N— [11- (N-benzyloxycarbamoylmethyl) -1-cyclopentanecarbonyl] -1-L-valine ethyl ester (compound No. 65), melting point 60-63 ° C. Example 26

N- [11- (N-hydroxycarbamoylmethyl) -1-cyclopentanecarbonyl] -L-parinethyl ester (Compound No.66), oil

lH-NMRCCDCh.ppm) 5: 0.94 (3H, d, J = 7.5Hz), 0.95C3H, d, J = 7.5Hz), 1.30 (3H, t, J = 7.5Hz), 1.60-2.30 (9H, m ), 2.50 (2H, s), 4.18 (2H, q, J = 7.5Hz), 4.45 (1H, m), 6.96 (lH.d, J = 8Hz)

Example 27 N- [11- (N-benzyloxycarbamoylmethyl) -1-cyclohexanecarbonyl] 1-L-tributophane benzyl ester (Compound No. 67), oil lH-N R (CDCl ₃ , ppm) ά: 1.10- 1.80 (10H, m), 2.22 (2H, s), 3.27 (2H, d-like, J = 6Hz), 4.76 (2H, s), 4.83 (1H, t, J = 6Hz), 5.05 (2H, s), 6.40-6.60 (1H, br), 6.80-7.4 0 (16H, m), 8.40-8.50C1H, br)

Example 28

N- [11- (N-methoxycarbamoylmethyl) -1-cyclohexanecarbonyl] glycine benzyl ester (Compound No. 68), melting point 113 ° C

Example 29

N- [11- (N-benzyloxycarbamoylmethyl) -1-cyclohexanecarbonyl] glycine tertiary butyl ester (Compound No. 69), melting point 120-125 ° C

Example 30

N- [11- (N-benzyloxycarbamoylmethyl) -1-cyclohexanecarbonyl] glycine (Compound No. 70), mp 120 ° C

Example 3 1

N— [1— (N-Methoxycarbamoylmethyl) -1-cyclohexanecarbonyl] glycine (Compound No. 71), melting point 153-155 ° C

Example 32

N-C1- (N-Hydroxycarbamoylmethyl) -1-cyclohexanecarbonyl] -L-isocyanate methyl ester (Compound No.72), oil

lH-NMR (CDCl ₃ , Ppm) 5: 0.96C6H, d, J = 4.5Hz), 1.10-2.20 (13H, m), 2.44 (2H, s), 3.77C3H, s), 4.40-4.70 (1H, br), 6.20-6.50 (1H, br)

Example 33

N- [11- (N-benzyloxy-1-N- (2,4-dimethoxybenzyl) carbamoylmethyl) -1-cyclohexanecarbonyl] glycine benzylester (Compound No. 73), oil

lH-NMR (CDCl3, ppm) <5: 1.30-1.70 (10H, m), 1.80-2.10C2H, m), 2.71 (2H.s), 3.80 (6H, s), 4.06C2H, d, J = 6Hz), 4.73 (2H, s), 4.8K2H, s), 5.18 (2H, s), 6.48 (2H, m), 7.10-7.40C12H, m)

Example 34

N- [11- (N-benzyloxy N- (2,4-dimethoxybenzyl) carbamoylmethyl) -1-cyclohexanecarbonyl] 1-L-proline benzyl ester (Compound No.74), oil

1H-NMR (CDCl ₃ , ppm) 5: 1.25-2.35 (16H, m). 2.70 (2H, s), 3.78 (3H, s), 3.80 (3H, s) .4.5-4.8C1H, m), 4.74 (2H, S), 4.83 (2H, s), 5.12 (1H.d, J = 12Hz), 5.15 (lH.d, J = 12Hz), 6.46C2H.m), 7.15-7.45C12H, m)

Example 35

N- [1- (N-benzyloxycarbamoylmethyl) _1-cyclopentanecarbonyl] 1-L-leucine benzyl ester (Compound No. 75), melting point 87-89 ° C, [H] ²⁵ _D = —27.2 ° (c = 0.75, methanol)

Example 36

N— [11- (N-benzyloxycarbamoylmethyl) -1-cyclopentanecarbonyl] —L-valine benzyl ester (Compound No. 76), oil

lH-N R (CDCl ₃ , PPm) <5: 0.88 (3H, d, J = 7.5Hz), 0.92 (3H, d.J = 7.5Hz), 1.20-1.90 (9H, m), 2.45 (2H, s), 4.50 (lH, m), 4.85 (2H, s), 5.10OH, d.J = 12Hz), 5.20 (lH, d, J = 12Hz), 6.70 (1H, br), 7.35 (10H, s), 8.90 (1H, br)

