IE902686A1 - Renin-inhibiting amino oligohydroxy derivatives - Google Patents

Renin-inhibiting amino oligohydroxy derivatives

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IE902686A1
IE902686A1 IE268690A IE268690A IE902686A1 IE 902686 A1 IE902686 A1 IE 902686A1 IE 268690 A IE268690 A IE 268690A IE 268690 A IE268690 A IE 268690A IE 902686 A1 IE902686 A1 IE 902686A1
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alkyl
amino
methyl
denotes
substituted
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IE268690A
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Hoechst Ag
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Priority claimed from DE3924506A external-priority patent/DE3924506A1/en
Priority claimed from DE19893932817 external-priority patent/DE3932817A1/en
Application filed by Hoechst Ag filed Critical Hoechst Ag
Publication of IE902686A1 publication Critical patent/IE902686A1/en

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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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    • 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
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    • 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
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic

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Abstract

The present invention relates to compounds of the formula I <IMAGE> in which A, R<2>, R<3>, R<4> and n are defined as indicated in the description, to processes for the preparation thereof, to the use thereof as medicines and to pharmaceutical compositions containing these.

Description

Renin-inhibiting amino oligohydroxy derivatives Amino diol derivatives having a renin-inhibiting action 5 are known from European Patent Applications EP-A 184,855, 189,203, 202,577, 229,667, 230,266 and 237,202 and International Patent Application WO 87/05302.
Renin-inhibiting amino diol derivatives are furthermore described in Biochem. Biophys. Res. Commun. 132, 155 10 161 (1985), in Biochem. Biophys. Res. Commun. 146, 959 963 (1987), in FEBS Lett. 230, 38 - 42 (1988) and in J. Med. Chem. 30, 976 - 982 (1987).
Surprisingly, it has now been found that those compounds which differ from the compounds described in the docu15 ments mentioned in that they contain additional hydroxyl functions on the C terminus are highly active renin inhibitors in vitro and in vivo and have advantageous properties compared with the known compounds.
The invention relates to compounds of the formula R2 R3 R4 ι ι ι A-N-CH-CO-NH-CH- (CHOH)n - CH2OH in which A denotes a radical of the formula II, III or IV R6 R5 O R I I H R1-N-CH-C(I) (II) R7 R5 O i ' R1 - CH - CH - C R5 0 ι I R1 - O - CH - C (III) (IV) R1 ax) denotes (C3-C8)-cycloalkyl, (CA-C10)-bicycloalkyl, (Ca-C12)-tricycloalkyl, (C3-C8)-eyeloalkyl-(C^-Cg) alkyl, (C4-Clo)-bicycloalkyl-(Ci-Cg)-alkyl, (C8C12) -tricycloalkyl- (Cj-C6) -alkyl, (C3-C8) -cyclo5 alkylcarbonyl or (C3-C8)-cycloalkylsulfonyl, in which the cycloalkyl, bicycloalkyl and tricycloalkyl substituent in each case can be substituted by one or two identical or different radicals from the series comprising F, Cl, Br, I, hydroxyl, (Cj-C6)-alkoxy, (Cx-C8)-alkyl, carboxyl, (Ci-Cg)-alkoxycarbonyl, carbamoyl, carboxymethoxy, amino, (Cx-Cg)-monoalkylamino, (Cx-C6)dialkylamino, amino-(Cj-C6)-alkyl, (Ci-Cg)-alkylamino- (Cx-Cg) -alkyl, di- (Cx-Cg) -alkylamino- (Cx-C6) 15 alkyl, amidino, hydroxyamino, hydroximino, hydrazono, imino, guanidino, (Cx-Cg)-alkoxysulfonyl, (Cx-Cg) -alkoxysulf enyl, tri fluoromethyl, (Ci-C<)-alkoxycarbonylamino and (C6-Cx2)-aryl() -alkoxycarbonyl-amino; hydroxyl, hydrogen, (ΰχ-ΰχ8)-alkyl, (Cx-C8)-alkoxy, (Cx-C18)alkanoyl, (Cx-C18)-alkoxycarbonyl, (Cx-Cx8)-alkylsulfonyl or (Cx-Cx8)-alkylsulfinyl, in which the alkyl radicals in each case can be substituted by optionally protected amino, trimethylsilyl, hydroxyl, mercapto, (Cx-C4)-alkylthio, halogen, (Cx-C J-alkoxy, mono- or di-(Cx-C8)-alkylamino, carboxyl, carbamoyl, guanidino, (Cx-C4)-alkoxycarbonyl, (Cx-C8)-alkanoyloxy, phenyl-(Cx-C4)-alkoxy or a radical C0NR8Rs; (Cg-CxJ-aryl, (C8-Cu)-aryl-(Cx-C J-alkyl or (C6ϋχ4)-aryl-(Cx-C4)-alkoxy, in which the aryl radical in each case can be substituted by one, two or three identical or different radicals from the series comprising (Cx-C6)-alkyl, amino, mono- or di-(Cx-C4)-alkylamino, amino-(Cx-C4)-alkyl, hydroxy-(Cx-CJ-alkyl, mono- or di-(Cx-C4)-alkylamino- (Cx-C4) -alkyl, hydroxyl, (Cx«C4)-alkoxy, halogen, formyl, (Cx~C4)-alkoxycarbonyl, carboxamido, mono- or di-(C1-C4)-alkylaminocarbonyl and nitro; Het or Het-(C^-CJ-alkyl, in which Het represents a 5-, 6- or 7-membered heterocyclic ring which can be additionally benzo-fused and either aromatic, partly hydrogenated or completely hydrogenated and contains one or two identical or different radicals from the series comprising N, 0, S, NO, SO and SO2 as the hetero element and can be substituted by one or two identical or different radicals from the series comprising (Ci-CJ-alkyl, (Cx-CJ-alkoxy, (Ci-CJ-alkoxycarbonyl, hydroxyl, halogen, amino, amino-(Cj-CJalkyl and mono- or di-(Cx-C4)-alkylamino, or a radical NReR9, in which R8 and R9 are identical or different and independently of one another denote hydrogen; (Cx-C8)alkyl, which can be substituted by amino, (Cj-C*) -alkylamino, di- (Cx-C4) -alkylamino, hydroxyl or (Cj-CJ -alkoxy; or (C3-C7-cycloalkyl; mercapto; (Cx-C4)-alkylthio; phenylthio; (Cx-CJ-alkoxycarbonyl; carboxyl or (C6-C1A)aryl, which can be substituted in the aryl radical as described above; or Het or Het25 (Cx-CJ-alkyl, in which Het is defined as described above, or in which R8 and R9, together with the nitrogen atom carrying them, form a 5- to 12-membered ring which can be mono- or bicyclic, can also contain 1 or 2 nitrogen atoms, 1 sulfur atom or 1 oxygen atom as further ring members and can be substituted by (Cx-C4)-alkyl, or R1 a2) denotes a radical of the formula V R1’ - W (V) in which R1’ is defined as R1 under aj) and W represents -CO-, -CS-, -O-CO-, -SO2-, -SO-, -NH -SO2-, -NH-CO-, -CH(OH)- or -N(OH)-; R1 and R5, together with the nitrogen atom carrying them, form a 5- to 12-membered ring which can be mono- or bicyclic, aromatic, partly hydrogenated or completely hydrogenated, and can also contain, as further ring members, 1 or 2 nitrogen atoms, 1 sulfur atom or 1 oxygen atom and can be substituted by (Ci-CJ-alkyl, R2 and R6 independently of one another denote hydrogen or (Ct-CJ-alkyl, R3 and R5 independently of one another are defined as R1 under aj; R* denotes (C3-C12)-alkyl; mono-, bi- or tricyclic (C315 C18)-cycloalkyl, (C3-C1B)-cycloalkylmethyl or (C3-C18)cycloalkylethyl, in which the cycloalkyl part is optionally substituted by (Cj-Cg)-alkyl; dithiolanyl; (C6-C1A)-ary lmethyl; dithiolany lmethyl; dithiolanylethyl; dithianyl; dithianylmethyl or dithianylethyl; R7 is hydrogen or (Cx-C8)-alkyl, or together with R1 or R5 and the atoms carrying these, forms a mono- or bicyclic, saturated or partly unsaturated ring system having 5-12 ring members, which, in addition to carbon, can also contain 1 sulfur atom, which can optionally be oxidized to sulfoxide or sulfone; and n denotes 2-10, and physiologically tolerated salts thereof.
The chirality centers in the compounds of the formula I can have the R, S or R-S configuration.
Alkyl can be straight-chain or branched. The same applies to radicals derived therefrom.
(C3-C8)-Cycloalkyl is understood as meaning cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
(C«-C10)-Bicycloalkyl or (C8-C12)-tricycloalkyl are under5 stood as meaning an isocyclic aliphatic non-aromatic radical which can optionally contain unsymmetrically distributed double bonds and can optionally also be substituted by open-chain aliphatic side chains. The two or three rings as components of such a radical are condensed or spiro-linked and linked via a ring carbon atom or a side chain carbon atom. Examples of these radicals are bornyl, norbornyl, pinanyl, norpinanyl, caranyl, norcaranyl, thujanyl, adamantyl, bicyclo(3.3.0)octyl, bicyclo(1.1.0)butyl and spiro(3.3) heptyl sub15 stituents.
If the rings mentioned carry more than one substituent, these can be either cis or trans to one another.
(C6-C14)-Aryl is, for example, phenyl, naphthyl, biphenylyl or fluorenyl; phenyl is preferred. The same applies to radicals derived therefrom, such as, for example, aryloxy, aroyl, aralkyl and aralkyloxy. Aralkyl is understood as meaning an unsubstituted or substituted aryl radical linked to alkyl such as, for example, benzyl, a- and βnaphthylmethyl, halobenzyl and alkoxybenzyl, but aralkyl would not be limited to the radicals mentioned.
A radical Het in the context of the above definition is, for example, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxal30 inyl, ^-carbolinyl or a benzo-fused or cyclopenta-, cyclohexa- or cyclohepta-fused derivative of these radicals. This heterocyclic radical can be substituted on a nitrogen atom by oxido, (Cj-Cg)-alkyl, for example methyl or ethyl, phenyl or phenyl-(Cx—C4) -alkyl, for example benzyl, and/or on one or more carbon atoms by (Cj-CU-alkyl, for example methyl, phenyl, phenyl-(Cx-C4)alkyl, for example benzyl, halogen, for example chlorine, hydroxyl, (C2-C4)-alkoxy, for example methoxy, phenyl5 (Cj-C4)-alkoxy, for example benzyloxy, or oxo and partly saturated and is, for example, 2- or 3-pyrrolyl, phenylpyrrolyl, for example 4- or 5-phenyl-2-pyrrolyl, 2-furyl, 2-thienyl, 4-imidazolyl, methyl-imidazolyl, for example 1- methyl-2-, -4- or -5-imidazolyl, l,3-thiazol-2-yl, 2-, 3- or 4-pyridyl, l-oxido-2-, -3- or -4-pyridyl, 2-pyrazinyl, 2-, 4- or 5-pyrimidinyl, 2-, 3- or 5-indolyl, substituted 2-indolyl, for example Ι-methyl-, 5-methyl-, 5-methoxy-, 5-benzyloxy-, 5-chloro- or 4,5-dimethyl-2indolyl, l-benzyl-2- or -3-indolyl, 4,5,6,7-tetrahydro15 2-indolyl, cyclohepta[b]-5-pyrrolyl, 2-, 3- or 4-quinolyl, 4-hydroxy-2-quinolyl, 1-, 3- or 4-isoquinolyl, 1oxo-1,2-dihydro-3-isoquinolyl, 2-quinoxalinyl, 2-benzofuranyl, 2-benzoxazolyl, 2-benzothiazolyl, benz[e]indol2- yl or ^-carbolin-3-yl.
