wherein R, and R3 each independently signify hydrogen, hydroxy, amino, mercapto, a straight-chain or branched-chain, saturated or unsaturated aliphatic group containing 1-15 carbon atoms, which can carry one or more substituents; an alkoxy, alkylamino, dialkylamino, alkylmercapto, alkylsulphinyl, alkylsulphonyl, alkenyl, alkynyl, alkenyloxy, alkenylmercapto, alkynyloxy, alkynylmercapto, alkylcarbonylamino, dialkylcarbonylamino, alkylaminocarbonyl, formyl, alkylcarbonyl, carboxyl, alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, carboxyalkyl, alkyloxy- carbonylalkyl, alkenyloxycarbonylalkyl, alkynyloxycarbonylalkyl, nitro, cyano, halo, trifluoromethyl or azido group; or phenyl or phenylcarbonyl, which can carry one or more similar or different substituents, a mono, bi-or tricyclic carbocyclic group containing 7-15 C atoms or a mono-, bi-or tricyclic heterocyclic ring system, R2 signifies hydrogen, hydroxy, amino, mercapto, a straight-chain or branched-chain, saturated or unsaturated aliphatic group containing 1-15 carbon atoms, which can carry one or more substituents; an alkoxy, alkylamino, dialkylamino, alkylmercapto, alkylsulphinyl, alkylsulphonyl, alkenyl, alkynyl, alkenyloxy, alkenylmercapto, alkynyloxy, alkynylmercapto, alkylcarbonylamino, dialkylcarbonylamino, alkylaminocarbonyl, formyl, alkylcarbonyl, carboxyl, alkoxycarbonyl, alkenyl- oxycarbonyl, alkynyloxycarbonyl, carboxyalkyl, alkyloxycarbonylalkyl, alkenyloxy- carbonylalkyl, alkynyloxycarbonylalkyl, nitro, cyano, halo, trifluoromethyl or azido

group; or phenyl or phenylcarbonyl, which can carry one or more similar or different substituents, a mono-, bi-or tricyclic carbocyclic group containing 7-15 C atoms or a mono-, bi-or tricyclic heterocyclic ring system, signifiesR8XON (R7) COCH2-, R6R5and each individually signify hydrogen, a straight-chain or branche, saturated or unsaturated aliphatic group containing 1-15 carbon atoms, which can carry one or more substituents; an alkoxy, alkylamino, dialkylamino, alkylmercapto, alkylsulphinyl, alkylsulphonyl, alkenyl, alkynyl, alkenyloxy, alkenylmercapto, alkynyloxy, alkynylmercapto, alkylcarbonylamino, dialkylcarbonylamino, alkylaminocarbonyl, formyl, alkylcarbonyl, carboxyl, alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, carboacyalkyl, alkyloacycarbonylalkyl) alkenyloxycarbonylalkyl, alkynyloxycarbonylalkyl, nitro, cyano, halo, trifluoromethyl or azido group; or phenyl or phenylcarbonyl, which can carry one or more similar or different substituents, a mono, bi-or tricyclic carbocyclic group containing 7-15 C atoms or a mono-, bi-or tricyclic heterocyclic ring system, R7 signifies hydrogen or alkyl, X signifies a valency bond, alkylene, carbonyl or carbonylalkylene, R8 signifies alkyl, which can carry one or more similar or different substituents selected from hydroxy, alkoxy, amino, alkylamino and dialkylamino, 1,3-dioxolan-4-yl optionally mono- or disubstituted in the 2-position, PO (Rll) (Rl2) or PO (OR13) (OR14) and, when X signifies other than a valency bond, R8 also signifies hydroxy, alkoxy, hydroxyalkoxy, alkanoyloxy, alkylcarbonylamino, alkoxycarbonyloxy, alkanoyloxyalkyl, carboxyvinyl, optionally substituted aminoalkanoyloxy, aminoalkylphenyl or amino- alkylbenzoyloxy, alkanoyloxyalkoxy or NR9Rlo,

R9 and Rio each individually signify hydrogen or alkyl which can carry one or more similar or different substituents selected from hydroxy, alkoxy, amino, alkylamino and dialkylamino, or Rg signifies hydrogen and RIO signifies hydroxy, imidazolin-2-yl or tetrazol-5-yl or R9 and Rio together with the nitrogen atom to which they are attache form a heterocyclic ring which is optionally interrupted by nitrogen or oxygen and which can be substituted by alkyl, alkoxy, hydroxy, hydroxyalkyl, oxo, carboxy, aminocarbonyl or alkoxycarbonyl and can be fused with a benzoid ring, Ril and R12 are the same or different and signify alkyl and R13 and R14 each individually signify hydrogen or alkyl, as well as their tautomers, enantiomers, diastereomers, racemates and physiologically compatible salts or esters and substances which are hydrolyzed or metabolised in vivo to compound of formula I.

The invention is also concerne with a process for the manufacture of the above compound, medicaments which contain such compound and the use of these compound in the production of medicaments.

Suprisingly, compound of general formula I are orally active metalloprotein inhibitors.

Metalloproteins play an inportant rôle in many physiological and pathophysiological processes. The metalloproteins are accordingly divided into various groups corresponding to their substrate. Many metalloproteins hydrolyze proteins (metalloproteases), while others cleave ester groups (e. g. phosphodiesterases). Examples of metalloproteases are Angiotensin Converting Enzyme (ACE) and the neutral endopeptidases (NEP, EC 3.4.24.11), which participate in the metabolism of a series of blood pressure-regulating peptides (e. g. angiotensin I and ANF (atrial natriuretic factor)). ACE catalyzes the cleavage of angiotensin I to the blood pressure-lowering angiotensin II. NEP is responsible for the degradation of the vasodilating peptide ANF. Endothelin Converting Enzyme (ECE) cleaves the endogenous, inactive big-endothelin to the effective vasoconstrictor endothelin-l) a peptide consisting of 21 amino acids. The inhibition of these enzymes has a great therapeutic significance-for the treatment of high blood pressure, cardiac

insufficiency, kidney failure and apoplexy. BMP-1 (bone morphogenic factor 1) has been recognized as a metalloprotease which plays a role in the conversion of procollagen into fibrillary collagen. Inhibitors of this enzyme are suitable for the treatment of fibroses and sclerotic processes and can also favourably influence scar formation in the healing of wounds (Proc. Natl. Acad. Sci. USA 93,5127,1996, Science 271,360).1996, While ACE inhibitors are already used therapeutically (e. g. captopril, enalapril, Exp. Opin.

Ther. Pat. 6,1147),1996, no clinically useful active substances which are free from undersirable side effects and which are orally available are known for the metalloproteases <BR> <BR> <BR> such as NEP and ECE (literature references: NEP: Pharmncol. Rev. 45,87;1993, ECE:<BR> <BR> <BR> <BR> Bioorg. Med. Chem. Lett. 6,2317,1996, literature re phosphoramido type inhibitors).

Hitherto, no low molecular inhibitors for BMP-1 are known.

The matrix metalloproteases (MMPs) represent one group of metalloproteases. Various groups of metalloproteases are known. One such group is as known as the matrix metalloproteases (MMPs). In normal tissue an equilibrium exists between the synthesis and degradation of the extracellular matrix. The extracellular matrix is synthesized by at least three groups of protases, namely collagenases, gelatinases and stromelysins.

Normally, specific inhibitors of these enzymes, such as e. g. α2-macroglobulin and TIMP (tissue inhibitor of metalloproteases), make sure that an excessive degradation of the extracellular matrix does not take place. A related group of protases comprises the adamalysins with their most prominent member being TNF-ct converting enzyme (TACE) (Moss et al. , Nature 385,733).1996, At least 11 different, but very homologous matrix metalloproteases have been characterized, inter alia the interstitial fibroblast collagenase (MMP-1, HFC), the neutrophilic collagenase (MMP-8, HNC), two gelatinases, stromelysins (e. g. HSL-1) and matrilysin (Birkedal-Hansen) H., Moore, W. G. I., Bodden, M. K. Windsor, L. J., Birkedahl- Hansen, B., DeCarlo, A., Engler, J. A. , Crit. Rev. Oral Biol. Med. 4,197-250).1993, These proteinases share a series of structural and functional properties, but differ in their substrate specificity. Only HNC and HFC cleave native triple helical collagen of types I, II <BR> <BR> <BR> and III. Fragments of 3/4 and 1/4 of the original length thereby result. The melting point of the collagen is lowered by this degradation. Subsequently, it can be attacked by other matrix-degrading enzymes.

The uncontrolled excessive degradation of these matrices is typical for many pathological situations which manifest themselves, such as e.g. rheumatoid arthritis, osteoarthritis, multiple sclerosis, tumour metastasing, corneal ulcerations, inflammatory processes and various disorders of the bones and teeth.

