SK9092002A3 - Carboxamide diazepin derivatives, preparation method, use as medicines, pharmaceutical compositions and use thereof - Google Patents

Abstract

The invention concerns products of formula (I) wherein: R1 represents in particular -C(O) -R5, -SO2 -R5 or -C(O) -NR6R5, R2 and R7 are such that either R7 represents a hydrogen atom and R2 is such that the group (a) represents the radical of a natural or non-natural amino acid, or R2 and R7 form together a cycle with the nitrogen and carbon atom whereto they are bound, R3 represents in particular the radical -CH=N2 or -CH2-L-R4, R4 represents in particular a linear or branched alkyl radical, and their additive salts with mineral or organic acids or with mineral or organic bases of said products of formula (I). The invention also concerns the method for preparing said products and their use as medicines.

Description

Technical field

The present invention provides novel 9 (S) -amino-6 _/ 10-dioxo-1,2,3,4,7,8 derivatives _; 9,10-octahydro-6 H -pyridazino [1,2- a] [1,2] diazepine-1 (S) -carboxamide, process for their preparation, their use as medicaments and pharmaceutical compositions containing these derivatives and the re-use of these derivatives.

In particular, the present invention provides the preparation of a library of enzymatic inhibitors using 9 (S) -amino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyridazino [1,2-a] [1,2] diazepine-1 (S) -carboxamide. Metabolic enzymes, such as proteinases or kinases, are enzymes that are widely distributed in the animal kingdom. As a non-limiting example of bibliographic references to proteinases, mention may be made of: "Metods in Enzymology XLII (1975) and" Journal of Medicinal Chemistry, Vol. 43, no. 3, ("D. Leung, G. Abbenante and D.P. Fairlie), and as a reference to kinases, reference may be made to:" Metods in Enzymology, Vol. 80 (1981) (Academic Press, Inc.).

Among the proteinases that are capable of selectively catalyzing the hydrolysis of polypeptide bonds, four major classes may be mentioned: aspartic, serine and cysteine proteinase and metalloproteinase.

As the aspart proteinase, mention may be made in particular of HIV-1 proteinase, renin, plasmepsins and cathepsin D.

• V t '

In particular, thrombin, factor Xa, elastase, tryptase, "convertase complements" and NS3 hepatitis C proteinase may be mentioned as serine proteinase.

Among the cysteine iproteinases there are three structurally distinct groups, namely the papain group (caspases) and the picorn-viral serine proteinases (in which it is cysteine).

and cathepsins, an ICE group (similar to serine replaced

Mention may be made in particular of cathepsin K, cathepsin B, cathepsin L, cathepsin S, caspases, rhinovirus 3C proteinase, and qualpains.

As metalloproteinase, mention may be made in particular of angiotensin converting enzyme, natural endopeptidase and a mixture of the two, metalloproteinase matrix, and also tumor necrosis factor-α-converting enzyme.

Particular mention may be made of cathepsin K, cathepsin B, cathepsin S, cathepsin L and papain, and more preferably cathepsin K, cathepsin B and papain.

These kinases or proteinase enzymes are involved in catabolization processes and intrinsic and intracellular communication: they play an important role in a large number of diseases in various domains such as cardiovascular domain, oncology, central nervous system, inflammation, osteoporosis as well as infectious, parasitic, fungal or viral diseases. This is why these proteins are of major concern to the pharmaceutical industry. Thus, within the scope of the invention, a chemical library directed against potential inhibitors of these enzymes has been designed and constructed, starting from a peptidomimetic intermediate, wherein the peptidomimetic intermediate herein corresponds to the product of formula II, which will be defined below. The products of the invention as defined in the specification are capable of inhibiting. metabolic enzymes as defined above, in particular kinases or proteinases, for example in particular cysteine proteinases or serine proteinases.

Thus, the products of the invention are particularly useful in the prevention or treatment of diseases in which these metabolic enzymes are involved, for example in the prevention or treatment of cardiovascular diseases, central nervous system diseases, inflammatory diseases, bone diseases such as osteoporosis, infectious diseases requiring treatment. in particular anti-infective agents, or also in the prevention or treatment of certain cancers.

The invention therefore relates to products of the general formula I:

R 1 represents a -C (O) -R 5, -SO ₂ -R 5 or -C (O) -NR 6 R 5 radical, wherein R 6 represents a hydrogen atom or a linear or branched alkyl radical containing up to 4 carbon atoms and R5 represents a linear or branched alkyl radical containing 6 carbon atoms maximum, cycloalkyl radical containing up to 6 carbon atoms, saturated or unsaturated

Or

A 6-membered phenyl, naphthyl or monocyclic heterocyclic radical containing 1 or more identical or different heteroatoms selected from oxygen, nitrogen or sulfur, wherein the alkyl, phenyl and heterocyclic radicals as defined above in relation to R1 are optionally substituted with at least one radical selected from the group consisting of halogen atoms, linear or branched alkyl radicals or alkoxy radicals containing up to 4 carbon atoms, hydroxyl radical, acyl radicals containing up to 7 carbon atoms, trifluoromethyl radical, cyanoradical, thienyl radical, phenoxy radical, phenyl radical;

R 2 and R 7 are such that either R 7 represents a hydrogen atom and

R 2

I

R2 is also that the -NH-CH-C (O) - group in the products of formula I represents a so-called " a natural or artificial amino acid residue

R 2

The NH ₂ -CH-C (O) OH structures, with the exception of aspartic acid, or R 2 and R 7 together with the nitrogen atom and the carbon atoms to which they are attached form a ring so that the group thus formed in the products of formula I:

R 2

-N represents the so-called. natural or synthetic amino acid residue of the following structure:

OH

R 3 represents a -CH = N ₂ radical or -CH ₂ -L-R 4 radical, wherein L represents a single bond or a divalent radical selected from -O-, -O-C (O) -, -NH- and -S- (CH ₂ ) _n - wherein n represents an integer from 0 to 6, and R 4 represents a linear or branched alkyl radical containing up to 6 carbon atoms, a saturated or unsaturated monocyclic or bicyclic carbocyclic or heterocyclic radical containing 5 to 10 members and 1 or more identical or various heteroatoms selected from oxygen, nitrogen, iminoradical or sulfur, which may contain a -C (O) group, wherein the carbocyclic and heterocyclic alkyl radicals as defined above in relation to R4 are optionally substituted with at least one radical selected from the group consisting of consisting of halogen atoms; hydroxyl radicals; free, salified or esterified carboxyl radicals; -C (O) -NH ₂ , -C (O) -NH (alkyl), -C (O) -N (alkyl) - (alkyl), -NHC (O) (alkyl), -N (alkyl) - C (O) - (alkyl); a thienyl radical; a phenyl radical; an alkylphenyl radical; alkyl radical and alkoxy radical per se and optionally substituted with at least 1 radical selected from the group consisting of acyl radicals containing up to 7 carbon atoms, cyanoradical, -NH ₂ , -NH (alkyl), -N (alkyl) - (alkyl) and phenyl radical, where in the above radicals the alkyl radicals and alkoxy radicals are to be understood as being linear or branched and containing a maximum of 4 carbon atoms, the * indicates carbon atoms on which S or

R configuration; said products of formula I exist in all possible racemic, enantiomeric and diastereoisomeric forms, as well as addition salts of these products of formula I with mineral and organic acids or mineral and organic bases.

In the products of formula I and in the following description:

the term linear or branched alkyl radical denotes a methyl radical, an ethyl radical, a propyl radical, an isopropyl radical, a butyl radical, an isobutyl radical, a sec-butyl radical, a tert-butyl radical, a pentyl radical, an isopentyl radical, a hexyl radical, a radical, an octyl radical, a nonyl radical and a decyl radical, as well as their linear or branched isomers; of which alkyl radicals may preferably be selected from alkyl radicals having a maximum of 6 carbon atoms or those containing a maximum of 4 carbon atoms;

the term linear methoxy radical, propoxy radical, butoxy radical, or branched ethoxy radical, linear, pentoxy radical as well as linear or denoting isocyanates thereof, or those alkoxy radical propoxy radical, secondary or tertiary or hexoxy radical, and branched position isomers;

is preferably selected.

alkoxy of up to 6 carbon atoms containing up to 4 carbon atoms;

the term halogen atom denotes a chlorine atom, a bromine atom, an iodine atom or a fluorine atom and preferably a chlorine atom, a bromine atom or an iodine atom;

the term cycloalkyl radical refers to a cyclopropyl radical, a cyclobutyl radical, a cyclopentyl radical and a cyclohexyl radical, and in particular a cyclopentyl radical and a cyclohexyl radical;

the term monocyclic heterocyclic radical refers to a saturated or unsaturated radical of 5 or 6 members wherein one or an oxygen, sulfur atom, a heterocyclic radical interrupted by one selected from oxygen, nitrogen or more, or thus represents a nitrogen atom, so that it denotes a plurality of carbocyclic sulfur heteroatoms meaning that the heterocyclic radicals may contain one or more heteroatoms selected from oxygen, nitrogen or sulfur atoms, and if the heterocyclic radicals contain more than one heteroatom, the heteroatoms of these heterocyclic radicals may be identical or different. Especially noteworthy are the following radicals: dioxolane radical, dioxane radical, dithiolane radical, thiooxolane radical, thiooxane radical, morpholinyl radical, piperazinyl radical, piperazinyl radical substituted with a linear or branched alkyl 4 radical, e.g. -thienyl radical and 3-thienyl radical, furyl radical, e.g. 2-furyl radical, pyrimidinyl radical, pyridyl radical, e.g. 2-pyridyl radical, 3-pyridyl radical and 4-pyridyl radical, pyrimidyl radical, pyrrolyl radical, thiazolyl radical, thiazole, diazolyl radical, thiadiazolyl radical, free or thiadiazolyl oxazolyl isoxazolyl radical, radical, radical, radical, radical, radical, especially radical, triazolyl salified tetrazolyl radical, thiatriazolyl oxadiazolylo radical may be mentioned a radical, 3 or 4-isoxazolyl radical; a morpholinyl radical, a thienyl radical and a 3-thienyl radical, for example a 2-thienyl furyl radical, for example a 2-furyl tetrahydrofuryl tetrahydrothienyl pyrrolinyl radical, a pyrrolidinyl radical;

a radical, a radical, a thienyl radical, a pyrrolyl pyridyl radical, a radical, a radical term or a bicyclic heterocyclic radical denotes a saturated unsaturated radical of 8 to 12 or more members representing a nitrogen atom or atom and one sulfur of the heterocyclic group containing selected from sulfur, nitrogen, benzothienyl radical a radical, a benzothiazolyl tetralone radical, a benzopyrrolyl radical, a benzoxazolyl radical, a radical or a purinyl member, such that the oxygen, atom fused in particular with at least one heteroatom and oxygen, for example in particular the 3-benzothienyl, quinolyl benzofuryl benzimidazolyl thionaphthyl radical;

such as] a radical, radical, radical, radical, indolyl term saturated or heterocyclic monocyclic containing 5 to 10 members, more identical selected from imino atoms and which is unsaturated or of different oxygen, nitrogen and may contain a carbocyclic or bicyclic radical containing or one or sulfur heteroatoms; or

-C (O), bridging the above definitions for the term monocyclic heterocyclic radical on the one hand and for the term bicyclic heterocyclic radical on the other, wherein the radicals are noted, the radical is a radical to be noted, optionally substituted; that in particular a phenyl radical as defined above and that containing a -C (O) tetralone radical;

However, all of which is further carbocyclic carbocyclic is, for example, the term alkylphenyl substituted with one branched alkyl. above, which radical denotes a phenyl radical or a plurality of linear or radicals as defined above containing a maximum of 4 carbon atoms;

NH (alk) and N (alk) (alk) denote an amino radical substituted with one or two alkyl radicals, respectively, wherein the alkyl radicals are linear or branched and preferably contain a maximum of 4 carbon atoms;

the term acylamino radical refers to -C (O) -NH ₂ , -C (O) -NH (alk), and -C (O) -N (alk) (alk) radicals wherein NH (alk) and N (alk) ( alk) radicals as defined above;

the term acyl radical denotes an RC (O)-radical, wherein R represents a radical selected from hydrogen, linear or branched alkyl radicals containing up to 6 carbon atoms, a phenyl radical or a pyrrolidinyl radical, and the term acyl radical thus denotes in particular a formyl radical, acetyl radical, a radical, butanoyl radical, pentanoyl radical, hexanoyl radical, benzoyl radical and pyrrolidinylcarbonyl radical;

the term alkenyl radical denotes linear or branched radicals containing up to 6 carbon atoms, with particular mention being made of vinyl radical, 1-propenyl radical, allyl radical, butenyl radical, 3-methyl-2-butenyl radical;

the term alkylthioradical denotes linear or branched radicals containing up to 6 carbon atoms, such as, in particular, methylthioradical, ethylthioradical, propylthioradical, butylthioradical, isobutylthioradical, isobutylthioradical, hexyl, tert-butylthioradical, tert-butylthioradical branched positional isomers, wherein the above-mentioned radicals containing a maximum of 4 carbon atoms are a suitable choice of these alkylthio radicals.

The so-called natural or synthetic amino acids are known to those skilled in the art and can be found in standard documents, for example, in "Amino Acids (1999), 16 (3-4), p. 345 to 379.

The carboxy radical (s) of the products of formula (I) may be salified or esterified by various groups known to those skilled in the art and among which may be mentioned: for example:

mineral bases such as sodium, potassium, lithium, calcium, magnesium or ammonia equivalent or organic bases such as methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N, N-dimethylethanolamine, tris (hydroxymethyl) amine methane may serve as salifying compounds, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine, methylglucamine;

N- as esterification compounds may serve, alkyl radicals which form alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, which alkyl radicals may be substituted by radicals selected from halogen, alkoxy radicals, hydroxy radicals an acyl radical, an acyloxy radical, an alkylthioradical, an amino radical or an aryl radical, for example, in a chloromethyl group, a hydroxypropyl group, a methoxymethyl group, a propionyloxymethyl group, a methylthiomethyl group,. dimethylaminoethyl, benzyl or phenethyl.

The mineral or acid addition salts of the products of formula (I) may be those formed with hydrochloric, hydrobromic, hydroiodic, phosphoric, acetic, trifluoroacetic, benzoic, organic such as nitric acid, propionic acid, maleic acid, sulfuric acid, formic acid. , fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid, glyoxylic acid, aspartic acid, ascorbic acid, alkyl monosulfonic acids such as methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, alkyldisulfonic acids such as melanic acid tandi sulfonic acid, alpha-ethanedisulfonic acid, beta-ethanedisulfonic acid, aryl monosulfonic acid, for example benzenesulfonic acid, and aryldisulfonic acid. It should be recalled that stereoisomerism can be defined in the broadest sense as isomerism of compounds having the same structural formulas but whose different groups are arranged in space in different ways, for example in monosubstituted cyclohexanes, the substituent can be located in axial or equatorial position, and there are various possible rotational configurations of ethane derivatives. However, there is another type of stereoisomerism that allows different spatial arrangements of fixed substituents, either on double bonds or on rings, often referred to as geometric isomerism or cis-trans isomerism. The term stereoisomers is used in its broadest sense to refer to all of the above compounds.

It should be noted that preferred products of formula (I) as defined above are those in which the carbon atoms have the * stereochemical configuration.

WITH.

It should be noted that in the products of formula I as defined above, the third carbon atom marked with * will not have R or S stereochemistry in the general formula of products of formula I, as long as R2 represents a hydrogen atom.

Accordingly, the invention relates in particular to the products of formula (I) as defined above, wherein R1 and R3 have the meanings indicated above and R2 represents the so-called " a natural amino acid residue with the exception of the residue derived from aspartic acid, said products of formula I exist in all possible racemic, enantiomeric and diastereomeric forms, as well as addition salts of said products of formula I with mineral and organic acids with organic bases.

or mineral and

The invention therefore also relates, in particular, to products of the formula I as defined above, in which R1 and R3 have the meanings indicated above and for R2 and R7:

either R 7 represents a hydrogen atom and R 2 represents a hydrogen atom or a linear or branched alkyl radical containing up to 6 carbon atoms, optionally substituted by at least one radical selected from an amino radical; acylamínoradikálu;

NH = C (NH ₂ ) -NH-; merkaptoradikálu; linear or branched alkylthio radicals containing maximum carbon atoms;

a hydroxyl radical;

linear alkoxy radicals containing maximum or branched carbon atoms;

an imidazolyl radical;

indolyl radicals;

a phenyl radical itself, optionally substituted with at least one radical selected from halogen atoms, a hydroxyl radical, a linear or branched alkoxy radical containing up to 4 carbon atoms and a phenoxy radical itself, optionally substituted with at least one radical selected from iodine atoms and a hydroxyl radical; and a -C (O) -O-R 8 radical, wherein R 8 represents a hydrogen atom or a linear or branched alkyl or alkenyl radical containing up to 6 carbon atoms;

or R 2 and R 7 together with the nitrogen and carbon atoms to which they are attached form a ring containing 5 to 7 members, which is optionally substituted with at least one hydroxyl radical or a linear or branched alkoxy radical containing up to 4 carbon atoms;

wherein said products of formula I exist in all possible racemic, enantiomeric and diastereoisomeric forms as well as addition salts of said products of formula I with mineral and organic acids or mineral and organic bases.

In particular, the invention relates to products of the formula I as defined above, wherein R1 and R3 have the meanings indicated above and R2 and R7 are defined such that:

either R 7 represents a hydrogen atom and R 2 is as defined above;

or R 2 and R 7 together with the nitrogen and carbon atoms form a pyrrolidinyl ring, optionally substituted with at least one hydroxyl radical or linear or branched alkoxy radicals containing up to 4 carbon atoms, said products of formula I exist in all possible racemic, enantiomeric and diastereoisomeric forms, and as well as addition salts of said products of the formula I with mineral and organic acids or mineral and organic bases.

Particular mention may be made of the products of formula (I) as defined above wherein R 2 and R 7 together with the nitrogen and carbon atoms to which they are attached form a pyrrolidinyl ring such that the amino acid residue is proline, or together form a pyrrolidinyl ring substituted with an optionally protected hydroxyl radical; then the amino acid residue is a hydroxyl.

