CA2021822A1 - Renin-inhibiting amino oligohydroxy derivatives - Google Patents

Abstract

Abstract of the disclosure:

Renin-inhibiting amino oligohydroxy derivatives The present invention relates to compounds of the formula I

Description

2~2~8~2 HOECHST AKTI~NGESELLSCHAFT HOE 89/F 245R Dr.WI/rh Description Renin-inhibiting amino oligohydroxy derivatives Amino diol derivatives having a renin-inhibiting action 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 -161 (1985), in Biochem. Biophys. Res. Commun. 146, 959 -963 (1987), in FEBS Lett. 230, 38 - 42 (1988) and in J.
Ned. Chem. 30, 976 - 982 (1987).

Surprisingly, it has now been found that those compounds which differ from the compounds described in the docu-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 I

A - N - CH - CO - NH - CH - (CHOH)n - CH2OH (I) in which A denotes a radical of the formula II, III or IV

Rl _ N - CH - C - (II) Rl _ CH - CH - C - (III) Rl - O - CH - C - (IV) 2 ~ 2 ~

R1 al) denotes (C3-C8)-cycloalkyl, (C4-C1O)-bicycloalkyl, (C8-Clz)-tricycloalkyl, (c3-c8)-cycloalkyl-(cl-cB)-alkyl, (C4-C10)-bicycloalkyl-(Cl-C6)-alkYl, ( CB_ C12)-tricycloalkyl-(C1-C6)-alkyl, (C3-C8)-cyclo-alkylcarbonyl or (C3-C8)-cycloalkylsulfonyl, in which the cycloalkyl, bicycloalkyl and tricyclo-alkyl substituent in each case can be substituted by one or two identical or different radicals from the series comprising F, Cl, Br, I, hydroxyl, (Cl-C6)-alkoxy, (Cl-C6)-alkyl, carboxyl, (Cl-C6)-alkoxycarbonyl,carbamoyl,carboxymethoxy, amino, (Cl-C6)-monoalkylamino, (Cl~c6)~
dialkylamino, amino-(Cl-C6)-alkyl, (C1-C6)-alkyl-amino-(Cl-C6)-alkyl,di-(Cl-C6)-alkYlamin-(C1-C6)-alkyl, amidino, hydroxyamino, hydroximino, hydrazono, imino, guanidino, (Cl-C6)-alkoxy-sulfonyl,(C1-C6)-alkoxysulfenyl,trifluoromethyl, (C1-C4)-alkoxycarbonylamino and (C6-C12)-aryl_ ( C1_C4 )-alkoxycarbonyl-amino; hydroxyl, hydrogen, (Cl-ClB)-alkyl, ( C1_CB ) -alkoxy, (C1-C13)-alkanoyl, (Cl-Cl8)-alkox~carbonyl, (C1-C1B)-alkyl-sulfonyl or (Cl-Cl8)-alkylsulfinyl, in which the alkyl radicals in each case can be substituted by optionally protected amino, trimethylsilyl, hydroxyl, mercapto, (Cl-C4)-alkylthio, halogen, (C1-C4)-alkoxy, mono- or di-(Cl-C8)-alkylamino, carboxyl,carbamoyl, guanidino,(Cl-C4)-alkoxycar-bonyl, ( C1_CB ) -a1kanOY10XY~ phenyl-(Cl-C4)-alkoxy or a radical CONR8R~;
(C6-Cl4)-aryl, (C8-Cl~)-aryl-(Cl-C4)-alkyl or (C6-Cl4)-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 (Cl-C6)-alkyl, amino, mono- or di-(Cl-C4)-alkylamino, amino-(Cl-C4)-alkyl, hydroxy-(Cl-C4)-alkyl, mono- or di-(Cl-C4)-alkyl-amino-(Cl-C4)-alkyl, hydroxyl, (Cl-C4)-alkoxy, haloqen, formyl, ~Cl-C4)-alkoxycarbonyl, 2 3 2 1 ~ 2 ~

carboxamido, mono- or di-(C1-C4)-alkylamino-carbonyl and nitro;
Het or Het-~Cl-C4)-alkyl, in which Het repre~ents a 5-, 6- or 7-membered heterocyclic ring which can be additionally benzo-fu~ed an~ either aromatic, partly hydrogenated or completely hydrogenated and contains one or two identical or different radicals from the series compri~ing N, O, S, NO, SO and SO2 as the hetero element and can be substituted by one or two identical or dif-ferent radicals from the series comprising (Cl-C4)-alkyl, (Cl-C4)-alkoxy, (Cl-C4)-alkoxy-carbonyl, hydroxyl, halogen, amino, amino-(Cl-C4)-alkyl and mono- or di-(C1-C4)-alkylamino, or a radical NRaR9, in which R8 and R~ are identical or different and independ-ently of one another denote hydrogen; (C1-C8)-alkyl, which can be substituted by amino, ~Cl-C4)-alkylamino, di-(C1-C4)-alkylamino, hydroxyl or (Cl-C4)-alkoxy; or (C3-C~-cyclo-alkyl; mercapto; (C1-C4)-alkylthio;phenylthio;
~C1-C4)-alkoxycarbonyl; carboxyl or ( C6-C14 ) -aryl, which can be substituted in the aryl radical as described above; or Het or Het-~C1-C4)-alkyl, in which Het is defined as described above, or in which R8 and R~, together with the nitrogen atom carry-ing them, form a S- to 12-membered ring which can be mono- or bicyclic, can al80 contain 1 or 2 nitrogen atoms, 1 sulfur atom or 1 oxygen atom as further ring members and can be substituted by (Cl-C4)-alkyl, or R1 a2) denotes a radical of the formula V

R1 - W (V) in which R1 is defined as Rl under al) and W

xepresents -CO-/ ~CS , -O-CO-, SO2-, -SO , -NH
-SO2-, -NH-CO-, -CH(OH)- or -N(OH)-;

R' and R5, together with ~he nitrogen atom carrying them, form a 5- to 12-membered ring which can be S mono- or bicyclic, aromatic, partly hydrogenated or completely hydrogenated, and can also contain, as further ring members, 1 ox 2 nitrogen atoms, sulfur atom or 1 oxygen atom and can be substituted by (Cl C4)-alkyl, R2 and R6 independently of one another denote hydrogen or (Cl C4)-alkyl, R3 and R5 independently of one another are defined as under al);

R4 denotes (C3-Cl2)-alkyl; mono-, bi- or tricyclic (C3-C18 ) -CyC loalkyl, ( C3-c 18 ) -cyc loalkylmethyl or ( C3-Cl8 ) -cycloalkylethyl, in which the cycloalkyl part is optionally substituted by (C1-C6)-alkyl; dithiolanyl;
( C6-C14 ) -arylmethyl; dithiolanylmethyl; dithiolanyl-ethyl; dithianyl; dithianylmethyl or dithianylethyl;

R7 is hydrogen or (Cl-C8)-alkyl, or together with Rl or R5 and the atoms carrying these, forms a mono~ or bi-cyclic, saturated or partly unsaturated ring system having 5 - 12 ring members, which, in addition to carbon, can also contain 1 ~ulfur atom, which can optionally be oxidized to ~ulfoxide 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 ther0from.

h J "; j_ ( ! ¦,, v (C~-C8)-Cycloalkyl is under~tood as meaning cyclopropyl, cyclobu~yl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

(C4-C10)-Bicycloalkyl or (C8-Cl2)-tricycloalkyl are under-s~ood as meaning an isocyclic aliphatic non-aromatic radical which can optionally contain unsymmetrically distribu~ed 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, ~hujanyl, adamantyl, bicyclo(3.3.0)-octyl, bicyclo(l.l.O~butyl and spiro(3.3)heptyl sub-stituents.

If the rings mentioned carry more than one substituent,these can be either cis or trans to one another.

(C6-C14)-Aryl is,forexample, phenyl, naphthyl, biphenylyl or fluorenyl; phenyl is preferred. The ~ame applies to 2~ radical~ deriv~d therefram, such a6, for example, ary--oxy, aroyl, aralkyl and aralkyloxy. Axalkyl is underætood as meaning an unsubstituted or substituted aryl radical linked to alkyl such as, for example, benzyl, ~- and ~-naphthylmethyl, halobenzyl and alkoxybenzyl, but aralkyl would not be limited to the radical6 mentioned.