The pathogenesis of these illnesses should be positively influence by the administration of metalloproteinase inhibitors. Some of such compound are to be found in the literature (a <BR> <BR> <BR> <BR> review will be found e. g. in Nigel R. A., Beeley et al., Curer. Opin. Ther. Patents 41994, (1), 7). These are primarily peptides shaving a hydroxamic acid, thiol or phosphine residue as the zinc-binding group (inter alia e. g. WO-A-9209563 of Glycomed, EP-A-497192 of Hoffmann-La Roche, WO-A-489577 of Celltech, EP-A-320118 of Beecham, US-A-4595700 of Searle).

Phosphodiesterases (PDEs) are a group of proteins which hydrolyze the regulatory-acting cyclic nucleotides (cAMP or CGMP) in cells to the inactive mononucleotides. The distribution of the PDE isoenzymes differs in individual types of cell. Thus, the isoform is quite prominent in monocytes/macrophages, the cells which synthesize the main amount of proinflammatory Tumour Necrosis Factor cs (TNFu). A zinc-binding domain in the catalytic centre has been detected for this enzyme and, moreover, its activity is dependent on divalent cations (J. Biol Chem. 1994,269,22477), rolipram inhibits PDE4 and thereby brings about an inhibition of the synthesis of TNFα in vitro and in vivo (J. Med. Chem.

1998,41,266). The further development of rolipram has, however, been severely disrupted by massive side effects (Pharmacol. Toxicol. 1996,78,44). PDE-inhibitors, which have an improved compatibility based on a selective activity profile, can play a great rôle as inhibitors of TNFot synthesis. Moreover, PDEs can dilate the smooth musculature in the bronchi by increasing cellular cAMPs, which is utilized in the treatment of asthma therapeutically with e.g. theophylline. <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P>Tumor necrosis factor a (TNFon) is a proinflammatory cytokine which has pathogenetic significance in a large number of illnesses. Clinically it has been shown in a multicentre, randomized double-blind study by Elliot et al. (Lancet 344,1105-1110)1994, that a neutralizing antibody against TNFct brings about a rapid and pronounced improvement of the disease symptoms in patients with rhumatoid arthritis. In the meanwhile, clinical data has been published by Dullemen et al. in Gastroenterology 109.129-1351995, which demonstrates a therapeutic activity of such an antibody in patients with Crohn's disease.

Furthermore, it has been shown in animal experiments that rolipram, which likewise blocks the synthesis of TNFce, has a very good activity in animal models for multiple sclerosis. Thalidomide, a further TNFct-inhibiting substance, has been used clinically for the trament for chronic graft versus host disorders, in the treatment of nodular leprosy and of patients with lupus erythematodes. Moreover, it has been shown that this substance supresses the proliferation of HIV.

TNFot appears to have direct pathogenic significance in the following disease conditions: degenerative joint diseases, rheumatoid arthritis, inflammation, allergy, ARDS, asthma, cardiac infarction, chronic cardiac insuffiency, HIV infection, Crohn's disease, ulcerative colitis, psoriasis, dermatitis, actinokeratoses, vasculitides, septic shock, transplant rejection, multiple sclerosis, ulcers, diabetes, chronic graft versus host disorders, leprosy and other infectious diseases, lupus erythematodes, paradontoses and in the case of other illnesses.

The clinical use of monoclonal anti-TNFcc antibodies can only by effected parenterally. The medicament is expensive to manufacture and requires a complex distribution logistic (refrigeration network, storage, expiry date etc.). Moreover, in 50% of patients who have received between 2 and 4 injections, the appearance of neutralizing HACAs (human anti-chimeric antibodies) has been established. This means that the trouble-free phases become shorter and shorter. The development of rolipram as an anti-TNFcc therapy principle is impaire by its emetic activity. The teratogenic side effects of thalidomide and the weak TNFu blockade can likewise appear to be difficulties in a clinical development of this substance.

As mentioned, the compound of general formula I are orally available inhibitors of metalloproteins. They inhibit TNFcc synthesis, which means inhibition of an antiinflammatory activity in the case of corresponding disease symptoms. The TNFcc synthesis inhibition was demonstrated not only in vitro, but also in vivo according to the following experimental procedures:

Experimental procedure in vitro TNFu synthesis assay Human leukocytes are obtained from heparinized full blood over a Ficol gradient, washed with RPMI 1640 medium having the prescribed additives and adjusted in the same medium to a cell count of 1 x 106 cells/ml. 20 1 of the substance to be tested in 10-fold concentration, 20 pLI of an LPS solution of 4 µg/ml and 160 pl of the adjusted cell suspension are incubated in the individual wells of a 96 well culture plate at 37°C for 2 hours. The experiments are carried out as double determinations. At the end of the incubation period the plates are carefully shaken and centrifuged. Two samples each of 50 zip are withdrawn from the clear culture supernatant for the analysis of TNFcc.

Analysis of TNFα in the cell supernatant by enzyme immunoassay Nunc-Maxisorb plates are coated with a mouse-anti-human-TNFcc antibody (1, ug/ml, 50, ul/well, Dianova/Pharmingen 18631D, carbonate buffer pH 9.5) and free binding capacity is saturated with a gelatine-and serum albumin-containing blocking buffer. After washing the plates there are pipette in in double determination in each case 25, ul of the analyte as well as on each plate a series of standard concentrations. For the detection of the analyte, 25 1 ouf a biotinylated mouse-anti-human-TNFct antibody (4tl/ml 25 µl/well, Dianova/Pharmingen 18642D, blocking buffer) are added and the plates are shaken at room ternperature for 2 hours. After washing incubation is carried out with streptavidin-alkaline phosphatase conjugate (50 µl/well) and finally with 4-nitrophenyl phosphate and evaluation is carried out on a photometer. The concentrations of the measured samples are determined using a computer program based on a calibration curve from the co-determined standard concentrations.

Determination of the ICso The percentage inhibition for the individual sample is calculated by comparing the TNFcc concentration obtained for the measured samples with the non-inhibited amples. The ICSO is determined by computer from the concentration relationship of the inhibitor value.

Experimental procedure in vivo 15 minutes prior to the intraperitoneal injection of 700 mg/kg of D-galactosamine (DGalN) and 70 Zg/kg of lipopolysaccharide (LPS) the indicated test substances are administered intraperitoneally or orally to NMRI-mice. 90 minutes after the injection of DGaIN/LPS blood is removed from the animal and the serum obtained therefrom is freeze-dried for the analysis of TNF by enzyme inmunoassay (EIA). The EIA is carried out analogously to that described above. However, anti-mouse TNF (x antibodies are used.

Results: inhibitionTNFαsynthesis Example number in vitro in vivo ICSO (tg/ml) active dosage (mg/kg) 4 0.03 30 i. p. 30 p.o. 20 0.05 10 i. p. 40 p.o. 31 0.1 20 i. p. 60 p.o.

The compound of general formula I, which are the object of the invention, will be described in more detail hereinafter. The invention is concerne with compound of general formula I,

wherein R, and R3 each individually signify hydrogen, hydroxy, amino, mercapto, a straight-chain or branched-chain, saturated or unsaturated aliphatic group containing 1-15 carbon atoms, which can carry one or more substituents selected from hydroxy, amino, mercapto, di-C1-C6-alkylamino,C1-C6-alkyl-C1-C6-alkylamino, mercapto, Cl-C6-alkylsulphinyl, Cl-C6-alkylsulphonyl, C2-C6-alkenyl, C2-C6-alkynyl, <BR> <BR> <BR> C2-C6-alkenyloxy, C2-C6-alkenylmercapto, C2-C6-alkynyloxy, C2-C6-alkynyl-<BR> <BR> <BR> <BR> mercapto, Cl-C6-alkylcarbonylamino, Cl-C6-alkylaminocarbonyl, formyl, Cl-C6- alkylcarbonyl, carboxyl, C2-C6-C2-C6-alkenyloxycarbonyl, alkynyloxycarbonyl,C1-C6-alkyloxycarbonyl-C1-C6-alkyl, C2-C6-alkenyloxycarbonyl-C1-C6-alkyl,C2-C6-alkynyloxycarbony l-C1-C6-alkyl, benzyloxy, phenylmercapto, phenyloxy, nitro, cyano, halo, trifluoromethyl, azido, formylamino and phenyl, a di-C1-C6-alkylamino,C1-C6-alkylmercapto,C1-C6-alkylamino, C1-C6-alkylsulphinyl,C2-C6-alkynyl,C2-C6-C2-C6-alkenyl, alkenyloxy, C2-C6-alkenylmercapto, C2-C6-alkynyloxy, C2-C6-alkynylmercapto, C1-C6-alkylamino-C1-C6-alkylcarbonylamino,di-C1-C6-alkylcarb onylamino, carbonyl, formyl, C-C6-alkylcarbonyl, carboxyl, Cl-C6-alkoxycarbonyl, C2-C6- alkenyloxycarbonyl, C2-C6-alkynyloxycarbonyl, carboxy-Cl-C6-alkyl, Cz-C6-alk- <BR> <BR> <BR> yloxycarbonyl-CI-C6-alkyl, C2-C6-alkenyloxycarbonyl-C,-C6-alkyl, C2-C6-alkynyl-<BR> <BR> <BR> <BR> oxycarbonyl-Cl-C6-alkyl, nitro, cyano, halo, trifluoromethyl or azido group, phenyl or phenylcarbonyl, which can carry one or more similar or different substituents selected from hydroxy, amino, mercapto, C1-C6-alkoxy, C1-C6-alkyl- amino, di-C,-C6-alkylamino, Cl-C6-alkylmercapto, Cl-C6-alkylsulphinyl, Cl-C6- alkylsulphonyl,C2-C6-alkenyl, C2-C6-alkynyl, C2-C6-alkenyloxy, C2-C6-alkenyl-

