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WO1994017036A1 - Composes s-carbonyle aliphatique lipophile [n-mercaptoacyl(acide amine ou peptide)] utilises comme antihypertenseurs - Google Patents

Composes s-carbonyle aliphatique lipophile [n-mercaptoacyl(acide amine ou peptide)] utilises comme antihypertenseurs Download PDF

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Publication number
WO1994017036A1
WO1994017036A1 PCT/EP1993/000147 EP9300147W WO9417036A1 WO 1994017036 A1 WO1994017036 A1 WO 1994017036A1 EP 9300147 W EP9300147 W EP 9300147W WO 9417036 A1 WO9417036 A1 WO 9417036A1
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alkyl
compound
acid
hydrogen
phenyl
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PCT/EP1993/000147
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English (en)
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Marie-Claude Fournie-Zaluski
Bernard-Pierre Roques
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Institut National De La Sante Et De La Recherche Medicale (Inserm)
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Priority to PCT/EP1993/000147 priority Critical patent/WO1994017036A1/fr
Priority to AU34940/93A priority patent/AU3494093A/en
Publication of WO1994017036A1 publication Critical patent/WO1994017036A1/fr

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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/20—Esters of monothiocarboxylic acids
    • C07C327/32—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • 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
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • 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
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C07K5/06043—Leu-amino acid
    • 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
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C07K5/06052—Val-amino acid
    • 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
    • C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr

Definitions

  • the present invention is directed to novel compounds useful as
  • the invention is also directed to pharmaceutical
  • compositions containing these novel compounds the preparation of these novel compounds, and methods for their pharmaceutical use.
  • U.S. Patent No. 4,053,651 discloses inhibitors of peptidyldipeptidase A (ACE) (EC3.4-15.1 ) wherein the mercapto moiety therein is substituted by hydrogen, lower alkanoyl wherein lower alkyl is defined as up to C 7 or benzoyl, or the mercapto moieties in two of the inhibitor molecules form a dimer by a disulfide linkage.
  • ACE peptidyldipeptidase A
  • German Patent No. DE 3,819,539 A1 discloses inhibitors of neutral endopeptidase (NEP) (EC 3.4-24.11) wherein the mercapto moiety therein is substituted by hydrogen, phenyl C 2-5 alkanoyl, thiophenyl C 2-5 alkanoyl, furanyl C 2-5 alkanoyl, pyridinyl C 2-5 alkanoyl or cycloalkyl C 2-5 alkanoyl.
  • NEP neutral endopeptidase
  • 4,684,660 discloses inhibitors of ACE wherein the mercapto moiety therein is substituted by hydrogen or C 2-7 alkanoyl, or the mercapto moieties in two of the inhibitor molecules form a dimer by a disulfide linkage.
  • This reference does not disclose that the mercapto group may be derivatized by a lipophilic aliphatic carbonyl radical.
  • This reference also does not disclose that the ACE inhibitors also have NEP inhibitory activity.
  • French Patent FR 8320024 (2,556,721 ) discloses inhibitors of
  • U.S. Patent No. 4,248,883 discloses inhibitors of ACE wherein the mercapto moiety therein is substituted by hydrogen, G 4 CO-, G 5 S- or
  • G 4 represents a lower alkyl group, a lower alkoxy group, a phenyl group, a substituted phenyl group, a phenyl-lower alkyl group, a substituted phenyl- lower alkyl group, a phenyl-lower alkoxy group, a substituted phenyl-lower alkoxy group, a phenoxy group, or a substituted phenoxy group;
  • G5 represents a lower alkyl group, a phenyl group, a substituted phenyl group, a phenyl-lower alkyl group, a substituted phenyl-lower alkyl group,
  • G 6 represents a hydrogen atom or a lower alkyl group
  • G 7 represents a lower alkyl group, a phenyl group or a substituted phenyl group
  • X represents an oxygen or sulfur atom.
  • the mercapto group may be derivatized by a lipophilic aliphatic carbonyl radical.
  • the ACE inhibitors also have NEP inhibitory activity.
  • U.S. Patent No. 4,474,799 discloses inhibitors of NEP wherein the mercapto moiety therein is substituted by hydrogen, C 1-4 alkanoyl or benzoyl.
  • the mercapto group may be derivatized by a lipophilic aliphatic carbonyl radical.
  • the NEP inhibitors possess antihypertensive activity.
  • U.S. Patent No. 4,798,904 discloses inhibitors of NEP wherein the mercapto moiety therein is substituted by hydrogen, phenyl C 2-5 alkanoyl, substituted phenyl C 2-5 alkanoyl, thiophenyl C 2-5 alkanoyl, furanyl C 2-5 alkanoyl, or pyridinyl C 2-5 alkanoyl.
  • This reference does not disclose that the mercapto group may be derivatized by a lipophilic aliphatic carbonyl radical.
  • This reference also does not disclose that the NEP inhibitors possess
  • U.S. Patent No. 4,513, 009 discloses inhibitors of NEP wherein the mercapto moiety therein is substituted hydrogen, C 1-4 alkanoyl, halo substituted C 1-4 alkanoyl, benzhydrylcarbonyl, benzoyl, phenyl C 2-5 alkanoyl, halo substituted phenyl C 2-5 alkanoyl, hydroxy C 2-5 alkanoyl or amino C 2-5 alkanoyl.
  • the mercapto group may be derivatized by a lipophilic aliphatic carbonyl radical.
  • the NEP inhibitors possess antihypertensive activity.
  • U.S. Patent No. 3,246,025 discloses mercaptopropionic acid derivatives that are useful for treating drug intoxication and poisoning wherein the mercapto moiety therein is substituted by hydrogen or a radical that is readily convertible to hydrogen, e.g., benzoyl or nitrobenzoyl.
  • This reference does not disclose that the mercapto group may be derivatized by a lipophilic aliphatic carbonyl radical.
  • This reference also does not disclose that the mercaptopropionic acid
  • NEP neutral endopeptidase
  • enkephalinase since the enzyme degrades the enkephalins which are endogenous opiate peptides of morphine receptors. These inhibitors are disclosed as useful analgesics. This reference does not disclose that NEP inhibitors possess antihypertensive activity. In Nature, 288, 286-288 (1980), Roques et al.
  • (R,S)-(2- mercaptomethyl-3-phenylpropionyl)glycine has an inhibitory power at a nanomolar concentration and behaves as an analgesic in potentiating the action of the enkephalins. This reference does not disclose that thiorphan possesses antihypertensive activity.