A radical Het in the contex~ of the above definition is, for example, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxal-inyl, ~-carbolinyl or a benzo-fused ox cyclopenta , cyclohexa- or cyclohepta-fused derivative of these radicals. This heterocyclic radical can be substituted on a nitrogen atom by oxido, (Cl-C6)-alkyl, for example methyl or ethyl, phenyl or phenyl-(Cl-C4)-alkyl, for ~2 ~ $2~

example benzyl, and/or on one or more carbon atoms by ( C~-C4 )-alkyl, for example methyl, phenyl, phenyl-(Cl-C4~-alkyl, for example benzyl, halogen, for example chlorine, hydroxyl, (Cl-C4)-alkoxy, for example methoxy, phenyl-(C1-C4)-alkoxy, for example benzyloxy, or oxo and partly saturated and is, for example, 2- or 3-pyrrolyl, phenyl-pyrrolyl, for example 4- or 5-phenyl-2-pyrroly~, 2-furyl, 2-thienyl, 4-imidazolyl, methyl-imidazolyl, for example l-methyl-2-, -4- or -5-imidazolyl, 1,3-thiazol-2-yl, 2-, 3- or 4-pyridyl, 1-oxido-2-, -3- or -4-pyridyl, 2-pyraz-inyl, 2-, 4- or 5-pyrimidinyl, 2-, 3- or 5-indolyl, substituted 2-indolyl, for example 1-methyl-, 5-methyl-, 5-methoxy-, 5-benzyloxy-, 5-chloro- or 4,5-dimethyl-2-indolyl, l-benzyl-2- or -3-indolyl, 4,5,6,7-tetrahydro-2-indolyl, cyclohepta[b]-5-pyrrolyl, 2-, 3- or 4-quino-lyl, 4-hydroxy-2-quinolyl, 1-, 3- or 4-isoquinolyl, 1-oxo-1,2-dihydro-3-isoquinolyl, 2-quinoxalinyl, 2-benzo-furanyl, 2-benzoxazolyl, 2-benzothiazolyl, benz~e]indol-2-yl or ~-carbolin-3-yl.

Partly hydrogenated or completely hydrogenated hetero-cyclic rings are, for example, dihydropyridinyl, pyrro-lidinyl, for example 2-, 3- or 4-N-methylpyrrolidinyl, piperidinyl, piperazinyl, morpholino or thiomorpholino.

Halogen repre~ents 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, Ng and Ca, and with physiologically tolerated organic amines, such as, for example, triethyl-amine and tri-(2-hydroxyethyl)-amine.

~?~2~.

Compounds of the formula I which contain basic group~, for example an amino group or a guanidino group, form salts with inorganic acids, such as, for example, hydro-chloric acid, sulfuric acid or phosphoric acid, and with organic carboxylic or ~ulfonic 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;

Rl denotes hydrogen or represents tC,-C10)-alkyl; cyclo-pentyl; cyclohexyl; cyclopentyl-(C1-C6)-alkyl; cyclo-hexyl-( Cl-c6 ) -alkyl; phenyl-( Cl-c4 ) -alkyl, in which the phenyl radical is optionally substituted as described on page 2; thienyl or thienyl-( Cl-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 tCl-C4)-alkyl, ( Cl-c4)-alkoxy and halogen, or 2-, 3- or 4-pyridyl or 2-, 3- or 4-pyri-dyl-(Cl-C4)-alkyl, in which the pyridine radical can be substituted by one or two identical or different radicals from the series compri~ing (C,-C4)-alkyl, ( C,-C4 )-alkoxy and halogen; amino-(C~-C10)-alkyl;
hydroxy-(C~-C10)-alkyl; ( Cl-C4 ) -alkoxy-(C~-C~0)-alkyl;
( Cl-C4 ) -alkoxycarbonyl-(C~-C~0)-alkyl; ( Cl-C8 ) -alkylsul-fonyl; (C1-C8)-alkylsulfinyl; (C~-C8)-hydroxyalkylsul-fonyl; (Cl-C8)-hydroxy-alkylsulfinyl; hydroxy-(Cl-C1O)-alkanoyl; ( Cl-C8 ) -alkanoyloxy-(C,_C,0)-alkyl; (C~-C11)-alkanoyl; optionally protected amino-(C1-C11)-alkanoyl, such as (3-amino-3,3-dLmethyl)-propionyl, 4-aminobuty-ryl, 5-aminopentanoyl, 6-aminohexanoyl, 4-N-tert.-butoxycarbonylaminobutyryl, 5-N-tert.-butoxycarbonyl-aminopentanoyl or 6-N-tert.-butoxycarbonylaminohexa-noyl; di-( Cl-C7 ) -alkylamino-( C2-Cll ) -alkanoyl; ( C3-C8 ) -cycloalkylcarbonyl; amino-substituted (C3-C8)-cyclo-alkyl-carbonyl; amino-~ubstituted (C3-C8)-cycloalkyl-2~2:~ ~2;~

sulfonyl or ( C6-Clo ) -aryl-~ C2-cl~ )-alkanoyl; 2-pyridyl-(C1-C~)-alkanoyl; 3-pyridyl-( Cl-c8 ) -alkanoyl; 4-pyridyl-(Cl-C~)-alkanoyl; benzoyl which i6 optionally substituted by halogen, (Cl-C6)-alkyl, (Cl-C4)-alkoxy or ( Cl-C4 ) -alkoxycarbonyl; benzenesulfonyl; (Cl-Cl~)-alkoxycarbonyl, optionally ~ubstituted by trimethyl-silyl, halogen, (Cl-C6)-alkyl or halo-(Cl-C6~-alkyl;
( C6-C14 ) -aryl-( Cl-C6 ) -alkoxy-carbonyl; 4-amino-piperi-dino-l-carbonyl; 4-aminomethyl-piperidino-1-carbonyl;
N-(4-piperidino)-carbamoyl;orN-methyl-t2-<N-(morpho-linocarbonyl)N-methylamino>-ethyl]aminocarbonyl;

Rl 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 (C1-C4)-alkyl, R3 and R5 independently of one another are defined as al) on page 2;

R4 denotes (C3-Cl2)-alkyl; mono-, bi- or tricyclic (C3-Cl~)-cycloalkyl or (C3-C1~)-cycloalkylmethyl, in which the cycloalkyl part i8 optionally substituted by ( Cl-C4 ) -alkyl; ( C~-C14 ) -arylmethyl; dithiolanyl; di-thiolanylmethyl; dithianyl or dithianylmethyl;

R7 denotes hydrogen or methyl, or together with Rl 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 9 ,_ ~i , ,J ,"_ f _ ~ J ~ ~

those in which R' denotes hydrogen, (Cl-C~) alkylsulfonyl; (cl-c8)-alkyl-sulfinyl; 2-hydroxye~hyl6ulfonyl; 2-hydroxypropyl-sulfonyl; ~-hydroxypropionyl; 3-hydroxypropionyl;-3-hydroxybutyryl; 2-hydroxy 3-methylbutyryl; ( C~-C8 ) -alkanoyloxy-(C1-C10)-alkyl; n-decanoyl, formyl; acetyl;
propionyl; pivaloyl; isovaleryl; iæobutyryl; (3-amino-3,3-dimethyl)-propionyl;4-aminobutyryl;5-aminopenta-noyl î 6-aminohexanoyl; dimethylaminoacetyl; piperi-dino-4-carbonyl; morpholino-4-carbonyl; cyclopropyl-carbonyl; cyclobutylcarbonyl; cyclopentylcarbonyl;
cyclohexylcarbonyl; 3-aminocyclobutylcarbonyl; 4-aminocyclohexylcarbonyl;3-aminocyclobutylsulfonyl;4-aminocyclohexylsulfonyl; phenylacetyl, phenylpropa-noyl; phenylbutanoyl; 2 pyridyl-(C1-C~)-alkanoyl; 3-pyridyl-( Cl-Ca ) -alkanoyl; 4-pyridyl~( Cl-C8 ) -alkanoyl; 4-chlorobenzoyl; 4-methylbenzoyl; 2-methoxycarbonyl-benzoyl; 4-methoxybenzoyl; pyrrolyl-2-carbonyl;
pyridyl-3-carbonyl; benæenesulfonyl; methoxycarbonyl;
ethoxycarbonyl; isobutoxycarbonyl; tert.-butoxycar~
bonyl; 2-(trLmethylsilyl)-ethoxycarbonyl; 2,2,2-trichloroethoxycarbollyl; l,1-dLmethyl-2,2,2-trichloro-ethoxycarbo:nyl; benzyloxy-carbonyl; 1- or 2-naphthyl-methoxycarbonyl; ~-fluorenylmethoxycaxbonyl; 4-amino-piperidino-l-carbonyl; 4-aminomethyl-piperidino 1-carbonyl; N-methyl-[2-<N-(morpholinocarbonyl)-N-methylamino~-ethyl]-aminocarbonyl, or N-(4~piperi-dino)-carbamoyl;

Rl and R5, together with the nitro~en atom carrying them, form an 8- to 12-membered bicyclic ring, which can be aromatic, partly hydrogenated or completely hydrogena-ted;

R2 and R6 independently of one anothex denote hydrogen or methyl;

