NO862632L - BICYCLIC RELATIONS. - Google Patents

Description

The present invention relates to pyridazo[1,2-a][1,2]diazepine derivatives, a method for their production and medicines containing these derivatives.

The pyridazo[1,2-a][1,2]diazepine derivs., which are prepd

according to the present invention are compounds of the general formula

where R<1> is hydroxy, alkyl, aralkyl, aralkoxyalkyl, hydroxy-alkyl, amino-alkyl, acylamino-alkyl, monoalkylamino-alkyl, dialkylamino-alkyl, alkoxycarbonylamino-alkyl, halo-alkyl, carboxy-alkyl, alkoxycarbonyl-alkyl,

alkoxy or aralkyl; R<2> and R<3> are each hydrogen,

alkyl or aralkyl; R<4> and R<5> each represent hydrogen or R<4>

and R<3> are together oxo; and X means an oxygen atom or the group -NR<6> in which R<6> means hydrogen, alkyl or aralkyl

or -{CH2)n- where n stands for zero, 1 or 2,

and pharmaceutically acceptable salts thereof.

The compounds of formula I contain two asymmetric carbon atoms and, when R<1> and OR<2> have different meanings, a chiral phosphorus atom. The present invention includes not only the optically uniform forms of these compounds, but also the diastereoisomeric racemates and mixtures of different diastereoisomeric racemates.

As used herein, the term "alkyl" alone or in combination means a straight or branched chain alkyl group containing from 1 to 8, preferably from 1 to 4 carbon atoms (eg methyl, ethyl, propyl, isopropyl, butyl, tert .butyl, pentyl, hexyl etc). The term "aralkyl" means an alkyl group as defined above in which a hydrogen atom is replaced by the phenyl group or a phenyl group containing one or more substituents selected from halogen, alkyl, alkoxy, trifluoromethyl, nitro, amino, iminoalkylamino etc, examples of aralkyl groups are benzyl, phenethyl , 3-phenylpropyl, 4-chlorobenzyl, 4-methoxybenzyl, 3-(4-chlorophenyl)propyl, 3-(4-methoxyphenyl)propyl, 4-nitrophenethyl, 4-aminophenethyl, 4-(1-iminoethylamino)phenethyl, etc. The term "halogen" here means fluorine, chlorine, bromine or iodine. Examples of hydroxyalkyl groups are hydroxymethyl, 2-hydroxyethyl etc.. The aminoalkyl group can e.g. be aminomethyl, 2-aminoethyl etc.. Methylaminomethyl, 2-methylaminoethyl and 2-ethylaminoethyl are examples of monoalkylaminoalkyl groups and 2-dimethylaminoethyl, 2-diethylaminoethyl and 3-dimethylaminopropyl are examples of dialkylaminoalkyl groups. The acyl group present in an acylaminoalkyl group can e.g. be derived from a saturated or unsaturated aliphatic carboxylic acid, from a cycloaliphatic carboxylic acid, from an aromatic carboxylic acid, from an araliphatic carboxylic acid or from a heterocyclic carboxylic acid, examples of such acids being acetic acid, propionic acid, butyric acid, valerian acid, cyclopropane carboxylic acid, cyclopentane carboxylic acid, benzoic acid, p-chlorobenzoic acid, phenylacetic acid, nicotinic acid, etc.. The term "halo-alkyl" means an alkyl group with a halogen substituent, and examples of halo-alkyl groups are chloromethyl, 2-chloroethyl, 3-bromopropyl, etc.. Examples of carboxyalkyl groups are carboxymethyl, 2-carboxyethyl, etc. The term "alkoxy", alone or in combination as in alkoxycarbonyl, means an alkyl group as defined above, which is attached through an oxygen atom. Thus, examples of alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert.butoxy, penetyloxy, hexyloxy, etc.. Examples of alkoxycarbonylamino-alkyl groups are methoxycarbonylaminomethyl, 2-ethoxycarbonylamino-ethyl, 3-ethoxycarbonylaminopropyl, etc.. can e.g. be methoxycarbonylmethyl, 2-methoxycarbonyl-ethyl, 3-ethoxycarbonylpropyl, etc.. The term "aralkyl" means an aralkyl group as defined above which is bonded through an oxygen atom, examples of aralkyl groups being benzyloxy, 4-chlorobenzyloxy, 2-phenylethoxy, 3- phenylpropoxy etc.

The compounds of formula I which are acidic form pharmaceutically acceptable salts with bases. Examples of such salts are alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts), ammonium salts and salts with organic amines (e.g. dicyclohexylamine salts). The compounds of formula I which are basic form pharmaceutically acceptable salts with acids. Examples of such salts are mineral acid salts such as hydrogen halides (e.g. hydrobromides, hydrochlorides, etc.), sulfates, phosphates, nitrates, etc. and organic acid salts such as acetates, maleates, fumarates, tartrates, citrates, salicylates, methanesulfonates, p-toluenesulfo -nater o.1..

R<1> in formula I preferably means hydroxy, alkyl, aralkyl or alkoxy. R<2> preferably means hydrogen. Preferably, R<3> means hydrogen. X is preferably an oxygen atom or the group -NH- or -(CH2)n- where n stands for zero or 1.

From the foregoing it will be clear that particularly preferred compounds of formula I above are those in which R<1> is hydroxy, alkyl, aralkyl or alkoxy, R<2> is hydrogen, R<3> is hydrogen and X is an oxygen atom or the group -NH- or -(CH2)n- where n stands for zero or 1.

Particularly preferred compounds of formula I above are: octahydro-9(S)-phosphonomethyl-10-oxo-6H-pyridazo[1,2-a][1,2]-diazepine-1(S)-carboxylic acid,

octahydro-9(S)-[[(hydroxy)methylphosphinyl]methyl]-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid,

octahydro-9(S)-phosphono-6,10-dioxo-6H-pyridazo[1,2-a][1,2]-diazepine-1(S)-carboxylic acid,

9(S)-diethoxyphosphinyl-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid,

octahydro-9(S)-[[hydroxy(methoxy)phosphinyl]methyl]-6,10-dioxo-6H-pyridazole[1,2-a][1,2]diazepine-1(S)-carboxylic acid.

octahydro-9(S)-phosphonomethyl-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid,

9(S)- [ [hydroxy(3-phenylpropyl)phosphinyl)]methyl]-octahydro-6,10-dioxo-6H-pyridazo[1,2-a] [1,2]diazepine-1(S)-carboxylic acid ,

9(S)-[[hydroxy(phenethyl)phosphinyl]amino]-octahydro-10-oxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid,

9(S)-[[hydroxy(2-phenethyl)phosphinyl]methyl]-octahydro-10-oxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid and

9(S)-[hydroxy(4-phenylbutyl)phosphinyl]-octahydro-10-oxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid.

Examples of other interesting compounds of formula I are: Methyl 9(S)-dimethoxyphosphinylmethyl-octahydro-6,10-dioxo-6H-pyridazo[1,2-a] [1,2]diazepine-1(S)-carboxylate,

methyl 9(S)-dimethoxyphosphinylmethyl-octahydro-10-oxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate,

methyl octahydro-9(S)-phosphonomethyl-10-oxo-6H-pyridazo[1,2-a] [1,2]diazepine-1(S)-carboxylate,

methyl 9(S)-[[(ethoxy)methylphosphinyl]methyl]-octahydro-6,10-dioxo-6H-pyridazo[1,2-a] [1,2]diazepine-1(S)-carboxylate,

methyl 9(S)-diethoxyphosphinyl-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate,

methyl 9(S)-diethoxyphosphinylmethyl-octahydro-6,10-dioxo-6H-pyridazo[1,2-a] [1,2]diazepine-1(S)-carboxylate,

methyl 9(S)-[[ethoxy(3-phenylpropyl)phosphinyl]methyl]-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate ,

benzyl 9(S)-[[benzyloxy(phenethyl)phosphinyl]amino]-octahydro-10-oxo-6H-pyridazo[1,2-a][1,2]diazepine-1(2)-carboxylate,

tert-butyl 9(S)-(dibenzylphosphonoxy)-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate,

tert.butyl 9(S)-[benzyloxy(phenethyl)phosphinyloxy]-octahydro-6,10-dioxo-6H-pyridazo[1,2]diazepine-1(S)-carboxylate,

benzyl 9(S)-[(dibenzyloxyphosphinyl)amino]-octahydro-10-oxo-6H-pyridazo[11,2-a][1,2]diazepine-1(S)-carboxylate and

9(S)-[dibenzyloxyphosphinyl)amino]-octahydro-10-oxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid.

Further examples of other interesting compounds of formula I are: Tert.butyl 9 (S)-[benzyloxy(4-phenylbutyl)phosphinyloxy]-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][l, 2]diazepine-1(S)-carboxylate,

9(S)-[hydroxy(4-phenylbutyl)phosphinyloxy]-octahydro-6,10-dioxo-6H-pyridazo [1,2-a][1,2]diazepine-1(S)-carboxylic acid,

benzyl 9(S)-[[benzyloxy(benzyl)phosphinyl]amino]-octahydro-10-oxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate,

benzyl 9(S)-[[benzyloxy(3-phenylpropyl)phosphinyl]amino]-octahydro-10-oxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate,

benzyl 9(S)-[[benzyloxy(4-phenylbutyl)phosphinyl]amino]-octahydro-10-oxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate,

9(S)-[[hydroxy(benzyl)phosphinyl]amino]-octahydro-10-oxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid,

9(S)-[[hydroxy(3-phenylpropyl)phosphinyl]amino]-octahydro-10-oxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid,

9(S)-[[hydroxy(4-phenylbutyl)phosphinyl]amino]-octahydro-10-oxo-6H-pyridazo [1,2-a] [1,2]diazepine-1(S)-carboxylic acid,

methyl 9(S)-[(ethoxy)(5-phenylpentyl)phosphinyl]-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate,

methyl 9(S)-[(ethoxy)(phenylbutyl)phosphinyl]-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate,

methyl 9(S)-[(ethoxyl)(3-phenylpropyl)phosphinyl]-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate,

methyl 9(S)-[(ethoxy)(phenethyl)phosphinyl]-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate,

9(S)-[Hydroxy(5-phenylpentyl)phosphinyl]-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid, 9 (S ) - [hydroxy (-1-phenylbutyl) phosphinyl]-octrahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid,

9(S)-[hydroxy(3-phenylpropyl)phosphinyl]-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid,

9(S)-[hydroxy(phenethyl)phosphinyl]octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid,

methyl 9(S)-[[ethoxy(phenethyl)phosphinyl]methyl]-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate,

9(S)-[[hydroxy(phenethyl)phosphinyl]methyl]octahydro-6,10-dioxo-6H-pyridazo [1,2-a] [1,2]diazepine-1(S)-carboxylic acid,

methyl 9(S)-[[ethoxy(phenethyl)phosphinyl]methyl]octahydro-10-oxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate,

methyl 9(S)-[(ethoxy)(4-phenylbutyl)phosphinyl]-octahydro-10-oxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate,

ethyl 9(S)-[[(4-benzyloxybutyl)(ethoxy)phosphinyl]methyl]-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S) -carboxylate,

9(S)-[[(4-benzyloxybutyl)(hydroxy)phosphinyl]methyl]octa-

hydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid,

9(S)-[[(4-hydroxybutyl)(hydroxy)phosphinyl]methyl]-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)- carboxylic acid,

9(S)-[[(4-aminobutyl)(ethoxy)phosphinyl]methyl]-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)- carboxylate,

9(S)-[[(4-aminobutyl)(hydroxy)phosphinyl]methyl]-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)- carboxylic acid,

tert.butyl octahydro-9(S)-[[methoxy(4-nitrophenethyl)phosphinyl]methyl]-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepin-1( S)-carboxylate,

octahydro-9(S)-[[methoxy(4-nitrophenethyl)phosphinyl]methyl]-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid,

octahydro-9(S)-[[hydroxy(4-nitrophenethyl)phosphinyl]methyl]-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid,

9(S)-[[(4-aminophenethyl)hydroxyphosphinyl]methyl]-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid,

9(S)-[[(4-aminophenethyl)methoxyphosphinyl]methyl]-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid and

octahydro 9(S)-[[(hydroxy)[4-(1-iminoethylamino)phenethyl]phospho-phenyl]methyl]-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine -1(S)-carboxylic acid.