mercapto, C1-C6-alkylcarbonylamino,C2-C6-alkynylmercapto, C1-C6-alkylcarbonyl,carboxyl,C1-C6-alkoxy-C1-C6-alkylaminoca rbonyl,formyl, carbonyl, carboxy-C1-C6-C2-C6-alkynyloxycarbonyl, alkyl,C2-C6-alkenyloxycarbonyl-C1-C6-alkyl, C2-C6-alkynyloxycarbonyl-C1-C6-alkyl, benzyloxy, phenylmercapto, phenyloxy, nitro, cyano, halo, trifluoromethyl, azido, formylamino, carboxy and phenyl, or a mono-, bi-or tricyclic carbocyclic group containing 7-15 C atoms or a mono-, bi- or tricyclic heterocyclic ring system, with unsaturated or aromatic carbocycles and heterocycles optionally being partially or completely hydrogenated, R2 signifies hydrogen, hydroxy, amino, mercapto, a straight-chain or branched-chain, saturated or unsaturated aliphatic group containing 1-15 carbon atoms, which can carry one or more substituents selected from hydroxy, amino, mercapto, Cl-C6- <BR> <BR> <BR> alkoxy, C1-C6-alkylamino, di-Cl-C6-alkylamino, CI-C6-alkylmercapto, C,-C6-alkyl- sulphinyl, C,-C6-alkylsulphonyl, C2-C6-alkenyl, C2-C6-alkynyl, C2-C6-alkenyloxy, <BR> <BR> <BR> C2-C6-alkenylmercapto, C2-C6-alkynyloxy, C2-C6-alkynylmercapto, C,-C6-alkyl-<BR> <BR> <BR> <BR> carbonylamino, C,-C6-alkylaminocarbonyl, formyl, C,-C6-alkylcarbonyl, carboxyl, C2-C6-alkynyloxycarbonyl,C1-C6-alkoxycarbonyl,C2-C6-alkenylo xycarbonyl, carboxy-C,-C6-alkyl, C,-C6-alkyloxycarbonyl-C-C6-alkyl, C-C6-alkenyloxy- carbonyl-C,-C6-alkyl, C-C6-alkynyloxycarbonyl-Cl-C6-alkyl, benzyloxy, phenyl- mercapto, phenyloxy, nitro, cyano, halo, trifluoromethyl, azido, formylamino and phenyl, a di-C1-C6-alkylamino,C1-C6-alkylmercapto,C1-C6-alkylamino, <BR> <BR> <BR> Cl-C6-alkylsulphinyl, C,-C6-alkylsulphonyl, C2-C6-alkenyl, C2-C6-alkynyl, C2-C6-<BR> <BR> <BR> <BR> alkenyloxy, C2-C6-alkenylmercapto, C2-C6-alkynyloxy, C2-C6-alkynylmercapto,<BR> <BR> <BR> <BR> C-C6-alkylcarbonylamino, di-Cz-C6-alkylcarbonylamino, C-C6-alkylamino- carbonyl, formyl, C,-C6-alkylcarbonyl, carboxyl, C1-C6-alkoxycarbonyl, C2-C6- alkenyloxycarbonyl, C2-C6-alkynyloxycarbonyl, carboxy-Cl-C6-alkyl, Cl-C6-alk- <BR> <BR> <BR> yloxycarbonyl-CI-C6-alkyl, C2-C6-alkenyloxycarbonyl-C,-C6-alkyl, C2-C6-alkynyl-<BR> <BR> <BR> <BR> oxycarbonyl-Cl-C6-alkyl, nitro, cyano, halo, trifluoromethyl or azido group, phenyl or phenylcarbonyl, which can carry one or more similar or different substituents selected from hydroxy, amino, mercapto, Cl-C6-alkoxy, Cl-C6-alkyl-

amino, di-Cl-C6-alkylamino, Cl-C6-alkylmercapto, Cl-C6-alkylsulphinyl, Cl-C6- alkylsulphonyl, C2-C6-alkenyloxy,C2-C6-alkenyl-C2-C6-alkynyl, mercapto, C2-C6-alkynyloxy, C2-C6-alkynylmercapto, C,-C6-alkylcarbonylamino, C1-C6-alkylaminocarbonyl, formyl, C1-C6-alkoxy-carboxyl, carbonyl, C2-C6-alkenyloxycarbonyl, C2-C6-alkynyloxycarbonyl, carboxy-C,-C6- alkyl,Cl-C6-alkyloxycarbonyl-Cl-C6-alkyl, C2-C6-alkenyloxycarbonyl-Cl-C6-alkyl, phenylmercapto,phenyloxy,C2-C6-alkynyloxycarbonyl-C1-C6-alky l,benzyloxy, nitro, cyano, halo, trifluoromethyl, azido, formylamino, carboxy and phenyl, or a mono-, bi-or tricyclic carbocyclic group containing 7-15 C atoms or a mono-, bi- or tricyclic heterocyclic heterocyclic ring system, with unsaturated or aromatic carbocycles and heterocycles optionally being partially or completely hydrogenated, signifiesR8XON (R7) COCH2-, R5 and R6 each individually signify hydrogen, a straight-chain or branched-chain, saturated or unsaturated aliphatic group containing 1-15 carbon atoms, which can carry one or more substituents selected from hydroxy, amino, mercapto, C1-C6-alkoxy, C1-C6- alkylamino, di-C,-C6-alkylamino, C,-C6-alkylmercapto, C,-C6-alkylsulphinyl, Ci-C6- alkylsulphonyl, C2-C6-alkenyloxy,C2-C6-alkenyl-C2-C6-alkynyl, mercapto, C2-C6-alkynyloxy, C2-C6-alkynylmercapto, Cl-C6-alkylcarbonylamino, Cl-C6-alkylaminocarbonyl, formyl, C-C6-alkylcarbonyl, carboxyl, C-C6-alkoxy- carbonyl, C2-C6-alkenyloxycarbonyl, C2-C6-alkynyloxycarbonyl, carboxy-Cl-C6- alkyl,C2-C6-alkenyloxycarbonyl-C1-C6-alkyl, C2-C6-alkynyloxyvarbonyl-Cl-C6-alkyl, benzyloxy, phenylmercapto, phenyloxy, nitro, cyano, halo, trifluoromethyl, azido, formylamino and phenyl, adi-C1-C6-alkylamino,C1-C6-alkylmercapto,C1-C6-alkylamino, C2-C6-alkenyl,C2-C6-alkynyl,C2-C6-C1-C6-alkylsulphinyl,C1-C6 -alkylsulphonyl, alkenyloxy, C2-C6-alkenylmercapto, C2-C6-alkynyloxy, C2-C6-alkynylmercapto, C1-C6-alkylamino-C1-C6-alkylcarbonylamino,di-C1-C6-alkylcarb onylamino, carbonyl, formyl, C-C6-alkylcarbonyl, carboxyl, Cl-C6-alkoxycarbonyl, C2-C6- alkenyloxycarbonyl, C2-C6-alkynyloxycarbonyl, carboxy-C-C6-alkyl, Cl-C6-alk-