Partly hydrogenated or completely hydrogenated heterocyclic rings are, for example, dihydropyridinyl, pyrrolidinyl, for example 2-, 3- or 4-N-methylpyrrolidinyl, piperidinyl, piperazinyl, morpholino or thiomorpholino.
Halogen represents fluorine, chlorine, bromine or iodine, fluorine, chlorine and bromine being preferred.
Salts of compounds of the formula I are to be understood as meaning, in particular, pharmaceutically usable or non-toxic salts.
Such salts are formed, for example, from compounds of the formula I which contain acid groups, for example carboxyl, with alkali metals or alkaline earth metals, such as Na, K, Mg and Ca, and with physiologically tolerated organic amines, such as, for example, triethylamine and tri-(2-hydroxyethyl)-amine.
Compounds of the formula I which contain basic groups, for example an amino group or a guanidino group, form salts with inorganic acids, such as, for example, hydrochloric acid, sulfuric acid or phosphoric acid, and with organic carboxylic or sulfonic acids, such as, for example, acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid and p-toluenesulfonic acid.
Preferred compounds of the formula I are those in which A is as defined on page 1; R1 denotes hydrogen or represents (Cx-Cxo)-alkyl; cyclopentyl; cyclohexyl; cyclopentyl-(Cx-C6)-alkyl; cyclohexyl- (Cx-C6)-alkyl; phenyl-(Cx-C4)-alkyl, in which the phenyl radical is optionally substituted as described on page 2; thienyl or thienyl-(Cx-C4)-alkyl, in which the thiophene radical can in each case be substituted by one or two identical or different radicals from the series comprising (Cx-C4)-alkyl, (Cx-C4)-alkoxy and halogen, or 2-, 3- or 4-pyridyl or 2-, 3- or 4-pyri20 dyl-(Cj-C4)-alkyl, in which the pyridine radical can be substituted by one or two identical or different radicals from the series comprising (Cx-C4)-alkyl, (Cx-C4)-alkoxy and halogen; amino-(Cx-Cxo)-alkyl; hydroxy- (Cx-Cxo) -alkyl; (Cx-C4) -alkoxy- (Cx-C10) -alkyl; (Cx-C4)-alkoxycarbonyl-(Cx-Cxo)-alkyl; (Cx-C8)-alkylsulfonyl; (Cx-Ce)-alkylsulfinyl; (Cx-C8) -hydroxyalkyl sulfonyl; (Cx-C8)-hydroxy-alkylsulfinyl; hydroxy- (CX~C1O)alkanoyl; (Cx-C8)-alkanoyloxy-(Cx-Cx0)-alkyl; (Cx-Cxx)alkanoyl; optionally protected amino-(Cx-Cxx)-alkanoyl, such as (3-amino-3,3-dimethyl)-propionyl, 4-aminobutyryl, 5-aminopentanoyl, 6-aminohexanoyl, 4-N-tert.butoxycarbonylaminobutyryl, 5-N-tert.-butoxycarbonylaminopentanoyl or 6-N-tert.-butoxycarbonylaminohexanoyl; di-(Cx-C7)-alkylamino-(C2-Cxx)-alkanoyl; (C3-C8)35 cycloalkylcarbonyl; amino-substituted (C3-C8)-cycloalkyl-carbonyl; amino-substituted (C3-C8) -cycloalkylIE 902686 sulfonyl or (C8-Cx0)-aryl-(C2-Cxx)-alkanoyl; 2-pyridyl(Cx-C0)-alkanoyl; 3-pyridyl-(Ci-Cg)-alkanoyl; 4-pyridyl(Cx-C8)-alkanoyl; benzoyl which is optionally substituted by halogen, (Cx-C6)-alkyl, (Cx—C4)-alkoxy or (Cx-C4)-alkoxycarbonyl; benzenesulfonyl; (Ci_C10) alkoxycarbonyl, optionally substituted by trimethylsilyl, halogen, (Cx-C6) -alkyl or halo- (Cx-C6) -alkyl; (C6-Cu) -aryl- (Cx-C8) -alkoxy-carbonyl; 4-amino-piperidino-l-carbonyl; 4-aminomethyl-piperidino-l-carbonyl; N-(4-piperidino)-carbamoyl; or N-methyl-[2--ethyl]aminocarbonyl; R1 and R5 together with the nitrogen atom carrying them, form a 5- to 12- membered ring, which can be mono- or bicyclic, aromatic, partly hydrogenated or completely hydrogenated; R2 and R6 independently of one another denote hydrogen or (Cj-CJ-alkyl, R3 and R5 independently of one another are defined as R1 ax) on page 2; R* denotes (C3-Cx2)-alkyl; mono-, bi- or tricyclic (C3Cx8)-cycloalkyl or (C3-C18)-cycloalkylmethyl, in which the cycloalkyl part is optionally substituted by (CX-CA)-alkyl; (C8-Cx4)-arylmethyl; dithiolanyl; dithiolanylmethyl; dithianyl or dithianylmethyl; R7 denotes hydrogen or methyl, or together with R1 or R5 and the atoms carrying these forms a mono- or bicyclic saturated or partly unsaturated ring system having 5 12 ring members which, in addition to carbon, can also contain 1 sulfur atom, which is optionally oxidized to sulfoxide or sulfone; and n denotes 2 - 8.
Particularly preferred compounds of the formula I are those in which R1 denotes hydrogen, (Ci-Ce)-alkylsulfonyl; (Cx-C8)-alkylsulfinyl; 2-hydroxyethylsulfonyl; 2-hydroxypropylsulfonyl; 2-hydroxypropionyl; 3-hydroxypropionyl;-35 hydroxybutyryl; 2-hydroxy-3-methylbutyryl; (Ci-Cg)alkanoyloxy-iCi-Cxo)-alkyl; n-decanoyl; formyl; acetyl; propionyl; pivaloyl; isovaleryl; isobutyryl; (3-amino3,3-dime thyl)-propionyl; 4 - aminobutyryl; 5-aminopentanoyl; 6-aminohexanoyl; dimethylaminoacetyl; piperi10 dino-4-carbonyl; morpholino-4-carbonyl; cyclopropylcarbonyl; cyclobutylcarbonyl; cyclopentylcarbonyl; cyclohexylcarbonyl; 3-aminocyclobutylcarbonyl; 4aminocyclohexylcarbonyl; 3-aminocyclobutylsulfonyl; 4aminocyclohexylsulfonyl; phenylacetyl; phenylpropa15 noyl; phenylbutanoyl; 2-pyridyl-(Ci-Ce)-alkanoyl; 3pyridyl-iCj-Cg)-alkanoyl; 4-pyridyl-(Cj-Ce)-alkanoyl; 4chlorobenzoyl; 4-methylbenzoyl; 2-methoxycarbonylbenzoyl; 4-methoxybenzoyl; pyrrolyl-2-carbonyl; pyridyl-3-carbonyl; benzenesulfonyl; methoxycarbonyl; ethoxycarbonyl; isobutoxycarbonyl; tert.-butoxycarbonyl; 2-(trimethylsilyl)-ethoxycarbonyl; 2,2,2trichloroethoxycarbonyl; 1,l-dimethyl-2,2,2-trichloroethoxycarbony1; benzyloxy-carbonyl; 1- or 2-naphthylmethoxycarbony1; 9-fluorenylmethoxyearbony1; 4-amino25 piperidino-1-carbonyl; 4-aminomethyl-piperidino-1carbonyl; N-methyl-[2--ethyl]-aminocarbonyl, or N-(4-piperidino)-carbamoyl; R1 and R5, together with the nitrogen atom carrying them, form an 8- to 12-membered bicyclic ring, which can be aromatic, partly hydrogenated or completely hydrogenated; R2 and R6 independently of one another denote hydrogen or methyl; R3 and R5 independently of one another denote hydrogen, methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, sec.-butyl, 3-guanidinopropyl, carbamoy lme thyl, 2carbamoylethyl, carboxymethyl, 2-carboxyethyl, mercaptomethyl, 2- (methylthio) -ethyl, (1-mercapto-l-methyl) ethyl, hydroxymethyl, 1-hydroxyethyl, aminomethyl, 25 aminoethyl, 3-aminopropyl, 4-aminobutyl, N,N-dimethylamino, cyclohexylmethyl, imidazol-4-yl-methyl, benzyl, 2-methyl-benzyl, 3-methylbenzyl, indol-3-yl-methyl, 4hydroxybenzyl, 4-methoxybenzyl, 3,4-dihydroxybenzyl, 3,4-dimethoxybenzyl, (benzodioxolan-5-yl)-methyl, 210 thienyl, 2-thienylmethyl, 2-(2-thienyl)-ethyl, 3thienyl, 3-thienylmethyl, 2-(3-thienyl)-ethyl, 4chlorobenzyl, 2-(methylsulfinyl)-ethyl, 2-(methylsulfonyl) -ethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4pyridylmethyl, cyclohexyl, (l-methyl-imidazol-4-yl)15 methyl, (3-methyl-imidazol-4-yl)-methyl, phenyl, 1naphthylmethyl, 2-naphthylmethyl, 2-phenylethyl, 2thiazolylmethyl, 4-thiazolylmethyl, 3-pyrazolylmethyl, 4-pyrimidinylmethyl, indol-2-yl-methyl, 2-benzo[b]thienylmethyl, 3-benzo[b]thienylmethyl, 2-furylmethyl, cyclohexyl or cyclopentyl; R* denotes (C3-C12)-alkyl; mono- or bicyclic (C3-C12)cycloalkyl or (C3-C12)-cycloalkylmethyl, in which the cycloalkyl part is optionally substituted by (Ci-C*)alkyl; (C6-C10)-aryl-methyl; dithiolanyl; dithiolanyl25 methyl; dithianyl or dithianylmethyl; R7 denotes hydrogen or, together with R1 and the atoms carrying these, forms a mono- or bicyclic saturated or partly unsaturated ring system having 5-12 ring members, which, in addition to carbon, also contains 1 sulfur atom, which is particularly preferably oxidized to sulfone, or together with R5 and the atoms carrying these forms a thiochromane system, the sulfur atom of which is particularly preferably oxidized to sulfone, and n denotes 3 - 6.
Compounds of the formula I which may furthermore be mentioned as particularly preferred are those in which R1 denotes hydrogen; (0χ-06)-alkylcarbonyl; (Cx-C6)-alkylsulfonyl; amino-(C5-C8)-cycloalkylcarbonyl; 4-aminopiperidino-1-carbonyl; 4-aminomethyl-piperidino-1carbonyl or N-methyl-[2--ethyl ]-aminocarbonyl; R1 and R5, together with the nitrogen atom carrying them, denote indolyl; R2, R6 and R7 denote hydrogen; R3 denotes (Cx-C6)-alkyl or imidazolyl-(Cx-C4)-alkyl; R4 denotes (C5-C8)-cycloalkyl-(Οχ-Ο,,)-alkyl; R5 denotes phenyl-(Cx-C4)-alkyl or thienyl-(0χ-04)-alkyl; and n denotes 2-4.