According to the method of the present invention, the compounds of formula I and their pharmaceutically acceptable salts are prepared by

a) for the preparation of a compound of formula I in which R<1> denotes alkyl, aralkyl, aralkyl, acylamino-alkyl, dialkylamino-alkyl alkoxycarbonylamino-alkyl, alkoxycarbonyl-alkyl, alkoxy or aralkyl, R<2> and R< 3> each means alkyl or aralkyl, R<4> and R<5> together means oxo and X means -(CHz)n- in which n has the meaning given above, reacts a compound with the general formula

wherein n has the meaning given above, R<30> means alkyl

or aralkyl and Hal means a halogen atom,

with a compound of the general formula

where R<10>means alkyl, aralkyl, aralkyl-alkyl, acylamino-alkyl, dialkylamino-alkyl, alkoxycarbonylamino-alkyl, alkoxycarbonylamino-alkyl, alkoxycarbonyl-alkyl, alkoxy

or aralkyl and R<20> means alkyl or aralkyl,

or

b) for the preparation of a compound of formula I in which R<1> denotes alkyl, aralkyl, aralkyl-alkyl, acylamino-alkyl, dialkylamino-alkyl, alkoxycarbonylamino-alkyl, alkoxycarbonyl-alkyl, alkoxy or aralkyl, R<2> and R <3>each means alkyl or aralkyl and X means an oxygen atom or the group -NR<6>in which R<6> means hydrogen, alkyl or aralkyl, reacts a compound of the general formula

in which R4 , R<9>and R<30>have the previously stated meaning and X<1>means an oxygen atom or the group -NR<6->, in which.. R6 has the

above stated meaning,

with a compound of the general formula

in which R10 , R<20> and Hal have the above meaning, or c) for the preparation of a compound of the formula I in which R<2> means alkyl or aralkyl, R" and R<3> together means oxo and X means -CH2-, reacts a compound of the general formula in which R<3> has the meaning given above, with a compound of the general formula

wherein R<1> and R<20> have the above meaning and R<7>

means alkyl, aralkyl or trialkylsilyl,

or

d) for the preparation of a compound of formula I in which R<1> means alkyl, aralkyl, aralkyl-alkyl, amino-alkyl, acylamino-alkyl, monoalkylamino-alkyl, dialkylamino-alkyl, alkoxycarbonylamino-alkyl, alkoxycarbonyl-alkyl, alkoxy or aralkyl, R<2>and R<3>each means alkyl or aralkyl, and R<4>and R<5>each means a hydrogen atom, reduces a compound of formula I in which R<1>means alkyl, aralkyl, aralkyl- alkyl, amino-alkyl, acylamino-alkyl, monoalkylamino-alkyl, dialkylamino-alkyl, alkoxycarbonylamino-alkyl, alkoxycarbonyl-alkyl, alkoxy or aralkyl, R<2> and R<3> each means alkyl or aralkyl, and R<4> and R<3> together mean oxo,

or

e) for the preparation of a compound of formula I in which R<1>means hydroxy, alkoxy or aralkoxy, R<2>means hydrogen, alkyl

or aralkyl and/or R<3>means hydrogen, alkyl or aralkyl, with the proviso that either R<1>means hydroxy and/or at least one of R<2>and<R3>means hydrogen, corresponding to ester cleavages a compound with formula I in which R<1> means hydroxy, alkoxy or

aralkyloxy, R<2>means hydrogen, alkyl or aralkyl and/or R<3>means hydrogen, alkyl or aralkyl, with the proviso that either R<1>means something other than hydroxy and/or at least one of R<2> and R<3>is different from hydrogen,

or

f) for the preparation of a compound of formula I in which R<1> denotes alkyl, aralkyl, aralkyl, hydroxyalkyl, aminoalkyl, acylaminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonylaminoalkyl, halogen- alkyl, carboxy-alkyl, alkoxycarbonyl-alkyl, alkoxy or aralkyl, R<2>and<R3>each means alkyl or aralkyl and X means the group -NR<61->whereinR<61>means alkyl or aralkyl, alkylates or aralkylates a compound of formula I in which R<1> denotes alkyl, aralkyl, aralkyl-alkyl, hydroxy-alkyl, amino-alkyl, acylamino-alkyl, monoalkylamino-alkyl, dialkylamino-alkyl, alkoxycarbonylamino-alkyl, halo-alkyl, carb<0> xy-alkyl, alkoxycarbonyl-alkyl, alkoxy or aralkyl, R<2> and R<3> each means alkyl or aralkyl and X means the group -NH-,

or

g) for the preparation of a compound of formula I in which R<1> denotes alkyl, aralkyl, aralkyl-alkyl, hydroxy-alkyl, amino-alkyl, acylamino-alkyl, monoalkylamino-alkyl, dialkylamino-alkyl, alkoxycarbonylamino-alkyl, halogen- alkyl, carboxy-alkyl, alkoxycarbonyl-alkyl, alkyl or aralkyl, R<2>means alkyl or aralkyl and R<3>means alkyl or aralkyl, correspondingly esterifies a compound of formula I, in which R<1>means alkyl, aralkyl, aralkyl -alkyl, hydroxy-alkyl, amino-alkyl, acylamino-alkyl, monoalkylamino-alkyl, dialkylamino-alkyl, alkoxycarbonylamino-alkyl, halo-alkyl, carboxy-alkyl, alkoxycarbonyl-alkyl, alkyl or aralkyl, R<2>means alkyl or aralkyl and R<3> means hydrogen,

or

h) for the preparation of a compound of formula I, in which R<1> means hydroxy-alkyl and R<2> and R<3> both mean hydrogen or

alkyl, both catalytically hydrogenating a compound of formula I, wherein R<1> is aryloxyalkyl and R<2> and R<3> each is hydrogen or alkyl,

or

i) for the preparation of a compound of formula I, in which R<1> means halo-alkyl and R<2> and R<3> each means alkyl or aralkyl, halogenates a compound of formula I, in which R<1> means hydroxy -alkyl and R<2>and R<3>each means alkyl or aralkyl,

or

j) for the preparation of a compound of formula I, in which R<1> means amino-alkyl or monoalkylamino-alkyl and R<2> and R<3> each means alkyl or aralkyl, transfers the hydroxy-alkyl group in a compound of formula I , in which R<1> means hydroxy-alkyl and R<2> and R<3> each means alkyl or aralkyl in an amino-alkyl or monoalkylamino-alkyl group,

or

k) for the preparation of a compound of formula I, in which R<1> means amino-alkyl or monoalkylamino-alkyl and R<2> and R<3> each means alkyl or aralkyl, reacts a compound of formula I, in which R< 1>means halo-alkyl and R<2>and R<3>each means alkyl or aralkyl with ammonia or a monoalkylamine,

or

1) for the preparation of a compound of formula I, wherein R<1>means acylamino-alkyl and R<2>and R<3>each means alkyl or aralkyl, acylate a compound of formula I, wherein R<1>means amino -alkyl and R2 and R<3> each means alkyl or aralkyl,

or

m) for the preparation of a compound of formula I, in which R<1> means carboxy-alkyl and R<2> and R<3> each means alkyl or aralkyl, oxidise a compound of formula I, in which R<1> means hydroxy -alkyl and R<2> and R<3> mean alkyl or aralkyl,

and

n) if desired, reduces a nitro-substituted phenyl group present in R<1> in a compound of formula I to an amino-substituted phenyl group,

and or

o) if desired, an amino-substituted phenyl group present in R<1> in a compound of formula li transfers an iminoalkylamino group by reaction with an alkylcyanide in the presence of a trialkylsilyl halide,

and or

p) if desired, separates a mixture of obtained diastereoisomeric racemates into the diastereoisomeric racemates or optically pure diastereoisomers,

and or

q) if desired, dissolves an obtained racemate in the optical antipodes,

and

r) if desired, transfer an obtained compound of formula I in a pharmaceutically acceptable salt.

The reaction of a compound of formula II with a compound of formula III according to embodiment a) of the method can be carried out in the presence or absence of an inert organic solvent. When an inert organic solvent is used, this can suitably e.g. be a hydrocarbon such as benzene, toluene etc., a halogenated hydrocarbon such as dichloromethane, chlorobenzene etc., an amide such as dimethylformamide etc. The reaction is preferably carried out at an elevated temperature, preferably at the reflux temperature of the reaction mixture. In certain cases, it may be advantageous to carry out the reaction under an inert gas atmosphere (eg, nitrogen, argon, etc.). Hal in the compound of formula II preferably means a bromine atom.

The reaction of a compound of formula IV with a compound of formula V according to embodiment b) of the method can. is carried out in a known manner in the presence of a base and an inert organic solvent around room temperature. When e.g. a compound of formula IV, in which X<1> is an oxygen atom is used, the reaction can conveniently be carried out by first treating this compound with an alkali metal hydride such as sodium hydride in an inert organic solvent such as a cyclic ether (e.g. tetrahydrofuran) and then adding the compound of formula V, suitably dissolved in the same organic solvent. Again, e.g. when a compound of formula IV, in which X<1>means the group -NR<6-> is used, the reaction can preferably be carried out in the presence of a tertiary amine such as a tri(lower alkyl)amine (e.g. triethylamine, diisopropylethylamine, etc. ), and in an inert organic solvent such as a halogenated hydrocarbon (eg dichloromethane, chloroform, carbon tetrachloride, etc.).

The reaction of a compound of formula VI with a compound of formula VII according to embodiment c) of the method can be carried out in the presence or absence of an inert organic solvent. When a solvent is used, it may conveniently be a halogenated hydrocarbon (eg, dichloromethane, chloroform, chlorobenzene, etc.) or an aromatic hydrocarbon (eg, benzene, toluene, a xylene, etc.). The reaction is preferably carried out at a temperature between approx. 20°C and approx. 150°C. The reaction is preferably carried out under an inert gas atmosphere such as nitrogen, argon, etc. When a compound of formula VII, in which R<7> is trialkylsilyl (e.g. trimethylsilyl) is used, this compound can conveniently be formed in situ. In some cases, depending on the reaction conditions used, when a compound of formula VI in which R<3> is hydrogen is reacted with a compound of formula VII in which R<7> is alkyl or aralkyl, a compound of formula I, in which R<3> means alkyl or aralkyl.

The reduction of a compound of formula I, in which R<1> is alkyl, aralkyl, aralkyl, aminoalkyl, acylaminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonylaminoalkyl, alkoxycarbonylalkyl, alkoxy or aralkyl, R<2>means alkyl or aralkyl, R<3>means alkyl or aralkyl and R<4>and R<3>together means oxo according to embodiment d) of the process, it is usually carried out using a borane complex such as a borane/tetrahydrofuran, borane/dimethyl sulphide, borane/N,N-diethylaniline etc. complex. This reduction is suitably carried out in an inert organic solvent and at room temperature or a temperature below room temperature, e.g. by using a borane/tetrahydrofuran complex in tetrahydrofuran at ca. 0°C to approx. 20°C.

The ester cleavage of a compound of formula I, in which R<1>means alkoxy or aralkyl, R<2>means alkyl or aralkyl and/or R<3>means alkyl or aralkyl according to embodiment e) of the method can be carried out according to in and of itself known methods. E.g. a compound of formula I, in which R<1>means alkoxy or aralkyl and R<2>means alkyl or aralkyl can be transferred into a corresponding compound of formula I, in which R<1>means hydroxy and R<2>means hydrogen by treatment with trimethylsilyl bromide, conveniently around room temperature. Again, e.g. a compound of formula I, in which R<1> is alkoxy or aralkyl and R<2> is alkyl or aralkyl, is transferred in a corresponding compound of formula I, in which R<1> is alkoxy or aralkyl and R<2> is hydrogen by treatment with lithium thiocyanate, conveniently in an inert organic solvent, such as an aliphatic ketone (eg acetone, 2-butanone, etc.) and at a higher temperature, e.g. at the reflux temperature of the reaction mixture. The transfer of a compound of formula I, in which R<3> means alkyl or aralkyl in a corresponding compound of formula I, in which R<3> means hydrogen can e.g. is carried out by treatment with a base, or where the alkyl group is tert.butyl, by treatment with acid. Suitable bases that can be used are alkali metal hydroxides (eg sodium hydroxide, potassium hydroxide, etc.) and ammonium hydroxide, and the treatment can be carried out at a temperature between about room temperature and the boiling point of the reaction mixture, preferably around room temperature. Anhydrous trifluoroacetic acid is a particularly suitable acid for ester cleavage of a compound of formula I, in which R<3> means tert.butyl, the treatment in this case being easily carried out at around room temperature. A compound of formula I, in which R<3> means aralkyl, can also be transferred into a corresponding compound of formula I, in which R<3> means hydrogen by hydrogenolysis in a manner known per se.

The alkylation or aralkylation of a compound of formula I, in which R<1> denotes alkyl, aralkyl, aralkyl-alkyl, hydroxy-alkyl, amino-alkyl, acylamino-alkyl, monoallylamino-alkyl, dialkylamino-alkyl, alkoxycarbonylamino-alkyl, halogen- alkyl, carboxy-alkyl, alkoxycarbonyl-alkyl, alkoxy or aralkyl, R<2>means alkyl or aralkyl, R<3>means alkyl or aralkyl and X means the group -NH- according to embodiment f) of the method, can be carried out on i and known manner. E.g. the compound of formula I can be reacted with a corresponding alkyl halide (eg, methyl bromide, ethyl chloride, etc.) or a corresponding aralkyl halide (eg, benzyl bromide, etc.) in the presence of a base.

The esterification according to embodiment g) of the method can be carried out according to methods known per se. E.g. the esterification can be carried out by reaction with a corresponding alcohol (e.g. methanol, ethanol, benzyl alcohol, etc.) in the presence of a mineral acid

(e.g. hydrochloric acid, etc.) or with an appropriate diazoalkane (e.g. diazomethane, phenyldiazomethane, etc.). A further method for the formation of a tert-butyl ester consists in carrying out the esterification using isobutene in the presence of sulfuric acid.

The catalytic hydrogenation according to embodiment h) of the method can be carried out in a manner known per se; e.g. in the presence of a noble metal catalyst such as a palladium catalyst in an inert organic solvent (eg an alkanol such as ethanol, etc.), conveniently at about room temperature and atmospheric pressure.

Conventional methods can be used for the halogenation according to embodiment i) of the process. For example the halogenation can be carried out by treatment with a suitable halogenating agent such as a thionyl halide (e.g. thionyl chloride, etc.), a phosphorus halide (e.g. phosphorus trichloride, phosphorus pentachloride, etc.) etc. Alternatively, the halogenation can be carried out by first transferring the compound of formula I, wherein R<1> is hydroxy-alkyl and R<2> and R<3> are each alkyl or aryl in the corresponding alkylsulfonate (e.g. mesylate) or arylsulfonate (e.g. tosylate), and then react this with an alkali metal halide (e.g. sodium fluoride, sodium chloride, lithium chloride, etc.) in acetone, or with a pyridine hydrogen halide at a temperature between approx. 0°C and 100°C.

The transfer of the hydroxy group in a compound of formula I, in which R<1> means hydroxy-alkyl and R<2> and R<3> each means alkyl or aralkyl in an amino-alkyl- or monoalkylamino-alkyl group according to embodiment j) of the method , can be carried out according to methods known per se. E.g. such a compound can first be transferred into the corresponding alkylsulfonate (e.g. mesylate) or arylsulfonate (e.g. tosylate), which is then reacted with ammonia or a corresponding monoalkylamine (e.g. methylamine, ethylamine, etc.). Alternatively, the alkylsulfonate or arylsulfonate can be reacted with an alkali metal azide (e.g. sodium azide) in a known manner, e.g. in an inert organic solvent such as 2-butanone and at a higher temperature (e.g. the reflux temperature of the reaction mixture) and give the corresponding azido-alkyl compound which can then be transferred into the desired amino-alkyl compound by catalytic hydrogenation in a manner known per se.

