AU639246B2 - Renin-inhibiting amino oligohydroxy derivatives - Google Patents

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

39246 Form COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952-69 COMPLETE SPECIFICATION

(ORIGINAL)

Class Int. Class Application Number: Lodged: Complete Specification Lodged: 'a Accepted: Published: Priority 0 Related Art Name of Applicant So SAddress of Applicant: HOECHST AKTIENGESELLSCHAFT 50 Bruningstrasse, D-6230 Frankfurt/Main of Germany 80, Federal Republic Actual Inventor Address for Service HEINZ-WERNER KLEEMANN, HANSJORG URBACH, ADALBERT WAGNER, DIETER RUPPERT, WOLFGANG LINZ, WERNER KRAMER WATERMARK PATENT TRADEMARK ATTORNEYS.

LOCKED BAG NO. 5, HAWTHORN, VICTORIA 3122, AUSTRALIA Complete Specification for the invention entitled: RENIN-INHIBITING AMINO OLIGOHYDROXY DERIVATIVES The following statement is a full description of this invention, including the best method of performing it known to us SHOECHST AKTIENGESELLSCHAFT HOE 89/F 245K 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.

Med. Chem. 30, 976 982 (1987).

Surprisingly, it has now been found that those compounds which differ from the compounds described in the docu- 15 ments mentioned in that they contain additional hydroxyl *s 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

R

2

R

3

R

4 20 A N CH CO NH CH (CHOH)n CH 2 0H in which A denotes a radical of the formula II, III or IV

R

6

R

5

O

1 N I 1

(II)

R1 N CH C

R

7

R

5

O

1 (III) R CH CH C

R

5 0 R o CH C (v) -2-

R

1 a 1 denotes (C 3 -C)-cycloalkyl, (C 4

-C

1 )-bicycloalkyl, (Ca-C 1 -tricycloalkyl, -cycloalkyl- (Cj-C 6 alkyl, (C 4

-C

1 0 -bicycloalkyl- (Cl-Cr,) -alkylI (Ca-

C

12 -tricyc loalkyl- (C 1 -Cr 6 -alkyl, (C 3

-C

8 -cyc loalkylcarbonyl or (C 3 -C,)-cycloalkylsulfonyl, in which the cycloalkyl, bicycloalkyl and tricycloalky. 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-C 8 -alkoxy, -alkyl, carboxyl, (Cl-C 6 -alkoxycarbonyl, carbamoyl, carboxymethoxy, amino, (C 1 -Cr)-monoalkylamino, (C 1

-C

6 dialkylamino, amino- (Cl-C, 6 -alkyl, (Cl-C 6 -alkylamino- -alkyl, ,di- -alkylamino- (C 1 -C6) :15 alkyl, amidino, hydroxyanino, hydroximino, Goose:hydrazono, imino, guanidino, -alkoxy- S* sulf onyl, (C 1

-C

6 -alkoxysulf enyl, trif luoromethyl, ,00:0, (C 1

-C

4 -alkoxycarbonylamino and (C 6

-C

12 -aryl- G'O (C 1

-C

4 -alkoxyc arbonyl -amnino; hydroxyl, -G2 hydrogen, (Cl-C 1 8 )-alkyl, (Cl-C,)-alkoxy, (Cl-C3 1 8 alkanoyl, -alkoxycarbonyl, (C 1

-C

18 -alkylsulfonyl or (Cl-C 1 )-alkylsulfinyl, in which the alkyl radicals in each case can be substituted by optionally protected a io trimethylsilyl, 25 hydroxyl, mercapto, (C,-C 4 )-alkylthio, halogen, (C.-CO)-alkoxy, mono- or di- -alkyl amino, carboxyl, carbamoyl, guanidino, (Cl-C 4 )-alkoxycarbonyl, (Cl-C 8 -alkanoyloxy, phenyl- (Cl-C 4 -alkoxy or a radical CONR 8

R

6

(C.-C

1 4 )-aryl, (C,-C 14 )-aryl-(C 1

-C

4 )-alkyl or

C

14 -aryl- (Cl-C 4 -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-C 4 -alkylamino, amino- (C 1

-C

4 -alkyl, hydroxy- (C 1

-C

4 -alkyl, mono- or di- (C 1

-C

4 -alkylamino- (Cl-C 4 -alkyl, hydroxyl, (C 1

-C

4 -alkoxy, halogen, formyl, (C 1

-C

4 -alkoxycarbonyl, 3 carboxamido, mono- or di-(C 1 -C )-alkylaminocarbonyl and nitro; Het or Het-(Ci-C 4 )-alkyl, in which Het represents a 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, O, S, NO, SO and SO 2 as the hetero element and can be substituted by one or two identical or different radicals from the series comprising (Ci-C 4 )-alkyl, -alkoxy, (Ci-C 4 -alkoxycarbonyl, hydroxyl, halogen, amino, amino-(Ci-C 4 alkyl and mono- or di-(C 1

-C

4 )-alkylamino, or a radical NR 8

R

9 in which

R

8 and R 9 are identical or different and independently of one another denote hydrogen; alkyl, which can be substituted by amino,

C-C

4 -alkylamino, di- (C 1 -C4) -alkylamino, 20 hydroxyl or (Ci-C 4 )-alkoxy; or (C 3

-C

7 -cycloalkyl; mercapto; (Ci-C 4 -alkylthio; phenylthio;

(CI-C

4 -alkoxycarbonyl; carboxyl or (C 6

-C

1 4 aryl, which can be substituted in the aryl radical as described above; or Het or Het- '25 (C 1

-C

4 )-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' W (V) in which R 1 is defined as R 1 under and W 4 represents -SO 2

-NH

-SOz-, -NH-CO-, -CH(OH)- or

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, 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-C 4 -alkyl,

R

2 and R 6 independently of one another denote hydrogen or (C 1

-C

4 )-alkyl,

R

3 and R 5 independently of one another are defined as R 1 under 0

R

4 denotes (C 3

-C

12 )-alkyl; mono-, bi- or tricyclic (C 3 *..015 C 1 )-cycloalkyl, (C 3

-C

1 )-cycloalkylmethyl or (C 3

-C

18 cycloalkylethyl, in which the cycloalkyl part is 00 optionally substituted by (Ci-Cs)-alkyl; dithiolanyl;

(C

6

-C

14 )-arylmethyl; dithiolanylmethyl; dithiolanylethyl; dithianyl; dithianylmethyl or dithianylethyl;

R

7 is hydrogen or (C 1 -C)-alkyl, or together with R 1 or R 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 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.

5

(C

3 -Ca)-Cycloalkyl is understood as meaning cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

(C

4

-C

1 o)-Bicycloalkyl or (C.-C 1 -tricycloalkyl are understood 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 substituents.