yloxycarbonyl-C,-C6-alkyl, C2-C6-alkenyloxycarbonyl-CI-C6-alkyl, C2-C6-alkynyl-<BR> <BR> <BR> <BR> oxycarbonyl-C1-C6-alkyl, nitro, cyano, halo, trifluoromethyl or azido group, phenyl or phenylcarbonyl, which can carry one or more similar or different substituents selected from mercapto,C1-C6-alkoxy,C1-C6-amino, alkylamino, di-Cl-C6-alkylamino, Cl-C6-alkylmercapto, Cl-C6-alkylsulphinyl, Cl-C6- alkylsulphonyl, C2-C6-alkenyl, C2-C6-alkynyl, C2-C6-alkenyloxy, C2-C6- alkenylmercapto, C2-C6-alkynyloxy, C2-C6-alkynylmercapto, Cl-C6-alkylcarbonyl- amino, Cl-C6-alkylaminocarbonyl, formyl, Cl-C6-alkylcarbonyl, carboxyl, Cl-C6- alkoxycarbonyl, carboxy-C1-C2-C6-alkynyloxycarbonyl, C6-alkyl, Cl-C6-alkyloxyvarbonyl-CI-C6-alkyl, C2-C6-alkenyloxycarbonyl-Cl-C6- alkyl, C2-C6-alkynyloxycarbonyl-C1-C6-alkyl, benzyloxy, phenylmercapto, phenyloxy, nitro, cyano, halo, trifluoromethyl, azido, formylamino, carboxy and phenyl, or a mono-, bi-or tricyclic carbocyclic residue containing 7-15 C atoms or a mono-, bi- or tricyclic heterocyclic ring system, with unsaturated or aromatic carbocycles and heterocycles optionally being partially or completely hydrogenated, R7 signifies hydrogen or C1-C6-alkyl, X signifies a valency bond, Cl-C6-alkylene, carbonyl or C-C6-carbonylalkylene, R8 signifies C1-C6-alkyl, which can carry one or more substituents selected from hydroxy, C1-C6-alkoxy, amino, di-C1-C6-alkylamino,1,3-dioxolan-4-yland optionally mono-or disubstituted in the 2-position, PO (Rll) (Rl2) or PO (ORl3) (ORl4) and, when X signifies other than a valency bond, R8 also signifies hydroxy, Cl-C6-alkoxy, C1-C6-alkylcarbonylamino,C1-C6-alkoxy-hydroxy-C1-C6-alkoxy,C 1-C6-alkanoyloxy, carbonyloxy, C1-C6-alkanoyloxy-C1-C6-alkyl, carboxyvinyl, an optionally N-substituted amino-C,-C6-alkanoyloxy, amino-Ci-C6-alkyl-phenyl or amino-C,-C6-alkyl-benzoyl group, NR9R10,and

R9 and RIO each individually signify hydrogen, C,-C6-alkyl, which can carry one or more similar or different substituents selected from hydroxy, Cl-C6-alkoxy, amino, C-C6-alkylamino and di-Ci-C6-alkylamino, or R9 signifies hydrogen and Rio signifies hydroxy, imidazolin-2-yl or tetrazol-5-yl or R9 and Rio together with the nitrogen atom to which they are attache form a heterocyclic ring which is optionally interrupted by nitrogen or oxygen and which can be substituted by Cl-C6-alkyl, Cl-C6-alkoxy, hydroxy, hydroxy-Cl-C6-alkyl, oxo, carboxy, aminocarbonyl or Cl-C6-alkoxycarbonyl and can be fused with a benzoid ring, R11 and R12 are the same or different and signify Cl-C6-alkyl, and R14R13and each individually signify hydrogen or C1-C6-alkyl, as well as their tautomers, enantiomers, diastereomers, racemates and physiologically compatible salts or esters and substances which are hydrolyzed or metabolised in vivo to compound of formula I.

Ein aliphatic group is a straight-chain, branched-chain or cyclic alkyl, alkenyl or alkynyl group containing 1-15, preferably 1-10, carbon atoms, such as e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Unsaturated groups are e. g. vinyl, allyl, dimethylallyl, butenyl, isobutenyl, pentenyl, ethynyl or propynyl.

A Cl-C6-alkyl group in Cl-C6-alkyl, Cl-C6-alkoxy, Cl-C6-alkylamino, di-Cl-C6-alkyl- amino, C1-C6-alkylsulphonyl,C1-C6-C1-C6-alkylsulphinyl, alkylcarbonylamino, Cl-C6-alkylaminocarbonyl, Cl-C6-alkoxycarbonyl, carboxy- Cl-C6-alkyl, Cl-C6-alkyloxycarbonyl-Cl-C6-alkyl, C2-C6-alkenyloxycarbonyl-Cl-C6- alkyl,C1-C6-C1-C6-alkanoyloxy, alkoxycarbonyloxy, C1-C6-alkanoyloxy-C1-C6-alkyl, amino-Cl-C6-alkanoyloxy, amino-Cl-C6-alkyl-phenyl, amino-C-C6-alkyl-benzoyl, C1-C6-alkanoyloxy-C1-C6-alkoxy or hydroxy-Cl-C6-alkyl signifies straight-chain, branched-chain or cyclic groups, preferably methyl, ethyl, propyl, isopropyl, butyl, sec-or tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, sec-butyloxy, tert-butyloxy,

propyloxycarbonyl,butyloxycarbonyl,carboxy-methoxycarbonyl,e thoxycarbonyl, methyl, carboxyethyl, carboxypropyl, methoxyvarbonylethyl, ethoxycarbonylethyl, methoxycarbonylpropyl, ethoxycarbonylpropyl, carboxymethoxy, carboxyethoxy, carboxypropyloxy, propoxycarbo-ethoxycarbonylethoxy, nylmethoxy, methoxycarbonylethoxy, ethoxycarbonylethoxy, aminomethyl, amino- ethyl, aminopropyl, methylmercapto, ethylmercapto and propylmercapto.

The C2-C6-alkynylgroupsinC2-C6-alkenyl,C2-C6-alkynyl,C2-C6-and <BR> <BR> <BR> alkenyloxy, C2-C6-alkenylmercapto, C2-C6-alkynyloxy, C2-C6-alkynylmercapto, C2-<BR> <BR> <BR> <BR> C6-alkenyloxycarbonyl, Cl--C6-alkynyloxycarbonyl, C2-C6-alkenyloxycarbonyl-Cl-C6- alkyl, C2-C6-alkynyloxycarbonyl-C1-C6-alkyl are straight-chain, branched-chain or cyclic groups. Vinyl, propenyl, butenyl, pentenyl, hexenyl, ethynyl, propargyl, vinyloxy, allyloxy, propargyloxy, allyloxycarbonyl, propargyloxycarbonyl, allyloxycarbonylmethyl, propargyl-allyloxycarbonylpropyl, oxycarbonylmethyl, propargyloxycarbonylethyl and propargyloxycarbonylpropyl are preferred.

A carbocyclic ring containing 7-15 C atoms can be mono-, bi-or tricyclic and can have 5-7 carbon atoms in each ring. This ring can be aromatic or partly or wholly saturated. Naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, acenaphthyl- enyl, norbornyl, adamantyl, C3-C7-cycloalkyl or C5-C8-cycloalkenyl are preferred.

Furthermore, the carbocyclic ring can carry 1-3 substituents selected from a straight- chain or branched-chain, saturated or unsaturated aliphatic group contaning 1-9 carbon atoms, mercapto,C1-C6-alkoxy,C1-C6-alkylamino,di-C1-6-amino, alkylamino, C1-C6-alkylsulphonyl,C1-C6-alkylsulphinyl, <BR> <BR> <BR> C2-C6-alkenyl, C2-C6-alkynyl, C2-C6-alkenyloxy, C2-C6-alkenylmercapto, C2-C6-<BR> <BR> <BR> <BR> alkynyloxy, C2-C6-alkynylmercapto, C,-C6-alkylcarbonylamino, C,-C6-alkylamino- carbonyl, carbonyl, C,-C6-alkylcarbonyl, carboxyl, Cl-C6-alkoxycarbonyl, C2-C6- alkenyloxycarbonyl, C2-C6-alkynyloxycarbonyl, carboxy-Cl-C6-alkyl, Cl-C6-alk- <BR> <BR> <BR> yloxycarbonyl-CI-C6-alkyl, C2-C6-alkenyloxycarbonyl-CI-C6-alkyl, C2-C6-alkynyl-<BR> <BR> <BR> <BR> oxycarbonyl-Ci-C6-alkyl, benzyloxy, phenylmercapto, phenyloxy, nitro, cyano, halo, trifluoromethyl, azido, formylamino and phenyl.

Alkylene groups in C1-C6-alkylene and C1-C6-alkylenecarbonyl are, for example, methylene, 1,1-ethylene, 1,2-ethylene, 1, 1-propylene, 1,2-propylene, 1,3-propylene, 1,1- butylene, 1,2-butylene, 1,3-butylene, 1,4-butylene, 1,1-pentylene and 1,1-hexylene.