  • U.S. Patent No. 4,879,309 discloses that compounds of formulae HS- CH 2 -CH(Q 2 )-CONH-CH(Q 1 )-COOQ 3 and HS-(CH 2 ) m -CH(Q 2 )-CONH-CH(Q 1 )- CO-A-COOQ 3 are useful for augmenting natriuresis and diuresis which thereby aids in reducing blood pressure.
  • This reference does not disclose that the inhibitors possess antihypertensive activity separate from their natriuretic and diuretic effects.
  • the present invention is directed to an S-lipophilic aliphatic carbonyl [N-mercaptoacyl(amino acid or peptide)] compound that, at very low
  • the invention is directed also to the preparation of the compound, pharmaceutical compositions containing it, and methods for its pharmaceutical use.
  • FIGURE Figure 1 is a time course plot of the percent of in vivo inhibition of ACE by the mixed NEP/ACE inbitors: N-(2-acetylthiomethyl-1-oxo-3-phenylbutyl)alanine as a mixture of four stereoisomers (- ⁇ -); N-(2-adamantylthiomethyl-1-oxo-3- phenylbutyl)alanine as a mixture of four stereoisomers (- O -); and
  • Alkyl means an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 20 carbon atoms in the chain.
  • “Lower alkyl” means alkyl having about 1 to about 8 carbon atoms.
  • “Higher alkyl” means alkyl having about 10 to about 20 carbon atoms.
  • the alkyl may be optionally substituted with one or more alkyl group substituents which may be the same or different, where "alkyl group substituent” includes halo, aryl, hydroxy, alkoxy, aryloxy, alkyloxy, alkylthio, arylthio, aralkyloxy, aralkylthio, carboxy
  • alkoxycarbonyl, oxo and cycloalkyl "Branched" means that a lower alkyl group such as methyl, ethyl or propyl is attached to a linear alkyl chain.
  • exemplary alkyl groups include methyl, ethyl, i-propyl, n -butyl, t-butyl, n -pentyl, heptyl, octyl, decyl or dodecyl.
  • exemplary substituted alkyl groups include cyclohexylm ethyl and trifluoromethyl.
  • Preferred alkyl groups include the lower alkyl groups.
  • Alkenyl means an alkyl group containing a carbon-carbon double bond. "Lower alkenyl” means alkenyl having about 1 to about 8 carbon atoms. “Higher alkenyl” means alkenyl having about 10 to about 20 carbon atoms. The alkenyl may be optionally substituted with one or more "alkyl group substituent”.
  • alkenyl groups include vinyl, allyl, n-pentenyl, decenyl, dodecenyl or tetradecadieneyl.
  • Preferred alkenyl groups include the lower alkenyl groups.
  • Alkynyl means an alkyl group containing a carbon-carbon triple bond.
  • “Lower alkynyl” means alkynyl having about 1 to about 8 carbon atoms.
  • “Higher alkynyl” means alkynyl having about 10 to about 20 carbon atoms.
  • the alkynyl may be optionally substituted with one or more "alkyl group substituent”.
  • alkynyl groups include ethynyl, propargyl, n-pentynyl, decynyl or dodecynyl.
  • Preferred alkynyl groups include the lower alkynyl groups.
  • Cycloalkyl means a non-aromatic mono or multi cyclic ring system of about 4 to about 10 carbon atoms.
  • the cycloalkyl may be optionally partially unsaturated.
  • the cycloalkyl may be also optionally substituted with an aryl group substituent, oxo or alkylene.
  • Preferred mono cyclic cycloalkyl rings include cyclopentyl, cyclohexyl or cycloheptyl.
  • Preferred multi cyclic cycloalkyl rings include adamantyl, octahydronaphthyl, decalin, camphor, camphane, noradamantyl, norbornane, bicyclo[2.2.2.]-oct-5-ene, cis-5-norborene, 5-norborene, (1 R)-(-)-myrtentane, norbane or anti-3-oxo-tricyclo[2.2.1.0 2,6 ]- heptane.
  • Alkyloxymethyl means an alkyl-O-CH 2 - group wherein alkyl is as previously described.
  • exemplary alkyloxymethyl groups include methoxymethyl, ethoxymethyl, n-propoxymethyl, Apropoxymethyl, n-butoxym ethyl and
  • alkyloxymethyl it is preferred that the alkyl contains about 1 to about 6 carbon atoms.
  • Aryl means aromatic carbocyclic radical containing about 6 to about 10 carbon atoms.
  • the aryl may be optionally substituted with one or more aryl group substituents which may be the same or different, where "aryl group substituent” includes alkyl, alkenyl, alkynyl, aryl, aralkyl, hydroxy, alkoxy, aryloxy, aralkoxy, carboxy, aroyl, halo, nitro, trihalomethyl, cyano,
  • aryl include phenyl or naphthyl or substituted phenyl or substituted naphthyl
  • Heteroaryl means about a 5- to about a 10- member monocyclic or multicyclic ring system wherein one or more of the atoms in the ring system is an element other than carbon chosen amongst nitrogen, oxygen or sulfur.
  • the heteroaryl may be optionally substituted by one or more aryl group substituents.
  • Exemplary heteroaryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N- methylpyrrolyl, quinolinyl, and isoquinolinyl.
  • Heterocyclyl means an about 4 to about 10 member monocyclic or multicyclic ring system wherein one or more of the atoms in the ring system is an element other than carbon chosen amongst nitrogen, oxygen or sulfur.
  • the heterocyclyl may be optionally substituted by one or more alkyl group
  • heterocyclyl moieties include quinuclidine, and .
  • Preferred substituents of the heterocyclyl include hydroxyl, alkoxy containing about 1 to about 4 carbon atoms, trifluoromethyl, fluorine or alkylene of about 3 to about 4 carbons which alkylene when substituted on the heterocyclyl forms a saturated or unsaturated
  • acyl have an alkyl containing about 1 to about 3 carbon atoms in the alkyl group.
  • exemplary groups include acetyl, propanoyl, 2-methylpropanoyl, butanoyl or palmitoyl.
  • “Aroyl” means an aryl-CO- group wherein alkyl is as previously described.
  • Exemplary groups include benzoyl and 1- and 2-naphthoyl.
  • Alkoxy means an alkyl-O- group wherein alkyl is as previously
  • alkoxy groups include methoxy, ethoxy,
  • Aryloxy means an aryl-O- group wherein the aryl group is as previously described.
  • exemplary aryloxy groups include phenoxy and naphthoxy.
  • Alkylthio means an alkyl-S- group wherein alkyl is as previously described.
  • Exemplary alkylthio groups include methylthio, ethylthio,
  • Arylthio means an aryl-S- group wherein the aryl group is as previously described.
  • Exemplary arylthio groups include phenthio and naphththio.