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

Se 14 )-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 pnaphthylmethyl, halobenzyl and alkoxybenzyl, but aralkyl 555 would not be limited to the radicals mentioned.

0" A radical Het in the context of the above definition is, for example, pyrrolyl, furyl, thienyl, imidazolyl, Spyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, p-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, (C,-C 6 )-alkyl, for example methyl or ethyl, phenyl or phenyl-(Ci-C 4 )-alkyl, for -6example benzyl, and/or on one or more carbon atoms by

(C

1

-C

4 )-alkyl, for example methyl, phenyl, phenyl-(Cl-C 4 alkyl, for example benzyl, halogen, for example chlorine, hydroxyl, (C,-C 4 )-alkoxy, for example methoxy, phenyl- (Cl-C 4 )-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-, or -5-imidazolyl, 1,3-thiazol-2-yl, 2-, 3- or 4-pyridyl, 1-oxido-2-, or -4-pyridyl, 2-pyrazinyl, 4- or 5-pyrimidinyl, 3- or substituted 2-indolyl, for example 1-methyl-, 5-benzyloxy-, 5-chloro- or 4,5-dimethyl-2indolyl, l-benzyl-2- or -3-indolyl, 4,5,6,7-tetrahydro- 2-indolyl, cyclohepta[b]-5-pyrrolyl, 3- or 4-quinolyl, 4-hydroxy-2-quinolyl, 3- or 4-isoquinolyl, 1oxo-1,2-dihydro-3-isoquinolyl, 2-quinoxalinyl, 2-benzofuranyl, 2-benzoxazolyl, 2-benzothiazolyl, benz[e]indol- 2-yl or p-carbolin-3-yl.

*20 Partly hydrogenated or completely hydrogenated heterocyclic rings are, for example, dihydropyridinyl, pyrrolidinyl, for example 3- or 4-N-methylpyrrolidinyl, piperidinyl, piperazinyl, morpholino or thiomorpholino.

goes 9Halogen 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 **go non-toxic salts.

*9 9 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.

-7 Compounds of the formula I which contain basic groups, for example an amino group or a guanidino group, f orm.

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 aci3A, 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; R' dei Otes hydrogen or represents (Cl-C 10 -alkyl; cyclopentyl; cyclohexyl; cyclopentyl-(C 1 -C,)-alkyl; cyclohexyl- (Cl-C 6 -alkyl; phenyl- (C 1

-C

4 -alkyl, in which the phenyl radical is optionally substituted as described page 2; thienyl or thienyl- (C 1

-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 (Cl-C 4 )-alkyl, (Cl-C 4 )-alkoxy and halogen, or 3- or 4-pyzidyl or 3- or 4-pyridyl-(Cl-C 4 )-alkyl, in which the pyridine radical can be substituted by one or two identical or different radicals from the series comprising (Cl-C 4 )-alkyl,

(C

1

-C

4 -alkoxy and, halogen; amino- (Cl-C 10 -alkyl; hydroxy- (C 1

-C

10 -alkyl; (%C 1

-C

4 -alkoxy- (Cl-CI 0 -alkyl;

(C

1

-C

4 -alkoxycarbonyl- (Cl-CI 0 -alkyl; -alkylsulfonyl; (C 1 -Ca) -alkyvlsu'Lfinyl; (Cl-CB) -hydroxyalkylsulfonyl; -hydroxy-alkylsulfinyl; hydroxy- (C 1 -Cj,< alkanoyl; (Cl-C)-alkanoylo),y-(Cl-C 1 )-alkyl; (Cj-Cjj) alkanoyl; optionally protected amino- (C,-C 11 -alkanoyl such as (3 -amino- 3, 3-dimethrl -propionyl, 4-aminobutyryl, 5-aminopentanoyl, 6-aminohexanoyl, 4-N-tert.butoxycarbonylaininobutyryl, aminopentanoyl or 6-N-tert. -butoxycarbonylaminohexanoyl; di- (Cl-C 7 -alkyl-mino- (C 2 -Cll) -alkanoyl; (C 3

-C

8 cycloalkylcarbonyl; amino- substituted (C 3 -CB) -cycloalkyl-carbonyl; amino -substituted (C 3 -cycloalkyl- 8sulfonyl or (C 6 -Cl 0 )-aryl-(C 2 -Cl 1 -alkanoyl; 2-pyridyl- -alkanoyl; 3-pyridyl- (C 1 -alkanoyl; 4-pyridyl-

(C

1

-C

8 -alkanoyl; benzoyl which is optionally substituted by halogen, (Cl-Cr,) -alkyl, (C 1

-C

4 -alkoxy or

(C.-C

4 -alkoxycarbonyl; benzenesulfonyl; (C 1

-C

10 alkoxycarbonyl, optionally substituted by trimethylsilyl, halogen, (C 1 -alkyl or halo- (C 1 -alkyl;

(C

6 -Cl 4 -aryl- (C 1

-C

6 -alkoxy-carbonyl; 4-amino-piperidino-l-carbonyl; 4-aminomethyl-piperidino-1-carbonyl; N- (4-piperidino) -carbamoyl; or N-methyl- (morpholinocarbonyl )N-methylamino>-ethyl aminocarbonyl; R' and R 5 together with the nitrogen atom carrying them, form a 5- to 12- memibered ring, which can be mono- or bicyclic, aromatic, partly hydrogenated or completely 4.00.15 hydrogenated; Oseo R 2 and R 6 independently of one another denote hydrogen or

(C

1

-C

4 -alkyl, R R 3 and R 5 independently of one another are defined as R on page 2; R 4 denotes (C 3

-C

12 )-alkyl; mono-, bi- or tricyclic

C

1 -cycloalkyl or (C 3 -cycloalkylmethyl, in which the cycloalkyl. part is optionally substituted by (Cl-C 4 -alkyl; (C 6

-C

14 -arylmethyl; dithiolanyl; dithiolanylmethyl; dith:Lanyl or dithianylmethyl; R 7 denotes hydrogen or methyl, or together with R 1 or R 0:90 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 sulf one; and n denotes 2 8.

