CA2004303A1 - .beta.-amino-boronic acid derivatives - Google Patents

Abstract

Abstract of the disclosure:
.beta.-Amino-boronic acid derivatives The invention relates to compounds of the formula I

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

(II) (III)

Description

2~ 3 HOECHST ARTIENGESELLSCHAFT HOE 88/F 336 Dr.WI/PP
Description ~-Amino-boronic acid derivative~
The invention relates to compounds of the formula I

A - N - CH - Co - NH - CH - ~H - R5 /~
oR6 oR7 in which A denotes a radical of the formula II, III or IV

R1 N - CH - C - (II) ~10 R8 o R1 CH - CH - C - (II~) R11 - (CH2)n - CH - C ~ (IV) ( CH2 ) m in which R1 al) denotes hydrogen, (Cl-Cl2)-alkyl, which i8 option-ally mono- or diunsaturated and i8 optionally sub~tituted by up to 3 identical or different radical~ from the series comprising hydroxyl, (Cl-C~)-alkoxy, carbamoyl, (Cl-C~)-alkanoyloxy, carboxyl, (Cl-C7)-alkoxycarbonyl, F, Cl, Br, I, amino, amidino, which can optionally be sub~ti-tuted by one, two or three (Cl-C8)-alkyl radical~, Z C3 ~ ) 3 guanidino, which can optionally be sub6tituted by one, two, three or four (Cl-CB)-alkyl radicals, (Cl-C7)-alkylalllino, di-(Cl-C7)-alkylalllino, (C~-C5)-alkoxycarbonylEmino, (C7-Cl5)-aralkoxycarbonyl-amino and 9-fluorenylmethoxycarbonylamino;
mono-, bi- or tricyclic (C3-Cl8)-cycloalkyl, (C3-Cl8)-cycloalkyl-(Cl-C6)-alkyl or (C6-Cl;)-aryl, the cycloalkyl part optionally being sub~tituted by (Cl-C6)-alkyl and 8ryl optionally being ~ub~ti-tuted by one or two identical or different radicals from the series comprising F, Cl, Br, I, hydroxyl, (Cl-C7)-alkoxy, (Cl~C7)-alkyl, (Cl C7 ) -alkoxycarbonyl, amino and trifluoromethyl;
(C6-Cl~)-aryl-(C1-C6)-alkyl, in which the aryl part is optionally substituted by one or two identical or different radicals from the series comprising F, Cl, Br, I, hydroxyl, (Cl-C7)-alkoxy, (Cl-C7)-alkyl, (Cl-C7)-alkoxycarbonyl, amino, (Cl-C,)-alkylamino, di-(Cl-C7)-alkylamino, carboxyl, carboxymethoxy, amino-(C1-C7)-alkyl, (Cl-C7)-alkylamino-(Cl-C7)-alkyl, -di-(Cl-C7)-alkylamino-(Cl-C7)-alkyl, (Cl-C7)-alkoxycarbonylmethoxy, car bamoyl, sulfamoyl, (C1-C7)-alkoxysulfonyl and sulfo- and guanidino-(Cl-CB)-alkyl; or represents the radical of a 5- or 6-membered monocycl$c or 9- or 10-membered bicyclic partly or completely hydrogenated heteroaromatic having at least 1 carbon atom, 1 - 4 nitrogen atom6 and/or 1 or 2 ~ulfur atomfi and/or 1 or 2 oxygen atoms as ring member~ and which is optionally mono-, di- or trisub~tituted like the (C6-Cl~)-aryl defined under al), or a2) denotes a radical of the formula V
Rl' W (V) in which R1 i~ defined as R1 under a1) and W
reprefient~ -CO-, -O-CO-, -S02-, -SO-, -NH-SOz-, -NH-CO-, -CH~OH)- or -N(OH)-;

2~ 3~3 R2 denote~ hydrogen or (Cl-C8)-alkyl, or, together with ~ R3 and the atoms carrying these, form~ a mono- or bicyclic, saturated or partly unsaturated ring system having 5-12 ring members;

R3 and R8 independently of one another are defined as under a~) or, together with R2 or with R9 and the atoms carrying these, form ring systems having 5-12 ring members, as defined above;

R4 denote~ (C3-Cl2)-alkyl, mono-, bi- or tricyclic (C3-Cl8~-cycloalkyl, (C3-Cl8~-cycloalkylmethyl or (C3-Cl8)-cycloalkylethyl, the cycloalkyl part option-ally beiny substituted by tCl-C6)-alkyl; dithiolanyl;
( C6-C14 )-arylmethyl; dithiolanylmethyl; di~hiolanyl-ethyl; dithianyl; dithianylmethyl or dithianylethyl;

R5 denote~ hydrogen; azido; azido-(C~-C~)-alkyl;
(C,-Cl2)-alkyl, which can optionally be ~ubstituted by hydroxyl, azido or hydroxyl and azido; (C3-C~)-cycloalkyl; ( C3-C~2) -cycloalkyl-( Cl-C6) -alkyl;
(C3-C12) -cycloalkylsulfonyl-(C~-C~)-alkyl; (C~-C6) -alkylsulfonyl-(C,-C6)-alkyl; (C6-Cl4)-aryl or (C6-C~
aryl-(Cl-C~)-alkyl, it also being pos~ible for aryl to represent the radical of a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic hetero-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 like-wise possible that aryl and heteroaryl can be substitut2d as defined under al), R6 and R7 independently of one another dznote hydrogen or (Cl-C6) -alkyl; or, together with the boron atom and the oxygen atoms, form a ~ono-, bi- or tricyclic, saturated or partly unsaturated, mono-, di-, tri- or tetra-(Cl-C6)-ZC~3~)3 alkylated or -phenylated ring sy~tem having 5-18 ring members, which, in addition to the boron atom, the oxygen atoms and the carbon atom(s), can al80 contain an -O- member, an -NRl3- member or a -CRl4Rl5-member;

R8 represents hydrogen or (Cl-Ca)-alkyl, or, together with Ra and the atom~ carrying the~e, form~ a mono-or bicyclic, ~aturated or partly unsaturated ring system having 5-12 ring members;

0 Rl iB hydrogen or (Cl-C8)-alkyl, or, together with Rl or R8 and the atoms carrying these, form~ a mono- or bicyclic, saturated or partly un~aturated ring By~tem having 5-12 rins members, which, in addition to the carbon atom, can also contain 1 sulfur atom, which can optionally be oxidized to the ~ulfoxide or sulfone;