Under a mono-, bi-or tricyclic heterocyclic ring system there is to be understood a saturated or unsaturated ring system having five-to seven-membered rings which contain 1-4 similar or different hetero atoms such as nitrogen, oxygen or sulphur, such as e. g. the pyridine, pyrimidine, pyridazine, pyrazine, triazine, pyrrole, pyrazole, piperidine, morpholine, imidazole, triazole, thiazole, oxazole, isoxazole, oxadiazole, furazan, furan, thiophene, indole, quinoline, isoquinoline, coumarone, thionaphthene, benzoxazole, benzthiazole, indazole, benzimidazole, benztriazole, chromene, phthalazine, quinazoline, quinoxaline, methylenedioxybenzene, carbazole, acridine, phenoxazine, phenothiazine, phenazine or purine system, with the unsaturated or aromatic carbocycles and heterocycles optionally being partly or completely hydrogenated. Furthermore, the heterocyclic system can carry one or more similar or different substituents selected from a straight-chain or branche- chain, saturated or unsaturated aliphatic group cuntaining 1-9 carbon atoms, hydroxy, amino, mercapto, Cl-C6-alkoxy, Cl-C6-alkylamino, di-Cl-C6-alkylamino, C1-C6-alkylsulphonyl,C2-C6-alkenyl,C1-C6-alkylmercapto,C1-C6 -alkylsulphinyl, <BR> <BR> <BR> C2-C6-alkynyl, C2-C6-alkenyloxy, C2-C6-alkenylmercapto, C2-C6-alkynyloxy, C2-C6-<BR> <BR> <BR> <BR> alkynylmercapto, Cl-C6-alkylcarbonylamino, Cl-C6-alkylaminocarbonyl, formyl, C1-C6-alkylcarbonyl, carboxyl, C2-C6-alkenyloxycarbonyl, <BR> <BR> <BR> C2-C6-alkynyloxycarbonyl, carboxy-C,-C6-alkyl, Cl-C6-alkyloxycarbonyl-C,-C6-<BR> <BR> <BR> <BR> alkyl, C2-C6-alkenyloxycarbonyl-C,-C6-alkyl, C2-C6-alkynyloxycarbonyl-Cl-C6-alkyl, benzyloxy, phenylmercapto, phenyloxy, nitro, cyano, halo, trifluoromethyl, azido, formylamino and phenyl. Pyrrolidine, piperidine, piperazine, morpholine, hexahydroazepine, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, 4,5- dihydroimidazole, pyrrole, imidazole, pyrazine, pyrimidine, pyridazine, lH-azepine, 3H-azepine, 1,2-diazepine, 1,4-diazepine, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, pyrazole, pyrrolidinone, imidazolidinone, piperidinone, indole, purine, quinoline and isoquinoline are preferred.

Preferred compound of general formula I are those in which R, and/or R3 signify hydrogen or C,-C6-alkoxycarbonyl, R2 signifies hydrogen, amino, Cl-C6- alkylcarbonylamino, di-C1-C6-alkylcarbonylamino, R5 and R6 signify hydrogen or C,-C6-alkoxy, R7 signifies hydrogen or C1-C6-alkyl, X signifies a valency bond, Cl-C6- alkylene, carbonyl or Cl-C6-carbonylalkylene, R8 signifies Cl-C6-alkyl, which can be substituted by one or more similar or different substituents selected from hydroxy,

C,-C6-alkoxy, amino, C,-C6-alkylamino and di-C,-C6-alkylamino, 2,2-di-Cl-C6- alkyl-1,3-dioxolan-4-yl or PO (OR13) (OR14), and, when X signifies other than a valency bond, R8 also signifies hydroxy, Cl-C6- alkoxy, hydroxy-Cl-C6-alkoxy or NR9Rlo in which R9 and Rlo signify hydrogen, Cl-C6-alkyl, which can carry one or more similar or different substituents selected from hydroxy and Cl-C6-alkoxy, or R9 and Rio together with the nitrogen atom to which they are attache form a heterocyclic ring which is optionally interrupted by nitrogen or oxygen and which can be substituted by Cl-C6-alkyl, Cl-C6- alkoxy, hydroxy, hydroxy-Cl-C6-alkyl, oxo, carboxy, aminocarbonyl or Cl-C6- alkoxycarbonyl and fused with a benzoid ring and Rl3 and R14 are the same or different and signify hydrogen or Cl-C6-alkyl.

Especially preferred substituent values are methoxycarbonyl, ethoxycarbonyl and tbutoxycarbonyl, particularly ethoxycarbonyl, for Rl and/or R3, amino for R2, hydrogen for R5 and R6, hydrogen or methyl for R7, carbonylmethylene, ethylene or a valency bond for X, 2,3-dihydroxypropyl, 2-hydroxy-3-methoxypropyl, 2,2- dimethyl-1,3-dioxolan-4-yl, 3-dimethylamino-2-hydroxypropyl or, where X signifies other than a valency bond, also hydroxy, ethoxy or NR90Rloo, for R8, with R90 and Rioo each individually signifying methoxyethyl, methyl or hydroxyethyl or R90 and Rloo together with the nitrogen atom forming a pyrrolidine, piperidine or morpholine ring.

Under the physiologically compatible salts of the compound of general formula I there are to be understood, for example, formates, acetates, caproates, oleates, lactates or salts of carboxylic acids containing up to 18 carbon atoms or salts of dicarboxylic acids and tricarboxylic acids such as citrates, malonates and tartrates or alkanesulphonates containing up to 10 carbon atoms or p-toluenesulphonates or salicylates or trifluoroacetates or salts of physiologically compatible mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid or phosphoric acid. The compound of formula I which have a free carboxyl group can also form salts with physiologically compatible bases. Examples of such salts are alkali metal, alkaline earth metal, ammonium and alkylammonium saluts, such as the sodium, potassium, calcium or tetramethylammonium salt.

Pure enantiomers of the compound of formula I can be obtained either by racemate resolution (via salt formation with optically active acids or bases) or by using optically active starting materials in the synthesis.

The compound of formula I can be solvate, especially hydrate. The hydration can be effected in the course of the manufacture or can occur gradually as a result of hygroscopic properties of an initially anhydrous compound of formula I.

Compound of formula I can be administered in liquid or solid form or in the form of aerosols orally, enterally, parenterally, topically, nasally, pulmonally or rectally in all usual non-toxic pharmaceutically acceptable carrier materials, adjuvants and additives. The term"parentally"embraces subcutaneous, intravenous and intramuscular injection or infusion. Oral administration forms are described e. g. in W. A. Ritschel, Die Tablette, 1996, Aulendorf, and can be e. g. tables, capsules, dragées, syrups, solutions, suspensions, mulsions, elixirs etc., which can contain one of more additives from the following groups, such as e. g. flavorants, sweeteners, colorants and preservatives. Oral administration forms contain the active ingredient together with non-toxic, pharmaceutically acceptable carrier materials which are suitable for the production of tables, capsules, dragées etc., such as e. g. calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; starch, mannitol, methylcellulose, talc, highly dispersible silicic acids, high molecular weight fatty acids (such as stearic acid), ground nut oil, olive oil, paraffin, miglyol, gelatine, agar-agar, magnesium stearate, beeswax, cetyl alcool, lecithin, glycerol, animal and vegetable fats and solid high molecular weight polymers (such as polyethylene glycols). Tables, capsules, dragées etc. can be provided with an appropriate coating, such as e. g. glyceryl monostearate or glyceryl distearate, in order to prevent undesired side effects in the stomach or to provide a longer duration of activity by delayed absorption in the gastrointestinal tract. Preferred injection media which are used are sterile injectable aqueous or oily solutions or suspensions which contain the usual additives, such as stabilizers and solubilizers. Such additives can be e. g. water, isotonic saline, 1,3-butanediol, fatty acids (such as oleic acid), mono-and diglycerides or miglyol. For rectal administration there can be used all suitable non- irritant additives which are solid at normal temperatures and which are liquid at the rectal temperature, such as e. g. cocoa butter and polyethylene glycol. Conventional pharmaceutical carrier media are used for administration as aeosols. Creams,

tinctures, gels, solutions or suspensions etc. containing conventional pharmaceutical additives are used for external application.

The dosage can depend on various factors, such as the mode of administration, species, age and/or individual condition. The daily dosage of active substance to be administered lies at 0.01 mg to approximately 100 mg/kg body weight, preferably at 0.1 to 10 mg/kg body weight, and can be administered in one dose or in several divided doses.

The manufacture of the compound of formula I is effected according to methods which are known per se and which are described in the literature (e. g. in standard works such as Houben-Weyl, Methoden der Organischen Chemie, Georg Thieme Verlag, Stuttgart; Organic Rections, John Wiley & Sons Inc., New York) using rection conditions which are known and suitable for the respective rections and which are also described in EP 97110533.3. Use can also be made of variants which are known per se, but not referred to in more detail herein. Furthermore, a compound of formula I can be converted into a different compound of formula I according to methods known per se.