The invention furthermore relates to a process for the preparation of compounds of the formula I, which comprises coupling a fragment having a terminal carboxyl group or a reactive derivative thereof with a correspond20 ing fragment having a free amino group, if appropriate splitting off (a) protective group(s) temporarily introduced to protect further functional groups and if appropriate converting the compound thus obtained into its physiologically tolerated salt.
Fragments of a compound of the formula I having a terminal carboxyl group have the following formulae VI and VII A - OH (VI) R2 R3 A-N-CH-C-OH (VII) O Fragments of a compound of the formula I having a terminal amino group have the following formulae VIII to X R6 R5 0 R2 R3 0 - 12 - R4 1 HN - 1 II 1 1 D 1 CH - C - N - CH - C - HN - CH - (CHOH) - CH2OH (VIII) R2 1 R3 1 0 II R4 1 (IX) HN - CH - C - HN - CH - (CHOH)- - CH20H H2N - CH - (CHOH)n - CH2OH Methods which are suitable for the production of an amide 5 bond are described, for example, in Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Volume 15/2; Bodanszky et al., Peptide Synthesis, 2nd ed. (Wiley & Sons, New York 1976) or Gross, Meienhofer, The Peptides: Analysis, synthesis, biology (Academic Press, New York 1979). The following methods are preferably used: Active ester method with N-hydroxy-succinimide, 1-hydroxybenzotriazole or 3-hydroxy-4-oxo-3,4-dihydro-l,2,3benzotriazine as the alcohol component, coupling with a carbodiimide, such as dicyclohexylcarbodiimide, with propanephosphonic anhydride or methylethylphosphinic anhydride and the mixed anhydride method with pivaloyl chloride or ethyl or isobutyl chloroformate, or coupling with phosphonium reagents, such as benzotriazol-l-yl-oxy20 tris-(dimethylamino)-phosphonium-hexafluorophosphate (BOP), or uronium reagents, such as 2-(lH-benzotriazol1-yl )-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) or 2-(ΙΗ-benzotriazol-l-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (for example Chem. Ber. 103 (1970) 788 and 2034, Z. Naturforsch. 21b (1966) 426; Angew.
Chem. Int. Ed. 19 (1980) 133 and US Patent 4,426,325).
Fragments of the formula VI which fall under a) formula II are synthesized by the generally known methods for the preparation of amino acids; b) formula III are synthesized either from the corresponding α-amino acids, the chirality center thereof being retained. Diazotization at -20°C to 50°C in dilute mineral acids leads to α-bromo carboxylic acids or, via lactic acid, to a-trifluoromethanesulfonyloxy carboxylic acids, which can be reacted with a nucleo5 phile carrying R1 and R7; or c) formula IV are synthesized from the corresponding α-amino acids, the chirality center thereof being retained. Diazotization at -20 °C to 50°C in dilute mineral acids leads to lactic acids, which can be reacted with an electrophile carrying R1.
Fragments of the formula VII are synthesized by generally known methods for the preparation of amino acids and peptides.
Fragments of the formula X are prepared from suitable carbohydrates by the corresponding protected γ-lactones.
Reaction with a C-nucleophile, such as a Grignard compound or an alkyllithium compound, first takes place, followed by aminoglycosidation and reductive ring opening with complex hydrides, such as LiAlH4 or catalytic hydro20 genation.
Alternatively, fragments of the formula X can be prepared from the suitable protected aralkylaminoglycosides. In this case the aralkyl radical is advantageously chosen so that hydrogenolytic removal is possible before the amide coupling.
Reaction with a C-nucleophile, such as an alkyllithium compound, in a solvent which is inert towards these nucleophiles, such as diethyl ether, tetrahydrofuran, tetrahydropyran, formaldehyde dimethyl acetal or 1,230 dimethoxyethane, at a temperature between -30*C and the boiling point of the solvent, preferably between 0eC and the boiling point of the solvent, gives the aralkyl derivative of the protected fragment of the formula X. This can be liberated, for amide coupling, by catalytic hydrogenation with hydrogen or catalytic transfer hydro14 genation with ammonium formate.
The preliminary and subsequent operations required for preparation of the compounds of the formula I, such as introduction and splitting off of protective groups, are known from the literature and are described, for example, in T.W. Greene Protective Groups in Organic Synthesis (John Wiley & Sons, New York, 1981). Salts of compounds of the formula I having salt-forming groups are prepared in a manner which is known per se, for example by react10 ing a compound of the formula I having a basic group with a stoichiometric amount of a suitable acid, or reacting compounds of the formula I having an acid group with a stoichiometric amount of a suitable base. Stereoisomer mixtures, in particular diastereomer mixtures, which are obtained, if appropriate, during the synthesis of compounds of the formula I, can be resolved in a manner which is known per se by fractional crystallization or by chromatography.
The compounds of the formula I according to the invention have enzyme-inhibiting properties, and in particular they inhibit aspartyl proteases, such as renin.
Renin is secreted into the blood circulation from the juxtaglomerular cells of the kidney as a consequence of various stimuli (volume depletion, sodium deficiency, β25 receptor stimulation). In the blood circulation it splits off the decapeptide angiotensin I from the angiotensinogen discharged by the liver. This decapeptide is converted by angiotensin converting enzyme (ACE) into angiotensin II. Angiotensin II plays an essential role in blood pressure regulation, since it directly increases the blood pressure by vasoconstriction. It additionally stimulates the secretion of aldosterone from the adrenals and in this manner increases the extracellular fluid volume via inhibition of sodium excretion, which in turn contributes towards increasing the blood pressure.
Inhibitors of the enzymatic activity of renin have the - 15 effect of a reduced formation of angtiotensin I, the consequence of which is a reduced formation of angiotensin II. The reduction in the concentration of this active peptide hormone is the direct cause of the antihyperten5 sive action of renin inhibitors.
The activity of renin inhibitors can be investigated by in vitro tests. In these, the reduction in the formation of angiotensin I is measured in various systems (human plasma and purified human renin). 1. Test principle For example, human plasma which contains both renin and angiotensinogen is incubated at 37 °C with the compound to be tested. During this incubation, angiotensin I is liberated from angiotensinogen by the action of renin and can then be measured using a commercially available radioimmunoassay. This angiotensin liberation is inhibited by renin inhibitors. 2. Isolation of the plasma The blood is obtained from volunteers (about 0.5 1 per person; Bluko sampler from ASID Bonz und Sohn, Unterschleifiheim) and collected in partly evacuated bottles, while cooling with ice. Coagulation is prevented by addition of EDTA (final concentration 10 mM) . After centrifugation (Rotor HS 4 (Sorvall), 3,500 revolutions per minute, 0 - 4eC, 15 minutes; repeated if necessary), the plasma is carefully pipetted off and frozen at -30C in suitable portions. Only plasmas having a sufficiently high renin activity are used for the test. Plasmas having a low renin activity are activated (prorenin -» renin) by a low temperature treatment (-4’C, 3 days). 3. Test procedure Angiotensin I is determined with a Renin-Maia* kit (Serono Diagnostics S.A., Coinsins, Switzerland). The plasma is incubated in accordance with the instructions given with the kits Incubation batch: 1000 μΐ of plasma (thawed at 0-4eC) 100 μΐ of phosphate buffer (pH 7.4, addition of 10'* M ramiprilat) 10 μΐ PMSF solution μΐ of 0.1% of Genapol PFIC μΐ of dimethyl sulfoxide or test preparation The test preparations are in general dissolved as a 10~2 M solution in 100% pure dimethyl sulfoxide (DMSO) and the solutions are diluted accordingly with water; the incubation mixture contains not more than 1% of DMSO.
The mixtures are mixed in ice and placed in a waterbath (37°C) for 1 hour for incubation. A total of 6 samples (in each case 100 μΐ) are removed from an additional mixture without an inhibitor and without further incubation in order to determine the starting angiotensin I content of the plasma used.
The concentrations of the test preparations are chosen so that approximately the range of 10 - 90% enzyme inhibi25 tion is covered (at least five concentrations). At the end of the incubation period, three 100 μΐ samples from each mixture are frozen on dry ice in pre-cooled Eppendorf vessels and kept at about -25’C for the angiotensin I determination (mean value of three individual samples). 4. Angiotensin I radioimmunoassay (RIA) The instructions for using the RIA kit (Renin-Maia* kit, - 17 Serono Diagnostics S.A., Coinsins, Switzerland) are followed exactly.
The calibration plot includes the range from 0.2 to 25.0 ng of angiotensin I per ml. The basal angiotensin I content of the plasma is subtracted from all the measured values. The plasma renin activity (PRA) is stated as ng of Ang I/ml x hour. PRA values in the presence of the test substances are related to a mixture without inhibitor (= 100%) and stated as % residual activity. The IC50 value is read off from the plot of % residual activity against the concentration (M) of the test preparation (logarithmic scale).
The compounds of the general formula I described in the present invention exhibit inhibitory actions at concen15 trations of about 10'5 to 10’10 mol/1 in the in vitro test.
In detail, the following values were determined: Table 1: Example IC50 [M] IC50 [M] No.human plasma renin purified human renin 1 4.2 X 10'7 1.2 X IO'7 2 4.0 X 109 4.0 X IO'9 3 2.2 X 10'8 1.2 X IO*8 4 1.6 X IO9 2.4 X 109 5 1.1 X 108 1.4 X 10‘8 7 2.2 X 10'7 3.0 X 10‘7 9 1.8 X 10'8 1.2 X 10'8 10 1.1 X 10’7 5.0 X IO’8 11 1.9 X IO’6 3.6 X 106 12 > 10'6 1.0 X 10'5 Renin inhibitors cause a reduction in blood pressure in animals with salt depletion. Since human renin differs from the renin of other species, primates, such as, for example, Rhesus monkeys, are used for in vivo testing of renin inhibitors. 1. Test principle Primate renin and human renin are largely homologous in their sequence. An endogenous secretion of renin is stimulated by intravenous injection of furosemide. The test compounds are then administered and their effect on blood pressure and heart rate is measured. 2. Test procedure Rhesus monkeys were pretreated orally with 10 10 mg/kg x day of furosemide on 6 successive days. On the 7th day, a further 10 mg/kg of furosemide were administered intravenously about 30 minutes before the start of the experiment. Anasthesia was then induced with 20 mg/kg of ketamine intramuscularly and continued with 40 mg/kg of pentobarbitone intravenously. A side arm of the femoral artery was exposed and a cannula inserted for blood pressure measurement by means of a blood pressure transducer (P 23 ID). Blood samples for determination of the plasma renin activity were removed via a Braunule in the saphena vein.
The title compound of Example 2 gives the following result: 2 mg/kg intraduodenally (in 0.1 N citric acid of 2 mg/ml) t [min.] Change in blood change in Change in plasma 25 pressure [%] pulse [%] renin activity Γ%1 1 - 0.72 -1.16 3 - 8.21 -1.61 5 -11.53 -2.42 30 10 -11.82 -2.51 15 -12.68 -3.49 -20 20 -13.48 -1.97 30 -16.43 -1.61 -62 45 -12.82 +0.09 -53 60 -13.98 -0.09 -58 75 - 8.79 +1.16 90 - 6.77 +3.04 -51 120 -47 The compounds of the present invention are effective here in a dose range of about 0.1-5 mg/kg intravenously, and in the dose range from about 0.5-50 mg.kg on intraduodenal administration by a gastroscope.
The compounds of the general formula I described in the present invention can be used as anti-hypertensives and for the treatment of cardiac insufficiency.
The invention furthermore relates to the use of compounds of the formula I for the preparation of pharmaceuticals for antihypertensive therapy and treatment of congestive cardiac insufficiency.
