NZ231578A

NZ231578A - Acylamino boronic acid derivatives; medicaments

Info

Publication number: NZ231578A
Application number: NZ231578A
Authority: NZ
Inventors: Heinz-Werner Kleemann; Hansjorg Urbach; Dieter Ruppert; Bernward Scholkens
Original assignee: Hoechst Ag
Priority date: 1988-12-01
Filing date: 1989-11-29
Publication date: 1992-02-25
Also published as: FI895718A0; EP0371467A2; KR900009663A; AU616819B2; IL92497A0; PH26584A; PT92442A; NO894790D0; DK605489A; NO894790L; CA2004303A1; DE3840452A1; EP0371467A3; AU4566589A; JPH02193997A; DK605489D0; ZA899152B

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £31 573 231 578 N.Z. No NEW ZEALAND Patents Act 19S3 COMPLETE SPECIFICATION -AMINO-BORONIC ACID DERIVATIVES 7 HOECHST AKTIENGESELISCHAFT, a corporation organized under the laws of the Federal Republic of Germany, of 0-6230 Frankfurt am Main 80, Federal Republic of Germany do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement - 1 - (Followed by 1A) 231578 - 1A - IieHCHBl Description /9-Amino-boronic acid derivatives The invention relates to compounds of the formula I R2 R3 R4 1 • c A - N - CH - CO - NH - CH - <pH - R5 B /\ OR6 OR7 in which A denotes a radical of the formula II, III or IV R9 R8 0 R1 - N - CH - C - <"> 10 R i - CH R8 i - CH O - C - (III) ,11 0 It - (CH2)n - CH - C - (IV) (CH2)m *12 in which R1 ax) denotes hydrogen, (C1-C12)-alkyl, which is optionally mono- or diunsaturated and is optionally substituted by up to 3 identical or different radicals from the series comprising hydroxyl, (Ci-CyJ-alkoxy, carbamoyl, (Cx-CB)-alkanoyloxy, carboxyl, (Ci-Cy)-alkoxycarbonyl, F, CI, Br, I, amino, amidino, which can optionally be substituted by one, two or three (C^CgJ-alkyl radicals, 2 231578 guanidino, which can optionally be substituted by one, two, three or four (C^-Cg)-alkyl radicals, (Ci-Cy)-alkylamino, di- (Cx-C7) -alkylamino, (Ci-Cs)-alkoxycarbonylamino, (C7-C15) -aralkoxycarbonyl-amino and 9-fluorenylmethoxycarbonylamino; mono-, bi- or tricyclic (C3-C18)-cycloalkyl, (C3-C18)-cycloalkyl-(Ci-C6) -alkyl or (C6-C14)-aryl, the cycloalkyl part optionally being substituted by (Cx—Cg) —alkyl and aryl optionally being substituted by one or two identical or different radicals from the series comprising F, CI, Br, 1, hydroxyl, (Cx-C7)-alkoxy, (Cx-Cy)-alkyl, (Cx-C7)-alkoxycarbonyl, amino and trifluoromethyl; (C6-C14)-aryl-(Cx-Cg)-alley 1, in which the aryl part is optionally substituted by one or two identical or different radicals from the series comprising F, CI, Br, I, hydroxyl, (Cx-C7)-alkoxy, (Cx-C7)-alkyl, (C1-C7)-alkoxycarbonyl, amino, (Cx-C7)-alkylamino, di- (Cx-C7) -alkylamino, carboxyl, carboxymethoxy, amino- (Cx-C7)-alkyl, (Ci-C7)-alkylamino- (Cx-C7) -alkyl, -di- (C1-C7) -alkyl ami no -(Cj-Cy)-alJcyl, (Ci-CyJ-alkoxycarbonylmethoxy, carbamoyl, sulfamoyl, (Cx-C^-alkoxysulfonyl and sulfo- and guanidino-(Cx-Cg)-alkyl? or represents the radical of a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic partly or completely hydrogenated heteroaromatic having at least 1 carbon atom, 1-4 nitrogen atoms and/or 1 or 2 sulfur atoms and/or 1 or 2 oxygen atoms as ring members and which is optionally mono-, di- or trisubstituted like the (C6-C14)-aryl defined represents -CO-, -0-C0-, -S02-; -SO-, -NH-S -NH-CO-, -CH(OH)- or -N(OH)-; denotes a radical of the form R1' - W in which R1' (V) is defined as .3 - 231578 ( J R denotes hydrogen or (Cj-Ca)-alkyl, or, together with R3 and the atoms carrying these, forms a mono- or bicyclic, saturated or partly unsaturated ring system having 5-12 ring members; 5 R3 and R8 independently of one another are defined as R1 under a,), or denote O mercapto, methylthio, heteroarylalkyl, amino, or dimethylamino, or, together with R2 or with R9 and the atoms carrying these, form ring systems having 5-12 ring members, as defined above; —>10 Ra denotes (Ca-C^)-alkyl, mono-, bi- or tricyclic (C3-C18)-cycloalkyl, (C3-C18)-cycloalkylmethyl or (C3-C18) -cycloalkylethyl, the cycloalkyl part optionally being substituted by (Cx-C6)-alkyl; dithiolanyl; (C6-C14)-arylmethyl; dithiolanylmethyl; dithiolanyl-15 ethyl; dithianyl; dithianylmethyl or dithianylethyl; R5 denotes hydrogen; azido; azido- (C^-C,,) -alkyl; (ci~ci2)-alkyl, which can optionally be substituted by hydroxyl, azido or hydroxyl and azido; (C3-Cu)-cycloalkyl; (C3-C12) -cycloalkyl-(Cx-C6)-alkyl; 20 (C3-C12)-cycloal3cylsulfonyl-(C1-C6)-alJcyl; (C^Ca)- alkylsulfonyl-tCt-Cg)-alkyl; (C6-C14)-aryl or (C6-C14)-aryl-fCi-Cg)-alkyl, it also being possible for aryl to represent the radical of a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic hetero-25 aromatic having at least carbon atom, 1-4 nitrogen atoms and/or 1 or 2 sulfur atoms and/or 1 or 2 oxygen atoms as ring members and which can also be partly or completely hydrogenated, and it is likewise possible that aryl and heteroaryl canr be 30 substituted as defined under ax), < £w ;• / ((n R6 and R7 independently of one another denote hydrogen Qg. (Ci-Cs)-alkyl; or, \ *6jANI992 A together with the boron atom and the oxygen adorns, , v form a mono-, bi- or tricyclic, saturated or partly 35 unsaturated, mono-, di-, tri- or tetra-fCj-Cg)- O 23 1578 alkylated or -phenylated ring system having 5-18 ring members, which, in addition to the boron atom, the oxygen atoms and the carbon atom(s), can also contain an -0- member, an -NR13- member or a -CR14R15-member; represents hydrogen or (Cj-Ce)-alkyl, or, together with R8 and the atoms carrying these, forms a mono-or bicyclic, saturated or partly unsaturated ring system having 5-12 ring members; is hydrogen or (C^Ce)-alkyl, or, together with R1 or Rb 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 the carbon atom, can also contain 1 sulfur atom, which can optionally be oxidized to the sulfoxide or sulfone; and R12 independently of one another denote hydrogen, hydroxyl or (C6-Cw) -aryl, aryl optionally being substituted by one or two identical or different radicals from the series comprising F, CI, Br, I, hydroxyl, (Cj-C^-alkoxy, (Ci-C7)-alkyl, (Cx-C7)-alkoxycarbonyl, amino, (Cj-C,) -alkylamino, di-(C!-C7)-alkylamino, carboxyl, carboxymethoxy, amino- (Ci-C7) -alkyl, (Cj-Cy)-alkylamino-(Ci-Cj)-alkyl, di-(C!-C7)-alkylamino- (Cx-C7) -alkyl, (C ,.-C7) -alkoxycarbonyl-methoxy, carbamoyl, sulfamoyl, (C1-C7)-alkoxysulfonyl and sulfo- and guanidino- (C^Cg) -alkyl; or represent the radical of a 5- or 6-membered monocyclic or 9-or 10-membered bicyclic, optionally partly or completely hydrogenated heteroaromatic having at least 1 carbon atom, 1-4 nitrogen atoms and/or 1 or 2 sulfur atoms and/or 1 or 2 oxygen atoms as ring members and which is optionally mono- or disubsti-tuted like (C6-C14)-aryl above, n and m independently of one another can be 0, 1, 2, 231578 - 5 - 3 or 4, R13 denotes hydrogen or (Ci-C^)-alkyl, which is optionally mono- or diunsaturated and is optionally substituted by up to 3 identical or different 5 radicals from the series comprising hydroxyl, (Cx-CyJ-alkoxy, amino and mono- or di-(Cx-C7)-alkylamino , and R1* and R1S independently of one another denote hydrogen, (Ci-Ce)-alkyl, hydroxymethyl, 2-hydroxyethyl, (3-10 hydroxysulfonyl, 2-hydroxypropyl)amino, (2-hydroxy- sul f onylethyl) amino, (2-hydroxysulfonylpropyl) amino, (carboxymethyl)amino or bis (2-hydroxyethyl)amino, and physiologically tolerated salts thereof. A radical of a 5- or 6-membered monocyclic or 9- or 10-15 membered bicyclic heteroaromatic having at least 1 carbon atom, 1-4 nitrogen atoms and/or 1 or 2 sulfur atoms and/or 1 or 2 oxygen atoms as ring members is understood as meaning radicals of heteroaromatics such as are defined, for example, in Katritzky and Lagowski, Chemie 20 der Heterocyclen [Chemistry of the Heterocyclics], Berlin, Heidelberg 1968. The heteroaromatic radical can be substituted by one, two or three, preferably one or two, identical or different radicals from the series comprising F, CI, Br, I, hydroxyl, (C1-C7)-alkoxy, (Cx-25 C7)-alkyl, (C1-C7)-alkoxycarbonyl, amino and trifluoro-methyl. Examples of monocyclic heteroaromatics are Q thiophene, furan, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-triazole, thia-zole, tetrazole, isothiazole, oxazole and isoxazole. 