R3 and R5 independently of one another denote hydrogenr methyl r ethyl, isopropyl, n-propyl, n ~utyl, isobutyl, J

sec.-butyl, 3-guanidinopropyl, carbamoylmethyl, 2-carbamoylethyl, carboxymethyl, 2-carboxyethyl, mercap-tomethyl,2-(methylthio)-e~hyl,(l-mercapto-1-methyl)-ethyl, hydroxymethyl, 1-hydroxyethyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl~ N,N-dimethyl-amino, cyclohexylmethyl, imidazol-4-yl-methyl, benzyl, 2-methyl-benzyl, 3-methylbenzyl, indol-3-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, 3-thienylmethyl, 2-(3-thienyl)-ethyl, 4-chlorobenzyl, 2-(methylsulfinyl)-ethyl, 2-(methyl-sulfonyl)-ethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, cyclohexyl, (l-methyl-imidazol-4-yl)-methyl, (3-methyl-imidazol-4-yl)-methyl, phenyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-phenylethyl, 2-thiazolylmethyl,4-thiazolylmethyl,3-pyrazolylmethyl, 4-pyrimidinylmethyl, indol-2-yl-methyl, 2-benzo[b]-thienylmethyl,3-benzo~b]thienylmethyl~2-furylmethyl~
cyclohexyl or cyclopentyl;

R4 denotes (C3-C12)-alkyl; mono- or bicyclic (C3-C12)-cycloalkyl or (C3-C12)-cycloalkylmethyl, in which the cycloalkyl part is optionally substituted by (C1-C4)-alkyl; ( C6-Clo ) -aryl-methyl; dithiolanyl; dithiolanyl-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.

~ ~ 2 ~ " 2 ~ J

Compounds of the formula I which may furthermore be mentioned as particularly preferred are those in which R1 denotes hydrogen; (Cl-C6)-alkylcarbonyl; (Cl-C6)-alkyl-sulfonyl; amino-(C5-~8)-cycloalkylcarbonyl; 4-amino-piperidino-l-carbonyl; 4-aminomethyl-piperidino-1-carbonyl or N-methyl-[2-<N-(morpholinocarbonyl)-N-methylamino>-ethyl]-aminocarbonyl;
R1 and R5, together wi~h the nitrogen atom carrying them, denote indolyl;
R2,R6 and R7 denote hydrogen;
R3 denotes (Cl-C6)-alkyl or imidazolyl-(Cl-C4)-alkyl;
R4 denotes ( C5-C~ ) -CyC loalkyl-(C1-C4)-alkyl;
R5 denotes phenyl-(C1-C4)-alkyl or thienyl-( Cl-c4 )-alkyl;
and n denotes 2-4.

The invention furthermore relates to a process for the preparation of compounds of the formula I, which com-prises coupling a fragment having a terminal carboxyl group or a reactive derivative thereof with a correspond-ing fragment having a free amino group, if appropriate splitting off (a) protective group(s) temporarily intro-duced to protect further functional groups and if approp-riate converting the compound thus obtained into its physiologically tolerated salt.

Fragments of a compound of the formula I having a ter-minal carboxyl group have tbe following formulae VI and VII

A - OH (VI) A - N - CH - C - OH (VII) Fragments of a compound of the formula I having a ter-minal amino group have the following formulae VIII to X

2 ~ 2 ~

R6 R5 o R2 R3 R4 u l I ~ I
HN - CH - C - N - CH - C - HN - CH - (CHOH)n - CH20H (VIII) R2 R3 R4 (IX) HN - CH - C - HN - CH - (CHOH)n - CH20H
R4 (X) H2N - CH - (CHOH)n - CH2OH
Methods which are suitable for the production of an amide S bond are described, for example, in Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Volume 15/2; ~odanszky 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, l-hydrox-ybenzotriazole or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine 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-oxy-~ris-(dimethylamino)-phosphonium-hexafluorophosphate (BOP), or uronium reagents, such as 2-(lH-benzotriazol-l-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate(TBTU) or 2-(lH-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 corres-ponding ~-amino acids, the chirality center thereof $ 2 ~

being retained. Diazotization at -20C to 50C in dilute mineral acid~ leads to ~-bromo carboxylic acids or, via lactic acid, to u-trifluoromethanesulfonyloxy carboxylic acids, which can be reacted with a nucleo-phile carrying Rl and R7; or c) formula IV are synthesized from the corresponding ~-amino acids, the chirality center thereof being retained. Diazotization at -20C to 50C in dilute mineral acids leads to lactic acids, which can be reacted with an electrophile carrying Rl.

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 ~-lactones.
Reaction with a C-nucleophile, such as a Grignard com-pound or an alkyllithium compound, first takes place, followed by aminoglycosidation and reductive ring opening with complex hydrides, such as LiAlH4 or catalytic hydro-genation.

Alternatively, fragments of the formula X can be prepared from the suitable protected aralkylaminoglycosides. In this case the aralky~ radical is advantageously chosen 80 that hydrogenolytic removal i8 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 1,2-dimethoxyethane, at a temperature between -30-C and the boiling point of the solvent, preferably between 0C 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 hydro-2~2:~ ~2~

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 i8 known per 6e, for example by react-ing a compound of the formula I having a basic group witha 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 ~uxtaglomerular cells of the kidney as a consequence of various stimuli ~volume depletion, sodium deficiency, ~-receptor sti~ulation). In the blood circulation it ~plitsoff the decapeptide angiotensin I from the angio-tensinogen 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, ~ince 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 ~i ` J r .

~ 15 ~
effect of a reduced formation of angtiotensin I, the consequence of which is a reduced formation of angioten-sin II. The reduction in the concentration of this active peptide hormone is the direct cause of ~he antihyperten-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 renin3.

l. Test prihciple For example, human plasma which contains both renin and angiotensinogen is incubated at 37C 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 in-hibited by renin inhibitors.

2. Isolation of the pl88ma The blood is obtained from volunteer6 (about 0.5 1 per person; Bluko sampler from ASID Bonz und Sohn, Unter-schleiBheim) 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 - 4DC, 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 tprorenin . renin) by a low temperature treatment (-4C, 3 days).

2 f~ 2 3. Test procedure Angiotensin I i8 determined with a Renin-Maia- kit (Serono Diagnostics S.A., Coinsins, Switzerland). The plasma is incubated in accordance with the instructions given with the kit:

Incubation batch: 1000 ~1 of plasma (thawed at 0-4C) 100 ~1 of phosphate buffer (pH 7.4, addition of 10-4 M ramiprilat) 10 ~1 PMSF solution 10 ~1 of 0.1% of Genapol PFIC
12 ~1 of dimethyl sulfoxide or test preparation The test preparations are in general dissolved as a 10-2 M solution in 100~ pure dimethyl sulfoxide (DMS0) and the solutions are diluted accordingly with water; the incuba-tion mixture contains not more than 1% of DNS0.

The mixtures are mixed in ice and placed in a waterbath (37C) for 1 hour for incubation. A total of 6 samples (in each case 100 ~1) 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 preparstions are chosen 80 that approximately the range of 10 - 90% enzyme inhibi-tion is covered (at }east five concentrations). At theend of the incubation period, three 100 ~1 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 radioi mNnoassay (RIA) The instructions for using the RIA kit (Renin-Maia kit, - 17 ~ , 3 Serono Diagnostics S.A./ Coinsins, Swi~zerland) are followed exactly.

The calibration plot includes the range from 0.2 to 25.0 ng of angiotensin I per ml. The bas 1 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. PR~ values in ~he pres0nce of the test substances are related to a mixture without inhibitor t= 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 scale3.

The compounds of the general formula I described in the present invention exhibit inhibitory actions at concen trations of abou~ 10-5 to 10-1 mol/l 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 1~-7 1.2 x 10-7 2 4O0 x 109 ~.0 x 10 3 2.2 x 10 1.2 x 10 4 .1.6 x 10 a 2.4 x 10 1 . 1 x 10 1 . 4 x 10 7 2 . 2 x 10-7 3 . 0 x 10-7 g 1.8 x 10-8 1.2 x 10-8 1 . 1 x 10-7 5 . 0 x 10-8 11 1.9 x 10-6 3.6 x 10-6 1;~ > 10 1.O x 10 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 - 18 - 2~2~
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 6 Rhesus monkeys were pretreated orally with 10 mg/kg x day of furosemide on 6 successive days. On the 7th day, a further 10 mg/kg of furosemide were adminis-tered 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 piasma 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 pressure [%] pulse [%] renin activity 1~
1 - 0.72 -1.16 3 - 8.21 -1.61 -11.53 -2.42 -11.82 -2.51 -12.68 -3.49 -20 -13.48 -1.97 -16.43 -1.61 -62 ~ ~ 2 ~ ~ ~ rJ

-12.82 +0.09 -53 -13.98 -0.09 -58 - 8.79 +1.16 - 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 intraduo-denal 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 pharmaceutical6 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, subcutane-ously, perorally or intraduodenally. The dosage of the active compound depend~ on the warm-blooded species, the body weight, the age and the mode of admini~tration.