The reaction of a compound of formula I, wherein R<1> means halo-alkyl and R<2> and R<3> each means alkyl or aralkyl with ammonia or a monoalkylamine (e.g. methylamine, ethylamine, etc.) according to embodiment k) of the method, can be carried out according to usual methods; e.g. in an inert organic solvent and in the presence of a suitable acid scavenger.

Usual methods can be used for the acylation of a compound of formula I, in which R<1> means amino-alkyl and R<2> and R<3> each means alkyl or aralkyl according to embodiment 1) of the method. E.g. the acylation can be carried out using a corresponding acyl halide (eg an acyl chloride such as acetyl chloride) in the presence of a corresponding acid scavenging agent.

The oxidation according to embodiment m) of the method can be carried out according to methods known per se; e.g. by treatment with a corresponding oxidizing agent such as an alkali metal dichromate (eg potassium dichromate, etc.).

The reduction of a nitro-substituted phenyl group to an amino-substituted phenyl group according to embodiment n) of the method can be carried out in a manner known per se; e.g. by catalytic hydrogenation in the presence of a noble metal catalyst, such as a palladium catalyst (eg palladium-on-carbon) in an inert organic solvent (eg an alkanol such as methanol, ethanol, etc.).

The transfer of an amino-substituted phenyl group into an iminoalkylamino group according to embodiment o) of the method is preferably carried out by using an excess of alkyl cyanide (e.g. acetonitrile, propionitrile, etc.), whereby this also serves as a solvent. The preferred trialkylsilyl halide is trimethylsilyl bromide, although other trialkylsilyl halides such as trimethylsilyl chloride, etc. may also be used. The turnover is suitably carried out at around room temperature.

The separation of diastereoisomeric mixtures into the diastereoisomeric racemates or optically pure diastereoisomers according to embodiment p) of the process can be carried out according to methods known per se; e.g. by chromatography (e.g. on silica gel) using an appropriate solvent system (e.g. ethyl acetate/n-hexane).

The resolution of a racemate in the optical antipodes according to embodiment q) of the method can also be carried out according to methods known per se; e.g. by treatment with a corresponding optically active acid or a corresponding optically active base as required, separate the optically active salts obtained (e.g. by fractional crystallization), and, if necessary, liberate the optically uniform compounds from these salts by conventional methods.

The transfer of a compound of formula I in a pharmaceutically acceptable salt according to embodiment r) of the method can be carried out in a manner known per se. E.g. a compound of formula I which is acidic can be converted into a pharmaceutically acceptable salt by treatment with a corresponding base, such as an alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), an alkaline earth metal hydroxide (e.g. calcium hydroxide, magnesium hydroxide, etc. ), ammonium hydroxide or an organic amine (e.g. dicyclohexylamine, etc.), again e.g. a compound of formula I can be converted into a pharmaceutically acceptable salt by treatment with an acid such as a mineral acid (e.g. a hydrohalic acid such as hydrobromic acid, hydrochloric acid, etc., sulfuric acid, phosphoric acid, nitric acid, etc.) or an organic acid such as acetic acid, maleic acid , furmaric acid, tartaric acid, citric acid, salicylic acid, methanesulfonic acid, p-toluenesulfonic acid, etc.

The compounds of formula II, in which n stands for zero, which are used as starting material in embodiment a) of the method, are known compounds.

The compounds of formula II, in which n stands for 1 or 2, which are also used as starting materials in embodiment a) of the method, are new compounds. They can e.g. is produced by reacting a compound with the general formula

wherein R<31> is alkyl and Bz is benzyl, with a compound of the general formula

in which Bz and Hal have the meaning given above, and n<1>

stands for 1 or 2,

remove the benzyl and benzyloxycarbonyl groups from the resulting compound of the general formula

in which R3 1 , Bz, Hal and n<1> have the meaning given above, and cyclize the resulting acid with the general formula

wherein R<31>, Hal and n<1> have the above meaning,

and, where a compound of formula II wherein n is 1 or 2 and R<30> is aralkyl is required, esterifying the resulting compound of formula II wherein n is 1 or 2 and R<30> is alkyl and esterifying the resulting acid to the corresponding aralkyl ester.

The reaction of a compound of formula VIII can be carried out in the usual way; e.g. in an inert organic solvent (eg, a halogenated hydrocarbon such as dichloromethane) and in the presence of a base (eg, an alkali metal carbonate such as sodium carbonate or an alkali metal bicarbonate such as sodium bicarbonate), conveniently at room temperature.

Removal of the benzyl and benzyloxycarbonyl groups from a compound of formula X can be carried out according to generally known methods; e.g. by using hydrogen in the presence of a noble metal catalyst (eg palladium-on-carbon) or, when R<30> has a meaning other than tert.butyl, by using hydrogen bromide in glacial acetic acid.

The cyclization of an acid of formula XI can be carried out on i and

known manner. In a preferred method, the cyclization is carried out by transferring an acid of formula XI by treatment in a known manner with a corresponding halogenating agent such as phosphorus pentahalide (e.g. phosphorus pentachloride, etc.) or a thionyl halide (e.g. thionyl chloride, etc.) in the corresponding acid halide (e.g. acid chloride), which is spontaneously cyclized to the compound of formula II, in which n stands for 1 or 2 and R<30>

means alkyl.

The ester cleavage of a compound of formula II, wherein n

stands for 1 or 2 and R<30> means alkyl which gives the corresponding acid, i.e. a compound corresponding to formula II, but in which R<30> means hydrogen, can e.g. is carried out by treatment with a base, or when the alkyl group is tert.butyl, by treatment with acid. Suitable bases that can be used are alkali metal hydroxides (e.g. sodium hydroxide, potassium hydroxide, etc.) and ammonium hydroxide, and the treatment can be carried out at a temperature between approx. room temperature and the boiling point of the reaction mixture, suitably around room temperature. Anhydrous trifluoroacetic acid is a particularly suitable acid for ester cleavage of a compound of formula II, in which R<30> means tert.butyl, the treatment in this case being easily carried out at room temperature.

The esterification of the acid thus obtained can be carried out according to

per se known methods; e.g. by reaction with a corresponding alcohol (eg, benzyl alcohol, etc.) in the presence of a mineral acid (eg, hydrochloric acid, etc.), or with a suitable diazoalkane (eg, phenyldiazomethane, etc.).

The compounds with formula II, in which n stands for 1 can e.g. also prepared by cleaving off the benzyloxycarbonyl group from a compound of formula VIII above, reacting the resulting compound of the general formula

wherein R<31> has the meaning given above,

with o-methylene-glutaric anhydride, cyclize the resulting compound of the general formula

wherein R<31> has the meaning given above,

replacing a tert.butyl group R<31>with a different alkyl group in the resulting compound of the general formula

wherein R<31> has the meaning given above,

treat the compound of formula Via, in which R<31> has a meaning other than tert.butyl with hydrogen halide, and where a compound of formula II, in which R<30>means tert.butyl or

aralkyl is required, esterify the resulting compound of formula II, where n is 1 and R<30>is an alkyl other than tert-butyl, and esterify the resulting acid to the corresponding tert-butyl or aralkyl ester.

The cleavage of the benzyloxycarbonyl group from a compound of formula VIII can be carried out according to known methods, e.g. using hydrogen in the presence of a catalyst such as a noble metal catalyst (eg palladium-on-carbon) and in the presence of an inert organic solvent (eg an alkanol such as methanol, etc.).

The reaction of a thus obtained compound of formula XII with α-methylene glutaric anhydride to a compound of formula XIII is readily carried out in an inert organic solvent such as a halogenated hydrocarbon (e.g. dichloromethane, etc.) or an ether (e.g. dioxane , tetrahydrofuran, etc.) at a temperature between approx. room temperature and the reflux temperature of the reaction mixture, preferably at around room temperature.

The cyclization of a compound of formula XIII can be carried out in a manner known per se. In a preferred method, the cyclization is carried out by transferring a compound of formula XIII by treatment in a known manner with a corresponding halogenating agent such as phosphorus pentahalide (e.g. phosphorus pentachloride, etc.) or a thionyl halide (e.g. thionyl chloride, etc.) in the corresponding acid halide (e.g. acid chloride) which spontaneously cyclizes to a compound of formula Via.

When <R31> in the cyclization product of formula Via means tert.butyl, this is replaced by another alkyl group before the treatment with hydrogen halide. This replacement is carried out by treatment with varian-free trifluoroacetic acid, which gives the free acid, which is then esterified to an alkyl ester other than the tert-butyl ester.

A compound thus obtained, i.e. a compound of formula Via, in which R<31> does not mean tert.butyl, is then treated with hydrogen halide and gives a compound of formula II, in which n stands for 1 and R<30> has a meaning other than tert.butyl. Hydrogen bromide is the preferred hydrogen halide. Preferably, the treatment is carried out in an inert organic solvent such as a halogenated hydrocarbon (eg dichloromethane, etc.) at around room temperature.

The ester cleavage of a compound of formula II, in which n stands for 1 and R<30> has a meaning other than tert.butyl, can be carried out in a known manner by treatment with a base. Suitable bases are alkali metal hydroxides (eg sodium hydroxide, potassium hydroxide, etc.) and ammonium hydroxide. The treatment is suitably carried out at a temperature between approx. room temperature and the boiling point of the reaction mixture, preferably around room temperature.

The transfer of a resulting acid into a tert-butyl ester can be carried out in a manner known per se; e.g. by reaction with isobutene in the presence of sulfuric acid. The esterification of a resulting acid to an aralkyl ester can be carried out in an analogous manner to that described previously.

The compounds of formula II, in which n stands for 1 or 2, are the subject of the present invention.

The compounds of formula III used as starting materials in embodiment a) of the method are known compounds.

Compounds of formula IV, in which X<1> represents an oxygen atom, which are used as starting materials in embodiment b) of the method, are new and are also the subject of the present invention. The compounds of formula IV, in which X<1> means an oxygen atom and R<30> means alkyl, can e.g. is prepared by reacting a compound of formula VIII with a compound of the general formula

wherein Bz is as defined above and R<8> is a

alkanoyl group (e.g. acetyl),

by removing the benzyl and benzyloxycarbonyl groups from the resulting compound of the general formula

wherein R 8 , R<31> and Bz have the above meaning, cyclization of the resulting acid with the general formula

where R<8> and R<31> have the above meaning,

and cleavage of the alkanoyl group from the thus obtained compounds of the general formula

where R<8> and R<31> have the above meaning,

or, where a compound of formula IV wherein X<1> is an oxygen atom and R<4> and R<5> are each hydrogen is required, reduction of the resulting compound of formula XVIII and then cleavage of the alkanoyl group.

The reaction of a compound of formula VIII with a compound of formula XV can be carried out in the usual manner; e.g. in an inert organic solvent (eg a hydrocarbon such as toluene) and in the presence of a base (eg an alkali metal carbonate such as sodium carbonate or an alkali metal bicarbonate such as sodium bicarbonate), conveniently at about room temperature.

The removal of the benzyl and benzyloxycarbonyl groups from a compound of formula XVI can be carried out in a manner known per se; e.g. by using hydrogen in the presence of a noble metal catalyst (eg palladium-on-carbon).

The cyclization of an acid of formula XVII can be carried out in a manner known per se. In a preferred method, the cyclization is carried out by transferring an acid of formula XVII by treatment in a known manner with a corresponding halogenating agent such as a phosphorus pentahalide (e.g. phosphorus pentachloride, etc.) or a thionyl halide (e.g. thionyl chloride, etc.) in the corresponding acid halide (eg, acid chloride) which spontaneously cyclizes to the compound of formula XVIII.

The cleavage of the alkanoyl group from a compound of formula XVIII can be carried out in the usual way; e.g. by treatment with a suitable base such as an alkali metal hydroxide (eg sodium hydroxide etc.) in an inert organic solvent (eg an alkanol such as methanol, ethanol etc.), conveniently at about room temperature.

When a compound of formula IV, in which X<1> represents an oxygen atom and R<4> and R<5> each represents hydrogen, a compound of formula XVIII is reduced and the alkanoyl group is cleaved off from the product obtained. The reduction is preferably carried out by using a complex of borane such as a borane/tetrahydrofuran, borane/dimethyl sulphide, borane/N,N-diethylaniline etc. complex. This reduction is conveniently carried out in an inert organic solvent and at room temperature or a temperature below room temperature; e.g. by using a borane/tetrahydrofuran complex in tetrahydrofuran at ca. 0°C to approx. 20°C. The cleavage of the alkanoyl group is carried out in the previously described manner.

The compounds of formula IV, in which X<1> means an oxygen atom and R<3>0 means aralkyl, can e.g. is prepared by esterifying a compound of formula IV, in which X<1>means an oxygen atom and R<30>means alkyl, and esterifying the resulting acid to the corresponding aralkyl ester.

The ester cleavage of a compound of formula IV, in which X<1> means an oxygen atom and R<30> means alkyl to the corresponding acid, i.e. a compound of formula IV, in which R<30> means hydrogen, can e.g. is carried out by treatment with a base, or when the alkyl group is tert.butyl, by treatment with acid. Suitable bases that can be used are alkali metal hydroxides (eg sodium hydroxide, potassium hydroxide, etc.) and ammonium hydroxide, and the treatment can be carried out at a temperature between about room temperature and the boiling point of the reaction mixture, preferably around room temperature. Anhydrous trifluoroacetic acid is a particularly suitable acid for the ester cleavage of a compound of formula IV, in which R<30> means tert.butyl, the treatment in this case being quickly carried out at room temperature.

The esterification of the acid thus obtained can be carried out according to methods known per se; e.g. by reaction with a corresponding alcohol (eg, benzyl alcohol, etc.) in the presence of a mineral acid (eg, hydrochloric acid, etc.) or with a suitable diazoalkane (eg, phenyldiazomethane, etc.).

The compounds of formula IV, in which X<1> denotes the group -NH-, which are used as starting materials in embodiment b) of the method, are known compounds.