30 Examples of bicyclic heteroaromatics are benzothiophene, benzofuran, indole, isoindole, indazole, benzimidazole, quinoline, isoquinoline, phthalazine, quinoxaline, quinazoline and cinnoline. Corresponding statements apply to radicals derived from heteroaryl, such as, for 35 example, completely or partly hydrogenated heteroaryl, inter alia also, for example, benzodioxolane, hetero- O 231578 aryloxy, heteroarylthio and heteroaryl-alkyl. Alkyl can be straight-chain or branched. The corresponding statement applies to radicals derived therefrom, such as, for example, alkoxy, alkylthio, alkylamino, dialkyl-5 amino, alkylsulfinyl, alkylsulfonyl, alkanoyl or aralkyl. (C6-Cu) -Aryl is, for example, phenyl, naphthyl, bi-phenylyl or fluorenyl; phenyl and naphthyl are preferred. Corresponding statements apply to radicals derived therefrom, such as, for example, aryloxy, aroyl, aralkyl 10 and aralkyloxy. Aralkyl is understood as meaning an unsubstituted or substituted (C6-C14)-aryl radical linked to (Cx-C6)-alkyl, such as, for example, benzyl, 1- and 2-naphthylmethy 1, halobenzyl and alkoxybenzyl, but aralkyl would not be limited to the radicals mentioned. 15 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 car-20 boxyl, 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 -hydroxy-et hy 1) -amine. Compounds of the formula I which contain basic groups, 25 for example an amino group or a guanidino group, form salts with inorganic acids, such as, for example, hydrochloric acid, sulfuric acid or phosphoric acid, and with organic carboxylic or sulfonic acids, such as, for example, acetic acid, citric acid, benzoic acid, maleic 30 acid, fumaric acid, tartaric acid and p-toluenesulfonic acid. Compounds of the formula I in which the radicals are defined as follows are preferred: 7 - 231578 is as defined on page 1, preferably denotes hydrogen or represents (Cx-C10)-alkyl; cyclopentyl; cyclohexyl; cyclopentyl-(C1-C10)-alkyl; cyclohexyl-(Ci-C10)-alkyl; optionally substituted phenyl-(Ci-Cg)-alkyl; 2-pyridyl-(C1-CB)-alkyl; 3-pyridyl-(Ci-Ca)-alkyl; 4-pyridyl-(Ci-Ce)-alkyl; H2N-(Ci-Cxo) -alkyl; HO- ( Cj-Cjq ) -alkyl; (Cj-C^) -alkoxy-(ci~cio) -alkyl; (Cx-C4) -alkoxycarbonyl- (Cx-Cxo) -alkyl; (Cx-C8)-alkylsulfonyl; (Cx-C8) -alkylsulf inyl; (Cx-C8)-hydroxyalkylsul fonyl; (Cx-C8) -hydroxy-alkylsulfinyl; hydroxy-(Cj-Cxo)-alkanoyl, such as 2-hydroxypropio-nylf 3-hydroxypropionyl, 3-hydroxybutyryl or 2-hydroxy-3-methyl-butyryl; (Cx-C8) -alkanoyloxy- (Cx-C10)-alkyl; (Cx-Cn)-alkanoyl, such as n-decanoyl, formyl, acetyl, propionyl, pivaloyl, isovaleryl or isobutyryl; optionally protected amino-(Cj-Cxx)-alkanoyl, such as (3-amino-3,3-dimethyl)propionyl, 4 -aminobutyry 1, 5 -aminopentanoyl, 6 -aminohexanoyl, 4-N-tert.-butoxycarbonylaminobutyryl, 5-N-tert.-butoxycarbonylaminopentanoyl or 6-N-tert. -butoxy-carbonylaminohexanoyl; di - (Cx-C7) -alkylamino- (C2-Cn)-alkanoyl, such as dimethylaminoacetyl; piperi-dino-4-carbonyl; morpholino-4-carbonyl; (C3-C9)-cycloalkylcarbonyl, such as cyclopropylcarbonyl, cyclobutylcarbonyl, eyelopentylcarbony 1 or cyclo-hexylcarbonyl; (C6-Cl0) -aryl- (C2-Cu) -alkanoyl, such as phenylacetyl, phenylpropanoyl or phenylbutanoyl; 2-pyridyl- (Cx-C8) -alkanoyl; 3-pyridyl- (Cx-Ce) -alkanoyl; 4-pyridyl-(Cx-C8)-alkanoyl; benzoyl which is optionally substituted by halogen, (Cx-C7)-alkyl, (Cx-C7)-alkoxy or (Cx-C7)-alkoxycarbonyl, such as 4-chloro-benzoyl, 4 -methylbenzoyl, 2 -methoxycarbonylbenzoyl or 4-methoxybenzoyl; pyrrolyl-2-carbonyl, pyridyl-3 -carbonyl; benzenesul fonyl; (Cx-C10) -alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, isobutoxy-carbonyl or tert.-butoxycarbonyl; substituted (Cx-Cxo)-alkoxycarbonyl, such as 2-(trimethylsilyl) - 2315 ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl or 1, l-dimethyl-2, 2,2-trichloroethoxycarbonyl; (C6-C14) -aryl-(Cj-C6)-alkoxycarbonyl, such as benzyloxycar-bonyl, 1- or 2-naphthylmethoxycarbonyl or 9-f luor eny lmethoxy car bony 1; or R1, together with R10, preferably 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 the sulfoxide or sulfone, is preferably hydrogen, methyl or ethyl, or, together with R3 and the atoms carrying these, preferably forms pyrrolidine or piperidine, each of which can also be fused with cyclopentyl, cyclohexyl or phenyl, and Rs independently of one another are preferably hydrogen; (C!-C10)-alkyl, which is optionally mono-or diunsaturated and which is optionally substituted by up to 3 identical or different radicals from the series comprising hydroxyl, (Cj-CjJ-alkoxy, (Cx-Cy)-alkanoyloxy, carboxyl, (Cx-C7) -alkoxycarbonyl, CI, Br, amino, amidino, guanidino, carbamoyl, (Cx-Cs)-alkoxycarbonylamino, (C6-C15) -aralkoxycarbonylamino and 9 - fluorenylmethoxycarbonylamino; (C3-Cu) -eye lo-alkyl, (C3—Cjjj) ~*cycloalkyl— (Cj—C3) —alkyl or mono- or bicyclic (C6-C14)-aryl-(C^Cg)-alkyl, which is optionally substituted by one or two identical or different radicals from the series comprising F, CI, Br, lt hydroxyl, (Cx-CyJ-alkoxy, (Cj-C,)-alkyl, (Cx-C7)-alkylcarbonyl, amino and trifluoromethyl; or preferably represents (Cj-Ca)-alkyl, substituted by the radical of a 5- or 6-membered monocyclic or 9-or 10-membered bicyclic, optionally partly or completely hydrogenated heteroaromatic having at least 1 carbon atom, 1-4 nitrogen atoms and/or 1 or 2 sulfur atoms and/or 1 or 2 oxygen atoms as ring members and which is optionally mono- or disubsti- - 9 - 231578 tuted as described for the aryl part on page 2, or, together with R2 or R9, form ring systems as described above under Rz; is preferably (C3-Ci2)-alkyl; mono-, bi- or tricyclic (C3-C18)-cycloalkyl or (C3-C18)-cycloalkylmethyl, the cycloalkyl part optionally being substituted by (Cx-Ch) -alkyl; (C6-C14) -arylmethyl; dithiolanyl; di thiol any lmethyl; dithianyl or dithianylmethyl; preferably represents hydrogen, azido, azido-(Cj-C*)-alkyl, (Cj-Cja) -alkyl, (C3-C12) -cycloalkyl, (C3-C12)-cycloallcyl- (Cx-C6) -alkyl, (2 -pyridyl) - (Cx-C*) -alkyl, (3-pyridyl) - (Cj-C*) -alkyl, (4-pyridyl) - (Cx-C4) -alkyl, imidazol-2-yl, imidazol-l-yl, imidazol-4-yl, (imidazol-2-yl) - (Cx-C4) -alkyl, (imidazol-l-yl) -(Cx-C4)-alkyl, (imidazol-4-yl)-(Cx-C4)-alkyl, [1-(Cx-C6) -alkylimidazol-2-yl ] - (Cx-C«) -alkyl, (imid-azolin-2-yl)-(Cx-CA)-alkyl or [ l-(Cx-C6)-alkylimidazoline-yl ] - (C1-C4) -alkyl; and R7 independently of one another are preferably hydrogen or, together with the boron atom and the oxygen atoms, form a mono-, bi- or tricyclic, saturated or partly unsaturated mono-, di-, tri- or tetraalkylated or -phenylated ring system having 5-18 ring members, which, in