The pharmaceutical preparations of the present invention are prepared in dissolving, mixing, granulating or tablet-coating proce~ses which are known per 8e.

For the oral use forms, the active compounds are mixed with the additives customary for these, such as excipi-ents, stabilizers or inert diluents, and the mixture is brought by customary methods into suitable pre3entation forms, such as tablets, coated tablets, two-piece cap-sules~ aqueous, alcoholic or oily su~pensions or aqueous, 2 ~

alcoholic or oily solutions. Inert excipients which can be used are, for example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, mag-nesium 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 subcutaneou6 or intravenous administration, the 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 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 BuLi n-butyllithium TLC thin layer chromatography DCC dicyclohexylcarbodiimide DCI desorption chemical ionization DIP diisopropyl ether DNP 2,4-dinitrophenyl DNE 1, 2-dimethoxyethane DMF dimethylformamide DMSO dimethyl sulfoxide EA ethyl acetate EI electron impact Etoc ethoxycarbonyl 2~2~2~

FAB fast atom bombardment H hexane Hep n-heptane HOBt l-hydroxybenzotriazole Iva isovaleryl M molecular peak MeOH methanol NS mass spectrum MTB methyl tert.-butyl ether NEM N-ethylmorpholine Nva norvaline Nle norleucine PPA N-propanephosphonic anhydride R . T . room temperature m.p. melting point b.p.~ boiling point at xx mm Hg TBTU 2-(lH-benzotriazol-1-yl)-1,1,3,3-tetra-methyluronium Thi 2-thienylalanine THF tetrahydrofuran Z benzyloxycarbonyl.

List of abbreviation~ of selected C termini (D)-manno-pentol (XX) (D)-manno-pentol (L)-gulo-pentol (XX) (L)-gulo-pentol -- 2 2 -- i ~ ",, ~, j;

~ o 7L
X ~ ~
(D)-talo-pentol (~X~ tD)-talo-pentol ~S ~ C~ C~

0~0 C~ ~
(L)-allo-pentol (XX) (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 859i 6trength aqueous trifluoroacetic acid and the mixture is stirred at R.~. for 2.5 hours. The sol-vents are remo~ed in vacuo and chromatographed on silicagel using CH2Cl2JMeOH 10:1. 140 mg of the title compound are obtained as a colorless amorphous powder.

Rf (CH2Cl2/MeOH 10:1) = U.06 MS (FAB + LiI~o 614 (M+Li) a) Iva-Phe-Nva-[(L)-gulo-pentol(XX)~

204 ~1 of pivaloyl chloride are added to 578 mg of Iva-Phe-Nva-OHI 229 ~1 of N-ethylpipsridine and 230 ~1 2 ~ 2 ~

of triethylamine, dissolved in 25 ml of anhydrous CH2Cl2, at -15C. The mixture is stirred at R.T. for 10 minutes and cooled to -10C and a solution of 599 mg of H-(L)-gulo-pentol(XX) in 10 ml of anhydrous CH2Cl2 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 KH2PO; solution each time and three times with 50 ml of NaHCO3 solution each time, the EA
phase is dried over R2C03 and the solvent is removed in vacuo. Chromatography on silica gel using DIP/MT~
gives 200 mg of the title compound as a colorless amorphous powder.

Rs (MTB/DIP 1:1) = 0.10 MS(FAB): 688 (M+l) b) tH-(L)-gulo-pentol(XX)~

740 mg of -~N-benzyl-(L)-gulopQntol(XX)] are dissolved in 20 ml of anhydrous NeOH, and 150 ml of Pd/C (10%) and 1.1 g of HC02NH4 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.

R (MTB) - 0.05 c) ~N-Benzyl-(L)-gulo-pentol(XX)]

880 mg of 2-benzylamino-2-cyclohexylmethyl-(3,4-isopropylidene)-3(S),4(S)-dihydroxy-5-(R)-t(l, 2-isopropylidene)-l(S)-2-dihydroxyethyl]-tetrahydrofuran are dissolved in 25 ml of anhydrous THF and 188 mg of LiAlH4 are added. The mixture is ~tirred at R.T. for 20 hour~, 50 ml of NaHCO3 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 - 2~ -compound are obtained as a colorless oil.

Rf (MTB/Hep 1:5~ = 0.31 MS (DCI): 448 (M+1) d) 2-~enzylamino-2-cyclohe~ylmethyl-(3,4 isopropylidene)-3(S),4(S)-dihydroxy-5-(R)-[(1,2-isopropylidene)-l(S)-2-dihydroxyethyl]-tetrahydrofuran 4.65 g of 2-cyclohexylmethyl-(3,4-isopropylidene)-2,3(S),4(S)-trihydroxy-5-(R)-[(1,2-isopropylidene)~
l(S),2-dihydroxyethyl]-tetrahydrofuran and 5.7 ml of benzylamine are dis~olved in 150 ml of anhydrous toluene, and 910 ~1 of TiC14 are added at -20C~ The mixture is stirred at R.T. for 3 hours, 100 ml of saturated aqueous NazCO3 solution are added and the mixture is diluted with 300 ml of EA and washed with XH2P04 solution until pH 5 is reached. The organic phase is dried with NazSO4 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+l) e) 2-Cyclohexylmethyl-(3,4-isopropylidene)-2,3(S),4(S)-trihydroxy--5-(R)-[(1,2-isopropylidene)-l(S)-2-di-hydroxyethy]L]-tetrahydrofuran 5.16 g of (2,3-5,6-diisopropylidene)-L-gulonic acid ~-lactone are suspended in 300 ml of diethyl ether and 1.1 equivalents of cyclohe~ylmethyl-magnesium bromide in 50 ml of diethyl ether are added dropwise at the reflu~ 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 E~ each time, the or~anic phase is dried over Na2S04 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.

2U~l2 ~

Rf (DIP) = 0.40 MS (DCI): 357 (M+l) f) (2,3-5,6-Diisopropylidene)-L-gulonic acid ~-lactone 42 g of L-gulonic acid ~-lactone and 100 mg of p-toluenesulfonic acid are heated under reflux in 300 ml of 2,2-dimethoxypropane for S hours. After 1 hour, a clear solution forms. The volatile constituents are removed in vacuo and the residue i8 recrystallized from DIP. 45 g of the title compound are obtained as colorless crystals, m.p.: 144C.

Rf (DIP) = 0-12 MS (DCI) t 259 (M+l) Fxample 2 (2(S)-Benzyl-3-t-butylsulfonyl)propionyl-Hi~-t(D)-manno-pentol]

960 mg of (2(S)-benzyl-3-t-butylsulfonyl)propionyl-Hi~-t(D)-manno-pentol(XX)] are dissolved witn 722 mg of p toluenesulfonic acid in 100 ml of methanol and 2 drops of water are added. The mixture i8 stirred at RT for 17 hours, the pH i~ then brought to 7 with NaHC03 ~olution, the methanol is removed in vacuo, the residue iB extrac-ted three times with 100 ml of MTB and the extract i8dried over NazSO4. 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+l) m.p. 100 - 110C (decomposition) a) (2-(S)-Benzyl-3-t-butylsulfonyl)propionyl-Hi~-t(D)-manno-pentol(XX)]

850 mg of (2(S)-benzyl-3-t-butyl~ulfonyl~propionyl-2~2 His(DNP)-[(D)-manno-pentol(XX)] and 0.94 ml of thio-phenol 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. ~ 160C (decompo6ition) 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)l 1.3 g of (2(S)-benzyl-3-t-butylsulfonyl)propionyl-His(DNP)-OH, 0.31 ml of N-ethylpiperidine and 0.31 ml of triethylamine are dissolved in 30 ml of CH2Cl2 and 0.28 ml of pivaloyl chloride are added dropwise at - 15C under argon. The mixture is stirred at RT for 10 minutes and cooled to -10C and a solution of 400 mg of H-(D)-manno-pentol(XX) in 5 ml of CH2Cl2 is added dropwise. The mixture is stirred at RT for 18 hours, diluted with 100 ml of NTB and extracted once each with 100 ml of 0.66 N KH2PO~ and 100 ml of snturated NaHCO3 solution. The extract is dried over Na2SO~ and the solvent is removed ln vacuo. 850 mq of the title compound are obtained a8 an amorphous powder which is further reacted without purification.