In particular, the invention relates to products of the formula I as defined above which correspond to the formula Ia:

a,

R 1a represents a -C (O) -R 5a, -SO ₂ -R 5a or -C (O) -NR 6a R 5a radical, wherein

R 6a represents a hydrogen atom or a linear or branched alkyl radical containing up to 4 carbon atoms and R 5a represents a radical selected from linear or branched alkyl radicals containing up to 6 carbon atoms; cycloalkyl radicals containing no more than 6 carbon atoms; a phenyl radical; a naphthyl radical; a furyl radical; a morpholinyl radical; a thienyl radical; pyridyl radical, wherein the alkyl radical, phenyl radical, thienyl radical and pyridyl radical are optionally substituted with at least 1 radical selected from the group consisting of halogen atoms, linear or branched alkyl radicals or alkoxy radicals containing at most 4 carbon atoms, acyl radical 7, acyl radical carbon atoms, phenoxy radical, trifluoromethyl radical, cyanoradical, thienyl radical, phenyl radical and isoxazolyl radical;

R 2a is as defined above when R 7 represents a hydrogen atom;

R 3a represents a -CH = N ₂ radical or -CH ₂ -La-R 4a radical, wherein "La represents a single bond or a divalent radical selected from -O-, -O-C (O) - and -S- (CH ₂ ) _n" and - wherein "na represents an integer from 0 to 3; and

R 4a represents a radical selected from linear or branched alkyl radicals containing up to 6 carbon atoms; a phenyl radical;

piperazinyl pyridyl quinolyl pyrimidinyl tetrazolyl radical;

radical;

radical;

radical;

radical; and the piperidyl benzothiazolyl thiadiazolyl tetralone radical;

radical;

radical;

radical;

wherein the alkyl radical, the phenyl radical, the tetrazolyl radical, the piperazinyl radical and the piperidyl radical, as defined above for R 4a, are optionally substituted with at least 1 radical selected from halogen atoms; hydroxyl radical, free, salified or esterified carboxy radicals;

-C (O) -NH ₂ ; -C (0) -NH (alkyl); -C (0) -N (alkyl) (alkyl); -NH-C (0) - (alkyl); -N (alkyl) -C (O) - (alkyl); a thienyl radical; a phenyl radical; an alkylphenyl radical; alkyl radical and alkoxy radical per se optionally substituted with at least 1 radical selected from acyl radicals containing up to 7 carbon atoms, cyanoradical, -NH _{2 /} -NH (alkyl), N (alkyl) (alkyl) and phenyl radical, it being understood that in the above radicals there are alkyl radicals. and the alkoxy radicals linear or branched and contain a maximum of 4 carbon atoms, said products of formula Ia exist in all possible racemic, enantiomeric and diastereoisomeric forms, as well as addition salts of said products of formulaaa with mineral and organic acids or mineral and organic bases.

A more preferred object of the invention is the products of formula I as defined above, which correspond to formula Ib:

R 1b represents -C (O) -R 5b,

-SO ₂ -R 5b or -C (O) -NR 6b R 5b radical wherein

R 6b represents a hydrogen atom or a methyl radical and R 5b represents a radical selected from linear or branched alkyl radicals containing up to 4 carbon atoms, optionally substituted with a thienyl radical; a cyclohexyl radical; a phenyl radical optionally substituted by a linear or branched alkoxy radical containing up to 4 carbon atoms, a phenoxy radical or a trifluoromethyl radical; a naphthyl radical; a furyl radical;

a morpholinyl radical; a thienyl radical optionally substituted with an isoxazolyl radical;

a pyridyl radical, optionally substituted with a trifluoromethyl radical;

R 2b represents a hydrogen atom or a linear or branched alkyl radical containing up to 6 carbon atoms, optionally substituted with either a phenyl radical as such, an optionally substituted hydroxyl radical, or a linear or branched alkoxy radical containing up to 4 carbon atoms, or -C (O) -O-R 8b radicals where. R 8b represents a linear or branched alkyl or alkenyl radical containing up to 6 carbon atoms, R 3b represents a -CH = N ₂ radical or -CH ₂ -Lb-R 4b radical, wherein "Lb represents a single bond or a divalent radical selected from -O-, -O- -C (O) - and -S- (CH ₂ ) n b -, wherein "nb" represents an integer of 0 or 1; and

R 4b represents a radical selected from pyridyl benzothiazolyl radical; a quinolyl thiadiazolyl radical; a pyrimidinyl radical;

radical;

radical;

tetralone radical; linear or branched alkyl radicals containing up to 4 carbon atoms optionally substituted by free.

a salified or esterified carboxy radical or thienyl radical;

phenyl radical, optionally substituted with at least one radical selected from halogen atoms, free, salified or esterified carboxy radical, a linear or branched alkyl radicals, and alkoxy radicals containing up to 4 carbon atoms, cyanoalkyl radicals, alkylphenyl radicals, -NH-C (0) _-CH3, -C (O) -N (alkyl) (alkyl) radicals; a tetrazolyl radical, optionally substituted with a phenyl radical; a piperazinyl radical optionally substituted on the second nitrogen atom with a phenyl radical or a linear or branched alkyl radical containing up to 4 carbon atoms per se, and optionally substituted with acyl- (pyrrolidinylcarbonyl) radical, 1 or 2 phenyl radicals or -NH ₂ , -NH (alkyl) or -N (alkyl) (alkyl); a piperidyl radical optionally substituted by a benzyl radical or a -C (O) N (alkyl) (alkyl) radical, it being understood that in the above radicals the alkyl radicals and alkoxy radicals are linear or branched and contain a maximum of 4 carbon atoms, and said general products The compounds of formula (Ib) exist in all possible racemic, enantiomeric and diastereoisomeric forms, as well as addition salts of said products of formula (Ib) with mineral and organic acids or mineral and organic bases.

In particular, the invention relates to products of the formula I as defined above, wherein R1 represents a radical selected from the following radicals:

where R 2 is, represents

R3 and R7 above are hydrogen and R2 is as defined above, those wherein R7

I represents a radical selected from the following radicals:

wherein R1 and R3 have the meanings indicated above, and those wherein R3 represents a radical selected from the following radicals:

wherein R 1, R 2 and R 7 are as defined above, wherein the products of formula Ib exist in all possible racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts of said products of formula Ib with mineral and organic acids or mineral and organic bases .

In the products of the general formula I according to the invention, R2 represents in particular an amino acid residue selected from natural amino acids: GLU, GLY, ALA, VAL, LEU, PHE, TYR or TYR (OtBU). TYR (OtBU) represents the amino acid TYR, where the hydroxyl radical is protected as a tert-butoxy radical.

A particularly preferred object of the invention is the products of formula I as defined above, which correspond to the following chemical name:

3- [9 (S) -Benzoylamino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyridazino [1,2-a] [1,2] diazepine 1 (S) -carboxamide] -5-methyl-l-benzoyloxyhexan-2-one;

3- [9 (S) - (2-furanoyl) amino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyridazino [1,2-a] [ 1,2] diazepine-1 (S) -carboxamide] -5-methyl-1- (2,6-dichlorobenzoyloxyhexan-2-one);

3 (S) - [9 (S) - (2-furanoyl) amino-6,10-dioxo-l, 2,3,4,7,8,9,10-octahydro-6H-pyridazin [1,2- a] [1,2] diazepine-1 (S) -carboxamide] -4- (4-hydroxyphenyl) -1- (2,6-dichlorobenzoyloxy) butan-2-one.

Especially preferred objects of the invention are also products of formula I as defined above, which correspond to the following chemical names:

(2-propenyl) (4 S) -6-diazo-4 - [[[(1 S, 95) -9 - [(2-methyl-l-oxo-propyl) amino] octahydro-6,10-dioxo-6H- pyridazino [1,2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate;

(2-propenyl) (45) 6-diazo-4 - [[[(15,95) -9 - [(3-methoxybenzoyl) amino] octahydro-6,10-dioxo-6H-pyridazin [1,2- a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate;

(2-Propenyl) (4S) -6-diazo-4 - [[[(1S, 9S) -9 - [[(2-furanyl) carbonyl] amino] octahydro-6,10-dioxo-6H-pyridazino [1] 2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate;

(2-propenyl) (45) 6-diazo-4 - [[[(15,95) -9 - [[(cyclohexylamino) carbonyl] amino] octahydro-6,10-dioxo-6H-pyridazin [1,2- [1,2] diazepin-1-yl] carbonyl] amino] -5-oxo-hexanoate;

(2-Propenyl) (45) -6-diazo-4 - [[[(15,95) -9 - [[[(4-phenoxyphenyl) amino] carbonyl] amino] octahydro-6,10-dioxo-6521 pyridazino [1,2-a] [1,2] diazepin-l-yl] carbonyl] amino] -5-oxohexanoate;

(2-Propenyl) (4S) -6-diazo-4 - [[[(1S, 9S) -9 - [[[[2- (β-2-yl) ethyl] amino] carbonyl] amino] octahydro-6] , 10-dioxo-6Hpyridazíno [1,2-a] [1,2] diazepin-l-yl] carbonyl] amino] -5-oxohexanoate;

(2-Propenyl) (4S) -6-diazo-4 - [[[(1S, 9S) -9 - [(methylsulfonyl) amino] octahydro-6,10-dioxo-6H-pyridazino [1,2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate;

(2-Propenyl) (4S) -6-diazo-4 - [[[(1S, 9S) -9 - [[[4- (trifluoromethyl) phenyl] sulfonyl] amino] octahydro-6,10-dioxo -6H-pyridazino [1,2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate;

(2-Propenyl) (4S) -6-diazo-4 - [[[(1S, 9S) -9 - [[(2-naphthalenyl) sulfonyl] amino] octahydro-6,10-dioxo-6H-pyridazino [ 1,2-a] [1,2] diazepin-l-yl] carbonyl] amino] -5-oxohexanoate;

(2-Propenyl) (4S) -6-diazo-4 - [[[(1S, 9S) -9 - [[[5- (isoxazol-3-yl) -2-thienyl] sulfonyl] amino] octahydro- 6,10-dioxo-6H-pyridazino [1,2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate;

9 - [(9S) - [[(4-Phenoxyphenyl) amino] carbonyl] amino] -N - [(2S) -4-diazo-1- [4 - [(1,1-dimethyl) ethoxy] phenyl] - 3-oxo-2-butyl] -6 H (1 S) pyridazine [1,2-a] [1,2] diazepine-1-carboxamide;

(2-propenyl) (4S) -6 - [(2,6-dichlorobenzoyl) oxy] -4 - [[[(1S, 9S) -9 - [[(2-furanyl) carbonyl] amino] octahydro-6, 10-dioxo-6H-pyridazino [1,2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate;

(2-Propenyl) (4S) -6 - [(2,6-dichlorobenzoyl) oxy] -4 - [[[(1S, 9S) -9 - [[[4- (trifluoromethyl) phenyl] sulfonyl] amino] octahydro -6,10-dioxo-6H-pyridazino [1,2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate;

(2-propenyl) (4S) -6- [4 - [[2-Oxo-2- (1-pyrrolidinyl) ethyl] piperazin-l-yl] -4 - [[[(1 S, 9S) -9- [ [[4- (trifluoromethyl) phenyl] sulfonyl] amino] octahydro-6,10-dioxo-6H-pyridazino [1,2a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxo hexanoate;

(2-Propenyl) (4S) -6- [4 - [[2-oxo-2- (1-pyrrolidinyl) ethyl] piperazin-1-yl] -4 - [[[(1S, 9S) -9- [ [(2-naphthalenyl) sulfonyl] amino] octahydro-6,10-dioxo-6H-pyridazino [1,2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate;

(2-Propenyl) (4S) -6 - [(2,6-dichlorobenzoyl) oxy] -4 - [[[(1S, 9S) -9 - [[(cyclohexylamino) carbonyl] amino] octahydro-6,10- dioxo-6H-pyridazin [1,2-a] [1,2] diazepin-l-yl] carbonyl] amino] -5-oxohexanoate;

(2-propenyl) (4 S) -6 - [(l-phenyl-lH-tetrazol-5-yl) thio] -4 - [[[(1 S, 9S) -9 - [[[(4-phenoxyphenyl) amino ] carbonyl] amino] octahydro-6,10-dioxo-6H-pyridazino [1,2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate;

(2-propenyl) (4 S) -6 - [(benzothiazol-2-yl) thio] -4 - [[[(1 S, 9S) -9 - [[[(4-phenoxyphenyl) amino] carbonyl] amino] octahydro -6,10-dioxo-, 6H-pyridazino [1,2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate;

(2-Propenyl) (4S) -6 - [[(4-methoxyphenyl) methyl] thio] -4 - [[[(1S, 9S) -9 - [[[(4-phenoxyphenyl) amino] carbonyl] amino] octahydro-6,10-dioxo-6H-pyridazino [1,2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate;

(2-Propenyl) (4S) -6 - [[(4-pyridinyl) carbonyl] oxy] -4 - [[[(1S, 9S) -9 - [[[(4-phenoxyphenyl) amino] carbonyl] amino] octahydro-6,10-dioxo-6 H -pyridazino [1,2- a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate;

(2-Propenyl) (4S) -6 - [(2,6-dichlorobenzoyl) oxy] -4 - [[[(1S, 9S) -9 - [[[(4-phenoxyphenyl) amino] carbonyl] amino] octahydro -6,10-dioxo-6H-pyridazino [1,2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate;

(2-Propenyl) (4S) -6-acetyloxy-4 - [[[(1S, 9S) -9 - [[[(4-phenoxyphenyl) amino] carbonyl] amino] octahydro-6,10-dioxo-6] pyridazino [1,2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate;

(2-propenyl) (4 S) -6- [l-oxo-2- (thien-3-yl) ethoxy] -4 - [[[(1 S, 9S) -9 - [[[(4-phenoxyphenyl) amino carbonyl] amino] octahydro-6,10-dioxo-6H-pyridazino [1,2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate;

(2-propenyl) (4 S) -6 - [(l-phenyl-lH-tetrazol-5-yl) thio] -4 - [[[(1 S, 9S) -9 - [[[[2- (thien 2-yl) ethyl] amino] carbonyl] amino] octahydro-6,10-dioxo-6H-pyridazino [1,2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate;

(2-Propenyl) (4S) -6 - [(2,6-dichlorobenzoyl) oxy] -4 - [[[(1S, 9S) -9 - [[[[2- (thien-2-yl) ethyl]] amino] carbonyl] amino] octahydro-6,10-dioxo-6H-pyridazino [1,2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate;

(2-Propenyl) (4S) -6 - [(2,6-dichlorobenzoyl) oxy] -4 - [[[(1S, 9S) -9 - [(methylsulfonyl) amino] octahydro-6,10-dioxo-6] # pyridazino [1,2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate;

9 - [(9S) [[(4-Phenoxyphenyl) amino] carbonyl] amino] -N - ((2S) -4-diazo-1-phenyl-3-oxo-2-butyl) octahydro-6,10-dioxo -6 N - (1 S) -pyridazino [1,2- a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - [[[2- (Thien-2-yl) ethyl] amino] carbonyl] amino] -N - ((2S) -4-diazo-1-phenyl-3-oxo-2-butyl) octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - [(2-Naphthalenyl) sulfonyl] amino] -N - ((2S) -4-diazo-1-phenyl-3-oxo-2-butyl) octahydro-6,10-dioxo-6H - (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - [[5- (Isoxazol-3-yl) -2-thienyl] sulfonyl] amino] -N - ((2S) -4-diazo-1-phenyl-3-oxo-2-butyl) octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - [[(4-Phenoxyphenyl) amino] carbonyl] amino] -N - ((2S) -4-diazo-3-oxo-2-butyl) octahydro-6,10-dioxo-6H - (1S) pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - [[[3- (Thien-2-yl) ethyl] amino] carbonyl] amino] -N - ((2S) -4-diazo-3-oxo-2-butyl) octahydro-6 10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - (3-Methoxybenzoyl) amino] -N - [(2S) -4 - [(2,6-dichlorobenzoyl) oxy] -1-phenyl-3-oxo-2-butyl] octahydro-6 , 10-dioxo-6Jí- (1 S) pyridazine [1,2-a] [1,2] diazepine-l-carboxamide;

9 - [(9S) - [(2-furanyl) carbonyl] amino] - N - [(2S) -4 - [(2,6-dichlorobenzoyl) oxy] -1-phenyl-3-oxo-2-butyl] octahydro-6,10-dioxo-6H- (1 S) pyridazine [1,2-a] [1,2] diazepine-l-carboxamide;

9 - [(9S) - [(cyclohexylamino) carbonyl] amino] -N - [(2S) -4 - [(2,6-dichlorobenzoyl) oxy] -1-phenyl-3-oxo-2-butyl] octahydro- 6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - [[(4-Phenoxyphenyl) amino] carbonyl] amino] -N - [(2S) -1-phenyl-4 - [(1-phenyl-1H-tetrazol-5-yl) thio] 3-oxo-2-butyl] octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9Sj - [[(4-phenoxyphenyl) amino] carbonyl] amino] -N - [(2S) -1-phenyl-4- [1-oxo-2- (3-thienyl) ethoxy] -3- oxo-2-butyl] -octahydro-6,10-dioxo-6H-1- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

(Methyl) [2-oxo-4-phenyl-3 - [(3S) - [[(4-phenoxyphenyl) amino] carbonyl] amino] octahydro-6,10-dioxo-6H- (1S) -pyridazino [1] 2a] [1,2] diazepin-1-yl] carbonyl] amino] butyl] pentanedionate;

9 - [(9S) - [[(4-Phenoxyphenyl) amino] carbonyl] amino] -N - [(2S) -4-

- [(4-Phenylmethyl) -1-piperidinyl] -1-phenyl-3-oxo-2-butyl] octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1, 2] -diazepine-1-carboxamide;

9 - [(9S) - [[[2- (Thien-2-yl) ethyl] amino] carbonyl] amino] -N-

- [(2S) -1-phenyl-4 - [(1-phenyl-1H-tetrazol-5-yl) thio] -3-oxo-2-butyl] octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9- [(9S) - [[[2- (thien-2-yl) ethyl] amino] carbonyl] amino] -N-

- [(2S) -1-phenyl-4 - [(2-benzothiazolyl) thio] -3-oxo-2-butyl] octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] ] [1,2] diazepine-1-carboxamide;

9- [(9S) - [[[2- (thien-2-yl) ethyl] amino] carbonyl] amino] -N-

- [(2S) -1-phenyl-4 - [(2,6-dichlorobenzoyl) oxy] -3-oxo-2-butyl] octahydro-6,10-dioxo-6H- (1S) -pyridazino [1] 2-a] [1,2] diazepine-1-carboxamide;

9- [(9S) - [[[2- (thien-2-yl) ethyl] amino] carbonyl] amino] -N-

- (2S) -1-phenyl-4- [4- [2- (1-pyrrolidinyl) -2-oxoethyl] -piperazin-1-yl]] - 3-oxo-2-butyl] octahydro-6,10-dioxo -6 H

- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - (methylsulfonyl) amino] -N - [(2S) -1-phenyl-4 - [(2,6-dichlorobenzoyl) oxy] -3-iso-2-butyl] octahydro-6,10 dioxo-6H

- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - [[[4- (trifluoromethyl) phenyl] sulfonyl] amino] -N - [(2S) -1-phenyl-4 - [(1-phenyl-1H-tetrazol-5-yl) thio] 3-oxo-2-butyl] octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - [[[4- (trifluoromethyl) phenyl] sulfonyl] amino] -N - [(2S) -1-phenyl-4- (2-benzothiazolyl) thio] -3-oxo-2-butyl octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - (Methylsulfonyl) amino] -N - [(3S) -5-methyl-1 - [(2,6-dichlorobenzoyl) oxy] -2-oxo-3-hexyl] octahydro-6,10 dioxo-6H

- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - [[[4- (trifluoromethyl) phenyl] sulfonyl] amino]] - N-

- [(3S) -5-Methyl-1 - [(2,6-dichlorobenzoyl) oxy] -2-oxo-3-

-hexyl] octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - [(2-naphthalenyl) sulfonyl] amino] -N - [(3S) -5-methyl-1-