The process in accordance with the invention for the manufacture of compound of formula I comprises a) reacting a compound of formula I in which Ri, R-,, R3, R5 and R6 have the given significance and R4 signifies HON (R7) COCH2-, wherein R7 has the given significance, or an alkali metal or alkaline earth metal salt thereof, with a compound yielding the group R8-X-, wherein X and R8 have the given significance, or b) reacting a compound of formula I in which R4 signifies carboxymethyl or a reactive group derived therefrom with a compound R8XON (R,) H, wherein X, R7 and R8 have the significance given above, and subsequently, if desired, converting the compound of formula I obtained into a different compound of formula I defined by the claim and, desired, converting a compound of formula I into a pharmacologically compatible salt.

As compound yielding the group R8-X-there come into consideration in accordance with the above alternative a) e. g. compound R8-X-Y in which X and R8 have the given significance and Y signifies a residue which participates as a leaving group in alkylation or acylation rections, such as, for example, halogen (preferably chlorine or bromine), azido, alkoxy, aryloxy, alkylthio, arylthio, acyloxy, imidazolyl, mesyloxy, tosyloxy or brosyloxy and inorganic groups such as, for example, sulphate and phosphate. Y can also represent an alcoholic hydroxy group, in which case the rection is carried out in the presence of a water-withdrawing agent, such as dicyclohexylcarbodiimide or N, N'-carbonyldiimidazole.

An amine R8H is combine with N, N'-carbonyldiimidazole for the introduction of carbamoyl groups R8-X- (see Example 33). If desired, the corresponding isocyanate can be used (see Example 29).

The rection is conveniently effected in a solvent such as a lower alcool, for example methanol, ethanol, propanol or isopropanol, or an ether such as diethyl ether or tetrahydrofuran or dimethylformamide, dimethyl sulphoxide or dimethylacetamide or in a mixture of the aforementioned solvents at temperature between 0°C and the boiling point of the solution, optionally in the presence of a base such as, for example, sodium hydroxide or potassium carbonate, an alkali alcoholate or a tertiary amine.

Compound R8-X-Y and R8-XON (R7) H are known from the literature or can be prepared from commercially available materials according to processes from the literature. Diethyl2-amino-6- [ (hydroxycarbamoyl)-methyl]-azulene-1,3- dicarboxylate is known from EP 97110533.3.

Preferred in the scope of the present invention are the following compound as well as the compound named in the Examples and compound derived by a combination of all substituent meanings set forth in the claims: Diethyl 2-amino-6- [ (dimethyl-phosphinoylmethoxycarbamoyl)-methylJ-azulene-1,3- dicarboxylate; diethyl 2-amino-6- [ (diethoxy-phosphoryloxycarbamoyl)-methyl]-azulene-1,3- dicarboxylate;

diethyl 2-amino-6- [ (2, 2-dimethyl-propanoyloxy)-methoxycarbamoyl-methyl]-azulene- 1,3-dicarboxylate; diethyl 2-amino-6- (ethoxymethoxycarbamoyl-methyl)-azulene-1,3-dicarboxylate ; diethyl 2-amino-6- [ (3-hydroxy-propoxycarbamoyl)-methyl]-azulene-1,3-dicarboxyla te; diethyl2-amino-6-{[2-(dimethyl-phosphinoyl)-ethoxycarbamoyl] -methyl}-azulene-1,3- dicarboxylate; diethyl 2-amino-6- [ (1-pyrrolidin-1-yl-ethoxycarbamoyl)-methyl]-azulene-1, 3- dicarboxylate; diethyl 2-amino-6- [ (1-ethoxy-1-methyl-ethoxycarbamoyl)-methyl]-azulene-1, 3- dicarboxylate; diethyl 2-amino-6- [(3-pyrrolidin-1-yl-propoxycarbamoyl)-methyl]-azulene-1, 3- dicarboxylate; diethyl 2-amino-6-{[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propoxyc arbamoyl]- methyl}-azulene-1,3-dicarboxylate; diethyl 2-amino-6- [ (pyrrolidin-1-ylcarbonyloxycarbamoyl)-methyll-azulene-1,3- dicarboxylate; diethyl 2-amino-6- [ (2-hydroxy-ethoxycarbonylmethoxycarbamoyl)-methyl]-azulene-1 , 3- dicarboxylate; diethyl 2-amino-6- (carboxymethoxycarbamoyl-methyl)-azulene-1, 3-dicarboxylate; diethyl 2-amino-6-{[(4,5-dihydro-1H-imidazol-2-ylcarbamoyl)-methoxyc arbamoyl]- methyl}-azulene-1,3-dicarboxylate; <BR> <BR> <BR> diethyl 2-amino-6-{ [ (lH-tetrazol-5-ylcarbamoyl)-methoxycarbamoyl]-methyl}-azulen e- 1,3-dicarboxylate; diethyl 2-amino-6- (hydroxycarbamoylmethoxycarbamoyl-methyl)-azulene-1, 3- dicarboxylate; diethyl 2-amino-6- [ (4-hydroxy-butoxycarbamoyl)-methyl]-azulene-1,3-dicarboxylat e ; diethyl 2-amino-6-{[2-(2-hydroxy-ethoxy)-ethoxycarbamoyl]-methyl}-az ulene-1,3- dicarboxylate; diethyl 2-amino-6-{[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethoxyca rbamoyl]-methyl}- azulene-1,3-dicarboxylate; diethyl 2-amino-6-{[(dimethyl-phosphinoylmethoxy)-methyl-carbamoyl]- methyl}- azulene-1,3-dicarboxylate; diethyl 2-amino-6- [ (methyl-phosphonomethoxy-carbamoyl)-methyl]-azulene-1,3- dicarboxylate; diethyl2-amino-6-{[(diethoxy-phosphorylmethoxy)-methyl-carba moyl]-methyl}-azulene- 1,3-dicarboxylate;

diethyl 2-amino-6- { [methyl- (3-pyrrolidin-1-yl-propoxy)-carbamoyl]-methyl}-azulene- 1,3-dicarboxylate; diethyl 2-amino-6-({[3-(1, 3-dioxo-1,3-dihydro-isoindol-2-yl)-propoxy]-methyl- carbamoyl}-methyl)-azulene-1,3-dicarboxylate; diethyl 2-amino-6- { [methyl- (2-oxo-2-pyrrolidin-1-yl-ethoxy)-carbamoyl]-methyl}- azulene-1,3-dicarboxylate; diethyl 2-amino-6- [ (ethoxycarbonylmethoxy-methyl-carbamoyl)-methyl]-azulene-1,3 - dicarboxylate; diethyl 2-amino-6- [ (carboxymethoxy-methyl-carbamoyl)-methyl]-azulene-1,3- dicarboxylate; diethyl 2-amino-6- [ (hydroxycarbamoylmethoxy-methyl-carbamoyl)-methyl]-azulene-1 ,3- dicarboxylate; diethyl 2-amino-6- { [ (2-ethoxy-ethoxy)-methyl-carbamoyl]-methyl}-azulene-1, 3- dicarboxylate; diethyl 2-amino-6- ( { [2- (2-hydroxy-ethoxy)-ethoxy]-methyl-carbamoyl}-methyl)-azulene - 1,3-dicarboxylate; diethyl 2-amino-6-{[(2-hydroxy-ethoxy)-methyl-carbamoyl]-methyl}-azu lene-1,3- dicarboxylate; diethyl 2-amino-6-({[2-(1, 3-dioxo-1,3-dihydro-isoindol-2-yl)-ethoxy]-methyl- carbamoyl}-methyl)-azulene-1,3-dicarboxylate; diethyl 2-amino-6-{[ethyl-(2-oxo-2-pyrrolidin-1-yl-ethoxy)-carbamoyl ]-methyl}-azulene- 1,3-dicarboxylate; diethyl 2-amino-6- ( { [ (4, 5-dihydro-1H-imidazol-2-ylcarbamoyl)-methoxyJ-ethyl- carbamoyl}-methyl)-azulene-1,3-dicarboxylate;and diethyl 2-amino-6-({[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethoxy] -ethyl-carbamoyl}- methyl)-azulene-1,3-dicarboxylate.

The following Examples illustrate the invention, but are not limiting: Example 1 Diethyl 2-amino-6- [ (2-oxo-2-piperidin-1-yl-ethoxycarbamoyl)-methyl]-azulene- 1,3-dicarboxylate.

A mixture of 0.96 g (2.5 mmol) of diethyl 2-amino-6-[(hydroxycarbamoyl)-methyl]- azulene-1,3-dicarboxylate sodium, 50 ml of methanol, 0.4 g (2.5 mmol) of N- chloroacetyl-piperidine and 20 mg of sodium iodide is heated at reflux for 20 hours.