addition to the boron atom, the oxygen atoms and the carbon atom(s), can also contain an -0- member, an -NR13- member or a -CRUR15- member; is preferably hydrogen, methyl or ethyl, or, together with R8 and the atoms carrying these, forms pyrrolidine or piperidine, each of which can additionally be fused with cyclopentyl, cyclohexyl or phenyl; is preferably hydrogen or methyl, or, together with R1 or R8 and the atoms carrying these, forms a mono- 231578 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 the sulfoxide or sulfone; and R1Z independently of one another are preferably hydrogen, hydroxyl, phenyl, 2- or 3-thienyl, 2-, 3-or 4-pyridyl, 1-, 2- or 4-imidazolyl, 1- or 2-naphthyl or 2- or 3-benzo[b]thienyl, n and m independently of one another can denote 0, 1, 2, 3 or 4, is preferably hydrogen or (Ci-C^)-alkyl; and and R1S independently of one another preferably denote hydrogen, hydroxymethyl, 2-hydroxyethyl, (3-hydroxysulfonyl, 2-hydroxypropyl)amino, (2-hydroxy-sul f onylethyl) amino, (2 -hydroxysul f onylpropyl) amino, (carboxymethyl) amino or bis (2-hydroxyethyl)amino. particularly preferably denotes (C^-Ce) -alkyl sul-fonyl; (C1-C8)-alkylsulfinyl; (C^-Cg) -hydroxyalkylsul-fonyl, in particular 2-hydroxyethylsulfonyl or 2-hydroxypropylsul f onyl; hydroxy- (Cj-C10) -alkanoyl, such as 2-hydroxypropionyl, 3-hydroxypropionyl, 3-hydroxybutyryl or 2-hydroxy-3-methylbutyryl; (Ci-C8)-alkanoyloxy-fCi-Cjc)-alkyl; (Cj-Cu)alkanoyl, such as n-decanoyl, formyl, acetyl, propionyl, pivaloyl, isovaleryl or isobutyryl; amino-(Cx-Cu)-alkanoyl, such as (3-amino, 3,3-dimethyl)propionyl, 4-amino-butyryl, 5-aminopentanoyl, 6-aminohexanoyl; di-(Cx-C7)-alkylamino-(C2-Cu)-alkanoyl, such as dimethyl-aminoacetyl; piperidino-4-carbonyl; morpholino-4-carbonyl; (C3-C8)-cycloalkylcarbonyl, such as cyclo-propylcarbonyl, cyclobutylcarbonyl, cyclpentylcar-bonyl or cyclohexylcarbonyl; (C6-C10)-aryl-(C2-Cu)-alkanoyl, such as phenyl acetyl, phenylpropanoyl or 231578 phenylbutanoyl; 2-pyridyl- (Cj-Ca) -alkanoyl; 3-pyr-idyl-fCx-Ca) -alkanoyl; 4-pyridyl- (C^-Ce) -alkanoyl; benzoyl which is optionally substituted by halogen, (Cx-C7)-alkyl, (Ci-C7)-alkoxy or (Cj-Cy)-alkoxycarbonyl, such as 4-chlorobenzoyl, 4-methylbenzoyl, 2-methoxycarbonylbenzoyl or 4-methoxybenzoyl; pyr-rolyl-2-carbonyl; pyridyl-3-carbonyl; benzenesul-fonyl; (Cx-C10)-alkoxycarbonyl, such as methoxycar-bonyl, ethoxycarbonyl, isobutoxycarbonyl or tert.-butoxycarbonyl; substituted (C1-C10)-alkoxycarbonyl, such as 2-(trimethylsilyl)-ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl or 1, l-dimethyl-2,2,2-trichloroethoxycarbonyl; or (C6-C14) -aryl-(Cj-Cg) -alkoxycarbonyl, such as benzyloxycarbonyl, 1- or 2-naphthylmethoxycarbonyl or 9-fluorenylmethoxycar-bonyl, particularly preferably denotes hydrogen or methyl, or, together with R3 and the -N-CH- group carrying these radicals, forms a tetrahydroisoquinoline or azabicyclooctane skeleton, and R* independently of one another are particularly preferably hydrogen, methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, sec.-butyl, 3-guanidino-propyl, carbamoylmethyl, 2-carbamoylethyl, carboxy-methyl, 2-carboxyethyl, mercaptomethyl, 2-(methyl-thio)ethyl, (1-mereapto,1-methyl)ethyl, hydroxy-methyl, 1-hydroxyethyl, amino, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, N,N-dimethylamino, cyclohexylmethyl, imidazol-4-yl-methyl, benzyl, 2-methylbenzyl, 3-methylbenzyl, indol-3-yl-methyl, 4-hydroxybenzyl, 4-methoxybenzyl, 3,4-dihydroxybenzyl, 3,4-dimethoxybenzyl,(benzodi-oxolan-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-(methylsulfonyl)ethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, cyclohexyl, (1- 12 - 231578 methyl-imidazol-4-yl)methylr (3-methyl-imidazol-4-yl)methyl, phenyl, 1-naphthylmethyl, 2-naphthyl-methyl, 2-phenylethyl, 2-thiazolylmethyl, 4-thi-azolylmethyl, 3-pyrazolylmethyl, 4-pyrimidinyl-methyl, indol-2-yl-methyl, 2-benzo[b]thienylmethyl, 3-benzo[b]thienylmethyl or 2-furylmethyl, or with R2 or R9 form ring systems as defined above under R2, is particularly preferably (C3-C12)-alkyl; mono- or bicyclic (C3-C12)-cycloalkyl or (C3-C12)-cycloalkyl -methyl, the cycloalkyl part optionally being substituted by (C1-CJ-aryl; (C6-C10)-arylmethyl; dithio-lanyl; dithiolanylmethyl; dithianyl or dithianyl-methyl, is particularly preferably hydrogen, azido, azido-methyl, 2-azidoethyl, (Cj-Ce) -alkyl, (Cs-Cja)-cycloalkyl, (Cs-C^)-cycloalkyl-(Cj-Cs)-alkyl, 3-(2-pyri-dyl)-propyl, 3-(3-pyridyl)-propyl, 3-(4-pyridyl )-propyl, imidazol-2-yl, imidazol-l-yl, imidazol-4-yl, (imidazol-2-yl) -propyl, (imidazol-l-yl) -propyl, (imidazol-4-yl)-propyl, [ 1- (CL-C4) -alkylimidazol-2-yl]-propyl or (imidazolin-2-yl)-propyl, and R7 are as defined on page 9, particularly preferably denotes hydrogen or methyl, or, together with R8 and the -N-CH- group carrying these radicals, forms a tetrahydroisoquinoline or azabicyclooctane skeleton, particularly preferably 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 the sulfone, or, together with R8 and the atoms carrying - 13 - 231578 these, forms a thiochroman system, the sulfur atom of which is particularly preferably oxidized to the sulfone, R11 and R12 independently of one another are particularly preferably hydrogen, hydroxyl, phenyl, 2-thienyl, 2-, 3- or 4-pyridyl, 1- or 2-imidazolyl, 1-naphthyl or 2- or 3-benzo[b]thienyl, n and m independently of one another are particularly preferably 0, 1 or 2, R13 is particularly preferably hydrogen or (Cj-C^)-alkyl. Ru and R15 are as defined on page 10. The invention furthermore relates to a process for the preparation of compounds of the formula I, which comprises coupling a fragment having one or more amino acids and having a terminal hydroxyl group or a reactive derivative thereof with a corresponding fragment having one or more amino acids and having a free amino group, if appropriate splitting off (a) protective group(s) temporarily introduced to protect other functional groups, and if appropriate converting the compound thus obtained into its physiologically tolerated salt. Fragments of a compound of the formula I having a terminal carboxyl group have the f<£L lowing formulae VI and and VII A - OH A-N-CH-C-OH II 0 (VII) s Fragments of a compound of the formula I having a terminal amino group have the following formulae VIII to X - 14 - 2315 r9 r8 o r2 r3 0 r4 ' • h i i il i (viii) hn - ch - c - n - ch - c - hn - ch - ch - r5 i b /\ or6 or7 R RJ I I hn - ch O II c - hn - ch - ch - r5 b /\ (IX) or6 or7 h2n ch - ch I b /\ or6 or7 (X) 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; and Bodanszky et al.. Peptide Synthesis, 2nd ed. (Wiley & Sons, New York 1976) or Gross and Meienhofer, The Peptides: Analysis, Synthesis, Biology (Academic Press, New York 1979). The following methods are preferably used: active ester methods with N-hydroxy-succinamide, 1-hydroxybenzotriazole or 3-hydroxy-4-oxo-3,4-dihydro-l,2,3-benzotriazine as the alcohol component, coupling with a carbodiimide, such as dicyclohexylcarbo-diimide, or with propanephosphonic anhydride and the mixed anhydride method with pivaloyl chloride or ethyl or isobutyl chlorofornate. Fragments of the formula VI where they a) fall under formula II are synthesized by the generally known methods for the preparation of amino 2315 78 acids; b) fall under formula III are synthesized starting from the corresponding amino acids, the