- [(2,6-dichlorobenzoyl) oxy] -2-oxo-3-hexyl] octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1 amide;

9 - [(9S) - (2-Methyl-1-oxopropyl) amino] -N - ((3S) -1-diazo-5-methyl-2-oxo-3-hexyl) octahydro-6,10-dioxo- 6H- (1S) pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - (3-Methoxybenzoyl) amino] -N - ((3S) -1-diazo-5-methyl-2-oxo-3-hexyl) octahydro-6,10-dioxo-6H- (1S) 1-Pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

- [(9S) - [(2-furanyl) carbonyl] amino] -N - ((3S) -1-diazo-5-methyl-2-oxo-3-hexyl) octahydro-6,10-dioxo-6H- (1 S) pyridazine [1,2-a] [1,2] diazepine-l-carboxamide;

9 - [(9S) - [(Cyclohexylamino) carbonyl] amino] -N - ((3Si-1-diazo-5-methyl-2-oxo-3-hexyl) octahydro-6,10-dioxo-6H- (1S) 1-Pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - [[(4-Phenoxyphenyl) amino] carbonyl] amino] -N - ((3S) -1-diazo-5-methyl-2-oxo-3-hexyl) octahydro-6,10- # dioxo-6 - (1 S) pyridazine [1,2-a] [1,2] diazepine-l-carboxamide;

9 - [(9S) - [[[2- (Thien-2-yl) ethyl] amino] carbonyl] amino] - N - ((3S) -1-diazo-5-methyl-2-oxo-3-hexyl) octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - (methylsulfonyl) amino] -N - ((3S) -1-diazo-5-methyl-2-oxo-3-hexyl) octahydro-6,10-dioxo-6H- (1S) - pyridazine [1,2-a] [1,2] diazepine-l-carboxamide;

- [(9S) - [[4- (Trifluoromethyl) phenyl] sulfonyl] amino] -N - ((3S) -1-diazo-5-methyl-2-oxo-3-hexyl) octahydro-6,10-dioxo -6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - [(2-Naphthalenyl) sulfonyl] amino] -N - ((3S) -1-diazo-5-methyl-2-oxo-3-hexyl) octahydro-6,10-dioxo-6H - (1S) pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - (3-methoxybenzoyl) amino] - N - [(3S) -1 - [(benzothiazol-2-yl) thio] -4-methyl-2-oxo-3-pentyl] octahydro-6 10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - [(2-furanyl) carbonyl] amino] -N - [(3S) -1 - [(benzothiazol-2-yl) thio] -4-methyl-2-oxo-3- pentyl] octahydro-6,10-dioxo-6H- (1 S) pyridazine [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - [(Cyclohexylamino) carbonyl] amino] -N - [(3S) -1 - [(benzothiazol-2-yl) thio] -4-methyl-2-oxo-3-pentyl] octahydro -6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - [[(4-Phenoxyphenyl) amino] carbonyl] amino] -N - [(3S) -1 - [(1-phenyl-1H-tetrazol-5-yl) thio] -4-methyl 2-oxo-3-pentyl] octahydro-6,10-dioxo-6H- (1 S) pyridazine [1,2-a] [1,2] -diazepín1-carboxamide;

9 - [(9S) - [[(4-Phenoxyphenyl) amino] carbonyl] amino] -N - [(3S) -1 - [(benzothiazol-2-yl) thio] -4-methyl-2-oxo-3 -pentyl] octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9 S) - [[[2- (thien-2-yl) ethyl] amino] carbonyl] amino] -N-

- [(3S) -1 - [(1-phenyl-1H-tetrazol-5-yl) thio] -4-methyl-2-oxo-3-pentyl] octahydro-6,10-dioxo-6H- (1S) ) pyridazine [1,2-a] [d, 2] diazepine-1-carboxamide;

9 - [(9 S) - [[[2- (thien-2-yl) ethyl] amino] carbonyl] amino] -N-

- [(3S) -1 - [(benzothiazol-2-yl) -thio] -4-methyl-2-oxo-3-

-pentyl] octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - [(Cyclohexylamino) carbonyl] amino] -N - [(2S) -4 - ((2,6-dichlorobenzoyl) oxy] -3-oxo-2-butyl] octahydro-6,10- dioxo-6ŕí- (1 S) pyridazine [1,2-a] [1,2] diazepine-1-carboxamide;

- [(9S) - [(2-furanyl) carbonyl] amino] -N - [(2S) -4 - [(2,6-dichlorobenzoyl) oxy] -3-oxo-2-butyl] octahydro-6,10 -dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - [[(4-Phenoxyphenyl) amino] carbonyl] amino] -N - [(2S) -4I]

- [(benzothiazol-2-yl) thio] -3-oxo-2-butyl] octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine -l-carboxamide;

9 - [(9 S) - [[(4-phenoxyphenyl) amino] carbonyl] amino] -N - [(2 S) -4 - [(2,6-dichlorobenzoyl) oxy] -3-oxo-2-butyl] octahydro -6,10-dioxo-6H- (1 S) pyridazine [1,2-a] [1,2] diazepine-l-carboxamide;

9 - [(9S) - (3-methoxybenzoyl) amino] -N - [(2S) -4 - [(2,6-dichlorobenzoyl) oxy] -3-oxo-2-butyl] octahydro-6,10-dioxo -6 H- (1 S) -pyridazino [1,2- a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - [[[2- (thien-2-yl) ethyl] amino] carbonyl] amino] -N - [(2S) -4 - [(2,6-dichlorobenzoyl) oxy] -3- oxo-2-butyl] octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - [[4- (trifluoromethyl) phenyl] sulfonyl] amino] -N - [(2S) -4 - [(2,6-dichlorobenzoyl) oxy] -3-oxo-2-butyl] octahydro -6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide; and

9 - [(9S) - [(cyclohexylamino) carbonyl] amino] -N - [(2S) -4 - [(benzothiazol-2-yl) thio] -1- [4 - [(1,1-dimethyl) ethoxy] 1-Phenyl] -3-oxo-2-butyl] -6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide.

The products of formula (I) according to the invention can be prepared using the general reaction scheme depicted in FIG. First

Accordingly, the present invention also provides a process for the preparation of the products of formula (I) as defined above, characterized in that the compound of formula (II):

II reacts with a compound of formula III:

RI '-X

III, where X represents a halogen atom and R1 for R1, where the reaction groups are optional, are optionally protected under the protective formula IV above:

the meaning indicated by the functional group of the product formation

IV, wherein R1 'is as defined above, and the product of formula IV is then subjected to a saponization reaction to give a product of formula V:

In which R1 'is as defined above, the product of formula (V) is reacted with the product of formula (VI) as follows:

VI wherein, R 2 and R 7 ¹ the meanings indicated above for R 2, respectively. R 7 and where optional reaction functionalities are optionally protected with protecting groups, to give the product of formula (Ix):

wherein R 1 ', R ^21' and ¹ R 7 'have the meanings indicated above, wherein the product of formula (Ix) can be subjected to a bromination reaction to give the product of formula (VII):

wherein R 1 ', R 2' and R 71 have ¹

as defined above, the product of formula VII is reacted with the product of formula VIII:

N'-L-R4 '

VIII, wherein L has the above-indicated meaning and R 4 ¹ is as indicated above for R 4, and optionally wherein the reactive functional group optionally protected by protective groups, to give a product of formula Iy:

(iy)) wherein R 1 ', R ²¹ ', R 4 'and R 7' have the meanings indicated above, wherein the products of formula (Ix) and (Iy) may be. the products of formula I and, if desired or necessary, can be converted to another product of formula I by undergoing one or more of the following conversion reactions, in any order:

a) esterification reaction of acidic functional group,

b) saponification reaction of an ester function providing an acid function,

c) oxidation reaction of the alkylthio group to the corresponding sulfoxide or sulfone,

d) conversion reaction of a ketone function to an oxime function,

e) reduction reaction of a free or esterified carboxyl function to an alcohol function,

f) conversion reaction of a functional alkoxy group to a hydroxyl function or conversely a conversion reaction of a hydroxyl function to a functional alkoxy group,

g) oxidation reaction of an alcohol function to an aldehyde, acid or ketone function,

(h) conversion reaction of nitrile radical to tetrazolyl;

(i) the elimination reaction of protecting groups which may not carry protected reaction functional groups;

(j) a salification reaction with a mineral or organic acid or base to form the corresponding salt; and

k) resolution reaction of the racemic forms to the resolved products, wherein the products of the formula I obtained in this way exist in all possible racemic, enantiomeric and diastereoisomeric forms.

It should also be noted that, prior to completion of the syntheses carried out using the reactions outlined in the above-described process scheme, the conversion reactions of substituents to other substituents can be carried out and the above-mentioned products and intermediates are used as starting materials.

The above-described process, which is represented by the reaction scheme shown in FIG. 1 is a method used to obtain all products of formula I according to the invention, and in particular the products described in Examples 1 to 3 in the Examples section of this invention

and so on as well as products whose the list states table on the Fig. 4th A method that is schematic shown on Fig. 1 is a consisting of 4 following steps: Step 1 allows you to get a product of of formula VI from amino acids in general formula Vla. Step 2 allows you to get a product of of formula V from

the starting product of formula (II) by reaction with the product of formula (III), i.e. R1-X, the preferred compounds of formula (III) being shown in Table 1 in FIG. Second

Step 3 allows the product of formula (Ix) to be obtained by peptide coupling of the product of formula (VI) obtained in step 1 to the product of formula (V) obtained in step 2.

Step 4 makes it possible to obtain the product of formula (Iy) from the product of formula (Ix) obtained in step 3 by reaction with a compound of formula (VIII), i.e. H-L-R 4 '. 3. This step 4 can be carried out by two different methods, the first being referred to as "KF / DMF (potassium fluoride in dimethylformamide) and the second being referred to as a" supported amine. "

By "supported amine" is meant an amine attached to a polystyrene carrier, which is commercially available such as dimethylaminomethylpolystyrene resin, diethylaminomethyl or other commercially available tertiary amine.

Under advantageous conditions for carrying out the invention, the method according to the invention, which schematically shows FIG. 1 and as defined above, in four steps, may be carried out as follows.

Step 1: Preparation of the Diazotized Amino Acid of Formula VI

This step 1 can be divided into 3 separate steps a1), b1) and c1).

al) Obtaining the product VIb from amino acid Vla

Addition of Fmoc to the N-terminal functional amino group of the starting amino acid: conditions for this reaction are described in, for example, the aforementioned article: "Mueller, A .; Vogt, C .; Sewald, N .; Synthesis (1998), (6), 837-841. In relation to Fmoc-amino acids, it is also possible to mention the document: "Metods Enzymol. (1997), 289 (Solid-phase peptide synthesis), 44-67.

Such reaction conditions can be applied to any so-called " a natural or synthetic amino acid.

b1) Obtaining the diazotized Fmoc product of formula (VIc) from the product of formula (VIb) obtained in step a1) in the two reactions bi) and bii) described below:

bi) Preparation of mixed anhydride

I

Under nitrogen and at -10 ° C, 1.5 equiv. Are gradually added to a suspension of the product of formula VIb obtained in step a1) in dichloromethane (3 ml / mmol). 4-methylmorpholine followed by drops of 1.03 equiv.

and isobutyl chloroformate. The reaction was hold for 1 h at at -10 ° C . quickly filtered. bii) Diazotization The filtrate was cool to -10 ° C, right after the Come nitrogen drop by drop added 2 equiv. solution of diazomethane v

dichloromethane (0.3M). The reaction mixture was gradually brought to room temperature and then allowed to stir for 1 h. The resulting solution was poured into saturated sodium bicarbonate solution (10 mL / mmol). The organic phase is washed with water (10 ml / mmol), dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude product is chromatographed on silica, using, as eluent a mixture of CH ₂ Cl ₂ / AcOEt 95/5.

c1) Obtaining the diazotized amino acid of formula VI from the product of formula VIc obtained in step b1) by removing the protective Fmoc-aminodiazoketones

A solution of the Fmoc-aminodiazoketone product of formula VIc obtained in step b1) in dichloromethane (3.5 mL / mmol) was treated with 2 equiv at 0 ° C and under nitrogen. The reaction is continued for 1.5 h, immediately after which the solution is loaded directly onto a silica column.

The amine was flash-eluted with CH ₂ Cl ₂ / MeOH 90/10. The crude free amine obtained is reacted directly to the reaction of step 3 to bind the peptide.

Step 2: Preparation of a Bicyclic Condensed Compound of Formula V

This step can be divided into two separate steps a2) and b2).

a2) Functionalization of an amine, i.e., obtaining a product of formula IV from a product of formula II by reaction with a product of formula III

The product of formula (II) is 9 (S) -amino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyridazino [1,2-a] [1,2-a] methyl ester ] diazepine-1 (S) -carboxylic acid. In order to obtain the product of the formula IV from the product of the formula II, the product of the formula II is reacted with the product R1-X of the formula III, for example selected from the compounds listed in Table 1 in FIG. 2 and the reaction is carried out as follows.

To a solution of the amine of formula II in dichloromethane (6 mL / mmol) at 0 ° C and under nitrogen was gradually added 1 equiv. acid chloride, sulfonyl chloride, carbamoyl chloride or isocyanate followed by 2 equiv. diisopropylethylamine (DIEA). The reaction mixture was then poured into 1N HCl solution (3 mL / mmol). The organic solution was washed successively with saturated NaCl solution (3 mL / mmol) followed by saturated sodium bicarbonate solution (3 mL / mmol). After drying over anhydrous magnesium sulfate, the solution is concentrated in vacuo. The crude product obtained is used directly in the next step where the saponification is an ester function.

b2) Obtaining a product of formula V from a product of formula IV by saponification of an ester function

The methyl ester obtained in step a) is treated with 2M methanolic lithium oxide solution (2 equiv.). After an overnight reaction at room temperature, the mixture was concentrated to half its volume on a rotary evaporator and an equal volume of water was added. The pH of the solution was adjusted to 1 by addition of concentrated acid. The mixture was extracted with ethyl acetate (2 x 5 mL / mmol). The organic phase is washed with saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solution is concentrated to dryness. If necessary, the product obtained is purified on silica using a 95/5 / 0.5 CH ₂ Cl ₂ / MeOH / AcOH mixture as eluent.

Step 3: Peptide Binding

The coupling of the peptide of formula VI obtained in the product of formula V to give the product of formula V is carried out in step 1 obtained

Ix.

To a solution of the free amine and the acid with nitrogen by reacting the product with step 2 to give the formula V at 0 ° C

TBTU (2- (1H-benzotriazole-1 in CH ₂ Cl ₂ (3.5 mL / mmol) was added sequentially with 1.1 eq. -Yl) -1,1,3,3-tetramethyluronium tetrafluoroborate) and 2 DIEA. Reaction equiv.

The solution is poured into the extraction overnight at room temperature, saturated NaHCO ₃ solution (20 mL / mmol) using ethyl acetate (2 x 10 mL / mmol). The phases obtained are washed with water (20 ml / mmol), followed by KHSO ₃ solution, dried over MgSO ₄ and concentrated under and to an organic saturated vacuum.

Step 4: Obtaining the product of formula I, i.e. Iy from another product of formula I, i.e. the product of formula Ix obtained in step 3 above

This step can be divided into two separate steps a4) and b4).

a4) Bromination of the diazoketone of the product of Formula Ix

The solution of diazoketone in CH ₂ Cl ₂ (6 mL / mmol) was treated at 0 ° C and under nitrogen with a solution of HBr (37%) and acetic acid 30/70 (0.6 mL / mmol). At the end of the reaction, the mixture was poured into saturated NaHCO ₃ solution (50 mL / mmol). The mixture was extracted with ethyl acetate (2 x 30 mL / mmol). The organic solution was washed with water (230 mL / mmol), dried over MgSO ₄ and concentrated to dryness. If necessary, the crude product is purified on silica using 95/5 CH ₂ Cl ₂ / MeOH as eluent.

b4) Substitution by two possible methods b4i) or b4ii) b4i) Method with CF

To a solution of bromoketone in DMF (6 mL / mmol) was added 2 equiv. potassium fluoride (KF) followed by 1.2 equiv. nucleophile of formula VIII, i.e., R4'-LH, which may be in the form of an acid, thiol or hydroxyl, as indicated in Table 2 below in FIG. 3. Stir the reaction overnight with stirring, immediately pour the mixture into saturated NaHCO ₃ (100 mL / mmol) and extract with ethyl acetate (2 x 50 mL / mmol). The combined organic phases are washed with water, dried over MgSO ₄ and concentrated to dryness.

If necessary, chromatography is carried out on silica using CH ₂ Cl ₂ / MeOH as the eluent.

b4ii) A method of using dimethylaminomethylpolystyrene resin

To a solution of bromoketone (1 eq) and nucleophile of formula VIII (1.1 eq) in DMF (15 mL / mmol) were added 2 eq. dimethylaminomethylpolystyrene resin (Fluka, 3 mmol to 4 mmol base / g). The reaction is carried out overnight with gentle stirring. The reaction mixture is filtered and then concentrated in vacuo. If necessary, the obtained products are purified on silica, as eluent, a mixture of methanol and CH ₂ C1 _2nd

An example of this method is the preparation of the products listed in the part of the application entitled "Examples of the invention as examples 1, 2 and 3".

It should be noted that step 1 in Example 1 relates to all products of formula I according to the invention, wherein R 2 represents an amino acid residue derived from leucine and thus all for which the starting amino acid of formula VIa is leucine (Leu); the same method is applicable to other amino acids, especially when the starting amino acid of the formula VIa is GLU-alloc, GLY, ALA, VAL, PHE or TYR (tBu). These amino acids as well as the GLU-alloc compound are commercially available.

In particular, amino acids (AA) in the form of the Fmoc-AA compound of formula VIb are commercially available.

If the starting amino acid of the formula VIa is tyrosine (TYR), then said process comprises one more step, as indicated in Example 3.

Reaction of the product of formula II with the product of formula

III, which results in the product of general formula

IV, in particular in the presence

DIEA, and in a solvent such as CH ₂ C1 _2, or also DMF.

The radical R ¹¹ represents, if necessary, in the product of formula III the meanings indicated above for R 1 in unprotected form, and X represents a halogen atom such as a chlorine atom or a bromine atom.

The product of formula (V) is prepared by subjecting the product of formula (IV) to a saponization reaction under conditions known to those skilled in the art which specifically means the presence of LiOH in an alcohol such as methanol or also ethanol in dioxane or dimethoxyethane and presence of soda or potash.

The product of formula (VIb) is obtained by linking the Fmoc radical to the terminal amino function of the amino acid of formula (VIa); wherein the amino acid of the formula VIa can be any of the above-indicated. a natural or synthetic amino acid.

The product of formula VIb is subjected in two steps to the diazotization reaction outlined above to give the product of formula VIc.

The product of formula VIc thus obtained is subsequently released from the Fmoc radical to give the product of formula VI.

For example, the coupling of the product of formula V to the product of formula VI in order to prepare the product of formula Ix is carried out in TBTU / DIEA and in a solvent such as DMF or also dichloromethane.

The products of formula (Ix) represent products of formula (I) in which the reactive functional groups are optionally protected and wherein R 3 represents the radical CH = N ₂ .