The compounds of formula IV, where X<1> means the group -NR<61>, where R<61> means alkyl or aralkyl, which are used as starting materials in embodiment b) are new and also form part of the present invention. They can e.g. is produced by corresponding alkylation or aralkylation of a corresponding compound of formula IV, where X<1> denotes the group -NH-. The alkylation or aralkylation can be carried out in a manner known per se. E.g. the compound of formula IV, in which X<1> represents the group -NH-, can be reacted with a corresponding alkyl halide (e.g. methyl chloride, ethyl bromide, etc.) or a corresponding aralkyl halide (e.g. benzyl bromide, etc.) in the presence of a base .

The compounds of formula V, which are used as starting materials in embodiment b) of the method, are known compounds or analogues of known compounds which can be prepared in an analogous manner to known compounds.

Compounds of formula VI, which are used as starting materials in embodiment c) of the method, are known compounds or analogues of known compounds which can be prepared in an analogous manner to known compounds. Those in which R<3> is alkyl correspond to the compounds of formula Via as indicated above. The compounds of formula VI, in which R<3> means hydrogen, can be prepared from the compounds of formula Via in a manner known per se by treatment with a base, or where R<31> in formula Via means tert.butyl, by treatment with anhydrous trifluoroacetic acid. The compounds of formula VI, in which R<3> means aralkyl can be prepared from the compounds of formula VI, in which R<3> means hydrogen by esterification in a manner known per se; e.g. by using a corresponding alcohol (eg, benzyl alcohol, etc.) in the presence of a mineral acid (eg, hydrochloric acid, etc.) or by using a suitable diazoalkane (eg, phenyldiazomethane, etc.).

The compounds of formula VII which are also used as starting materials in embodiment c) of the method are known compounds or analogues of known compounds which can be prepared in an analogous manner to the known compounds.

The compounds of formula I and their aforementioned pharmaceutically acceptable salts are useful as antihypertensive agents. They inhibit angiotensin-converting enzyme (ACE), which is responsible for the conversion of angiotensin I to angiotensin II, and are therefore useful for reducing or alleviating angiotensin-related hypertension.

The activity of the present compounds in inhibiting angiotensin converting enzyme in vitro can be measured by the following experiment.

The procedure is based on the method of Cushman and Cheung (Biochem. Pharmacol,. 20. 1637-1648) and entails the modifications introduced by Hayakari et al (Anal. Biochem., 8_4. 361-369). The substrate (hippuryl-histidyl leucine, 2 mM) is incubated with angiotensin-converting enzyme in the presence or absence of various concentrations of test substance in potassium phosphate buffer (pH 8.3; 100 mM) containing sodium chloride (300 mM) for 24 min. at 37°C (total value 500 µl). (If the test substance is an ester, it is appropriate to cleave it using pig liver esterase before carrying out the test). The reaction is terminated by the addition of 3 ml of potassium phosphate buffer (pH 8.3; 200 mM) at 0°C. 2,4,6-trichloro-s-triazine (3%) in 1.5 ml of dioxane is added, and the mixture is stirred until the yellow chromophore is fully developed. The samples are then centrifuged to remove any precipitate that has formed. The yellow chromophore formed by the reaction of the 2,4,6-trichloro-s-triazine with free hippuric acid is measured spectrophotometrically at 382 nm. IC 50 values are defined as the concentration of the test substance which by 50% reduces the cleavage of hippuryl-histidyl-leucine by angiotensin-converting enzyme under the aforementioned conditions.

They obtained results in the previous experiment using

representative compounds produced according to the invention as test substances are listed in the following table:

Compound A = Octahydro-9(S)-phosphonomethyl-10-oxo-6H-pyridazo

[1,2-a] [1,2]diazepine-1(S)-carboxylic acid

Compound B = 9(S)-[[hydroxy(phenethyl)phosphinyl]amino]-octahydro-10-oxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid disodium salt.

Compound C = 9(S)-[hydroxy(4-phenylbutyl)phosphinyl]-octahydro-10-oxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid dipotassium salt.

Compound D = 9(S)-[[(hydroxy)[4-(1-iminoethylamino)phenethyl]-phosphinyl]methyl]-6,10-dioxo-6H-pyridazo[1,2-a] [1,2] diazepine-1(S)-carboxylic acid.

The compounds of formula I and their aforementioned pharmaceutically acceptable salts can be used as drugs in the form of pharmaceutical preparations containing them in connection with a tolerable pharmaceutical carrier material. This carrier material can be an organic or inorganic carrier material which is suitable for enteral (e.g. oral) or parenteral administration, examples of such carrier materials being water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils , polyalkylene glycols, vaseline etc.. The pharmaceutical preparations can be formulated in a solid form (e.g. as tablets, dragees, suppositories or capsules) or in a liquid form (e.g. as solutions, suspensions or emulsions ). The pharmaceutical preparations may be subjected to standard pharmaceutical treatments such as sterilization and/or may contain auxiliary substances such as preserving, stabilizing, wetting or emulsifying agents, salts for varying the osmotic pressure or buffers. The pharmaceutical preparations may also contain other therapeutically valuable substances.

The compounds of formula I and their aforementioned pharmaceutically acceptable salts can be given to adults in a daily dose from approx. 0.1 mg to 100 mg, preferably approx. 1 mg to 50 mg, per kilograms of body weight. The daily dose can be given as a single dose or in divided doses. It will be clear that the foregoing dosage range is given as an example only, and may be varied upward or downward depending on such factors as the particular compound or salt administered, the route of administration, the degree of indication being treated, and the condition of the patient as determined by the attending physician.

The following examples illustrate the present invention:

Example 1

1 g of methyl 9(S)-bromomethyl-octahydro-6,10-dioxo-6H-pyridazo-[1,2-a][1,2]diazepine-1(S)-carboxylate was dissolved in 3 ml of trimethylphosphite and the solution was heated at reflux for 20 hours. Excess trimethylphosphite was removed in vacuo and the residue was chromatographed on silica gel using methanol/ethyl acetate for the elution. 720 mg of methyl 9(S)-dimethoxyphosphinylmethyl-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate were obtained in the form of a light yellow oil .

NMR: δ (300 MHz, CDCl 3 ): 5.45 (1H, m); 4.6 (1H, m); 3.75 (9H, s and two t); 3.4 (1H, m); 3.1 (1H, m); 2.85 (1H, m); 2.25-2.55 (4H, m); 1.65-1.95 (5H, m).

Methyl 9(S)-bromomethyl-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate used as the starting material was prepared as follows: A solution of 10 g (0.0313 mol) 1-benzyloxycarbonyl-S-piperazinic acid tert.butyl ester in 100 ml of methanol was hydrogenated at room temperature and atmospheric pressure over 5% palladium/carbon. The catalyst was removed by filtration and the filtrate was evaporated to dryness. The resulting crude piperazine tert-butyl ester was taken up in 100 ml dioxane, and the solution was cooled to 0°C and treated with a solution of 3.94 g (0.0313 mol) α-methylene glutaric anhydride in 100 ml dioxane. The mixture was stirred at 20°C for 18 hours and the solvent was removed by evaporation. The residue was partitioned between methyl tert-butyl ether and saturated sodium bicarbonate solution. The aqueous phase was acidified with hydrochloric acid and extracted with dichloromethane, yielding 8.34 g (85%) of 3(S)-tert-butoxycarbonyl-hexahydro-α-methylene-5-oxo-1-pyridazinepentanoic acid as white crystals with melting point 96°-99°C. 5.0 g (16 mmol) of this acid was taken up in 350 ml of tetrahydrofuran, and the solution was cooled to 0°C. 3.75 g (18 mmol) of phosphorus pentachloride was added and the mixture was stirred at 0°C for 1 hour and at 20°C for 18 hours. The solvent was removed by evaporation, and the residue partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic phase was evaporated and the residue was chromatographed on silica gel using ethyl acetate/n-hexane for the elution. 3.7 g (79%) of tert.butyl octahydro-9-methyl-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate were obtained as a white solid with melting point 105-106°C (from hexane).

10 g of tert.butyl octahydro-9-methylene-6,10-dioxo-6H-pyridazo-[1,2-a][1,2]diazepine-1(S)-carboxylate were stirred with 40 ml of trifluoroacetic acid at 20° C for 3 hours. The mixture was evaporated, and the oil obtained was treated with diethyl ether to give 7.6 g of octahydro-9-methylene-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-( S) - carboxylic acid in the form of a white solid with a melting point of 169-172° C.

7.6 g of octahydro-9-methylene-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid was slurried in 200 ml of ethyl acetate, and the suspension was stirred at 0°C while adding 100 ml of diazomethane dissolved in ether. After 30 min. the excess of diazomethane was destroyed by the dropwise addition of acetic acid. The mixture was washed with aqueous sodium bicarbonate solution, dried over sodium sulfate and evaporated to give 5.17 g of methyloctahydro-9-methylene-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S )-carboxylate in the form of a white solid with a melting point of 73-75°C (from n-hexane).

Hydrogen bromide was introduced into a stirred solution of 5 g of methyloctahydro-9-methylene-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1 ( S )-carboxylate in 125 ml of dichloromethane during 4 hours at 20°C. The mixture was washed with saturated aqueous sodium bicarbonate solution, dried and evaporated. The residue was chromatographed on silica gel using ethyl acetate/n-hexane for the elution. 5.03 g of methyl 9(S)-bromomethyl-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate were obtained in the form of a white solid with melting point 82-83°C (from ethyl acetate/n-hexane).

Example 2

700 mg of methyl 9(S)-dimethoxyphosphinylmethyl-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate was dissolved in 15 ml of dry tetrahydrofuran, and the solution was stirred at 0°C under a nitrogen atmosphere during dropwise addition over a period of 5 min. of 4 ml of a 0.5 molar solution of borane in tetrahydrofuran. Stirring was continued for 30 min. at 0°C and

a further 3 hours at room temperature. The mixture was diluted with 75 ml of dichloromethane and cooled, while 40 ml of 2N hydrochloric acid was carefully added. Stirring was continued for an additional 30 min., the mixture was adjusted to pH 9 with sodium carbonate, and the phases were separated. The aqueous phase was washed with dichloromethane, and the combined organic extracts were dried over anhydrous sodium sulfate and evaporated. The residue was chromatographed on silica gel using methanol/ethyl acetate for the elution. 510 mg of methyl 9(S)-dimethoxyphosphinylmethyl-octahydro-10-oxo-6-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate were obtained in the form of a colorless oil.

Analysis for Ci 4 H2 3 N2 06 P :

Calculated: C, 48.27; H, 7.23; N, 8.04%

Found: C, 48.47; H, 7.38; N, 7.89%

Example 3

470 mg of methyl 9(S)-dimethoxyphosphinylmethyl-octahydro-10-oxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate were treated with 2 ml of trimethylsilyl bromide at room temperature for 17 hours . After evaporation, the residue was taken up in acetone and water was added. Evaporation gave 490 mg of methyloctahydro-9(S)-phosphonomethyl-10-oxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate hydrobromide as a waxy solid.

Analysis for C12H21N2 OeP.HBr:

Calculated: C, 35.93; H, 5.52; N, 6.98%

Found: C, 36.26; H, 5.30; N, 6.92%.

Example 4

450 mg of methyloctahydro-9(S)-phosphonomethyl-10-oxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate hydrobromide was taken up in 6 ml of water containing 350 mg sodium hydroxide, and the mixture was allowed to stand at 20°C for 4 hours. The solution was washed with dichloromethane, the aqueous phase was diluted with an equal volume of methanol and applied to a column of Amberlite CG 120 resin. Elution with aqueous methanol and evaporation of the eluate gave 360 mg of octahydro-9(S)-phosphonomethyl-10-oxo-6H-pyridazo[1,2-a][1,2]dia-

zepin-1(S)-carboxylic acid hydrobromide in the form of an amorphous powder after trituration with diethyl ether.

Analysis for Ci i Hi 9 N2 Oe P . HBr:

Calculated: C, 34.13; H, 5.21; N, 7.24%

Found: C, 33.91; H, 5.14; N, 7.04%.

Example 5

515 mg of methyl 9(S)-bromomethyl-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate were dissolved in 1.5 ml of diethoxy- methylphosphine and the solution was heated at 120°C under a nitrogen atmosphere for 7 hours. After evaporation, the residue was chromatographed on silica gel using ethyl acetate for elution. 480 mg of methyl 9(S)-[(ethoxy)methylphosphinyl]methyl]-octahydro-6,10-dioxo-6H-pyridazo-[1,2-a][1,2]diazepine-1(S)- carboxylate in the form of a colorless gum.

MS: m/e 360 (M<*>).

Example 6

470 mg of methyl 9(S)-[[(ethoxy)methylphosphinyl]methyl]-octahydro-6,10-dioxo-6H-pyridazo [1,2-a] [1,2]diazepine-1(S)-carboxylate were stirred at 20°C with 2 ml of trimethylsilyl bromide for 17 hours. After evaporation, the residue was taken up in acetone, treated with water and evaporated again. The residue was taken up in 6 ml of water containing 350 mg of sodium hydroxide, and the solution was allowed to stand at 20°C for 3 hours and was then washed with dichloromethane. The aqueous layer was diluted with an equal volume of methanol and applied to a column of Amberlite CG 120 resin. Elution with aqueous methanol gave 250 mg of octahydro-9(S)-<[>[(hydroxy)methylphosphinyl]methyl]-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1 (S)-carboxylic acid in the form of a white lyophilisate.

Analysis for Ci 2 Hi 9 N2 Ob P :

Calculated: C, 45.3; H, 6.0; N, 8.8%

Found: C, 45.4; H, 5.6; N, 8.55%.

Example 7

2.5 g of methyl 9(RS)-bromo-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate were heated under reflux with 15 ml of triethyl phosphite for 12 hours. Evaporation followed by chromatography on silica gel using methanol/ethyl acetate for elution afforded 1.4 g of methyl 9(S)-diethoxyphosphinyl-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2] diazepine-1(S)-carboxylate in the form of a light yellow oil.