Pharmaceutical preparations contain an active amount of the active compound of the formula I together with an inorganic or organic pharmaceutically usable excipient.
They can be used intranasally, intravenously, subcutaneously, perorally or intraduodenally. The dosage of the active compound depends on the warm-blooded species, the body weight, the age and the mode of administration.
The pharmaceutical preparations of the present invention are prepared in dissolving, mixing, granulating or tablet-coating processes which are known per se.
For the oral use forms, the active compounds are mixed with the additives customary for these, such as excipients, stabilizers or inert diluents, and the mixture is brought by customary methods into suitable presentation forms, such as tablets, coated tablets, two-piece capsules, aqueous, alcoholic or oily suspensions or aqueous, alcoholic or oily solutions. Inert excipients which can be used are, for example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, magnesium stearyl fumarate or starch, in particular maize starch. The formulation here can be in the form either of dry granules or of moist granules. Examples of possible oily excipients or solvents are vegetable or animal oils, such as sunflower oil and cod-liver oil.
For subcutaneous or intravenous administration, the 10 active compounds or physiologically tolerated salts thereof are dissolved, suspended or emulsified if desired with the substances customary for this purpose, such as solubilizing agents, emulsifiers or other auxiliaries.
Possible solvents are, for example: water, physiological 15 saline solutions or alcohols, for example ethanol, propanediol or glycerol, and in addition also sugar solutions, such as glucose solutions or mannitol solutions, or a mixture of the various solvents mentioned.
List of abbreviations used: Ac acetyl Boc tert.-butoxycarbonyl BOP benzotriazol-l-yl-oxy-tris-(dimethyl- amino )-phosphonium 25 BuLi n-butyllithium TLC thin layer chromatography DCC dicyclohexylcarbodiimide DC I desorption chemical ionization DIP diisopropyl ether 30 DNP 2,4-dinitrophenyl DME 1,2-dimethoxyethane DMF dimethyl formamide DMSO dimethyl sulfoxide EA ethyl acetate 35 EI electron impact EtOC ethoxyc arbony1 FAB H Hep HOBt Iva M MeOH MS MTB NEM Nva Nle PPA R.T. m.p. b-P-xx TBTU Thi THF Z fast atom bombardment hexane n-heptane 1- hydroxybenzotriazole isovaleryl molecular peak methanol mass spectrum methyl tert.-butyl ether N-ethylmorpholine norvaline norleucine N-propanephosphonic anhydride room temperature melting point boiling point at xx mm Hg 2- (ΙΗ-benzotriazol-l-yl)-1,1,3,3-tetra methyluronium 2-thienylalanine tetrahydrofuran benzyloxycarbonyl.
(L)-gulo-pentol (XX) ch Ch (L)-allo-pentol The other abbreviations used for amino acids correspond to the three-letter code customary in peptide chemistry, such as is described, for example, in Eur. J. Biochem. 138, 9 - 37 (1984). Unless expressly stated otherwise, the amino acids are always in the L configuration.
The following examples serve to illustrate the present invention without limiting it to these.
Example 1 Iva-Phe-Nva-[(L)-gulo-pentol] 200 mg of Iva-Phe-Nva-[(L)-gulo-pentol(XX)] are dissolved in 10 ml of 85% strength agueous trifluoroaoetic acid and the mixture is stirred at R.T. for 2.5 hours. The sol15 vents are removed in vacuo and chromatographed on silica gel using CH2Cl2/MeOH 10:1. 140 mg of the title compound are obtained as a colorless amorphous powder.
Rf (CH2Cl2/MeOH 10:1) = 0.06 MS (FAB + Lil): 614 (M+Li) a) Iva-Phe-Nva-[(L)-gulo-pentol(XX)] 204 μΐ of pivaloyl chloride are added to 578 mg of Iva-Phe-Nva-OH, 229 μΐ of N-ethylpiperidine and 230 μΐ of triethylamine, dissolved in 25 ml of anhydrous CH2C12, at -15’C. The mixture is stirred at R.T. for 10 minutes and cooled to -10°C and a solution of 599 mg of H-(L)-gulo-pentol(XX) in 10 ml of anhydrous CH2C12 is added. The mixture is stirred at R.T. for 20 hours, the solvent is removed in vacuo and the residue is taken up in 150 ml of EA. The mixture is washed three times with 50 ml of KH2PO4 solution each time and three times with 50 ml of NaHC03 solution each time, the EA phase is dried over K2CO3 and the solvent is removed in vacuo. Chromatography on silica gel using DIP/MTB 1:1 gives 200 mg of the title compound as a colorless amorphous powder.
Rf (MTB/DIP 1:1) = 0.10 MS(FAB): 688 (M+l) b) [H-(L)-gulo-pentol(XX)] 740 mg of [N-benzyl-(L)-gulopentol(XX)] are dissolved in 20 ml of anhydrous MeOH, and 150 ml of Pd/C (10%) and 1.1 g of HCO2NH4 are added under argon. The mixture is heated under reflux for 1.5 hours, the catalyst is filtered off and the solvent is removed in vacuo. 600 mg of the title compound are obtained as a pale yellow oil, which is employed further without purification.
Rf (MTB) = 0.05 c) [N-Benzyl-(L)-gulo-pentol(XX)] 880 mg of 2-benzylamino-2-cyclohexylmethyl-(3,4isopropylidene)-3(S),4(S)-dihydroxy-5-(R)-[(1, 2isopropylidene)-1(S)-2-dihydroxyethyl]-tetrahydrofuran are dissolved in 25 ml of anhydrous THF and 188 mg of LiAlH4 are added. The mixture is stirred at R.T. for hours, 50 ml of NaHC03 solution are added and the mixture is extracted three times with 100 ml of EA each time. The extract is dried over Na2SO4 and the solvent is removed in vacuo. 690 mg of the title compound are obtained as a colorless oil.
Rf (MTB/Hep 1:5) = 0.31 MS (DCI): 448 (M+1) d) 2-Benzylamino-2-cyclohexylmethyl-( 3,4-isopropylidene)3 (S),4(S)-dihydroxy-5-(R)-[(1,2-isopropylidene)-1(S)5 2-dihydroxyethyl]-tetrahydrofuran 4.65 g of 2-cyclohexylmethyl-(3,4-isopropylidene)2,3(S),4(S)-trihydroxy-5-(R)-[(1,2-isopropylidene)1(S),2-dihydroxyethyl]-tetrahydrofuran and 5.7 ml of benzylamine are dissolved in 150 ml of anhydrous toluene, and 910 μΐ of TiCl4 are added at -20°C. The mixture is stirred at R.T. for 3 hours, 100 ml of saturated aqueous Na2CO3 solution are added and the mixture is diluted with 300 ml of EA and washed with KH2PO4 solution until pH 5 is reached. The organic phase is dried with Na2SO4 and the solvent is removed in vacuo. Chromatography on silica gel using MTB/Hep 1:5 gives 1.0 g of the title compound as a colorless oil.
Rf (MTB/Hep 1:5) = 0.24 MS (DCI): 446 (M+1) e) 2-Cyclohexylmethyl-(3,4-isopropylidene)-2,3(S) ,4(S)trihydroxy-5-(R) -[(1,2-isopropylidene)-1(S)-2-dihydroxyethyl]-tetrahydrofuran .16 g of (2,3-5,6-diisopropylidene)-L-gulonic acid γlactone are suspended in 300 ml of diethyl ether and 1.1 equivalents of cyclohexylmethyl-magnesium bromide in 50 ml of diethyl ether are added dropwise at the reflux temperature under argon in the course of 2 hours. 100 ml of saturated aqueous NaHCO3 solution are then added, the mixture is extracted twice with 100 ml of EA each time, the organic phase is dried over Na2SO4 and the solvent is removed in vacuo. 4.9 g of the title compound are obtained as a colorless oil slightly contaminated with the bis-adduct.
Rf (DIP) = 0.40 MS (DCI): 357 (M+1) f) (2,3-5,6-Diisopropylidene)-L-gulonic acid γ-lactone g of L-gulonic acid γ-lactone and 100 mg of ptoluenesulfonic acid are heated under reflux in 300 ml of 2,2-dimethoxypropane for 5 hours. After 1 hour, a clear solution forms. The volatile constituents are removed in vacuo and the residue is recrystallized from DIP. 45 g of the title compound are obtained as colorless crystals, m.p.: 144‘C.
Rf (DIP) = 0.12 MS (DCI): 259 (M+1) Example 2 (2 (S) -Benzyl-3-t-butylsulfonyl)propionyl-His-[(D)-mannopentol] 960 mg of (2(S)-benzyl-3-t-butylsulfonyl)propionyl-His15 [ (D)-manno-pentol(XX)) are dissolved with 722 mg of ptoluenesulfonic acid in 100 ml of methanol and 2 drops of water are added. The mixture is stirred at RT for 17 hours, the pH is then brought to 7 with NaHCO3 solution, the methanol is removed in vacuo, the residue is extrac20 ted three times with 100 ml of MTB and the extract is dried over Na2SO4. The solvent is removed in vacuo and the residue is chromatographed on silica gel using acetone/ water 10:1. 120 mg of the title compound are obtained as white crystals.
Rf (acetone/water 10:1) = 0.46 MS (FAB): 681 (M+1) m.p. 100 - 110°C (decomposition) a) (2-(S)-Benzyl-3-t-butylsulfonyl)propionyl-His-[(D) — manno-pentol(XX)] 850 mg of (2(S)-benzyl-3-t-butylsulfonyl)propionylIE 902686 His(DNP)-[(D)-manno-pentol(XX)] and 0.94 ml of thiophenol are dissolved in 15 ml of acetonitrile and the solution is stirred at RT for 2 hours. The solvent is removed in vacuo, the residue is digested with DIP, and the residue is chromatographed on silica gel using toluene/MeOH 5:1. 400 mg of the title compound are obtained as pale yellow crystals. m.p. ~ 160°C (decomposition) Rf (toluene/MeOH 5:1) = 0.39 MS (FAB): 761 (M+l) b) ( 2 (S)-Benzyl-3-t-butylsulfonyl) propionyl-His (DNP) [(D)-manno-pentol(XX)] 1.3 g of (2(S)-benzyl-3-t-butylsulfonyl)propionylHis (DNP) -OH, 0.31 ml of N-ethylpiperidine and 0.31 ml of triethylamine are dissolved in 30 ml of CH2C12 and 0.28 ml of pivaloyl chloride are added dropwise at - 15°C under argon. The mixture is stirred at RT for 10 minutes and cooled to -10eC and a solution of 400 mg of H-(D)-manno-pentol(XX) in 5 ml of CH2C12 is added dropwise. The mixture is stirred at RT for 18 hours, diluted with 100 ml of MTB and extracted once each with 100 ml of 0.66 M KH2PO4 and 100 ml of saturated NaHCO3 solution. The extract is dried over Na2SO4 and the solvent is removed in vacuo. 850 mg of the title compound are obtained as an amorphous powder which is further reacted without purification.
Rf (EA/MeOH 10:1) = 0.53 MS (FAB): 927 (M+l) c) (2(S)-Benzyl-3-t-butylsulfonyl)propionyl)-His (DNP)-OH .7 g of (2(S)-benzyl-3-t-benzylsulfonyl)propionic acid N-hydroxy-succinimide ester and 11.3 g of H30 His(DNP)-OH hydrochloride are dissolved in 500 ml of THF/ethanol 1:1, and 470 ml of saturated aqueous NaHCO3 solution are added. The mixture is stirred at RT for 5 hours, the organic solvents are removed in vacuo, the pH is brought to 1-2 with NaHSO4 solution, the mixture is extracted three times with 500 ml of EA each time, the extract is dried over Na2SO4 and the solvent is removed in vacuo. The residue is taken up in 350 ml of acetone/EA 1:1 and the product is precipitated with diethyl ether in an ultrasonic bath. 12.5 g of the title compound are obtained as a yellow powder.