  • Alkyl means an aryl-alkyl- group wherein aryl and alkyl are as previously described Exemplary aralkyl groups include benzyl, phenylethyl and naphthylmethyl.
  • Alkyloxy means an aralkyl-O- group wherein the aralkyl group is as previously described.
  • An exemplary aralkyloxy group is benzyloxy.
  • Alkylthio means an aralkyl-S- group wherein the aralkyl group is as previously described.
  • An exemplary aralkylthio group is benzylthio.
  • Dialkylamino means an -NZZ' group wherein both Z and Z' are alkyl groups as previously described.
  • Exemplary alkylamino groups include ethylmethylamino, dimethylamino and diethylamino.
  • Alkoxycarbonyl means an alkyl-O-CO- group.
  • alkoxycarbonyl groups include methoxy- and ethoxy- carbonyl.
  • Aryloxycarbonyl means an aryl-O-CO- group.
  • aryloxycarbonyl groups include phenoxy- and naphthoxy- carbonyl.
  • Alkoxycarbonyl means an aralkyl-O-CO- group.
  • An exemplary aralkoxycarbonyl group is benzyloxycarbonyl.
  • Carbamoyl means an H 2 N-CO- group.
  • Alkylcarbamoyl means an Z'ZN-CO- group wherein one of Z and Z' is hydrogen and the other of Z and Z' is alkyl as defined previously.
  • Dialkylcarbamoyl means an Z'ZN-CO- group wherein both Z and Z' are alkyl as defined previously.
  • acyloxy means an acyl-O- group wherein acyl is as defined previously.
  • acylamino means an acyl-NH- group wherein acyl is as defined previously.
  • Aroylamino means an aroyl-NH- group wherein aroyl is as defined previously.
  • Alkylene means a straight or branched bivalent hydrocarbon chain group having from about 1 to about 8 carbon atoms. The alkylene group may be also optionally unsaturated. There may be optionally inserted along the alkylene group one or more oxygen or sulphur atoms, or substituted nitrogen atoms wherein the substituent is alkyl as previously described.
  • alkylene group has about 2 to about 3 carbon atoms.
  • Halo mean fluoro, chloro or bromo.
  • amino Acid may be naturally occurring or synthetic.
  • exemplary amino acids include proline, hydroxy proline, 4,4-ethylenedioxyproline, methoxyproline, thiazolidinecarboxylic acid, trytophane, glycine alanine, leucine, isoleucine, valine, tyrosine, O-benzylserine, 2-carboxylpiperidine, 1-amino-1-phenylacetic acid and 1-amino-1-indan-2-ylacetic acid.
  • Peptide may be about 2 to about 6 amino acid residues bonded by peptide linkages. Preferred are peptides having about 2 to about 3 amino acid residues.
  • Lipophilic aliphatic carbonyl radical means higher alkyl carbonyl, higher alkenyl carbonyl, higher alkynyl carbonyl, multi cycloalkyl carbonyl or multicyclic heterocyclyl carbonyl wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl are as previously described.
  • Multi cycloalkyl carbonyl radicals are preferred, and more preferred are the multi cycloalkyl carbonyl radicals wherein the multi cycloalkyl moiety thereof has bridging carbons, for example
  • exemplary lipophilic aliphatic carbonyl radical groups include 1- or 2-adamantylacetyl, 3-methyl adamant-1-ylacetyl, 3-methyl-3-bromo-1-adamantylacetyl, 1-decalinacetyl, camphoracetyl, camphaneacetyl, noradamantylacetyl, norbornaneacetyl, bicyclo[2.2.2.]-oct-5- eneacetyl, 1 -methoxybicyclo[2.2.2.]-oct-5-ene-2-carbonyl, cis-5-norborene-endo- 2,3-dicarbonyl, 5-norbomen-2-yl acetyl, (1 R)-(-)-myrtentaneacetyl,
  • N-mercaptoacyl(amino acid or peptide) compounds which are derivatized by an S-lipophilic aliphalic carbonyl group to form the compounds according to the invention, include the N-mercaptoacyl(amino acid or peptide) compounds disclosed in the following: U.S. Patent Nos. 4,053,651 ; 4,684,600; 4,248,883; 4,474,799; 4,798,904; 4,513,009; 4,879,309; German Patent No. DE 3,819,539 A1; French Patent No. FR 8320024 (2,556,721); European Patent Nos. EP 0038758; 0 136883; PCT/EP Application Nos.
  • N-mercaptoacyl(amino acid or peptide) compounds N-mercaptoacyl(amino acid or peptide) compounds.
  • Preferred mercaptoalkanoyl (amino acid or peptide) species which are derivatized by an S-Iipophilic aliphalic carbonyl group to form the
  • R is a lipophilic aliphatic carbonyl radical;
  • R 1 is aryl or heteroaryl;
  • R 2 is alkyl, or alkylene attached to the moiety and R 1 ;
  • R 3 is hydrogen, alkyl, aryl, alkoxy or aryloxy
  • R' is hydrogen, alkyl, aralkyl, acyl or aroyl; or a pharmaceutically acceptable salt thereof.
  • R 2 is alkylene
  • the alkylene preferably attaches at an ortho position on R 1
  • R is higher alkyl carbonyl or multi cycloalkyl carbonyl;
  • R 1 is aryl or heteroaryl;
  • R 2 lower alkyl, or alkylene attached to the moiety and R 1 ;
  • R 3 is hydrogen, lower alkyl, aryl or heteroaryl, lower alkoxy or aryloxy
  • R' is hydrogen, lower alkyl, aryl lower alkyl, acyl or aroyl.
  • R is adamantoyl or palmitoyl
  • R 1 is phenyl, 2-, 3- or 4-pyridyl, N-methyl-2- or -3-pyrrolyl, 2- or 3-furyl or 2- or 3-thienyl radical, optionally substituted with one or more identical or different aryl group substituents chosen from halo, hydroxy, C 1-4 acyloxy, C 1-4 alkoxy, phenoxy, phenylthio and amino radicals, C 1-4 dialkylamino, methylenedioxy and ethylenedioxy;
  • R 2 is methyl or trifluoromethyl radical, or -CH 2 -Y-, -Y-CH 2 - or
  • R 1 is phenyl, 2-, 3- or 4-pyridyl, N-methyl-2- or -3-pyrrolyl, 2- or 3-furyl or 2- or 3-thienyl
  • Y is oxygen, sulphur or nitrogen substituted by methyl, or alkylene is optionally substituted with a methyl
  • R 3 is hydrogen, trifluoromethyl, C 1-8 alkoxy, phenoxy, phenyl or thienyl or C 1-8 alkyl optionally substituted with phenyl, hydroxy, C 1-4 alkoxy, phenoxy, C 1-4 alkylthio, phenylthio, benzyloxy or benzylthio, wherein the phenyl and the phenyl portions of the phenoxy, phenylthio, benzyloxy or benzylthio radicals are optionally substituted with one or more identical or different aryl group
  • R' is hydrogen, methyl, ethyl, benzyl, cyclohexylmethyl, palmitoyl or pamoyl radical.