NMR: δ (300 MHz, CDCl 3 ): 5.4 (1H, m); 4.6 (1H, m); 4.3

(2H, m); 4.1 (2H, m); 3.75 (3H, s); 3.45 (1H, m); 3.25

(1H, m) ; 2.8 (1H, m); 2.45 (3H, m); 2.25 (1H, m); 1.9 (1H, m); 1.65 (2H, m); 1.3 (6H, m).

Example 8

330 mg of methyl 9(S)-diethoxyphosphinyl-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate were treated with 2 ml of trimethylsilyl bromide and the mixture was stirred at 200 C for 17 hours. The solution was evaporated to dryness and the residue was taken up in acetone and treated with water. After evaporation, the residue was dissolved in 5 ml of water containing 200 mg of sodium hydroxide, and the solution was allowed to stand at 20°C for 4 hours. After washing with dichloromethane, the aqueous phase was applied to a column of Amberlite CG 120 resin, which was then eluted with water. The eluate was evaporated and the residue was triturated with diethyl ether to give 110 mg of octahydro-9(S)-phosphono-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)- carboxylic acid in the form of an amorphous powder.

NMR: δ (400 MHz, CD 3 OD): 5.4 (1H, m); 4.55 (1H, m): 3.55 (1H, m); 3.25 (1H, m); 2.95 (1H, m): 2.4 (2H, m); 2.3 (2H, m); 1.95 (1H, m), 1.6-1.8 (2H, m m).

Example 9

2.8 g of methyl 9(S)-diethoxyphosphinyl-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate were dissolved in 40 ml of ethanol, and the solution was treated with a solution of 305 mg of sodium hydroxide in 10 ml of water. After 30 min. at 20°C the solution was evaporated. The rest was taken up in salt water, washed with it

diethyl ether, acidified with 2N hydrochloric acid and extracted with dichloromethane. The dichloromethane extracts were dried over anhydrous sodium sulfate and evaporated. The residue was crystallized from ethanol/diethyl ether/n-hexane to give 1.4 g of 9(S)-diethoxyphosphinyl-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1 (S)-carboxylic acid in the form of a white solid which melted at 187-189°C (decomposition).

Analysis for C14H23N2O7P:

Calculated: C, 46.41; H, 6.4; N, 7.73%

Found: C, 46.7; H, 6.42; N, 7.79%

Example 10

700 mg of methyl 9(S)-dimethoxyphosphinylmethyl-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate was

dissolved in 10 ml of 2-butanone and 320 mg of lithium thiocyanate monohydrate were added. The mixture was heated under reflux for 24 hours and then evaporated. The residue was dissolved in 5 ml of methanol, and 3.9 ml of 1N sodium hydroxide solution was added. After 5 min. at 20°C

the solution was applied to a column of Amberlite GC 120 resin. Elution with aqueous methanol gave 620 mg of octahydro-9(S)-[[hydroxy-(methoxy)phosphinyl]methyl]-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine -1 ( S )-carboxylic acid in the form of a white solid with a melting point of 80°C (decomposition) (after trituration with diethyl ether).

Analysis for Ci 2 Hi 9 N2 O7 P :

Calculated: C, 43.12; H, 5.73; N, 8.38%

Found (anhydrous): C, 43.31; H, 5.57; N, 8.20%

Example 11

In an analogous manner as described in example 1, from 500 mg of methyl 9(S)-bromomethyl-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S) -carboxylate and 1 ml of triethyl phosphite gave 300 mg of methyl 9(S)-diethoxyphosphinylmethyl-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate as was isolated in the form of a colorless gum.

NMR: δ (CDCl 3 , 300 MHz) 5.45 (1H, m); 4.6 (1H, m); 4.1 (4H, m); 3.8 (3H, s); 3.4 (1H, m); 3.1 (1H, m); 2.85 (1H, m); 2.25-2.55 (4H, m), 1.6-2.0 (5H, m); 1.3 (6H, m) .

Example 12

In an analogous manner to what is described in example 8 from 300 mg of methyl 9(S)-diethoxyphosphinylmethyl-octahydro-6,10-dioxo-6H-pyridazo[1,2-a] [1,2]diazepine-1(S )-carboxylate gave 250 mg of octahydro-9 (S)-phosphonomethyl-6,10-dioxo-6H-pyridazo[1,2-a] [1,2]-diazepine-1(S)-carboxylic acid in the form of a white lyophilisate.

NMR: δ(D 2 O, 300 MHz) 5.35 (1H, m); 4.4 (1H, m); 3.3 (1H, m); 3.1 (2H, m); 2.45 (1H, m); 2.3 (2H, m); 2.15 (1H, m); 1.95 (2H, m); 1.75 (3H, m).

Example 13

In an analogous manner as described in example 5, 200 mg of methyl 9(S)-bromomethyl-octahydro-6,10-dioxo-6H-pyridazo-[1,2-a][1,2]diazepine-1( S)-carboxylate and 700 mg diethoxy-(3-phenylpropyl)phosphine 110 mg methyl 9(S)-[[ethoxy(3-phenylpropyl)phosphinyl]methyl]-octahydro-6,10-dioxo-6H-pyridazo[ 1,2-a][1,2]dia-zepin-1 ( S )-carboxylate in the form of a colorless gum.

MS: m/e E.I. 464 (M<+>).

Example 14

100 mg methyl 9(S)-[ethoxy(3-phenylpropyl)phosphinyl]methyl-octahydro-6,10-dioxo-6H-pyridazo[1,2-a] [1,2]diazepine-1(S)-carboxylate was dissolved in 1 ml of methanol, and the solution was treated with 1 ml of water containing 50 mg of sodium hydroxide. The solution was allowed to stand at 20°C for 5 hours and was then applied to a column of Amberlite CG 120 resin. Elution with aqueous methanol and evaporation of the eluate gave a gum which was dissolved in 1 ml of acetonitrile. 0.5 ml of trimethylsilyl bromide was added to the solution, which was then stirred at 20°C for 17 hours and evaporated. The residue was dissolved in acetone and treated with water. Evaporation gave 60 mg of 9(S)-[[hydroxy(3-phenylpropyl)phosphinyl]methyl]-octahydro-6,10-

dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid in the form of a light yellow foam.

NMR: 5(CD 3 OD, m 300 MHz) 7.2 (5H, m); 5.3 (1H, m); 4.45 (1H, m); 3.5 (1H, m); 3.1 (1H, m); 2.9 (1H, m); 2.7 (2H, t); 2.35 (2H,m m); 2.2 (2H, m); 1.85 (4H, m); 1.7 (5H, m) .

Example 15

1.2 g of benzyl 9(S)-amino-octahydro-10-oxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate was dissolved in 25 ml of dichloromethane. 0.56 ml of triethylamine was added followed by a solution of 0.79 g of benzylphenethylphosphochloridate in 5 ml of dichloromethane. The mixture was stirred at 20°C for 4 hours, washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/n-hexane for the elution. 550 mg of benzyl 9(S)-[[benzyloxy(phenethyl)phosphinyl]amino]-octahydro-10-oxo-6H-pyridazo[1,2-a] [1,2]diazepine-1(S)-carboxylate were obtained in the form of a light yellow gum.

MS: m/e 576 (M+H)f .

Example 16

250 mg benzyl 9(S)-[[benzyloxy(phenethyl)phosphinyl]amino]-octahydro-10-oxo-6H-pyridazo [1,2-a] [1,2]diazepine-1(S)-carboxylate and 73 mg of sodium bicarbonate was dissolved in 100 ml of 25% aqueous ethanol and the mixture was hydrogenated over 10% palladium-on-carbon at atmospheric pressure for 17 hours. The catalyst was removed by filtration and the filtrate was evaporated. The residue was taken up in water and freeze-dried to give 145 mg of 9(S)-[[hydroxy(phenethyl)phosphinyl]amino]-octahydro-10-oxo-6H-pyridazo[1,2-a] [1 ,2]-diazepine-1(S)-carboxylic acid disodium salt in the form of a white lyophilisate.

Analysis for Ci a H2 4 N3 Os PNa2 . 2H2 0:

Calculated: C, 43.82; H, 6.12 , N, 8.51%

Found: C, 43.69; H, 5.9; N, 8.6%

Example 17

30 mg of 80% sodium hydride was added to a stirred solution of 298 mg of tert.butyl octahydro-9(S)-hydroxy-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine -1(S)-carboxylate in 4 ml of tetrahydrofuran, and the mixture was stirred at room temperature for 5 min. A solution of 297 mg of dibenzyl chlorophosphonate in 3 ml of carbon tetrachloride was added, the mixture was stirred at room temperature for 1 hour, and the solvents were then removed by evaporation. The residue was chromatographed on silica gel using diethyl ether/methanol (19:1) for the elution to give 95 mg of tert.butyl 9(S)-(dibenzylphosphonoxy)-octahydro-6,10-dioxo-6H-pyridazo[1,2 -a][1,2]diazepine-1(S)-carboxylate in the form of a light yellow gum.

Analysis for C2 0 H3 5 N2 Oa P :

Calculated: C, 60.2; H, 6.3; N, 5.0%

Found: C, 59.9; H, 6.2; N, 4.9%

The tert-butyl octahydro-9(S)-hydroxy-6,10-dioxo-6H-pyridazo-[1,2-a][1,2]diazepine-1(S)-carboxylate which was used as the starting material can be prepared as follows: 9.6 g of 1-benzyl 3-tert.butyl hexahydropyridazine-1,3(S)-dicarboxylate was stirred at 8-10°C with 50 ml of toluene and 70 ml of 10% aqueous sodium bicarbonate solution while adding a solution in 45 ml of toluene of the acid chloride formed from 89.1 g of 2-acetoxy-4-benzyloxycarbonylbutyric acid. The mixture was stirred at room temperature for 1 hour, and the organic layer was separated. Chromatography on Florisil using toluene for the elution gave 15.3 g of 1-benzyl 3-tert.butyl 2-[2(S)-acetoxy-4-(benzyloxycarbonyl)butyryl]-hexahydro-1,3(S)-pyridazine dicarboxylate in the form of a colorless gum.

14.5 g of 1-benzyl 3-tert.butyl 2-[2(S)-acetoxy-4-(benzyloxy-carbonyl)butyryl]-hexahydro-1,3(S)-pyridazine dicarboxylate in 150 ml of dimethylformamide was hydrogenated over 0 .5 g of 10% palladium-on-carbon at room temperature and atmospheric pressure. The catalyst was removed by filtration, and the solvent was then removed by evaporation. The residue was taken up in 150 ml of dichloromethane, and the solution was cooled and stirred under a slow stream of nitrogen

while adding 2.97 g of thionyl chloride. The solution was stirred at room temperature for 2 hours and then washed with 10% aqueous potassium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel using diethyl ether/ethyl acetate (1:1) for the elution. 5.7 g of tert.butyl 9(S)-acetoxy-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate were obtained in the form of a white solid

with melting point 80-81°C (from diethyl ether/n-hexane).

A solution of 0.68 g of tert.butyl 9(S)-acetoxy-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate in 5 ml of ethanol was treated with 10 ml of 0.4N aqueous sodium hydroxide solution at room temperature for 1 hour. The solvent was removed by evaporation, the residue was partitioned between water and dichloromethane. The organic phase was separated and evaporated to give 0.52 g of tert.butyl octahydro-9(S)-hydroxy-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine- 1(S)-carboxylate in the form of a white solid with melting point 137-138°C (from diethyl ether).

Analysis for C29H37N2O7P:

Calculated: C, 56.4; H, 7.4; N, 9.4%

Found: C, 56.2; H, 7.5, N, 9.35%.

Example 18

0.15 g of 80% sodium hydride was added to a stirred solution of 1.49 g of tert.butyl octahydro-9(S)-hydroxy-6,10-dioxo-6H-pyridazo[1,2-a][1,2 ]diazepine-1(S)-carboxylate in 20 ml of tetrahydrofuran and the mixture was stirred at room temperature for 5 min. A solution of 1.47 g of benzyl phenethyl phosphochloridate in 10 ml of tetrahydrofuran was added, the mixture was stirred at room temperature for 1 hour and the solvents were then removed by evaporation. The residue was chromatographed on silica gel using diethyl ether/methanol (19:1) for the elution. 1.44 g of tert.butyl 9(S)-[benzyloxy(phenethyl)phosphinyloxy]-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]-diazepine-1( S)-carboxylate in the form of a colorless gum.

Analysis for C29H37N2O7P:

Calculated: C, 62.6; H, 6.7; N, 5.0%

Found: C, 62.7; H, 6.7; N, 5.1%.

Example 19

0.1 g of triethylamine and 0.35 g of dibenzyl chlorophosphonate in 3.6 ml of carbon tetrachloride were added to a stirred solution, cooled to 0° C., of 0.32 g of benzyl 9(S)-amino-octahydro-10-oxo-6H -pyridazo-[1, 2-a] [1,2]diazepine-1(S)-carboxylate in 5 ml of dichloromethane. The mixture was stirred at room temperature for 16 hours, and the solvents were then removed by evaporation. The residue was chromatographed on silica gel using ethyl acetate/n-hexane (2:1) for the elution. 0.25 g of benzyl 9(S)-[(dibenzyloxyphosphinyl)amino]-octahydro-10-oxo-6H-pyridazo[1,2-a] [1,2]diazepine-1(S)-carboxylate were obtained in the form of a colorless gum.

NMR: 5H(CDCl 3 , 300 MHz): 1.3-1.9 (6H, m); 2.0 (1H, m); 2.34 (1H, broad); 2.41 (1H, m); 2.88 (1H, broad); 2.98 (1H, m); 3.13 (1H, m); 4.03 (1H, m); 4.71 (1H, m); 5.0-5.1 (5H, m); 5.14 (1H, d); 5.20 (1H, d); 7.2-7.5 (13H, m).