Ff (EA/MeOH lOsl) = 0.53 NS (FAB): 927 (N+l) c) (2(S)-Benzyl-3-t-butylsulfonyl)propionyl)-His(DNP)-OH

10.7 g of (2(S)-benzyl-3-t-benzylsulfonyl)propionic acid N-hydroxy-succinimide ester and 11.3 g of H-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 2~2~2~

RT for 5 hours, the organic solvents are removed in vacuo, the pH i6 brought to 1-2 with NaHS04 ~olution, the mixture is extracted three times with 500 ml of EA
each time, the extract is dried over Na2S04 and the solvent is removed in vacuo. The residue is taken up in 350 ml of acetone/E~ 1:1 and the product is pre-cipitated with diethyl ether in an ultrasonic bath.
12.5 g of the title compound are obtained a~ a yellow powder.
Rr (MeOH/CH2Cl2 1:5) = 0.11 MS (FAB): 588 (M+l) d) (2(S)-Benzyl-3-t-butylsulfonyl)propionic acid N-hydroxysuccinimide ester 8.0 g of (2(S)-benzyl-3-t-butylsulfonyl)propionic acid (J. Med. Chem. 31, 1839 (1988)) and 3.3 g of N-hydroxysuccinimide are dissolved in 200 ml of 1,2-dimethoxyethane, and a solution of 5.8 g of DCC in 50 ml of 1,2-dimethoxyethane is added dropwise at 0C.
The mixture is left to stand at 6-C for 18 hours, the solvent is removed in vacuo at 20C and the residue is taken up in 100 ml of acetonitrile. The urea is filtered off and the solvent is removed at 20C in vacuo. 10.7 g of the title compound are obtained as a colorless oil which i8 reacted further without purifi-cation.
e) H-(D)-Manno-pentol(XX) The compound was prepared analogously to Example lb from N-benzyl-(D)-manno-pentol(XX).
f) tN-Benzyl-(D)-manno-pentol(XX)]

8.8 g of 2-benzylamino-(3,4-isopropylidene)-3(S),4(S)-dihydroxy-5(R)-[(1,2-isopropylidene)-l(R)-2-dihydroxy-ethyl]-tetrahydrofuran and 7.1 ml of cyclohexylmethyl bromide are dissolved in 250 ml of THF and reacted 2 ~ 2 ~

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 i8 extracted three times with 300 ml of MTB.
The extract is dried over Na2S04, the solvent i8 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 a~ a colorless oil.
Rf (MTB/Hep 1:1) = 0.39 MS(DCI): 448 (N+l) g) 2-Benzylamino-(3,4-isopropylidene)-3(S), 4 ( s ) -di-hydroxy-5(R)-[(1,2-isopropylidene)-l(R)-2-dihydroxy-ethyl]-tetrahydrofuran 31.5 g of 2,3-5,6-diisopropylidene-D-mannofuranoside 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 4A and the mixture is heated under reflux for a further 16 hours. The solvent is then removed in vacuo, the residue i~ tsken up in 500 ml of EA and the mixture is washed three times with 250 ml of 0.67 M RH2PO4 ~olution. The mixture i~ dried over Na2S04 and the ~olvent is removed in vacuo. 41.5 g of the white crystalline title compound are obtained.
F~ (toluene/EA 2:1) = 0.29 MS(DCI): 350 (M+l) Alternative syntheses h) (2(S)-Benzyl-3-t-butylsulfonyl)-propionyl-~is-[(D)-manno-pentol(XX)~ (2a)) 785 mg of (2(S)-benzyl-3-t-butylsulfonyl)-propionic acid and 382 ~1 of triethylamine are dissolved in 20 ml of DMF, 1.1 g of 0-benzotriazol-1-yl-1,1,3, ~ ~;Vi ~ 2 ~

3-tetramethyluronium hexafluorophosphate are added at RT and the mixture is stirred at RT for 5 minuteg. A
solution of 1.6 g of H-Hi~-[(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 i8 removed in vacuo, the residue is taken up in 500 ml of EA and the mixture is washed three times with 100 ml of NaaCO3 solution. It is dried over Na2SO4, the solvent is removed in vacuo and the re~idue i~ 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)]

3 g of Z-His-t(D)-manno-pentol(XX)] and 3 g of 2mmo-nium 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 i8 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-Hi~ (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 DNF under argon, and first 303 ~1 of diphenylphosphoryl azide and then 208 ~1 of 1-diethylamino-2-propanol are subsequently added at 0C. The mixture is stirred at 0C 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 RH2PO~ solution and 100 ml of saturated NaHCO3 solution. It is dried over Na2SO~ and chromatographed on silica gel using EA/MeOH 10:1.
530 mg of the title compound, colorless foam, are obtained.

R (EA/MeOH 10:1) = 0.17 MS (FAB): 629 (M+l) 1) H-(D)-manno-pentol(XX) 410 mg of N-benzhydryl-(D)-manno-pentol(XX) and 490 mg of ammonium formate are dissolved in 15 ml of anhy-drous methanol, 82 mg of Pd/C (10% strength) are added and the mixture is stirred under argon at RT for 6 hours. The solvent i8 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 pha8e i8 dried with Na2SO4 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)-tl,2-isopropylidene)-l(R)-2-dihydroxyethyll-tetrahydrofuran and 1.2 ml of cyclo-hexylmethyl bromide are dissolved in 40 ml of formal-dehyde dimethyl acetal (distilled from ~/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 40-60C for another hour. The reaction mixture i8 poured into 200 ml of NaHCO3 solution and extracted three times with 100 ml of MTB. It i8 dried over Na2SO~, the solvent is removed in vacuo snd the residue i8 chroma-tographed on Bilica 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+l) 2~c2~

n) 2-Benzhydrylamino-(3,4-isopropylidene)-3~S),4(S)-dihydroxy-5(R)-tl,2-isopropylidene-l(R)-2-dihydroxy-ethyl]-tetrahydrofuran 10 g of D(+)-mannose and about 10 mg of p-toluenesul-S fonic acid are suspended in 40 ml of 2,2-dimethoxypro-pane and the suspension i8 stirred at 40C for 1 hour.
A clear solution i8 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 2,2-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 i8 washed three times with 100 ml of NaHC03 solution. It is dried over Na2S04, the solvent is removed in vacuo and the residue i8 chromatographed on silica gel using DIP/toluene 1:5. 17 g of the title compound are obtained as pale yellow crystals, melting ; points 82-84C.

R~ (DIP/toluene 1:3) = 0.41 NS(DCI): 426 (M+l) The title compound of Example 2g) can also be prepared analogously from D(+)-mannose in a one-pot process.

Esample 3 cis-4-Aminocyclohexylcarbonyl-Phe-His-~(D)-manno-pentol]

180 mg of (N-tert.-butoxycarbonyl-cis-4-amino-cyclohexyl-carbonyl)-Phe-His-t(D)-manno-pentol(XX)] are dissolved in S ml of CH2C12, and S ml of trifluoroacetic acid are added at 0C. The mixture is stirred at RT for 24 hours, 100 ml of ~aturated Na2C03 solution are added and the mixture iB
extracted 3 time~ with 100 ml of EA. The extract is dried over Na2S0~, 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/H2Otconcentrated N~3 100:10:5) = 0.12 MS(FAB): 687 (M~l) a) (N-tert.-Butoxycarbonyl-cis-4-aminocyclohexylcarb-onyl)--Phe-His-[(D)-manno-pentol(XX)]

The title compound is prepared analogously to Example 2a), 2b~ from (N-tert.-butoxycarbonyl-cis-4-amino-cyclohexylcarbonyl)-Phe-His(DNP)-OH and H-(D)-manno-pentol(XX).

0 Rf (EA/MeOH 5:1) = 0.43 MS~FAB): 868 (M+l) b) (N-tert.-Butoxycarbonyl~cis-4-aminocyclohexylcarb-onyl)-Phe~His(DNP)-OH

The title compound is prepared analogously to Example 2c), 2d) from (N-tert.-butoxycarbonyl-cis-4-amino-cyclohexylcarbollyl) Phe-OH and H-His(DNP)-OH.

R~ (EA/MeOH 3:1) = 0.20 MS(FA~): 694 (M+l) c) N-tN-tert.-Butoxycarbonyl-c i8 -4~aminocyclohexylcarb-onyl)-L-phenylalanine 5.5 g of N--(N-tert.-butoxycarbonyl-ci~-4 aminocyclo-hexylcarbonyl)-L phenylalanine ~enzyl ester are hydrogenated in 230 ml of ethanol over 1 g of Pd/char-coal 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 - 161C (decomposition) MS(DCI): 391 (M+l) f~ J .~
~ 33 -d) N-(N-ter~.-Butoxycarbonyl-cis-4-aminocyclohexylcarb-onyl)-L-phenylalanine benzyl ester 6.0 g of N-tert.~butoxycarbonyl cis-1,4-aminocyclo-hexanecarboxylic acid and 6.3 g of L-phenylalanine benzyl ester are di~solved in 75 ml of DMF, the solution was mixed with 24 ml of n-PPA and 15.7 ml of NEM at 0~C and the mixture is reacted overnight at RT.
The solution is dilu~ed with CH2Cl2, washed in each ~ase with semi~saturated NaHCO3 solution, 10% ~trength citric acid and water, dried oYer MgSO4 and concentra-ted in vacuo. Flash chromatography ga~e 5.7 g of pure product.