  • R' is hydrogen, methyl, ethyl, benzyl, cyclohexylmethyl, palmitoyl or pamoyl radical.
  • Presently preferred also is a compound of the formula (II)
  • R is a lipophilic aliphatic carbonyl ra dical
  • R 4 and R 5 are independently hydrogen, alkyl, aryl, aralkyl, alkoxy, alkyloxymethyl or aralkyloxy;
  • a 1 and A 2 are independently hydrogen, alkyl, or together with -CH- R 4 or -CH-R 5 , respectively, form phenyl, or alkylene which together with -CH- R 4 or -CH-R 5 , respectively, form benzocycloalkyl;
  • R 6 is hydrogen or alkyl
  • G 7 is cycloalkyl, aralkyl or aryloxymethyl or alkoxymethyl, or R 6 and G 7 and the carbon and nitrogen atoms through which R 6 and G 7 are attached taken together form heterocyclyl; and
  • R" is hydrogen, alkyl, aralkyl, cycloalkyl lower alkyl or palmitoyl; or a pharmaceutically acceptable salt thereof.
  • R is higher alkyl carbonyl or multi cycloalkyl carbonyl;
  • R 4 and R 5 are independently hydrogen, lower alkyl, phenyl, aryl lower alkyl, lower alkoxy, lower alkyloxymethyl or aryl lower alkyloxy;
  • a 1 and A 2 are independently hydrogen, lower alkyl or together with -CH- R 4 or -CH-R 5 , respectively, form phenyl, or alkylene which together with -CH- R 4 or -CH-R 5 , respectively, form benzocycloalkyl;
  • R 6 is hydrogen or lower alkyl
  • G 7 is cycloalkyl, aryl lower alkyl or aryloxymethyl or lower alkoxymethyl, or R 6 and G 7 and the carbon and nitrogen atoms through which R 6 and G 7 are attached taken together form heterocyclyl; and
  • R" is hydrogen, lower alkyl, aryl lower alkyl, cycloalkylmethyl or palmitoyl.
  • R is adamantoyl or palmitoyl
  • R 4 and R 5 are independently lower alkyl, lower alkoxy, phenyl, benzyl or benzyloxy
  • a 1 and A 2 are independently hydrogen, methyl, or together with -CH- R 4 or -CH-R 5 , respectively, form phenyl, or alkylene together with -CH- R 4 or -CH-R 5 , respectively, form indanyl
  • G 7 is benzyl wherein the phenyl ring is optionally substituted by hydroxyl, or R 6 and G 7 and the carbon and nitrogen atoms through which R 6 and G 7 are attached taken together form a saturated 5 or 6 member heterocyclyl; and
  • R" is hydrogen.
  • the compounds of the present invention may be useful in the form of the free base or acid or in the form of a pharmaceutically acceptable salt thereof. All forms are within the scope of the invention. Where the compound of the invention is substituted with an acidic moiety, base addition salts may be formed and are simply a more convenient form for use; in practice, use of the salt form inherently amounts to use of the free acid form.
  • the bases which can be used to prepare the base addition salts preferably include those which produce, when combined with the free acid, pharmaceutically acceptable salts, that is, salts whose cations are non-toxic to the animal organism in pharmaceutical doses of the salts, so that the inhibition of NEP and/or ACE, and preferably beneficial mixed NEP and ACE inhibition, inherent in the compound of the invention is not vitiated by side effects ascribable to the cations.
  • compositions within the scope of the invention include those derived from the following bases: sodium hydroxide, potassium
  • hydroxide calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methyl- glucamine, lysine, arginine, omithine, choline, N.N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine,
  • Metal salts of compounds of the present invention may be obtained by contacting a hydroxide, carbonate or similar reactive compound of the chosen metal in an aqueous solvent with the free acid form of the compound.
  • the aqueous solvent employed may be water or it may be a mixture of water with an organic solvent, preferably an alcohol such as methanol or ethanol, a ketone such as acetone, an aliphatic ether such as tetrahydrofuran, or an ester such as ethyl acetate.
  • Such reactions are normally conducted at ambient temperature but they may, if desired, be conducted with heating.
  • Amine salts of compounds of the present invention may be obtained by contacting an amine in an aqueous solvent with the free acid form of the compound.
  • Suitable aqueous solvents include water and mixtures of water with alcohols such as methanol or ethanol, ethers such as tetrahydrofuran, nitriles such as acetonitrile, or ketones such as acetone.
  • Amino acid salts may be similarly prepared.
  • Preferred base addition salts have a cation selected from the group consisting of ammonium, sodium, calcium, protonated N-methyl-D-glucamine, protonated lysine, protonated arginine and protonated dicyclohexylamine.
  • acid addition salts may be formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free base form.
  • the acids which can be used to prepare the acid addition salts include preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non- toxic to the animal organism in pharmaceutical doses of the salts, so that the inhibition of NEP and/or ACE, and preferably beneficial mixed NEP and ACE inhibition, inherent in the compound of the invention is not vitiated by side effects ascribable to the anions.
  • salts within the scope of the invention are those derived from the following acids: mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid; and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid, and the like.
  • the corresponding acid addition salts comprise the following: hydrochloride, sulfate, phosphate, sulfamate, acetate, citrate, lactate, tartarate, malonate,
  • methanesulfonate methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate, respectively.
  • the acid addition salts of the compounds of this invention are prepared either by dissolving the free base in aqueous or aqueous-alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, wherein case the salt separates directly or can be obtained by concentration of the solution.
  • the compound according to the invention contains several asymmetric centers and may exist in the form of pure stereoisomers or in the form of mixtures of stereoisomers.
  • the carbon atoms marked by an asterisk (*) designate asymmetric centers.
  • configurations at the carbon atoms marked by an asterisk relate: sequentially startin from the carbon atom closest to the O-terminal side of the molecule, i.e., the amino acid residue.
  • Preferred compounds according to the invention include those wherein any of the carbon atoms marked by an asterisk (*) have the S configuration.
  • Preferred also include the compounds of formula (I) according to the invention having a stereochemical designation selected from the group consisting of R,R,S, S,R,S, S,S,S and R,S,S form, and it is more preferred having a stereochemical designation S,S,S or R,S,S.
