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WO1994015908A1 - Derive de propionamide et son utilisation medicinale - Google Patents

Derive de propionamide et son utilisation medicinale Download PDF

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Publication number
WO1994015908A1
WO1994015908A1 PCT/JP1993/000051 JP9300051W WO9415908A1 WO 1994015908 A1 WO1994015908 A1 WO 1994015908A1 JP 9300051 W JP9300051 W JP 9300051W WO 9415908 A1 WO9415908 A1 WO 9415908A1
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WIPO (PCT)
Prior art keywords
substituted
hydroxycarbamoylmethyl
aralkyl
lower alkyl
ester
Prior art date
Application number
PCT/JP1993/000051
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English (en)
Japanese (ja)
Inventor
Yoichi Naka
Yoshitaka Fukumasu
Kunitomo Adachi
Ikuko Kishi
Hiroki Tamakawa
Original Assignee
Yoshitomi Pharmaceutical Industries, Ltd.
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Filing date
Publication date
Application filed by Yoshitomi Pharmaceutical Industries, Ltd. filed Critical Yoshitomi Pharmaceutical Industries, Ltd.
Priority to PCT/JP1993/000051 priority Critical patent/WO1994015908A1/fr
Publication of WO1994015908A1 publication Critical patent/WO1994015908A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

  • the present invention relates to a propionic acid amide derivative having a neutral endopeptidase inhibitory activity and a pharmaceutical use thereof.
  • Atrial natriuretic peptide 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.
  • 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 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.
  • NEP neutral endopeptidase
  • R-A-A aldosterone
  • 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.
  • 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.
  • 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.
  • 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.
  • An object of the present invention is to find a compound having a neutral endopeptidase inhibitory activity and useful as a medicament.
  • 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.
  • they have found that they are effective in treating various diseases caused by the present enzyme, and have completed the present invention.
  • the present invention provides (1) a general formula
  • 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— ⁇ —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 — ⁇ —, 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, Araru
  • 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 ⁇ N (R n ) one R 12 (where R 7 , R 1 ′, R 12 Is as defined in claim 1.
  • R 7 , R 1 ′, R 12 Is as defined in claim 1.
  • 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 ,
  • a neutral endopeptidase inhibitor comprising the propionic acid amide derivative and the salt thereof according to (1) to (3) as an active ingredient
  • 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
  • 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.
  • propionic acid amide derivatives of the present invention preferred are:
  • 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.
  • 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.
  • alkynyl are ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, etc.
  • 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.
  • 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
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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, methylbenzyl ester,
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • the compound of the general formula (I) can be produced by the following method:
  • Carboxylic acid compound or its reactive derivative with the general formula ZR 5 is represented by
  • 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.
  • 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.
  • 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.
  • 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 ′ represents an ester-forming residue.
  • 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
  • a base catalyst 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.
  • an inorganic base lithium hydroxide, sodium hydroxide, potassium hydroxide, hydroxylamine, magnesium hydroxide, hydroxide
  • an inorganic base lithium hydroxide, sodium hydroxide, potassium hydroxide, hydroxylamine, magnesium hydroxide, hydroxide
  • organic bases triethylamine, dicyclohexylamine, dimethylmorpholine, pyridine, etc.
  • amino acids lysine, histidine, ordinine, arginine, etc.
  • ammonia It can be a salt.
  • the compound (I) of the present invention 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.
  • 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.
  • 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 ⁇ l 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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