Rl1 and R~ independently of one another denote hydrogen, hydroxyl or (C6-Cl4)-aryl, aryl optionally being sub-stituted by one or two identical or different radical~ from the ~eries compri~ing F, Cl, Br, I, hydroxyl, (Cl-C7)-alkoxy, ( C,-C7 )-alkyl, (Cl-C7)-alkoxycarbonyl,amino,(Cl-C,)-alkylamino,di-(Cl-C7)-alkylamino, carboxyl, carboxymethoxy, amino-(C1-C~)-alkyl, (Cl-C7)-alkylamino-(Cl-C7)-alkyl, di-(Cl-C~)-alkylamino-(C1-C~)-alkyl, (cl-c~)-alkoxycarbonyl-methoxy,c~rbamoyl, sulfamoyl, (Cl-C7~-alkoxysulfonyl and sulfo- and guanidino-(C1-C8)-alkyl; or represent the radical of a 5- or 6-membered monocyclic or 9-or 10-membered bicyclic, optionally partly or com-pletely hydrogenated heteroaromatic having at least 1 carbon atom, 1 - 4 nitrogen atom~ and/or 1 or 2 ~ulfur atom~ and/or 1 or 2 oxygen atom~ a~ r~ng m~mbers and which is optionally mono- or di~ubsti-tuted like (C6-C~)-aryl abo~e, n and m independently of one another can be 0, 1, 2, 2~ 3 3 or 4, R13 denotes hydrogen or (C1-C1z)-alkyl, which i8 option-ally mono- or diunsaturated and i8 optionally substituted by up to 3 identical or different radical6 from the ~eries comprisinq hydroxyl, (Cl-C7)-alkoxy, zmino and mono- or di-tCl-C7~-alkyl-amino, and R14 and R15 independently of one another denote hydrogen, (Cl-Ct)-alkyl, hydroxymethyl, 2-hydroxyethyl, (3-hydroxysulfonyl, 2-hydroxypropyl)amino, (2-hydroxy-sulfonylethyl)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-membered bicyclic heteroaromatic having at leas~ 1 carbon atom, 1 - 4 nitrogen atoms and/or 1 or 2 sulfur atoms and/or 1 or 2 oxygen atoms as ring member~ is understood a~ meaning radicals of heteroaromatics such a~ are defined, for example, in Ratritzky and Lagow~ki, Chemie der Heterocyclen tChemistry of the ~eterocyclics]~
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 compri~ing F, Cl, Br, I, hydroxyl, (Cl-C7)-alkoxy, (Cl-C7)-alkyl, (Cl-C7)-alkoxycarbonyl, amino and trifluoro-methyl. Examples of monocyclic heteroaromatic~ are thiophene, furan, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-triazole, thia-zole, tetrazole, isothiazole, oxazole and isoxazole.
Example3 of bicyclic heteroaromatics are benzothiophene, benzofuran, indole, i30indole, indazole, benzimidazole, quinoline, isoguinoline, phthalazine, quinoxaline, quinazoline and cinnoline. Corresponding statemants apply to radicals derived from heteroaryl, such as, for example, completely or partly hydrogenated heteroaryl, inter alia al~o, for exa~ple, benzodioxolane, hetero-~C~ )3 aryloxy, heteroarylthio and heteroaryl-alkyl.

Alkyl can be straiqht-chain or branched. The correspond-ing ~tatement applies to radicals derived therefr~m, ~uch a~, for example, alkoxy, alkylthio, alkylamino, dialkyl-amino, alkylsulfinyl, alkyl~ulfonyl, alkanoyl or aralkyl.

( C6-C14 ) -Aryl i5, 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 and aralXyloxy. Aralkyl is understood as meaning an unsubstituted or ~ubstituted (C6-C,;)-aryl radical linked to (Cl C6)-alkyl, such as, for example, benzyl, 1- and 2-naphthylmethyl, halobenzyl and alkoxybenzyl, but aralkyl would not be limited to the radicals mentioned.

Salts of compounds of the formula I are to be under~tood as meaning, in particular, pharmaceutically u6able or non-toxic salts.

Such salt~ are formed, for example, from compounds of the formula I which contain acid groups, for example car-boxyl, with alkali metal~ or alkaline earth metals, sucha~ Na, R, Mg and Ca, and with physiologically tolerated organic amines, such as, for example, triethylamine and tri-(2-hydroxy-ethyl)-amine.

Compounds of the formula I which contain ba~ic groups, for oxample an amino group or a guanidino group, form salts with inorganic acids, ~uch as, for ex~mple, hydro-chloric acid, sulfuric acid or phosphoric acid, snd with organic carboxylic or sulfonic acids, such as, for example, acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid and p-toluenesulfonic acid.

Compounds of the formula I in which the radical~ are defined as follows are preferred:

2C t~3~3 A is as defined on page 1, Rl preferably denotes hydrogen or represents ~Cl-C,0)-alkyl; cyclopentyl; cyclohexyl; cyclopentyl-(C1-C10)-alkyl; cyclohexyl-(C1-C10)-alXyl; optionally BUbsti tuted phenyl-( Cl-C8 3-alkyl; 2-pyridyl-(Cl-C~)-alkyl;
3-pyridyl-(Cl-C~)-alkyl;4-pyridyl-( Cl-Ca ) -alk~l;X2N~
(C~-clO)-alkyl; H0-(C1-C10)-alkyl;( Cl-C4 )-alkoxy-(C1-C~0)-alkyl; ( Cl-C4 )-alkoxycarbonyl-(cl-clo)-alkyl;
(Cl-Ca)-alkylsulfonyl; (C,-C~)-alkylsulfinyl; (C,-C8)-hydroxyalkylsulfonyl;( Cl-C8 )-hydroxy-alkylsulfinyl;
hydroxy-(C~-C~0)-alkanoyl, such a~ 2-hydroxypropio-nyl, 3-hydroxypropionyl, 3-hydroxybutyryl or 2-hydroxy-3-methyl-butyryl; ( C1_CB) -alkanoyloxy-( Clo)-alkyl; (Cl-C~,)-alkanoyl, such as n-decanoyl, formyl, acetyl, propionyl, pivaloyl, isovaleryl or isobutyryl; optionally protected amino-(C,-C")-alkanoyl, such a~ (3-amino-3,3-dLmethyl)propionyl, 4-aminobutyryl, 5-aminopentanoyl, 6-aminohexanoyl, 4-N-tert.-butoxycarbonylaminobutyryl, S-N-t~rt.-butoxycarbonylaminopentanoyl or 6-N-tert.-butoxy-carbonylaminohexanoyl; di-( Cl-C7 ) -alkylamino-( C2-Cl1)-alkanoyl, such as dimethylaminoaGetyl; piperi-dino-4-carbonyl; morpholino-4-carbonyl; (C3-ca)-cycloalkylcarbonyl, such as cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl or cyclo-hexylcarbonyl;(C~-C~ aryl-( C2-Cll )-alkanoyl,sucha~
phenylacetyl, phenylpropanoyl or phenylbutanoyl; 2-pyridyl-(C1-Ca)-alkanoyl;3-pyridyl-( C1_CB ) -a1kanOY1;
4-pyridyl-(C1-C~)-alkanoyl; benzoyl which is option-ally Eub~tituted by halogen, (C1-C7)-alkyl, (C1-C7)-alkoxy or (Cl-C7)-alkoxycarbonyl, such as 4-chloro-benzoyl, 4-methylbenzoyl, 2-methoxycarbonylbenzoyl or 4-methoxybenzoyl; pyrrolyl-2-carbonyl, pyridyl-3-carbonyl;benzenesulfonyl;(C1-C10)-alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, isobutoxy-carbonyl or tert.-butoxycarbonyl; substituted (Cl-C10)-alkoxycarbonyl, such as 2-(trLme~hyl~ilylJ-ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl or ~ 1,1-dimethyl-2,2,2-trichloroethoxycarbonyl;( C6-C14 ) -aryl-(C~-C6)-alkoxycarbonyl, such a~ benzyloxycar-bonyl, 1- or 2-naphthylmethoxycarbonyl or 9-fluorenylmethoxycarbonyl; or R1, together with R10, preferably forms a mono- or bicyclic ~aturated 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 ~ulfone, R2 i8 preferably hydrogen, methyl or ethyl, or, together with R3 and the atoms carrying the~e, preferably forms pyrrolidine or piperidine, each of which can also be fused with cyclopentyl, cyclohexyl or phenyl, R3 and R8 independently of one another are preferably hydrogen; (Cl-C~O)-alkyl, which i~ optionally mono-or diunsaturated and which i8 optionally substituted by up to 3 identical or different radicals from the series comprising hydroxyl, (C1-C~)-alkoxy, (Cl-C7) alkanoyloxy, carboxyl, (Cl-C7)-alkoxycarbonyl, Cl, Br, amino, amidino, guanidino, carbamoyl, (Cl-C5)-alkoxycarbonylamino, (C6-C15)-aralkosycarbonylamino and 9-fluorenylmethoxycarbonyl2mino; (C3-C~)-cyclo-alkyl, (C3-Cl2)-cycloalkyl-(Cl-C3)-alkyl or mono- or bicyclic (C6-C~ aryl-(C1-C3)-alkyl, which iB option-ally substituted by one or two identical or dif-ferent radicals from the serie~ comprising F, Cl, Br, I, hydroxyl, (Cl-C7)-alkoxy, (Cl-C,)-alkyl, (Cl-C7)-alkylcarbonyl, amino and trifluoromethyl; or preferably represent~ (Cl-C3)-alkyl, sub~titu~ed by the radical of 8 5- or 6-membered monocyclic or 9-or 10-membered bicyclic, optionally partly or com-pletely hydrogenated heteroaro~atic having st least 1 carbon atom, 1 - 4 nitrogen ato~s nnd/or 1 or 2 sulfur atoms and/or 1 or 2 oxygen atoms A8 ring members and which is optionally mono- or disubsti-3~)3 _ g tuted as described for the aryl part on pag2 2, or, together with R2 or R~, form ring systems as described above under R2;