Example 37

N- [1- (N-benzyloxy N-benzylcarbamoylmethyl) 1-11 cyclopentanecarbonyl] glycine benzyl ester (Compound No. 77), oil

lH-N R (CDCl ₃ , PPm) 5: 1.35-1.78 (8H, m), 2.20 (2H, m), 2.82 (2H, s), 4.03 (2H, d, J = 5Hz), 4.73C2H, s ), 4.76 (2H, s), 5.15C2H, s), 7.32 (15H, m)

Example 38

N— [11 (N-benzyloxy N-benzylcarbamoylmethyl) —11-cyclopentanecarbonyl] proline benzyl ester (Compound No.78), mp 80-82, [H] D = —52.1 ° ( c = 0.47, methanol) Example 39 N-C 1-(N-benzyl N-hydroxycarbamoylmethyl) -11-cyclopentanecarbonyl] glycine (Compound No. 79), melting point 94-95 ° C

Example 40

N- [1- (N-benzyl-N-hydroxycarbamoylmethyl) -1-cyclopentanecarbonyl] proline (compound No.80), oil

_{1H-NMR (CD 3 0D,} ppm) 5: 1.50-2.38C12H, m), 2.86C1H, d, J = 14Hz), 3.03C1H, d, J = 14Hz), 3.72C2H, m), 4.43 (lH, m), 4.66 (1H, d, J = 16Hz), 4.85C1H, d.J = 16Hz), 7.32 (5H, s)

Example 4 1

N-C 1-(N-hydroxycarbamoylmethyl) -1-cyclopentanecarbonyl) L-valine (Compound No. 85), oil

1H-N R (CDSOD, ppm) (: 1.00 (6H, d, J = 8Hz), 1.50-1.80 (9H, m), 2.45 (2H, s), 4.30 (1H, d, J = 6Hz)

Example 42

N- [11- (N-benzyloxycarbamoylmethyl) -11-cyclohexanecarbonyl] glycine ethyl ester (Compound No. 86)

Dissolve 2.91 g of 1- (N-benzyloxycarbamoylmethyl) 1-1-cyclopentanecarbonic acid in 40 ml of tetrahydrofuran and, under ice cooling, glycine ethyl ester hydrochloride 1.40 g, 1-ethyl 1.92 g of 3- (3-dimethylaminopropyl) carposimid hydrochloride and 7.0 ml of diisopropylethylamine were sequentially added. The mixture was gradually warmed to room temperature and stirred overnight. The reaction solution was poured into ice water, extracted with a black form, washed with water, and dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluted with hexane: ethyl acetate = 1: 1), and the crystals were collected from hexane-ethyl acetate by filtration. 2.5 g of glycine ethyl ester (melting point: 80-82 ° C) was obtained.

Example 43

N- [11- (N-hydroxycarbamoylmethyl) -1-cyclohexanecarbonyl] glycine ethyl ester (Compound No.87) Dissolve 2.00 g of N- [1- (N-benzyloxycarbamoylmethyl) -1-cyclopentanecarbonyl] glycine ethyl ester in 20 ml of ethanol, add 5% palladium on carbon as a catalyst, and add hydrogen atmosphere at room temperature and normal pressure. Vigorously stirred for about 5 hours. After completion of the reaction, the catalyst was filtered, and the filtrate was concentrated to give N- [1- (N-hydroxycarbamoylmethyl) -11-cyclopentanecarbonyl] glycine ethyl ester (melting point: 106 to 108 ° C) 1.26 g was obtained.

Example 44

N- [11- (N-benzyloxycarbamoylmethyl) -1-cyclohexanecarbonyl] glycine 2-phenylethyl ester (Compound No. 100)

Dissolve 5.83 g of 1- (N-benzyloxycarbamoylmethyl) -11-cyclopentanecarbonic acid in 140 ml of tetrahydrofuran and, under ice cooling, glycine 2-phenylethyl ester tosylate 7.03 g, 3-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (3.83 g) and 4-ethylmorpholine (5.35 ml) were sequentially added, and the mixture was gradually raised to room temperature and stirred under nitrogen. The reaction solution was poured into iced water, extracted with chloroform, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. Ethyl acetate was added to the residue, and the precipitated crystals were collected by filtration. The obtained crystals were dissolved in black hole form, washed with water and dried. After concentration, the residue was crystallized from hexane-ethyl acetate, and the crystals were collected by filtration. The crystals were recrystallized from hexane-monoethyl acetate to give N- [11- (N-benzyloxycarbamoyl) -11-cyclohexane. Pentanecarbonyl] glycine 2-phenylethyl ester (melting point: 11-11 ° C) 6.00 g was obtained.