  • Preferred compounds of formula II according to the invention are those wherein the carbon atoms of the principal chain marked by an asterisk (*) have the L configuration.
  • the S-lipophilic aliphatic carbonyl is S-lipophilic aliphatic carbonyl
  • N-mercaptoacyl(amino acid or peptide)] compound may be prepared by acylating the appropriate N-mercaptoacyl(amino acid or peptide) with the appropriate lipophilic aliphatic carbonyl halide.
  • the reaction may be carried out in the absence or presence of a base such as aqueous sodium hydroxide or pyridine, and may be carried out under an inert atmosphere such as nitrogen. It is also preferred that the reaction medium should be degassed to prevent the mercapto compound from forming a disulfide linked dimer.
  • a base such as aqueous sodium hydroxide or pyridine
  • N-(mercaptoacyl)amino acids may be prepared by hydrolyzing the product formed by the acylation of an amino acid of formula (III)
  • the hydrolysis is
  • the acylation is performed in the presence of a condensing agent such as dicyclohexylcarbodiimide, optionally in the presence of 1-hydroxybenzo-triazole.
  • a condensing agent such as dicyclohexylcarbodiimide
  • 1-hydroxybenzo-triazole optionally in the presence of 1-hydroxybenzo-triazole.
  • thioacetic acid or thiobenzoic acid is used as a sulphur derivative of formula (V).
  • the acrylic acid of formula (VI) may be obtained by saponification of a corresponding ester in a basic medium.
  • the methyl or ethyl ester is used.
  • H 2 C C- COOR 8 (VII) wherein R 1 and R 2 are defined as above and R 6 preferably represents an alkyl radical containing 1 to 4 carbon atoms, may be obtained by a Mannich reaction on the monoester of formula (VIII)
  • the Mannich reaction is performed by means of formaldehyde in the presence of a secondary amine such as diethylamine at a temperature of about 20°C.
  • the monoester of formula (VIII) is obtained by monosaponification in a basic medium of a malonic ester of formula (IX)
  • R 1 , R 2 and R 8 are defined as above.
  • the malonic ester of formula (IX) may be obtained by the action of a halide of formula (X)
  • Halo- N (X) wherein R 1 and R 2 are defined as above and Halo represents a halide atom, preferably a bromide atom, on an alkyl malonate anionised beforehand, for example by means of an alkali metal alcoholate optionally prepared in situ.
  • the malonic ester of formula (IX) may also be obtained by condensation of a ketone of formula (XI)
  • R 1 and R 2 are defined as above, with an alkyl malonate anionised beforehand as described above, to form the product of formula (XII) 1 8 8 XII
  • R 1 , R 2 and R 8 are defined as above, which is reduced catalytically, for example with hydrogen in the presence of palladium on charcoal, to the product of formula (IX).
  • the product of formula (VII) may also be obtained by a Wittig reaction with formaldehyde on a phosphonate of formula (XIII)
  • the reaction is generally performed in the presence of a strong base such as sodium hydride.
  • N-(mercaptoacyl)peptides may be prepared by hydrolyzing the product formed the acylation of a dipeptide of the formula
  • a 2 , R 2 , R 3 , R 4 and R' are as defined above, by an acid of the formula
  • R LA , A 1 and R 1 are as defined above, under the usual conditions used in peptide chemistry and described, for example, by Bodansky et al., "Peptide Synthesis", J. Wiley and Sons Edit.
  • the hydrolysis is preferably carried out in an alkaline medium, working in an inert medium so as to avoid oxidation of the mercapto group.
  • the acid reactant may be prepared from the corresponding ⁇ -amino acid by halogenating deamination according to Fischer, Ann., 357, 1-24 (1907), followed by nucleophilic substitution of the halogen atom.
  • Lipophilic aliphatic carbonyl halides may be prepared from the following lipophilic aliphatic carboxylic compounds when they are in the acid or anhydride forms: camphorcarboxylic acid, camphanecarboxylic acid, 3-methyl adamantyl carboxylic acid, noradamantyl carboxylic acid, norbornane carboxylic acid, 3- methyl 3-bromo-1-adamantyl carboxylic acid, methyl 1-methoxybicyclo[2.2.2.]- oct-5-ene-2-carboxylate, mono methyl cis-5-norborene-endo -2,3-dicarboxylate, methyl-5-norborene-2,3-dicarboxylic anhydride, (1R)-(-)-myrtentoic acid, cis-5- norbornene-endo -2,3-dicarboxylic acid, 5-norbornen-2-yl acetate, 2- norbaneacetic acid, anti-3-o
  • the resolved forms of the compounds according to the invention may be prepared by standard practices known to those skilled in the art such as fractional crystallization and column chromatography.
  • compounds of formula (IV) such as an acylthioalkanoic acid may be resolved by fractional recrystallization with optically active bases such as methylbenzylamine or 1-(1- naphthyl)ethylamine and then the resolved compounds of formula (IV) may be reacted with an optically active amino acid according to the acylation reaction described above to yield a resolved N-(mercaptoacyl)amino acid.
  • Ethyl malonate (4.1 mL) is added to a solution of sodium ethoxide prepared from sodium metal (0.75 g) and ethanol (40 mL).
  • 1-Bromo-1- phenylethane (6 g) is added at 0°C and the mixture is then stirred for 20 hours at 30°C.
  • the residue is taken up with water (100 mL) and then extracted three times with ethyl acetate (75 mL).
  • the organic phase is washed with water and then with saturated sodium chloride solution and finally dried over magnesium sulphate.
  • the product thereby obtained (2.2 g) is treated with of sodium hydroxide (1.5 eq) in an acetone/water (2:1 by volume) mixture overnight at a temperature of about 20°C.
  • the mixture is concentrated to dryness and the residue is then taken up with water (30 mL).
  • the aqueous phase is acidified to pH 2 by adding hydrochloric acid.
  • the diethyl 2-(1-phenylethyl)phosphonoacetate (40.3 g) is dissolved in 37 % formaldehyde (65 mL), and potassium carbonate (51 g) is then added.
  • N-(2-Mercaptomethyl-1-oxo-3-phenylbutyl)tyrosine 1 g of the product obtained in Example G is dissolved in an degassed acetone/water (2:1 by volume) mixture. 1M sodium hydroxide (4 eq) is added at 0°C and under a nitrogen atmosphere. The mixture is stirred for 5 hours at a temperature of about 20°C. After filtering and acidifying to pH 1 , the product is extracted three times with degassed chloroform (15 mL). The organic phase is dried over sodium sulphate.