R4 i~ preferably (C3-Cl2)-alkyl; mono-, bi- or tricyclic S (C3-Cl8)-cycloalkyl or (C3-C18~-cycloalkylmethyl, the cycloalkyl part optionally being ~ubstituted by (C1-C4)-alkyl; (C6-C14)-arylmethyl; dithiolanyl;
dithiolanylmethyl; dithianyl or dithianylmethyl;

R5 preferably represent~ hydrogen, azido, azido-(Cl-C4)-alkyl, (Cl-Clz)-alkyl, (C3-Cl2)-cycloalkyl, (C3-Cl2)-cycloalkyl-(Cl-C6)-alkyl, (2-pyridyl)-(Cl-C4)-alkyl, (3-pyridyl)-(Cl-C4)-alkyl,(4-pyridyl)-(Cl-C~)-alkyl, imidazol-2-yl, imidazol-l-yl, imidazol-4-yl, (imidazol-2-yl)-(Cl-C~)-alkyl, (imidazol-l-yl)-(Cl-C4)-alkyl, (imidazol-4-yl)-(Cl-C4)-alkyl, [1-(Cl-C6)-alkylimidazol-2-yl]-(Cl-C~)-alkyl, (Lmid-azolin-2-yl)-(Cl-C4)-alkyl or [1-(Cl-C6)-alkylimida-zolin-2-yl]-(C1-C4)-alkyl;

R6 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 ~y~tem having 5 - 18 ring members, which, in addition to the boron atom, the oxygen atoms and the carbon atom(s), can al~o contain an -O- member, an -NRl3- m~mber or a -CR14Rl5- member;

R~ i~ preferably hydrogen, methyl or ethyl, or, to-gether with R8 and the atoms carrying these, forms pyrrolidine or piperidine, each of which can ~ddi-tionally be fused with cyclopentyl, cyclohexyl or phenyl;

Rl i8 preferably hydrogen or methyl, or, together with R1 or R8 and the atoms carrying these, forms a mono-Z~CO ~3~)3 or bicyclic saturated or partly unsaturated ring 8y8tem having 5 - 12 ring member~, which, in addi-tion to carbon, can also contain 1 ~ulfur atom, which can optionally be oxidized to the ~ulfoxide or sulfone;

R1l and R12 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, Rl3 is preferably hydrogen or (Cl-Cl2)-alkyl; and R14 and R15 independently of one another preferably denote hydrogen, hydroxymethyl, 2-hydroxyethyl, (3-hydroxysulfonyl, 2-hydroxypropyl~amino, (2-hydroxy-sulfonylethyl)amino, (2-hydroxysulfonylpropyl) ~ino, (carboxymethyl)amino or bis(2-hydroxyethyl)amino.

R1 particularly preferably denotes (Cl-C8)-alkylsul-fonyl; ( Cl-C9 ) -alkyl8ulfinyl; ( Cl-C8 )-hydroxyalkylsul-fonyl, in particular 2-hydroxyethylsulfonyl or 2-hydroxypropylsulfonyl; hydroxy-(C1-C10)-alkanoyl, such as 2-hydroxypropionyl, 3-~ydroxypropionyl, 3-hydroxybutyryl or2-hydroxy-3-methylbutyryl; (Cl-Ca)-alkanoyloxy-(Cl-C10)-alkyl; (C1-C11)alkanoyl, such a~
n-decanoyl, for~yl, acetyl, propionyl, pivaloyl, isovaleryl or isobutyryl; amino-tCl-C11)-alkanoyl, such a~ (3-amino, 3,3-dimethyl)propionyl, 4-amino-butyryl, 5-aminopentanoyl, 6-aminohexanoyl; di-(C1-C7 )-alkylamino-tC2-C11)-alkanoyl, such as dimethyl-aminoacetyl; piperidino-4-carbonyl; morpholino-4-carbonyl; (C3-C9)-cycloalkylcarbonyl, ~uch as cyclo-propylcarbonyl, cyclobutylcarbonyl, cyclpentylcar-bonyl or cyclohexylcarbonyl; ( C6-C10 ) -aryl-( C2-Cll ) -alkanoyl, such as phenylacetyl; phenylpropanoyl or 2(:~0 ~3~3 phenylbutanoyl; 2-pyridyl-( C1_CB )-alkanoyl; 3-pyr-idyl-(C1-C~)-alkanoyl; 4-pyridyl-(Cl-C~)-alkanoyl;
benzoyl which i8 optionally ~ubstituted by halogen, (Cl-C7)-alkyl, (Cl-C7)-alkoxy or (Cl-C7)-alkoxycar-bonyl, such as 4-chlorobenzoyl, 4-methylbenzoyl, 2-methoxycarbonylbenzoyl or 4-methoxybenzoyl; pyr-rolyl-2-carbonyl; pyridyl-3-carbonyl; benzene6ul-fonyl; (Cl-C1O)-alkoxycarbonyl, ~uch a~ methoxycar-bonyl, ethoxycarbonyl, isobutoxycarbonyl or tert.-butoxycarbonyl; substituted (C,-ClD)-alkoxycarbonyl, such a6 2-(trimethylsilyl)-etho~ycarbonyl, 2,2,2-trichloroethoxycarbonyl or 1,1-dLmethyl-2,2,2-trichloroethoxycarbonyl; or ( C6-C14 ) -aryl-( ~1-c6 ) -alkoxycarbonyl, such as benzyloxycarbonyl, 1- or 2-naphthylmethoxycarbonyl or 9-fluorenylmethoxycar-bonyl, R2 particularly preferably denote~ hydrogen or methyl, or, together with R3 and the -~-CH- group carrying these radicals, form~ a tetrahydroi~oquinoline or azabicyclooctane ~keleton, R3 and R4 independently of one another are particularly preferably hydrogen, methyl, ethyl, i~opropyl, n-propyl, n-butyl, isobutyl, zec.-butyl, 3-guanidino-propyl, carbamoylmethyl, 2-carbamoylethyl, carboxy-methyl, 2-carboxyethyl, mercaptomethyl, 2-(methyl-thio)ethyl, (1-mercapto,l-methyl)ethyl, hydroxy-methyl, 1-hydroxyethyl, amino, aminomethyl, 2-bminoethyl, 3-aminopropyl, 4-aminobutyl, 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-thienyl~ethyl, 2-(2-thienyl)-ethyl, 3-thienyl, 3-thienylmethyl, 2-(3-thienyl)ethyl, 4-chlorobenzyl, 2-tmethylsulfinyl)-ethyl, 2-(methylsulfonyl)ethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, cyclohexyl, (1-2 0 ~