Example 45

N- [1- (N-Hydroxycarbamoylmethyl) -1-cyclohexanecarbonyl] glycine 2-phenylethyl ester (Compound No.98)

N- [11- (N-benzyloxycarbamoylmethyl) -11-cyclopentanecarbonyl] glycine 2-phenylethyl ester 7.00 g was dissolved in 60 ml of dioxane and 10 ml of water, and 10% Palladium carbon was added as a catalyst, and the mixture was vigorously stirred under a hydrogen atmosphere at normal temperature and normal pressure for about 5 hours. After completion of the reaction, the catalyst was filtered and the filtrate was concentrated to give N- [1- (N-hydroxycarbamoylmethyl) -1-s Pentanecarbonyl] glycine 2-phenylethyl ester (melting point: 120 to 121.5 ° C) 4.59 g was obtained.

Example 4 6

N- [11- (N-benzyloxycarbamoylmethyl) -11-cyclohexanecarbonyl] glycine n-methyloctyl ester (Compound No. 101), melting point 54-56 ° C

Example 4 7

N- [11- (N-hydroxy-1-N- (2,4-dimethoxyphenyl) methylcarbamoylmethyl) -1-cyclohexanecarbonyl] glycine (Compound No.102), oil

_{1H-NMR (CD 3 0D,} ppm). (5: 1.25-2.20C12H, m), 2.83 (2H, s), 3.77 (. 3H s), 3.80 (3H, s), 3.90C2H s), 4.7K2H .S), 6.47 (1H, d, J = 9Hz), 6.52 (lH, s) .7.12 (1H, d, J = 9Hz)

Example 4 8

N- [1- (N-benzyloxycarbamoylmethyl) -1-cyclohexanyl propyl] glycine hexadecyl ester (Compound No. 121), melting point 58-60 ° C

Example 4 9

N— [1 -— (N-hydroxycarbamoylmethyl) -1-cyclohexanecarbonyl] glycine hexadecyl ester (Compound No. 122), melting point 89-90 ° C. Example 50

N- [1-(N-benzyloxycarbamoylmethyl)-1-cyclohexane power ponyl] glycine 2- (4-methoxyphenyl) ethyl ester (Compound No.123), melting point 66-70 ° C

Example 5 1

N- [1- (N-hydroxycarbamoylmethyl) -11-cyclohexanecarbonyl] glycine 2- (4-methoxyphenyl) ethyl ester (Compound No.124), melting point 105-106 ° C

Example 5 2 N- [1-((N-benzyloxycarbamoylmethyl) -1-cyclohexane power ponyl] glycine 3-phenylpropyl ester (Compound No. 125), mp 97-99 ° C

Example 5 3

N— [1- (N-hydroxycarbamoylmethyl) -1-cyclohexanecarbonyl] glycine 3-phenylpropyl ester (Compound No. 126), mp 98-100 ° C

Example 5 4

N- [1- (N-benzyloxycarbamoylmethyl) -1-cyclohexanol ruponyl] glycine n-butyl ester (Compound No. 127), melting point 67-69 ° C Example 55

N— [1- (N-hydroxycarbamoylmethyl) —1-cyclohexanecarbonyl] glycine n-butyl ester (Compound No. 128), melting point 1 15 ° C. Example 56

N- [1- (N-benzyloxycarbamoylmethyl) -1-cyclohexanyl carbonyl] 1-L-alanine benzyl ester (Compound No. 50), mp 92-94. C

Example 5 7

N— [1- (N-hydroxycarbamoylmethyl) -1-cyclohexanecarbonyl] —L-alanine (Compound No. 51), melting point 1 38 ° C

Example 5 8

N- [1- (N-benzyloxycarbamoylmethyl) -1-1-cyclohexane power ponyl] glycine 2-indanyl ester (Compound No. 129), mp 146-148. C