The products of formula I wherein R 3 represents the radical _-CH2-L-R4, are obtained by the product of formula IX firstly brominated under the conditions defined above, and which gives the product of formula VII. In the preparation of the products of formula (Iy) above, the products of formula (VII) are subsequently exposed to the products of formula (VIII) HL-R4 '; this reaction can be advantageously carried out using the two different reaction methods outlined above.

Depending on the meanings of the substituents R1, R2 ', R4' and R7 ', whether the products of formula Ix and Iy form or do not form the products of formula I and whether they can provide products of formula I or can be converted to other products of formula I are subjected to at least one of the above reactions a) to k).

The various reaction functional groups bearing the particular compounds involved in the above reactions may be protected if necessary. This applies, for example, to a hydroxyl radical, an acyl radical, a free carboxy radical or else an amino radical and a monoalkylamino radical which can be protected using suitable protecting groups.

It is worth noting the following non-exhaustive list of examples of protecting functional groups:

hydroxyl groups can be protected, for example, by alkyl radicals, such as the tert-butyl radical, the trimethylsilyl radical, the tert-butyldimethylsilyl radical, the methoxymethyl radical, the tetrahydropyranyl radical, the benzyl radical or the acetyl radical;

amino groups can be protected, for example, with an acetyl radical, a trityl radical, a benzyl radical, a tert-butoxycarbonyl radical, a benzyloxycarbonyl radical, a phthalimidoradical or other radicals known in the peptide art;

acyl groups such as a formyl group may be, for example, a protector in the form of cyclic or non-cyclic ketals or thioketals, such as dimethyl ketal or diethyl ketal or ethylenedioxyketal or diethylthioketal or ethylenedithioketal;

- the acid functionality of the products described above is possible, if desired, with a primary or secondary amine, for example in methylene chloride, in the presence of 1-ethyl-3- (dimethylaminopropyl) carbodiimide hydrochloride at room temperature:

acid functional groups can be protected, for example, in the form of esters formed with readily cleavable esters, for example with benzyl or tert-butyl esters or esters known in the art of peptide chemistry.

The reactions to which the products of the above formulas Ix and Iy can be subjected, if desired or necessary, can be carried out, for example, as described below.

a) The products described above can, if desired, be subjected to esterification reactions on possible carboxyl functional groups which can be carried out by conventional methods known in the art.

b) Optional conversions of ester functional groups to acid functional groups of the above-described products can, if desired, be carried out under conventional conditions known to those skilled in the art, preferably using acidic or alkaline hydrolysis, for example by soda or potash, in an alcoholic medium. , for example in methanol, or also with hydrochloric or sulfuric acid.

The products are correspondingly customary, for example, peracetic by the action it is responsible for

c) Optional alkylthio groups as described above can be converted, if desired, to sulfoxide or sulfone functionalities known to those skilled in the art by treatment with peracids such as methachloroperbenzoic acid or acid, or also ozone, oxone, sodium periodate in a solvent such as methylene chloride or dioxane at room temperature.

The recovery of the sulfoxide functionality can be promoted by an equimolar mixture of an alkylthio-containing product and a reagent such as preferably a peracid.

The recovery of the sulfone functionality can be promoted by mixing an alkylthio-containing product with an excess of a reagent such as preferably a peracid.

d) Conversion reaction of ketone functions to oxime functions may be accomplished using conventional techniques known in the art, preferably in particular by reaction in the presence of an optionally O-substituted hydroxylamine in an alcohol such as ethanol at room temperature or with heating.

e) If desired, any free or esterified functional carboxy groups of the products described above are reduced to which those skilled in the esterified functional carboxy group are reduced to the alcohol functional needs to which alcohol functional groups are known to those skilled in the art by methods known in the art; where possible in the case of a group by methods, and preferably by treatment with lithium aluminum hydride in a solvent such as, for example, tetrahydrofuran or else dioxane or ethyl ether.

The optional free carboxy functionalities of the products described above can, if desired, be reduced to alcohol functional groups, preferably by treatment with boron hydride.

f) Optional functional alkoxy groups, for example methoxy groups, of the above-described products can, if desired, be converted into hydroxyl functionalities under conventional conditions known in the art, for example by treatment with boron tribromide in a solvent such as methylene chloride or pyridine hydrobromide. or hydrochloride, or else by treatment with hydrobromic acid or hydrochloric acid in water or trifluoroacetic acid under reflux.

g) Optional alcohol functional groups of the products described above can, if desired, be converted to aldehyde or acid functional groups by oxidation under conventional conditions known to those skilled in the art, for example by treatment with manganese oxide leading to the formation of aldehydes or Jones reaction. agents which result in an excess of acid.

h) Optional nitrile functional groups of the above-described products can, if desired, be converted to tetrazolyl groups under conventional conditions known to those skilled in the art, for example by cycloaddition of a metal azide such as sodium azide, or a trialkyltin azide to the nitrile functionality as outlined in with the following reference: J. Organometallic Chemistry., 33, 337 (1971) KOZIMA S. et al. It should be noted that the conversion reactions of carbamate to urea, and in particular sulfonylcarbamate to sulfonylurea, can be carried out, for example, under reflux at a solvent such as toluene in the presence of a suitable amine.

It is to be understood that the above-described reactions may be carried out in the manner indicated or, if appropriate, using other methods known in the art.

i) Deprotection, such as those outlined above, may be carried out under conventional conditions known in the art, preferably by acid hydrolysis using an acid such as hydrochloric acid, benzenesulfonic acid or paratoluenesulfonic acid, formic acid or trifluoroacetic acid. or also by catalytic hydrogenation.

The phthalimido group can be eliminated with hydrazine.

A list of the various protecting groups that can be used can be found, for example, in BF 2 499 995.

j) The products described above may, if desired, be subjected to salification reactions, for example with a mineral or organic acid, or a mineral or organic base, using conventional methods known in the art. For example, the salification reaction may be carried out in the presence of hydrochloric acid or else in the presence of tartaric acid, citric acid or methanesulfonic acid, in an alcohol such as ethanol or methanol.

k) Optically optically active forms of the products described above can be prepared by resolution of racemic mixtures using conventional methods known in the art.

Illustrative examples of the above reactions are part of the processes for preparing the products of the invention described below.

The products of formula (I) as defined above and also

their addition pharmacological salts with acids features. show usable Products according to the invention may to be endowed

by the ability to inhibit one or more of the metabolic enzymes defined above, in particular kinases or proteinases. Accordingly, certain products of the formula (I) of the invention as defined above may in particular have the ability to inhibit certain protein kinases or also proteinases.

Several kinase inhibitors have been described and include, for example, butyrolactone, flavopiridol, and 2- (2-hydroxyethylamino) -6-benzylamino-9-methylpurine, also referred to as olomoucine.

Similarly, several proteinase inhibitors have been described, particularly in "Journal of Medicinal Chemistry, Vol. 43 no. 3 (D. Leung, G. Abbenante, and D. P. Fairlie). Thrombin inhibitors include, but are not limited to, argatroban, napsagatran, inogatran, efegatran, CVS1123, as well as melagatran.

DX-9065a, 60-60828 and ZK 807191, or FX 2212, may also be mentioned as effective inhibitors of factor Xa.

As elastase inhibitors, mention may be made of ICI-200800, MR 889, L-658.758, MDL 101,146, ZD 8321 or various heterocyclic derivatives such as penicillins, penems, βlactams, isocoumarins, benzisothiazolones and alkylazetidinones.

APC-366 may be mentioned as a tryptase inhibitor; sepimostat mesylate (FUT-187) or naphamostat mesylate (FUT 175) may be mentioned as 'complement convertase inhibitors'.

As an effective cathepsin K inhibitor, mention may be made of CbzLeu-Leu-Leu-CHO, 1,3-bis (acylamino) -2-propanone or 1,5-diacylcarbohydrazide derivatives; caspase inhibitors include 5-aminopyrimidine-6-one derivatives, phenylketomethyl ether or aminomethylene ketone derivatives; as calpain inhibitors, mention may be made of peptide aldehydes such as Cbz-Val-Phe-CHO and calpeptin.

The level, regulation and activity of a number of protein kinases or proteinases play a role in serious human pathologies. In particular, the activity of protein kinases or proteinases may be associated with receptors having transmembrane domains or intracellular proteins.

Certain kinases or proteinases may play a role in initiating, developing and completing cell cycle event sequences, and inhibitory molecules of these kinases or proteinases are therefore capable of reducing unwanted cell proliferation, such as can be seen in cancer, psoriasis, mold growth, parasites ( animals, microorganisms from the group designated as protist): such inhibitory molecules of these kinases or proteinases are therefore also capable of playing a role in the regulation of neurodegenerative diseases such as Alzheimer's disease. Thus, certain products of the formula I according to the invention may be provided with antimitotic properties.

In particular, certain products of formula I as defined above may have as kinase or proteinase inhibitors the ability to inhibit bone resorption mediated by osteoclasts and can therefore be used in the therapeutic or prophylactic treatment of diseases caused by, at least partially, unwanted increases in bone resorption, e.g. .

Thus, for example, certain products of Formula I of the invention may inhibit the adhesion of osteoclast to the bone surface and may thus inhibit bone resorption by osteoclasts.

Bone diseases whose treatment or prevention requires the use of compounds of formula I or prodrugs thereof include, in particular, osteoporosis, hypercalcemia, osteopenia, for example caused by bone metastases, dental diseases such as periodontitis, hyperparathyroidism, periarticular erosion in rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis and immobilization-induced osteopenia. The compounds of formula I may also be used to alleviate, prevent or treat bone diseases caused by glucocorticoid therapy, steroid or corticosteroid related therapies, or male or female hormone deficiency.

All these diseases are characterized by bone

Also the loss caused by the loss of the balance between bone formation and bone destruction and which can be favorably influenced by inhibition of bone resorption by osteoclasts.

Certain products of the formula I according to the invention may, in addition to their specific ability to inhibit kinases or proteinases, exhibit useful cell-level capabilities, for example antiproliferative properties, and in particular an effect on apoptosis.

It is known from the literature, for example in WO 97/20842, that there is a certain relationship between the cell cycle and apoptosis. Some of the pathways leading to apoptosis are dependent on kinases or proteinases.

The products of the invention are particularly useful in the treatment of cancer.

Thus, the products of the invention may also enhance the therapeutic effects of the currently used antitumor agents. The products of the formula I according to the invention thus have antimitotic and antineurodegenerative properties.

Certain products of the invention may act as inhibitors of vasoconstrictive and hypertensive effects and may therefore elicit an anti-ischemic effect or may also combat stimulatory effects at the level of certain cell types, particularly smooth muscle cells, fibroblasts, neurons and bone cells.

Thus, the products of the invention can be used in the treatment of diseases such as proliferative diseases, cancer, stenosis recurrence, inflammation; allergies, cardiovascular diseases or certain infectious diseases.

The products of the invention may also be used in the treatment of certain gastrointestinal and gynecological diseases, and in particular for uterine release.

Accordingly, the products of formula (I) of the present invention may exhibit useful pharmacological properties justifying their use in therapeutic agents.

The invention therefore relates to the products of formula I as defined above, which exist in all possible racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts of these products of formula I with pharmaceutically acceptable mineral and organic acids or with mineral and organic bases as medicaments.

More preferably, the invention relates to products of the formulas Ia or Ib as defined above, which exist in all possible racemic, enantiomeric and diastereoisomeric forms, as well as addition salts of these products of formula Ia or Ib with pharmaceutically acceptable mineral and organic acids or with mineral and organic bases, as medicines.

The invention, in particular as medicaments, is described below in the Examples.

products and in particular products of the formula I as defined above, which correspond to the following formulas:

3- [9 (S) -benzoylamino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyridazino [1,2-a] [1,2] Diazepine-1 (S) -carboxamide] -5-methyl-1-benzoyloxyhexan-2-one;

3- [9 (S) - (2-furanoyl) amino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyridazino [1,2-a] [ 1,2] diazepine-1 (S) -carboxamide] -5-methyl-1- (2,6-dichlorobenzoyloxyhexan-2-one);

3 (S) - [9 (S) - (2-furanoyl) amino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyridazino [1, 2-a] [1,2] diazepine-1 (S) -carboxamide] -4- (4-hydroxyphenyl) -1- (2,6-dichlorobenzoyloxy) butan-2-one;

as well as the products of formula I as defined above, which correspond to the following formulas:

(2-Propenyl) (4S) -6-diazo-4 - [[[(1S, 9S) -9 - [(2-methyl-1-oxopropyl) amino] octahydro-6,10-dioxo-6H- pyridazine [1,2-a] [1,2] diazepin-l-yl] carbonyl] amino] -5-oxohexanoate;

(2-Propenyl) (4S) -6-diazo-4 - [[[(1S, 9S) -9 - [(3-methoxybenzoyl) amino] octahydro-6,10-dioxo-6 H -pyridazino [1, 2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate;

(2-Propenyl) (4S) -6-diazo-4 - [[[(1S, 9S) -9 - [[(2-furanyl) carbonyl] amino] octahydro-6,10-dioxo-6H-pyridazino [1] 2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate;

(2-Propenyl) (4S) -6-diazo-4 - [[[(1S, 9S) -9 - [[(cyclohexylamino) carbonyl] amino] octahydro-6,10-dioxo-6H-pyridazino [1,2a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxo-hexanoate;

(2-Propenyl) (4S) -6-diazo-4 - [[[(1S, 9S) -9 - [[[(4-phenoxyphenyl) amino] carbonyl] amino] octahydro-6,10-dioxo-6H-pyridazino [1] 2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate;

(2-Propenyl) (4S) -6-diazo-4 - [[[(1S, 9S) -9 - [[[[2- (β-2-yl) ethyl] amino] carbonyl] amino] octahydro- 6,10-dioxo-6H-pyridazino [1,2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate;

(2-Propenyl) (4S) -6-diazo-4 - [[[(1S, 9S) -9 - [(methylsulfonyl) amino] octahydro-β, 10-dioxo-6 H -pyridazino [1,2- a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate;

(2-Propenyl) (4S) -6-diazo-4 - [[[(1S, 9S) -9 - [[[4- (trifluoromethyl) phenyl] sulfonyl] amino] octahydro-6,10-dioxo-6H- pyridazino [1,2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate;

(2-Propenyl) (4S) -6-diazo-4 - [[[(1S, 9S) -9 - [[(2-naphthalenyl) sulfonyl] amino] octahydro-6,10-dioxo-6H-pyridazino [1] 2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate;

(2-Propenyl) (4S) -6-diazo-4 - [[[(1S, 9S) -9 - [[[5- (isoxazol-3-yl) -2-thienyl] sulfonyl] amino] octahydro- 6,10-dioxo-6H-pyridazino [1,2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate;

9 - [(9S) - [[(4-Phenoxyphenyl) amino] carbonyl] amino] -N - [(2S) -4-diazo-1- [4 - [(1,1-dimethyl) ethoxy] phenyl] - 3-oxo-2-butyl] -6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

(2-propenyl) (4S) -6 - [(2,6-dichlorobenzoyl) oxy] -4 - [[[(1S, 9S) -9 - [[(2-furanyl) carbonyl] amino] octahydro-β, 10-dioxo-6H-pyridazino [1,2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate;

(2-Propenyl) (4S) -6 - [(2,6-dichlorobenzoyl) oxy] -4 - [[[(1S, 9S) -9 - [[[4- (trifluoromethyl) phenyl] sulfonyl] amino] octahydro54

-6,10-dioxo-6 / s-pyridazine [1,2-a] [1,2] diazepin-l-yl] carbonyl] amino] -5-oxohexanoate;

(2-Propenyl) (4S) -6- [4 - [[2-oxo-2- (1-pyrrolidinyl) ethyl] piperazin-1-yl] -4 - [[[(1S, 9S) -9-] - [[[4- (trifluoromethyl) phenyl] sulfonyl] amino] octahydro-6,10-dioxo-6H-pyridazino [1,2a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxo hexanoate;

(2-propenyl) (4S) -6- [4 - [[2-Oxo-2- (1-pyrrolidinyl) ethyl] piperazin-l-yl] -4 - [[[(lS, 9S) -9- [ [(2-naphthalenyl) sulfonyl] amino] octahydro-6,10-dioxo-6 H -pyridazino [1,2- a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate;

(2-Propenyl) (4S) -6 - [(2,6-dichlorobenzoyl) oxy] -4 - [[[(1S, 9S) -9 - [[(cyclohexylamino) carbonyl] amino] octahydro-6,10- dioxo-6H-pyridazino [1,2-a] [1,2] diazepin-1'-yl] carbonyl] amino] -5-oxohexanoate;

(2-propenyl) (4 S) -6 - [(l-phenyl-lH-tetrazol-5-yl) thio] -4-

- [[[(1S, 9S) -9 - [[[(4-phenoxyphenyl) amino] carbonyl] amino] octahydro-6,10-dioxo-6H-pyridazino [1,2-a] [1,2] diazepine -1-

yl] carbonyl] amino] -5-oxohexanoate;

(2-Propenyl) (4S) -6 - [(benzothiazol-2-yl) thio] -4 - [[[(1S, 9S) -9 - [[[(4-phenoxyphenyl) amino] carbonyl] amino] octahydro-6,10-dioxo-6H-pyridazin [1,2-a] [1,2] diazepin-l-yl] carbonyl] amino] -5-oxohexanoate;

(2-propenyl) (4 S) -6 - [[(4-methoxyphenyl) methyl] thio] -4 - [[[(13,9S) -9 - [[[(4-phenoxyphenyl) amino] carbonyl] amino] octahydro-6,10-dioxo-6H-pyridazino [1,2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate;

(2-Propenyl) (4S) -6 - [[(4-pyridinyl) carbonyl] oxy] -4-

- [[[(1S, 9S) -9 - [[[(4-phenoxyphenyl) amino] carbonyl] amino] octahydro-6,10-dioxo-6H-pyridazino [1,2-a] [1,2] ] diazepin-l-yl] carbonyl] amino] -5-oxohexanoate;

(2-Propenyl) (4S) -6 - [(2,6-dichlorobenzoyl) oxy] -4 - [[[(1S, 9S) -9 - [[[(4-phenoxyphenyl) amino] carbonyl] amino] octahydro -6,10-dioxo-6H-pyridazin [1,2-a] [1,2] diazepin-l-yl] carbonyl] amino] -5-oxohexanoate;

(2-Propenyl) (4S) -6-acetyloxy-4 - [[[(1S, 9S) -9 - [[[(4-phenoxyphenyl) amino] carbonyl] amino] octahydro-6,10-dioxo-6 # pyridazine [1,2-a] [1,2] diazepin-l-yl] carbonyl] amino] -5-oxohexanoate;

(2-propenyl) (4 S) -6- [l-oxo-2- (thien-3-yl) -ethoxy] -4-

- [[[(1S, 9S) -9 - [[[(4-phenoxyphenyl) amino] carbonyl] amino] octahydro-6,10-dioxo-6H-pyridazino [1,2-a] [1,2] diazepine -1-yl] carbonyl] amino] -5-oxohexanoate;

(2-propenyl) (4 S) -6 - [(l-phenyl-lH-tetrazol-5-yl) thio] -4-

- [[[(1S, 9S) -9 - [[[[2- (thien-2-yl) ethyl] amino] carbonyl] amino] octahydro-6,10-dioxo-6H-pyridazino [1,2- a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate;