chirality center thereof being retained. Diazotization at -20°C to 5 50°C in dilute mineral acids leads to a-bromo- car boxy lie acids or, via the lactic acids, to a-trifluoromethanesulfonyloxy-carboxylic acids, which can be reacted with a nucleophile carrying R1 and R10; 10 c) fall under formula IV are prepared starting from malonic esters, alkylation of which with arylalkyl halides gives mono- or disubstituted malonic esters, which, after hydrolysis, can be converted into the desired derivatives by decarboxylation. In the case 15 where one of the radicals R11 or R12 denotes hydroxyl, the corresponding amino acid is used as the starting substance and diazotization (as described above) gives the lactic acid (number of CH2 groups carrying R11 or R12 = 0), or the substituted malonic acid is 20 used as the starting substance, monohydrolysis and selective reduction (with, for example, diborane or LiAlH4) giving the 2-substituted 3-hydroxy-propionic acid. Fragments of the formula VII are synthesized by the 25 generally known methods for the preparation of amino acids and peptides. For the synthesis of the fragments of the formula X, N-protected o-amino acids are converted into the a-amino-aldehydes in accordance with the method of B. Castro et 30 al. (Synthesis 1983, 676). A Wittig reaction with a phosphonium salt carrying the radical Rs then takes place, followed by hydroboronation. The preliminary and subsequent operations required for the preparation of compounds of the formula I, such as 0^ 5 15 20 0 25 30 231578 - 16 - 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 with 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 obtained, if appropriate, in 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 exhibit enzyme-inhibiting properties, and in particular they inhibit aspartyl proteases, such as renin. Renin is secreted into the blood circulation by the juxtaglomerular cells of the kidneys as a result of various stimuli (volume depletion, sodium deficiency, p-receptor stimulation). In the blood circulation it splits off the decapeptide angiotensin I from the angioten-sinogen secreted from the liver. This angiotensin I is converted into angiotensin II by "angiotensin converting enzyme" (ACE). Angiotensin II plays an essential role in blood pressure regulation, since it increases the blood pressure directly by vasoconstriction. In addition, it stimulates the secretion of aldosterone from the adrenal gland and in this way, via inhibition of the excretion of sodium, increases the extracellular fluid volume, which in turn contributes towards increasing the blood pressure. Inhibitors of the enzymatic activity of renin cause reduced formation of angiotensin I, which results in reduced formation of angiotensin II. The reduction in the concentration of this active peptide hormone is the * - 17 - 23 1578 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 of the formation 5 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 10 be tested. During this incubation, angiotensin I is liberated from the angiotensinogen under the action of renin, and can subsequently be measured with a commercially available radioimmunoassay method. This angiotensin liberation is inhibited by renin inhibitors. 15 2. Isolation of -the plasma The blood is obtained from volunteer subjects (about 0.5 1 per person; Bluko withdrawal apparatus from ASID Bonz und Sohn, Unterschleissheim) and is collected in partially evacuated bottles, while cooling with ice. The 20 coagulation is prevented by addition of EDTA (final concentration 10 mH). After centrifugation (Rotor HS 4 (Sorvall), 3500 r.p.m., 0-4°C, 15 minutes; repeat if necessary), the plasma is carefully pipetted off and frozen in suitable portions at -30°C. Only plasmas with a 25 sufficiently high renin activity are used for the test. Plasmas with a lower renin activity are activated (prorenin -> renin) by a low temperature treatment (-4°C, 3 days). 3. Test procedure 30 Angiotensin I is determined with the Renin-Maia® kit (Seronon Diagnostics S.A., Coinsins, Switzerland). The plasma is incubated in accordance with the instructions o 2315; given with the kit: Incubation batch: 1000 pi of plasma (thawed at 0-4°C) 100 pi of phosphate buffer (pH 7.4) addition of 10~* M ramipri 5 late) 100 pi of PMSF solution 10 pi of 0.1 % strength Genapol PFIC 12 pi of DMSO or test preparation The test preparations are in general dissolved in a 10 concentration of 10~2 M in 100 % pure dimethyl sulfoxide (DMSO) and the solutions are diluted appropriately with DMSO; the incubation batch contains not more than 1 % of DMSO. The batches are mixed with ice and placed in a water bath 15 (37°C) for 1 hour for incubation. A total of 6 samples (in each case 100 /il) are taken from an additional batch without inhibitor and without further incubation in order to determine the initial angiotensin I content of the plasma used. 20 The concentrations of the test preparations are chosen so :,wJ that approximately the range from 10 - 90 % enzyme inhibition is covered (at least five concentrations). At the end of the incubation time, three 100 pi samples from each batch are frozen on dry ice in pre-cooled Eppendorf 25 vessels and kept at about -25°C for the angiotensin I determination (mean value of three individual samples). Angiotensin I radioimmunoassay (RXA) The use instructions of the RIA kit (Renin Maie« kit, Serono Diagnostics S.A., Coinsins, Switzerland) are 30 followed exactly. The calibration curve covers the range from 0.2 to 25.0 ng of angiotensin I per ml. The base angiotensin I 231578 - 19 - content: of the plasma is subtracted from all the measurement values. The plasma renin activity (PRA) is given in ng of Ang I/ml x hour. The PRA values in the presence of the test substances are based on a batch without in-5 hibitor (= 100 %) and given as % residual activity. The ICS0 value is read off from the plot of the % residual activity against the concentration (M) of the test preparation (logarithmic scale). The compounds of the general formula I described in the 10 present invention exhibit inhibiting actions in the in vitro test at concentrations of about 10~5 to 10~10 mol/1. 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 15 example, rhesus monkeys, are used for the in vivo test of renin inhibitors. Primate renin and human renin are largely homologous in their sequence. An endogenous renin secretion is stimulated by intravenous injection of furosemide. The test compounds are then administered and 20 their action on the blood pressure and heart rate is measured. The compounds of the present invention are active here in a dose range of about 0.1 - 5 mg/kg intravenously, on intraduodenal administration by a gastroscope in the dose range of about 1-50 mg/kg. The 25 compounds of the general formula I described in the present invention can be used as antihypertensives and for the treatment of cardiac insufficiency. 30 35 - 20 - 231578 5 The Invention furthermore relates to the use of compounds 10 of the formula I for the preparation of pharmaceuticals for the therapy of high blood pressure and treatment of congestive cardiac insufficiency and to the pharmaceuticals mentioned. 