Thereafter, the mixture is concentrated and the residue is chromatographed on silica gel. Elution with isohexane: ethyl acetate 1: 1 gives 0.42 g (35% of theory) of the title m.p.compoundof 153-155°C.

Example 2 <BR> <BR> <BR> <BR> <BR> Diethyl 2-amino-6- [ (2-oxo-2-pyrrolidin-1-yl-ethoxycarbamoyl)-methyl]-azulene-1, 3- dicarboxylate In an analogous manner to that described in Example 1, from diethyl 2-amino-6- [(hydroxycarbamoyl)-methyl]-azulene-1,3-dicarboxylate sodium and N-chloroacetyl- pyrrolidine the title compound of m. p. 168-170°C is obtained in 24% yield.

Example 3 <BR> <BR> <BR> <BR> <BR> Diethyl 2-amino-6- [ (2-oxo-2-morpholin-4-yl-ethoxycarbamoyl)-methyl]-azulene-1,3 -<BR> <BR> <BR> <BR> dicarboxylate In an analogous manner to that described in Example 1, from diethyl 2-amino-6- [ (hydroxycarbamoyl)-methyl]-azulene-1,3-dicarboxylate sodium and N-chloroacetyl- morpholine the title compound of m. p. 196-198°C is obtained in 33% yield.

Example 4 <BR> <BR> <BR> <BR> <BR> Diethyl 2-amino-6- { [2-oxo-2- (N, N-bis-2-methoxyethyl-amino)-ethoxycarbamoyl]-<BR> <BR> <BR> <BR> methyl}-azulene-1,3-dicarboxylate In an analogous manner to that described in Example 1, from diethyl 2-amino-6- [(hydroxycarbamoyl)-methyl]-azulene-1, 3-dicarboxylate sodium and N-chloroacetyl- N, N-bis-2-methoxyethyl-amine the title compound of m. p. 109-112°C is obtained in 31% yield.

Example 5 Diethyl 2-amino-6- [ (2-oxo-2-N, N-dimethylamino-ethocycarbamoyl)-methyl)-azulene- 1,3-dicarboxylate In an analogous manner to that described in Example 1, from diethyl 2-amino-6- [(hydroxycarbamoyl)-methyl]-azulene-1, 3-dicarboxylate sodium and 2-chloro-N, N- dimethylacetamide the title compound of m. p. 177-179°C is obtained in 27% yield.

Example6 Diethyl 2-amino-6- [ (2-oxo-2-ethoxy-ethoxycarbamoyl)-methyl]-azulene-1,3- dicarboxylate In an analogous manner to that described in Example 1, from diethyl 2-amino-6- [ (hydroxycarbamoyl)-methyl]-azulene-1,3-dicarboxylate sodium and ethyl bromoacetate the title compound is obtained in 24% yield as a wax.

Example7 Diethyl 2-amino-6- [ (2-hydroxy-ethoxycarbamoyl)-methyl]-azulene-1,3-dicarboxylat e In an analogous manner to that described in Example 1, from diethyl 2-amino-6- [ (hydroxycarbamoyl)-methyl]-azulene-1,3-dicarboxylate sodium and 2-bromo-ethanol the title compound of m. p. 190-192°C is obtained in 15% yield.

Example8 Diethyl 2-amino-6- [ (2,2-dimethyl-1,3-dioxolan-4-yl-methoxycarbamoyl)-methyl]- azulene-1,3-dicarboxylate In an analogous manner to that described in Example 1, from diethyl 2-amino-6- [ (hydroxycarbamoyl)-methyll-azulene-1,3-dicarboxylate sodium and 2,2-dimethyl-4- (4- methyl-benzenesulphonyloxy-methyl)-1,3-dioxolan the title compound of m. p. 135-137°C is obtained in 15% yield.

Example 9 Diethyl 2-amino-6- [ (2,3-dihydroxy-propoxycarbamoyl)-methyl]-azulene-1,3- dicarboxylate By reacting the compound described in Example 8 with dilute hydrochloric acid and subsequent chromatographic purification the title compound of m. p. 151-153°C is obtained in 13% yield.

Example 10 Diethyl 2-amino-6- [ (2-hydroxy-3-methoxy-propoxycarbamoyl)-methyl]-azulene-1, 3- dicarboxylate In an analogous manner to that described in Example 1, from diethyl 2-amino-6- [ (hydroxycarbamoyl)-methyll-azulene-1,3-dicarboxylate sodium and 2-methoxymethyl- oxirane the title compound is obtained in 15% yield as a wax.

Example 11 Diethyl 2-amino-6- { [2-oxo-2- (N, N-bis-2-hydroxyethyl-amino)-ethoxycarbamoyl]- methyl}-azulene-1,3-dicarboxylate In an analogous manner to that described in Example 1, from diethyl 2-amino-6- [ (hydroxycarbamoyl)-methyl]-azulene-1,3-dicarboxylate sodium and N-chloroacetyl- N, N-bis-2-hydroxyethyl-amine the title compound is obtained in 23% yield as a wax.

Example 12 Diethyl 2-amino-6- { [ (N, N-dimethylamino)-carbonyloxy-carbamoyl]-methyl}-azulene- 1,3-dicarboxylate In an analogous manner to that described in Example 1, but using N, N-dimethyl- formamide in place of methanol, from diethyl 2-amino-6- [ (hydroxycarbamoyl)-methyl]- azulene-1,3-dicarboxylate sodium and chloroformic acid dimethylamide the title compound of m. p. 167-169°C is obtained in 17% yield.

Example 13 Diethyl 2-amino-6-{ [2-oxo-2- (N, N-bis-2-methoxyethyl-amino)-N-methyl- ethoxycarbamoyl]-methyl}-azulene-1,3-dicarboxylate In an analogous manner to that described in Example 1, from diethyl 2-amino-6- [ (N- methyl-hydroxycarbamoyl)-methyl]-azulene-1,3-dicarboxylate sodium and N-chloroacetyl-N, N-bis-2-methoxyethyl-amine the title compound is obtained in 60% yield as a wax.

Example 14 Diethyl 2-amino-6- [ (2-piperidin-1-yl-ethoxycarbamoyl)-methyl]-azulene-1,3- dicarboxylate In an analogous manner to that described in Example 1, from diethyl 2-amino-6- [ (hydroxycarbamoyl)-methylJ-azulene-1, 3-dicarboxylate sodium and 2-piperidino-ethyl bromide the title compound of m. p. 163-165°C is obtained in 7% yield.

Example 15 Diethyl 2-amino-6- [ (3-dimethylamino-2-hydroxy-propoxycarbamoyl)-methyl]-azulene - 1,3-dicarboxylate A mixture of 1.14 g (3 mmol) of diethyl 2-amino-6- [ (hydroxycarbamoyl)-methyl]- azulene-1, 3-dicarboxylate sodium, 50 ml of ethanol, 0.1 ml of triethylamine and 0.25 ml of epichlorohydrin is heated to reflux for 20 hours, subsequently concentrated and the residue is chromatographed on silica gel. Elution with isohexane: ethyl acetate 1: 1 gives 0.2 g of the desired epoxide which is treated with excess ethanolic dimethylamine solution. After standing at room temperature for one day the mixture is chromatographed on silica gel. Elution with isohexane: ethyl acetate 1: 1 gives 60 mg (4% of theory) of the title compound as a wax.

Example 16 Diethyl 2-amino-6- [ (diethoxy-phosphorylmethoxycarbamoyl)-methyl]-azulene-1, 3- dicaboxylate.

A solution of 2.5 mmol of diethyl 2-amino-6-carboxymethyl-azulene-1,3- dicarboxylate in 50 mi of tetrahydrofuran is treated portionwise at 45°C with 2.5 mmol of N, N-carbonyldiimidazole. The mixture is stirred for 30 minutes, a solution of 2.5 mmol of diethoxyphosphorylmethoxylamine (L. Maier, Phosphorus, Sulphur, and Silicon 1993, Vol. 76,119-122) in 20 ml of tetrahydrofuran is added and the resulting mixture is heated to reflux for 3 hours. The mixture is concentrated and the residue is chromatographed on silica gel. Elution with isohexane: ethyl acetate 1: 1 gives 78% of the title compound of m. p. 146-147°C.

Example 17 Diethyl 2-amino-6- (phosphonomethoxycarbamoyl-methyl)-azulene-1, 3-dicarboxylate In an analogous manner to that described in Example 26, from diethyl 2-amino-6- carboxymethyl-azulene-1,3-dicarboxylate and phosphonomethoxyamine (L. Maier, Phosphorus, Sulfur, and Silicon 1993, Vol. 76,119-122) the title compound is obtained as an amorphous powder.