[~]20 -14.6 (c = 1.1 in CH30H) Example 4 2(S)-{N-Methyl-N-<2-[N-(morpholinocarbonyl)-N-methyl-amino]-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-[N-(morpholinocarbonyl)-N-methylamino]ethyl>-aminocarbonyl-oxy]-3-phenylpropionic acid.

R~ (EA/MeOH 1:1) = 0.22 MS(FAB): 790 (M+1) a) 2(S)-{N-methyl-N-<2-[N-(morpholinocarbonyl)~N-methyl-amino]ethyl>-aminocarbonyloxy]-3-phenylpropioni~ acid 840 g of ethyl 2(S)-{N-methyl-N-<2-~N-(morpholinocarb-onyl)-N-methylamino]ethyl~-aminocarbonyloxy]-3-phenyl-propionate 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 hydro-chloric acid. Extraction with EA 3 times gives, after 2~2~

drying with Na2S04 and concentration, the title com-pound (24%), which i8 used for the next reaction without further purification.
MS tDCI): 394 (M+l) b) Ethyl 2(S)-{N-methyl-N-<2-[N-(morpholinocarbonyl)-N-methylamino]ethyl~-aminocarbonyloxy}-3-phenylpropio-nate 0.9 q of ethyl phenyllactate in CH2C12 (10 ml) are added dropwise to 2 g of di(4-benzotriazolyl) car-bonate and 0.23 ml of pyridine in CH2C12 (20 ml) at RT.
After 6 hours, 900 mg of N-methyl-N-2-tN-(morpholino-carbonyl)-N-methylamino]-ethylamine in 10 ml of CH2Cl2 are added dropwise. After 16 hours, 100 ml of ethyl acetate are added, and the mixture is then washed twice with saturated Na2C03 solution, twice with saturated NaHS04 and once with saturated NaCl solution.
After drying with Na2S04 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)-N-methylamino]ethylamine are stirred in 75 ml of a ~6N
solution of HCl in DME at RT for 3 hours. After concentration, 50 ml of ~aturated Na2C03 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 reaction~ without additional purification.

d) Boc-N-methyl-N-2-[N-(morpholinocarbonyl)-N-methyl-amino]ethylamine ~f : i ~ ; j .J '_i ! J , _ . .- ..t~;
~ 3~ -The title compound is obtained analogously to Example 4b~ from 2.1 g of morpholine, 10 g of di~ benzotri-azolyl)carbonate, 2 ml of pyridine and 4.7 g of Boc-N-methyl-2~(methylamino)ethylamine.

Rf (EA) = 0.25 MS (DCI): 302 (M+l) e) Boc-N-methyl-2-~methylaminn)ethylamine 12.5 g of di-t-butyl dicarbonate in 25 ml of CH2C12 are added dropwise to 100 g of N,N'-dimethylethylenedi-amine at 5C. After 4 hour~ at RT, the exces~ diamine is distilled off. The residue i~ taken up in EA
(100 ml) and the mixture is washed with saturated NazCO3 ~olution and sa~urated NaCl ~olution. 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)-benzylpropionyl~
His-[(D)-manno-pentol]

The title comE~ound is prepared analogously to Example 3 from 3-[4-(tert.-butoxycarbonyl)amino-1-piperidinyl-carbonyl]-2(R)-benzylpropionic acid.

R (acetone/H2O/concentrated NH3 100:10:5) = 0.15 MS (FAB): 687 ~M+1) a) 3-[4-(tert.-Butoxycarbonyl)amino-1-piperidinyl-carb-onyl]-2(R)-benzylpropionic acid 1.3 g of benzyl 3-[4~(tert.-~utoxycarbonyl~amino-1-piperidinyl-carbonyl]-2(R)~benzylpropionate are hydrogenated in 60 ml of EtOH with 200 mg of PdtC at RT for 1 hour. After filtration and removal of the 2~23L~22 solvent in vacuo, the title compound crystallizes out of cold diethyl ether.

m.p.: 135 - 136C
Rf (CH2Cl2/MeOH 9:1) = 0.30 MS (DCI): 391 (M+l) b) Benzyl 3-~4-(tert.-butoxycarbonyl)amino-l-piperidinyl-carbonyl]-2(R)-benzylpropionate 1.0 g of benzyl 2(R)-(carboxymethyl)-3-phenyl-propion-ate (J. Med. Chem. 31 2277 (1988)) are stirred in 50 ml of CH2Cl2 with 0.31 ml of oxalyl chloride and 1 ml of DNF at 0C for 1 hour. The ~olvent 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 0C 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 NaHC03 solution. The mixture is dried over MgS04 and the solvent is removed in vacuo to give 1.3 g of the title compound as a colorless oil.

Rf (CH2Cl2/NeOH 9sl) = 0.50 NS (DCI)s 479 (M+H) c) 4-(tert.-Butoxycarbonyl)amino-piperidine 10.0 g of l-benzyl-4-[(tert.-butoxycarbonyl)amino]
piperidine are hydrogenated in 60 ml of ethanol/glac-ial 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 scetic acid are distilled off azeotropically with toluene) and the residue is taken up in 100 ml of EA. The mixture i8 then washed once each with 100 ml of saturated NaHC03 solution and saturated NaCl solu-tion and dried over NgS04 and the solvent is removed in ?.', ~'~ ', ' i , ,) vacuo. The residue is recrystallized from EA to give 5.5 g of the title compound as white crystals~

m.p.: 159 - 161C
R~ (CH2Cl2/MeOH 9:1) = 0.11 MS (DCI)o 201 (M+l) d~ l~Benzyl-4-[(tert.-butoxycarbonyl)amino]-piperidine 10.O g of 4-amino-N-benzylpiperidine are dissolved in 100 ml of CH2Cl2, 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 recrys~allized from EA. 12.9 g of the title compound are obtained as white crystals.

m.p.: 123C
Rf (CH2Clz/MeOH 8:1) = 0.23 MS (DCI): 291 (M+l) ~xample 6 2(S)-(4-Amino-l-piperidinocarbonyloxy)-3-phenylpropionyl-His-[(D)-manno-pentol]

The title compound i5 prepared analogously to Example 3 from 2(S)-[4-(t:ert.~utoxycarbonyl)amino-l-piperidinocar-bonyloxy]-3-ph~nylpxopionic acid.

R~ (acetone/H2O/concentrated NH3 100:10:5) = 0.15 MS (FAB): 689 (M+l) a) 2(S)-[4-(tert.-Butoxycarbonyl)amino-l-piperidinocarb-onyloxy]-3-phenylpropionic acid 1.8 g of ethyl (2(S)-[4-(tert.-buto~ycarbonyl)amino-l-piperidinocarbonyloxy]-3-phenylpropionate and 5.1 ml of lN 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 H2ol the ethanol is removed in ~2~

vacuo and the pH is brought to 1 - 2 with NaHS04 solution. The mixture is extracted three times with 100 ml of EA, the extract is dried over Na2S04 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 - 101C
Rf (CH2Cl2/MeOH) = 0.29 MS (DCI): 393 (M+l) b) Ethyl 2(S)-t4-(tert.-butoxycarbonyl)amino-1-piperi-dinocarbonyloxy]-3-phenylpropionate 825 mg of ethyl phenyllactate and 1.8 g of di-(l-benzotriazolyl)carbonate (70~) are dissolved in 40 ml of CH2Cl2, 386 ~1 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 CH2Cl2, are then added dropwise and a further 386 ~1 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 Na2C03 solution and 100 ml of NaHS04 solution and dried over Na2S0~ and the solvent is removed in vacuo. 1.8 g of the title compound are obtained a~ a colorless oil which is employed further without purification.

R~ (Hep/EA 2:1) = 0.2 MS (DCI): 421 (M+l) ~ample 7 2(S)-(4-Aminomethyl-l-piperidinocarbonyloxy)-3-phenylpro-pionyl-His-[( D)-manno-pentol]

The title compound is synthesized analogously to Example 6.

~2~

Rf ( acetone/H20/concentrated NH3 lOO:lOs5) = 0.15 MS (FAB)s 703 (N+l) E~cample 8 (3-t-Butoxysulfonyl-2-thienylmethyl)propionyl-His-t(D)-manno-pentol]

The title compound i8 synthesized analogously to Example 2.

R (acetone/water lOsl) = 0.50 MS (FAB)s 687 (M+l) E~cample 9 (2(S)-Benzyl-3-t-butylsulfonyl)propionyl-His-4(S)-(5-cyclohexyl-l,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 NEN in 8 ml of DNF (absolute) and the 801u-tion is cooled to 0C. The solution, described under 9a) of 4(S)-(5-cyclohexyl-1~2~3-trihydroxy)pentylamine is then added. After warming up, the solution remains at RT
for 48 hours. 0.5 ml of H20 are added to the reaction solution, the dicyclohexylurea formed is then filtered off and the filtrate i8 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/CH30H 20sl.
The product of Rf 0.5 (CH2Cl2/CH30H 9:1 on silica gel) is obtained as a vitreous solid in ~I yield of 60 mg.