Example 5 9

N- [1- (N-Hydroxycarbamoylmethyl) -11-cyclohexanecarbonyl] glycine 2-indanyl ester (Compound No. 130), mp 137-139. C

Example 6 0 N- [1- (N-benzyloxycarbamoylmethyl) -1-1-cyclohexane power ponyl] glycine cyclohexyl ester (Compound No. 131), melting point 132-213 ° C

Example 6 1

N-C1- (N-Hydroxycarbamoylmethyl) -1-cyclohexanecarbonyl] glycine cyclohexyl ester (Compound No. 132), mp 126-127 ° C

Example 6 2

N- [1- (N-Hydroxycarbamoylmethyl) -1-cyclohexanecarbonyl] -L-phenylalanine cyclohexyl ester (Compound No. 133), melting point 11 11 to 11 3, [H] ²⁴ _D = — 17.6 ° (c = 0.5, ethanol) Example 6 3

N- [1- (N-benzyloxycarbamoylmethyl) -1-cyclohexanyl propylon] -L-phenylalanine benzyl ester (Compound No.134), mp 107-110

Example 64

N- [1- (N-Hydroxycarbamoylmethyl) -1-cyclohexanecarbonyl] -L-phenylalananine (Compound No.135), oil

lH-NMRCCDCls.ppm) δ: 1.00-1.75 (10H.m), 2.30 (2H, s), 3.2-3.5 (2H, m). 4.70-5.00 (1H, m), 6.50-6.75 (1H, br), 7.24 (5H, s), [H] ² =-13.0 ° (c = 0.50, methanol)

Example 6 5

N- [1-(N-benzyloxycarbamoylmethyl) -1-cyclohexanic acid luponyl] 1-D-phenylalanine benzyl ester (Compound No.136), melting point 100-104 ° C

Example 6 6

N— [1— (N-hydroxycarbamoylmethyl) -1-cyclohexanecarbonyl] —D-phenylalananine (Compound No. 137), oil

_{1H-NMR (CDC1 3, ppm} ) 5:. 1.10-1.50C10H, m) 2.20-2.60 (2H, br- s), 3.0-3.4 (2H, m ), 4.70-4.90C1H, m), 6.40-6 · 71 (1H, br), 7.24 (5H, s), [] ²⁴ _D = + 13.0 ° (c = 0.54, methanol)

Example 67

N— [1— (N-Hydroxycarbamoylmethyl) -1-cyclohexanecarbonyl] —L-Tributophan (Compound No.138), oil

1H-N RCCDC13, ppm) ά: 1.20-1.60 (1 OH, m), 2.21 (2H, s), 3.3-3.4 (2H, m), 4.70- 4.90C1H, t, J = 6Hz), 7.00-7.80 (6H, m). [H] ²⁴ _D =-15.0 ° (c = 0.5

5, methanol)

Example 68

N- [1- (N-benzyloxycarbamoylmethyl) -1-cyclohexane power ponyl] glycine N- (2-phenylethyl) amide (Compound No.139)

11- (N-benzyloxycarbamoylmethyl) 1-1-cyclohexacarbonic acid 2.91 g was dissolved in 200 ml of acetonitrile, and glycine-1-phenylphenylamido trifluoroacetate was dissolved under ice-cooling. 2.92 g, 1-ethyl-3-((3-dimethylaminopropyl) carbodiimide hydrochloride (1.91 g) and disopropylletylamine (3.5 ml) were sequentially added, and the mixture was gradually warmed to room temperature and stirred for about 2 weeks. The reaction mixture was poured into iced water, extracted with chloroform, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica column chromatography (chloroform: methanol = 30: 1). The crystals are collected by filtration from hexane, and N- [1- (N-benzyloxycarbamoylmethyl) -1-cyclohexanecarbonyl] glycine N- (2-phenylethyl) amide (melting point 170-175 °) C) 2.08 g were obtained.

Example 69

N- [1- (N-Hydroxycarbamoylmethyl) -1-cyclohexanecarbonyl] glycine N- (2-phenylethyl) amide (Compound No.140)

N- [11 (N-benzyloxycarbamoylmethyl) -1-cyclohexanecarbonyl] glycine N- (2-phenylethyl) amide 1.80 g was dissolved in 65 ml of dioxane and 10 ml of water, and 1 0% palladium carbon was added as a catalyst, and the mixture was vigorously stirred under a hydrogen atmosphere at normal temperature and normal pressure for about 5 hours. After the reaction is complete, the catalyst is filtered The filtrate was concentrated to give N- [1- (N-hydroxycarbamoylmethyl) -1-six-cyclohexanecarbonyl] glycine N- (2-phenylethyl) amide (melting point 1

(57-160 ° C) 1.25 g was obtained.