Example 18 Diethyl 2-amino-6- [ (2-oxo-2-pyrrolidin-1-yl-N-methyl-ethoxycarbamoyl)-methyl]- azulene-1,3-dicarboxylate In an analogous manner to that described in Example 1, from diethyl 2-amino-6- [ (N- methyl-hydroxycarbamoyl)-methyl]-azulene-1,3-dicarboxylate sodium and N- chloroacetyl-pyrrolidine the title compound is obtained in 77% yield as a wax.

Example 19 Diethyl 2-amino-6- [ (2-amino-2-oxo-ethoxycarbamoyl)-methyl]-azulene-1, 3- dicarboxylate In an analogous manner to that described in Example 1, from diethyl 2-amino-6- [(hydroxycarbamoyl)-methyl]-azulene-1, 3-dicarboxylate sodium and 2-chloroacetamide the title compound of m. p. 208-210°C is obtained in 26% yield.

Example 20 Diethyl 2-amino-6-{[2-(morpholin-1-yl)-ethoxycarbamoyl]-methyl}-azul ene-1,3- dicarboxylate In an analogous manner to that described in Example 1, from diethyl 2-amino-6- [ (hydroxycarbamoyl)-methyl]-azulene-1,3-dicarboxylate sodium and 2-morpholino-ethyl chloride the title compound of m. p. 198-200°C is obtained in 37% yield.

Example 21 Diethyl 2-amino-6-{[3-(N,N-bis-2-methoxyethyl-amino)-propoxycarbamoy l]-methyl}- azulene-1,3-dicarboxylate In an analogous manner to that described in Example 1, from diethyl 2-amino-6- [ (hydroxycarbamoyl)-methyl]-azulene-l,'D-dicarboxylate sodium and 3-(N, N-bis-2- methoxyethyl-amino)-propyl chloride the title compound of m. p. 113-115°C is obtained in 49% yield.

Example 22 Diethyl 2-amino-6-{[3-oxo-3-ethoxy)-2-propoxycarbamoyl]-methyl}-azul ene-1,3- dicarboxylate In an analogous manner to that described in Example 1, from diethyl 2-amino-6- [(hydroxycarbamoyl)-methyl]-azulene-1,3-dicarboxylate sodium and ethyl 2-bromo- propionate the title compound of m. p. 173-175°C is obtained in 40% yield.

Example 23 Diethyl 2-amino-6- { [ (3- (piperidin-1-yl)-proxpoxycarbamoyl]-methyl}-azulene-1, 3- dicarboxylate In an analogous manner to that described in Example 1, from diethyl 2-amino-6- [ (hydroxycarbamoyl)-methyl]-azulene-1,3-dicarboxylate sodium and 3-piperidino-propyl chloride the title compound of m. p. 174-176°C is obtained in 43% yield.

Example 24 Diethyl 2-amino-6- [ (3-diethylamino-propoxycarbamoyl)-methyl]-azulene-1,3- dicarboxylate In an analogous manner to that described in Example 1, from diethyl 2-amino-6- [ (hydroxycarbamoyl)-methyll-azulene-1,3-dicarboxylate sodium and 3-diethylamino- propyl chloride the title compound of m. p. 125-127°C is obtained in 42% yield.

Example25 Diethyl 2-amino-6- { [ (3-amino-3-oxo)-2-propoxycarbamoyl]-methyl}-azulene-1, 3- dicarboxylate In an analogous manner to that described in Example 1, from diethyl 2-amino-6- [(hydroxycarbamoyl)-methyl]-azulene-1, 3-dicarboxylate sodium and 2-chloro- propionamide the title compound of m. p. 232-234°C is obtained in 19% yield.

Example26 Diethyl 2-amino-6- { [ (2-methylamino-2-oxo)-ethoxycarbamoyl]-methyl}-azulene-1,3- dicarboxylate In an analogous manner to that described in Example 1, from diethyl 2-amino-6- [ (hydroxycarbamoyl)-methyl]-azulene-1,3-dicarboxylate sodium and chloroacetic acid N- methylamide the title compound of m. p. 194-196°C is obtained in 24% yield.

Example 27 Diethyl 2-amino-6-{ [ (2-ethylamino-2-oxo)-ethoxycarbamoyl]-methyl}-azulene-1, 3- dicarboxylate In an analogous manner to that described in Example 1, from diethyl 2-amino-6- [ (hydroxycarbamoyl)-methyl]-azulene-1, 3-dicarboxylate sodium and chloroacetic acid N- ethylamide the title compound of m. p. 176-178°C is obtained in 21% yield.

Example 28 Diethyl 2-amino-6-{[(2-n-butylamino-2-oxo)-ethoxycarbamoyl]-methyl}- azulene-1,3- dicarboxylate In an analogous manner to that described in Example 1, from diethyl 2-amino-6- [(hydroxycarbamoyl)-methyl]-azulene-1,3-dicarboxylate sodium and chloroacetic acid N- n-butylamide the title compound of m. p. 148-150°C is obtained in 33% yield.

Example 29 Diethyl 2-amino-6-{[(N-methylamino)-carbonyloxy-carbamoyl]-methyl}-a zulene-1,3 dicarboxylate A mixture of 0.2 g (0.55 mmol) of diethyl 2-amino-6- [(hydroxycarbamoyl)-methyl]- azulene-1,3-dicarboxylate, 5 ml of dimethyl sulphoxide and 35tl (0.6 mmol) of methyl isocyanate is stirred at room temperature for 18 hours. Thereafter, the mixture is diluted with water, extracted with dichloromethane and the extract is chromatographed on silica gel. Elution with ethyl acetate gives 60 mg (36% of theory) of the title compound of m. p.

222-224°C.

Example 30 Diethyl 2-amino-6- { [ (N-n-butylamino)-carbonyloxy-carbamoyl]-methyl}-azulene-1, 3- dicarboxylate In an analogous manner to that described in Example 29, from diethyl 2-amino-6- [(hydroxycarbamoyl)-methyl]-azulene-1,3-dicarboxylate und n-butyl isocyanate the title compound of m. p. 178-179°C is obtained in 47% yield.

Example 31 Diethyl 2-amino-6- { [ (4-methyl-piperazino)-carbonyloxy-carbamoyl]-methyl}-azulene - 1,3-dicarboxylate 90 mg of N, N'-carbonyldiimidazole are added to a mixture of 0.2 g (0.55 mmol) of diethyl 2-amino-6-[(hydroxycarbamoyl)-methyl]-azulen-1,[(hydroxycarb amoyl)-methyl]-azulen-1, 3-dicarboxylate and 20 ml of dichloromethane, the resulting mixture is stirred at room temperature for 2 hours, 61 1 (0.55 mmol) of N-methyl-piperazine are added dropwise thereto and the mixture obtained is stirred for 1 hour. The mixture is concentrated and the residue is triturated with ethyl acetate, there being isolated 152 mg (57% of theory) of the title compound as a wax.

Example 32 Diethyl 2-amino-6- { [ (1-morpholino)-carbonyloxy-carbamoyl]-methyl}-azulene-1, 3- dicarboxylate In an analogous manner to that described in Example 31, from diethyl 2-amino-6- [ (hydroxycarbamoyl)-methyl]-azulene-1,3-dicarboxylate und morpholine the title compound is obtained in 61% yield as a wax.

Example 33 Diethyl-2-amino-6-{[(4-amino-butylamino)-carbonyloxy-carbamo yl]-methyl}-azulene- 1,3-dicarboxylate 45 mg of N, N'-carbonyldiimidazole are added to a mixture of 0.1 g (0. 28 mmol) of diethyl 2-amino-6- [ (hydroxycarbamoyl)-methyl]-azulene-1,3-dicarboxylate and 10 ml of dichloromethane, the resulting mixture is stirred at room temperature for 2 hours, treated with 36 mg of N-methyldiisopropylamine and 107 mg (0.28 mmol) of 4-(N-tritylamino)-butylamine and stirred for 1 hour. The mixture is concentrated and the residue is chromatographed on silica gel. Elution with methyl acetate: heptane 3: 1 gives 100 mg of trityl compound which is dissolve in 3 ml of dichloro- methane and treated with 500 1 ouf trifluoroacetic acid. After stirring for 10 minutes the mixture is concentrated and the residue is triturated with diethyl- ether. 68 mg (51% of theory) of the title compound of m. p. 150-150°C are isolated.

Example 34 <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> Diethyl 2-amino-6- [ (ethoxycarbonyloxy-carbamoyl)-methyl]-azulene-1, 3-dicarboxylate In an analogous manner to that described in Example 12, from diethyl 2-amino-6- [ (hydroxycarbamoyl)-methyll-azulene-1, 3-dicarboxylate and ethyl chloroformate the title compound is obtained in 47% yield as an oil.