  • EXAMPLE K N-(2-Acetylthiomethyl-1-oxo-3-phenylbutyl)-O-benzylserine Benzyl Ester Using the procedure described in Example G, starting with
  • ATBA-I 2-Acetylthiomethyl-3-phenylbutanoic acid (5 g) is dissolved in ethanol (50 mL) and (R)-(+)-1-(1-naphthyl)ethylamine (3.4 g) is added to the ethanol solution. Ethyl ether (50 mL) is then added. The mixture is cooled in an ice bath and after scratching the reaction vessel a white precipitate is formed. The solution is stored at about 0°C for about 18 hours. The precipitate is filtered and washed with ethyl ether.
  • the colorless crystalline product is filtered, washed with ethyl ether and dried to yield 2 g of ATBA-III salt.
  • the product is recrystallized twice from a mixture of ethyl acetate/ethanol (2:1) (25 mL) to yield 1 g of ATBA-III salt.
  • the free acid ATBA-III is regenerated by contacting the ATBA-III salt with aqueous acid (10% hydrochloric acid) and extracting with methylene chloride. The methylene is evaporated and 0.67 g of ATBA-III is obtained as a colorless crystalline solid.
  • hydroxybenzotnazole (0.11 g) and N-methylmorpholine (0.19 g) are added to the solution and the mixture is stirred at 20°C for 18 hours.
  • the solvent is removed in vacuo, the residue is contacted with aqueous acid (10% hydrochloric acid) and extracted with ethylacetate.
  • the organic phase is separated and washed consecutively with water (20 mL) saturated sodium bicarbonate solution (20 mL) and water (20 mL).
  • the organic phase is dried and evaporated to yield a light yellow gum.
  • the gum is chromatographed on silica gel using a mixture of hexane/ethyl acetate (1 :1) to yield a colorless gum (ATBAT-IV) (0.26 g; 65%) having the following
  • Example AF(a) Using the procedure of Example AF(a), except starting with the product (ATBA-I) of Example AE(a), the product (ATBAT-I) is obtained after crystallization having the characteristics: m.p. 135-137°C.
  • the diastereomers of N-(2-acetylthiomethyl-1-oxo-3-phenylbutyl)tyrosine benzyl ester are also obtained by column chromatography using Hewlett- Packard ODS Hypersil column (5 ⁇ , 200 x 4.6 mm i.d.).
  • the product of Example G is dissolved in methanol and placed on the column.
  • a mobile phase of methanol/water (62:38 by volume) with 0.2% trifluoroacetic acid is employed in effecting the separation.
  • the flow rate is 1.0 mL/min.
  • the product is detected at UV of 215 nm.
  • the retention times of the four diastereomers are 22.7, 24.75, 28.5 and 30 minutes respectively.
  • Lithium hydroxide hydrate (18 mg) is dissolved in solvent comprising tetrahydrofuran/methanol/water (1 :1:1 by volume). The solvent is purged with nitrogen gas.
  • the product (ATBAT-IV) (21 mg) of Example AF(a)is added to the solution and stirred for 75 minutes at 20°C.
  • the solution is then diluted with water (5 mL), washed twice with chloroform (3 mL), acidified with 10% hydrochloric acid (2 mL) and extracted five times with chloroform (4 mL).
  • the combined organic phases are dried over magnesium sulphate and evaporated to leave 16 mg of a colorless gum (MTBT-I) having > 95% purity.
  • MTBT-I colorless gum
  • Example AH(a) Using the procedure of Example AH(a), except starting with the product (ATBAT-II) of Example AF(b), 9.7 mg the product (MTBT-II) is obtained after crystallization having > 98% purity.
  • R f 0.25 [methylene chloride/methanol/acetic acid (9:1 :05 by volume)].
  • the residue obtained is dissolved in ethyl acetate and then washed successively with a 10% citric acid solution (w/v), with water, with a 10% sodium carbonate solution (w/v), with water, then with a saturated sodium chloride solution.
  • the organic phase is dried over sodium sulphate. After filtration and concentration to dryness, the residue is purified by
  • the product obtained above is dissolved in degassed methanol and a 1 M sodium hydroxide solution (3 equivalents) is added at 0°C.
  • the mixture is stirred for 2 hours at a temperature close to 20°C and then a partition is carried out between degassed water and degassed ethyl acetate.
  • the organic phase is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate, filtered and then concentrated under reduced pressure.
  • the residue obtained is chromatographed on silica gel, eluting with a methylene chloride/methanol/acetic acid mixture (9:0.5:0.5 by volume).
  • N-(2- mercapto-3-phenylpropanoyl)-Val-Tyr is thus obtained with a yield of 65% in the form of a white solid having the following characteristics: high performance liquid chromatography: retention time: 8 minutes [acetonitrile/0.05%
  • N-(2-Mercapto-3-phenylpropanoyl)-lle-Tyr-OMe The coupling of 2-acetylthio-3-phenylpropanoic acid with the protected dipeptide lle-Tyr-OMe is carried out under the conditions described in Example BA.
  • N-(2-Acetylthio-3-phenylpropanoyl)-lle-Tyr-OMe is obtained with a yield of 75% in the form of an oily product.
  • R f 0.17 [hexane/ethyl acetate (5:5 by volume)].
  • Deprotection is carried out under the conditions of Example BA.
  • N-(2- Mercapto-3-phenylpropanoyl)-lle-Tyr-OMe is thus obtained with a yield of 70% in the form of a white solid melting at 185°C.
  • R f 0.28 [methylene
  • N-(2-Mercapto-3-phenylpropanoyl)-lle-Pip is thus obtained with a yield of 65% in the form of a white solid.
  • R f 0.48 [methylene chloride/methanol/acetic acid (9:0-5:0-25 by volume)]; proton nuclear magnetic resonance spectrum (deuterated dimethyl sulphoxide; chemical shifts in ppm): 0.80 [CH 3 ( lle)]; 1.02, 1.50 and 2.05 [CH 2 ⁇ , ⁇ and ⁇ (Pip)]; 2.6 (HS); 2.80 and 3.05 [CH 2 ⁇ (Phe)]; 3.7 [CH 2 ⁇ (Pip)]; 4.20, 4.70 and 4.95 (CH ⁇ ; 7.20 [Ar (Phe)]; 8.20 and 8.40 (NH); 12.78 (COOH).
  • R f 0.53 [methylene chloride/methanol (9:1 by volume)]; proton nuclear magnetic resonance spectrum (deuterated dimethyl sulphoxide; chemical shifts in ppm): 0.80 [CH 3 (Nle)]; 1.25 and 1.50 [CH 2 ⁇ ,g and ⁇ (Nle)]; 2.00 (HS); 2.75 and 2.95 [CH 2 ⁇ (Phe + Tyr)]; 3.70 and 4.20 [CH ⁇ (Nle, Phe, Tyr)]; 6.60 and 6.95 [Ar (Tyr)]; 7.20 [Ar (Phe)]; 8.10 and 8.20 (NH); 9.15 [OH (Tyr)]; 12.3 (COOH); high performance liquid chromatography:
  • Example BA N-(2-Acetylthic-4-phenylbutanoyl)-Val-Tyr-OCH 3 is thus obtained with a yield of 82% in the form of an oily product.