(2-Propenyl) (4S) -6 - [(2,6-dichlorobenzoyl) oxy] -4 - [[[(1S, 9S) -9 - [[[[2- (thien-2-yl) ethyl]] amino] carbonyl] amino] octahydro-6,10-dioxo-6H-pyridazino [1,2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate;

(2-Propenyl) (4S) -6 - [(2,6-dichlorobenzoyl) oxy] -4 - [[[(1S, 9S) -9 - [(methylsulfonyl) amino] octahydro-6,10-dioxo- ôHpyridazíno [1,2-a] [1,2] diazepin-l-yl] carbonyl] amino] -5-oxohexanoate;

9 - [(93) [[(4-Phenoxyphenyl) amino] carbonyl] amino] - N - ((2 S) -4-diazo-1-phenyl-3-oxo-2-butyl) octahydro-6,10-dioxo -6 H- (13) -pyridazino [1,2- a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - [[[2- (Thien-2-yl) ethyl] amino] carbonyl] amino] -N-

- ((2S) -4-Diazo-1-phenyl-3-oxo-2-butyl) octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine -l-carboxamide;

9 - [(93) - [(2-Naphthalenyl) sulfonyl] amino] -N - ((2S) -4-diazo-1-phenyl-3-oxo-2-butyl) octahydro-6,10-dioxo-6H - (13) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

- [(9S) - [[5- (Isoxazol-3-yl) -2-thienyl] sulfonyl] amino] -N-

- ((2S) -4-Diazo-1-phenyl-3-oxo-2-butyl) octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine -l-carboxamide;

9 - [(9S) - [[(4-Phenoxyphenyl) amino] carbonyl] amino] -N - ((2S) -4-diazo-3-oxo-2-butyl) octahydro-6,10-dioxo-6H- (1 S) pyridazine [1,2-a] [1,2] diazepine-l-carboxamide;

9 - [(9S) - [[[3- (Thien-2-yl) ethyl] amino] carbonyl] amino] -N - ((2S) -4-diazo-3-oxo-2-butyl) octahydro-6 10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - (3-Methoxybenzoyl) amino] -N - [(2S) -4 - [(2,6-dichlorobenzoyl) oxy] -1-phenyl-3-oxo-2-butyl] octahydro-6 , 10-dioxo-6Jí-

- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - [(2-furanyl) carbonyl] amino] -N - [(2S) -4 - [(2,6-dichlorobenzoyl) oxy] -1-phenyl-3-oxo-2-butyl ] octahydro-6,10-dioxo-6H- (13) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

- [(9S) - [(cyclohexylamino) carbonyl] amino] - N - [(2S) -4 - [(2,6-dichlorobenzoyl) oxy] -1-phenyl-3-oxo-2-butyl] octahydro-6 10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - [[(4-Phenoxyphenyl) amino] carbonyl] amino] -N - [(2S) -1-phenyl-4 - [(1-phenyl-1H-tetrazol-5-yl) thio] 3-oxo-2-butyl] octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - [[(4-Phenoxyphenyl) amino] carbonyl] amino] -N - [(2S) -1-phenyl-4- [1-oxo-2- (3-thienyl) ethoxy] -3 -oxo-2-butyl] -octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

(Methyl) [2-oxo-4-phenyl-3 - [(3 S) - [[(4-phenoxyphenyl) amino] carbonyl] amino] octahydro-6,10-dioxo-6H- (1 S) -pyridazíno- [1 , 2a] [1,2] diazepin-l-yl] carbonyl] amino] butyl] -pentandionát;

9 - [(9S) - [[(4-Phenoxyphenyl) amino] carbonyl] amino] -N - [(2S) -4 - [(4-phenylmethyl) -1-piperidinyl] -1-phenyl-3-oxo -2-butyl] octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9- [OS] - [[[2- (thien-2-yl) ethyl] amino] carbonyl] amino] -N - [(2S) -1-phenyl-4 - [(1-phenyl-1H-tetrazole- 5-yl) thio] -3-oxo-2-butyl] octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9- [OS] - [[[2- (thien-2-yl) ethyl] amino] carbonyl] amino] -N - [(2S) -1-phenyl-4 - [(2-benzothiazolyl) thio] -3 -oxo-2-butyl] octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9 S) - [[[2- (thien-2-yl) ethyl] amino] carbonyl] amino] -N - [(2S) -l-phenyl-4 - [(2,6-dichlorobenzoyl) oxy 3-oxo-2-butyl] octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - [[[2- (Thien-2-yl) ethyl] amino] carbonyl] amino] -N - [(2S) -1-phenyl-4- [4- [2- (1- pyrrolidinyl) -2-oxoethyl] -piperazin-1-yl] -3-oxo-2-butyl] octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] ] diazepine-l-carboxamide;

9 - [(9S) - (Methylsulfonyl) amino] -N - [(2S) -1-phenyl-4 - [(2,6-dichlorobenzoyl) oxy] -3-oxo-2-butyl] octahydro-6,10 -dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9 S) - [[[4- (trifluoromethyl) phenyl] sulfonyl] amino] -N - [(2S) -l-phenyl-4 - [(l-phenyl-lH-tetrazol-5-yl) thio 3-oxo-2-butyl] octahydro-6,10-dioxo-6,7- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9 S) - [[[4- (trifluoromethyl) phenyl] sulfonyl] amino] -N - [(2S) -l-phenyl-4- (2-benzothiazolyl) thio] -3-oxo-2-butyl Octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - (Methylsulfonyl) amino] -N - [(3S) -5-methyl-1 - [(2,6-dichlorobenzoyl) oxy] -2-oxo-3-hexyl] octahydro-. 6,10-dioxo-6ŕí- (1 S) pyridazine [1,2-a] [1,2] diazepine-l-carboxamide;

«

9 - [(9 S) - [[[4- (trifluoromethyl) phenyl] sulfonyl] amino]] - N

- [(3S) -5-Methyl-1 - [(2,6-dichlorobenzoyl) oxy] -2-oxo-3-

-hexyl] octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - [(2-Naphthalenyl) sulfonyl] amino] -N - [(3S) -5-methyl-1-

- [(2,6-dichlorobenzoyl) oxy] -2-oxo-3-hexyl] octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine -l-carboxamide;

9 - [(9S) - (2-Methyl-1-oxopropyl) amino] -N - ((3S) -1-diazo-5-methyl-2-oxo-3-hexyl) octahydro-6,10-dioxo- N 6 - (1 S) pyridazino [1,2- a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - (3-Methoxybenzoyl) amino] -N - ((3S) -1-diazo-5-methyl-2-oxo-3-hexyl) octahydro-6,10-dioxo-6H- (1S) 1-Pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - [(2-furanyl) carbonyl] amino] -N - ((3S) -1-diazo-5-methyl-2-oxo-3-hexyl) octahydro-6,10-dioxo-6 N - (1 S) pyridazino [1,2- a] [1,2] diazepine-1-carboxamide;

9 - [(9 S) - [(cyclohexylamino) carbonyl] amino] -N - ((3S) -1-diazo-5-methyl-2-oxo-3-hexyl) octahydro-6,10-dioxo-6H- ( 1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - [[(4-Phenoxyphenyl) amino] carbonyl] amino] -N - ((3S) -1-diazo-5-methyl-2-oxo-3-hexyl) octahydro-6,10- dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - [[[2- (Thien-2-yl) ethyl] amino] carbonyl] amino] -N - ((3S) -1-diazo-5-methyl-2-oxo-3-hexyl) octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - (Methylsulfonyl) amino] -N - ((3S) -1-diazo-5-methyl-2-oxo-3-hexyl) octahydro-6,10-dioxo-6H- (1S) - pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - [[4- (Trifluoromethyl) phenyl] sulfonyl] amino] -N - ((3S) -1-diaza-5-methyl-2-oxo-3-hexyl) octahydro-6,10- dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - [(2-Naphthalenyl) sulfonyl] amino] -N - ((3S) -1-diazo-5-methyl-2-oxo-3-hexyl) octahydro-6,10-dioxo-6H - (1S) pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - (3-Methoxybenzoyl) amino] -N - [(3S) -1 - [(benzothiazol-2-yl) thio] -4-methyl-2-oxo-3-pentyl] octahydro-6 10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - [(2-furanyl) carbonyl] amino] -N - [(3 S) -1 - [(benzothiazol-2-yl) thio] -4-methyl-2-oxo-3-pentyl] octahydro-6,10-dioxo-6Z- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - [(Cyclohexylamino) carbonyl] amino] -N - [(3S) -1 - [(benzothiazol-2-yl) thio] -4-methyl-2-oxo-3-pentyl] octahydro- 6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - [[(4-Phenoxyphenyl) amino] carbonyl] amino] -N - [(3S) -1 - [(1-phenyl-1H-tetrazol-5-yl) thio] -4 -methyl-2-oxo-3-pentyl] octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-carboxamide;

9 - [(93) - [[(4-Phenoxyphenyl) amino] carbonyl] amino] - N - [(33) -1 - [(benzothiazol-2-yl) thio] -4-methyl-2-oxo-3 -pentyl] octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - [[[2- (Shadow-2-yl) ethyl] amino] carbonyl] amino] -N - [(3 S) -1 - [(1-phenyl-1 H -tetrazol-5-yl)] - 1-thio] -4-methyl-2-oxo-3-pentyl] octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide;

9 - [(9S) - [[[2- (thien-2-yl) ethyl] amino] carbonyl] amino] -N - [(3 S) -1 - [(benzothiazol-2-yl) thio] -4- methyl 2-oxo-3-pentyl] octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] - [1,2] diazepine-1-carboxamide;

9 - [(9S) - [(cyclohexylamino) carbonyl] amino] -N - [(2S) -4 - [(2,6-dichlorobenzoyl) oxy] -3-oxo-2-butyl] octahydro-6,10- dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide; and

- [(9S) - [(2-furanyl) carbonyl] amino] -N - [(2S) -4 - [(2,6-dichlorobenzoyl) oxy] -3-oxo-2-butyl] octahydro-6,10 dioxo-6H- (1 S) pyridazine [1,2-a] [1,2] diazepine-1-carboxamide.

Accordingly, the products of the formula I according to the invention can be used in particular in the form of medicaments intended to inhibit the undesired pathology-inducing mechanisms due to the action of one or more proteinases or kinases: the medicament can therefore be administered to a patient whose treatment requires inhibiting the proteinase or kinase inducing this inhibitory effect.

The medicaments of the present invention can therefore be used in the treatment and prevention of cardiovascular diseases associated with vasomotion or volemia alteration, myocardial infarction and its consequences, heart failure, renal insufficiency, angina pectoris, hyperaldosteronism, arterial hypertension and its consequence and in particular in the treatment and prevention of complications of cardiac and vascular hypertrophy as well as the development of fibrosis at the target organ level, in the treatment and prevention of hypertension, metabolic diseases, endocrinological and neurological diseases, endotoxic shocks, "subarachnoid haemorrhage, arrhythmias" asthma, acute renal injury, pre-eclampsia and diabetes.

Thus, the medicaments of the invention can be used in the treatment of vascular spasms, in the treatment of cerebral hemorrhage, in the treatment of coronary spasms and peripheral vascular spasms. In particular, they can be used in the treatment of blood accumulation - cardiac insufficiency, in the prevention of postangioplastic recurrence of stenosis, in the prevention of cardiac and vascular fibrosis, in the treatment of atherosclerosis and certain forms of hypertension such as pulmonary hypertension, as well as asthma. These medicaments of the invention can also be used in the treatment of glaucoma and various types of visceral spasms, as well as neuronal preservatives, or also in the prevention of post-angioplastic recurrence of stenosis.

The medicaments of the invention can be used mainly because of their antihypertrophic and antifibrotic effects at the heart and vascular levels. In particular, they can be used in the treatment or prevention of cardiovascular diseases associated with diabetes.

The medicaments of the invention can also be used in the treatment of osteoporosis and as neuronal protectors.

The medicaments of the invention can also be used in the treatment of memory and cognitive impairment as well as in the treatment of anxiety.

The medicaments of the invention can also be used as antimitotic agents in cancer chemotherapy or also in the treatment of psoriasis, parasitosis, for example parasitosis caused by microorganisms of the " protista " group, or also in the treatment of Alzheimer's disease or neuronal apoptosis.

A particularly important object of the invention are pharmaceutical compositions comprising as active ingredient at least one of the medicaments defined above.

A particularly important object of the invention is the pharmaceutical compositions as defined above, characterized in that they are useful as medicaments as defined above.

The above-described pharmaceutical compositions of the invention may be administered by the buccal, parenteral, or topical routes by topical application to the skin or mucous membranes, or by injection, either intravenously or intramuscularly.

These compositions may be solid or liquid and may be in all pharmaceutical forms commonly used in human medicine, such as plain or sugar-coated tablets, pills, gelatin capsules, drops, granules, injectables, ointments, creams or gels. which are prepared by known methods. As a rule, the active ingredient may be incorporated into pharmaceutical preparations together with excipients such as talc, acacia, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, animal or vegetable fatty substances, paraffin derivatives, glycols, various wetting agents. , dispersing or emulsifying agents and preservatives.

The usual dose, which may vary somewhat in the particular cases of the products according to the invention and which is to be administered to a patient suffering from one of the aforementioned diseases, may range, for example, from 0.05 g / day to 5 g / day or preferably from 0, 1 g / day to 2 g / day.

Advantageously, the invention relates to pharmaceutical compositions as defined above, characterized in that they are used as antimitotic drugs, in particular in the chemotherapy of cancer or also in the treatment of psoriasis, parasitosis, for example caused by fungi or animals of the group designated "protista" or Alzheimer's.

More preferably, the invention also relates to pharmaceutical compositions as defined above, characterized in that they are used as antineurodegenerative drugs, in particular neuronal anti-apoptotic drugs.

In particular, the invention relates to the general formula I of the defined compositions requiring a metabolic enzyme.

intended for treatment by inhibiting the use of the above products for the manufacture of pharmaceuticals or preventing the diseases of at least one as defined above

Accordingly, the present invention provides, in particular, the use of the products of formula I as defined above for the manufacture of pharmaceutical compositions for the treatment of diseases which are caused by anomalies at the level of regulation or activity of a number of metabolic enzymes. These anomalies play a role in the human pathologies targeted by the present invention.

The invention thus relates in particular to the use of the products of the formula I according to the invention as proteinase or kinase inhibitors. Thus, the invention relates to the inhibition of some of said proteinase or kinase enzymes and claims the use of the products of the invention as inhibitors when inhibition of such a proteinase or kinase is indicated.

Accordingly, the invention relates in particular to the use of the products of the formula I as defined above or of pharmaceutically acceptable salts of the products of the formula I for the manufacture of medicaments for preventing or treating diseases in which metabolic enzymes such as proteinases or kinases are involved.

More preferably, the invention relates to the use of the products of formula I as defined above or of pharmaceutically acceptable salts of the products of formula I, characterized in that the diseases to be prevented or treated are selected from the following group of diseases including cardiovascular diseases, cancer, diseases of the central nervous system, inflammatory diseases, infectious diseases or also bone diseases.

In particular, the invention relates to the use of the products of formula I as defined above or of pharmaceutically acceptable salts of said products of formula I, characterized in that the diseases are prevented or to be treated, which are central nervous system diseases or bone diseases, in particular osteoporosis. .

Accordingly, the present invention provides the use of the products of formula (I) as defined above or pharmaceutically acceptable salts of the products of formula (I) for the manufacture of a medicament for the prevention or treatment of diseases of bone metabolism.

Accordingly, the present invention provides, in particular, the use of the products of formula I as defined above for the manufacture of pharmaceutical compositions for the treatment of arterial hypertension, cardiac insufficiency, postangioplastic recurrence of stenosis, vascular spasms, sequelae of cerebral bleeding and renal insufficiency.

Accordingly, the invention relates in particular to the use of the products of the formula I as defined above for the preparation of pharmaceutical compositions intended for the treatment of myocardial infarction, for the prevention of postangioplastic recurrence of stenosis and for the prevention of cardiac and vascular fibrosis.

The invention therefore relates in particular to the use of the products of formula I as defined above for the manufacture of pharmaceutical compositions for the treatment of renal insufficiency.

The invention therefore relates in particular to the use of the products of the formula I as defined above for the production of pharmaceutical compositions intended for the prevention of cardiovascular disorders associated with diabetes.

The present invention relates to the use of the products of formula I as defined above for the manufacture of medicaments for cancer chemotherapy, for the treatment of psoriasis, parasitosis, for example caused by fungi or animals of the group referred to as "protista" or for the treatment of Alzheimer's or neurodegenerative diseases, in particular neuronal apoptosis.

The starting products of the formula VIa, which are therefore natural or synthetic amino acids, are commercially available or can be prepared using conventional techniques known in the art.

Particular mention may be made of the following products of the formula VIa: Glu, Gly, Ala, Val, Phe or Tyr, these amino acids may optionally be in protected form when they have, for example, an alloc or a tert-butyl group as a protecting group.

The products of general formula (VIb) are possible from so-called " of natural or synthetic amino acids of formula VIa defined above by preparing the Fmoc radical on the

The N-terminal amino functional group of said amino acid, such a reaction is described, for example, in an article with the following reference: "Mueller, A .; Vogt, C .; Sewald, N .;

Synthesis (1998), (6), 837-841.

The plurality of products of formula VIb, which are essentially amino acids with a Fmoc protecting group that may form, are starting products for the process of the invention, which is schematically shown in FIG. 1 is also commercially available.

Particular mention may be made of the following products of formula VIb: Fmoc-Leu, Fmoc-L-Glu (Alloc); Fmoc-Gly; Fmoc-Ala; Fmoc-Val; Fmoc-Phe or Fmoc-Tyr (OtBu).

The product of formula (II) is 9 (S) -amino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyridazino [1,2-a] [1,2-a] methyl ester ] diazepine-1 (S) -carboxylic acid. This starting product of formula (II) can be prepared using conventional methods known in the art or also as outlined in European Patent Application EP 94095 or in the following publications:

- Attwood M. et al., J. Chem. Soc. . Perkin trans. I (1986) (6), p. 1011 to 19; and - Thomas, W et al. , J. Chem. Soc. . Perkin trans. 2 (1986) (5), p. 747 to 55.

The starting product of formula III, i.e. R 1 X, where X represents a halogen atom, can be selected, in particular, from the compounds listed in Table 1 of Fig. 1. 2 of the patent application. In this table, X represents a chlorine atom but can also represent a bromine atom. Such a product of formula (III) is commercially available or can be prepared using conventional methods known in the art.

Of note are, for example, the following products of formula III: benzoyl chloride, isopropanoic chloride, cyclohexyl isocyanate, methanesulfonyl chloride or also benzenesulfonyl chloride.

As the starting product of formula (VIII), i.e., R4'-LH, wherein R4 'and L have the meanings indicated above, the compounds listed in Table 2 of FIG. 3 of the patent application. Such a product of formula (VIII) is commercially available or can be prepared using conventional methods known in the art.