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Abstract

L'invention concerne un dérivé de propionamide représenté par la formule générale (I), ainsi qu'un sel de ce dérivé, dans laquelle R1 et R2 représentent chacun hydrogène, etc.; R3 et R4 sont combinés ensemble pour représenter alkylène C¿2?-C7 à substitution facultative, etc.; R?5¿ représente hydrogène, etc.; et R6 représente -X-CO-O-R7, etc. Ces composés inhibent l'activité de l'endopeptidase neutre, ils présentent une meilleure capacité d'absorption par voie orale, et ils peuvent augmenter les effets biologiques d'un peptide natriurétique auriculaire constituant une hormone natriurétique, diurétique et hypotensive puissante. Par conséquent, ils sont utiles dans le traitement de diverses maladies des organes circulatoires parmi lesquelles l'hypertension, l'insuffisance cardiaque, l'angine de poitrine, les insuffisances rénales, le syndrôme prémenstruel, les ÷dèmes cycliques, le syndrôme de Ménière, l'hyperaldostéronisme (primaire et secondaire), l'÷dème pulmonaire, l'hyperémie, l'ascite ainsi que l'hypercalciurie, et dans le traitement du glaucome. Lesdits composés sont également utiles dans le traitement de maladies gastro-intestinales, notamment de la diarrhée et du côlon irritable, ainsi que de douleurs.
PCT/JP1993/000051 1993-01-14 1993-01-14 Derive de propionamide et son utilisation medicinale WO1994015908A1 (fr)

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* Cited by examiner, † Cited by third party
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JP2004535398A (ja) * 2001-05-11 2004-11-25 ギルフォード ファーマシューティカルズ インコーポレーティッド ＮＡＡＬＡＤａｓｅ阻害剤としてのヒドロキサム酸およびアシルヒドロキサミン
US7045653B2 (en) 2002-12-23 2006-05-16 Pfizer, Inc. Pharmaceuticals
US7153822B2 (en) 2002-01-29 2006-12-26 Wyeth Compositions and methods for modulating connexin hemichannels
US7468390B2 (en) 2002-01-17 2008-12-23 Novartis Ag Methods of treatment and pharmaceutical composition
EP2340828A1 (fr) 2005-11-09 2011-07-06 Novartis AG Combinaisons pharmaceutiques d'un antagoniste de récepteur de l'angiotensine et inhibiteurs de nep
US20120122764A1 (en) * 2010-11-16 2012-05-17 Novartis Ag Substituted carbamoylcycloalkyl acetic acid derivatives as nep
WO2014029848A1 (fr) 2012-08-24 2014-02-27 Novartis Ag Inhibiteurs de nep pour le traitement de maladies caractérisées par un agrandissement atrial ou une remodélisation atriale
WO2017033128A1 (fr) 2015-08-25 2017-03-02 Novartis Ag Dérivés d'acide 4-aminé-butyrique substitués par le biphényle, et leur utilisation dans la synthèse d'inhibiteurs de nep
WO2017072636A1 (fr) 2015-10-29 2017-05-04 Cadila Healthcare Limited Association pharmaceutique synergique
US10131671B2 (en) 2014-08-07 2018-11-20 Intra-Cellular Therapies, Inc. Organic compounds
US10238660B2 (en) 2009-05-13 2019-03-26 Intra-Cellular Therapies, Inc. Organic compounds
WO2019152697A1 (fr) 2018-01-31 2019-08-08 Intra-Cellular Therapies, Inc. Nouvelles utilisations
US10398698B2 (en) 2013-02-17 2019-09-03 Intra-Cellular Therapies, Inc. Uses
US10682354B2 (en) 2016-03-28 2020-06-16 Intra-Cellular Therapies, Inc. Compositions and methods

Non-Patent Citations (1)