Rf (MeOH/CH2Cl2 1:5) = 0.11 MS (FAB): 588 (M+1) d) (2(S)-Benzyl-3-t-butylsulfonyl)propionic acid Nhydroxysuccinimide ester 8.0 g of (2(S)-benzyl-3-t-butylsulfonyl)propionic acid (J. Med. Chem. 31, 1839 (1988)) and 3.3 g of N15 hydroxysuccinimide are dissolved in 200 ml of 1,2dimethoxyethane, and a solution of 5.8 g of DCC in 50 ml of 1,2-dimethoxyethane is added dropwise at 0eC. The mixture is left to stand at 6 °C for 18 hours, the solvent is removed in vacuo at 20°C and the residue is taken up in 100 ml of acetonitrile. The urea is filtered off and the solvent is removed at 20°C in vacuo. 10.7 g of the title compound are obtained as a colorless oil which is reacted further without purification. e) H-(D)-Manno-pentol(XX) The compound was prepared analogously to Example lb from N-benzyl-(D)-manno-pentol(XX). f) [N-Benzyl-(D)-manno-pentol(XX)] 8.8 g of 2-benzylamino-(3,4-isopropylidene)-3(S),4(S)30 dihydroxy-5(R)-[ (l,2-isopropylidene)-l(R)-2-dihydroxyethyl]-tetrahydrofuran and 7.1 ml of eyelohexylmethyl bromide are dissolved in 250 ml of THF and reacted with 0.7 g of lithium wire (3.2 mm diameter, about 1% of Na) in an ultrasonic bath at RT under argon. After 6 hours, the solvent is removed in vacuo, the residue is taken up in 500 ml of 0.67 M KH2PO4 solution and the mixture is extracted three times with 300 ml of MTB.
The extract is dried over Na2SO4, the solvent is removed in vacuo and the residue is chromatographed on silica gel using MTB/Hep 1:1. 3.3 g of the title compound are obtained as a colorless oil.
Rf (MTB/Hep 1:1) = 0.39 MS(DCI): 448 (M+l) g) 2-Benzylamino-(3,4-isopropylidene)-3(S),4(S)-dihydroxy-5 (R) -[(1,2-isopropyiidene)-1(R)-2-dihydroxyethyl]-tetrahydrofuran 31.5 g of 2,3-5,6-diisopropylidene-D-mannofuranoside 15 and 20.0 ml of benzylamine are heated in 250 ml of toluene using a water separator. After 7 hours, the water separator is replaced by a Soxhlet extractor filled with molecular sieve 4k and the mixture is heated under reflux for a further 16 hours. The solvent is then removed in vacuo, the residue is taken up in 500 ml of EA and the mixture is washed three times with 250 ml of 0.67 M KH2PO4 solution. The mixture is dried over Na2SO4 and the solvent is removed in vacuo. 41.5 g of the white crystalline title compound are obtained.
Rf (toluene/EA 2:1) = 0.29 MS(DCI): 350 (M+l) Alternative syntheses h) (2(S)-Benzyl-3-t-butylsulfonyl)-propionyl-His-[(D)— manno-pentol(XX)] (2a)) 785 mg of (2(S)-benzyl-3-t-butylsulfonyl)-propionic acid and 382 μΐ of triethylamine are dissolved in ml of DMF, 1.1 g of O-benzotriazol-l-yl-1,1,3, 3-tetramethyluronium hexafluorophosphate are added at RT and the mixture is stirred at RT for 5 minutes. A solution of 1.6 g of H-His-[(D)-manno-pentol(XX)] in 15 ml of DMF is then added dropwise and the mixture is stirred at RT for 20 hours. The solvent is removed in vacuo, the residue is taken up in 500 ml of EA and the mixture is washed three times with 100 ml of Na2CO3 solution. It is dried over Na2S04, the solvent is removed in vacuo and the residue is chromatographed on silica gel using EA/MeOH 5:1. 1.1 g of the title compound of Example 2a) are obtained. i) H-His-[(D)-manno-pentol(xx)] g of Z-His-[(D)-manno-pentol(XX)] and 3 g of ammonium formate are dissolved in 50 ml of methanol, 2 g of Pd/C (10% strength) are added and the mixture is stirred under argon at RT for 5 hours. The catalyst is then filtered off, the solvent is removed in vacuo, the residue is taken up in 500 ml of EA and the mixture is washed three times with 50 ml of Na2CO3 solution. It is dried over Na2SO4 and the solvent is removed in vacuo. 1.8 g of the title compound are obtained as a foam, which is kept under argon and is further reacted as soon as possible. k) Z-His-((D)-manno-pentol(XX)] 500 mg of H-(D)-manno-pentol(XX) and 405 mg of Z-His-OH are dissolved in 20 ml of DMF under argon, and first 303 μΐ of diphenylphosphoryl azide and then 208 μΐ of l-diethylamino-2-propanol are subsequently added at 0eC. The mixture is stirred at 0"C for 2 hours and then at RT for 4 days. The reaction mixture is diluted with 200 ml of EA and washed in each case once with 100 ml of 0.7 M KH2PO4 solution and 100 ml of saturated NaHC03 solution. It is dried over Na2SO4 and chromatographed on silica gel using EA/MeOH 10:1. 530 mg of the title compound, colorless foam, are obtained.
Rf (EA/MeOH 10:1) = 0.17 MS (FAB): 629 (M+1) 1) H-(D)-manno-pentol(XX) 410 mg of N-benzhydryl-(D)-manno-pentol(XX) and 490 mg 5 of ammonium formate are dissolved in 15 ml of anhydrous methanol, 82 mg of Pd/C (10% strength) are added and the mixture is stirred under argon at RT for hours. The solvent is removed in vacuo, the residue is taken up in 100 ml of EA and the mixture is washed three times with 50 ml of Na2CO3 solution. The organic phase is dried with Na2S04 and the solvent is removed in vacuo. After drying under a fine vacuum to remove the diphenylmethane, 275 mg of the title compound of Example 2e) are obtained. m) N-Benzhydryl-(D)-manno-pentol(XX) 1.8 g of 2-benzhydrylamino-(3,4-isopropylidene)3(S),4(S)-dihydroxy-5 (R)-[1,2-isopropylidene)-1(R)-2dihydroxyethyl]-tetrahydrofuran and 1.2 ml of cyclohexylmethyl bromide are dissolved in 40 ml of formal20 dehyde dimethyl acetal (distilled from K/Na alloy) and are reacted with 115 mg of lithium wire (3.2 mm diameter, about 1% of Na) under argon in an ultrasonic bath at 20-40°C for 3.5 hours. 115 mg of lithium wire and 1.2 ml of cyclohexylmethylbromide are then added again and the mixture is reacted at 40-60 C for another hour. The reaction mixture is poured into 200 ml of NaHCO3 solution and extracted three times with 100 ml of MTB. It is dried over Na2SO4, the solvent is removed in vacuo and the residue is chroma30 tographed on silica gel using DIP/toluene 1:3. 1.1 g of the title compound are obtained as a colorless oil.
Rf (DIP/toluene 1:3) = 0.28 MS(DCI): 524 (M+1) η) 2-Benzhydrylamino-(3,4-isopropylidene)-3(S),4(S)dihydroxy-5 (R) - [ 1,2-isopropylidene-l (R) -2-dihydroxyethyl ]-tetrahydrofuran g of D(+)-mannose and about 10 mg of p-toluenesul5 fonic acid are suspended in 40 ml of 2,2-dimethoxypropane and the suspension is stirred at 40 *C for 1 hour.
A clear solution is formed by this procedure. 10 ml of benzhydrylamine are added and the mixture is boiled under reflux for 24 hours. A further 10 ml of 2,210 dimethoxypropane and 2 ml of benzhydrylamine are then added and the mixture is boiled under reflux for a further 18 hours. Volatile constituents are removed in vacuo, the residue is taken up in 100 ml of EA and the mixture is washed three times with 100 ml of NaHCO3 solution. It is dried over Na2SO4, the solvent is removed in vacuo and the residue is chromatographed on silica gel using DIP/toluene 1:5. 17 g of the title compound are obtained as pale yellow crystals, melting point: 82-84°C.
Rf (DIP/toluene 1:3) = 0.41 MS(DCI): 426 (M+l) The title compound of Example 2g) can also be prepared analogously from D(+)-mannose in a one-pot process.
Example 3 cis-4-Aminocyclohexylcarbonyl-Phe-His-[(D)-manno-pentol] 180 mg of (N-tert.-butoxycarbonyl-cis-4-amino-cyclohexylcarbonyl)-Phe-His-[(D)-manno-pentol(XX)] are dissolved in 5 ml of CH2C12, and 5 ml of trifluoroacetic acid are added at O’C. The mixture is stirred at RT for 24 hours, 100 ml of saturated Na2CO3 solution are added and the mixture is extracted 3 times with 100 ml of EA. The extract is dried over Na2SO4, the solvent is removed in vacuo and the residue is chromatographed on silica gel using acetone/ H20/concentrated NH3 100:10:5. 24 mg of the title compound are obtained as a colorless powder.
Rf (acetone/H20/concentrated NH3 100:10:5) = 0.12 MS(FAB): 687 (M+1) a) (N-tert. -Butoxycarbonyl-cis-4-aminocyclohexylcarb5 onyl)-Phe-His-[(D)-manno-pentol(XX)] The title compound is prepared analogously to Example 2a), 2b) from (N-tert.-butoxycarbonyl-cis-4-aminocyclohexylcarbonyl)-Phe-His(DNP)-OH and H-(D)-mannopentol (XX) .
Rf (EA/MeOH 5:1) = 0.43 MS(FAB): 868 (M+1) b) (N-tert. -Butoxycarbonyl-cis-4-aminocyclohexylcarbonyl)-Phe-His(DNP)-OH The title compound is prepared analogously to Example 2c), 2d) from (N-tert.-butoxycarbonyl-cis-4-amino15 cyclohexylcarbonyl)-Phe-OH and H-His(DNP)-OH.
Rf (EA/MeOH 3:1) = 0.20 MS(FAB): 694 (M+1) c) N-(N-tert.-Butoxycarbonyl-cis-4-aminocyclohexylcarbonyl)-L-phenylalanine .5 g of N-(N-tert.-butoxycarbonyl-cis-4-aminocyclo20 hexylcarbonyl)-L-phenylalanine benzyl ester are hydrogenated in 230 ml of ethanol over 1 g of Pd/charcoal under normal pressure. When the reaction had ended, the catalyst was filtered off and the solvent was distilled off. Recrystallization from n-heptane/ ethyl acetate gave 4.1 g of colorless product.