Example 20

A solution of 1.88 g of benzyl 9(S)-[(dibenzyloxyphosphinyl)-amino]-octahydro-10-oxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate in 20 ml of methanol was treated with 4.9 ml of 1N aqueous sodium hydroxide solution at room temperature for 16 hours. The solution was diluted with 50 ml of water, and the volume was then reduced to 20 ml. The pH was adjusted to 3.5 and the solution was extracted with dichloromethane. The organic solution was evaporated, and the residue was chromatographed on silica gel to give 1.42 g of 9(S)-[(dibenzyloxy-phosphinyl)amino]-octahydro-10-oxo-6H-pyridazo[1,2-a][l ,2]diazepine-1(S)-carboxylic acid in the form of a lyophilisate (from benzene).

Analysis for C2 4 H3 0 N3 06 P :

Calculated: C, 59.2; H, 6.2; N, 8.6%

Found (anhydrous): C, 58.95; H , 5.9; N, 8.3%

Example 21

In an analogous way as described in example 18, one obtains from

1.1 g tert.butyl octahydro-9(S)-hydroxy-6,10-dioxo-6H-pyridazo-[1,2-a] [1,2]diazepine-1(S)-carboxylate and 1.21 g benzyl 4-phenylbutylphosphochloridate 0.90 g tert.butyl 9(S)-[benzyloxy(4-phenylbutyl-)phosphinyloxy]-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2 ]dia-zepin-1 ( S )-carbosylate in the form of a colorless gum.

MS: m/e 584 (M<*>).

Example 22

A solution of 0.4 g of tert.butyl 9 (S)-[benzyloxy(4-phenylbutyl)L-phosphinyloxy]-octahydro-6,10-dioxo-6H-pyridazo[1,2-a] [1,2] -diazepine-1(S)-carboxylate in 40 ml of isopropanol was hydrogenated over 10% palladium-on-carbon at atmospheric pressure for 16 hours. The catalyst was removed by filtration and the filtrate was evaporated. The resulting gum was dissolved in 10 ml of trifluoroacetic acid, the solution was allowed to stand at 20°C for 1 hour and then evaporated to give 0.24 g of 9(S)-[hydroxy(4-phenylbutyl)phosphinyloxy]-octahydro-6,10 -dioxo-6H-pyridazo[1,2-a][l,2]diazepine-l(S)~ carboxylic acid in the form of a colorless gum.

MS: m/e 439 (M + H) + .

Example 23

In an analogous manner as described in example 15, 0.8 g of benzyl 9(S)-amino-octahydro-10-oxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S )-carboxylate and 0.49 g benzyl benzyl phosphochloride 0.127 g benzyl 9(S)-[[benzyloxy(benzyl)phosphinyl]amino]-octahydro-10-oxo-6H-pyridazo[1,2-a][1,2 ]diazepine-1(S)-carboxylate in the form of a colorless gum.

MS: m/e 561 (M<+>).

Example 24

In an analogous manner as described in example 15, 1.15 g of benzyl 9(S)-amino-octahydro-10-oxo-6H-pyridazo[1,2-a]-

[1,2]diazepine-1(S)-carboxylate and 0.73 g benzyl 3-phenylpropyl phosphochloridate 0.31 g benzyl 9 ( S )-[[benzyloxy(3-phenylpropyl)phosphinyl]amino]-octahydro -10-oxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate in the form of a colorless gum.

MS: m/e 589 (M* ).

Oak semp el 25

In an analogous manner as in example 15, 1.13 g of benzyl 9(S)-amino-octahydro-10-oxo-6H-pyridazo[1,2-a][1,2]diazepin-1 was obtained (S)-carboxylate and 0.83 g benzyl 4-phenylbutylphosphochloridate 0.33 g benzyl 9(S)-[[benzyloxy(4-phenylbutyl)phosphinyl]amino]-octahydro-10-oxo-6H-pyridazo[1,2 -a][l,2]diazepine-l(S)-carboxylate in the form of a colorless gum.

MS: m/e 603 (M<+>).

Example 26

In an analogous manner as described in example 16, 260 mg of benzyl 9(S)-[[benzyloxy(benzyl)phosphinyl]amino]-octahydro-10-oxo-6H-pyridazo[1,2-a][1, 2]diazepine-1(S)-carboxylate 190 mg 9(S)-[[hydroxy(benzyl)phosphinyl]amino]-octahydro-10-oxo-6H-pyridazo[1,2-a][1,2]diazepine -1(S)-carboxylic acid disodium salt in the form of a white lyophilisate.

MS: m/e 426 (M+H) + .

Example 27

In an analogous manner as described in example 16, 290 mg of benzyl 9(S)-[[benzyloxy(3-phenylpropyl)phosphinyl]amino]-octahydro-10-oxo-6H-pyridazo[1,2-a][ 1,2]diazepine-1(S)-carboxylate 230 mg 9(S)-[[hydroxy(3-phenylpropyl)phosphinyl]amino]-octahydro-10-oxo-6H-pyridazo[1,2-a][l ,2]diazepine-1(S)-carboxylic acid disodium salt in the form of a white lyophilisate.

Analysis for Ci 9 H2 e N3 05 P Na2 . 2. 2 H2O:

Calculated C, 46.29; H, 6.21; N, 8.52; P 6.28; H 2 O, 8.04% Found: C, 46.15; H, 6.40; N, 8.20; P6.30; H 2 O, 8.00%.

Example 28

In an analogous manner as described in example 16, 280 mg of benzyl 9(S)-[[benzyloxy(4-phenylbutyl)phosphinyl]amino]-octahydro-10-oxo-6H-pyridazo[1,2-a][ 1,2]diazepine-1(S)-carboxylate 200 mg 9(S)-[[hydroxy(4-phenylbutyl)phosphinyl]amino]-octahydro-10-oxo-6H-pyridazo[1,2-a][1 ,2]diazepine-1(S)-carboxylic acid disodium salt in the form of a white lyophilisate.

Analysis for C2 o H2 a N3 Os P Na2 . 2 .1 H2 0 :

Calculated: C, 47.54; H, 6.42; N, 8.32; H2O 7.48%

Found: C, 47.40; H, 6.30; N, 8.10; H2O 7.55%.

Example 29

3 g of methyl 9(RS)-bromo-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate and 8.1 g of diethyl 5-phenylpentyl -phosphonite was heated together at 150°C for 12 hours. Evaporation followed by chromatography on silica gel using methanol/ethyl acetate as the eluent gave 1.3 g of methyl 9(S)-[(ethoxy)(5-phenylpentyl)phosphinyl]-octahydro-6,10-dioxo-6H-pyridazo [1,2-a][1,2]diazepine-1(S)-carboxylate in the form of a colorless gum.

MS: m/e 479 (M+H) + .

Example 30

In an analogous way as described in example 29, it was obtained from

1 g of methyl 9(RS)-bromo-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate and 3 g of diethyl 4-phenylbutylphosphonite 350 mg methyl 9(S)-[(ethoxy)(4-phenylbutyl)phosphinyl]-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)- carboxylate in the form of a gum.

NMR: δ (CDCl 3 , 300 MHz); 7.20 (SH, m); 5.39 (1H, dd, J = 3.7Hz); 4.56 (1H, m); 4.08 (2H, m); 3.74 (3H, s); 3.45 (1H, m); 3.20 (1H, m); 2.80 (1H, m); 2.63 (2H, t, J = 7Hz); 2.44 (2H, m); 2.25 (3H, m); 1.90-1.55 (8H, m); 1.30 (3H, t, J = 7.5 Hz).

Example 31

In an analogous way as described in example 29, it was obtained from

1 g of methyl 9(RS)-bromo-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate and 2.25 g of diethyl 3-phenylpropyl -phosphonite 220 mg methyl 9(S)-[(ethoxy)(3-phenylpropyl)phosphinyl]-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S )-carboxylate in the form of a gum.

NMR: δ (CDCl 3 , 400 MHz): 7.24 (5H, m); 5.40 (1H, dd, J = 3.7Hz); 4.60 (1H, m); 4.17 - 3.99 (2H, m); 3.76 (3H, s); 3.44 (1H, m); 3.20 (1H, m); 2.86 (1H, m); 2.72 (2H, m); 2.40 (2H, m); 2.24 (3H, m); 2.10 (1H, m); 1.91 (3H, m); 2.70 (2H, m); 1.30 (3H, t, J = 7.5Hz) .

Example 32

In an analogous way as described in example 29, it was obtained from

1 g of methyl 9(RS)-bromo-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate and 2.6 g of diethyl 2-phenethylphosphonite 410 mg methyl 9(S)-[(ethoxy)(phenethyl)phosphinyl]-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate in shape of a rubber.

MS: m/e 436 (M<+>).

Example 33

1.2 g of methyl 9(S)-[(ethoxy)(5-phenylpentyl)phosphinyl]-octahydro-6,10-dioxo-6H-pyridazo [1,2-a] [1,2]diazepine-1(S )-carboxylate was treated with a solution of 1 g of sodium hydroxide in 15 ml of water and the mixture was stirred at 20°C for 24 hours. The mixture was placed on a sulfonic acid ion exchange resin and eluted with 50% methanol/water. The eluate was evaporated and the residue was chromatographed on silica gel using chloroform/methanol/acetic acid/water (120:-14:3:2) for the elution. The product was dissolved in 20 ml of acetonitrile and the solution was treated with 5 ml of trimethylsilyl bromide. The solution was stirred at 20°C for 17 hours and then evaporated. The residue was dissolved in 30 ml of acetone and 20 ml of water was added. After 2 hours the mixture was evaporated and the residue treated with diethyl ether to give 520 mg of 9(S)-[hydroxy(5-phenylpentyl)-phosphinyl]-octahydro-6,10-dioxo-6H-pyridazo[1,2- a][1,2]diazepine-

carboxylic acid in the form of a white solid with a melting point of 218-220° C (from methanol).

Analysis for C2 1 H2 9 N2 06 P :

Calculated: C, 57.79; H, 6.70; N, 6.42%

Found: C, 57.85; H, 6.68; N, 6.52%

Example 34

In an analogous manner as described in example 6, 300 mg of methyl 9(S)-[(ethoxy)(4-phenylbutyl)phosphinyl]-octahydro-6,10-dioxo-6H-pyridazo[1,2-a] was obtained [1,2]diazepine-1(S)-carboxylate 150 mg 9(S)-[hydroxy(4-phenylbutyl)phosphinyl]-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1 ,2]diazepine-1(S)-carboxylic acid in the form of a white lyophilisate.

NMR: δ(CD 3 OD, 300 MHz): 7.20 (5H, m); 5.30 (1H, m); 4.45 (1H, m); 3.48 (1H, m); 3.20 (1H, m); 2.82 (1H, m); 2.61 (2H, m); 2.30 (4H, m); 2 , 10 - 1.50 (9H, m) .

Example 35

In an analogous manner as described in example 6, 210 mg of methyl 9(S)-[(ethoxy)(3-phenylpropyl)phosphinyl]-octahydro-6,10-dioxo-6H-pyridazo[1,2-a] was obtained [1,2]diazepine-1(S)-carboxylate 80 mg 9(S)-[hydroxy(3-phenylpropyl)phosphinyl]-octahydro-6,10-dioxo-6H-pyridazo[1,2-a] [ 1 ,2]diazepine-1(S)-carboxylic acid as an amorphous white solid.

Analysis for C19H23N2O6P:

Calculated: C, 55.88; , 6.17; N, 6.86%

Found: C, 55.66; H, 6.00; N, 6.69%.

Example 36

In an analogous manner as described in example 33, 340 mg of methyl 9(S)-[(ethoxy)(phenethyl)phosphinyl]-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1 ,2]diazepine-1(S)-carboxylate 100 mg 9(S)-[hydroxy(phenethyl)phosphinyl]-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine -1(S)-carboxylic acid in the form of a brown lyophilisate.

NMR: δ(CD 3 OD, 300 MHz): 3.24 (5H, m); 5.32 (1H, m); 4.46 (1H, m); 3.50 (1H, m); 3.15 (1H, m); 2.90 (3H, m ); 2.50 - 2.15 (6H, m); 1.90 (1H, m); 1.65 (2H, m).

Example 37

In an analogous way as described in example 5, it was obtained from

1 g methyl 9(S)-bromomethyl-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate and 2 g diethyl 2-phenethylphosphonite 630 mg methyl 9(S)-[[ethoxy(phenethyl)phosphinyl]methyl]octahydro-6,10-dioxo-6H-pyridazo[1,2-a] [1,2]diazepine-1(S)-carboxylate in the form of a bright yellow rubber.

NMR: δ (CDCl 3 , 300 MHz); 7.26 (5H, m); 5.42 (1H, dd, J = 37Hz); 4.60 (1H, m); 4.05 (2H, m); 3.73 (2H, s); 3.40 (1H, m); 3.18 (1H, m); 2.90 (3H, m); 2.35 (4H, m); 2.05 (2H, m); 1.87 (2H, m); 1.65 (3H, m); 1.30 (3H, t, J = 7.5 Hz).

Example 38

In an analogous manner as described in example 6, 630 mg of methyl 9(S)-[[ethoxy(phenethyl)phosphinyl]methyl]octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1 ,2]diazepine-1(S)-carboxylate 430 mg 9(S)- [[hydroxy(phenethyl)phosphinyl]methyl]octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2 ]diazepine-1(S)-carboxylic acid in the form of a white lyophilisate.

Analysis for Ci 9 H2 5 N2 Oe P . 0 . 5H2 0 :

Calcd: C, 54.67, H, 6.27; N, 6.71; H2O 2.16%

Found: C, 54.55; H, 6.12; N, 6.40; H2O 1.98%.

Example 39

In an analogous manner as described in example 2, 1.34 g of methyl 9(S)-[[ethoxy(phenethyl)phosphinyl]methyl]octahydro-6,10-dioxo-6H-pyridazo[1,2-a ][1,2]diazepine-1(S)-carboxylate 350 mg methyl 9(S)-[[ethoxy(phenethyl)phosphinyl]methyl]octahydro-10-oxo-6H-pyridazo[1,2-a][1 ,2]diazepine-1(S)-carboxylate in the form of a colorless oil.

MS: m/e 436 (M<+>).