Particularly preferred compounds of the formula I are 9those in which R' denotes hydrogen, (Cl-C,)-alkylsulfonyl; (Cl-C,)-alkylsulfinyl; 2-hydroxyethylsulfonyl; 2-hydroxypropylsulfonyl; 2-hydroxypropionyl; 3-hyc xypropionyl hydroxybutyryl; 2-hydroxy-3-methylbutyryl; (Ci-Ca) alkanoyloxy- (Cl-Cl.) -alkyl; n-decanoyl; f ormyl; acetyl; propionyl; pivaloyl; isovaleryl; isobutyryl; (3-amino- 3, 3-dimethyl) -propionyl; 4-aminobutyryl; noyl; 6 -aminohexanoyl; dimethylaminoacetyl; piperidino-4-carbonyl; morpholino-4-carbonyl; cyclopropylcarbonyl; cyclobutylcarbonyl; cyclopentylcarbonyl; cyclohexylcarbonyl; 3-aiinocyclobutylcarbonyl; 4aminocyclohexylcarbonyl; 3-aminocyclobutylsulfonyl; 4aiinocyclohexylsulfonyl; phenylacetyl; phenyipropanoyl; phenylbutanoyl; 2-pyridyl-(Cl-C,)-alkanoyl; 3- 0 pyridyl- (Cl-C 8 -alkanoyl; 4-pyridyl- (Cl-Cs) -alkanoyl; 4- $Gas.:chlorobenzoyl; 4-methylbenzoyl; 2-methoxycarbonyl- *ezol 0-ehxbnol yroy--abn o pyridyl-3-carbonyl; benzenesulfonyl; methoxycarbonyl; ethoxycarbonyl; isobutoxycarbonyl; tert. '-butoxycar- ~u bonyl; 2-(trimethylsilyl) -ethoxycarbonyl; 2,2,2trichioroethoxycarbonyl; 1, 1-dimethy.-2, 2, 2-trichioroethoxycarbonyl; benzyloxy-carbonyl; 1- or 2-naphthylmethoxycarbonyl; 9-f luorenylmethoxycarbonyl; 4-amino- 25 piperidino-1-carbonyl; 4-aminomethyl-piperidino-l- ~:'.carbonyl; N-methyl- (morpholinocarbonyl) -Nmethylamino>-ethyl -aminocarbonyl, or N- (4-piperidino) -carbamoyl;

R

1 and R 5 together with the nitrogen atom carrying them, 30form an 8- to 12-membered bicyclic ring, which can be :aromatic, partly hydrogenated or completely hydrogenated; R 2 and Rr 6 independently of one another denote hydrogen or methyl; R 3 and R 5 independently of one another denote hydrogen, methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, 10 sec.-butyl, 3-guanidinopropyl, carbamoylmethyl, 2carbamoylethyl, carboxymethyl, 2-carboxyethyl, mercaptomethyl, 2- (methyithic) -ethyl, (1-mercapto-l-methyl) ethyl, hydroxymethyl, l-hydroxyethyl, aminomethyl, 2aminoethyl, 3-aminopropyl, 4-aminobutyl, N,N-dimethylamino, cyclohexylmethyl, imidazol-4-yl-methyll benzyl, 2-methyl-benzyl, 3-methylbenzyl, indol-3-yl-methyl, 4hydroxybenzyl, 4-methoxybenzyl, 3, 4-dihydroxybenzyl, 3, 4-dimethoxybenzyl, (benzodioxolan-5-yl )-methyl, 2thienyl, 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) methyl, (3-methyl-imnfdazol-4-yl)-methyl, phenyl, 1- 660:4,naphthylmethyl, 2-nalhthylmethyl, 2-phenylethyl, 2thiazolylmethyl, 4-thiazolylmethyl, 3-pyrazolylmethyl, 4-pyrimidinylmethyl, indol-2-yl-methyl, 2-benzo thienylmethyl, 3-benzo [b)thienylmethyl, 2-f urylmethyl, ?0 cyclohexyl or cyclopentyl; .0.1 R 4 denotes (C 3

-C

12 )-alkyl; mono- or bicyclic (C,-Cl 2 cycloalkyl or (C 3 -Cl 2 )-cycloalkylmethyl, in which the cycloalkyl part is optionally substituted by (Cl-C 4 alkyl; (C 6

-C

10 -aryl-methyl; dithiolanyl; dithiolanylmethyl; dithianyl or dithianylmethyl; 7 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 0' 30 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.

11 Compounds of the formula I which may furthermore be mentioned as particularly preferred are those in which

R

1 denotes hydrogen; (Ci-Cs)-alkylcarbonyl; (Ci-C 6 )-alkylsulfonyl; amino-(C 5 -cycloalkylcarbonyl; 4-aminopiperidino-l-carbonyl; 4-aminomethyl-piperidino-lcarbonyl or N-methyl-[2-<N-(morpholinocarbonyl)-Nmethylamino>-ethyl]-aminocarbonyl;

R

1 and R 5 together with the nitrogen ato.a carrying them, denote indolyl;

R

2

R

6 and 7 denote hydrogen;

R

3 denotes (Ci-C)-alkyl or imidazolyl-(Ci-C 4 )-alkyl;

R

4 denotes (C 5

-C

8 -cycloalkyl-(C-C 4 -alkyl;

R

5 denotes phenyl-(Ci-C 4 )-alkyl or thienyl-(Ci-C 4 )-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 corresponding fragment having a free amino group, if appropriate splitting off protective group(s) temporarily introdured to protect further functional groups and if appropriate converting the compound thus obtained into its physiologically tolerated salt.

25 Fragments of a compound of the formula I having a terminal carboxyl group have the following formulae VI and

VII

A- OH (VI) 2 3

R

2

R

3 I I A N- CH- C- OH (VII) 0 Fragments of a compound of the formula I having a terminal amino group have the following formulae VIII to X 12

R

6

R

5 0 R 2

R

3 0 R 4 I I II I I t I HN- CH C N CH C HN CH (CHOH) CH20H (VIII)

R

2

R

3

R

4

(IX)

I I 11 1 HN CH C HN CH (CHOH)n

R

(X)

H2N CH (CHOH)n Methods which are suitable for the production of an amide 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,2,3- S* 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 ith phosphonium reagents, such as benzotriazol-1-yl-oxytris-(dimethylamino)-phosphonium-hexafluorophosphate (BOP), or uronium reagents, such as 2-(1H-benzotriazoll-yl) 3,3-tetramethyluronium tetrafluoroborate (TBTU) or 2-(H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (for example Chem. Ber. 103 (1970) 5 788 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 a-amino acids, the chirality center thereof 13 being retained. Diazotization at -20 0 C to 50 0 C in dilute mineral acids leads to a-bromo carboxylic acids or, via lactic acid, to a-trifluoromethanesulfonyloxy carboxylic acids, which can be reacted with a nucleophile carrying R 1 and R 7 or c) formula IV are synthesized from the corresponding a-amino acids, the chirality center thereof being retained. Diazotization at -20 0 C to 50 0 C in dilute mineral acids leads to lactic acids, which can be reacted with an electrophile carrying R 1 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 15 carbohydrates by the corresponding protected 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 LiAlH 4 or catalytic hydro- *20 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 0.4 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 1,2dimethoxyethane, at a temperature between -30°C and the boiling point of the solvent, preferably between 0°C 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- 14 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 reacting 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 15 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, sodiam deficiency, 9- 25 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 "0 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 antihypertensive 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 15 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, UnterschleiBheim) 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 4°C, 15 minutes; repeated if necessary), "o the plasma is carefully pipetted off and frozen at 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 3 days).