15 Pharmaceutical preparations contain an effective amount of the active compounds of the formula I together with an inorganic or organic pharmaceutically usable excipient. They can be administered intranasally, intravenously, subcutaneous ly, perorally or intraduodenally. The dosage 20 of the active compound depends on the warm-blooded species, the body weight, the age and the mode of administration. The pharmaceutical preparations of the present invention are prepared by dissolving, mixing, granulating or 25 tablet-coating processes which are known per se. For the oral use form, 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 presentation 30 forms, such as tablets, coated tablets, hard gelatine push-fit capsules, aqueous, alcoholic or oily suspensions or aqueous, alcoholic or oily solutions. Examples of inert excipients which can be used are gum arabic, magnesia, magnesium carbonate, potassium phosphate, 23 15 78 lactose, glucose, magnesium stearylfumarate or starch, in particular maize starch. Formulation can be effected here either in the form of dry granules or in the form of moist granules. Examples of possible oily excipients or 5 solvents are vegetable or animals oils, such as sunflower oil and cod-liver oil. For subcutaneous or intravenous administration, the active compounds or physiologically tolerated salts thereof are brought into solutions, suspensions or 10 emulsions, if desired with the substances customary for these, such as solubilizing agents, emulsifiers or other additives. Examples of possible solvents are: water, physiological saline solutions or alcohols, for example ethanol, propanediol or glycerol, and in addition also 15 sugar solutions, such as glucose solutions or mannitol solutions, or a mixture of the various solvents mentioned. List of abbreviations used Ac acetyl 20 Boc tert.-butoxycarbonyl bP« boiling point under xx mm Hg BuLi n-butyllithium DCC dicyc lohexy lcarbodi imide DCI desorption chemical ionization 25 DIP diisopropyl ether DMF dimethylformamide DMSO dimethyl sulfoxide DNP 2,4-dinitrophenyl EA ethyl acetate 30 EI electron impact Etoc ethoxycarbonyl FAB fast atom bombardment H hexane HOBt 1-hydroxybenzotriazole 35 Iva isovaleryl M molecular peak - 22 - 0 23 1578 M.p. melting point NeOH methanol MS mass spectrum MTB methyl tert.-butyl ether Nle norleucine Nva norvaline R.T. room temperature THF tetrahydrofuran Thi 0-2-thienylalanine TLC thin layer chromatography Z benzyloxycarbonyl. 10 The other abbreviations used for amino acids correspond to the three-letter code customary in peptide chemistry, such as is described in Eur J. Biochem. 138. 9-37 15 (1984). Unless expressly indicated otherwise, the amino acids are always in the L-configuration. The following examples serve to illustrate the present invention, without this being limited thereto. Example 1 20 [ 3-tert. -Butyl su If onyl, 2-(2) -thienylmethyl ] propionyl- Nva- [ 1-cyclohexylmethyl, 2-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl), 5-methyl ] hexylamide 346 mg of [3-tert.-butylsulfonyl,2-(2)-thienylmethyl]-propionyl-Nva-OH are dissolved in 40 ml of THF and first 25 98 pi of N-methylmorpholine and then 115 pi of isobutyl chloroformate are injected in at -20°C. After 10 minutes at -20°C, 123 pi of triethylamine are added. The mixed anhydride thus obtained is injected into a solution of 400 mg of [1-cyclohexylmethyl, 2-(4,4,5,5-tetramethyl-30 1,3,2-dioxaborolan-2-yl), 5-methyl ] hexylammonium tri-fluoroacetate in 40 ml of THF. The mixture is stirred at -20°C for 1 hour and left to stand at R.T. for 22 hours. It is diluted with 100 ml of MTB and washed twice with 30 ml of 5 % strength aqueous NaHSO* solution each time * - 23 - 23 1 5 7 8 and twice with 30 ml of 5 % strength aqueous Na2C03 solution each time. The organic phase is dried over Na2S0* and the solvent is removed in vacuo. Chromatography on silica gel with MTB/DIP = 1:1 gives 160 mg of the title compound as colorless crystals. Rf (MTB/DIP 1:1) = 0.50 MS (FAB): 709 (M+l) a) [ 3-t-Butylsulfonyl, 2-( 2-thienylmethyl) ] prop i onyl-Nva-OH 490 mg of [3-t-butylsulfonyl, 2-(2-thienylmethyl)]propio-10 nyl-Nva-OMe are dissolved in 4 ml of methanol, 0.4 ml of H20 and 0.7 ml of 2N NaOH are added and the mixture is stirred at R.T. for 5 hours. It is acidified to pH = 2 with NaHSO* solution and extracted 3x with 50 ml of EA. The extract is then dried over Na2S04 and the solvent is 15 removed in vacuo. 470 mg of pale yellow resin are obtained . Rz (EA) = 0.24 MS (FAB): 390 (M+l) b) [3-t-Butylsulfonyl, 2-(2-thienylmethyl) ]propionyl-Nva-OMe 20 1.5 g of [3-t-butylsulfonyl, 2-(2-thienylmethyl)]propionic acid and 0.95 g of Nva-OMe x HCl are dissolved in 40 ml of CH2C12, and first 3.8 ml of triethylamine and then 3.5 ml of a 50 % strength solution of propanephos-phonic anhydride in CH2C12 are added at 10°C. The mixture 25 is stirred at R.T. for 20 hours, the solvent is removed in vacuo, the residue is taken up in 100 ml of MTB and the mixture is washed with 100 ml each of NaHS04 solution and NaHC03 solution. It is dried over Na2S0*, the solvent is removed in vacuo and the residue is chromatographed 30 with EA/H 1:1. 2 diastereomeric oils are obtained and are further processed separately. - 24 - 231578 Diastereomer 1 Rf (EA/H 1:1) = 0.30 0.95 g Diastereomer 2 Rf (EA/H 1:1) = 0.20 0.95 g MS (DCI/ the same for both diastereomers): 404 (M+l) c) [3-t-Butylsulfonyl,2-(2-thienylmethyl)]propionic acid 4.4 g of methyl [3-t-butylsulfonyl,2-(2-thienylmethyl)]-propionate are suspended in 50 ml of 5N HCl and the suspension is heated under reflux for 2 hours. After cooling, it is extracted 3x with 50 ml of EA, the extract is dried over Na2S04 and the solvent is removed in vacuo. 4.0 g of the title compound are obtained as a pale yellow oil. Rf (MTB) = 0.15 - 0.25 MS (DCI): 291 (M+l) d) Methyl [3-t-butylsulfonyl, 2-(2-thienylmethyl)]pro-pionate 8.4 g of methyl [3-t-butylsulfonyl,2-(2-thienylmethyl) ]-propionate are dissolved in 100 ml of CH2Cl2f and 10.6 g of m-chloroperbenzoic acid are added in portions, while cooling with ice. The mixture is stirred at R.T. for 1 hour and then washed first with 100 ml of 10 % strength Na2S03 and then with 100 ml of NaHC03. It is dried over Na2S0* and the solvent is removed in vacuo. 7.2 g of the title compound are obtained as a colorless oil. Rf (MTB) = 0.56 MS (DCI): 305 (M+l) e) Methyl [3-t-butylthio, 2-(2-thienylmethyl)]propionate 6.1 ml of t-butyl mercaptan are dissolved in 100 ml of MeOH (anhydrous) and 130 mg of NaH are added under argon. 7.6 g of methyl 2-(2-thienylmethyl)acrylate are then added dropwise and the mixture is stirred at R.T. for 4 hours. The solvent is removed in vacuo, the residue is 2315 78 taken up in 100 ml of MTB and the mixture is washed with 100 ml of 5 % strength NaHSO* solution. It is dried over Na2S04 and the solvent is removed in vacuo. 10.4 g of the title compound are obtained as a pale yellow liquid, 5 which is used further without purification and characterization. O o Rf (DIP/H 1:5) « 0.31 f) Methyl 2-(2-thienylmethyl )acrylate 11.8 g of monomethyl 2-thienylmethylmalonate, 5.8 ml of 10 diethylamine and 5.0 ml of 36 % strength aqueous formaldehyde solution are stirred at R.T. under argon for 1 hour. The water is then removed in vacuo and the residue is chromatographed. 7.6 g of the title compound are obtained as a colorless liquid. 