Example 40

In an analogous manner as described in example 6, 330 mg of methyl 9(S)-[[ethoxy(2-phenethyl)phosphinyl]methyl]octahydro-10-oxo-6H-pyridazo[1,2-a][ 1,2]diazepine-1(S)-carboxylate 240 mg 9(S)-[[hydroxy(2-phenethyl)phosphinyl]methyl]octahydro-10-oxo-6H-pyridazo[1,2-a][1, 2]diazepine-1(S)-carboxylic acid in the form of a light yellow lyophilisate from acetic acid.

NMR: δ(CD 3 OD, 300 MHz): 7.20 (5H, m); 4.95 (1H, m): 3.28 (1H, m); 3.48 (1H, m); 3.10 (2H, m); 2.87 (2H, m); 2.65 (1H, m); 2.34 (2H, m); 1.95 (4H, m); 1.70 (4H, m); 1.40 (2H, m) .

Example 41

In an analogous manner as described in example 2, 2.5 g of methyl 9(S)-[(ethoxy)(4-phenylbutyl)phosphinyl]-octahydro-6,10-dioxo-6H-pyridazo[1,2 -a][1,2]diazepine-1(S)-carboxylate 820 mg methyl 9(S)-[(ethoxy)(4-phenylbutyl)phosphinyl]-octahydro-10-oxo-6H-pyridazo[1,2- a][1,2]diazepine-1(S)-carboxylate in the form of a light yellow viscous oil.

MS: m/e 450 (m<+>).

Example 42

In an analogous manner as described in example 6, 670 mg of methyl 9(S)-[(ethoxy)(4-phenylbutyl)phosphinyl]-octahydro-10-oxo-6H-pyridazo [1,2-a] [ 1,2]diazepine-1(S)-carboxylate 270 mg 9(S)-[(hydroxy)(4-phenylbutyl)phosphinyl]-octahydro-10-oxo-6H-pyridazo[1,2-a][1, 2]diazepine-1(S)-carboxylic acid dipotassium salt in the form of a white lyophilisate.

NMR: δ(CD 3 OD, 400 MHz): 7.15 (5H, m); 4.70 (1H, m); 3.70 (1H, m); 3.60 (1H, m); 3.00 (2H, m); 2.60 (3H, m); 2.38 (1H, m); 1.97 (2H, m); 1.82 (2H, m); 1.60 (8H, m); 1.26 (1H, m) .

Example 43

A mixture of 1.2 g of 9-methylene-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid and 4.3 g of diethyl 4- benzyloxybutylphosphonite in 25 mL of xylene was heated at 110°C under nitrogen for 24 hours. The solvent was removed in vacuo and the residue was chromatographed on silica gel using 5% methanol in ethyl acetate for elution. 2.0 g of ethyl 9(S)-[[(4-benzyloxybutyl) (ethoxy)phosphinyl]methyl]-octahydro-6,10-dioxo-6H-pyridazo[1,2-a] [ 1,2]diazepine-1(S)-carboxylate in the form of a viscous oil.

MS: m/e 523 (M+H)* .

9-methylene-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid used as the starting material was prepared as follows: 10 g tert.Butyloctahydro-9-methylene-6,10-dioxo-6H-pyridazo-[1,2-a][1,2]diazepine-1(S)-carboxylate, prepared as described in Example 48, was stirred with 40 ml of trifluoroacetic acid at 20°C for 3 hours. The mixture was evaporated and the resulting oil treated with diethyl ether to give 7.6 g of 9-methylene-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-(S)- carboxylic acid in the form of a white solid with a melting point of 169°-172°C.

Example 44

In an analogous manner as described in example 6, 700 mg of ethyl 9(S)-[[(4-benzyloxybuty1)(ethoxy)phosphiny1]-octac-hydro-6,10-dioxo-6H-pyridazo[1, 2-a] [1,2]diazein-1(S)-carboxylate 400 mg 9(S)-[[(4-benzyloxybutyl)(hydroxy)phosphinyl]methyl]-octahydro-6,10-dioxo-6H-pyridazo [1,2-a][1,2]diazepine-1(S)-carboxylic acid in the form of a colorless gum.

NMR: δ(CD 3 OD, 300 MHz): 7.28 (5H, m); 5.32 (1H, dd, J = 3.7Hz); 4.49 (2H, s); 4.47 (1H, m); 3.50 (3H, m); 3.12 (1H, m); 2.92 (1H, m); 2.35 (2H, m); 2.20 (2H, m); 1.90 (2H, m); 1.70 (9H, m).

Example 45

275 mg 9(S)-[[(4-benzyloxybutyl)(hydroxy)phosphinyl]methyl]-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S )-carboxylic acid was dissolved in 30 ml of ethanol containing 3 ml of acetic acid, and the solution was hydrogenated over 10% palladium-on-carbon for 16 hours. The catalyst was removed by filtration and

the filtrate was evaporated. The residue was taken up in water and the pH was adjusted to 7 with potassium bicarbonate. Evaporation and treatment with acetone gave 190 mg of 9(S)-[[(4-hydroxybutyl)(hydroxy)phosphinyl]-methyl]-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1, 2]diazepine-1(S)-carboxylic acid dipotassium salt in the form of a white hygroscopic solid.

NMR: δ(DzO, 300 MHz); 5.00 (1H, m); 4.35 (1H, m); 3.58 (3H, m); 3.08 (2H, m); 2.45 (1H, m); 2.22 (3H, m); 2.07 (2H, m); 1.93 (2H, m); 1.74-1.40 (7H, m).

Example 46

350 mg ethyl 9(S)-[[(4-benzyloxybuty1)(ethoxy)phosphinyl]-methyl]-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1 The (S)-carboxylate was dissolved in a mixture of 20 ml of ethanol and 2 ml of acetic acid and the solution was hydrogenated over 10% palladium-on-carbon for 16 hours. The catalyst was removed by filtration and the filtrate was evaporated. The residue was taken up in 5 ml of dichloromethane and stirred at 20°C, while 0.18 ml of triethylamine and then a solution of 0.075 ml of methanesulfonyl chloride in 4 ml of dichloromethane were added. Stirring was continued for 2 hours and the mixture was then washed sequentially with 2N hydrochloric acid, sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate and evaporated. The residue was taken up in 20 ml of 2-butanone and 60 mg of sodium azide was added. The mixture was heated under reflux for 20 hours and then evaporated. The residue was partitioned between ethyl acetate and water. The organic layer was evaporated, and the residue was chromatographed on silica gel using 10% methanol in ethyl acetate for the elution, whereby 130 mg of ethyl 9(S)- [ [ (4-azidobutyl) (ethoxy)phosphinyl]methyl]-octahydro was obtained -6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate in the form of a gum. This gum was taken up in 15 ml of ethanol, and the solution was hydrogenated over 10% palladium-on-carbon for 3 hours. Filtration and evaporation of the filtrate gave 120 mg of ethyl 9(S)-[[(4-aminobutyl)(ethoxy)phosphinyl]methyl]-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1, 2]diazepine-1(S)-carboxylate in the form of a gum.

MS: m/e 431 (M<+>).

Example 47

In an analogous manner as described in example 6, 120 mg of ethyl 9(S)-[[(4-aminobutyl)(ethoxy)phosphinyl]methyl]-octahydro-6,10-dioxo-6H-pyridazo[1, 2-a][1,2]diazepine-1(S)-carboxylate 55 mg 9(S)-[[(4-aminobutyl)(hydroxy)phosphinyl]methyl-octahydro-6,10-dioxo-6H-pyridazo[ 1,2-a][1,2]diazepine-1(S)-carboxylic acid in the form of a light yellow gum.

Analysis for Ci 5 H2 e N3 Oe P . 1.12O:

Calcd: C, 45.59; H, 7.19; N, 10.63; H2O 5.01%

Found: C, 45.72; H, 6.87; N, 10.54; H2O 5.12%.

Example 48

A solution of 2.8 g of 1-[2-(methoxyphosphinyl)ethyl]-4-nitrobenzene and 3.6 g of tert.butyloctahydro-9-methylene-6,10-dioxo-6H-pyridazo[1,2- a][1,2]diazepine-1(S)-carboxylate in 80 ml of toluene was treated under nitrogen with 2.49 g of N,0-bis(trimethylsilyl)acetamide. After heating at 60°C for 65 hours, the solution was diluted with 100 ml of dichloromethane, washed with water and evaporated. The residue was chromatographed on silica gel using 10% methanol in ethyl acetate for the elution, and thus 1.0 g of tert.butyl-octahydro-9(S)-[[methoxy(4-nitrophenethyl)phosphinyl]methyl]6,10 was obtained -dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate in the form of a pale yellow foam.

NMR: δ (CDCl 3 , 300MHz): 8.16 (2H, d, J = 8Hz); 7.40 (2H, dd, J = 3, 8Hz); 5.30 (1H, m); 4.60 (1H, m); 3.72 (1.5H, d, J = 9Hz); 3.68 (1.5H, d, J = 9Hz); 3.49 (1H, m); 3.05 (4H, m); 2.50 - 1.65 (11H, m); 1.48 (9H, p).

Tert.Butyloctahydro-9-methylene-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate used as the starting material can be prepared as follows: A solution of 10 g (0.0313 mol) of 1-benzyloxycarbonyl-S-piperazine acid tert-butyl ester in 100 ml of methanol was hydrogenated at room temperature and atmospheric pressure over 5% palladium/carbon. The catalyst was removed by filtration and the filtrate was evaporated to dryness. The resulting crude piperazine tert-butyl ester was taken up in 100 ml dioxane, and the solution was cooled to 0°C and treated with a solution of 3.94 g (0.0313 mol) α-methylene glutaric anhydride in 100 ml dioxane. The mixture was stirred at 20°C for 18 hours and the solvent was removed by evaporation. The residue was partitioned between methyl tert-butyl ether and saturated sodium bicarbonate solution. The aqueous phase was acidified with hydrochloric acid and extracted with dichloromethane, yielding 8.34 g (85%) of 3(S)-tert-butoxycarbonyl-hexahydro-α-methylene-5-oxo-1-pyridazinepentanoic acid as white crystals with melting point 96-99°C. 5.0 g (16 mmol) of this acid was taken up in 350 ml of tetrahydrofuran, and the solution was cooled to 0°C. 3.75 g (18 mmol) of phosphorus pentachloride was added and the mixture was stirred at 0°C for 1 hour over 20°C for 18 hours. The solvent was removed by evaporation, and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic phase was evaporated and the residue was chromatographed on silica gel using ethyl acetate/n-hexane for the elution. 3.7 g (79%) of tert.butyloctahydro-9-methylene-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylate were obtained as a white solid with melting point 105°-106°C (from hexane).

1-[2-(Methoxyphosphinyl)ethyl]-4-nitrobenzene mentioned in the first paragraph of the first paragraph of this example was prepared as follows: 0.665 g of crystalline hypophosphorous acid was treated under nitrogen with 1.73 g of trimethyl orthoformate, and the mixture was stirred at 20°C for 2 hours. The resulting solution of crude methyl hypophosphite was added dropwise at 0°C to a solution of 1 g of 4-nitrostyrene and 0.43 g of diisopropylethylamine in 5 ml of methanol. After 65 hours at 20°C, the same amount of methyl hypophosphite was added again, and the mixture was stirred at 20°C for another 24 hours. The mixture was diluted with 30 ml of water and the pH was adjusted to 7 with aqueous sodium bicarbonate solution. After extraction with dichloromethane and chromatography on silica gel using 10% methanol in ethyl acetate for elution, 0.5 g of 1-[2-(methoxyphosphinyl)-ethyl]-4-nitrobenzene was obtained in the form of a yellow liquid.

Example 49

0.48 g tert.butyloctahydro-9(S)-[[methoxy(4-nitrophenethyl)-phosphinyl]methyl]-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine- 1(S)-carboxylate was stirred in 2 ml of trifluoroacetic acid at 20°C for 1 hour. The mixture was evaporated, and the residue was partitioned between sodium bicarbonate solution and dichloromethane. The aqueous phase was acidified with 2N hydrochloric acid, and then extracted with dichloromethane. Evaporation of the extract gave 0.29 g of octahydro-9(S)-[[methoxy(4-nitrophenethyl)phosphinyl]methyl]-6,10-dioxo-6H-pyridao[1,2-a] [1,2]- diazepine-1(S)-carboxylic acid in the form of a white foam.

NMR: δ(CD 3 OD, 300 MHz): 8.19 (2H, dd, J = 8Hz); 7.53 (2H, dd, J = 3.8Hz); 5.36 (1H, m); 4.51 (1H, m); 3.73 (1.5H, d, J = 9Hz); 3.69 (1.5H, d, J = 9Hz); 3.50 (1H, m); 3.05 (4H, m); 2.5 - 1.6 (11H, m) .

Example 50

A solution of 0.1 g of octahydro-9(S)-[[methoxy(4-nitrophenethyl)phosphinyl]methyl]-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine- 1(S)-carboxylic acid in 1 ml of acetonitrile was treated under nitrogen with 1 ml of trimethylsilyl bromide. The solution was stirred at 20°C for 30 min. and then evaporated. The residue was dissolved in aqueous acetone, and the solution was stirred for 30 min. and then evaporated. The residue was treated with diethyl ether to give 0.075 g of octahydro-9(S)-[[hydroxy(4-nitrophenethyl)phosphinyl]methyl]-6,10-dioxo-6H-pyridazo-[1,2-a] [1 ,2]diazepine-1(S)-carboxylic acid in the form of an amorphous solid.

NMR: δ(CD 3 OD, 400 MHz) 8.19 (2H, d, J = 8Hz); 7.52 (2H, d, J = 8Hz); 5.35 (1H, m); 4.50 (1H, m); 3.52 (1H, m); 3.15 (1H, m); 2.98 (3H, m); 2.40 (2H, m ); 2.24 (2H, m) 2.07 (2H, m); 1.90 (2H, m); 1.70 (3H, m) .