16 3. Test procedure Angiotensin I is determined with a Renin-Maia® kit (Serono Diagnostics Coinsins, Switzerland). The plasma is incubated in accordance with the instructions given with the kit: Incubation batch: 1000 pl of plasma (thawed at 0-4 0

C)

100 pl of phosphate buffer (pH 7.4, addition of 10 4 M ramiprilat) pl PMSF solution 10 pl of 0.1% of Genapol PFIC 12 yi 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.

o* 0 S*.o The mixtures are mixed in ice and placed in a waterbath (37 0 C) for 1 hour for incubation. A total of 6 samples (in each case 100 pl) 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 inhibition is covered (at least five concentrations). At the end of the incubation period, three 100 pi samples from 0 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 Coinsins, Switzerland) are followed exactly.

The calibration plot includes the range from 0.2 to 25.0 rg 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 ICo 0 value is read off from the plot of residual activity against the concentration of the test preparation (logarithmic scale).

The compounds of the general formula I described in the present invention exhibit inhibitory actions at concentrations of about 10-5 to 10-10 mol/1 in the in vitro test.

In detail, the following values were determined: *006 0 00 90006 0* f 0So agog 9

G

25 0 Table 1: Example No.

1 2 3 4 ICso [M] human plasma renin 4.2 x 10 7 4.0 x 10 9 2.2 x 10-8 1.6 x 10 9 1.1 x 10 8 ICo 0

[M]

purified human renin 1.2 x 10 7 4.0 x 10- 9 1.2 x 10-8 2.4 x 10 9 1.4 x 10-8 2.2 x 10 7 1.8 x 10- 8 1.1 x 10 7 1.9 x 10-6 10' 6 3.0 x 10 7 1.2 x 10-8 5.0 x 10-8 3.6 x 10 6 1.0 x 10 s 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 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 administered intravenously about 30 minutes before the start of the experiment. Anasthesia was then induced with 20 mg/kg 2 of ketamine intramuscularly and continued with 40 mg/kg *.15 of pentobarbitone intravenously. A side arm of the get 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 Braunile 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 [%l 1 0.72 -1.16 3 8.21 -1.61 -11.53 -2.42 10 -11.82 -2.51 -12.68 -3.49 -13.48 -1.97 -16.43 -1.61 -62 19 -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 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 S15 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.

'120 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 5 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, 20 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 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: *Coo :000 .000 0 @0 b.

Ac Boc

BOP

25 BuLi

TLC

DCC

DCI

DIP

DNP

DME

DMF

DMSO

EA

El Etoc acetyl tert.-butoxycarbonyl benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium n-butyllithium thin layer chromatography dicyclohexylcarbodiimide desorption chemical ionization diisopropyl ether 2,4-dinitrophenyl 1,2-dimethoxyethane dimethylformamide dimethyl sulfoxide ethyl acetate electron impact ethoxycarbonyl 21

FAB

H

flep HOBt Iva

M

IMeOH

MS

MTB

NEM

Nva Nie

PPA

R. T.

15 .p.x

TBTU

fast atom bombardment hexane n-heptane 1-hydroxybenzotriazole isovaleryl molecular peak methanol mass spectrum methyl tert.-butyl ether N-ethylmorpho line norvaline norleucine N-propanephosphonic anhydride room temperature melting point boiling point at xx mm Hg 2- (lH-benzotriazol-l-yl) 3-tetramethyluronium 2 -thienylalanine tetrahydro furan benzyloxycarbonyl.

S S .5

S

S.

0@ *5* :20

S*

S S

S

Thi

THF

z List of abbreviations of selected C termini 0SOS

S

5

S.

S

.0 o4 cu 0) R O -manno-pentol -manno-pentol (XX)

S

*50 *5 S Se

S.

OH CH (L)-gulo-pentol (XX) ()-uopno (L)-gulo-pentol -22-

OOH

SOH OH 22 o 0 0 0 OH OH (D)-talo-pentol (XX) (D)-talo-pentol o ss O oCo OH OH (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.

0 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 aqueous trifluoroacetic acid and the mixture is stirred at R.T. for 2.5 hours. The solvents are removed in vacuo and chromatographed on silica gel using CHzCl 2 /MeOH 10:1. 140 mg of the title compound are obtained as a colorless amorphous powder.

S. 0 R, (CH 2 Cl 2 /MeOH 10:1) 0.06 MS (FAB LiI): 614 (M+Li) a) Iva-Phe-Nva-[(L)-gulo-pentol(XX)] 204 pl of pivaloyl chloride are added to 578 mg of Iva-Phe-Nva-OH, 229 Al of N-ethylpiperidine and 230 pl 23 of triethylamine, dissolved in 25 ml of anhydrous

CH

2 C1 2 at -15 0 The mixture is stirred at R.T. for minutes and cooled to -10°C and a solution of 599 mg of H-(L)-gulo-pentoi(XX) in 10 ml of anhydrous CH 2 C12 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 KH 2

PO

4 solution each time and three times with 50 ml of NaHCO 3 solution each time, the EA phase is dried over K 2 CO, 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.

R, (MTB/DIP 1:1) 0.10 MS(FAB): 688 (M+1) 15 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 and 1.1 g of HCO 2

NH

4 are added under argon. The mixture 0 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.

*S

R, (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 LiAlH 4 are added. The mixture is stirred at R.T. for 20 hours, 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 Na 2

SO

4 and the solvent is removed in vacuo. 690 mg of the title 24 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)- 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 pl of TiC14 are added at -20 0 C. The mixture is stirred at R.T. for 3 hours, 100 ml of saturated aqueous Na 2

CO

3 solution are added and the mixture is diluted with 300 ml of EA and washed with KHzPO 4 solution until pH 5 is reached. The organic phase is dried with Na 2

SO

4 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.

R, (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 5.16 g of (2,3-5,6-diisopropylidene)-L-gulonic acid ylactone 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 Na 2

SO

4 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.

25 R, (DIP) 0.40 MS (DCI): 357 (M+1) f) (2,3-5,6-Diisopropylidene)-L-gulonic acid y-lactone 42 g of L-gulonic acid y-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, 144"C.

Rf (DIP) 0.12 MS (DCI): 259 (M+l) Example 2 .0 0406: (2(S)-Benzyl-3-t-butylsulfonyl)propionyl-His-[(D)-mannopentol] 960 mg of (2(S)-benzyl-3-t-butylsulfonyl)propionyl-His- [(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 NaHCO 3 solution, the methanol is removed in vacuo, the residue is extrac- 20 ted three times with 100 ml of MTB and the extract is dried over Na 2

SO

4 The solvent is removed in vacuo and the *a.

residue is chromatographed on silica gel using acetone/ water 10:1. 120 mg of the title compound are obtained as white crystals.