  • R f 0.49 [cyclohexane/ethyl acetate (5:5 by volume)].
  • N-(2-Mercapto-4-phenylbutanoyl)-Val-Tyr is thus obtained with a yield of 98% in the form of a white product melting at 105°C.
  • R f 0.65 [methylene chloride/methanol/acetic acid (9:1:0.5 by volume)]; high performance liquid chromatography: retention time: 9.10 minutes[acetonitrile/0.05% trifluoroacetic acid (45:55 by volume)]; proton nuclear magnetic resonance spectrum
  • N-(2-Acetylthio-3-methylbutanoyl)-lle-Tyr-OCH 3 is obtained with a yield of 85% in the form of an oily product.
  • R f 0.28 [n-hexane/ethyl acetate (4:6 by volume)].
  • Example N The product (1.7 g) of Example N is dissolved in degassed water (18 mL). To the solution under a nitrogen atmosphere and at 0°C is added a solution 1.3 X 10 -2 M sodium hydroxide (2.2 eq) and adamantoyl chloride (1.33 g, 1.1 eq). The mixture is stirred for four hours at ambient temperature. The mixture is then acidified to pH 3 with 1 M hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water and then a saturated NaCI solution. The organic phase is dried over anhydrous Na 2 SO 4 , filtered and evaporated to dryness. A white solid (2 g) is obtained in a yield of 74% having the following characteristics: m.p.
  • Compounds within the scope of the present invention when administered to mammals, are potent ACE and/or NEP inhibitors; preferably antihypertensives due to double inhibitory action where they inhibit both NEP and ACE.
  • the ACE inhibitors within the scope of the present invention are capable of blocking the increase in the blood pressure caused by an increase in the vascular resistance and the blood volume due to the formation of angiotensin II from angiotensin I since ACE inhibitors block the production of angiotensin II.
  • the NEP inhibitors within the scope of the present invention regulate auricular natriuretic peptide which is implicated in the regulation of arterial pressure.
  • This peptide is liberated by the heart, endowed with a vasodilatory property and capable of controlling diuresis and natriuresis.
  • Auricular natriuretic peptide is inactivated by NEP in the peripheral tissues.
  • NEP and ACE may be used to alleviate hypertension of various origins without the co-administration of other diuretics.
  • compounds according to the present invention are effective in the treatment of congestive heart failures and various types of hypertension, in particular hypertension connected with an increase in the blood volume.
  • the antihypertensive properties of the present compounds are:
  • Table III presents selected pharmacological data for the N- mercaptoacyl (amino acid or peptide) compounds having both ACE and NEP inhibitory properties. These compounds may be acylated with an S-lipophilic aliphatic acyl radical to form compounds within the scope of the present invention.
  • the results in Table III also gives the results with N-(2-mercaptomethyl-3-phenyl-1-oxopropyl)glycine (thiorphan), which is very closely related structure to the N-mercaptoacylamino acid portion of the compound of formula I, for comparison to show that thiorpan manifests activity only against NEP.
  • This invention is directed to the unexpected finding that protection of the thiol group was protected by a lipohilic aliphatic carbonyl results in compounds have an increased ACE and/or NEP inhibitory activity over the compounds that are acylated with an acylating group, e.g., acetyl, have lower lipophilic character.
  • mice administered by i.v. route to a mouse.
  • the mouse is killed 15 minutes
  • the kidney rapidly set apart, and homogenized at 4°C in a Tris HCI buffer 50 mM (pH 7.4).
  • the homogenate is filtered and the radioactivity bound to the filter is measured by liquid scintillation.
  • the non-specific binding is determined after co-injection of [3 H]HACBOGIy with 10,000 equivalents of the specific NEP inhibitor, retrothiorphan (Roques et al., PNAS, 1983, 80, 3178- 3182).
  • the inhibition of NEP in the kidney is expressed as the difference (in %) between specific [ 3 H]HACBOGIy binding in the absence (controls injected with saline) and presence of inhibitor.
  • the inhibition values in Table IV are the mean value of three determinations.
  • Example 3 The protocol in Example 3 is used also to determine NEP inhibition except for the following: the selective tritiated ACE inhibitor is
  • [ 3 H]Trandaloprilate (0.5 ⁇ Ci); and the non-specific binding is determined by the co-administration of [ 3 H]Trandaloprilate with 1000 eq. of captopril.
  • the NEP inhibition values are given in Table IV above.
  • ACE inhibition is determined at 30, 60, 120 and 240 minutes for N-(2-acetylthiomethyl-1-oxo-3- phenylbutyl)alanine as a mixture of four stereoisomers (- ⁇ -), N-(2- adamantylthiomethyl-1-oxo-3-phenylbutyl)alanine as a mixture of four stereoisomers (- O -) and the single stereoisomer (S,S,S)-N-(2-adamantyl- thiomethyl-1-oxo-3-phenylbutyl)alanine (- ⁇ -).
  • Figure 1 graphically represents the results and shows that the adamantylcarbonyl derivatized compounds exhibit unexpectedly greater inhibition than the acetylated compound.
  • the products according to the invention may generally be administered orally or parenterally for the treatment of patients suffering from hypertension.
  • the products according to the invention, in base or salt form may be presented in forms permitting administration by the most suitable route and the invention also relates to pharmaceutical compositions containing at least one product according to the invention which are suitable for use in human or veterinary medicine.
  • These compositions may be prepared according to the customary methods, using one or more pharmaceutically acceptable adjuvants or excipients.
  • the adjuvants comprise, inter alia, diluents, sterile aqueous media and the various non-toxic organic solvents.
  • the compositions may be presented in the form of tablets, pills, granules, powders, aqueous solutions or
  • suspensions injectable solutions, elixirs or syrups, and can contain one or more agents chosen from the group comprising sweeteners, flavorings, colorings, or stabilizers in order to obtain pharmaceutically acceptable preparations.
  • excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acids and certain complex silicates combined with lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used for preparing tablets.
  • lactose and high molecular weight polyethylene glycols When aqueous suspensions are used they can contain emulsifying agents or agents which facilitate suspension. Diluents such as ethanol, propylene glycol, glycerol and chloroform or mixtures thereof may also be used.