Example 70

N- [1- (N-Hydroxycarbamoylmethyl) 1-1-cyclohexanecarbonyl] glycine N-methyl-N- (2-phenylethyl) amide (Compound No. 141), mp 137-138 ° C

Example 7 1

N- [11- (N-benzyloxycarbamoylmethyl) -1-cyclohexane power rubonyl] glycyl-L-phenylalanine benzyl ester (Compound No. 142)

Dissolve 2.9 g of 1- (N-benzyloxycarbamoylmethyl) -1-cyclohexanecarboxylate in 15 Om 1 of tetrahydrofuran and cool under ice-cooling to glycyl-L-phenylalanine benzyl ester trifluoroacetate 4 26 g, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 1.92 g, disopropylethylamine 3. Oml were added sequentially, and the temperature was gradually raised to room temperature. Stir for 3 hours. The reaction solution was poured into iced water, extracted with chloroform, washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the crystals were collected by filtration from hexane-ethyl acetate. Benzyloxycarbamoylmethyl) 1-cyclohexanecarbonyl] glycyl-L-phenylalanine benzyl ester (melting point 1

60-162 ° C) 3.83 g was obtained.

Example 72

N- [11- (N-hydroxycarbamoylmethyl) -1-cyclohexanecarbonyl] glycyl-L-phenylalanine (Compound No. 143)

N- [1— (N-benzyloxycarbamoylmethyl) -1-cyclohexanecarbonyl] glycyl-L-phenylalanine benzyl ester (3.00 g) was dissolved in 60 ml of dioxane and 5 ml of water, and 10% Palladium carbon was added as a catalyst, and the mixture was vigorously stirred under a hydrogen atmosphere at normal temperature and normal pressure for about 5 hours. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated to give N- [1- (N-hydroxycarbamoylmethyl) -1 Cyclohexanecarbonyl] glycyl-L-phenylalanine (melting point 170-172 ° C, [H] ²⁴ D = + 2.3 ° (c = 0.54, methanol)) 1.91 g was obtained. .

Example 73

N- [1- (N-Hydroxycarbamoylmethyl) -1-cyclohexanone liponyl] glycyl-L-aspartic acid (Compound No. 144), mp 135-136. C

Example Ί 4

3- (2- (4-Fluorophenyl) ethokine) -1-2- [1- (N-hydroxycarbamoylmethyl) -1-cyclohexanecarboxamide] propionic acid (Compound No. 169)

a) Reaction treatment of 1- (N-benzyloxycarbamoylmethyl) 1-1-cyclohexanecarbonic acid and 0- (2- (4-fluorophenyl) ethyl) serine benzyl ester in the same manner as in Example 1 b) By doing so, 3- (2- (4-fluorophenyl) ethoxyquin) 1-2- [11- (N-benzyloxycarbamoylmethyl) -11-cyclohexanecarboxamide] propionic acid benzyl ester is obtained.

b) Example of benzyl 3- (2- (4-fluorophenyl) ethoxy) _1- (1- (N-benzyloxycarbamoylmethyl) -1-cyclohexanecarboxamide) propionate obtained by a) 1- (2- (4-Fluorophenyl) ethoxy) -3- (1- (N-hydroxycarbamoylmethyl) -11-cyclohexanecarboxamide] propionic acid .

Example 75

3- (2- (4-Fluorophenyl) ethoxy) -1-2- (1- (N-hydroxycarbamoylmethyl) -11-cyclohexanecarboxamide) Ethyl propionate (Compound No. 170)

a) 1- (N-benzyloxycarbamoylmethyl) 1-cyclohexanecarbonic acid and 〇- (2- (4-fluorophenyl) ethyl) serine ethyl ester And 3- (2- (4-fluorophenyl) ethoxy) —2- [11- (N-benzyloxycarbamoylmethyl) -11-cyclohexanecarboxamide To obtain ethyl propionate. b) Example 4 of 3- (2- (4-fluorophenyl) ethoxy) -2- (1- (N-benzyloxycarbamoylmethyl) -1-cyclohexanecarboxamide) propionate obtained by a) 3- (2- (4-Fluoro.phenyl) ethoxy) -12- [1- (N-hydroxycarbamoylmethyl)-1-cyclohexanecarboxamide] propionic acid Obtain the ethyl ester.