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Title
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JP2004535398A (ja) * 2001-05-11 2004-11-25 ギルフォード ファーマシューティカルズ インコーポレーティッド ＮＡＡＬＡＤａｓｅ阻害剤としてのヒドロキサム酸およびアシルヒドロキサミン
US7468390B2 (en) 2002-01-17 2008-12-23 Novartis Ag Methods of treatment and pharmaceutical composition
US8101659B2 (en) 2002-01-17 2012-01-24 Novartis Ag Methods of treatment and pharmaceutical composition
US8796331B2 (en) 2002-01-17 2014-08-05 Novartis Ag Methods of treatment and pharmaceutical composition
US7153822B2 (en) 2002-01-29 2006-12-26 Wyeth Compositions and methods for modulating connexin hemichannels
US7045653B2 (en) 2002-12-23 2006-05-16 Pfizer, Inc. Pharmaceuticals
US9388134B2 (en) 2005-11-09 2016-07-12 Novartis, Ag Compounds containing S-N-valeryl-N-{[2′-(1H-tetrazole-5-yl)-biphenyl-4-yl]-methyl)-valine and (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester moieties and cations
EP2340828A1 (fr) 2005-11-09 2011-07-06 Novartis AG Combinaisons pharmaceutiques d'un antagoniste de récepteur de l'angiotensine et inhibiteurs de nep
US11642329B2 (en) 2005-11-09 2023-05-09 Novartis Pharmaceuticals Corporation Amorphous solid form of compounds containing S—N-valeryl-N- {[2′-( 1 H-tetrazole-5-yl)-biphenyl-4-yl]-methyl}-valine and (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester moieties and sodium cations
US11096918B2 (en) 2005-11-09 2021-08-24 Novartis Pharmaceuticals Corporation Amorphous solid form of compounds containing S—N-valeryl-N-{[2′-(1H-tetrazole-5-yl)-biphenyl-4-yl]-methyl}-valine and (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester moieties and sodium cations
EP3685833A1 (fr) 2005-11-09 2020-07-29 Novartis AG Composé comprenant un arb et un nepi
US8877938B2 (en) 2005-11-09 2014-11-04 Novartis Pharmaceuticals Corporation Compounds containing S-N-valeryl-N-{[2′-(1H-tetrazole-5-yl)-biphenyl-4-yl]-methyl}-valine and (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester moieties and cations
US10238660B2 (en) 2009-05-13 2019-03-26 Intra-Cellular Therapies, Inc. Organic compounds
US20120122764A1 (en) * 2010-11-16 2012-05-17 Novartis Ag Substituted carbamoylcycloalkyl acetic acid derivatives as nep
US8877815B2 (en) 2010-11-16 2014-11-04 Novartis Ag Substituted carbamoylcycloalkyl acetic acid derivatives as NEP
WO2012065953A1 (fr) * 2010-11-16 2012-05-24 Novartis Ag Dérivés d'acide carbamoylcycloalkyle acétique substitué en tant qu'inhibiteurs de la nep
CN103249715A (zh) * 2010-11-16 2013-08-14 诺瓦提斯公司 作为nep抑制剂的取代的氨基甲酰基环烃基乙酸衍生物
EP3943084A1 (fr) 2012-08-24 2022-01-26 Novartis AG Inhibiteurs de nep pour le traitement de maladies caractérisées par un agrandissement atrial ou une remodélisation atriale
WO2014029848A1 (fr) 2012-08-24 2014-02-27 Novartis Ag Inhibiteurs de nep pour le traitement de maladies caractérisées par un agrandissement atrial ou une remodélisation atriale
US10398698B2 (en) 2013-02-17 2019-09-03 Intra-Cellular Therapies, Inc. Uses
US10131671B2 (en) 2014-08-07 2018-11-20 Intra-Cellular Therapies, Inc. Organic compounds
WO2017033128A1 (fr) 2015-08-25 2017-03-02 Novartis Ag Dérivés d'acide 4-aminé-butyrique substitués par le biphényle, et leur utilisation dans la synthèse d'inhibiteurs de nep
WO2017072636A1 (fr) 2015-10-29 2017-05-04 Cadila Healthcare Limited Association pharmaceutique synergique
US10682354B2 (en) 2016-03-28 2020-06-16 Intra-Cellular Therapies, Inc. Compositions and methods
WO2019152697A1 (fr) 2018-01-31 2019-08-08 Intra-Cellular Therapies, Inc. Nouvelles utilisations
US11759465B2 (en) 2018-01-31 2023-09-19 Intra-Cellular Therapies, Inc. Uses
US11839614B2 (en) 2018-01-31 2023-12-12 Intra-Cellular Therapies, Inc. Methods for treating or mitigating cardiotoxicity characterized by inhibition of adenosine A2 signaling and/or adenosine A2 receptor expression

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