MS (FAB) 787 (N+l) The product is dissolved in 5 ml of CH2C12 (absolute) and the solution was stirred at RT with 0.2 ml of thiophenol ~ i~ 2 ~ ~ t~

for 4 hours. After the solvent has been filtered off in vacuo, the crude mixture is chromatographed on silica gel using CH2Cl2/CH30H 20:1. 16 mg of the title compound are obtained.

5 MS (FAB): 621 (M+l) Rf (CH2C12/MeOH 9:1) = 0.25 a) 4(S)-(5-Cyclohexyl-1,2,3-trihydroxy)-pentylamine 130 mg of (2RS,3RS,4S)-4-tert.-butoxycarbonylamino-5-cyclohexyl-1,2,3-trihydroxypentane (Example ~b) are dissolved in 2 ml of DNE, 4 ml of saturated HCl~DNE
solution are added and the mixture is stirred at 0C
for 30 minutes. After w~rming up to RT, the solution is concentrated in vacuo and the residue is concentra-ted three times, in each case after addition of toluene (absolute). This oil thus obtained is immedi-ately employed as a solution in DNF in the subsequent reaction step.

b) (2RS,3RS,4S)-4-tert.-Butoxycarbonylamino-5-cyclohexyl-1,2,3-trihydroxypentane 293 mg of the pentenol obtained in Example 9c) are dissolved in 10 ml of THF (ab~olute) 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 i8 stirred overnight at RT. 10~ strength NaHS03 solution i8 added to the solution, the mixture is stirred for 30 minutes and then concentrsted in vacuo, the residue i8 taken up in 50 ml of ethyl acetate and the aqueous phase is separated off. The organic phase is washed with 1N HCl, 10% strength Na2S0~, dried and concentrated in vacuo.
An amorphous solid of 140 mg remains.
MS (DCI): 318 (M+l) ~2~822 c) 4S-tert~Butoxycarbonylamino-5-cyclohexyl-cis-2-pentenol 5.5 ml of a 1.2 M solution of diisobutylaluminum hydride in toluene were added to 0.98 g of 4S-tert.-butoxycarbonylamino-5-cyclohexyl-cis-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 -78C. 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 CH2Cl2 the solution i8 shaken in each case once with 10% ~trength K Na tartrate solution, 10~ strength citric acid solution and 6aturated NaCl solution. The solution is dried over MgSO4 and con-centrated in vacuo and the resulting oily crude product is chromatographed over silica gel (cyclo-hexane/ethyl acetate). 480 mg of a slightly yellow oil are obtained.

E~ample 10 Iva-Phe-Nva-t(D)-manno-pentol]

The compound is prepared snalogously to Example 1) and la) from Iva-Phe-Nva-OH and H-(D)-manno-pentol(XX).

Rf (CH2Cl2/MeOH) = 0.06 NS (FAB + LiI)s 614 (N+Li) The title compounds of Examples 11 and 12 are prepared analogously to Example 2:

E~ Iple 11 Indolyl-2-carbonyl-His-[(D)-manno-pentol]

R~ (CH2CH2:MeOH:concentrated aqueous NH3 = 50:10:1) = 0.10 MS (FAB): 558 (M+l) b:, ' : ~ ,. ., `j Example 12 2(S)-~ydroxy-3-phenylpropionyl-His-[~D)-manno-pentol]

R~ (acetone/H20 10:1) = 0~25 MS (FAB): 563 (M+l)

Claims (10)

1. A compound of the formula I

(I) in which A denotes a radical of the formula II, III or IV

(II) (III) (IV) R1 a1) denotes (C3-C8)-cycloalkyl, (C4-C10)-bicyclo-alkyl, (C8-C12)-tricycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, (C4-C10)-bicycloalkyl-(C1-C6)-alkyl, (C8-C12)-tricycloalkyl-(C1-C6)-alkyl, (C3-C8)-cycloalkyl-carbonyl 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, (C1-C6)-alkoxy, (C1-C8)-alkyl, carboxyl, (C1-C6)-alkoxycarbonyl, carbamoyl, carboxymethoxy, amino, (C1-C8)-monoalkylamino, (C1-C6)-dialkylamino, amino-(C1-C6)-alkyl, (C1-C6)-alkylamino-(C1-C6)-alkyl,di-(C1-C6)-alkylamino-(C1-C6)-alkyl, amidino, hydroxyamino, hydroximino, hydrazono, imino, guanidino, (C1-C6)-alkoxysulfonyl, (C1-C6)-alkoxysulfenyl, trifluoromethyl, (C1-C6)-alkoxycarbonylamino and (C8-C12)-aryl-(C1-C4)-alkoxycarbonyl-amino;
hydrogen, hydroxyl, (C1-C18)-alkyl, (C1-C8)-alkoxy, (C1-C8)-alkanoyl, (C1-C18)-alkoxycar-bonyl, (C1-C16)-alkylsulfonyl or (C1-C18)-alkyl-sulfinyl, in which the alkyl radicals in each case can be substituted by optionally protected amino, trimethylsilyl, hydroxyl, mercapto, (C1-C4)-alkylthio,halogen,(C1-C4)-alkoxy,mono-or di-(C1-C8)-alkylamino, carboxyl, carbamoyl, guanidino, (C1-C4)-alkoxycarbonyl, (C1-C8)-alkanoyloxy, phenyl-(C1-C4)-alkoxy or a radical CONR8R0; (C1-C4)-alkoxy;
(C8-C14)-aryl, (C8-C14)-aryl-(C1-C4)-alkyl or (C8-C14)-aryl-(C1-C4)-alkoxy, in which the aryl radi-cal in each case can be substituted by one, two or three identical or different radicals from the series comprising (C1-C6)-alkyl, amino, mono- or di-( C1-C4 ) -alkylamino, amino-(C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl, mono- or di-(C1-C4)-alkylamino-(C1-C4)-alkyl, hydroxyl, (C1-C4)-alkoxy, halogen, formyl, (C1-C4)-alkoxy-carbonyl, carboxamido, mono- or di-(C1-C4)-alkylaminocarbonyl and nitro;
Het or Het-(C1-C4)-alkyl, in which Het repres-ents a 5-, 6- or 7-membered heterocyclic ring which can be additionally benzo-fused and either aromstic, partly hydrogenated or com-pletely hydrogenated and can contain one or two identical or different radicals from the series comprising N, O, S, NO, SO or SO2 as the hetero element and can be substituted by one or two identical or different radicals from the series comprising (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4-alkoxycarbonyl, hydroxyl, halogen, amino, amino-(C1-C4)-alkyl and mono- or di-(C1-C4)-alkylamino; or a radical NR3R9, in which R6 and R9 are identical or different and independ-ently of one another denote hydrogen; (C1-C8)-alkyl, which can be substituted by amino, (C1-C4)-alkylamino, di-(C1-C4)-alkylamino, hydroxyl or (C1-C4)-alkoxy; (C3-C7)-cycloalkyl;

mercapto;(C1-C4)-alkylthio;phenylthio;(C1-C4)-alkoxycarbonyl; carboxyl or (C6-C14) aryl, which can be substituted in the aryl radical as described above; or Het or Het-(C1-C4)-alkyl, in which Het is defined as described above, or in which R8 and R9, together with the nitrogen atom carry-ing 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 sub-stituted by (C1-C4)-alkyl, or R1 a2) denotes a radical of the formula V

R1'- W (V) in which R1 is defined as R1 under a1) and W repres-ents -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 and can also contain, as further ring members, 1 or 2 nitrogen atoms, 1 sulfur atom or 1 oxygen atom and can be sub-stituted by (C1-C4)-alkyl, R2 and R6 independently of one another denote hydrogen or (C1-C4)-alkyl;

R3 and R5 independently of one another are defined as R1 under a1);

R4 denotes (C3-C12)-alkyl; mono-, bi- or tricyclic (C3-C18)-cycloalkyl, (C3-C18)-cycloalkylmethyl or (C3-C18)-cycloalkylethyl, in which the cycloalkyl part is optionally substituted by (C1-C6)-alkyl;

dithiolanyl; (C6-C14) arylmethyl; dithiolanyl-methyl; dithiolanylethyl; dithianyl; dithianyl-methyl or dithianylethyl;

R7 is hydrogen or (C1-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 sulf-oxide 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;