15 R* (MTB/H 1:5) = 0.49 g) Monomethyl 2-thieny lmethylmalonate 20.1 g of dimethyl 2-thienylmethylmalonate are dissolved in 300 ml of MeOH and 5.0 g of KOH are added. The mixture is stirred at R.T. for 7 hours, the solvent is removed in 20 vacuo and the residue is taken up with 100 ml each of 5 % strength Na2C03 solution and EA. The aqueous phase is then acidified to pH » 2 and extracted 3x with 100 ml of EA each time. The extract is dried over NazS04 and the solvent is removed in vacuo. 16.0 g of the title compound 25 are obtained as a pale yellow oil. Rf (EA/MeOH 6:1) = 0.3 - 0.4 h) Dimethyl 2-thienylmethylmalonate 30 87.8 g of dimethylmalonate and 41.0 g of potassium t-butylate are dissolved in 1.1 1 of THF (anhydrous), while cooling with ice, and 44.1 g of 2-thienylmethyl chloride - 26 - 231578 in 500 ml of THF are added dropwise, under argon. The mixture is stirred at R.T. for 3 hours, the KC1 is filtered off, the solvent is removed in vacuo and the residue is chromatographed. 33.8 g of the title compound 5 (I) are obtained as a colorless oil alongside 8.8 g of dimethyl bis-(2-thienylmethyl)malonate (II) © © Rf (I) (toluene/DIP 20:1) = 0.35 Rf (II) (toluene/DIP 20:1) = 0.44 g) 2-Thienylmethyl chloride 10 252 g of thiophene are suspended in 128 ml of concentrated aqueous HCl and HCl gas is passed in at 0°C for 1 hour. 255 ml of 35 % strength aqueous formaldehyde solution are then added dropwise without interrupting the stream of HCl, and the mixture is stirred at 0°C for a 15 further 15 minutes. After removal of the organic phase, the aqueous phase is extracted twice more with 600 ml of CH2C12. The extract is then washed twice with 600 ml of saturated aqueous Na2C03 solution and dried over Na2S04, the solvent is removed in vacuo and the residue is 20 distilled. 174 g of the title compound are obtained as a colorless liquid. bp^ = 81 - 84°C h) [1-Cyclohexylmethyl, 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl), 5-methyl ]hexylammonium trifluoro-iss& 25 acetate 520 mg of Z-[1-cyclohexylmethyl, 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl), 5-methyl ] hexylamine and 95 j*l of trifluoroacetic acid are dissolved in 10 ml of EtOH, 105 mg of Pd/C are added and hydrogenation is carried out 30 at R.T. under a pressure of 1 bar for 2.5 hours. The catalyst is then filtered off and the solvent is removed in vacuo. 400 mg of the title compound are obtained as a colorless oil which is used further without purification. * . 27 . 2 3 1 5 7 8 MS (DCI) : 338 (M+l) i) Z-[1-Cyclohexylmethyl, 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl), 5-methyl ]hexylamine 6.5 g of Z-( 1-cyclohexylmethyl, 5-methyl)-hex-2-en-amine 5 are dissolved in 190 ml of THF under argon. 5.7 ml of BH3-S(CH3)2 are added dropwise at 0°C and the mixture is stirred at R.T. for 1 hour. Water is then slowly added dropwise until the evolution of hydrogen has ended. The solvent is removed in vacuo and subsequently evaporated 10 twice on a rotary evaporator with 100 ml of toluene each time. The residue is dissolved in 120 ml of CH2C12 and 11.2 g of pinacol are added. The mixture is boiled for 4 hours over a water separator, the CH2C12 is removed in vacuo and the residue is chromatographed on silica gel 15 with EA/n-hexane = 1:8. 4.7 g of the title compound are obtained as a diastereomer mixture, which can be separated by renewed chromatography. Rf (EA/n-hexane = 1:8) =0.25 MS (DCI) s 472 (M+l) 0.22 20 k) Z-( 1-Cyclohexylmethyl, 5-methyl)-hex-2-en-amine 13.1 g of (isopentyl, triphenyl)phosphonium bromide are suspended in 280 ml of THF, and 3.2 g of potassium tert.-butylate are added. The mixture is stirred at R.T. for 2.5 hours and then cooled to 0°C, and 8.3 g of Z-(2(S)-25 cyclohexylmethyl)-aminoacetaldehyde in 100 ml of THF are added dropwise. The mixture is stirred at R.T. for 1 hour, 200 ml of MTB are added and the mixture is washed twice with 50 ml of 5 % strength aqueous NaHSO* solution each time and twice with 50 ml of 5 % strength aqueous 30 NaHC03 solution each time. The organic phase is dried over Na2S04 and the solvent is removed in vacuo. Chromatography on silica gel gives 6.5 g of the title compound as a colorless oil. 231578 - 28 - Rf (EA/n-hexane = 1:8) = 0.28 MS (DCI) : 344 (M+l) Examples 2 and 3 were synthesized analogously to Example 1: Example 2 [ 2- (S) -Benzyl, 3-tert. -butylsulf onyl ]propionyl-Nva- [ 1-cyclohexylmethyl,2-(4,4,5,5-tetramethyl-l,3,2-dioxa-borolan-2-yl), 5-methyl ]hexylamide Rf (MTB/DIP 1:1) = 0.52 MS (FAB) : 703 (M+l) Example 3 [3-tert. -Butylsulfonyl, 2- (1-naphthylmethyl) ] propionyl-Val- [ 1-cyclohexylmethyl ,2-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl),2-cyclopentyl]methyl amide Rf (MTB/DIP 1:1) = 0.42 MS (FAB) : 751 (M+l) Example 4 Boc-Phe-His- [ 1-Cyclohexylmethyl ,2-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl), 5-methyl ]hexylamide 300 mg of Boc-Phe-His(DNP)-[Cyclohexylmethyl,2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl), 5-methyl ] -hexylamide are dissolved in 5 ml of acetonitrile and 281 ft 1 of thiophenol are added. The mixture is stirred for 3 hours at R.T., the solvent is removed in vacuo and the residue is chromatographed on silica gel with MeOH/EA 1:20. 130 mg of the title compound are obtained as a colorless amorphous powder. Rf (EA/MeOH 20:1) = 0.35 MS (FAB) : 722 (M+l) </div>

Claims

<div class="application article clearfix printTableText" id="claims"> o - 29 - 23 1578 a) Boc -Phe-His (DNP) - [ 1 -Cyc lohexy lmethy 1,2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl), 5-methyl ]hexylamide The title compound was synthesized analogously to Example 1. 5 Rf (MTB) = 0.27 MS (FAB) s 872 (M+l) Example 5 was synthesized analogously to Example 4: Example 5 [ 2- (S) -Benzyl, 3-tert. -butyl sulf onyl ] propionyl-His- [ 1-cyc lohexy lmethy 1,2- (4,4,5, 5-tetramethyl-l,3,2-dioxa-10 borolan-2-yl), 5-methyl]hexylamide Rf (EA/MeOH 10:1) = 0.20 MS (FAB) : 741 (M+l) Example 6 [ 2- (S) -Benzyl, 3-tert. -butyl sul f onyl ] propionyl-His - [ 1 -cyc lohexy lmethy 1,2-dihydroxyboryl, 5-methyl ] hexylamide 15 217 mg of the title compound of Example 5 and 220 pi of titanium isopropoxide are dissolved in 100 ml of n-propanol and boiled for 8 hours under a Soxhlet extractor which is filled with 0.3 nm molecular sieve. The reaction solution is poured onto 100 ml of saturated NaHC03 solu-20 tion, the Ti02 is filtered off, the solution is extracted 3 times with 50 ml of EA and dried over Na2S04. The solvent is removed in vacuo and chromatographed on silica gel with CH2Cl2/MeOH 10:1. 43 mg of the title compound are obtained as a white amorphous powder. 25 Rf (CH2Cl2/MeOH 10:1) = 0.28 MS (FAB) : 659 (M+l) - 30 231578 WHAT WE CLAIM IS:

1. A compound of the formula I R2 R3 R4 I 1 I c N - CH - CO - NH - CH - CH - R5 I B /\ OR6 OR7 in which A denotes a radical of the formula II, III or IV R' i N - R8 0 • I* CH - C - (II) ,10 r8 0 n i • ii R1 - CH - CH - C - R I (III) >11 " <CH2)n - CH - i <?H2>m d12 (IV) in which R1 ax) denotes hydrogen, (Cx-Cu)-alkyl, which is optionally mono- or diunsaturated and is optionally substituted by up to 3 identical or different radicals from the series comprising hydroxyl, (Cx-C7)-alkoxy, carbamoyl, (C^Cg) -alkanoyloxy, carboxyl, (Cx-C7)-alkoxycarbonyl, F, CI, Br, I, amino, amidino, which can optionally be substituted by one, two or three (Cx-Ce)-alkyl radicals, guanidino, which can optionally be substituted by one, two, three or four (CX-CB)-alkyl radicals, (Cx-C7) -alkylamino, di-(C1-C7)-alkylamino, (Cx-C5)- - 31 - 231578 alkoxycarbonylami.no, (C7-C15) -aralkoxycarbonyl-amino and 9-fluorenylmethoxycarbonylamino; mono-, bi- or tricyclic (C3-C18) -cycloalkyl, (C3-C18)-cycloalkyl-(C1-C6)-alkyl or (C6-C14)-aryl, the cycloalkyl part optionally being substituted by (Cj—Cg) —alkyl and aryl optionally being substituted by one or two identical or different radicals from the series comprising F, CI, Br, I, hydroxyl, (Cx-Cy)-alkoxy, (Ci-Cy) -alkyl, (Ci-Cy)-alkoxycarbonyl, amino and trifluoromethyl; (C6-C14)-aryl-(C^Cg)-alkyl, in which the aryl part is optionally substituted by one or two identical or different radicals from the series comprising F, CI, Br, I, hydroxyl, (Ci-Cy)-alkoxy, (Cx-Cy)-alkyl, (Ci-Cy) -alkoxycarbonyl, amino, (Cx-Cy)-alkylamino, di- (Cx-Cy) -alkylamino, carboxyl, carboxymethoxy, amino- (Cx-C7) alkyl, (Cx-C7)-alkyl-amino-(Cj-Cy) alkyl, di- (Cx-C7)-alkylamino-(Cx-C7) -alkyl, (Ci-Cy)—alkoxycarbonylmethoxy, carbamoyl, sulfamoyl, (Cx-C7)-alkoxysulfonyl and sulfo- and guanidino-fCi-Cg)-alkyl; or represents the radical of a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic partly or completely hydrogenated heteroaromatic having at least 1 carbon atom, 1-4 nitrogen atoms and/or 1 or 2 sulfur atoms and/or 1 or 2 oxygen atoms as ring members and which is optionally mono-, di- or trisubsti- tuted like the (C6-C14)-aryl defined under at); pyridylalkanoyl; or a2) denotes a radical of the formula V R1' - W (V) in which R1' is defined as R1 under ax) and W represents -CO-, -0-C0-, -S02-, -SO-, -NH-S02-, -NH-C0-, —CH(OH)— or -N(OH)-; /ja. R2 denotes hydrogen or (Cx-Cg) -alkyl, or, together, with R3 and the atoms carrying these, forms a mono^or '' bicyclic, saturated or partly unsaturated/; ,ring •• ; system having 5-12 ring members; , '' V » \ • t ' •> - 32 ?31578 ( ^ o R3 and R8 independently of one another are defined as R1 under at), or denote mercapto, methylthio, heteroarylalkyl, amino, or dimethylamino, or, together with R2 or with R9 and the atoms carrying these, form ring systems having 5-12.ring members, as defined above; R* denotes -alkyl, mono-, bi- or tricyclic (C3-C18)-cycloalkyl, (C3-C18)-cycloalkylmethyl or (C3-C18)-cycloalkylethyl, the cycloalkyl part optionally being substituted by (Ci-Cg)-alkyl; dithiolanyl; (C6-C14) -arylmethyl; dithiolanylmethyl; dithiolanyl-ethyl; dithianyl; dithianylmethyl or dithianylethyl; Rs denotes hydrogen; azido; azido-(Cx-C*)-alkyl; (Ci-Cja)-alkyl, which can optionally be substituted by hydroxyl, azido or hydroxyl and azido; (Ca-C^)-cycloalkyl; (C3-C12) -cycloalkyl-(Ci-Cg) -alkyl; (c3_ci2) -cyc loalkylsulf onyl- (Cx-Ce) -alkyl; (Cj-C6) -alkylsulfonyl-(C1-C6)-alkyl; (C6-Cn)-aryl or (C6-C14)-aryl-(Cj.-C6)-alkyl, it also being possible for aryl to represent the radical of a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaromatic having at least 1 carbon atom, 1-4 nitrogen atoms and/or 1 or 2 sulfur atoms and/or 1 or 2 oxygen atoms as ring members and which can also be partly or completely hydrogenated, and it is likewise possible that aryl and heteroaryl can be substituted as defined under ax), R6 and R7 independently of one another denote hydrogen or (Ci-C6)-alkyl; or, together with the boron atom and the oxygen atoms, form a mono-, bi- or tricyclic, saturated or partly unsaturated, mono-, di-, tri- or tetra-(C1-C6)- alkylated or -phenylated ring system havin ring members, which, in addition to the boror the oxygen atoms and the carbon atom(s), ca contain an -0- member, an -NR13- member or a - member; - 33 - 23 1578 represents hydrogen or (Cx-C8)-alkyl, or, together with R8 and the atoms carrying these, forms a mono-or bicyclic, saturated or partly unsaturated ring system having 5-12 ring members; is hydrogen or (Cj-Cg)-alkyl, or, together with R1 or R8 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 the carbon atom, can also contain 1 sulfur atom, which can optionally be oxidized to the sulfoxide or sulfone; and R12 independently of one another denote hydrogen, hydroxyl or (C6-Cu)-aryl, aryl optionally being substituted by one or two identical or different radicals from the series comprising F, CI, Br, I, hydroxyl, (Cx-C7)-alkoxy, (Ca-C7)-alkyl, (Cx-C7)-alkoxycarbonyl, amino, (Cx-C7)-alkylamino, di-(Cx-C7)-alkylamino, carboxyl, carboxymethoxy, amino-(Cx-C7)-alkyl, (Cx-C7)-alkylamino-(Cx-C7)-alkyl, di-(Cx-C7)~ alkylamino- (Cx-C7) -alkyl, (Cx-C7) -alkoxycarbonyl-methoxy, carbamoyl, sulfamoyl, (Cj-C7)-alkoxysulfonyl and sulfo- and guanidino-(Cx-C8)-alkyl; or represent the radical of a 5- or 6-membered monocyclic or 9-or 10-membered bicyclic, optionally partly or completely hydrogenated heteroaromatic having at least 1 carbon atom, 1-4 nitrogen atoms and/or 1 or 2 sulfur atoms and/or 1 or 2 oxygen atoms as ring members and which is optionally mono- or disub-stituted like (C6-CM)-aryl above, n and m independently of one another can be 0, 1, 2, 3 or 4, denotes hydrogen or (Cx-C12)-alkyl, which is optionally mono- or diunsaturated and is optionally substituted by up to 3 identical or different 231578 radicals from the series comprising hydroxyl, (Cj-Cy)-alkoxy, amino and mono- or di-CCi-Cj)-alkylamino , and and R15 independently of one another denote hydrogen, (Ci—C8) -alkyl, hydroxymethyl, 2-hydroxyethyl, (3-hydroxysulfonyl, 2-hydroxypropyl)amino, (2-hydroxy-sulf onylethyl) amino, (2-hydroxysulf onylpropyl) amino, (carboxymethyl) amino or bis (2-hydroxyethyl) amino, a physiologically tolerated salt thereof. A compound of the formula I as claimed in claim 1, wherein denotes hydrogen or represents (Cx-Cu)-alkyl; cyclopentyl; cyclohexyl; cyclopentyl- (C1-C10) -alkyl; cyclohexyl- (Cx-C10) -alkyl; optionally substituted phenyl- (Cx-C8) -alkyl; 2-pyridyl- (Cx-C8) -alkyl; 3-pyridyl-(Cx-C8)-alkyl; 4-pyridyl-(Cj-Cb)-alkyl; H2N-(Ci-C10)-alkyl; HO-(Cx-C10)-alkyl; (Cx-C4)-alkoxy-(Cj-C10) -alkyl; (Cx-C 4) -alkoxycarbonyl- (C1-C10) -alkyl; (Ci-CaJ-alkylsulfonyl; (Cx-C8)-alkylsulfinyl; (Cx-C8)-hydroxyalkylsulfonyl; (Cx-C8) -hydroxyalkylsulf inyl; hydroxy- (Cx-C10 ) -alkanoyl; (Cx-C8) -alkanoyloxy-(Ci-Cio)-alkyl; (Cl-C11)-alkanoyl; optionally protected amino-(Ci-Cn)-alkanoyl; di-(C1-C7)-alkylamino-(C2-Cu)-alkanoyl; piperidino-4-carbonyl; morpholino-4-carbonyl; (C3-CB)-cycloalkylcarbonyl; (C6-C10)-aryl-(C2-CX1) -alkanoyl; 2-pyridyl- (Cx-C8) -alkanoyl; 3-pyridyl-(Cx-C8) -alkanoyl; 4-pyridyl-(C^Cb) -alkanoyl; benzoyl which is optionally substituted by halogen, (Cj-C,)-alkyl, (C^-Cj)-alkoxy or (Cx-C7)-alkoxycarbonyl ; pyrrolyl-2 -carbonyl, pyridyl-3-carbonyl; benzenesul fonyl; ( Ci-C10) -alkoxycarbonyl; substituted (Ci-Cjo)-alkoxycarbonyl; or (C6-C14)-aryl-(C1-C6)-alkoxycarbonyl, or, together with R10, 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 - 35_ 231578 can optionally be oxidized to the sulfoxide or sulfone, is hydrogen, methyl or ethyl, or, together with R3 and the atoms carrying these, forms pyrrolidine or piperidine, each of which can also be fused with cyclopentyl, cyclohexyl or phenyl, and Ra independently of one another denote hydrogen; (Ci-Cjo)-alkyl, which is optionally mono- or diunsaturated and is optionally substituted by up to 3 identical or different radicals from the series comprising hydroxyl, (Cx-C7) -alkoxy, (Cj-C?) -alkanoyl-oxy, carboxyl, (C^-C-,)-alkoxycarbonyl, CI, Br, amino, amidino, guanidino, carbamoyl, (Cj-Cs) -alkoxycarbonyl amino, (C6-C15)-aralkoxycarbonylamino and 9-f luorenylmethoxycarbonylamino; (Ca-C^) -cycloalkyl, (Cs-C^)-cycloalkyl-(Ci-Ca)-alkyl or mono- or bicyclic (C6-C14)-aryl-(C!