Example 7 6

3- (2- (4-Fluorophenyl) ethoxy) 1-2- [11- (N-hydroxycarbamoylmethyl) -1-cyclohexanecarboxamide] Propionic acid methyl ester (Compound No. 171)

a) Reaction of 1- (N-benzyloxycarbamoylmethyl) -1-cyclohexanecarbonic acid with 0- (2- (4-fluorophenyl) ethyl) serine methyl ester in the same manner as in Example 42 3- (2- (4-Fluorophenyl) ethoxy) 1-2- [11- (N-benzyloxycarbamoylmethyl) -1-cyclohexanecarboxamide] Propionic acid methyl ester is obtained. b) Example of 3- (2- (4-fluorophenyl) ethoxy) 1-1 (11- (N-benzyloxycarbamoylmethyl) -11-cyclohexanecarboxamide) propionic acid methyl ester obtained by a) 4 3- (2- (4-Fluorophenyl) ethoxy) 1-2- [11- (N-hydroxycarbamoylmethyl)-1-cyclohexanecarboxamide] Propionic acid methyl ester Get.

Example 77

4- (4-Fluorophenyl) -1-2- (1-1- (N-hydroxycarbamoylmethyl) -1-cyclohexanecarboxamide) Butanoic acid (Compound No.172) a) 1-1- (N-benzyloxycarbamoyl) Methyl) — 1-cyclohexane carboxylic acid and 2-amino-4- (4-fluorophenyl) butanoic acid Benzyl ester And 4- (4-fluorophenyl) —2- [111- (N-benzyloxycarbamoylmethyl) -11-cyclohexanecarboxamide] butane The acid benzyl ester is obtained.

b) 4- (4-Fluorophenyl) 1-2- [1- (N-benzyloxylrubamoylmethyl) -11-cyclohexanecarboxamide) butyric acid benzyl ester obtained in a) was prepared in the same manner as in Example 1c). In the same manner, the reaction is carried out to obtain 4- (4-fluorophenyl) 1-2- [1- (N-hydroxycarbamoylmethyl) -11-cyclohexanecarboxamide] butanoic acid.

Example 7 8

4- (4-fluorophenyl) -12- [1- (N-hydroxycarbamoylmethyl) -11-cyclohexanecarboxamide] Butyl acid ethyl ester (Compound No.173)

a) Reaction of 1- (N-benzyloxycarbamoylmethyl) 1-1-cyclohexancarbonic acid with 2-ethylamino 4- (4-monofluorophenyl) butanoate in the same manner as in Example 42 — (4-Monofluorophenyl) -2- (11- (N-benzyloxycarbamoylmethyl) -11-cyclohexanecarboxamide) Ethyl butanoate is obtained.

b) 4- (4-Fluorophenyl) —2- (1- (N-benzyloxylrubamoylmethyl) —1-cyclohexanecarboxamide) obtained in a) was prepared in the same manner as in Example 43. By the reaction treatment, 4- (4-fluorophenyl) 1-2- [1- (N-hydroxycarbamoylmethyl) -11-cyclohexancarboxamide] ethyl butyrate is obtained.

Example 7 9

4- (4-fluorophenyl) -12- [1- (N-hydroxycarbamoylmethyl) -11-cyclohexanecarboxamide] Butanoic acid methyl ester (Compound No. 174)

a) Reaction treatment of 1- (N-benzyloxycarbamoylmethyl) -1-cyclohexanecarbonic acid and 2-amino-4- (4-fluorophenyl) butanoic acid methyl ester in the same manner as in Example 42 By 4-one (4-fluorophenyl ) — 2— [11- (N-benzyloxycarbamoylmethyl) -1-cyclohexanecarboxamide] Butanoic acid methyl ester is obtained.

b) 4- (4-fluorophenyl) -1-2- [1- (N-benzyloxylrubamoylmethyl) -11-cyclohexanecarboxamide obtained in a)] Butanoic acid methyl ester was used in the same manner as in Example 43. To give 4- (4-fluorophenyl) 1-2- [11- (N-hydroxycarbamoylmethyl) -11-cyclohexanecarboxamide] butanoic acid methyl ester.