*25 R, (acetone/water 10:1) 0.46 MS (FAB): 681 (M+1) m.p. 100 110C (decomposition) a) (2-(S)-Benzyl-3-t-butylsulfonyl)propionyl-His-[(D)manno-pentol(XX)] 850 mg of (2(S)-benzyl-3-t-butylsulfonyl)propionyl- 26 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+1) b) (2(S)-Benzyl-3-t-butylsulfonyl)propionyl-His(DNP)- [(D)-manno-pentol(XX)] 1.3 g of (2(S)-benzyl-3-t-butylsulfonyl)propionyl- His(DNP)-OH, 0.21 ml of N-ethylpiperidine and 0.31 ml of triethylamine are dissolved in 30 ml of CH 2 Cl 2 and 0.28 ml of.pivaloyl chloride are added dropwise at 15 0 C under argon. The mixture is stirred at RT for minutes and cooled to -10 0 C and a solution of 400 mg of H-(D)-manno-pentol(XX) in 5 ml of CH 2 Cl 2 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 KH 2

PO

4 and 100 ml of saturated NaHCO 3 solution. The extract is dried over Na 2

SO

4 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.

R (EA/MeOH 10:1) 0.53 MS (FAB): 927 (M+1) 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 27 RT for 5 hours, the organic solvents are removed in vacuo, the pH is brought to 1-2 with NaHSO 4 solution, the mixture is extracted three times with 500 ml of EA each time, the extract is dried over Na 2

SO

4 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/CH 2 Cl 2 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 Med. Chem. 31, 1839 (1988)) and 3.3 g of Nhydroxysuccinimide 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 0°C.

The mixture is left to stand at 6 0 C for 18 hours, the solvent is removed in vacuo at 20 0 C and the residue is taken up in 100 ml of acetonitrile. The urea is filtered off and the solvent is removed at 20 0 C in •o vacuo. 10.7 g of the title compound are obtained as a colorless oil which is reacted further without purifi- S* cation.

a '25 e) H-(D)-Manno-pentol(XX) The compound was prepared analogously to Example lb from N-benzyl-(D)-manno-pentol(XX).

a f) [N-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-dihydroxyethyl]-tetrahydrofuran and 7.1 ml of cyclohexylmethyl bromide are dissolved in 250 ml of THF and reacted 28 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 KH 2

PO

4 solution and the mixture is extracted three times with 300 ml of MTB.

The extract is dried over Na 2

SO

4 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+1) g) 2-Benzylamino-(3,4-isopropylidene)-3(S),4(S)-di- ,2-isopropylidene)(R)hydroxy-5(R- opllydroxyethyl]-tetrahydrofuran 31.5 g of 2,3-5,6-diisopropylidene-D-mannofuranoside 15 and 20.0 mi of benzylamine are heated in 250 ml of toluene using a water separator. After 7 hours, the a e* water separator is replaced by a Soxhlet extractor filled with molecular sieve 41 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 KH 2

PO

4 solution. The mixture is dried over NazSO 4 and the solvent is removed in vacuo. 41.5 g of the white crystalline title 25 compound are obtained.

R, (toluene/EA 2:1) 0.29 MS(DCI): 350 (M+1) 0 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 pl of triethylamine are dissolved in ml of DMF, 1.1 g of O-benzotriazol-l-yl-1,1,3, 29 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 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 Na 2

CO

3 solution. It is dried over Na 2

SO

4 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)] 3 g of Z-His-[(D)-manno-pentol(XX)] and 3 g of ammonium formate are dissolved in 50 ml of methanol, 2 g 15 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 Na 2

CO

3 solution. It is dried over Na 2

SO

4 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)] e** 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 pl of diphenylphosphoryl azide and then 208 pl of l-diethylamino-2-propanol are subsequently added at 0°C. 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 KH 2

PO

4 solution and 100 ml of saturated NaHCO 3 solution. It is dried over Na 2

SO

4 and chromatographed on silica gel using EA/MeOH 10:1.

530 mg of the title compound, colorless foam, are 30 obtained.

R, (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 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 6 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 Na 2

CO

3 solution. The organic phase is dried with NazSO 4 and the solvent is removed in vacuo. After drying under a fine vacuum to remove the diphenylmethane, 275 mg of the title compound of 0 *9 Example 2e) are obtained.

'015 m) N-Benzhydryl-(D)-manno-pentol(XX) S* 1.8 g of 2-benzhydrylamino-(3,4-isopropylidene)- 3(S),4(S)-dihydroxy-5(R)-[1,2-isopropylidene)-l(R)-2dihydroxyethyl]-tetrahydrofuran and 1.2 ml of cyclohexylmethyl bromide are dissolved in 40 ml of formal- 20 dehyde dimethyl acetal (distilled from K/Na alloy) and are reacted with 115 mg of lithium wire (3.2 mm e* 9 diameter, about 1% of Na) under argon in an ultrasonic bath at 20-40 0 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 0 C for Sanother hour. The reaction mixture is poured into 200 ml of NaHCO 3 solution and extracted three times with 100 ml of MTB. It is dried over Na 2

SO

4 the solvent is removed in vacuo and the residue is chromatographed 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 31 n) 2-Benzhydrylamino-(3,4-isopropylidene)-3(S),4(S)dihydroxy-5(R)-[1,2-isopropylidene-1(R)-2-dihydroxyethyl]-tetrahydrofuran g of D(+)-mannose and about 10 mg of p-toluenesulfonic acid are suspended in 40 ml of 2,2-dimethoxypropane and the suspension is stirred at 40 0 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 2,2dimethoxypropane 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 NaHCO 3 5 solution. It is dried over Na 2

SO

4 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 0

C.

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

S Example 3 cis-4-Aminocyclohexylcarbonyl-Phe-His-[(D)-manno-pentol] 25 180mg of (N-tert.-butoxycarbonyl-cis-4-amino-cyclohexyl- *I carbonyl)-Phe-His-[(D)-manno-pentol(XX)] are dissolved in ml of CH 2 Cl 2 and 5 ml of trifluoroacetic acid are added at OOC. The mixture is stirred at RT for 24 hours, 100 ml of saturated Na 2

CO

3 solution are added and the mixture is extracted 3 times with 100 ml of EA. The extract is dried over Na 2

SO

4 the solvent is removed in vacuo and the residue is chromatographed on silica gel using acetone/

H

2 0/concentrated NH 3 100:10:5. 24 mg of the title compound 32 are obtained as a colorless powder.