R1 denotes hydrogen or represents (C1-C10)-alkyl;
cyclopentyl; cyclohexyl; cyclopentyl-(C1-C6)-alkyl; cyclohexyl-(C1-C6)-alkyl; phenyl-(C1-C4)-alkyl, in which the phenyl radical is optionally substituted as described in claim 1, thienyl or thienyl-(C1-C4)-alkyl, in which the thiophene radicnl can in each case be substituted by one or two identical or different radicals from the series comprising (C1-C4)-alkyl, (C1-C4)-alkoxy and halogen, or 2-, 3- or 4-pyridyl or 2-, 3- or 4-pyridyl-(C1-C4)-alkyl, in which the pyridine radical can be substituted by one or two identi-cal or different radicals from the series com-prising (C1-C4)-alkyl, (C1-C10)-alkoxy and halogen;
amino-(C1-C10)-alkyl; hydroxy-(C1-C10)-alkyl;
(C1-C4)-alkoxy-(C1-C10)-alkyl; (C1-C8)-alkoxycar-bonyl-(C1-C10)-alkyl; (C1-C8)-alkylsulfonyl; (C1-C8)-alkylsulfinyl; (C1-C8)-hydroxyalkylsulfonyl;
(C1-C8) -hydroxy-alkylsulfinyl;

hydroxy-(C1-C10)-alkanoyl;(C1-C8)-alxanoyloxy-(cl-C10)-alkyl, (C1-C11)-alkanoyl; optionally protected amino-(C1-C11)-alkanoyl, such as (3-amino-3,3-dimethyl)-propionyl,4-aminobutyryl,5-aminopent-anoyl,6-aminohexanoyl,4-N-tert.-butoxycarbonyl-aminobutyryl, 4-N-tert.-butoxycarbonylamino-pentanoyl or 6-N-tert.-butoxycarbonylaminohex anoyl; di-(C1-C7)-alkylamino-(C2-C11)-alkanoyl; (C3-C8)-cycloalkylcarbonyl; amino-substituted(C3-C8)-cycloalkyl-carbonyl; amino-substituted (C3-C8)-cycloalkyl-sulfonyl or (C6-C10)-aryl-(C2-C11)-alkanoyl; 2-pyridyl-(C1-C8)-alkanoyl; 3-pyridyl-(C1-C8)-alkanoyl; 4-pyrldyl-(C1-C8)-alkanoyl;
benzoyl which is optionally substituted by halogen, (C1-C6)-alkyl, (C1-C4)-alkoxy or (C1-C4)-alkoxycarbonyl;benzenesulfonyl;(C1-C10)-alkoxyc-arbonyl, optionally substituted by trimethyl-silyl, halogen, (C1-C6)-alkyl or halo-(C1-C6)-alkyl; (C6-C14)-aryl-(C1-C6)-alkoxycarbonyl; 4-amino-piperidino-l-carbonyl 4-aminomethyl-piperidino-l-carbonyl; N-(4-piperidino)-car-bamoyl; or N-methyl-[2-<N-(morpholinocarbonyl)-N-methylamino>-ethyl]-aminocarbonyl;

R1 and R5, together with the nitroge~ atom carrying them, form a 5- to 12- membered ring, which can be mono- or bicyclic, aromat$c, partly hydrogen-ated o:r completely hydrogenated;

R2 and R~ independently of one another denote hydrogen or ( C~-C4 )-alkyl, R3 and Rs independently of one another are defined as in claLm l;

R4 denotes (C3-C~2~-alkyl; mono°, bi- or tricyclic (C3-C1B~-cycloalkyl or (C3-C1~)-cycloalkylm~thyl, in which the cycloalkyl part i~ optionally substituted by ( Cl-C4 )-alkyl~ (C6-Cl4)-arylmethyl;

dithiolanyl; dithiolanylmethyl; dithianyl or dithianylmethyl;

R7 denotes hydrogen or methyl, or together with 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.

3. A compound of the formula I as claimed in either of claims 1 and 2, in which R1 denotes hydrogen, (C1-C8) -alkylsulfonyl; (C1-C8)-alkylsulfinyl; 2-hydroxy-ethylsulfonyl; 2-hydroxy-propylsulfonyl; 2-hydroxypropionyl; 3-hydroxypropionyl; 3-hydroxybutyryl; 2-hydroxy-3-methylbutyryl; (C1-C6) -alkanoyloxy-(C1-C10)-alkyl;
n-decanoyl; formyl; acetyl; propionyl; pivaloyl;
isovaleryl; isobutyryl; (3-amino-3,3-dimethyl)-propionyl; 4-aminobutyryl; 5-aminopentanoyl; 6-aminohexanoyl; dimethylaminoacetyl; piperidino-

4-carbonyl; morpholino-4-carbonyl; cyclopropyl-carbonyl; cyclobutylcarbonyl; cyclopentylcar-bonyl; cyclohexylcarbonyl; 3-aminocyclobutylcar-bonyl; 4-aminocyclohexylcarbonyl; 3-aminocyclo-butylsulfonyl;4-aminocyclohexylsulfonyl;phenyl-acetyl; phenylpropanoyl; phenylbutanoyl; 2-pyridyl-(C1-C8) -alkanoyl; 3-pyridyl-(C1-C8)-alka-noyl;4-pyridyl-(C1-C8)-alkanoyl;4-chlorobenzoyl;
4-methylbenzoyl; 2-methoxycarbonylbenzoyl; 4-methoxybenzoyl; pyrrolyl-2-carbonyl; pyridyl-3-carbonyl; benzenesulfonyl; methoxycarbonyl;
ethoxycarbonyl; isobutoxycarbonyl; tert.-butoxy-carbonyl; 2-(trimethylsilyl)-ethoxycarbonyl;
2,2,2-trichloroethoxycarbonyl; 1,1-dimethyl-2,2,2-trichloroethoxycarbonyl;

benzyloxy-carbonyl; 1- or 2-naphthylmethoxy-carbonyl; 9-fluorenylmethoxycarbonyl; 4-amino-piperidino-l-carbonyl; 4-aminomethyl-piperidino-1-carbonyl; N-methyl-[2-<N-(morpholinocarbonyl)-N-methylamino>-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 particu-larly hydrogen or methyl;

R3 and R5 independently of one another denote hydrogen, methyl, ethyl, isopropyl, n-propyl, n-butyl, iso-butyl, BeC .-butyl, 3-guanidinopropyl, oarbamoyl-methyl, 2-carbamoylethyl, carboxymethyl, 2-carboxyethyl, mercaptomethyl, 2-(methylthio)-ethyl, (1-mercapto-1-methyl)-ethyl, hydroxy-methyl, l-hydroxyethyl, aminomethyl, 2-amino-ethyl, 3-aminopropyl, 4-aminobutyl, N,N-dimethyl-amino, cyclohexylmethyl, imidazol-4-yl-methyl, benzyl, 2-methyl-benzyl, 3-methylbenzyl, indol-3-yl-methyl, 4-hydroxybenzyl, 4-methoxybenzyl, 3,4-dihydroxybenzyl, 3,4-dimethoxybenzyl, (benzodioxolan-5-yl)-methyl, 2-thienyl, 2-thi-enylmethyl, 2-(2-thienyl)-ethyl, 3-thienyl, 3-thienylmethyl, 2-(3-thienyl)-ethyl, 4 chloro-benzyl, 2-(methylsulfinyl)-ethyl, 2-(methyl-sulfonyl)-ethyl, 2-pyridylmethyl, 3-pyridyl-methyl, 4-pyridylmethyl, cyclohexyl, (1-methyl-imidazol-4-yl)-methyl, (3-methyl-imidazol-4-yl)-methyl, phenyl, l-naphthylmethyl, 2 naphthyl-methy, 2-phenylathyl, 2-thiazolylmethyl, 4-thiazolylmethyl, 3-pyrazolylmethyl, 4-pyrimid inylmethyl,indol-2-yl-methyl,2 benzo[b]thienyl-methyl, 3-benzo[b]thienylmethyl, 2-furylmethyl, cycloahexyl or cyclopentyl;

R4 denotes (C3-C12)-alkyl; mono- or bicyclic (C3-C12)-cycloalkyl or (C3-C12)-cycloalkylmethyl, in which the cycloalkyl part is optionally substituted by (C1-C4)-alkyl; (C8-C10)-aryl-methyl; dithiolanyl;
dithiolanylmethyl; 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.

4. A compound of the formula I as claimed in any one of claims 1 to 3, in which R1denotes hydrogen; (C1-C6)-alkylcarbonyl; (C1-C6)-alkylsulfonyl; amino-(C5-C8)-cycloalkylcarbonyl; 4-aminopiperidino-1-carbonyl; 4-aminomethyl-piperi-dino-l-carbonyl or N-methyl-[2-<N-(morpholino-carbonyl)-N-methylamino>-ethyl]-aminocarbonyl;
R1and R5, together with the nitrogen atom carrying them, denote indolyl;
RZ, R6 and R7 denote hydrogen;
R3denotes (C1-C6)-alkyl; or imidazolyl-(C1-C4)-alkyl;
R4denotes (C5-C8)-cycloalkyl-(C1-C4)-alkyl;
R5denotesphenyl-(C1-C4)-alkylorthienyl-(C1-C4)-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. The compound as claimed in claim 1 and substantially as described herein.