Mention may be made in particular of the following products of formula VIII: mercaptobenzimidazole, benzoic acid, 1-phenylpiperazine, 4-fluorophenol and piperidine.

The following experimental section gives some examples of starting products.

Finally, the present invention also relates to compounds of formula (VII) defined as novel industrial products in the process of the invention.

The tables enclosed in FIG. 1 to 4 and the table on the following pages 84 to 88 represent the products obtained by the process of the invention described above; these products are exemplary of the products of formula (I) according to the invention and in the tables mentioned are characterized by their molecular weights, for which the abbreviation "MW." The "MW" values given in the tables were determined as follows.

The products presented in the tables appended to FIG. 4 and characterized by HPLC-MS spectra, i.e. high pressure chromatography accompanied by mass spectroscopy: such chromatography is performed using an ODS-AQ column and an acetonitrile / water elution mixture in various proportions as a function of the compounds. The electrospray ionisation method in positive mode was used to determine the molecular weights. The weight of each product was determined as the weight of H ⁺ molecular ion or the weight of sodium ion or acetonitrile adduct ion.

It should be noted that the starting amino acid for the products of Examples 1 and 2 is leucine: in fact the corresponding product of formula VIb, i.e. Fmoc-Leu is commercially available and forms the starting point for the synthesis of the product of Example 1.

In the case of further examples of the invention, which are listed in the tables in FIG. 4, wherein the amino acid is also Leu, step 1 of the synthesis of these products is carried out as described below. Example 1 of the Examples section.

In the case of further examples of the invention, which are listed in the tables in FIG. 4, wherein the amino acid is an amino acid other than Leu, step 1 of the synthesis of these products is also carried out as in Example 1 of the Examples below, using a compound of formula VIb corresponding to the desired amino acid, i.e. wherein the following Fmoc amino acids are used: Fmoc-L-Glu (Alloc); Fmoc-Gly; Fmoc-Ala; Fmoc-Val; Fmoc-Phe; and Fmoc-Tyr (OtBu): in this way, the final products are obtained wherein the amino acid residue is Glu or Glu (Alloc), Gly, Ala, Val, Phe, respectively. Tyr (OtBu).

For the other examples of the invention listed in the tables of Figure 4, wherein the amino acid is tyrosine, the preparation described in Example 3 below and the product of formula VI Fmoc-Tyr (OtBu) are used to give the corresponding final product of formula I wherein the hydroxyl radical is tert-butoxyform: the hydroxyl function is subsequently released to the product of formula (I) obtained in this manner to give a new product of formula (I) wherein the amino acid residue is then a tyrosine residue. Removal of a protecting group from derivatives of formula I wherein R 2 represents (tBuO) PhCH ₂ can be carried out, for example. by a standard method using trifluoroacetic acid in a 50/50 mixture with dichloromethane. The reaction scheme for this reaction is outlined below.

The examples given in the tables of FIG. 4, illustrate the method described above, but it should be noted that they do not limit the invention in any way.

Thus, the examples described in the part of the patent application designated as "Examples of embodiments of the invention represent examples 1 to 3 of the tables in FIG. 4, but it should be noted that the examples below are for illustrative purposes only and are not intended to limit the scope of the invention, which is clearly defined by the appended claims.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

- [9 (S) -benzoylamino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyridazino [1,2-a] [1,2] diazepine- 1 (S) -carboxamide] -5-methyl-1-benzoyloxyhexan-2-one

Step 1

N-Fmoc-3-amino-l-diazo-5-methylhexane-2-one

To a suspension of 3.52 g of Fmoc-leucine (11.3 mmol) in 35 mL of dichloromethane under a nitrogen atmosphere at -10 ° C was added successively 1.3 mL of 4-methylmorpholine (11.9 mmol; 1.05 equiv.). ) and dropwise 1.5 ml of isobutyl chloroformate (11.6 mmol; 1.03 equiv.). The reaction mixture is initially black and then a 4-methylmorpholine hydrochloride precipitate appears. After stirring at -10 ° C for 1 h, the precipitate was filtered off.

The resulting solution was cooled to -10 ° C, then 75 mL (19.1 mmol, 2 equiv.) Was added under nitrogen. 0.3 M solution of diazomethane in CH ₂ C1 _2nd

The temperature of the reaction mixture was gradually raised to room temperature. After reaction at room temperature for 1 h, the mixture was poured into 100 mL of saturated sodium bicarbonate solution. The organic phase is washed with water (100 ml), dried over anhydrous magnesium sulfate and then concentrated to dryness. The crude product is directly chromatographed on 500 g of silica using CH ₂ Cl ₂ / AcOEt 95/5 as the eluent.

2.6 g (65% yield) of a yellowish solid are isolated.

and

MS: MH ⁺ 3 78 ^X 1 HNMR (CDCl ₃₎ (250 MHz) 0.95 (6H, d, 2 CH _3), 1.40 1.85 (3H,

2 m; ICH and 1CH ₂ ), 4.18 (1H, t, CH Fmoc), 4.4-4.55 (2H; m; ICH and 1CHN ₂ ), 5.28 (1H, bd, NHCO), 4.42 (2H, bd, _CH2 Fmoc), 5.12 (1H, bs, CHN ₂₎ 6.90 to 7.45 (9H, m, aromatic H's), 7.55 (2H, bt;

aromatic H's), 7.77 (2H; bd; aromatic H's).

Step 2

(a) 9 (S) -Benzoylamino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyridazino [1,2-a] [1,2] methyl ester diazepine-1 (S) -carboxylic acid

To a solution of 500 mg of amine (1) (1.96 mmol) in 12 mL of CH ₂ Cl ₂ at 0 ° C and under nitrogen was gradually added 0.68 mL of diisopropylethylamine (2 mmol; 2 equiv.) Followed by 0.26 mL benzoyl chloride (2.16 mmol, 1.1 equiv). The temperature was raised to room temperature. After stirring for 1 h, 12 mL of 1N HCl was added. The mixture is decanted and the organic phase is washed successively with 12 ml of saturated NaCl solution and 12 ml of saturated sodium bicarbonate solution. The organic solution was dried over magnesium sulfate and then concentrated to dryness. 0.424 mg (54% yield) of methylbenzoylaminopyrazepate is isolated.

MS: [MH] + 358; MH ⁺ 360; MNa ⁺ 382

b) 9 (S) -Benzoylamino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyridazino [1,2-a] [1,2] diazepine acid 1 (S) -carboxylic acid

To a solution of 424 mg (1.18 mmol) of 9 (S) benzoylamino-octahydro-6,10-dioxo-6H-pyridazino [1,2-a] [1,2] diazepine-1 (S) -carboxylic acid methyl ester in 10 mL of methanol at 0 ° C was added 99 mg of lithium hydroxide (2.36 mmol; 2 equiv.). The temperature of the reaction mixture was raised to room temperature and the reaction was carried out overnight. The solution is concentrated to 5 ml on a rotary evaporator. 5 ml of water are added and the pH of the solution is adjusted to 1 by adding a few drops of concentrated HCl. The mixture was extracted with 2 x 5 mL of ethyl acetate. The organic phase is washed with 5 ml saturated NaCl, dried over _MgSO4 and evaporated to dryness. 305 mg of 9 (S) benzoylamino-octahydro-6,10-dioxo-6H-pyridazino [1,2a] [1,2] diazepine-1 (S) -carboxylic acid is obtained (75% yield).

MS: [MH] + 344, MH + 346, MNa ⁺ 368

1 H NMR (CDCl ₃ ) (300MHz): 1.76 (2H; m; CH ₂ ), 1.96 and 2.35 (2H;

2 m; CH ₂ ), 1.97 and 2.84 (2H; 2m; CH ₂ ), 2.41 and 3.48 (2H; 2m; CH ₂ ),

4.96 and 4.68 (2H, bd m, _CH2), 5.17 (1H, m, NH), 5.47 (1H, dd,

CHCO ₂ H), 7.26 (1H; d; CONH), 7.38-7.53 (3H; m; aromatic)

H's), 7.81 (2H; bd; aromatic 2H's).

Step 3

3- [9 (S) -Benzoylamino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyridazino [1,2-a] [1,2] diazepine -1 (S) -carboxamide] -5-methyl-1-diazohexan-2-one

ABOUT

A solution of N-Fmoc-3-amino-1-diazo-5-methylhexan-2-one (378 mg, 1 mmol) in CH ₂ Cl ₂ (3.5 mL ₎ was treated with DBU (0.31 mL ₎ at 0 ° C under nitrogen. 2.1 mmol; 2.1 equiv.). After 1 h reaction, the solution was placed on a column packed with silica (40 g), and flash eluted with CH ₂ C1 ₂ and methanol 90/10. The resulting yellow oil (198 mg, 100% yield) was dissolved in 3.5 mL of CH ₂ Cl ₂ immediately after which 0.35 g (1 mmol) of the acid obtained in step 2b) was added. Under nitrogen and at 0 ° C, 625 mg of TBTU (1.1 mmol; 1.1 equiv) was added sequentially followed by 0.35 mL of DIEA (2 mmol; 2 equiv). The reaction is carried out overnight at room temperature, then the reaction mixture is poured into 20 ml of saturated NaHCO ₃ solution and extracted twice with 10 ml of ethyl acetate. The combined organic phases were washed with water (20 mL) followed by 20 mL of saturated KHSO ₃ solution. The solution is dried over MgSO ₄ and concentrated to dryness. 244 mg of foam is isolated (50% yield).

MS: [M + Na] + 505; MH ⁺ N _2455; MH ⁺ 483 ¹ HNMR (CDCl ₃ ) (300 MHz): 0.95 (6H; dd; 2CH ₃ ), 1.56 (2H m; CH ₂ ),

1.69 (IH; m; CH), 4.53 (2H, rn; CH ₂ ); 6.40 (1H; bd; NH), 1.66 (2H, m; CH ₂ ), 1.92 (2 H; m; ch ₂ ) , 1.90 and 2.90 (2H; 2m, CH ₂ ); 2,3 9 a 3.24 (2H, ldd and ldt; ch ₂ ) , 3.01 and 4.66 (2H; ldt and lm; CH ₂ ), 4.66 (IH; td; CH), 5.17 (1H, ; m; CH) 7 O2 (1H, d; NH), 5.4 0 (1H; bs; CHN ₂ ) 7.46 (2H; d; aromatic 2H's in meta- position).

7.51 (1H; m; aromatic H's in the para- position), 7.81 (2H; dd; aromatic H's in the ortho position).

Step 4

3- [9 (S) -Benzoylamino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyridazino [1,2-a] [1,2] diazepine -1 (S) -carboxamide] -5-methyl-1-benzoyloxyhexan-2-one

a) 3- [9 (S) -Benzoylamino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyridazino [1,2-a] [1,2] Diazepine-1 (S) -carboxamide -5-methyl-1-bromohexan-2-one

To 219 mg (0.38 mmol) dissolved in 2 mL of CH ₂ C1 ₂ at 0 ° C under nitrogen, treated with 0.2 ml of HBr (37%) / AcOH

30/70. After reaction at 0 ° C for 1.5 h, the mixture is poured into 20 mL of saturated NaHCO ₃ solution. The mixture was extracted with 2 x 10 mL AcOEt.

The organic phases are washed with water (20 ml), dried over MgSO ₄ and concentrated in vacuo. 203 mg (94% yield) of bromoketone is isolated as a yellow foam.

MS: M + H < ^{+ >} 535

1 H NMR (CDCl ₃ ) (300 MHz):? 0.97 (6H; d; 2CH ₃ , 1.67 (1H; m; CH), 1 51 up to 1.69 (2H, 2m; 2H), 1.66 (2H, m; CH ₂ ), 1.94 (2H; m; ch ₂ ), 1 88 up to 1.98 and 2.12 up to 2.90 (2H, 2 m; CH ₂ ), 2.40 and 3 16 to

3.47 (2H, d am, _CH2), 3.01 to 4.61 (2H, 2 m, _CH2), 4.57 (1H, t, CH), 5.16 (1H, m, CH) ; 7.00 (lH, d, NH), 4.05 (2H, AB, _CH2);

7.47 (2H; td; aromatic 2H's in the meta-position), 7.53 (1H; m; aromatic H in the para-position), 7.82 (2H; dd; aromatic 2H's in the para-position).

b) 3- [9 (S) -Benzoylamino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-677-pyridazino [1,2-a] [1,2] Diazepine-1 (S) -carboxamide -5-methyl-1-benzoyloxyhexan-2-one

To a solution of already obtained bromoketone (0.093 mmol)

0.6 mL of DMF was added 11 mg of KF (0.186 mmol; 2 equiv.) Followed by 13.7 mg of benzoic acid. The reaction is run overnight with stirring at room temperature. The reaction mixture was poured into 10 mL of saturated NaHCO ₃ solution and extracted with 2 x 5 mL of ethyl acetate. The combined organic phases were washed with water (10 mL), dried over MgSO ₄ and concentrated in vacuo. 42 mg of pale yellow resin are obtained (78% yield).

MS: MH ⁺ 577; MNa ⁺ 599

1 H NMR: 0.97 (6H; d; 2CH ₃ ), 1.71 (1H; m; CH), 1.52-1.75 (2H;

2 m; CH ₂ ), 4.82 (1H; m; CHNH), 6.27 (1H; d; CHNH), 2.40 to

3.19 (2H, 2 m, _CH2), 3.02 to 4.60 (2H, 2 m, _CH2), l, 50 2.20 (2H,

m; CH ₂ ), 5.03 (2H; AB J = 17Hz; COCH ₂ O), 5.17 (2H; m; 2CH),

7.10 (1H; d; CONHCH), 7.40-7.65 (6H; m; aromatic 6H's),

7.81 and 8.09 (4H; dd; aromatic 2x 2H's in ortho position CO)

Example 2

3- [9 (S) - (2-furanoyl) amino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyridazino [1,2-a] [ 1,2] diazepine-1 (S) -carboxamide] -5-methyl-1- (2,6-dichlorobenzoyloxyhexan-2-one)

The procedure starts from the product obtained in step 3b) of Example 1 and follows the following reaction scheme. To a solution of 11.6 mg (0.022 mmol) of 3 (S) - [9 (S) - (2-furanoyl) amino-6,10

-dioxo-1,2,3,4,7,8,9,10-octahydro-6 H -pyridazino [1,2- a] [1,2] diazepine-1 (S) -carboxamide] -5- methyl-1-bromohexan-2-one v

0.35 ml of DMF was added 11 mg of dimethylaminomethylpolystyrene resin (0.044 mmol; 2 equiv.). The reaction is carried out overnight with stirring. The mixture is filtered on a sintered glass and the resin is rinsed with 2 x 2 mL CH ₂ Cl ₂ . After intensive evaporation in vacuo, 9 mg of the expected product is isolated (82% yield).

LC-MS (purity > 80%) MH ⁺ 636

Example 3

3 (S) - [9 (S) - (2-furanoyl) amino-6,10-dioxo-l, 2,3,4,7,8,9,10-octahydro-6H-pyridazin [1,2- a] [1,2] diazepine-1 (S) -carboxamide] -4- (4-hydroxyphenyl) -1- (2,6-dichlorobenzoyloxy) butan-2-one

Step 1

3 (S) - [9 (S) - (2-Furanoyl) amino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyridazino [1,2- a] [1,2] diazepine-1 (S) -carboxamide] -4- (4-tert-butyloxyphenyl) -1- (2,6-dichlorobenzoyloxy) butan-2-one

The process was carried out as in step 1 of Example 1 and using another compound of formula VI: Fmoc-TYR (OtBu) instead of a compound of formula VI: Leu-Fmoc in equal amounts. The operation is carried out under the same reaction conditions as in steps 2 to 4 of Example 1 to give the expected product.

Step 2 of (S) - [9 (S) - (2-furanoyl) amino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyridazino [1,2] -a] [1,2] diazepine-1 (S) -carboxamide] -4- (4-hydroxyphenyl) -1- (2,6-dichlorobenzoyloxy) butan-2-one

To the solution

mg (0.022

of step 1 of trifluoroacetic acid. of the product obtained in the above CH ₂ Cl ₂ is treated with 0.25 ml of acid. The reaction is carried out under stirring for one hour. The solvent was evaporated to dryness.

14.4 mg of the expected product is isolated (95% yield).

in 0.25 ml

LC-MS (purity > 80%) MH ⁺ 686

By the above operation, the products of Examples 4 to 609 are prepared, the structure of which is shown in the tables in FIG. 4th

Example 610

Pharmaceutical composition

I

Tablets corresponding to the following composition are prepared:

tablet excipient added to the product of Example 1

0.2 g (detailed excipient formulation: lactose, talc, starch, magnesium stearate)

Pharmacological study

Cathepsin K inhibition study

Test products (10 mM) are diluted to 1 MW in DMSO and distributed to Nunc polystyrene 96-well plates at a concentration of 2 μΐ per well. 12. The plate column is reserved for inspection and then received 1 μΐ DMSO (no products) per well. Plates are stored at -80 ° C and allowed to dissolve on the day of the experiment.

The products are diluted to 50 μΜ by adding 38 μΐ reaction buffer: sodium acetate 100 mM, EDTA 5 mM, DTT 1 MW pH 5.5. For addition of solutions as well as for all pipette operations, use a CybiWell 96 tip. After mixing the solutions, each product is transferred to 2 wells (duplicates) of a Greiner black 384-well plate at a concentration of 10 μΐ per well. . Thus, two 96-well plates can be tested on a 384-well plate.

Prepare 50 μΜ of Z-Val-arg-AMC substrate solution (Calbiochem) in the reaction buffer. This substrate is then distributed to all wells of a 384-well plate (20 μΐ per well).

A 12.5 ng / ml cathepsin K solution is prepared in the reaction buffer and distributed to all wells of a 384-well plate (20 μΐ per well) except 16 wells, which serve as a 100% inhibition control (columns 23 and 24, line I). to P) and which receive 20 μΐ of enzyme without buffer. 100%

The inhibition control is performed in columns 23 and 24, rows A to H, which do not contain products.

Plates are incubated at room temperature for 2 h and read on a Fluoroskan (Labsysems): 390 nm excitation; emission 460 nm.

The final concentrations of each of the reagents are as follows: products 10 μΜ, substrate 20 μΜ, enzyme 5 ng / ml.

Percent inhibition for all products is calculated by creating a scale of values for which reference values of 0% and 100% inhibition are used on each plate. Products showing significant inhibition are then subjected to another test in the concentration range of 50 μΜ to 0,5 μΜ and the values obtained are used to determine the ic ₅₀ value.

Cathepsin B inhibition study

The protocol is identical to the protocol used for cathepsin K with the following differences:

Z-arg-arg-AMC substrate (Calbiochem), 50 μΜ solution, 20 μΜ final cathepsin B (Calbiochem), 40 ng / ml solution, 16 ng / ml final concentration

incubation for 1 hour at room temperature

Papain inhibition study

The protocol is identical to the protocol used for cathepsin K with the following differences:

papain (Sigma), 50 ng / ml solution, 20 ng / ml final concentration

Incubation for 30 min at room temperature

The results

The IC ₅₀ values of the products of the examples obtained are given in Table I below in micromoles (μΜ).