methyl-imidazol-4-yl)methyl, (3-methyl-imidazol-4-yl)methyl, phenyl, l-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-benzotb]thienylmethyl or 2-furylmethyl, or with R2 or R~ form ring systems as defined above under R2, R~ is particularly preferably (C3-Cl2)-alkyl; mono- or bicyclic (C3-Cl2)-cycloalkyl or (C3-C,2)-cycloalkyl-methyl, the cycloalkyl part optionally being 6ub~ti-tuted by (Cl-C~)-aryl; ( C6-clo )-arylmethyl; dithio-lanyl; dithiolanylmethyl; dithianyl or dithianyl-methyl, R5 iB particularly preferably hydroqen, azido, azido-methyl, 2-azidoethyl, (Cl~C6)-alkyl, (C3-C12)-cyclo-alkyl, (C3-Cl2)-cycloalkyl-(Cl-C3)-alkyl, 3-(2-pyri-dyl)-propyl, 3-(3-pyridyl)-propyl, 3-(4-pyridyl)-propyl, imidazol-2-yl, imidazol-1-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, R6 and R7 are as defined on page 9, R~ particularly preferably denotes hydrogen or methyl, or, together with R~ and the -~-CH- group carrying these radical~, forms a tetrahydroi~oquinoline or azabicyclooctane ~keleton, Rl particularly preferably denote6 hydrogen, or, together with R1 and the atoms carrying these, forms a mono- or b~cyclic saturnted or partly un~aturated ring sy~tem having 5-12 ring m~mber~, which, in addition to carbon, also contain~ 1 ~ulfur atom, which i~ particularly preferably oxidized to the sulfone, or, together with R8 and the atoms carrying 2 ~ )3 these, forms a thiochroman system, the ~ulfur atom of which i8 particularly preferably oxidized to the sulfone, R~1 and R12 independently of one another are particularly preferably hydrogen, hydroxyl, phenyl, 2-thienyl, 2-, 3- or 4-pyridyl, 1- or 2-imidazolyl, l-naphthyl or 2- or 3-benzo[b]thienyl, n and m independently of one another are particularly preferably 0, 1 or 2, Rl3 is particularly preferably hydrogen or [C~-C4)-alkyl, and R1~ 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 com-prises coupling a fragment havin~ a terminal hydroxyl group or a reactive derivative thereof with a correspond-ing fragment having a free amino group, if appropriate splitting off (a) protective group(s) temporarily intro-duced to protect other functional groups, and if appro-priate converting the compound thus obtained into its physiologically tolerated ~alt.

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

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

2C~'~*3~3 R9 R8 o R2 R3 R4 P ~ ( YI I I ) HN - CH - C - N - CH - C - HN - C~ - CH - R5 oR6 oR7 R2 R3 R4 ( I2~ ) HN - CH - C - HN - CH - CH - R
B

oR6 oR7 .4 ~2N - C}I - CH - R5 B (X) OR OR

Methods which are suitable for the production of an emide bond are described, for exzmple, in Houben-Weyl, Methoden der oryanischen Chemie [Method~ of Organic Chemistry~, Volume 15/2; and Bodanszky et al., Peptide Synthesis, 2nd ed. (Wiley & Sons, New York 1976) or Gro~s and Meienhofer, The Peptides: Analysis, Synthesis, Biology (Academic Pre6s, New York 1979). The following method~
are preferably u~ed: active ester methods with N-hydroxy-succinhmide, l-hydroxybenzotriazole or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine as the alcohol co~ponent, coupling with a carbodiimide, such as dicyclohexylcarbo-di~mide, or with propanephosphonic anhydride and the mixed anhydride method with pivaloyl chloride or ethyl or isobutyl chloroformate.

Pragments of the formula VI where they a) fall under formula II are ~nthesized by the gener-ally known methods for the preparation of amino ZC~ )3 acids;

b) fall under formula III are synthesized ~tarting from the corresponding amino acids, the chirality center thereof being retained. Diazotization at -20C to 50C in dilute mineral acids leads to ~bromo-carboxylic acids or, via the lactic acids~ to ~-trifluoromethanesulfonyloxy-carboxylic acids, which can be reacted with 2 nucleophile carrying Rl and Rl;

c) fall under formula IV are prepared ~tartinq from malonic ester~, alkylation of which with arylalkyl halides gives mono- or disub~tituted malonic ester~, which, after hydrolysis, can be converted into the desired derivatives by decarboxylation. In the ca e where one of the radicals Rll or Rl2 denotes hydroxyl, the corresponding amino acid is used as the starting ~ubstance and diazotization (as de~cribed above) gives the lactic acid (number of CH2 groups carrying Rll or Rl2 = 0), or the substituted malonic acid i8 used as the ~tarting substance, monohydrolysis and ~elective reduction (with, for example, diborane or LiAlH4) giving the 2-Eubstituted 3-hydroxy-propionic acid.

Fragments of the formula VII are synthesized by the generally known methods for ~he preparation of amino acids and peptides.

For the synthesis of the fragments of the formula X, N-protected ~-amino acid~ are converted into the ~-amino-aldehydes in Accordance with the method of B. Castro et al. (Synthesis 1983, 676). A Wittig reaction with a pho~phonium ~alt carrying the radical R5 then ~akes place, followed by hydroboronation.

The preliminary and ~ubsequent operations required for the preparation of compound3 of the formula I, such as 2C~ )3 introduction and splitting off of protec~ive groups, are known from the literature and are described, for example, in T.W. Greene "Protective Groups in Organic Synthesi~"
(John Wiley ~ Sons, New York, 1981). Salts of compounds of the formula I with salt-forming qroups are prepared in a manner which is known per ~e, for example by reacting a compound of the formula I having a ba~ic group with a stoichiometric amount of a suitable acid, or reactin~
compounds of ~he formula I having an acid group with a stoichiometric amount of a suitable base. Stereoisomer mixtures, in particular diastereomer mixture~, which are obtained, if appropriate, in the synthe6i6 of compounds of the formula I, can be resolved in a manner which i~
known per se by fractional crystallization or by chroma-tography.

The compounds of the formula I accordin~ to the inventionexhibit enzyme-inhibiting properties, and in particular they inhibit aspartyl proteases, such a~ renin, Renin i8 secreted into the blood circulation by the ~uxtaglomerular cells of the kidneys as a result of Yarious stimuli (volume depletion, sodium deficiency, ~-receptor ~timulation). In the blood circulation it splits off the decapeptide angiotensin I from the angioten-sinogen secreted from the liver. This angioten~in I i8converted into angiotensin II by "angiotensin converting enzymen (ACE~. An~iotensin II plays an essential role in blood pre~sure regulation, since it increases the blood pressure directly by vasoconstriction. In addition, it stimulates the ~ecretion 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 increa~ing the blood pres-sure. Inhibitors of the enzymatic activity of renin cause reduced formation of angiotensin I, which results in reduced formation of angiotensin II. The reduction ~n the concentration of this active peptide hormone i3 the 20~3~:3 direct cause of the antihypertensive action of renin inhibitors.

The activity of renin inhibitors can be investigated by in vitro te6ts. In these, the reduction of the formation S of angioten~in I i8 measured in various ~ystems ~human plasma and purified human renin).

1. Test principle For example, human plasma which contains both renin and angiotensinogen i8 incubated at 37C with the compound to be tested. During this incubation, angiotensin I i8 liberated from the angiotensinogen under the action of renin, and can ~ubsequently be measured with a commer-cially available radioimmunoas6ay method. This angio-tensin liberation i8 inhibited by renin inhibitors.

2. Isolation of the pla~ma The blood is obtained from volunteer sub~ects (about 0.5 1 per person; ~luko withdrawal apparatus from ASID
Bonz und Sohn, Unterschleissheim) and is collected in partially evzcuated bottles, while coolin~ with ice. The coagulation is prevented by addition of EDTA (final concentration 10 mM). After centrifu~ation (Rotor HS 4 (Sorvall), 3500 r.p.m., 0-4C, 15 minutes; repeat if neces~ary), the plasma i8 carefully pipetted off and frozen in suitable portion at -30C. Only plasmas with a sufficiently high renin activity are used for the test.
Pla~mas with a lower renin activity are activated (prorenin -> renin) by a low temperature treatment (-4C, 3 day8).

3. Te~t procedure Angiotensin I i6 determined with the Renin-MaiaO kit (Seronon Diagnostics S.A., Coinsins, Switzerland). The plasma i8 incubated in accordance with the instructions 2~

given with the kit:

Incubation batch: 1000 ~1 of pla~ma (thawed at 0-4C) 100 ~1 of phosphate buffer (pH 7.4) addition of 10-~ ~ ramipri late) 100 ~1 of PMSF solution 10 ~1 of 0.1 % strength Genapol ~FIC
12 ~1 of DMS0 or test preparation The test preparation~ are in general di~601ved in a concentration of 10-~ M in 100 ~ pure dLmethyl ~ulfoxide (DNS0~ and the solutions are diluted appropriately with DMS0; the incubation batch contains not more than 1 % of DNS0.