-C3)-alkyl, which is optionally substituted by one or two identical or different radicals from the series comprising F, CI, Br, I, hydroxyl, (C^Cy)-alkoxy, (Cj-Cy)-alkyl, (Cx-Cy)-alkoxycarbonyl, ami no and trifluoromethyl, or represent (Ci-Ca)-alkyl, substituted by the radical of a 5- or 6-membered monocyclic or 9- or 10-mem-bered bicyclic, optionally partly or completely hydrogenated hetero ring having at least 1 carbon atom, 1-4 nitrogen atoms and/or 1 or 2 sulfur atoms and/or 1 or 2 oxygen atoms as ring members and which is optionally mono- or disubstituted as described for the aryl part in claim 1, or, together with R2 or R8, form ring systems as described above under R2; is (Ca-Cxa)-alkyl; mono-, bi- or tricyclic (C3-C18)-cycloalkyl or (C3-C18)-cycloalkylmethyl, the cycloalkyl part optionally being substituted by (Ci-Ci)-^^*^ alkyl; (C6-C14) -arylmethyl; dithiolanyl; dithiolanyp^ f methyl; dithianyl or dithi any lmethy 1; /'v fa. %. A _ 36 _ ?31578 R5 represents hydrogen, azido, azido-(Cj.—C4)-alkyl, (Cx-C12) -alkyl, (Ca-Cia)-cycloalkyl, (Ca-C^) -cycloalkyl-(Ci-Ce)-alkyl, (2-pyridyl)-(C1-C4)-alkyl, (3-pyridyl)-(Cj-C*)-alkyl, (4-pyridyl)-(C1-C4)-alkyl, imidazol-2-yl, imidazol-l-yl, imidazol-4-yl, (imidazol-2-yl)-(Ci-C4) -alkyl, ( imidazol-l-yl) - (Cj.-C4)-alkyl, (imidazol-4-yl) - (Cj.-C4) -alkyl, [ 1- (Ci-C6) -alkylimida-zol-2-yl ] - (Ci-C*) -alley 1, (imidazolin-2-yl) - (Ci-C^) -alkyl or [l-(C1-C6)-alkylimidazolin-2-yl]-(C1-C4)-alkyl; R6 and R7 independently of one another are hydrogen, or, together with the boron atom and the oxygen atoms, are a mono-, bi- or tricyclic, saturated or partly unsaturated mono-, di-, tri- or tetraalkylated or -phenylated ring system having 5-18 ring members, which, in addition to the boron atom, the oxygen atoms and the carbon atom(s), can also contain an -O-member, an -NR13- member or a -CRUR15- member; R9 is hydrogen, methyl or ethyl, or, together with R8 and the atom carrying these, forms pyrrolidine or piperidine, each of which can additionally be fused with cyclopentyl, cyclohexyl or phenyl; R10 is hydrogen or methyl, or, together with R1 or R8 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 the sulfoxide or sulfone; R11 and R12 independently of one another are hydrogen, hydroxyl, phenyl, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 1-, 2- or 4-imidazolyl, 1- or 2-naphthyl or 2- or 3-benzo[b]thienyl; n and m independently of one another denote 0, 1 3 or 4; //"? ;; 16 JAN 1992 23 15 78 is hydrogen or (Cx-C12)-alkyl; and and R15 independently of one another denote hydrogen, hydroxyl, hydroxymethyl, 2-hydroxyethyl, (3-hydroxy-sulfonyl,2-hydroxypropyl)amino, (2-hydroxysulfonyl-ethyl) amino, (2-hydroxysulfonylpropyl) amino, (car-boxymethyl)amino or bis (2-hydroxyethyl)amino, a tolerated salt thereof. A compound of the formula I as claimed in either of claims 1 and 2, wherein denotes (Cx-C8)-alkylsulfonyl; (Cx-C8)-alkylsulfinyl; (Ci-Ce) -hydroxyalkylsul f ony 1; hydroxy- (Cx-C^) -alkanoyl; (Ci-C8)-alkanoyloxy-(Cx-C10)-alkyl; (Cx-Cu)-alkanoyl; amino-(Cx-Cu)-alkanoyl; di-(Cj-C7)-alkylamino- (C2-Cxx) -alkanoyl; piperidino-4-carbonyl; morphol ino-4 -carbonyl; (C3-C9) -cyc loalkylcarbonyl; (C6-C10) -aryl- (C2-Cn) -alkanoyl; 2-pyridyl- (Cj-C8) -alkanoyl; 3-pyridyl- (Cx-C8) -alkanoyl; 4-pyridyl- (Cx-C8)-alkanoyl; benzoyl which is optionally substituted by halogen, (Cx-C7)-alkyl, (Cx-C7)-alkoxy or (Ca-C7)-alkoxycarbonyl; pyrrolyl-2-carbonyl; pyridyl-3-carbonyl; benzenesulfonyl; (Cx-C10)-alkoxycarbonyl; substituted (Cx-C10)-alkoxycarbonyl or (C6-C14)-aryl-(Cx-C6) -alkoxycarbonyl, denotes hydrogen or methyl, or, together with R3 and the -N-CH- group carrying these radicals, forms a tetrahydroisoquinoline or azobicyclooctane skeleton, and R8 independently of one another are hydrogen, methyl, ethyl, isopropyl, n-propyl, n-butyl, iso-butyl, sec.-butyl, 3-guanidinopropyl, carbamoyl-methyl, 2-carbamoylethyl, carboxymethyl, 2-car-boxyethyl, mercaptomethyl, 2-(me thy It hio) ethyl, (1-mercapto, 1-methyl)ethyl, hydroxymethyl, 1-hydroxy-ethyl, amino, aminomethyl, 2-aminoethyl, 3-amino-propyl, 4-aminobutyl, N,N-dimethylamino, cyclohexyl- 2 3 15 7 8 propyl, 4-aminobutyl, N,N-dimethylamino, cyclohexyl-methyl, imidazol-4-yl-methyl, benzyl, 2-methylben-zyl, 3-methylbenzyl, indol-3-yl-methyl, 4-hydroxy-benzyl, 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-pyridylmethy 1, 4-pyridylmethyl, cyclohexyl, (l-methylimidazol-4-yl)methyl, (3-methyl-imidazol-4-yl)methyl, phenyl, 1 -naphthylmethy 1, 2 -naphthylmethy 1, 2 -phenylethyl,

2-thiazolylmethyl, 4-thiazolylmethyl, 3-pyrazolyl-methyl, 4-pyrimidinylmethyl, indol-2-yl-methyl, 2-benzo [ b ] thienylmethyl, 3 -benzo [ b ] thienylmethyl or 2 -fury lmethy 1, or with R2 or Rs form ring systems as defined above under R2, is (C3-C12)-alkyl; mono- or bicyclic (Ca-C^J-cyclo-alkyl or (C3-C12)-cycloalkylmethyl, the cycloalkyl part optionally being substituted by (C1-C4)-allcyl; (C6-C10)-arylmethyl; dithiolanyl; dithiolanylmethy 1; dithianyl or dithianylmethyl, is hydrogen, azido, azidomethyl, 2-azidoethyl, (Cx-Ce) -alkyl, (C3-C12)-cycloalkyl, (Ca-CxaJ-cycloalkyl-(Ci-Cj)-alkyl, 3-(2-pyridyl)-propyl, 3-(3-pyridyl)-propyl, imidazol-2-yl, imidazol-l-yl, imidazol-4-yl,

3-(

4-pyridyl)-propyl, (imidazol-2-yl)-propyl, (imidazol-l-yl)-propyl, (imidazol-4-yl) propyl, [1-(C1-C4)-alkylimidazol-2-yl]-propyl or (imidazolin-2-yl)-propyl, and R7 are as defined in claim 2, denotes hydrogen or methyl, or, together with R8 and the -N-CH- group carrying these radicals, forms a tetrahydroisoquinoline or azabicyclooctane skeleton, ?31578 - 39 - R10 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 the sulfone, or, together with R8 and the atoms carrying these, form a thiochroman system, the sulfur atom of which is particularly preferably oxidized to the sulfone, O Ru and R12 independently of one another are hydrogen, hydroxyl, phenyl, 2-thienyl, 2-, 3- or 4-pyridyl, 1-or 2-imidazolyl, 1-naphthyl or 2- or 3-benzo[b]-thienyl, n and m independently of one another are 0, 1 or 2, R13 is hydrogen or (Ci-C*)-alkyl and R1* and Rls are as defined in claim 2, or a physiologically tolerated salt thereof. 4. A process for the preparation of a compound of the formula I as claimed in one or more of claims 1 - 3, which comprises coupling a fragment having one or more amino acids and having a terminal carboxyl group or a reactive derivative thereof with a corresponding fragment having one or more amino acids and having a free amino group, if appropriate splitting off (a) protective group(s) temporarily introduced to protect other functional groups, and if appropriate converting the compound thus obtained into its physiologically tolerated salt. 5. A compound of the formula I as claimed in one or more of claims 1-3, for use as a medicine.

6. A compound of the formula I as claimed in one more of claims 1-3, for use as a medicine in 0 treatment of high blood pressure. ''V2 16 JAN1992 V]1 16 JAN1992 ) - ii'C - 231578 o 8. 9. 10. A pharmaceutical agent containing a compound of the formula I as claimed in one or more of claims 1-3. A compound according to claim 1 substantially as herein described or exemplified. A process according to claim A substantially as herein described or exemplified. A pharmaceutical agent according to claim 7 substantially as herein described or exemplified. </div>