  • suspensions or solutions of the products according to the invention in sesame oil, groundnut oil or olive oil or aqueous solutions of propylene glycol, as well as sterile aqueous solutions of the pharmaceutically acceptable salts are used.
  • the solutions of the salts of the products according to the invention are especially useful for administration by intramuscular or subcutaneous injection.
  • the aqueous solutions also be used.
  • compositions of the salts in pure distilled water may be used for intravenous administration with the proviso that their pH is suitably adjusted, that they are judiciously buffered and rendered isotonic with a sufficient quantity of glucose or sodium chloride and that they are sterilized by heating or
  • the doses used in the methods according to the invention are those which lead to a maximal therapeutic effect until an improvement is obtained.
  • the doses used are those which are therapeutically effective for lowering blood pressure during the treatment of hypertension.
  • the doses administered orally are between 0.1 and 100 mg/kg, and preferably between 1 and 10 mg/kg, and those administered intravenously are between 0.01 and 10 mg/kg, and preferably between 0.1 and 5 mg/kg, on the
  • the doses will be determined in accordance with the factors distinctive to the subject to be treated, such as age, weight, general state of health and other characteristics which can influence the efficacy of the medicinal product.
  • the products according to the invention may be administered as frequently as necessary in order to obtain the desired therapeutic effect. Some patients may respond rapidly to a higher or lower dose and may find much weaker maintenance doses adequate. For other patients, it may be necessary to have long-term treatments at the rate of 1 to 4 doses per day, in accordance with the physiological requirements of each particular patient. Generally, the active product may be administered orally 1 to 4 times per day. It goes without saying that, for other patients, it will be necessary to prescribe not more than one or two doses per day.
  • the products according to the invention may be used in injectable form in emergency cases of acute hypertension. Such a treatment may be followed by an intravenous perfusion of the active product so as to obtain and maintain the desired therapeutic effect.

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Abstract

La présente invention concerne des composés S-carbonyle aliphatique lipophile [N-mercaptoacyl(acide aminé ou peptide)] de la formule (I) ou de la formule (II). Dans ces formules, R est un groupe carbonyle aliphatique lipophile; R1 est un aryle ou un hétéroaryle; R2 est un alkyle ou un alkylène fixé au groupe (a) et à R1; R3 est un hydrogène, un alkyle, un aryle, un alcoxy ou un aryloxy; R4 et R5 sont, d'une manière indépendante, hydrogène, un alkyle, un aryle, un aralkyle, un alcoxy, un alkyloxyméthyle ou un aralkyloxy; A1 et A2 sont, d'une manière indépendante, hydrogène, un alkyle, ou ils forment, respectivement avec -CH-R4 ou -CH-R5, des groupes phényle ou alkylène qui forment, respectivement avec -CH-R4 ou -CH-R5, un benzocycloalkyle; R6 est hydrogène ou un alkyle; R7 est un cycloalkyle, un aralkyle ou un aryloxyméthyle ou un alcoxyméthyle, ou R6 et R7 forment ensemble un groupe hétérocyclique avec les atomes de carbone et d'azote auxquels R6 et R7 sont fixés; et R' est hydrogène, un alkyle, un aralkyle, un cycloalkyle-alkyle inférieur, ou un palmitoyle. L'invention concerne également les sels de ces composés acceptables sur le plan pharmaceutique. A très faible concentration, ces composés inhibent l'endopeptidase neutre (NEP) et/ou la peptidyldipeptidase A (ACE) et ils sont utiles pour le traitement de l'hypertension, de préférence par inhibition simultanée de l'ACE et de la NEP. L'invention concerne également la préparation de ces composés, des compositions pharmaceutiques les contenant et des méthodes d'utilisation de ces composés en pharmacie.
PCT/EP1993/000147 1993-01-22 1993-01-22 Composes s-carbonyle aliphatique lipophile [n-mercaptoacyl(acide amine ou peptide)] utilises comme antihypertenseurs WO1994017036A1 (fr)

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WO1997024341A1 (fr) * 1995-12-28 1997-07-10 Zambon Group S.P.A. Derives thiol presentant une activite inhibitrice de metallopeptidase (ace/nep)
WO1999019346A1 (fr) * 1997-10-14 1999-04-22 Basf Aktiengesellschaft Dipeptides pour le traitement de maladies liees a l'effet biologique de l'endotheline
US5994539A (en) * 1995-12-28 1999-11-30 Zambon Group S.P.A. Mercapto acyl aminoacid derivatives endowed with dual ACE-NEP inhibitory activity, useful in the treatment of cardiovascular diseases
WO2000050392A1 (fr) * 1999-02-24 2000-08-31 Sankyo Company, Limited Derives de l'acide 2-mercaptocarboxylique
US6352976B1 (en) 1998-12-31 2002-03-05 Aventis Pharmaceuticals Inc. Selective inhibitors of MMP-12
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USRE42461E1 (en) 1993-09-21 2011-06-14 Schering Corporation Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents
FR2729668A1 (fr) * 1995-01-23 1996-07-26 Adir Nouveaux derives de mercaptoalcanoyldipeptides, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
EP0723974A1 (fr) * 1995-01-23 1996-07-31 Adir Et Compagnie Dérivés de mercaptoalcanoyldipeptides, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
AU699204B2 (en) * 1995-01-23 1998-11-26 Institut National De La Sante Et De La Recherche Medicale New mercaptoalkanoyldipeptide compounds, a process for their preparation and pharmaceutical compositions containing them
WO1997024341A1 (fr) * 1995-12-28 1997-07-10 Zambon Group S.P.A. Derives thiol presentant une activite inhibitrice de metallopeptidase (ace/nep)
US5994539A (en) * 1995-12-28 1999-11-30 Zambon Group S.P.A. Mercapto acyl aminoacid derivatives endowed with dual ACE-NEP inhibitory activity, useful in the treatment of cardiovascular diseases
EA002339B1 (ru) * 1995-12-28 2002-04-25 Замбон Груп С.П.А. Тиольные производные, обладающие ингибирующей активностью в отношении металлопептидаз (ace/nep)
CN1108295C (zh) * 1995-12-28 2003-05-14 萨宝集团公司 具有金属肽酶(ace/nep)抑制活性的巯基衍生物
WO1999019346A1 (fr) * 1997-10-14 1999-04-22 Basf Aktiengesellschaft Dipeptides pour le traitement de maladies liees a l'effet biologique de l'endotheline
US6352976B1 (en) 1998-12-31 2002-03-05 Aventis Pharmaceuticals Inc. Selective inhibitors of MMP-12
WO2000050392A1 (fr) * 1999-02-24 2000-08-31 Sankyo Company, Limited Derives de l'acide 2-mercaptocarboxylique

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