The batche~ are mixed with ice and placed in a water bath (37C) for 1 hour for incubation. A total of 6 ~amples (in each case 100 ~1) 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.

The concentrations of the test preparations are chosen ~o that approxlmately the range from 10 - 90 % enzyme inhibition is ccvered ~at least five concentrations). At the end of the incubation time, three 100 ~1 ~amples from each batch are frozen on dry ice in pre-cooled Eppendorf vessels and kept at about -25C for the angiotensin I
determination (mean value of three individual ~ample~).

An~iotensin I radioim~unoas~ay tRIA) The use instructions of the RIA kit (Renin Maie0 kit, Serono Diagno~tics S.A., Coinsins, Swit~erland) are followed exac~ly.

The calibration curve cover~ the range from O . 2 to 25 . O
ng of angioten~in I per ml. ~he base angiotensin I

~c~

content of the plasma is subtracted from all the measure-ment 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-hibitor (= 100 %) and given as % residual activity. TheIC5~ 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 present invention exhibit inhibiting actions in the in vitro test at concentrations of about 10-5 to 10-1 mol/l.

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 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 in~ection of furosemide. The test compounds are then administered and 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 ~ S mg/kg intravenously, on intraduodenal administration by a gastroscope in the dose range of about l - 50 mg/kg. The compounds of the general formula I described in the present invention can be used as antihypertensives and for the treatment of cardiac insufficiency.

- 20 ~
2C0~

The invention furthermore relates to the use of compound6 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.

Pharmaceutical preparations contain an effective amount of the acti~e compounds of the formula I together wi~h an inorganic or organic pharmaceutically usable excipient.

They can be administered intranasally, intravenou61y, 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 admini-6tration.

~he pharmaceutical preparations of the present invention are prepared by dissolving, mixing, granulating or tablet-coating proce~ses which are known per se.

For the oral use form, the active compounds are mixed with the additives customary for these, ~uch as excipi-ents, stabilizer6 or tnert diluent~, and the ~ixture is brought by cufitomary methods into suitable presentation forms, such a~ tablets, coated tablets, hard gelatine push-fit capsules, aqueous, alcoholic or oily sus~en~ion~
or aqueous, alcoholic or oily solutions. Examples of inert excipients which can be u~ed are gum arabic, magnesia, magnesium carbonate, potas~ium phosphate, ~C~ )3 lactose, glucose, magnesium stearylfumarate or starch, inparticular maize starch. Formulation can be effected here either in the form of dry granules or in the form of moist granules. Examples of pos~ible oily excipients or solvents are vegetable or anLmals oil~, such as ~unflower oil and cod-liver oil.

For subcu~aneou~ or intravenous administration, the active compounds or physiolo~ically tolerated salt~
thereof are brought into solutions, suspension~ or emulsions, if desired with the substances customary for these, such as solubilizing agents, emulsifiers or other additives. Examples of po~sible solvent~ are: 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 men-tioned.

Li~t of abbreviations used Ac acetyl 20Boc tert.-butoxycarbonyl bp~ boiling point under xx mm Hg BuLi n-butyllithium DCC dicyclohexylcarbodiimide DCI desorption chemical ionization 25DIP dii~opropyl ether DMF dimethylformamide DNSO dimethyl ~ulfoxide DNP 2,4-dinitrophenyl EA ethyl acetate EI electron impact Etoc ethoxycarbonyl FAB fast atom bombardment H hexane HOBt l-hydroxybenzotriazole Iva i~ovaleryl M molecular peak 2C~

M.p. melting point MeOH methanol NS mass spectrum MTB methyl tert.-butyl ether Nle norleucine Nva norvaline R . T . room temperature THF tetrahydrofuran Thi ~-2-thienylalanine TLC thin layer chromatography Z benzyloxycarbonyl.

The other abbreviations used for amino acids correspond to the three-letter code customary in peptide chemistry, such afi is described in Eur J. Biochem. 138, 9 - 37 (1984). Unles~ expres~ly indicated otherwise, the amino acids are always in the L-confiquration.

The following examples ~erve to illustrate the present invention, without this being limited thereto.

~sample 1 t3-tert.-Butylsulfonyl, 2-(2)-thienylmethyl]propionyl-Nva-[l-cyclohexylmethyl, 2-(4,4,5,5-tetramethyl-1,3,2-dio~aborolan-2-yl), 5-methyl]hexylamide 346 mg of [3-tert.-butyl6ulfonyl,2-(2)-thienylmethyl]-propionyl-Nva-OH are dissolved in 40 ml of THF and first 98 ~1 of N~methylmorpholine and then 115 ~1 of isobutyl chloroformate are in~ected in at -20C. After 10 minute~
at -20C, 123 ~1 of triethylamine are added. The mixed anhydride thus obtained is in~ected into a solution of 400 mg of tl-cyclohexylmethyl, 2-(4,4,5,5-tetramathyl-1,3,2-dioxaborolan-2-yl), 5-methyl]hexylammoniu~ tri-fluoroacetate in 40 ml of THF. The mixture is ~tirred at -20C for 1 hour and left to stand at ~.T. for 22 hours.
It i~ diluted with 100 ml of NTB and wa~hed twice with 30 ~1 of 5 ~ ~trenqth aqueous NaHSO~ solution each time ~0~ )3 and twice with 30 ml of 5 % strength aqueous Na2CO3 601ution each time. The organic phase i8 dried over Na2SO4 and the solvent is removed in vacuo. Chromatography on silica gel with NTB/DIP = 1:1 give~ 160 mg of the title S compound as ~olorless cry~tals.

Rf (MTB/DIP 1:1) = 0.50 MS (FAB): 709 (M+l) a~[3-t-Butyl~ulfonyl,2-(2-thienylmethyl)]propionyl-Nva-OH

490 mg of [3-t-butylsulfonyl, 2-(2-thienylmethyl)lpropio-nyl-Nva-ONe 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 NaHSO4 solution and extracted 3x with 50 ml of EA.
The extract is then dried over Na2SO4 and the solvent i~
removed in vacuo. 470 mg of pale yellow resin are ob-tained.

R (EA) = 0.24 MS (FAB): 390 (M+1) b)[3-t-Butylsulfonyl,2-t2-thienylmethyl)]propionyl-Nva-OMe 1.5 g of t3-t-butyl~ulfonyl, 2-t2-thienylmethyl)]pro-pionic acid and 0.95 g of Nva-OMe x HCl are di~solved in 40 ml of CH2Cl2, and first 3.8 ml of triethylamine and then 3.5 ml of 8 50 ~ strength solution of propanephos-phonic anhydride in CH2Cl2 are hdded at lO~C. The mixture i6 stirred at R.T. for 20 hour~, the 601vent is removed in vacuo, the residue is taken up in 100 ml of NTB and the mixture is washed with 100 ml each of NaHSO~ 301ution and NaHCO3 solution. It is dried over Na2SO~, the solvent is removed in vacuo and the re~idue is chromatographed with ~/H 1:1. 2 diastereomeric oils are obtained and are further processed separately.