Formulation example 1: Tablet

Compound of the present invention 50.Omg lactose 50.Omg corn starch 20.Omg crystalline cellulose 29.Omg polyvinylpyrrolidone K 30.05mg talc 5.7mg magnesium stearate 0.3mg

160. Omg The compound of the present invention, lactose, corn starch and crystalline cellulose were mixed, kneaded using a polyvinylpyrrolidone K30 paste solution, and granulated through a 20-mesh sieve. After drying at 50 ° C for 2 hours, the mixture was passed through a 24-mesh sieve, talc and magnesium stearate were mixed, and a tablet of 16 Omg was produced using a 7 mm diameter punch.

Formulation example 2: Capsule

Compound of the present invention 50.Omg lactose 70.0 mg corn starch 3 5.Omg polyvinylpyrrolidone K30.2 Omg talc 2.7 mg magnesium stearate 0.3 mg

1 6 0.Omg The compound of the present invention, lactose, corn starch and crystalline cellulose were mixed, kneaded using polyvinylpyrrolidone K30 size solution, and granulated through a 20-mesh sieve. After drying at 50 ° C for 2 hours, the mixture was passed through a 24 mesh sieve, talc and magnesium stearate were mixed, and the mixture was filled into hard capsules (No. 4) to produce 16 mg of capsules.

Although the present invention has been described in detail with reference to the specification including reference examples and examples, various changes and modifications can be made without departing from the spirit and scope of the present invention.

Claims

The scope of the claims

(1) General formula

R ³

R '-0-N (R ² ) — CO-CH ₂ — C— CON (I)

R ⁴ , R

[Wherein, R ′ and R ² are the same or different and represent hydrogen, lower alkyl, substituted lower alkyl, alkanol, substituted alkanol, aralkyl, substituted aralkyl, benzoyl, substituted benzoyl,

R ³ and R ⁴ are the same or different and are lower alkyl, substituted lower alkyl, aralkyl, substituted aralkyl or R ³ , R ⁴ together with 2 to 7 carbon atoms which may have a substituent; Shows an alkenylene having 2 to 7 carbon atoms which may have a substituent,

R ⁶ is phenyl, substituted phenyl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, formula — X—C〇—0—R ⁷ (where X is a straight or branched chain having 1 to 20 carbon atoms) Alkylene, cycloalkylene, lower alkyl-substituted cycloalkylene, phenylene, substituted phenylene, formula CH (R ⁸ ) 1 (where R ⁸ is aralkyl, substituted aralkyl, heteroaryl lower alkyl, formula — Q.—Z— R ⁹ (where Q represents lower alkylene, Z represents —〇, one S—, one N (R ¹⁰ ) —, and R ⁹ is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, Substituted alkynyl, alkanoyl, substituted alkanol, aryl, substituted aryl, aralkyl, substituted aralkyl, R ^{1 ()} is hydrogen, lower alkyl, substituted lower alkyl, α Represents aralkyl or substituted aralkyl.) Or R ⁸ represents a group which forms a heterocycle together with R ⁵ )) and R ⁷ represents hydrogen or an ester-forming residue.) X—C 一 —N (RH) —R ′ ² (where R ¹¹ represents hydrogen, lower alkyl, substituted lower alkyl, aralkyl, substituted aralkyl, and R ¹² Is aralkyl, substituted aralkyl, formula — Y—CO—0—R ⁷ (where Y is a linear or branched alkylene having 1 to 20 carbon atoms, cycloalkylene, lower alkyl-substituted cycloalkylene, phenylene , Substituted phenylene, formula I CH (R ¹³ )-(where R ¹³ is lower alkyl, substituted lower alkyl, aralkyl, substituted aralkyl, heteroaryl lower alkyl, formula I Q—Z—R ⁹ (where Q, Z, R ⁹ has the same meaning as defined above.) Or R ¹³ represents a group which forms a heterocyclic ring together with RH.) Represents X) and X and R ⁷ have the same meanings as defined above. Show. ]

And a salt thereof.