(acetone /H 2 0/concentrated NH 3 100:10:5) 0.12 MS(FAB): 687 (M+1) a) (N-tert Butoxycarbonyl-cis-4-aminocyclohexylcarbonyl) -Phe-His- -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- -mannopentol(XX).

Rf (EA/MeOH 5:1) 0.43 MS(FAB): 868 (14+1) e40.6 06 b) (N-tert. -Butoxycarbonyl-cis-4-aminocyclohexylcarb- *ses:onyl) -Phe-His (DNP) -OH The title compound is prepared analogously to Example 2d) from (N-tert butoxycarbonyl-cis-4-amino- (EA/MeOH 3:1) 0.20 MS(FAB): 694 (M4+1) so c) N- (N-tert. -Butoxycarbonyl-cis-4-aminocyclohexylcarbonyl) -L-phenylalanine *0 5.5 g of N- (N-tert butoxycarbonyl-cis-4-aminocyclohexylcarbonyl)-L-phenylalanine .jenzyl ester are 0:90hydrogenated in 230 ml of ethanol over 1. g of Pd/char- 0060 coal under normal pressure. When the reaction had S. 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 0 C (decomposition) MS(DCI): 391 (M+1) 33 d) N- (N-tert. -Butoxycarbonyl-cis-4-aminocyclohexylcarbonyl) -L-phenylalanine benzyl ester 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 the solution was mixed with 24 ml of n-PPA and 15.7 ml of NEX at 0 0 C and the mixture is reacted overnight at RT.

The solution is diluted with CH 2 Cl., washed in each case with semi-saturated NaHCO, solution, 10% strength citric acid and water, dried over MgSO 4 and concentrated in vacuo. Flash chromatography gave 5.7 g of pure product.

-14.60 (c 1.1 in CH 3

OH)

Example 4 J-I5 2(S) -{N-Methyl-N-<2-[N-(morpholinocarbonyl) -N-methylamino] -ethyl>-aiminocarbonyloxy}-3-phenylpropionyl-Hisg~e 5 Imannopentol] The title compound is prepared analogously to Example 2a), 2b), 2c) and 2d) from 2(S)-{N-methyl-N-<2-[N- (morpholinocarbonyl) -N-methylamino 3ethyl>-aminocarbonyloxy]-3 -phenylpropionic acid.

R. (EA/MeOH 1: 1) 0. 22 MS(FAB): 790 (IM+l) a) 2(S) -{N-methyl-N-<2- (morpholinocarbonyl) -N-methylamino ]ethyl>-aminocarbonyloxy] -3-phenylpropionic acid 840 g of ethyl 2(S)-{N-methyl-N-<2-[N-(morpholinocarbonyl) -N-methylamino 3ethyl>-aminocarbonyloxy] -3-phenylpropionate are dissolved in 100 ml of methanol, and 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 34 drying with Na 2

SO

4 and concentration, the title compound which is used for the next reaction without further purification.

MS (DCI): 394 (M+1) b) Ethyl 2(S)-{N-methyl-N-<2-[N-(morpholinocarbonyl)-Nmethylamino]ethyl>-aminocarbonyloxy}-3-phenylpropionate 0.9 g of ethyl phenyllactate in CH 2 Cl 2 (10 ml) are added dropwise to 2 g of di(4-benzotriazolyl) carbonate and 0.23 ml of pyridine in CH 2 Cl 2 (20 ml) at RT.

After 6 hours, 900 mg of N-methyl-N-2-[N-(morpholinocarbonyl)-N-methylamino]-ethylamine in 10 ml of CH 2 Cl 2 are added dropwise. After 16 hours, 100 ml of ethyl acetate are added, and the mixture is then washed twice with saturated Na 2 CO, solution, twice with saturated NaHSO 4 and once with saturated NaCI solution.

After drying with Na 2

SO

4 and concentration, a yellow oil is obtained which, after chromatography on SiO 2 (eluent EA), gives the title compound.

Rf (EA) 0.3 MS (DCI): 422 (M+l)

S**

c) N-Methyl-N-2-[N-(morpholinocarbonyl)-N-methylamino]ethylamine 0 2.1 g of Boc-N-methyl-N-2-[N-(morpholinocarbonyl)-Nmethylamino]ethylamine are stirred in 75 ml of a ~6N solution of HC1 in DME at RT for 3 hours. After a concentration, 50 ml of saturated NaCO 3 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 35 The title compound is obtained analogously to Example 4b) from 2.1 g of morpholine, 10 g of di-(l-benzotriazolyl)carbonate, 2 ml of pyridine and 4.7 g of Boc- N-methyl-2- (methylamino )ethylaniine.

Rf (EA) 0 25 MS (DCI): 302 (M+1) e) Boc-N-methyl-2- (methylamino)ethylamine 12.5 g of di-t-butyl dicarbonate in 25 ml of CH 2 Cl 2 are added dropwise to 100 g of N,N'-dimethylethylenediamine at 5 0 C. After 4 hours at RT, the excess diamine is distilled of f. The residue is taken up in EA (100 ml) and the mixture is washed with saturated 040:0,6Na 2

CO

3 solution and saturated NaCI solution. Drying so with Na 2

SO

4 and concentration gives the title compound, which is used in the crude for, o uterratos MS (DCI): '189 (M+1) of see aExample 3- (4-Amino-1-piperidinyl-carbonyl -ben zylpropiony1- His- -manno-pentol] GO a The title compound is prepared analogously to Example 3 020 from 3- (tert. -butoxycarbonyl) amino-1-piperidinylcarbonyl]-2 (R)-benzylpropionic acid.

aR1% (acetone /H 2 0/ concentrated NH 3 100:10:5) 0.15 MS (FAB): 687 (M+1) a) 3-[F4- (tert Butoxycarbonyl )amino-1-piperidinyl-carbonyl]-2 (R)-benzylpropionic acid 1.3 g of benzyl 3- 4- (tert. -butoxycarbonyl) amino- 1piperidinyl-carbonyl]-2 -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 36 solvent in vacuo, the title compound crystallizes >ut of cold diethyl ether.

135 136°C R, (CH 2 C12/MeOH 9:1) 0.30 MS (DCI): 391 (M+1) b) Benzyl 3-[4-(tert.-butoxycarbonyl)amino-l-piperidinylcarbonyl]-2(R)-benzylpropionate g of ben z 1 2(R)-(carboxymethyl)-3-phenyl-propionate ed. Chem. 31 2277 (1988)) are stirred in ml of CHzC1 2 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 CH 2 C12, 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 CH 2 Cl 2 are 15 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 HCI and saturated NaHCO 3 solution. The mixture is dried over MgSO 4 and the solvent is removed in vacuo to give 1.3 g of the title compound as a colorless oil.

S.