)3 Diastereomer 1 Rr ( EA/H 1: 1 ) = O . 3 0 0 . 9 5 g Diastereomer 2 R~ (EA/H 1:1) = 0.20 O.9S g MS (DCI, the same for both diastereom0rs): 404 (~+1) c) ~3-t-Butylsulfonyl,2-(2 thienylmethyl)]propionic acid 4.4 g of met~yl [3-t-butylsulfonyl,2-(2-thienylmethyl)]-propionate are suspended in 50 ml of 5N HCl and the suspension i8 heated under reflux for 2 hours. After cooling, it is extracted 3x with 50 ml of EA, the extract is dried over Na2SO4 and the solvent i8 removed in vacuo.
4.0 g of the title compound are obtained a~ a pale yellow oil.
R~ (MTB) = 0.15 - 0.25 MS (DCI): 291 (M~l) d) Methyl t3-t-butylsulfonyl, 2-(2-thienylmethyl)]pro-pionate 8.4 g of methyl [3-t-butylsulfonyl,2-(2-thienylmethyl)]-propionate are dis~olved in 100 ml of CH2Cl2, and 10.6 g of m-chloroperbenzoic acid are added in portiGns, while cooling with ice. The mixture i~ stirred at R.T. for 1 hour and then washed first with 100 ml of 10 % strength Na2SO3 and then with 100 ml of NaHCO3. It i8 dried over Na2SO~ and the solvent is removed in vacuo. 7.2 g of the title compound are obtained as a colorle~ oil.
R~ (MTB) = 0.56 MS (DCI)s 305 tM~l) e) Nethyl t3-t-butylthio, 2-(2-thienylmethyl)]propionate 6.1 ml of t-butyl ~ercaptan are di~solved in 100 ml of MeOH (anhydrou~) and 130 mg of ~aH are added under argon.

7.6 g of methyl 2-(2-thienylmethyl)acrylatR are then added dropwise and the mixture i8 ~tirred at R.T. for 4 hours. The ~olvent i8 removed in vacuo, the residue is 2IG~

taken up in 100 ml of MTB and the mixture iB washed with 100 ml of 5 % ~trength NaHSO4 solution. It i8 dried over Na~SO~ and the solvent is removed in vacuo. 10.4 g of the title compound are obtained as a pale yellow liquid, which is used further without purification and charac-terization.
R~ (DIP/H 1:5) = 0.31 f) Methyl 2-(2-thienylmethyl)acrylate 11.8 g of monomethyl 2-thienylmethylmalonate, 5.8 ml of diethylamine and 5.0 ml of 36 ~ strength aqueous form-aldehyde fiolution are stirred at R.T. under argon for 1 hour. The water is then removed in vacuo and the residue i~ chromatographed. 7.6 g of the title compound are obtained as a colorless liquid.
~k (NTB/H 1:5) = 0.49 g) Monomethyl 2-thienylmethylmalonate 20.1 g of dimethyl 2-thienylmethylmalonate are di~solved in 300 ml of MeOH and 5.0 g of ROH are added. The mi~ture i8 ~tirred at R.T. for 7 hour~, the ~olvent i8 removed in vacuo and the residue i~ taken up with 100 ml each of 5 %
strength Na2CO3 solution and EA. The aqueous phase i8 then ~cidified to pH = 2 and extracted 3x with 100 ml of EA
each time. The ~xtract i8 dried over Na2SO4 and the solvent i8 r~moved in vacuo. 16.0 g of the title compound are obtained a~ a pale yellow oil.
F4 (EA/MeOH 6:1) = 0.3 - 0.4 h) Dimethyl 2-thienylmethylmalonate 87.8 g of dimethylmalonate and 41.0 g of pota88ium t-butylate are dissolved in 1.1 1 of THF (anhydrous), while cooling with ice, and 44.1 g of 2-thienylmethyl chloride 21~3~3 in 500 ml of THF are added dropwi6e, under argon. The mixture i8 stirred at R.T. for 3 hours, the ~Cl is filtered off, the solvent is removed in vacuo and the residue is chromatographed. 33.8 ~ of the title compound S (I) are obtained as a colorless oil alongside 8.8 g of dimethyl bis-(2-thienylmethyl)malonate (II) Rf (I) (toluene/DIP 20:1) = G.35 R~ (II) (toluene/DIP 20:1) = 0.44 g) 2-Thienylmethyl chloride 252 g of thiophene are su6pended in 128 ml of concen-trated aqueous HCl and HCl gas is passed in at 0C for 1 hour. 255 ml of 35 % strength aqueous formaldehyde ~olution are then added dropwi6e without interrupting the stream of HCl, and the mixture i6 stirred at 0C for a further 15 minutes. After removal of the organic phase, the aqueous pha6e i8 extracted twice more with 600 ml of CH2Cl2. The extract i8 then wa6hed twice with 600 ml of saturated aqueous Na2CO3 solution and dried over Na2SO~, the solvent i8 removed in vacuo and the residue is distilled. 174 g of the title compound are obtained as a colorless liquid.
bp~ = 81 - 84C

h) [1-Cyclohexylmethyl, 2-(4,4,5,5-~etramethyl-1,3,2-dioxaborolan-2-yl), 5-methyl]hexylammonium trifluoro-acetate 520 mg of Z-~1-cyclohexylmethyl, 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl), 5-methyl]hexylamine and 95 ~1 of trifluoroacetic acid are di~solved in 10 ml of EtOH, 105 mg of Pd/C are added and hydrogenation i6 carried out at R.T. under a pres~ure of 1 bar for 2.5 hourg. The c~talyst i6 then filtered off and the solvent is r~moved in vacuo. 400 mg of the title compound are obtained a~ a colorle~ oil which i8 u~ed further without purification.

~C~ )3 MS (DCI) s 338 (M+l) i) Z-[l-Cyclohexylmethyl, 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl), 5-methyl]hexylamine 6.5 g of Z-(l-cyclohexylmethyl, 5-methyl)-hex-2-en-amine are dissolved in 190 ml of THF under argon. 5.7 ml of BH3-S(CH3)2 are added dropwise at 0C and the mixture is stirred at R.T. for 1 hour. Water is then 810wly added dropwise until the evolution of hydrogen has ended. The solvent i8 removed in vacuo and subsequently evaporated twice on a rotary evaporator with 100 ml of toluene each time. The residue is dissolved in 120 ml of CH2Cl2 and 11.2 g of pinacol are added. The mixture is boiled for 4 hours over a water separator, the CH2C12 i8 removed in vacuo and the residue is chromatographed on silica gel with EA/n-hexane = 1:8. 4.7 g of the title compound are obtained as a diastereomer mixture, which can be separ-ated by renewed chromatography.

h~ (EA/n-hexane = 1:8) = 0.25 NS (DCI) s 472 (N+l) 0.22 k~ Z-(l-Cyclohexylmethyl, 5-methyl)-hex-2-en-amine 13.1 g of (isopentyl, triphenyl)phosphonium bromide arç
suspended in 280 ml of THF, and 3.2 g of potassium tert.-butylate are added. The mixture i~ stirred at R.T. for 2.5 hours and then cooled to 0C, snd 8.3 g of Z-(2(S)-cyclohexylmethyl)-aminoacetaldehyde in 100 ml of THF are added dropwise. The mixture i8 ~tirred at R.T. for 1 hour, 200 ml of NTB are added and the mixture i~ washed twice with 50 ml of 5 ~ strength aqueous NaHS0~ ~olution each time and twice with 50 ml of 5 % ~trength aqueous Na~C03 solution each time. The organic phase is dried over Na2S04 and the solvent i~ removed in vacuo~ Chromatography on silica gel give~ 6.5 g of the title compound as a colorles~ oil.

2C~3~

R~ ~EA/n-hexane = 1:~) = 0.28 MS (DCI) : 344 (M+1~

xamples 2 and 3 were ~ynthesized analogously to Fsa~ple ~ample 2 [2-(S)-Benzyl,3-tert.-butylsulfonyl]propionyl-Nva-[l-cyclohexylmethyl,2-(4,4,5,5-tetramethyl-1j3,2-dioxa-borolan-2-yl),5-methyl]hexylamide F~ ~NTB/DIP 1:1) = 0.52 MS (FAB) : 703 (M+1) ~xample 3 ~3-tert.-Butylsulfonyl,2-(1-n~phthylmethyl)]propionyl-Val-[l-cyclohexylmethyl,2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl),2-cyclopentyl]methylamide F~ (MTB/DIP 1:1) = 0.42 MS (FAB) : 751 (M+l) ~sample 4 Boc-Ph0-His-[l-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]-hexylEmide are di~solved in 5 ml of acetonitrile and 281 ~1 of thiophenol are added. The mixture i8 ~tirred for 3 hours at R.T., the solvent iB removed in vacuo and the re~idue i8 chromatographed on silica gel with MeOH/EA 1:20. 130 mg of the title compound are obtained as a colorless amorphou~ powder.