Melting point 160 - 161 °C (decomposition) MS(DCI): 391 (M+1) - 33 d) N- (N-tert. -Butoxycarbonyl-cis-4-aminocyclohexylcarbonyl)-L-phenylalanine benzyl ester 6.0 g of N-tert.-butoxycarbonyl-cis-1,4-aminocyclohexanecarboxylic acid and 6.3 g of L-phenylalanine benzyl ester are dissolved in 75 ml of DMF, the solution was mixed with 24 ml of n-PPA and 15.7 ml of NEM at O’C and the mixture is reacted overnight at RT. The solution is diluted with CH2C12, washed in each case with semi-saturated NaHC03 solution, 10% strength citric acid and water, dried over MgSO4 and concentrated in vacuo. Flash chromatography gave 5.7 g of pure product. [a]o° : -14.6° (c = 1.1 in CH3OH) Example 4 2 (S)-{N-Methyl-N-<2-[N- (morpholinocarbonyl) -N-methylamino ]-ethyl>-aminocarbonyloxy}-3-phenylpropionyl-His[(D)]mannopentol] The title compound is prepared analogously to Example 2a), 2b), 2c) and 2d) from 2(S)-{N-methyl-N-<2-[N2 0 (morpholinocarbonyl) -N-methylamino ] ethyl >-aminocarbony1oxy]-3-phenylpropionic ac id.
Rf (EA/MeOH 1:1) = 0.22 MS(FAB): 790 (M+l) a) 2 (S) -{N-methyl-N-<2-[N-(morpholinocarbonyl) -N-methylamino ]ethyl>-aminocarbonyloxy]-3-phenylpropionic acid 840 g of ethyl 2(S)-{N-methyl-N-<2-[N-(morpholinocarbonyl ) -N-methylamino ]ethyl>-aminocarbonyloxy]-3-phenylpropionate are dissolved in 100 ml of methanol, and 20 ml of 0.1 N sodium hydroxide solution are added. After 16 hours at RT, the methanol is distilled off and the residue is brought to pH 1 - 2 with hydrochloric acid. Extraction with EA 3 times gives, after drying with Na2SO4 and concentration, the title compound (24%), which is used for the next reaction without further purification.
MS (DCI): 394 (M+l) b) Ethyl 2(S)-{N-methyl-N-<2-[N-(morpholinocarbonyl)-Nmethylamino] ethyl >-aminocarbonyl oxy}-3-phenyl propionate 0.9 g of ethyl phenyllactate in CH2C12 (10 ml) are added dropwise to 2 g of di(4-benzotriazolyl) car10 bonate and 0.23 ml of pyridine in CH2C12 (20 ml) at RT.
After 6 hours, 900 mg of N-methyl-N-2-[N-(morpholinocarbonyl) -N-methylaminoJ-ethylamine in 10 ml of CH2C12 are added dropwise. After 16 hours, 100 ml of ethyl acetate are added, and the mixture is then washed twice with saturated Na2CO3 solution, twice with saturated NaHSO4 and once with saturated NaCl solution. After drying with Na2SO4 and concentration, a yellow oil is obtained which, after chromatography on SiO2 (eluent EA), gives the title compound.
Rf (EA) = 0.3 MS (DCI): 422 (M+l) c) N-Methyl-N-2- [N- (morpholinocarbonyl) -N-methylamino] ethylamine 2.1 g of Boc-N-methyl-N-2-[N-(morpholinocarbonyl)-Nmethylamino]ethylamine are stirred in 75 ml of a ~6N solution of HCl in DME at RT for 3 hours. After concentration, 50 ml of saturated Na2CO3 solution are added and the mixture is extracted three times with EA. Drying and concentration give the title compound, which is employed for the further reactions without additional purification. d) Boc-N-methyl-N-2-[N-(morpholinocarbonyl)-N-methylamino ]ethylamine The title compound is obtained analogously to Example 4b) from 2.1 g of morpholine, 10 g of di-(1-benzotriazolyl)carbonate, 2 ml of pyridine and 4.7 g of BocN-methyl-2-(methylamino)ethylamine.
Rf (EA) = 0.25 MS (DCI): 302 (M+l) e) Boc-N-methyl-2-(methylamino)ethylamine 12.5 g of di-t-butyl dicarbonate in 25 ml of CH2C12 are added dropwise to 100 g of N,N'-dimethylethylenediamine at 5°C. After 4 hours at RT, the excess diamine is distilled off. The residue is taken up in EA (100 ml) and the mixture is washed with saturated Na2CO3 solution and saturated NaCl solution. Drying with Na2SO4 and concentration gives the title compound, which is used in the crude form for further reactions.
MS (DCI): 189 (M+l) Example 5 3- (4-Amino-l-piperidinyl-carbonyl)-2(R)-benzylpropionylHis-[(D)-manno-pentol] The title compound is prepared analogously to Example 3 from 3-[4-(tert.-butoxycarbonyl)amino-l-piperidinylcarbonyl]-2(R)-benzylpropionic acid.
Rf (acetone/H20/concentrated NH3 100:10:5) = 0.15 MS (FAB): 687 (M+l) a) 3-[4-(tert.-Butoxycarbonyl)amino-l-piperidinyl-carb25 onyl]-2(R)-benzylpropionic acid 1.3 g of benzyl 3-[4-(tert.-butoxycarbonyl)amino-1piperidinyl-carbonyl]-2(R)-benzylpropionate are hydrogenated in 60 ml of EtOH with 200 mg of Pd/C at RT for 1 hour. After filtration and removal of the solvent in vacuo, the title compound crystallizes out of cold diethyl ether. m.p.: 135 - 136°C Rf (CH2Cl2/MeOH 9:1) = 0.30 MS (DCI): 391 (M+1) b) Benzyl 3-[4-(tert.-butoxycarbony1)amino-1-piperidinylcarbonyl]-2(R)-benzylpropionate 1.0 g of benzyl 2(R)—(carboxymethyl)-3-phenyl-propionate (J. Med. Chem. 31 2277 (1988)) are stirred in 50 ml of CH2C12 with 0.31 ml of oxalyl chloride and 1 ml of DMF at 0°C for 1 hour. The solvent is removed in vacuo, the residue is taken up in 25 ml of CH2C12, the pH is brought to 7 with 2 drops of triethylamine, 0.71 g of 4-(tert.-butoxycarbonyl)-amino-piperidine and 0.47 ml of triethylamine in 50 ml of CH2C12 are added dropwise to this solution, the mixture is stirred at 0°C for 3 hours, the solvent is removed in vacuo, the residue is taken up in 50 ml of EA and the mixture is washed once each with 50 ml of 2N HCl and saturated NaHCO3 solution. The mixture is dried over MgSO4 and the solvent is removed in vacuo to give 1.3 g of the title compound as a colorless oil.
Rf (CH2Cl2/MeOH 9:1) = 0.50 MS (DCI): 479 (M+H) c) 4-(tert.-Butoxycarbonyl) amino-piperidine .0 g of 1-benzyl-4-[(tert.-butoxycarbonyl)amino]piperidine are hydrogenated in 60 ml of ethanol/glacial acetic acid 9:1 with 1 g of Pd/C for 1 hour at RT under a pressure of 1 bar. The catalyst is filtered off, the solvent is removed in vacuo (residues of glacial acetic acid are distilled off azeotropically with toluene) and the residue is taken up in 100 ml of EA. The mixture is then washed once each with 100 ml of saturated NaHCO3 solution and saturated NaCl solution and dried over MgSO4 and the solvent is removed in - 37 vacuo. The residue is recrystallized from EA to give .5 g of the title compound as white crystals. m.p.s 159 - 161°C Rf (CH2Cl2/MeOH 9:1) = 0.11 MS (DCI): 201 (M+1) d) l-Benzyl-4-[(tert.-butoxycarbonyl)amino]-piperidine .0 g of 4-amino-N-benzylpiperidine are dissolved in 100 ml of CH2C12, 11.5 g of di-tert.-butyldicarbonate are added and the solution is stirred at RT for 2 hours and left to stand overnight. The solvent is removed in vacuo and the residue is recrystallized from EA. 12.9 g of the title compound are obtained as white crystals. m.p.: 123°C Rf (CH2Cl2/MeOH 8:1) = 0.23 MS (DCI): 291 (M+1) Example 6 (S) - (4-Amino-l-piperidinocarbonyloxy)-3-phenylpropionylHis-[(D)-manno-pentol] The title compound is prepared analogously to Example 3 from 2(S)-[4-(tert.-butoxycarbonyl) amino-1-piperidinocar20 bonyloxy]-3-phenylpropionic acid.
Rf (acetone/H20/concentrated NH3 100:10:5) = 0.15 MS (FAB): 689 (M+1) a) 2 (S) -[4-(tert.-Butoxycarbonyl)amino-1-piperidinocarbonyloxy]-3-phenylpropionic acid 1.8 g of ethyl (2(S)-[4-(tert.-butoxycarbonylJaminol-piperidinocarbonyloxy]-3-phenylpropionate and 5.1 ml of IN NaOH are dissolved in 30 ml of ethanol and the mixture is stirred at RT for 18 hours. It is then diluted with 50 ml of H20, the ethanol is removed in vacuo and the pH is brought to 1 - 2 with NaHSO4 solution. The mixture is extracted three times with 100 ml of EA, the extract is dried over Na2SO4 and the solvent is removed in vacuo. The title compound, which crystallizes from ether/n-heptane, is obtained, 1.0 g of white crystals. m.p.: 100 - 101°C Rf (CH2Cl2/MeOH) = 0.29 MS (DCI): 393 (M+l) b) Ethyl 2(S)-[4-(tert.-butoxycarbonyl)amino-1-piperi10 dinocarbonyloxy]-3-phenylpropionate 825 mg of ethyl phenyllactate and 1.8 g of di-(lbenzotriazolyl)carbonate (70%) are dissolved in 40 ml of CH2C12, 386 μΐ of ethyl diisopropylamine are added and the mixture is stirred at RT for 18 hours. 850 mg of 4-(tert.-butoxycarbonyl)aminopiperidine (Example 5c)), dissolved in 10 ml of CH2C12, are then added dropwise and a further 386 μΐ of ethydiisopropylamine are added. The mixture is stirred at RT for a further 2 hours, the solvent is removed in vacuo and the residue is taken up in 100 ml of MTB. The mixture is washed with in each case 100 ml of Na2CO3 solution and 100 ml of NaHSO4 solution and dried over Na2SO4 and the solvent is removed in vacuo. 1.8 g of the title compound are obtained as a colorless oil which is employed further without purification.
Rf (Hep/EA 2:1) = 0.2 MS (DCI): 421 (M+l) Example 7 (S) - (4-Aminomethyl-l-piperidinocarbonyloxy) -3-phenylpropionyl-His-[(D)-manno-pentol] The title compound is synthesized analogously to Example 6.
Rf (acetone/H20/concentrated NH3 100:10:5) = 0.15 MS (FAB): 703 (M+1) Example 8 ( 3-t-Butoxysulf onyl-2-thienylmethyl)propionyl-His- [ (D) 5 manno-pentol] The title compound is synthesized analogously to Example 2.
Rf (acetone/water 10:1) = 0.50 MS (FAB): 687 (M+1) Example 9 ( 2 (S) -Benzyl-3-t-butylsulfonyl )propionyl-His-4 (S) - (5cyclohexyl-1,2,3-trihydroxy)-pentylamide 240 mg of (2(S)-benzyl-3-t-butylsulfonyl)propionyl-His(DNP)-OH are dissolved with 69 mg of HOBt, 93 mg of DCC and 0.3 ml of NEM in 8 ml of DMF (absolute) and the solu15 tion is cooled to O’C. The solution, described under 9a) of 4(S)-(5-cyclohexyl-l,2,3-trihydroxy)pentylamine is then added. After warming up, the solution remains at RT for 48 hours. 0.5 ml of H2O are added to the reaction solution, the dicyclohexylurea formed is then filtered off and the filtrate is taken up in 25 ml of EA. This solution is washed with 10% strength NaHCO3 solution, water and saturated NaCl solution and filtered over cotton absorbent and the filtrate is concentrated in vacuo. The oily crude product thus obtained is chromatographed over silica gel using CH2C12/CH3OH 20:1.