R (CH 2 C1 2 /MeOH 9:1) 0.50 MS (DCI): 479 (M+H) c) 4-(tert.-Butoxycarbonyl)amino-piperidine 10.0 g of l-benzyl-4-[(tert.-butoxycarbonyl)amino]- 25 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 NaHCO 3 solution and saturated NaC1 solution and dried over MgSO 4 and the solvent is removed in 37 vacuo. The residue is recrystallized from EA to give g of the title compound as white crystals.

159 161 0

C

Rf (CH 2 Cl 2 /MeOH 9:1) 0.11 MS (DCI): 201 (M+1) d) 1-Benzyl-4- [(tert. -butoxycarbonyl )amino] -piperidine 10.0 g of 4-amino-N-benzylpiperidine are dissolved in 100 ml of CH 2 Cl 2 11.5 g of di-tert.-butyldicarbonate are added and the solution is stirred at RT f or 2 hours and lef t to stand overnight. The solvent is removed in vacuc and the residue is recrystallized from EA. 12.9 g of the title compound are obtained as white crystals.

123*C

(CH

2 Cl,/MeOH 8:1) =0.23 MS (DCI): 291 (MI-i) Example 6 2(S) -(4-Amino-1-piperidinocarbonyloxy) -3-phenylpropionyl- His- -manno-pentol] of..

The title compound is prepared analogously to Example .3 000.1, from 2(S) (tert butoxycarbonyl) amino-1-piperidinocar- 0 bonyloxy] -3-phenylpropionic acid.

Rf (acetone /H 2 0 /concentrated NH, 100:10:5) 0.15 MS (FAB): 689 (MI-i) woof of' a) 2(S) (tert. -Butoxycarbonyl )amino-l-piperidinocarbonyloxy] -3-phenylpropionic acid 1.8 g of ethyl (2 -[4-(tert. -butoxycarbonyl) amino- 1-piperidinocarbonyloxy] -3-phenylpropionate and 5. 1 ml of 1N 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 H 2 01 the ethanol is removed in 38 vacuo and the pH is brought to 1 2 with NaHSO 4 solution. The mixture is extracted three times with 100 ml of EA, the extract is dried over NazSO, and the solvent is removed in vacuo. The title compound, which crystallizes from ether/n-heptane, is obtained, 1.0 g of white crystals.

100 101°C Rf (CH 2 Cl 2 /MeOH) 0.29 MS (DCI): 393 (M+1) b) Ethyl 2(S)-[4-(tert.-butoxycarbonyl)amino-l-piperidinocarbonyloxy]-3-phenylpropionate 825 mg of ethyl phenyllactate and 1.8 g of di-(lbenzotriazolyl)carbonate are dissolved in 40 ml of CH 2 C1 2 386 pj of ethyl diisopropylamine are added and the mixture is stirred at RT for 18 hours. 850 mg 15 of 4-(tert.-butoxycarbonyl)aminopiperidine (Example S0.* dissolved in 10 ml of CH 2 C1 2 are then added Op dropwise and a further 386 pl 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 Na 2

CO

3 solution and ease 100 ml of NaHSO 4 solution and dried over Na 2

SO

4 and the solvent is removed in vacuo. 1.8 g of the title compound are obtained as a colorless oil which is '25 employed further without purification.

Rf (Hep/EA 2:1) 0.2 MS (DCI): 421 (M+1) Example 7 2(S) (4-Aminomethyl-l-piperidinocarbonyloxy) -3-phenylpropionyl-His-[(D)-manno-pentol] The title compound is synthesized analogously to Example 39 R, (acetone/H 2 0/concentrated NH 3 100:10:5) 0.15 MS (FAB): 703 (M+l) Example 8 (3-t-Butoxysulfonyl-2-thienylmethyl)propionyl-His-[(D)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 solution is cooled to 0°C. 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 H 2 0 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 S. solution is washed with 10% strength NaHC 3 O 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 CH 2 Cl 2

/CH

3 OH 20:1.

The product of Rf 0.5 (CH 2 Cl 2

/CH

3 OH 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 CH, 2

C

2 (absolute) and the solution was stirred at RT with 0.2 ml of thiophenol 40 for 4 hou After the solvent has been filtered off in vacuo, the crude mixture is chromatographed on silica gel using CH 2 Cl 2 /CHOH 20:1. 16 mg of the title compound are obtained.

MS (FAB): 621 (M+1) Rf (CH 2 C1 2 /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 HC1/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 15 toluene (absolute). This oil thus obtained is immediately employed as a solution in DMF in the subsequent *4 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 0*00 *0 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 HC1, 10% strength Na 2

SO

4 dried and concentrated in vacuo.

An amorphous solid of 140 mg remains.

MS (DCI): 318 (M+l) 41 c) 4S-tert-Butoxycarbonylamino-5-cyclohexyl-cis-2pentenol 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 -78"C. 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 CH 2 C1 2 the solution is shaken in each case once with 10% strength K Na tartrate solution, strength citric acid solution and saturated NaCl solution. The solution is dried over MgSO 4 and concentrated 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 20 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).

R, (CH 2

C'

2 /MeOH) 0.06 MS (FAB LiI): 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] R, (CHzCHz:MeOH:concentrated aqueous NH 3 50:10:1) 0.10 MS (FAB): 558 (M+1) 42 Example 12 2(S) -Hydroxy-3-phenylpropionyl-His- -manno-pentol] RfE (acetone/H 2 0 10:1) =0.25 MS (FAB): 563 (M+1) *as*

G**C

a so

Claims (6)