R~ (EA/MeOH 20:1) = 0.35 MS (FAB) : 722 ~+1) 2C~ 3~:~

a) Boc-Phe-His(DNP)-[1-Cyclohexylmethyl,2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl),5-methyl]hexylamide The title compound was ~ynthesized analogously to Example 1.

Rf (MTB) = 0.27 MS (FAB) : 872 (M+l) Example 5 wss synthesized analogou~ly to Example 4:

Example 5 [2-(S)-Benzyl,3-tert.-butylsulfonyl]propionyl-His-[l-cyclohexylmethyl,2-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl),5-methyl]hexylamide R~ (EA/M~OH 10:1) = 0.20 NS (FAB~ : 741 (M+l) E~ample 6 [2-(S)-Benzyl,3-tert.-butylsulfonyl]propionyl-His-[1-cyclohexylmethyl,2-dihydroxyboryl,5-methyl]hexylamide 217 mg of the title compound of Example 5 and 220 ~1 of titanium isopropoxide are di~solved in 100 ml of n-propanol and boiled for 8 hours under a Soxhlet extractor which i8 filled with 0.3 nm molecular ~ieve. The reaction ~olution is poured onto 100 ml of saturated NaHCO3 801u-tion, the TiO2 i8 filtered off, the solution is extracted 3 time~ with 50 ml of EA and dried over Na2SO~. The solvent is removed in vacuo and chromatographed on 8ilica gel with CH2Cl2/MeOH 10:1. 43 mg of the title compound are obtained aR a white amorphous powder.

Rf (CH2Cl2/MeOH 10:1) = 0.28 MS tFAB) : 659 (M+l),

Claims (8)

1. A compound of the formula I

in which A denotes a radical of the formula II, III or IV
(II) (III) (IV) in which R1 a1) denotes hydrogen, (C1-C12)-alkyl, which is option-ally mono- or diunsaturated and is optionally substituted by up to 3 identical or different radicals from the series comprising hydroxyl, (C1-C7)-alkoxy, carbamoyl, (C1-C8)-alkanoyloxy, carboxyl, (C1-C7)-alkoxycarbonyl, F, Cl, Br, I, amino, amidino, which can optionally be substi-tuted by one, two or three (C1-C8)-alkyl radicals, guanidino, which can optionally be substituted by one, two, three or four (C1-C8)-alkyl radicals, (C1-C7)-alkylamino, di-(C1-C7)-alkylmino, (C1-C5)-alkoxycarbonylamino, (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 (C1-C6)-alkyl and aryl optionally being substi-tuted by one or two identical or different radicals from the series comprising F, Cl, Br, I, hydroxyl, (C1-C7)-alkoxy, (C1-C7)-alkyl, (C1-C7)-alkoxycarbonyl, amino and trifluoromethyl;
(C6-C14)-aryl-(C1-C6)-alkyl, in which the aryl part is optionally substituted by one or two identical or different radicals from the series comprising F, Cl, Br, I, hydroxyl, (C1-C7)-alkoxy, (C1-C7)-alkyl, (C1-C7)-alkoxycarbonyl, amino, (C1-C7)-alkylamino, di-(C1-C7)-alkylamino, carboxyl, carboxymethoxy, amino-(C1-C7)alkyl, (C1-C7)-alkyl-amino-(C1-C7)alkyl, di-(C1-C7 )-alkylamino-(C1-C7)-alkyl, (C1-C7)-alkoxycarbonylmethoxy, carbamoyl, sulfamoyl, (C1-C7)-alkoxysulfonyl and sulfo- and guanidino-(C1-C8)-alkyl; or represents the radical of a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic partly or completely hydrogen-ated hetaroaromatic 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 (C8-C14)-aryl defined under a1), or a2) denotes a radical of the formula V
R1' - W (V) in which R1 is defined as R1 under a1) and W
represents -CO-, -O-CO-, -SO2-, -SO-, -NH-SO2-, -NH-CO-, -CH(OH)- or -N(OH)-;

R2 denotes hydrogen or (C1-C8)-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;

R3 and R3 independently of one another are defined as under a1) or, together with R2 or with R9 and the atoms carrying these, form ring systems having 5-12 ring members, as defined above;

R4 denotes (C3-C12)-alkyl, mono-, bi- or tricyclic (C3-C16)-cycloalkyl, (C3-C18)-cycloalkylmethyl or (C3-C18)-cycloalkylethyl, the cycloalkyl part option-ally being substituted by (C1-C6 )-alkyl; dithiolanyl;
(C6-C14)-arylmethyl; dithiolanylmethyl; dithiolanyl-ethyl; dithianyl; dithianylmethyl or dithianylethyl;
R5 denotes hydrogen; azido; azido-(C1-C4)-alkyl;
(C1-C12)-alkyl, which can optionally be substituted by hydroxyl, azido or hydroxyl and azido; (C3-C12)-cycloalkyl; (C3-C12)-cycloalkyl-(C1-C6)-alkyl;
(C3-C12)-cycloalkylsulfonyl-(C1-C6)-alkyl; (C1-C6)-alkylsulfonyl-(C1-C6)-alkyl; (C6-C14)-aryl or (C6-C14)-aryl-(C1-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 hetero-aromatic having at least 1 carbon atom, 1 - 4 nitro-gen 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 like-wise possible that aryl and heteroaryl can be substituted as defined under a1).

R6 and R7 independently of one another denote hydrogen or (C1-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 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 -CR14R15-member;

R9 represents hydrogen or (C1-C8)-alkyl, or, together with R6 and the atoms carrying these, forms a mono-or bicyclic, ssturated or partly unsaturated ring system having 5-12 ring members;

R10 is hydrogen or (C1-C8)-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;

R11 and R12 independently of one another denote hydrogen, hydroxyl or (C6-C14)-aryl, aryl optionally being sub-stituted by one or two identical or different radicals from the series comprising F, Cl, Br, I, hydroxyl, (C1-C7)-alkoxy, (C1-C7)-alkyl, (C1-C7)-alkoxycarbonyl, amino, (C1-C7)-alkylamino,di-(C1-C7)-alkylamino, carboxyl, carboxymethoxy, amino-(C1-C7)-alkyl, (C1-C7)-alkylamino-(C1-C7)-alkyl, di-(C1-C7)-alkylamino-(C1-C7)-alkyl, (C1-C7)-alkoxycarbonyl-methoxy, carbamoyl, sulfamoyl,(C1-C7)-alkoxysulfonyl snd sulfo- and guanidino-(C1-C6)-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 (C8-C14)-aryl above, n and m independently of one another can be 0, 1, 2, 3 or 4, R13 denotes hydrogen or (C1-C12)-alkyl, which is option-ally mono- or diunsaturated and is optionally substituted by up to 3 identical or different radicals from the series comprising hydroxyl, (C1-C7)-alkoxy, amino and mono- or di-(C1-C7)-alkyl-amino, and R14 and R15 independently of one another denote hydrogen, (C1-C8)-alkyl, hydroxymethyl, 2-hydroxyethyl, (3-hydroxysulfonyl, 2-hydroxypropyl)amino, (2-hydroxy-sulfonylethyl)amino, (2-hydroxysulfonylpropyl)amino, (carboxymethyl)amino or bis(2-hydroxyethyl)amino, or a physiologically tolerated salt thereof.