TABLE I

Example # Cathepsin K IC ₅ o μΜ Cathepsin B IC ₅₀ μΜ Papain IC ₅ p μΜ 38 5 20 (31%) 20 (26%) 39 3 20 20 (31%) 40 1.8 20 (41%) 20 (31%) 42 4 20 (39%) 20 (26%) 43 1.5 15 20 (26%) 44 2 20 (41%) 20 45 0.9 20 (36%) 0 46 6 20 (31%) 20 (31%)

47 5 20 (41%) 20 (41%) 48 3 7 20 (21%) 54 0 20 (31%) 15 91 6 <0.2 0 101 0 6 20 (21%) 107 20 0 0 117 7 20 (26%) 0 122 18 0.7 20 (46%) 128 20 (31%) 20 (41%) 6 129 0 20 (30%) 4 130 20 (36%) 20 (31%) 6 131 7 0 9 132 20 (41%) 2 6 133 20 (26%) 0 20 134 20 (26%) 20 (31%) 7 135 20 (36%) 0 (18%) 136 20 20 (26%) 20 (21%) 138 29 (21%) 0 8

141 9 0.7 20 150 6 0.6 0 161: 0 9 19 162 20 (31%) 20 (21%) 20 165 20 (41%) 20 (31%) 20 166 20 (21%) 20 (21%) 2 171 8 20 (31%) 20 (21%) 172 20 20 (21%) 20 (11%) 185 0 7 0 192 20 (16%) 18 0 206 0 20 20 211 20 (21%) 20 (31%) 6 216 0 20 (41%) 6 217 20 (31%) 0 7 218 20 (26%) 20 20 220 20 (21%) 20 (31%) 6 221 20 (26%) 20 (31%) 7 224 20 (21%) 9 8 229 20 (41%) 18 20 (16%)

234 20 (31%) 18 20 (15%) 240 0 0 20 241 0 20 (21%) 7 304 12 1.5 0 313 0 5 0 322 20 (21%) 6 20 (21%) 339 10 0 0 340 7 20 (0%) 0 341 8 20 (26%) 0 343 14 20 (21%) 0 '344 5 0 20 (41%) 345 5 20 (26%) 0 346 6 0 0 347 12 20 (26%) 0 348 10 20 (36%) 20 (21%) 366 0 0 17 374 20 (21%) 0 7 382 20 (21%) 0 9 389 20 (21%) 20 (31%) 6

390 20 (21%) 19 6 397 20 (21%) 0 18 398 0 20 (21%) 9 433 20 (21%) 4 0 443 0 5 0 450 20 (26%) 20 (21%) 18 453 20 (31%) 9 20 (41%) 463 0 1.5 0 473 20 (26%) 1.5 0 481 0 6 0 526 0 0 18 534 20 (21%) 0 7 562 20 (21%) 20 (21%) 19 563 0 20 (21%) 18

tl

Claims (22)