(2) R ¹ and R ² are hydrogen, R ³ and R ⁴ are alkylene having 2 to 7 carbon atoms which may have a substituent together, R ⁵ is hydrogen, R ^{6 is} —X—C 0-0-R ⁷ or one X—CO—N (RH) —R ′ ² (where R ⁷ , RH, and R ¹⁸ are as defined in claim 1) The propionamide derivative and the salt thereof according to the above (1), wherein

(3) R ′ and R ² are hydrogen, R ³ and R ⁴ are alkylene having 5 to 6 carbon atoms which may have a substituent together, R ⁵ is hydrogen, R ^{6 is} X—C 0-0-R ⁷ (where X is a straight-chain or branched alkylene having 1 to 20 carbon atoms, formula — CH (R ⁸ )-(where R ⁸ Ararukiru, substituted Ararukiru formula - Q -ZR ⁹ (here, Q is a lower alkylene, Z is shown a one hundred and one, R ^s represents § aralkyl, substituted Ararukiru.) shows a) shows a. , R ⁷ represents hydrogen or an ester-forming residue.), Formula —X—CO—N (R ¹¹ ) —R ¹² (where R ′ ¹ represents hydrogen, lower alkyl, R ¹² represents aralkyl, Y—C—I—R ⁷ (where Y represents the formula CH (R ¹³ ) — (where R ¹³ represents lower alkyl, substituted lower alkyl, aralkyl).) X and R ⁷ are as defined above. 3. The propionic acid amide derivative according to claim 1 or 2, and a salt thereof.

(4) ◎ N— [1- (N-hydroxycarbamoylmethyl) -1-cyclohexanecarbonyl] glycine

◎ N— [11- (N-hydroxycarbamoylmethyl) -1-cyclohexane power rubonyl] glycine 2-phenylethyl ester

◎ N— [1— (N-hydroxycarbamoylmethyl) -1-cyclohexane power Rubonyl) glycine ethyl ester

◎ N— [11- (N-hydroxycarbamoylmethyl) 1-1-cyclopentane power ponyl] glycine

◎ 3— [1— (N-hydroxycarbamoylmethyl) -1-cyclohexane power lipoxamide] Propionic acid

◎ N— [1- (N-Hydroxycarbamoylmethyl) -1-cyclopentane L-ponyl] L-Fenylalanine

◎ N— [1- (N-hydroxycarbamoylmethyl) 1-cyclopentane-propionate] 1-L-isoleucine

◎ N— [1— (N-Hydroxycarbamoylmethyl) -1-cyclopentane power rubonyl] — L-valine ethyl ester

◎ N— [1- (N-Hydroxycarbamoylmethyl) -1-cyclohexane power rubonyl] glycine 2-phenylethyl ester

◎ N— [11- (N-hydroxycarbamoylmethyl) -1-cyclohexane power rubonyl] glycine n-butyl ester

◎ N— [11- (N-hydroxycarbamoylmethyl) -1-cyclohexane power ponyl] glycine 2-indanyl ester

◎ N— [1_ (N-hydroxycarbamoylmethyl) -1-cyclohexane power ponyl] glycine cyclohexyl ester

◎ N— [1- (N-Hydroxycarbamoylmethyl) — 1-cyclohexanyl rubonyl] 1 L-phenylalanine cyclohexyl ester

◎ N— [1- (N-Hydroxycarbamoylmethyl) -1-cyclopentane L-ponyl] glycine N— (2-phenylethyl) amide

◎ N— [1- (N-Hydroxycarbamoylmethyl) -1-1-cyclohexane power ponyl] Glycine N-methyl-N- (2-phenylethyl) amide

◎ N— [11- (N-hydroxycarbamoylmethyl) -1-cyclohexane power rubonyl] glycyl-L-phenylalanine

◎ N— [1— (N-hydroxycarbamoylmethyl) -1-cyclohexane power luponyl] glycyl-L-aspartic acid The propionic amide derivative according to claims 1 to 3, which is selected from the group consisting of:

(5) A neutral endopeptidase inhibitor comprising the propionic acid amide derivative according to any one of claims 1 to 4 and a salt thereof as an active ingredient.

(6) A pharmaceutical composition comprising, as an active ingredient, the propionic acid amide derivative according to any one of claims 1 to 4 and a salt thereof.

(7) A diuretic comprising the propionic acid amide derivative according to claims 1 to 4 and a salt thereof as an active ingredient.

(8) A therapeutic agent for hypertension, comprising the propionic acid amide derivative according to claims 1 to 4 and a salt thereof as an active ingredient.

(9) A therapeutic agent for heart failure, comprising the propionic acid amide derivative according to claims 1 to 4 and a salt thereof as an active ingredient.