1. A compound of the formula I R

2 R

3 R I I I 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 6 R 5 0 R CHCH- C- 0 R 5 0 R CH C IV alkyl, (C 8 -tricycloalkyl, C 3 -C cycloalkyl- (Cl-C 6 -alkyl, (C 4 -C 10 -bicyclo 1- (C 1 -C, 6 -alkyl, (C.-C 12 -tricycloalkyl- C 1 -C 6 alkyl, (C 3 -CO)-cycloalkyl-carbony o, (C 3 8 cycloalkylsulfonyl, in which the /ycloalkyl, 00y c each case *can be substitute by one or two *identical or different radic s from the series comprising F, Cl, Br, I hydroxyl, (Cl-Cr) alkoxy, (Cl-C 6 -alkyl, carboxyl, (C 1 -C 6 alkoxycarbonyl, car oyl, carboxymethoxy, amino, (Cl-C 6 -noalkylamino, (C 1 -C 6 dialkylamino, ino- (Cl-C 6 -alkyl, (C 1 -C 6 alkylamino- (C 1 6) -alkyl, di- -alkylamino- (Cl-C 6 -alky amidino, hydroxyamino, hydroximin hydrazono, imino, guanidino, (C 1 C 6 )-alko sulfonyl, (Cj-Cr,) -alkoxysulf enyl, trif 1 omethyl, (C,-C 4 -alkoxycarbonylamino and (C 6 12) -aryl- (Cl-C 4 -alkox'trc arbonyl -amino; Pig di bl dithianylmethyl; R7 denotes hydrogen or methyl, or tog er with R 1 or R9 and the atoms carrying the forms a mono- or bicyclic saturated or par unsaturated ring system having 5 12 .g members which, in addition to carbon, n also contain 1 sulfuc atom, which is o onally oxidized to sulfoxide or sulfone; ,00:00ound of the formula I as claimed in either of R denotes hydrogen, (Cl-C 8 )-alkylsulfonyl; (Cl-Ca)- **alkylsulfinyl; 2-hydroxy-ethylsulfonyl; 2- hydroxy-propylsulfonyl; 2-hydroxypropionyl; 3- *hydroxy propionyL; 3-hydroxybutyryl; 2-hydroxy-3- methylbutyryl; (C,-C 8 -alkanoyloxy- (Cl-C 10 -alkyl; n-decanoyl; formyl; acetyl; propionyl; pivaloyl; isovaleryl; isobutyryl; (3 -amino- 3, 3 -dimethyl) ~0eepropionyl; 4-aminobutyryl; 5-aminopentanoyl; 6- aminohexanoyl; dimethylaminoacetyl; piperidino-

4-carbonyl; morpholino-4-carbonyl; cyclopropyl- carbonyl; cyclobutylcarbonyl; cyclopentylear- 0 seebonyl; cyclohexylcarbonyl; 3-aminocyclobutylcar- bonyl; 4-aminocyclohexylcarbonyl; 3-aminocyclo- butylsulf onyl; 4-aminocyclohexylsulf onyl; phenyl- .:acetyl; phenyipropanoyl; phenylbutanoyl; 2- pyriyl-Cl-C,) -alkanoyl; 3-pyridyl- (Cl-C 8 -alka- noyl; 4 -pyridyl- -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; B RA4/2,2, 2-trichioroethoxycarbonyl; 1, 1-dimethyl- 2,2,2-trichioroethoxycarbonyl; benzyloxy-carbonyl; 1- or 2-naphthylmethoxy- carbonyl; 9-f luorenylmethoxycarbonyl; 4-amino- piperidino-l-carbonyl; 4-aminomethyl-piperidino- 1-carbonyl; N-methyl- (morpholinocarbonyl) N-methylamino>-ethyl 3-aminocarbonyl; or N- (4- piperidino) -carbamoyl; R' and together with the nitrogen atom carrying them, form an 8- to 12-mexubered bicyclic ring which can be aromatic, partly hydrogenated or completely hydrogenated; R 2 and R 6 independently of one another denote particu- larly hydrogen or methyl; 3* R and R 5 independently of one another denote hydrogen, methyl, ethyl, isopropyl, n-propyl, n-butyl, iso- V, butyl, sec. -butyl, 3-guanidinopropyl, carbamoyl- methyl, 2-carbamoylethyl, carboxymethyl, 2- carboxyethyl, mercaptomethyl, 2- (methylthio) ethyl, (1-mercapto--methyl)y, hydroxy- methyl, l-hydroxyethyl, aminomethyl, 2-amino- ethyl, 3-aminopropyl, 4-aininobutyl, N, N-dimethyl- benzyl, 2-methyl-benzyl, 3-methylbenzyl, indol- 3-yl-methyl,. 4-hydroxybenzyl, 4-methoxybenzyl, 3, 4-dihydroxybenzyl, 3, 4-dimethoxybenzyl, -methyl, 2-thienyl, 2-thi- enylmethyl, 2- (2-thienyl) -ethyl, 3-thienyl, 3- thienylmethyl, 2- (3-thienyl) -ethyl, 4-chloro- S 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, 1-naphthylmethyl, 2-naphthyl- methyl, 2-phenylethyl, 2-thiazolylmethyl, 4- r4, kAl) thiazolylmethyl, 3-pyrazolylmethyl, 4-pyrimid- inylmethyl, indol-2-yl-methyl, 2-benzo[b]thienyl- w methyl, 3-benzo[b]thienylmethyl, 2-furylmethyl, cyclohexyl or cyclopentyl; R 4 denotes (C 3 -C 12 )-alkyl; mono- or bicyclic (C 3 -C 12 cycloalkyl or (C,-C 2 )-cycloalkylmethyl, in which the cycloalkyl part is optionally substituted by (Cl-C 4 )-alkyl; (CB-Co) -aryl-methyl; dithiolanyl; dithiolanylmethyl; dithianyl or dithianylmethyl; R 7 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 R 5 and the atoms carrying these forms a thiochromane system, the sulfur atom of 0 which is particularly preferably oxidized to sulfone, and *a. 0 n denotes 3 6. SA compound of the formula I as claimed in any vne=a clai.- 1 t in which **ae a* R 1 denotes hydrogen; -alkylcarbonyl; (Ci-C) 4000 alkylsulfonyl; amino- (C 5 -cycloalkylcarbonyl; 4- aminopiperidino-1-carbonyl; 4-aminomethyl-piperi- i o dino-l-carbonyl or N-methyl-[2-<N-(morpholino- carbonyl)-N-methylamino>-ethyl]-aminocarbonyl; R and R 5 together with the nitrogen atom carrying 0*.0 them, denote indolyl; 0 R R 6 and R 7 denote hydrogen; R 3 denotes (Cl-Cr)-alkyl; or imidazolyl-(C-C 4 )-alkyl; R 4 denotes (C 5 -cycloalkyl-(Cl-C 4 )-alkyl; R 5 denotes phenyl- (C 1 -C 4 -alkyl or thienyl- (C,-C 4 -alkyl; and n denotes 2-4. 3 SA process for the preparation of a compound of the formula as claimed in any one of claims 1 to J47 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 protective group(s) temporarily introduced to protect further functional groups and if appropriate converting the compound thus obtained into its physiologically tolerated salt. 4. The use of a compound as claimed in any one of claims 1 to 2 as a medicine in the treatment of high blood pressure and congestive cardiac insufficiency.

A pharmaceutical formulation containing a compound as claimed in any one of claims 1 to 2 in adjunct with pharmaceutically acceptable carriers and excipients. *0

6. A process for the preparation of a formulation as claimed in claim 5, which S• comprises bringing the active compound into a suitable administration form together with a physiologically acceptable excipient and if appropriate other s additives, auxiliaries and/or preservatives. S. S• DATED this 4th day of May 1993 HOECHST AKTIENGESELLSCHAFT SS••• WATERMARK PATENT TRADEMARK ATTORNEYS THE ATRIUM 290 BURWOOD ROAD S HAWTHORN VICTORIA 3122 AUSTRALIA