Example 51

0.12 g of octahydro-9(S)-[[hydroxy(4-nitrophenethyl)phosphinyl]-methyl]-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1( S)-carboxylic acid in 50 mL of methanol was hydrogenated over 10% palladium-on-carbon for 5 hours. The catalyst was removed by filtration, and

the filtrate was evaporated. After treatment of the residue with diethyl ether, 0.1 g of 9(S)-[[(4-aminophenethyl)hydroxyphosphinyl]methyl]-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1, 2]diazepine-1(S) - carboxylic acid in the form of an amorphous solid.

NMR: δ(D 2 O, 300 MHz): 7.43 (2H, d, J = 8Hz); 7.36 (2H, d, J = 8Hz); 5.23 (1H, m); 4.40 (1H, m); 3.39 (1H, m); 3.08 (2H, m); 2.90 (2H, m); 2.26 (4H, m); 1.91 (4H, m); 1.70 (2H, m); 1.58 (1H, m) .

Example 52

In an analogous manner to what is described in example 51, 0.125 g of octahydro-9(S)-[[methoxy(4-nitrophenethyl)phosphinyl]methyl]-6,10-dioxo-6H-pyridazo[ 1,2-a][1,2]diazepine-1(S)-carboxylic acid 0.112 g 9(S)-[[(4-aminophenethyl)methoxyphosphinyl]methyl]-octahydro-6,10-dioxo-6H-pyridazo[ 1,2-a][1,2]diazepine-1(S) - carboxylic acid in the form of a gum.

MS: m/e 437 (M« ).

Example 53

0.11 g 9(S)-[[(4-aminophenethyl)methoxyphosphinyl]methyl]-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S) -carboxylic acid was dissolved in 3 ml of acetonitrile, and 3 ml of trimethylsilyl bromide was added. The solution was stirred at 20° C. for 90 hours. Evaporation and treatment of the residue with aqueous acetone followed by further evaporation gave, after preparative high pressure liquid chromatography, 0.025 g of octahydro 9(S)-[[(hydroxy)[4-(1-iminoethylamino)phenethyl]phosphinyl]methyl]-6, 10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid in the form of an amorphous solid.

NMR: δ(CD 3 OD, 300 MHz); 7.4 5 (2H, d, J = 8Hz); 7.26 (2H, d, J =

8Hz); 5.35 (1H, m); 4.50 (1H, m); 3.49 (1H, m); 3.15 (1H, m); 2.97 (3H, m); 2.39 (3H, s); 2.38 (2H, m); 2.24 (2H, m); 2.05 (2H, m); 1.89 (2H, m ); 1.70 (3H, m).

The following examples illustrate pharmaceutical preparations containing the compounds produced according to the present invention:

Claims (14)

1. Procedure for making compounds with it general formula where R <1> means hydroxy, alkyl, aralkyl, aralkyl-alkyl, hydroxy-alkyl, amino-alkyl, acylamino-alkyl, monoalkylamino-alkyl, dialkylamino-alkyl, alkoxycarbonylamino-alkyl, halo-alkyl, carboxy-alkyl, alkoxycarbonyl- alkyl, alkoxy or aralkyl; R<2> and R<3> each means hydrogen, alkyl or aralkyl; R" and R <5> each means hydrogen or R <4> and R <5> together means oxo; and X means an oxygen atom or the group -NR <6-> in which R <6> means hydrogen, alkyl or aralkyl or - (CH2 )n - where n stands for zero, 1 or 2, and pharmaceutically acceptable salts thereof, characterized by the fact that one a) for the preparation of a compound of formula I-~ in which RJ stands for alkyl, aralkyl, aralkyl-alkyl, acylamino-alkyl, dialkylamino-alkyl, alkoxycarbonylamino-alkyl, alkoxycarbonyl-alkyl, alkoxy or aralkyl, R <2> and R <3> each means alkyl or aralkyl, R <4> and R <5> together mean oxo and X means -(CføU- in which n has the above meaning, reacts a compound with the general formula where n has the above meaning, R<30> means alkyl or aralkyl and Hal means a halogen atom, with a compound of the general formula where R <10> means alkyl, aralkyl, aralkyl-alkyl, acylamino-alkyl, dialkylamino-alkyl, alkoxycarbonylamino-alkyl, alkoxycarbonyl-alkyl, alkoxy or aralkyl and R <20> means alkyl or aralkyl, or b) for the preparation of a compound of formula I in which R <1> means alkyl, aralkyl, aralkyl-alkyl, acylamino-alkyl, dialkylamino-alkyl, alkoxycarbonylamino-alkyl, alkoxycarbonyl-alkyl, alkoxy or aralkyl, R <2> and R <3> each means alkyl or aralkyl, and X means an oxygen atom or the group -NR <6-> , in which R <6> means hydrogen, alkyl or aralkyl, reacts a compound with the general formula in which R4 , R <9> and R <30> have the above meaning and X <1> means an oxygen atom or the group -NR <6-> , in which R <6> has the above meaning, with a compound of the general formula wherein R <10> , R <20> and Hal have the above meaning, or c) for the preparation of a compound of formula I in which R <2> means alkyl or aralkyl, R <4> and R <5> together means oxo and X means -CH2 -, reacts a compound with the general formula wherein R <3> has the above meaning, with a compound of the general formula in which R <1> and R <20> have the above meaning, and R <7> means alkyl, aralkyl or trialkylsilyl, or d) for the preparation of a compound of formula I in which R<1> means alkyl, aralkyl, aralkyl-alkyl, amino-alkyl, acylamino-alkyl, monoalkylamino-alkyl, dialkylamino-alkyl, alkoxycarbonylamino-alkyl, alkoxycarbonyl-alkyl, alkoxy or aralkyl, R <2> and R <3> each means alkyl or aralkyl and R <4> and R <5> each means a hydrogen atom, reduces a compound of formula I, wherein R <1> means alkyl, aralkyl, aralkyl , R <2> and R <3> each means alkyl or aralkyl, and R" and R <5> together means oxo, or e) for the preparation of a compound of formula I in which R <1> means hydroxy, alkoxy or aralkyl, R <2> means hydrogen, alkyl or aralkyl and/or R <3> means hydrogen, alkyl or aralkyl, with the proviso that either R <1> means hydroxy and/or at least one of R <2> and R <3> means hydrogen, corresponding to ester cleavages of a compound of formula I, in which R <1> means hydroxy, alkoxy or aralkyl, R <2> means hydrogen, alkyl or aralkyl and/or R <3> means hydrogen, alkyl or aralkyl, with the proviso that either R <1> has a meaning other than hydroxy and/or at least one of R <2> and R <3> has a meaning other than hydrogen, or f) for the preparation of a compound of formula I in which R<1> means alkyl, aralkyl, aralkyl-alkyl, hydroxy-alkyl, amino-alkyl, acylamino-alkyl, monoalkylamino-alkyl, dialkylamino-alkyl, alkoxycarbonylamino-alkyl, halo-alkyl, carboxy-alkyl, alkoxycarbonyl-alkyl, alkoxy or aralkyl, R <2> and R <3> each means alkyl or aralkyl, and X means the group -NR <61-> in which R <61> means alkyl or aralkyl, alkylates or aralkylates a compound of formula I, in which R <1> means alkyl, aralkyl, aralkyl-alkyl, hydroxy-alkyl, amino-alkyl, acylamino-alkyl, monoalkylamino-alkyl, dialkylamino-alkyl, alkoxycarbonylamino- alkyl, halo-alkyl, carboxy-alkyl, alkoxycarbonyl-alkyl, alkoxy or aralkyl, R <2> and R <3> each means alkyl or aralkyl, and X means the group -NH-, or g) for the preparation of a compound of formula I, in which R <1> means alkyl, aralkyl, aralkyl, hydroxy-alkyl, amino-, alkyl, acylamino-alkyl, monoalkylamino-alkyl, dialkylamino-alkyl, alkoxycarbonylamino-alkyl, halo-alkyl, carboxy-alkyl, alkoxycarbonyl-alkyl, alkyl or aralkyl, R <2> means alkyl or aralkyl and R <3> means alkyl or aralkyl, similarly esterifies a compound of formula I, in which R<1> means alkyl, aralkyl, aralkyl, hydroxyalkyl, aminoalkyl, acylaminoalkyl, alkyl or aralkyl, R <2> means alkyl or aralkyl and R <3> means hydrogen, or h) for the preparation of a compound of formula I, wherein R <1> means hydroxyalkyl and R <2> and R <3> each means hydrogen or alkyl, catalytically hydrogenates a compound of formula I, wherein R <1> means aryloxyalkyl and R <2> and R <3> each means hydrogen or alkyl, or i) for the preparation of a compound of formula I, wherein R <1> means haloalkyl and R <2> and R <3> each means alkyl or aralkyl, halogenates a compound of formula I, wherein R <1> means hydroxyalkyl and R <2> and R <3> each means alkyl or aralkyl, or j) for the preparation of a compound of formula I, in which R <1> means amino-alkyl or monoalkylamino-alkyl and R <2> and R <3> each means alkyl or aralkyl, transfers the hydroxy-alkyl group in a compound of formula I , wherein R <1> means hydroxy-alkyl and R <2> and R <3> each means alkyl or aralkyl in an amino-alkyl or monoalkylamino-alkyl group, or k) for the preparation of a compound of formula I, in which R <1> means amino-alkyl or monoalkylamino-alkyl and R <2> and R3 each means alkyl or aralkyl, reacts a compound of formula I, in which R <1> means halo-alkyl and R <2> and R <3> each means alkyl or aralkyl, with ammonia or monoalkylamine, e lier 1) for the preparation of a compound of formula I, wherein R <1> means acylamino-alkyl and R <2> and R <3> each means alkyl or aralkyl, acylate a compound of formula I, wherein R <1> means amino -alkyl and R <2> and R <3> each means alkyl or aralkyl, or m) for the preparation of a compound of formula I, in which R <1> means carboxy-alkyl and R <2> and R <3> each means alkyl or aralkyl, oxidise a compound of formula I, in which R <1> means hydroxy -alkyl and R <2> and R <3> each means alkyl or aralkyl, and n) if desired, reduces a nitro-substituted phenyl group present in R <1> in a compound of formula I to an amino-substituted phenyl group, and or o) if desired, transfers an amino-substituted phenyl group present in R <1> in a compound of formula I into an iminoalkylamino group by reaction with an alkyl cyanide in the presence of a trialkylsilyl halide, and or p) if desired, separates a mixture of diastereoisomeric racemates that have been prepared into diastereoisomeric racemates or optically pure diastereoisomers, and or q) if desired, dissolve a racemate obtained in the optical antipodes, and r) if desired, transfer an obtained compound of formula I in a pharmaceutically acceptable salt. 2. Method according to claim 1, characterized in that the compounds of formula I and their pharmaceutically acceptable salts are prepared according to embodiments a), b), d), e), f), g), h), i), j), k), 1), m) , p) , q) and/or r) . 3. Process according to claim 1 or 2 in the preparation of compounds of formula I, in which R <1> means hydroxy, alkyl, aralkyl or alkoxy, R <2> means hydrogen, R <3> hydrogen and X means an oxygen atom or the group - NH- or -(CH2 )n -, where n stands for zero or 1, characterized by using correspondingly substituted starting materials. 4. Method according to claim 2 in the preparation of octahydro-9 (S)-phosphonomethyl-10-oxo-6H-pyridazo [1,2-a] [1,2]diazepine-1(S)-carboxylic acid, characterized by using correspondingly substituted starting materials. 5. Process according to claim 2 in the preparation of octahydro-9 (S)-[[(hydroxy)methylphosphinyl]methyl]-6,10-dioxo-6H-pyridazo[1,2-a] [1,2]diazepine-1 (S)-carboxylic acid, characterized by using correspondingly substituted starting materials. 6. Process according to claim 2 in the preparation of octahydro-9 (S)-phosphono-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine-1(S)-carboxylic acid, characterized by using correspondingly substituted starting materials. 7. Process according to claim 2 in the preparation of 9(S)-diethoxyphosphinyl-octahydro-6,10-dioxo-6H-pyridazo[1,2-a] [1,2]di-azepine-1 (S)-carboxylic acid, characterized by using correspondingly substituted starting materials. 8. Method according to claim 2 in the preparation of octahydro-9 (S)-[[hydroxy(methoxy)phosphinyl]methyl]-6,10-dioxo-6H-pyridazo[1,2-a][1,2]diazepine- 1(S)-carboxylic acid, characterized by using correspondingly substituted starting materials. 9. Method according to claim 2 in the preparation of octahydro-9 (S)-phosphonomethyl-6,10-dioxo-6H-pyridazo [1,2-a] [1,2]diazepine-1 (S)-carboxylic acid, characterized by using correspondingly substituted starting materials. 10. Process according to claim 2 in the preparation of 9(S)-[[hydroxy(3-phenylpropyl)phosphinyl)]methyl]-octahydro-6,10-dioxo-6H-pyridazo[1,2-a][1,2 ]diazepine-1(S)-carboxylic acid, characterized by using correspondingly substituted starting materials. 11. Process according to claim 2 in the preparation of 9(S)-[[hydroxy(phenethyl)phosphinyl]amino]-octahydro-10-oxo-6H-pyridazo[1,2-a][1,2]diazepine- 1(S)-carboxylic acid, characterized by using correspondingly substituted starting materials. 12. Process according to claim 1 in the preparation of 9(S)-[[hydroxy(2-phenethyl)phosphinyl]methyl]-octahydro-10-oxo-6H-pyridazo[1,2-a] [1,2]diazepine- 1(S)-carboxylic acid, characterized by using correspondingly substituted starting materials. 13. Process according to claim 1 in the preparation of 9(S)-[hydroxy(4-phenylbutyl)phosphinyl]-octahydro-10-oxo-6H-pyridazo-[1,2-a] [1,2]diazepine-1( S)carboxylic acid, characterized by using correspondingly substituted starting materials. 14. Connections characterized by the general formula where R <30> means alkyl or aralkyl, Hal means a halogen atom and n <1> stands for 1 or 2, or where R <4> and R <5> each means hydrogen or R <4> and R <3> together means oxo; R<30> means alkyl or aralkyl; and X <2> means an oxygen atom or the group -NR <61> , in which R <61> means alkyl or aralkyl.