The product of Rf 0.5 (CH2C12/CH3OH 9:1 on silica gel) is obtained as a vitreous solid in a yield of 60 mg.
MS (FAB) 787 (M+1) The product is dissolved in 5 ml of CH2C12 (absolute) and the solution was stirred at RT with 0.2 ml of thiophenol for 4 hours. After the solvent has been filtered off in vacuo, the crude mixture is chromatographed on silica gel using CH2C12/CH3OH 20s 1. 16 mg of the title compound are obtained.
MS (FAB): 621 (M+1) Rf (CH2Cl2/MeOH 9:1) = 0.25 a) 4(S)-(5-Cyclohexyl-l,2,3-trihydroxy)-pentylamine 130 mg of (2RS,3RS,4S)-4-tert.-butoxycarbonylamino-5cyclohexyl-l,2,3-trihydroxypentane (Example 9b) are dissolved in 2 ml of DME, 4 ml of saturated HCl/DME solution are added and the mixture is stirred at 0°C for 30 minutes. After warming up to RT, the solution is concentrated in vacuo and the residue is concentrated three times, in each case after addition of toluene (absolute). This oil thus obtained is immediately employed as a solution in DMF in the subsequent reaction step. b) (2RS, 3RS, 4S) -4-tert. -Butoxycarbonylamino-5-cyclohexyl1,2,3-trihydroxypentane 293 mg of the pentenol obtained in Example 9c) are dissolved in 10 ml of THF (absolute) together with 240 mg of trimethylamine N-oxide, and 11 mg of osmium tetroxide are added. After a few minutes, the solution changes color to green-brown and is stirred overnight at RT. 10% strength NaHSO3 solution is added to the solution, the mixture is stirred for 30 minutes and then concentrated in vacuo, the residue is taken up in 50 ml of ethyl acetate and the aqueous phase is separated off. The organic phase is washed with 1N HCl, % strength Na2SC>4, dried and concentrated in vacuo.
An amorphous solid of 140 mg remains.
MS (DCI): 318 (M+1) c) 4S-tert-Butoxycarbonylamino-5-cyclohexyl-cis-2 pentenol .5 ml of a 1.2 M solution of diisobutylaluminum hydride in toluene were added to 0.98 g of 4S-tert.5 butoxycarbonylamino-5-cyclohexyl-cie-2-pentenoic acid (prepared in accordance with the method of W.C. Still et al. Tetrahedron Lett. 1983, 4405) in 20 ml of absolute methylene chloride at -78eC. After 1 hour, the mixture was allowed to warm to RT. Addition of 1 ml of methanol ends the reaction, and after dilution with 80 ml of CH2C12 the solution is shaken in each case once with 10% strength K Na tartrate solution, 10% strength citric acid solution and saturated NaCl solution. The solution is dried over MgSO4 and con15 centrated in vacuo and the resulting oily crude product is chromatographed over silica gel (cyclohexane /ethyl acetate). 480 mg of a slightly yellow oil are obtained.
Example 10 0 Iva-Phe-Nva-[(D)-manno-pentol] The compound is prepared analogously to Example 1) and la) from Iva-Phe-Nva-OH and H-(D)-manno-pentol(XX).
Rf (CH2Cl2/MeOH) = 0.06 MS (FAB + Lil)s 614 (M+Li) The title compounds of Examples 11 and 12 are prepared analogously to Example 2: Example 11 Indolyl-2-carbonyl-His-[(D)-manno-pentol] Rf (CH2CH2: MeOH: concentrated agueous NH3 = 50:10:1) = 0.10 MS (FAB): 558 (M+l) Example 12 2(S)-Hydroxy-3-phenylpropionyl-His-[(D)-manno-pentol] Rf (acetone/H20 10:1) = 0.25 MS (FAB): 563 (M+l)

Claims (14)

1. A compound of the formula I HOE 89/F 245K Patent Claims; R z R 3 R* A-N-CH-CO-NH-CH - (CHOH) n - CH 2 OH (I) in which A denotes a radical of the formula II, III or IV R° R 3 0 - i i » R 1 - N - CH - C R 7 R 3 0 i i » CH - CH - C (II) (HI) R 3 0 - o - « - c - (IV) R 1 βχ) denotes (C 3 -C 8 )-cycloalkyl, (C 4 -Cx 0 )-bicycloalkyl, (C 8 -Cx 2 )-tricycloalkyl, (C 3 -C 8 )cycloalkyl- (Cx-C 6 ) -alkyl, (C 4 -C 10 ) -bicycloalkyl(Οχ-Cg) -alkyl, (C 8 -Cx 2 ) -tricycloalkyl- (Cx-C 6 ) alkyl, (C 3 -C 8 )-cycloalkyl-carbonyl or (C 3 -C 8 )cycloalkylsulfonyl, in which the cycloalkyl, bicycloalkyl and tricycloalkyl substituent in each case can be substituted by one or two identical or different radicals from the series comprising F, Cl, Br, I, hydroxyl, (Cx-C 6 )alkoxy, (Cx-C 6 )-alkyl, carboxyl, (Cx-C 6 )alkoxycarbonyl, carbamoyl, carboxymethoxy, amino, (Cx-C 6 )-monoalkylamino, (Cx-C 6 )dialkylamino, amino-(Cx-C 6 )-alkyl, (Cx-C 6 )alkylamino- (Cx-C 6 ) -alkyl, di- (Cx-C 6 ) -alkylamino(Ci-C 6 )-alkyl, amidlno, hydroxyamino, hydroximino, hydrazono, imino, guanidino, (CxC 6 )-alkoxysulfonyl, (Cx-C 6 )-alkoxysulfenyl, tri fluoromethyl, (Cx-C 4 )-alkoxycarbonylamino and (C 6 -Ci 2 ) -aryl- (Cx-C 4 ) -alkoxycarbonyl-amino; hydrogen, hydroxyl, (ϋχ-ΰχ 8 )-alkyl, (Cx-C 8 )IE 902686 alkoxy, (Οχ-ϋχ 8 )-alkanoyl, (C x -C lB ) -alkoxycarbonyl, (Cx-C 18 )-alkylsulfonyl or (Οχ-Οχβ)-alkylsulfinyl, in which the alkyl radicals in each case can be substituted by optionally protected amino, trimethylsilyl, hydroxyl, mercapto, (Cx-CJ-alkylthio, halogen, (Cj-C 4 )-alkoxy, monoor di-(Cx-C 8 )-alkylamino, carboxyl, carbamoyl, guanidino, (Cx-C 4 )-alkoxycarbonyl, (Cx-C 8 )alkanoyloxy, phenyl-(C x -C 4 )-alkoxy or a radical CONR 8 R 9 ; (Cx-CJ-alkoxy; (C e -C 14 )-aryl, (C 6 -Cx 4 )-aryl-(C 2 -C 4 )-alkyl or (C 8 Cn)-aryl-(C1-C4)-alkoxy, in which the aryl radical in each case can be substituted by one, two or three identical or different radicals from the series comprising (Cx-C 6 )-alkyl, amino, mono- or di-(Cx-C 4 )-alkylamino, amino-(Cx-C 4 )alkyl, hydroxy-(Cx-C 4 )-alkyl, mono- or di(Cx~C 4 ) -alkylamino- (Cx~C 4 ) -alkyl, hydroxyl, (Cx-C 4 )-alkoxy, halogen, formyl, (Cx-C 4 )-alkoxycarbonyl, carboxamido, mono- or di-(Cx-C 4 )alkylaminocarbonyl and nitro; Het or Het-(Cx-C 4 )-alkyl, in which Het represents a 5-, 6- or 7-membered heterocyclic ring which can be additionally benzo-fused and either aromatic, partly hydrogenated or completely hydrogenated and can contain one or two identical or different radicals from the series comprising N, 0, S, NO, SO or S0 2 as the hetero element and can be substituted by one or two identical or different radicals from the series comprising (0χ-0 4 )-alkyl, (0χ-0 4 )-alkoxy, (0χ-0 4 )alkoxycarbonyl, hydroxyl, halogen, amino, amino-(Cx-C 4 )-alkyl and mono- or di-(Cx-C 4 )alkylamino; or a radical NR®R 9 , in which R® and R 9 are identical or different and independently of one another denote hydrogen; (0 χ -0 8 )alkyl, which can be substituted by amino, (0χ-0 4 )-alkylamino, di-(0χ-0 4 )-alkylamino, hydroxyl or (Cx-C 4 )-alkoxy; (C 3 -C 7 )-cycloalkyl; - 45 mercapto; (Cj-CJ-alkylthio; phenylthio; (Cj-C^)alkoxycarbonyl; carboxyl or (C 6 -C 14 )-aryl, which can be substituted in the aryl radical as described above; or Het or Het-(Cx-CJ-alkyl, in which Het is defined as described above, or in which R 8 and R 9 , together with the nitrogen atom carrying them, form a 5- to 12-membered ring which can be mono- or bicyclic, can also contain 1 or 2 nitrogen atoms, 1 sulfur atom or 1 oxygen atom as further ring members and can be substituted by (Ci-C 4 )-alkyl, or R 1 a 2 ) denotes a radical of the formula V R 1 ' - W (V) in which R 1 ’ is defined as R 1 under a x ) and W represents -CO-, -CS-, -O-CO-, -SO 2 -, -SO-, -NH-SO 2 -, -NH-CO-, -CH(OH)- or -N(OH)-; R 1 and R 5 , together with the nitrogen atom carrying them, form a 5- to 12-membered ring, which can be mono- or bicyclic and can also contain, as further ring members, 1 or 2 nitrogen atoms, 1 sulfur atom or 1 oxygen atom and can be substituted by (Cj—C 4 )—alkyl, R 2 and R 6 independently of one another denote hydrogen or (Cx-CJ-alkyl, R 3 and R 5 independently of one another are defined as R 1 under a x ); R* denotes (C 3 -C 12 )-alkyl; mono-, bi- or tricyclic (C 3 -C ie )-cycloalkyl, (C 3 -C 1B )-eye loalky lmethyl or (C 3 -C 18 )-cycloalkylethyl, in which the cycloalkyl part is optionally substituted by (C x -C 6 )-alkyl; dithiolanyl; (C 6 -C u )-arylmethyl; dithiolanylmethyl; dithiolanylethyl; dithianyl; dithianylmethyl or dithianylethyl; R 7 is hydrogen or (Ci-Ce)-alkyl, or together with R 1 or R 5 and the atoms carrying these, forms a monoor bicyclic, saturated or partly unsaturated ring system having 5- 12- ring members, which, in addition to carbon, can also contain 1 sulfur atom, which can optionally be oxidized to sulfoxide or sulfone; and n denotes 2 - 10, or physiologically tolerated salts thereof.