1. Products of formula I: where: R 1 represents a -C (O) -R 5, -SO ₂ -R 5 or -C (O) -NR 6 R 5 radical, wherein R 6 represents a hydrogen atom or a linear or branched alkyl radical containing up to 4 carbon atoms and R5 represents a linear or branched alkyl radical containing a maximum of 6 carbon atoms, a cycloalkyl radical containing a maximum of 6 carbon atoms, a saturated or unsaturated membered or 6-membered phenyl, naphthyl or monocyclic heterocyclic radical containing 1 or more identical or different heteroatoms selected from oxygen, nitrogen or phenyl sulfur and alkyl, the heterocyclic radical as defined above in connection with R1 is optionally substituted with at least one radical selected from the group consisting of halogen atoms, linear or branched alkyl radicals or alkoxy radicals containing up to 4 carbon atoms, hydroxyl radical, acyl radicals containing up to 7 carbon atoms, trifluoromethyl radical, cyanoradical, thienyl radical, phenyl radical, phenoxy radical and isoxazolyl radical; R 2 and R 7 are such that either R 7 represents a hydrogen atom and R 2 I R2 is also that the -NH-CH-C (O) - group in the products of formula I represents a so-called &quot; a natural or artificial amino acid residue R2 ¹ The NH ₂ -CH-C (O) OH structures, with the exception of aspartic acid, or R 2 and R 7 together with the nitrogen atom and the carbon atoms to which they are attached form a ring so that the group thus formed in the products of formula I: represents so-called. natural or synthetic amino acid residue of the following structure: Λ o / R 3 represents a -CH = N ₂ radical or -CH ₂ -L-R 4 radical, wherein L represents a single bond or a divalent radical selected from -O-, -O-C (O) -, -NH- and -S- (CH ₂ ) _n - / wherein n represents an integer from 0 to 6, and R 4 represents a linear or branched alkyl radical containing up to 6 carbon atoms, a saturated or unsaturated monocyclic or bicyclic carbocyclic or heterocyclic radical containing 5 to 10 members and 1 or more identical or various heteroatoms selected from oxygen, nitrogen, iminoradical or sulfur, which may contain a -C (O) group, wherein the carbocyclic and heterocyclic alkyl radicals as defined above in relation to R4 are optionally substituted with at least one radical selected from the group consisting of consisting of halogen atoms; hydroxyl radicals; free, salified or esterified carboxyl radicals; -C (O) -NH ₂ , -C (O) -NH (alkyl), -C (O) -N (alkyl) - (alkyl), -NHC (O) (alkyl), -N (alkyl) - C (0) - (alkyl); a thienyl radical; a phenyl radical; an alkylphenyl radical; alkyl radical and alkoxy radical per se and optionally substituted with at least 1 radical selected from the group consisting of acyl radicals containing up to 7 carbon atoms, cyanoradical, -NH ₂ , -NH (alkyl), -N (alkyl) - (alkyl) and phenyl radical, wherein in the above radicals the alkyl radicals and alkoxy radicals are to be understood as being linear or branched and containing a maximum of 4 carbon atoms, the * indicates carbon atoms on which the S or R configuration may be; said products of formula I exist in all possible racemic, enantiomeric and diastereoisomeric forms, as well as addition salts of these products of formula I with mineral and organic acids or mineral and organic bases. Products of formula I according to claim 1, wherein R 1 a R3 has the meanings defined in claim 1 and R2 represents the so-called &quot; a natural or synthetic amino acid residue with the exception of aspartic acid, wherein the products of formula I exist in all possible racemic, enantiomeric and diastereomeric forms, as well as addition salts of these products of formula I with mineral and organic acids or mineral and organic bases. Products of formula I according to any one of claims 1 and 2, wherein R 1 and R 3 have the meanings defined in claim 1 or 2 a R 2 and R 7 are defined such that: either R 7 represents a hydrogen atom and R 2 represents a hydrogen atom or a linear or branched alkyl radical containing up to 6 carbon atoms, optionally substituted by at least one radical selected from an amino radical; acylamínoradikálu; NH = C (NH ₂ ) -NH-; merkaptoradikálu; linear or branched alkylthio radicals containing max 4 carbon atoms; a hydroxyl radical; linear or branched alkoxy radicals 4 carbon atoms; an imidazolyl radical; indolyl radicals; a phenyl radical itself, optionally substituted with at least one radical selected from halogen atoms, a hydroxyl radical, a linear or branched alkoxy radical containing up to 4 carbon atoms and a phenoxy radical itself, optionally substituted with at least one radical selected from iodine atoms and a hydroxyl radical; and a -C (O) -O-R 8 radical, wherein R 8 represents a hydrogen atom or a linear or branched alkyl or alkenyl radical containing up to 6 carbon atoms; or R 2 and R 7 together with the nitrogen atom and the carbon atoms to which they are attached form a ring containing 5 to 7 members, which is optionally substituted with at least one hydroxyl radical or a linear or branched alkoxy radical containing up to 4 carbon atoms; wherein said products of formula I exist in all possible racemic, enantiomeric and diastereoisomeric forms as well as addition salts of said products of formula I with mineral and organic acids or mineral and organic bases. Products of formula I according to any one of claims 1 to 3, wherein R 1 and R 3 have the meanings defined in any one of claims 1 to 3, R2 and R7 are defined such that: either R 7 represents a hydrogen atom and R 2 is as defined in claim 3; or R 2 and R 7 together with the nitrogen and carbon atoms form a pyrrolidinyl ring, optionally substituted with at least one hydroxyl radical or linear or branched alkoxy radicals containing up to 4 carbon atoms, said products of formula I exist in all possible racemic, enantiomeric and diastereoisomeric forms, and as well as addition salts of said products of the formula I with mineral and organic acids or mineral and organic bases. Products of formula I according to any one of claims 1 to 3, which correspond to formula Ia: la kde: R 1a represents a -C (O) -R 5a, -SO ₂ -R 5a or -C (O) -NR 6a R 5a radical, wherein R 6a represents a hydrogen atom or a linear or branched alkyl radical containing up to 4 carbon atoms and R 5a represents a radical selected from linear or branched alkyl radicals containing up to 6 carbon atoms; cycloalkyl radicals containing no more than 6 carbon atoms; a phenyl radical; a naphthyl radical; a furyl radical; a morpholinyl radical; a thienyl radical; the alkyl radical, the phenyl radical, the thienyl radical, and the pyridyl radical are optionally substituted with at least 1 radical selected from the group consisting of halogen atoms, linear or branched alkyl radicals or alkoxy radicals containing at most 4 carbon atoms, acyl radical 7, acyl radical carbon atoms, phenoxy radical, trifluoromethyl radical, cyanoradical, thienyl radical, phenyl radical and isoxazolyl radical; R 2a is as defined in any one of claims 1 to 4 when R 7 represents a hydrogen atom; R 3a represents a -CH = N ₂ radical or -CH ₂ -La-R 4a radical, wherein "La represents a single bond or a divalent radical selected from -O-, -O-C (O) - and -S- (CH ₂ ) _on -, wherein "na represents an integer from 0 to 3; and R 4a represents a radical selected from linear or branched alkyl radicals containing up to 6 carbon atoms; a phenyl radical; a tetrazolyl radical; a piperazinyl radical; piperidyl radical; a pyridyl radical; a benzothiazolyl radical; a quinolyl radical; a thiadiazolyl radical; a pyrimidinyl radical; and a tetralone radical; wherein the alkyl radical, phenyl radical, tetrazolyl radical, piperazinyl radical and piperidyl radical as defined above for R 4a are optionally substituted with at least 1 radical selected from halogen atoms; hydroxyl radical, free, salified or esterified carboxy radicals; -C (O) -NH ₂ ; -C (0) -NH (alkyl); -C (0) -N (alkyl) (alkyl); -NH-C (0) - (alkyl); -N (alkyl) -C (O) - (alkyl); a thienyl radical; a phenyl radical; an alkylphenyl radical; an alkyl radical and an alkoxy radical per se, optionally substituted with at least 1 radical selected from acyl radicals containing up to 7 carbon atoms, cyanoradical, -NH ₂ , -NH (alkyl), -N (alkyl) (alkyl) and phenyl radical, it being understood that in the above radicals the alkyl radicals and alkoxy radicals are linear or branched and contain a maximum of 4 carbon atoms, said products of formula (Ia) being in all possible racemic, enantiomeric and diastereoisomeric forms, as well as addition salts of said products of formula (Ia) with mineral and organic acids or mineral and organic bases. Products of formula I according to any one of claims 1 to 5, which correspond to formula Ib: R 1b represents -C (O) -R 5b, -SO ₂ -R 5b or -C (O) -NR 6b R 5b radical wherein R 6b represents a hydrogen atom representing a radical selected or a methyl radical, and R 5b from linear or branched alkyl radicals containing up to 4 carbon atoms optionally substituted by a thienyl radical; a cyclohexyl radical; a phenyl radical optionally substituted by a linear or branched alkoxy radical containing 95 carbon, phenoxy radical or naphthyl radical; a furyl radical; an isoxazolyl thienyl radical optionally substituted with up to 4 atoms with a trifluoromethyl radical; radical; a morpholinyl substituted optionally pyridyl trifluoromethyl radical, a radical; radical; R 2b represents an alkyl, optionally optionally linear or branched alkoxy radical containing up to 4 carbon atoms, or a -C (O) -O-R 8b radical, wherein R 8b represents a linear or branched alkyl or alkenyl radical containing up to 6 carbon atoms, R 3b represents -CH = N ₂ a radical or -CH ₂ -Lb-R 4b radical, wherein "Lb represents a single bond or a divalent radical selected from an integer hydrogen atom radical or a linear or maximum 6 atoms containing either a phenyl radical as a substituted hydroxyl radical or branched alkoxy radicals of -O-, -O-C (O) - and -S- (CH ₂ ) n b -, wherein "n b represents branched carbon, such as, or 0 or 1; and R 4b represents a radical selected from pyridyl benzothiazolyl radical; a quinolyl thiadiazolyl radical; a pyrimidinyl radical; radical; radical; tetralone radical; linear or branched alkyl radicals containing up to 4 carbon atoms optionally substituted by a free, salified or esterified carboxy radical or thienyl radical; phenyl radical, optionally substituted with at least one radical selected from halogen atoms, free, salified or esterified carboxy radical, a linear or branched alkyl radicals, and alkoxy radicals containing up to 4 carbon atoms, cyanoalkyl radicals, alkylphenyl radicals, -NH-C (0) _-CH3, -C (O) -N (alkyl) (alkyl) radicals; a tetrazolyl radical, optionally substituted with a phenyl radical; a piperazinyl radical optionally substituted on the second nitrogen atom with a phenyl radical or a linear or branched alkyl radical containing up to 4 carbon atoms per se, and optionally substituted with acyl- (pyrrolidinylcarbonyl) radical, 1 or 2 phenyl radicals or -NH ₂ , -NH (alkyl) or -N (alkyl) (alkyl); a piperidyl radical optionally substituted by a benzyl radical or a -C (O) N (alkyl) (alkyl) radical, it being understood that in the above radicals the alkyl radicals and alkoxy radicals are linear or branched and contain a maximum of 4 carbon atoms, and said general products The compounds of formula (Ib) exist in all possible racemic, enantiomeric and diastereoisomeric forms, as well as addition salts of said products of formula (Ib) with mineral and organic acids or mineral and organic bases. Products of formula I according to any one of claims 1 to 6, wherein R 1 represents a radical selected from the following radicals: and R2, R3 and R7 have the meanings indicated in claim 1. Products of formula I according to any one of claims 1 to 7, wherein R 7 represents a hydrogen atom and R 2 represents a radical selected from the following radicals: and R 1 and R 3 have the meanings indicated in claim 1. Products of formula I according to any one of claims 1 to 8, wherein R 3 represents a radical selected from the group consisting of the following radicals: and R1, R2 and R7 have the meanings indicated in claim 1. 10. Products of the formula I having the following chemical names: -3- [9 (S) -benzoylamino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyridazino [1,2-a] [1,2] diazepine-1 (S) -carboxamide] -5-methyl-1-benzoyloxy-hexan-2-one; 3- [9 (S) - (2-furanoyl) amino-6,10-dioxo-l, 2,3,4,7,8,9,10-octahydro-6H-pyridazin [1,2-a] [1,2] diazepine-1 (S) -carboxamide] -S-methyl-1- (2,6-dichlorobenzoyloxy-hexan-2-one); -3 (S) - [9 (S) - (2-Furanoyl) amino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyridazino [1,2] [α] [1,2] diazepine-1 (S) -carboxamide] -4- (4-hydroxyphenyl) -1- (2,6-dichlorobenzoyloxy) -butan-2-one. 11. Products of formula I having the following chemical names: (2-Propenyl) (4S) -6-diazo-4 - [[[(1S, 9S) -9 - [(2-methyl-1-oxopropyl) amino] octahydro-6,10-dioxo-6J] -pyridazino [1,2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate; (2-propenyl) (4 S) -6-diazo-4 - [[[(1 S, 9S) -9 - [(3-methoxybenzoyl) amino] octahydro-6,10-dioxo-6H-pyridazin [1,2- a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate; (2-propenyl) (4 S) -6-diazo-4 - [[[(1 S, 9S) -9 - [[(2-furanyl) carbonyl] amino] octahydro-6,10-dioxo-6H-pyridazin [1 , 2-a] [1,2] diazepin-l-yl] carbonyl] amino] -5-oxohexanoate; (2-propenyl) (4 S) -6-diazo-4 - [[[(1 S, 9S) -9 - [[(cyclohexylamino) carbonyl] amino] octahydro-6,10-dioxo-6H-pyridazin [1,2- ] [1,2] diazepin-l-yl] carbonyl] amino] -5-oxo-hexanoate; (2-propenyl) (4 S) -6-diazo-4 - [[[(1 S, 9S) -9 - [[[(4-phenoxyphenyl) amino] carbonyl] amino] octahydro-6,10-dioxo-6Hpyridazíno [ 1,2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate; (2-Propenyl) (4S) -6-diazo-4 - [[[(1S, 9S) -9 - [[[[2- (β-2-yl) ethyl] amino] carbonyl] amino] octahydro-6] 10-dioxo-6H-pyridazino [1,2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate; 100 (2-propenyl) (4S) -6-diazo-4 - [[[(1S, 9S) -9 - [(methylsulfonyl) amino] octahydro-6,10-dioxo-6H-pyridazino [1,2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate; (2-Propenyl) (4S) -6-diazo-4 - [[[(1S, 9S) -9 - [[[4- (trifluoromethyl) phenyl] sulfonyl] amino] octahydro-6,10-dioxo-6H- pyridazino [1,2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate; (2-Propenyl) (4S) -6-diazo-4 - [[[(1S, 9S) -9 - [[(2-naphthalenyl) sulfonyl] amino] octahydro-6,10-dioxo-6H-pyridazino [1] , 2-a] [1,2] diazepin-l-yl] carbonyl] amino] -5-oxohexanoate; (2-Propenyl) (4S) -6-diazo-4 - [[[(1S, 9S) -9 - [[[5- (isoxazol-3-yl) -2-thienyl] sulfonyl] amino] octahydro-6 10-dioxo-6H-pyridazino [1,2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate; 9 - [(9 S) - [[(4-phenoxyphenyl) amino] carbonyl] amino] -N - [(2 S) -4-diazo-1- [4 - [(1,1-dimethyl) ethoxy] phenyl] - 3-oxo-2-butyl] -6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide; (2-Propenyl) (4S, 6 - [(2,6-dichlorobenzoyl) oxy] -4 - [[[(1S, 9S) -9 - [[(2-furanyl) carbonyl] amino] octahydro-6,10] -dioxo-6H-pyridazino [1,2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate; (2-Propenyl) (4S) -6 - [(2,6-dichlorobenzoyl) oxy] -4 - [[[(1S, 9S) -9 - [[[4- (trifluoromethyl) phenyl] sulfonyl] amino] octahydro -6,10-dioxo-6H-pyridazino [1,2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate; (2-Propenyl) (4S) -6- [4 - [[2-oxo-2- (1-pyrrolidinyl) ethyl] piperazin-1-yl] -4 - [[[(1S, 9S) -9- [ [[4- (trifluoromethyl) 101 phenyl] sulfonyl] amino] octahydro-β, 10-dioxo-65-pyridazino [1,2a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxo hexanoate; (2-Propenyl) (4S) -6- [4 - [[2-oxo-2- (1-pyrrolidinyl) ethyl] piperazin-1-yl] -4 - [[[( 12,95) - 9 - [[(2-naphthalenyl) sulfonyl] amino] octahydro-6,10-dioxo-6H-pyridazino [1,2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate; (2-propenyl) (4S) -6 - [(2,6-dichlorobenzoyl) oxy] -4 - [[[(15.95) -9 - [[(cyclohexylamino) carbonyl] amino] octahydro-6,10- dioxo-6H-pyridazino [1,2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate; (2-Propenyl) (4S) -6 - [(1-phenyl-1H-tetrazol-5-yl) thio] -4 - [[[(1S, 95) -9 - [[[(4-phenoxyphenyl) amino] carbonyl] amino] octahydro-6,10-dioxo-6H-pyridazino [1,2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate; (2-Propenyl) (4S) -6 - [(benzothiazol-2-yl) thio] -4 - [[[(1S, 9S) -9 - [[[(4-phenoxyphenyl) amino] carbonyl] amino] octahydro -6,10-dioxo-6H-pyridazino [1,2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate; (2-Propenyl) (4S) -6 - [[(4-methoxyphenyl) methyl] thio] -4 - [[[(1S, 95) -9 - [[[(4-phenoxyphenyl) amino] carbonyl] amino] octahydro-6,10-dioxo-6H-pyridazino [1,2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate; (2-Propenyl) (4S) -6 - [[(4-pyridinyl) carbonyl] oxy] -4 - [[[(1S, 9S) -9 - [[[(4-phenoxyphenyl) amino] carbonyl] amino] octahydro-6,10-dioxo-6H-pyridazino [1,2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate; (2-Propenyl) (4S) -6 - [(2,6-dichlorobenzoyl) oxy] -4 - [[[(15,9S) -9 - [[[(4-phenoxyphenyl) amino] carbonyl] amino] octahydro -6.10102 -dioxo-6H-pyridazino [1,2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate; (2-Propenyl) (4S) -6-acetyloxy-4 - [[[(1S, 9S) -9 - [[[(4-phenoxyphenyl) amino] carbonyl] amino] octahydro-6,10-dioxo-6H-pyridazino [ 1,2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate; (2-Propenyl) (4S) -6- [1-oxo-2- (thien-3-yl) ethoxy] -4 - [[[(1S, 9S) -9 - [[[(4-phenoxyphenyl) amino] carbonyl] amino] octahydro-6,10-dioxo-6H-pyridazino [1,2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate; (2-propenyl) (4S) -6 - [(1-phenyl-1H-tetrazol-5-yl) thio] -4 - [[[(13,9S) -9 - [[[[2- (thien- 2-yl) ethyl] amino] carbonyl] amino] octahydro-6,10-dioxo-6H-pyridazino [1,2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate; (2-Propenyl) (4S) -6 - [(2,6-dichlorobenzoyl) oxy] -4 - [[[(13,9S) -9 - [[[[2- (thien-2-yl) ethyl]]] amino] carbonyl] amino] octahydro-6,10-dioxo-6H-pyridazino [1,2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate; (2-Propenyl) (4S) -6 - [(2,6-dichlorobenzoyl) oxy] -4 - [[[(1S, 93) -9 - [(methylsulfonyl) amino] octahydro-6,10-dioxo-6H-pyridazino] [1,2-a] [1,2] diazepin-1-yl] carbonyl] amino] -5-oxohexanoate; 9 - [(9S) [[(4-Phenoxyphenyl) amino] carbonyl] amino] -N - ((2S) -4-diazo-1-phenyl-3-oxo-2-butyl) octahydro-6,10-dioxo -6 H (1 S) pyridazine [1,2-a] [1,2] diazepine-l-carboxamide; 9 - [(9S) - [[[2- (Thien-2-yl) ethyl] amino] carbonyl] amino] -N - ((2S) -4-diazo-1-phenyl-3-oxo-2-butyl) octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide; 103 9 - [(9S) - [(2-Naphthalenyl) sulfonyl] amino] -N - ((2S) -4-diazo-1-phenyl-3-oxo-2-butyl) octahydro-6,10-dioxo-6H - (1 S) pyridazine [1,2-a] [1,2] diazepine-l-carboxamide; 9 - [(9S) - [[5- (Isoxazol-3-yl) -2-thienyl] sulfonyl] amino] -N - ((2S) -4-diazo-1-phenyl-3-oxo-2-butyl) octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide; 9 - [(9S) - [[(4-Phenoxyphenyl) amino] carbonyl] amino] -N - ((2S) -4-diazo-3-oxo-2-butyl) octahydro-6,10-dioxo-6H- (1S) pyridazino [1,2-a] [1,2] diazepine-1-carboxamide; 9 - [(9 S) - [[[3- (thien-2-yl) ethyl] amino] carbonyl] amino] -N - ((2S) -4-diazo-3-oxo-2-butyl) octahydro-6 10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide; 9 - [(9S) - (3-Methoxybenzoyl) amino] -N - [(2S) -4 - [(2,6-dichlorobenzoyl) oxy] -1-phenyl-3-oxo-2-butyl] octahydro-6 , 10-dioxo-6JJ- (1 S) pyridazine [1,2-a] [1,2] diazepine-l-carboxamide; 9 - [(9S) - [(2-furanyl) carbonyl] amino] -N - [(2S) -4 - [(2,6-dichlorobenzoyl) oxy] -1-phenyl-3-oxo-2-butyl ] octahydro-6,10-dioxo-6H- (1 S) pyridazine [1,2-a] [1,2] diazepine-l-carboxamide; 9 - [(9S) - [(cyclohexylamino) carbonyl] amino] -N - [(2S) -4 - [(2,6-dichlorobenzoyl) oxy] -1-phenyl-3-oxo-2-butyl] octahydro- 6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide; 9 - [(9 S) - [[(4-phenoxyphenyl) amino] carbonyl] amino] -N - [(2 S) -1-phenyl-4 - [(l-phenyl-lH-tetrazol-5-yl) thio] 3-oxo-2-butyl] octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine 1-carboxamide; 9 - [(9S) - [[(4-Phenoxyphenyl) amino] carbonyl] amino] -N - [(2S) -1-phenyl-4- [1-oxo-2- (3-thienyl) ethoxy] -3 2-oxo-butyl] -oktahydro104 6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide; (methyl) [2-oxo-4-phenyl-3 - [(3S) - [[(4-phenoxyphenyl) amino] carbonyl] amino] octahydro-6,10-dioxo-6H- (1S) -pyridazino- [1] , 2I a] [1,2] diazepin-1-yl] carbonyl] amino] butyl] pentanedionate; 9 - [(9S) - [[(4-Phenoxyphenyl) amino] carbonyl] amino] -N - [(2S) -4 - [(4-phenylmethyl) -1-piperidinyl] -1-phenyl-3-oxo- 2-butyl] octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-carboxamide; 9 - [(9S) - [[[2- (Thien-2-yl) ethyl] amino] carbonyl] amino] -N - [(2S) -1-phenyl-4 - [(1-phenyl-1H-tetrazole)] -5-yl) thio] -3-oxo-2-butyl] octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide; 9 - [(9S) - [[[2- (Thien-2-yl) ethyl] amino] carbonyl] amino] -N - [(2S) -1-phenyl-4 - [(2-benzothiazolyl) thio] - 3-oxo-2-butyl] octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide; 9 - [(9S) - [[[2- (thien-2-yl) ethyl] amino] carbonyl] amino] -N - [(2S) -1-phenyl-4 - [(2,6-dichlorobenzoyl) oxy] 3-oxo-2-butyl] octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamides d; 9 - [(9S) - [[[2- (Thien-2-yl) ethyl] amino] carbonyl] amino] -N - [(2S) -1-phenyl-4- [4- [2- (1- pyrrolidinyl) -2-oxoethyl] -piperazin-1-yl] -3-oxo-2-butyl] octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine -l-carboxamide; 9 - [(9S) - (Methylsulfonyl) amino] -N - [(2S) -1-phenyl-4 - [(2,6-dichlorobenzoyl) oxy] -3-oxo-2-butyl] octahydro-6,10 -dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide; 105 9 - [(9S) - [[[4- (Trifluoromethyl) phenyl] sulfonyl] amino] -N - [(2S) -1-phenyl-4 - [(1-phenyl-1H-tetrazol-5-yl) thio] 3-oxo-2-butyl] octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide; 9 - [(9S) - [[[4- (trifluoromethyl) phenyl] sulfonyl] amino] -N - [(2S) -1-phenyl-4- (2-benzothiazolyl) thio] -3-oxo-2-butyl octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide; 9 - [(9S) - (Methylsulfonyl) amino] -N - [(3S) -5-methyl-1 - [(2,6-dichlorobenzoyl) oxy] -2-oxo-3-hexyl] octahydro-6,10 dioxo-6Jí- (1 S) pyridazine [1,2-a] [1,2] diazepine-l-carboxamide; 9 - [(9 S) - [[[4- (trifluoromethyl) phenyl] sulfonyl] amino]] - N - [(3S) -5-Methyl-1 - [(2,6-dichlorobenzoyl) oxy] -2-oxo-3- -hexyl] octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide; 9 - [(9S) - [(2-Naphthalenyl) sulfonyl] amino] -N - [(3S) -5-methyl-1- - [(2,6-dichlorobenzoyl) oxy] -2-oxo-3-hexyl] octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1 amide; 9 - [(9S) - (2-Methyl-1-oxopropyl) amino] -N - ((3S) -1-diazo-5-methyl-2-oxo-3-hexyl) octahydro-6,10-dioxo- 6H- (1S) pyridazino [1,2-a] [1,2] diazepine-1-carboxamide; 9 - [(9S) - (3-methoxybenzoyl) amino] -N - ((3S) -l-diazo-5-methyl-2-oxo-3-hexyl) octahydro-6,10-dioxo-6H- (1 S 1-Pyridazino [1,2-a] [1,2] diazepine-1-carboxamide; 9 - [(9S) - [(2-Furanyl) carbonyl] amino] -N - ((3S) -1-diazo-5-methyl-2-oxo-3-hexyl) octahydro-6,10-dioxo 6H- (1S) pyridazino [1,2-a] [1,2] diazepine-1-carboxamide; 106 9 - [(9S) - [(Cyclohexylamino) carbonyl] amino] -N - ((3S) -1-diazo-5-methyl-2-oxo-3-hexyl) octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide; 9 - [(9S) - [[(4-Phenoxyphenyl) amino] carbonyl] amino] -N - ((3S) -1-diazo-5-methyl-2-oxo-3-hexyl) octahydro-6,10- dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide; 9 - [(9S) - [[[2- (Thien-2-yl) ethyl] amino] carbonyl] amino] - N - ((3S) -1-diazo-5-methyl-2-oxo-3-hexyl) octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide; 9 - [(9S) - (Methylsulfonyl) amino] -N - ((3S) -1-diazo-5-methyl-2-oxo-3-hexyl) octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide; 9 - [(9S) - [[4- (Trifluoromethyl) phenyl] sulfonyl] amino] -N - ((3S) -1-diazo-5-methyl-2-oxo-3-hexyl) octahydro-6,10- dioxo-6H- (1 S) pyridazine [1,2-a] [1,2] diazepine-l-carboxamide; 9 - [(9S) - [(2-Naphthalenyl) sulfonyl] amino] -N - ((3S) -1-diazo-5-methyl-2-oxo-3-hexyl) octahydro-6,10-dioxo-6H - (1S) pyridazino [1,2-a] [1,2] diazepine-1-carboxamide; 9 - [(9S) - (3-methoxybenzoyl) amino] -N - [(3 S) -1 - [(benzothiazol-2-yl) thio] -4-methyl-2-oxo-3-pentyl] octahydro-6 10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide; 9 - [(9S) - [(2-furanyl) carbonyl] amino] -N - [(3S) -1 - [(benzothiazol-2-yl) thio] -4-methyl-2-oxo-3-pentyl] octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide; 9 - [(9S) - [(Cyclohexylamino) carbonyl] amino] -N - [(3S) -1 - [(benzothiazol-2-yl) thio] -4-methyl-2-oxo-3-pentyl] octahydro- 6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide; 107 9 - [(9S) - [[(4-phenoxyphenyl) amino] carbonyl] amino] -N - [(3S) -1- - [(1-phenyl-1H-tetrazol-5-yl) thio] -4-methyl-2-oxo-3-pentyl] octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2- a] [1,2] diazepine-carboxamide; 9 - [(9S) - [[(4-phenoxyphenyl) amino] carbonyl] amino] -N - [(3S) -1- - [(benzothiazol-2-yl) thio] -4-methyl-2-oxo-3-pentyl] octahydro- 6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide; 9- [(9S) - [[[2- (thien-2-yl) ethyl] amino] carbonyl] amino] -N- - [(3S) -1 - [(1-phenyl-1H-tetrazol-5-yl) thio] -4-methyl-2-oxo-3-pentyl] octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide; 9- [(9S) - [[[2- (thien-2-yl) ethyl] amino] carbonyl] amino] -N- - [(3S) -1 - [(benzothiazol-2-yl) -thio] -4-methyl-2-oxo-3- -pentyl] octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide; 9 - [(9S) - [(cyclohexylamino) carbonyl] amino] -N - [(2S) -4 - [(2,6-dichlorobenzoyl) oxy] -3-oxo-2-butyl] octahydro-6,10- dioxo-6H- - (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide; 9 - [(9S) - [(2-furanyl) carbonyl] amino] -N - [(2S) -4 - [(2,6-dichlorobenzoyl) oxy] -3-oxo-2-butyl] octahydro-6, 10-dioxo-6H- - (1R) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide; 9 - [(9S) - [[(4-phenoxyphenyl) amino] carbonyl] amino] -N - [(2S) -4- - [(benzothiazol-2-yl) thio] -3-oxo-2-butyl] octahydro-6,10- -dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide; 9 - [(9S) - [[(4-phenoxyphenyl) amino] carbonyl] amino] -N - [(2S) -4- - [(2,6-Dichlorobenzoyl) oxy] -3-oxo-2-butyl] octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1 amide; 108 9 - [(9S) - (3-methoxybenzoyl) amino] -N - [(2 S) -4 - [(2,6-dichlorobenzoyl) oxy] -3-oxo-2-butyl] octahydro-6,10-dioxo -6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide; 9- [(9S) - [[[2- (thien-2-yl) ethyl] amino] carbonyl] amino] -N- - [(2S) -4 - [(2,6-dichlorobenzoyl) oxy] -3-oxo-2-butyl] octahydro-6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [ 1,2] diazepin-1 amide; 9 - [(9S) - [[4- (trifluoromethyl) phenyl] sulfonyl] amino] -N - [(2S) -4 - [(2,6-dichlorobenzoyl) oxy] -3-oxo-2-butyl] octahydro -6,10-dioxo-6H- (1S) -pyridazino [1,2-a] [1,2] diazepine-1-carboxamide; and 9- [(9S) - [(cyclohexylamino) carbonyl] amino] -N - [(2S) -4- - [(benzothiazol-2-yl) thio] -1- [4 - [(1,1-dimethyl) ethoxy] phenyl] -3-oxo-2-butyl] -63- (13) -pyridazino [1,2- a] [1,2] diazepine-1-CARBOXAMIDE. 12. of claim 1, a compound A process for preparing a product having the formula (II): of formula I according to that and by J F N ) h ₂ n 1J with. 0 0 II 109 reacts with a compound of formula III: R ¹ -X III, where X represents a halogen atom and R ¹¹ has the meaning indicated for R 1 in claim 1, wherein the optional reaction functionalities are optionally protected with protective formulas IV: groups to form xz x / IV, wherein RI ¹ as outlined above is subjected to the general formula IV to obtain a product wherein RI ¹ vv * of formula V has the meaning, and a saponization reaction, whereby the product of the general formula xz outlined below is given the following meaning: V, product of general reaction with product of formula VI: VI wherein, R 2 and R 7 ¹ the meanings indicated for R @ 2, respectively. R7 in claim 1 and wherein optional reaction functional groups are optionally protected with protecting groups to give the product of formula (Ix): 110 fV-n H, wherein R @ 1 ^1, R 2 ¹ and R 7 ¹ above indicated meanings, the product of formula IX can be subjected to a bromination reaction leading to the formation of the product of formula VII wherein R @ 1 ¹ above indicated meanings, the product of formula VII is brought into reaction with the product of formula VIII: N'-L-R4 'VIII wherein L has the meaning indicated in Claim 1 and R 4 ¹ is as indicated for R 4 in claim 1 and optionally wherein the reactive functional "groups or protected by protective groups, to give a product of formula Iy: 111 wherein R @ 1 ^1, R 2 ^1, R 4 and R 7 ¹ above indicated values, the products of formula Ix and Iy can be products of formula I and, if desired or necessary, they may be converted to other products of formula I, by undergoing one or more of the following conversion reactions, in any order: a) esterification reaction of acidic functional group, b) saponification reaction of an ester function providing an acid function, c) oxidation reaction of the alkylthio group to the corresponding sulfoxide or sulfone, d) conversion reaction of a ketone function to an oxime function, e) reduction reaction of a free or esterified carboxyl function to an alcohol function, f) conversion reaction of a functional alkoxy group to a hydroxyl function, or conversely a conversion reaction of a hydroxyl function to a functional alkoxy group, g) oxidation reaction of an alcohol function to an aldehyde, acid or ketone function, 112 (h) conversion reaction of nitrile radical to tetrazolyl; (i) the elimination reaction of protecting groups which may carry protected reaction functional groups; (j) a salification reaction with a mineral or organic acid or base to form the corresponding salt; and k) resolution of the racemic forms to the resolved products, wherein the products of formula I obtained in this way exist in all possible racemic, enantiomeric and diastereoisomeric forms. Products of formula I according to claims 1 to 4 as well as addition salts of said products of formula I with pharmaceutically acceptable mineral or organic acids or mineral or organic bases as medicaments. Products of formula Ia and Ib according to claim 5 or 6 as well as of formula Ia and addition salts of said products Ib with pharmaceutically acceptable mineral or organic acids or mineral or organic bases as medicaments. Products of formula I according to claims 7 to 9 as well as addition salts of said products of formula I with pharmaceutically acceptable mineral or organic acids or mineral or organic bases as medicaments. Products of formula I according to claim 10 or 11 as well as addition salts of said products of formula I with pharmaceutically acceptable mineral or 113 organic acids or mineral or organic bases as medicaments. Pharmaceutical compositions, characterized in that they contain as active ingredient at least one of the medicaments according to claims 13 to 16. Use of the products according to any one of claims 1 to 11 or pharmaceutically acceptable salts thereof for the preparation of medicaments for the prevention or treatment of diseases in which metabolic enzymes such as proteinase or kinase are involved. Use according to claim 18 for the preparation of medicaments for the prevention or treatment of diseases in which cathepsin K, cathepsin B or papain is involved. Use according to claim 18, wherein the diseases to be prevented or treated are selected from the following group of diseases: cardiovascular disease, cancer, central nervous system disease, inflammatory disease, infectious disease, or also bone disease. Use according to claim 18, wherein the diseases to be prevented or treated are diseases of the central nervous system or diseases of the bone, such as osteoporosis. 22. Compounds of formula VII as industrial products.