2. A compound of the formula I as claimed in claim 1, wherein R1 denotes hydrogen or represents (C1-C10)-alkyl;
cyclopentyl; cyclohexyl-; cyclopentyl-(C1-C10)-alkyl;
cyclohexyl-(C1-C10)-alkyl; optionally substituted phenyl-(C1-C8)-alkyl; 2-pyridyl-(C1-C8)-alkyl; 3-pyridyl-(C1-C8)-alkyl; 4-pyridyl-(C1-C8)-alkyl; H2N-(C1-C16)-alkyl; HO-(C1-C10)-alkyl; (C1-C4)-alkoxy-(C1-C10)-alkyl; (C1-C4)-alkoxycarbonyl-(C1-C10)-alkyl;
(C1-C8)-alkylsulfonyl; (C1-C8)-alkylsulfinyl; (C1-C8)-hydroxyalkylsulfonyl; (C1-C8)-hydroxyalkylsulfinyl;
hydroxy-(C1-C10)-alkanoyl; (C1-C8)-alkanoyloxy-(C1-C10)-alkyl; (C1-C11)-alkanoyl; optionally protec-ted amino-(C1-C11)-alkanoyl; di-(C1-C7)-alkylamino-(C2-C11)-alkanoyl;piperidino-4-carbonyl;morpholino-4-carbonyl;(C3-C9)-cycloalkylcarbonyl;(C6-C10)-aryl-(C2-C11)-alkanoyl; 2-pyridyl-(C1-C8)-alkanoyl; 3-pyridyl-(C1-C8)-alkanoyl;4-pyridyl-(C1-C8)-alkanoyl;
benzoyl which is optionally substituted by halogen, (C1-C7)-alkyl, (C1-C7)-alkoxy or (C1-C7)-alkoxycar-bonyl; pyrrolyl-2-carbonyl, pyridyl-3-carbonyl;
benzenesulfonyl;(C1-C10)-alkoxycarbonyl;substituted (C1-C10)-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 can optionally be oxidized to the sulfoxide or sulfone, R2 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, R3 and R8 independently of one another denote hydrogen;
(C1-C10)-alkyl, which is optionally mono- or diun-saturated and is optionally substiuted by up to 3 identical or different radicals from the series comprising hydroxyl, (C1-C7)-alkoxy, (C1-C7)-alkanoyl-oxy, carboxyl, (C1-C7)-alkoxycarbonyl, Cl, Br, amino, amidino, guanidino, carbamoyl, (C1-C5)-alkoxycar-bonylamino, (C6-C15)-aralkoxycarbonylamino and 9-fluorenylmethoxycarbonylamino; (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C3)-alkyl or mono- or bicyclic (C6-C12)-aryl-(C1-C3)-alkyl, which is optionally substituted by one or two identical or different radicals from the series comprising F, Cl, Br, I, hydroxyl, (C1-C7)-alkoxy, (C1-C7)-alkyl, (C1-C7)-alkoxycarbonyl, amino and trifluoromethyl, or represent (C1-C3)-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 atom 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 R9, form ring systems as described above under R2;

R4 is (C3-C12)-alkyl; mono-, bi- or tricyclic (C3-C15)-cycloalkyl or (C3-C18)-cycloalkylmethyl, the cyclo-alkyl part optionally being substituted by (C1-C4)-alkyl; (C5-C14)-arylmethyl; dithiolanyl; dithiolanyl-methyl; dithianyl or dithianylmethyl;

R5 represents hydrogen, azido, azido-(C1-C4)-alkyl, (C1-C12)-alkyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C6)-alkyl, (2-pyridyl)-(C1-C4)-alkyl, (3-pyridyl)-(C1-C4)-alkyl, (4-pyridyl)-(C1-C4)-alkyl, imidazol-2-yl, imidazol-1-yl, imidazol-4-yl, (imidazol-2-yl)-(C1-C4)-alkyl, (imidazol-1-yl)-(C1-C4)-alkyl, (imidazol-4-yl)-(C1-C4)-alkyl,[1-(C1-C8)-alkylimida-zol-2-yl]-(C1-C4)-alkyl, (imidazolin-2-yl)-(C1-C4)-alkyl or [1-(C1-C6)-alkylimidazolin-2-yl]-(C1-C4)-alkyl;

RB and R7 independently of one another are hydrogen, or, together with the boron atom and the oxygen atom, 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 atom and the carbon atom(s), can also contain an -O-member, an -NR13- member or a -CR14R15- 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, 2, 3 or 4;

R13 is hydrogen or (C1-C12)-alkyl; and R14 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, or a tolerated salt thereof.

3. A compound of the formula I as claimed in either of claims 1 and 2, wherein R1 denotes (C1-C8)-alkylsulfonyl; (C1-C8)-alkylsulfinyl;
(C1-C6)-hydroxyalkylsulfonyl; hydroxy-(C1-C10)-alkanoyl; (C1-C8)-alkanoyloxy-(C1-C10)-alkyl;(C1-C11)-alkanoyl; amino-(C1-C11)-alkanoyl; di-(C1-C7)-alkyl-amino-(C2-C11)-alkanoyl; piperidino-4-carbonyl;
morpholino-4-carbonyl; (C3-C9)-cycloalkylcarbonyl;
(C6-C10)-aryl-(C2-C11)-alkanoyl; 2-pyridyl-(C1-C8)-alkanoyl; 3-pyridyl-(C1-C8)-alkanoyl; 4-pyridyl-(C1-C9)-alkanoyl; benzoyl which is optionally substituted by halogen, (C1-C7)-alkyl, (C1-C7)-alkoxy or (C1-C7)-alkoxycarbonyl; pyrrolyl-2-carbonyl; pyridyl-3-carbonyl; benzenesulfonyl; (C1-C10)-alkoxycarbonyl;
substituted (C1-C10)-alkoxycarbonyl or (C8-C14)-aryl-(C1-C8)-alkoxycarbonyl, R2 denotes hydrogen or methyl, or, togethar with R3 and the -N-CH- group carrying these radicals, forms tetrahydroisoquinoline or azobicyclooctane skeleton, R3 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-(methylthio)ethyl, (1-marcapto, 1-methyl)ethyl, hydroxymethyl, 1-hydroxy-ethyl, amino, aminomethyl, 2-aminoethyl, 3-amino-propyl, 4-aminobutyl, N,N-dimethylamino, cyclohexyl-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-pyridylmethyl, 4-pyridylmethyl, cyclohexyl, (1-methylimidazol-4-yl)methyl, (3-methyl-imidazol-4-yl)methyl, phenyl, 1-naphthylmethyl, 2-naphthylmethyl, 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-furylmethyl, or with R2 or R9 form ring systems as defined above under R2, R4 is (C3-C12)-alkyl; mono- or bicyclic (C3-C12)-cyclo-alkyl or (C3-C12)-cycloalkylmethyl, the cycloalkyl part optionally being substituted by (C1-C4)-alkyl;
(C6-C10)-arylmethyl; dithiolanyl; dithiolanylmethyl;
dithianyl or dithianylmethyl, R5 is hydrogen, azido, azidomethyl, 2-azidoethyl, (C1-C6)-alkyl, (C3-C12) -cycloalkyl, (C3-C12)-cycloalkyl-(C1-C3)-alkyl, 3-(2-pyridyl)-propyl, 3-(3-pyridyl)-propyl, imidazol-2-yl, imidazol-1-yl, imidazol-4-yl, 3-(4-pyxidyl)-propyl, (imidazol-2-yl)-propyl, (imidazol-1-yl)-propyl, (imidazol-4-yl)propyl, [1-(C1-C4)-alkylimidazol-2-yl]-propyl or (imidazolin-2-yl)-propyl, R5 and R7 are as defined in claim 2, R9 denotes hydrogen or methyl, or, together with R8 and the -N-CH- group carrying these radicals, forms a tetrahydroisoquinoline or azabicyclooctane skeleton, 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 R6 and the atoms carrying these, form a thiochroman system, the sulfur atom of which is particularly preferably oxidized to the sulfone, R11 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 (C1-C4)-alkyl and R14 and R15 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 a ter-minal carboxyl group or a reactive derivative thereof with a corresponding fragment having a free amino group, if appropriate splitting off (a) protective group(s) temporarily introduced to protect 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 or more of claims 1 - 3, for use as a medicine in the treatment of high blood pressure.

7. A pharmaceutical agent containing a compound of the formula I as claimed in one or more of claims 1 - 3.

8. The compound as claimed in claim 1, and substantially as described herein.