2. A compound of the formula I as claimed in claim 1, in which A is as defined in claim 1; R 1 denotes hydrogen or represents (Οχ-Οχ 0 ) -alkyl; cyclopentyl; cyclohexyl; cyclopentyl-(Cx-C 6 )alkyl; cyclohexyl-(Cx-C 6 )-alkyl; phenyl-(Cx-C 4 )alkyl, in which the phenyl radical is optionally substituted as described in claim 1, thienyl or thienyl-(Cx-C 4 )-alkyl, in which the thiophene radical can in each case be substituted by one or two identical or different radicals from the series comprising (Cx~C 4 )-alkyl, (Cj-C^)-alkoxy and halogen, or 2-, 3- or 4-pyridyl or 2-, 3- or 4pyridyl-(Cx-C 4 )-alkyl, in which the pyridine radical can be substituted by one or two identical or different radicals from the series comprising (Cx-C 4 )-alkyl, (Cx-C 4 )-alkoxy and halogen; amino- (Οχ-Οχ 0 ) -alkyl; hydroxy- (Ci-C i0 ) -alkyl; ( c i” c 4) -alkoxy- (Οχ-Οχ 0 ) -alkyl; (C x -C 4 ) -alkoxycarbonyl- (Cx-Cxo) -alkyl; (Cx-C 8 )-alkylsulfonyl; (ϋχC 8 ) -alkylsulfinyl; (Cx-C 8 ) -hydroxyalkylsul fonyl; (Cx-C 8 ) -hydroxy-alkyl sul f inyl; hydroxy- (C x -C xo ) -alkanoyl; (C x -C 8 ) -alkanoyloxy- (C x C x0 )-alkyl; (C x -C xx )-alkanoyl; optionally protected amino-(C X -C 1X )-alkanoyl, such as (3-amino-3,3dimethyl)-propionyl, 4-aminobutyryl, 5-aminopentanoyl, 6-aminohexanoyl, 4-N-tert.-butoxycarbonylaminobutyryl , 5-N-tert.-butoxycarbonylaminopentanoyl or 6-N-tert.-butoxycarbonylaminohexanoyl; di- (C x -C 7 ) -alkylamino- (C 2 -C xx ) -alkanoyl; (C 3 C 8 )-cycloalkylcarbonyl; amino-substituted (C 3 -C 8 )cycloalkyl-carbonyl; amino-substituted (C 3 -C 8 )cycloalkyl-sulfonyl or (C 6 -C x0 )-aryl-(C 2 -C xx )alkanoyl; 2-pyridyl-(C x -C 8 )-alkanoyl; 3-pyridyl(C x -C 8 ) -alkanoyl; 4-pyridyl- (C x -C 8 ) -alkanoyl; benzoyl which is optionally substituted by halogen, (C x -C 6 )-alkyl, (C x -C 4 )-alkoxy or (C x -C 4 )alkoxycarbonyl; benzenesulfonyl; (C x -C xo )-alkoxycarbonyl, optionally substituted by trimethylsilyl, halogen, (C x -C 6 )-alkyl or halo-(C x -C 6 )alkyl; (C 6 -C X4 )-aryl-(C x -C 6 )-alkoxycarbonyl; 4amino-piperidino-l-carbonyl; 4-aminomethylpiperidino-1-carbonyl; N-(4-piperidino)-carbamoyl; or N-methyl-[2--ethyl]-aminocarbonyl; R 1 and R 5 , together with the nitrogen atom carrying them, form a 5- to 12- membered ring, which can be mono- or bicyclic, aromatic, partly hydrogenated or completely hydrogenated; R 2 and R 6 independently of one another denote hydrogen or (C x -C 4 )-alkyl, R 3 and R 5 independently of one another are defined as in claim 1; R* denotes (C 3 -C X2 )-alkyl; mono-, bi- or tricyclic (C 3 -C X8 )-cycloalkyl or (C 3 -C X8 )-eye loalky Imethyl, in which the cycloalkyl part is optionally substituted by (C X -C A )-alkyl; (C 6 -C X4 )-aryImethyl; dithiolanyl; dithiolanylmethyl; dithianyl or dithianylmethyl; R 7 denotes hydrogen or methyl, or together with R 1 or R 5 and the atoms carrying these forms a monoor bicyclic saturated or partly unsaturated ring system having 5-12 ring members which, in addition to carbon, can also contain 1 sulfur atom, which is optionally oxidized to sulfoxide or sulfone; and n denotes 2-8.
3. A compound of the formula I as claimed in either of claims 1 and 2, in which R 1 denotes hydrogen, (C x -C 8 )-alkylsulfonyl; (Ci-C 8 )alkylsulfinyl; 2-hydroxy-ethylsulfonyl; 2hydroxy-propylsulfonyl; 2-hydroxypropionyl; 3hydroxypropionyl; 3-hydroxybutyryl; 2-hydroxy-3methylbutyryl; (C x -C 8 ) -alkanoyloxy- (C x -C 10 ) -alkyl; n-decanoyl; formyl; acetyl; propionyl; pivaloyl; isovaleryl; isobutyryl; (3-amino-3,3-dimethyl)propionyl; 4-aminobutyryl; 5-aminopentanoyl; 6aminohexanoyl; dimethylaminoacetyl; piperidino4-carbonyl; morpholino-4-carbonyl; cyclopropylcarbonyl; cyclobutylcarbonyl; cyclopentylcarbonyl; cyclohexylcarbonyl; 3-aminocyclobutylcarbonyl; 4-aminocyclohexylcarbonyl; 3-aminocyclobutylsulfonyl; 4-aminocyclohexylsulfonyl; phenylacetyl; phenylpropanoyl; phenylbutanoyl; 2pyr idyl- (C x -C 8 ) -alkanoyl; 3-pyridyl- (ϋ χ -0 8 ) -alkanoyl; 4-pyridyl-(Cx-Ce)-alkanoyl;4-chlorobenzoyl; 4-methylbenzoyl; 2-methoxycarbonylbenzoyl; 4methoxybenzoyl; pyrrolyl-2-carbonyl; pyridyl-3carbonyl; benzenesulfonyl; methoxycarbonyl; ethoxycarbonyl; isobutoxycarbonyl; tert.-butoxycarbonyl ; 2-(trimethylsilyl)-ethoxycarbonyl; 2,2,2-trichloroethoxycarbonyl; 1,1-dimethyl2,2,2-trichloroethoxycarbonyl; - 49 benzyloxy-carbonyl; 1- or 2-naphthylmethoxycarbonyl; 9-fluorenylmethoxycarbonyl; 4-aminopiperidino-l-carbonyl; 4-aminomethyl-piperidino1-carbonyl; N-methyl-[2--ethyl]-aminocarbonyl; or N-(4piperidino)-carbamoyl; R 1 and R 5 , together with the nitrogen atom carrying them, form an 8- to 12-membered bicyclic ring which can be aromatic, partly hydrogenated or completely hydrogenated; R 2 and R 6 independently of one another denote particularly hydrogen or methyl; R 3 and R 5 independently of one another denote hydrogen, methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, sec.-butyl, 3-guanidinopropyl, carbamoylmethyl, 2-carbamoylethyl, carboxymethyl, 2carboxyethyl, mercaptomethyl, 2-(methylthio)ethyl, (1-mercapto-l-methyl)-ethyl, hydroxymethyl, 1-hydroxyethyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, N,N-dimethylamino, eyelohexylmethy1, imidazol-4-yl-methyl, benzyl, 2-methyl-benzyl, 3-methylbenzyl, indol3-yl-methyl, 4-hydroxybenzyl, 4-methoxybenzyl, 3,4-dihydroxybenzyl, 3,4-dimethoxybenzyl, (benzodioxolan-5-yl)-methyl, 2-thienyl, 2-thienylmethyl, 2-(2-thienyl)-ethyl, 3-thienyl, 3thienylmethyl, 2-(3-thienyl)-ethyl, 4-chlorobenzyl, 2-(methylsulfinyl)-ethyl, 2-(methylsulfonyl)-ethyl, 2-pyridylmethyl, 3-pyridylmethy1, 4-pyridylmethyl, cyclohexyl, (1-methylimidazol-4-yl)-methyl, (3-methyl-imidazol-4-yl)methyl, phenyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-phenylethyl, 2-thiazolylmethyl, 4thiazolylmethyl, 3-pyrazolylmethyl, 4-pyrimidinylmethyl, indol-2-yl-methyl, 2-benzo[b]thienylmethyl, 3-benzo[b]thienylmethyl, 2-furylmethyl, cyclohexyl or cyclopentyl; R* denotes (C 3 -C 12 )-alkyl; mono- or bicyclic (C 3 -C 12 )cycloalkyl or (C 3 -C 12 )-eye loalky lmethyl, in which the cycloalkyl part is optionally substituted by (Cx-C,)-alkyl; (C 6 -C 10 ) -aryl-methyl; dithiolanyl; dithiolanylmethyl; dithianyl or dithianylmethyl; R 7 denotes hydrogen or, together with R 1 and the atoms carrying these, forms a mono- or bicyclic saturated or partly unsaturated ring system having 5-12 ring members, which, in addition to carbon, also contains 1 sulfur atom, which is particularly preferably oxidized to sulfone, or together with R 5 and the atoms carrying these forms a thiochromane system, the sulfur atom of which is particularly preferably oxidized to sulfone, and n denotes 3 - 6.
4. A compound of the formula I as claimed in any one of claims 1 to 3, in which R 1 denotes hydrogen; (C x -C 6 )-alkylcarbonyl; (Cx-C 6 )alkylsulfonyl; amino-(C 5 -C 8 )-cycloalkylcarbonyl; 4aminopiperidino-1-carbonyl; 4-aminomethyl-piperidino- 1 -carbonyl or N-methyl-[2--ethyl]-aminocarbonyl; R 1 and R 5 , together with the nitrogen atom carrying them, denote indolyl; R 2 , R 6 and R 7 denote hydrogen; R 3 denotes (Cx-Cg)-alkyl; or imidazolyl-(Cx-C 4 )-alkyl; R* denotes (C 5 -C 8 ) -cycloalkyl- (Cx-C 4 ) -alkyl; R 5 denotes phenyl- (Cx-C 4 ) -alkyl or thienyl- (C x -C 4 ) -alkyl; and n denotes 2-4.
5. A process for the preparation of a compound of the formula (I) as claimed in any one of claims 1 to 4, which comprises coupling a fragment having a terminal carboxyl group or a reactive derivative thereof with a corresponding fragment having a free amino group, if appropriate splitting off (a) protective group(s) temporarily introduced to protect further functional groups and if appropriate converting the compound thus obtained into its physiologically tolerated salt.
6. The use of a compound as claimed in any one of claims 1 to 4 as a medicine.
7. The use of a compound as claimed in any one of claims 1 to 4 as a medicine in the treatment of high blood pressure and congestive cardiac insufficiency.
8. A pharmaceutical formulation containing a compound as claimed in any one of claims 1 to 4.
9. A process for the preparation of a formulation as claimed in claim 8, which comprises bringing the active compound into a suitable presentation form together with a physiologically acceptable excipient and if appropriate other additives, auxiliaries and/or preservatives.
10. A compound of the formula (I) given and defined in claim 1, or a physiologically tolerated salt thereof, substantially as hereinbefore described and exemplified.
11. A process for the preparation of a compound of the formula (I) given and defined in claim 1, or a physiologically tolerated salt thereof, substantially as hereinbefore described and exemplified.
12. A compound of the formula (I) given and defined in claim 1, or a physiologically tolerated salt thereof, whenever prepared by a process claimed in claim 5 or 11.
13. Use according to claim 6, substantially as hereinbefore described.
14. A pharmaceutical formulation according to claim 8, substantially as hereinbefore described.
IE268690A 1989-07-25 1990-07-24 Renin-inhibiting amino oligohydroxy derivatives IE902686A1 (en)

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DE3924506A DE3924506A1 (en) 1989-07-25 1989-07-25 New poly:hydroxy:amide derivs.
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