HRP20020558A2 - 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

The subject of the invention is therefore new derivatives of 9(S)-amino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyridazino[1,2-a]diazepine 1( S)-carboxamides, methods of their preparation, their use as drugs, pharmaceutical preparations containing them, and new uses of such derivatives.

A special subject of this invention is the preparation of a library of enzyme inhibitors using 9(S)-amino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyridazino[1,2-a ]diazepine 1(S)-carboxamide. Metabolic enzymes, such as protease or kinase, are enzymes that are widely distributed in the animal kingdom. As incomplete examples, in the form of bibliographic references, one can cite for protease - document: "XLII (1975)" and "Journal of Medicinal Chemistry" vol. 43 no. 3 ("D. Leung, G. Abbenante and D. P: Farlie"), and for kinase - document: "Methods in Enzymology", vol. 80 (1981) (Academic Press Inc.)".

Among the proteases that can selectively catalyze the hydrolysis of polypeptide bonds, four main classes can be mentioned: asparagine, serine, cysteine protease, and metallo-protease.

Examples of aspartic proteases include HIV-1 protease, renin, plasmepsins, and cathepsin D.

Examples of serine proteases include thrombin, factor Xa, elastase, tryptase, "complement convertase", and hepatitis C protease NS3.

Among the cysteine proteases there are three different groups, the papain group, and the cathepsins, the ICE group (caspases) and the picornavirus group (similar to serine proteases in which serine is replaced by cysteine).

In particular, cathepsin K, cathepsin B, cathepsin L, cathepsin S, caspases, rhinovirus 3C protease, and calpains can be mentioned here.

Examples of metalloproteases include angiotensin-converting enzyme, neutral endopeptidase, and a mixture of two matrix metalloproteases, as well as tumor necrosis factor-α-converting enzyme.

In particular, cathepsin K, cathepsin B, cathepsin S, cathepsin L and papain can be mentioned, and even more precisely cathepsin K, cathepsin B and papain.

These kinase or protease enzymes are involved in catabolic processes, and in the processes of inter- and intra-cellular communication: they play an important role in a large number of diseases in different domains, such as in particular the cardiovascular domain, oncology, the central nervous system, inflammation, osteoporosis, as and infectious, parasitic, fungal or viral diseases. This is the reason why these proteins are extremely interesting target compounds for pharmaceutical testing. Within the scope of this invention, starting from a peptidomimetic intermediate, a chemical library directed against potential inhibitors of these enzymes has been devised: the peptidomimetic intermediate here corresponds to product formula (II), as will be defined below. The product of this invention, as defined above and below, has inhibitory properties of metabolic enzymes such as those defined above, especially kinases or proteases, such as especially cysteine proteases or serine proteases.

Therefore, the products of this invention can be especially used in the prevention or treatment of diseases in which such metabolic enzymes are involved, such as certain cardiovascular diseases, diseases of the central nervous system, inflammatory diseases, bone diseases such as, for example, osteoporosis, infectious diseases that in their therapy especially requires anti-infective agents or certain cancers.

Therefore, the subject of this invention is the product of formula (I):

[image]

where:

R1 represents -C(O)-R5, -SO2-R5 or -C(O)-NR6R5 radical, where R6 represents a hydrogen atom or a straight or branched alkyl radical containing at most 4 carbon atoms, and R5 represents a straight or branched alkyl radical containing at most 6 carbon atoms, a cycloalkyl radical containing at most 6 carbon atoms, phenyl, naphthyl, or a 5- or 6-membered monocyclic heterocyclic saturated or unsaturated radical containing one or more identical or different heteroatoms selected from the group consisting of O, N or WITH,

alkyl, phenyl and heterocyclic radicals, as defined above for R1, which are preferably substituted with one or more radicals selected from the group consisting of halogen atoms, and straight or branched alkyl or alkoxyl radicals containing at most 4 carbon atoms, hydroxyl, acyl radicals containing a maximum of 7 carbon atoms, trifluoromethyl, cyano, thienyl, phenyl phenoxy and isoxazolyl radicals;

R2 and R7 are such that

or R7 represents a hydrogen atom, and R2 is such that the [image] group in the product of formula (I) represents a so-called natural or non-standard amino acid residue of the [image] structure with the exception of aspartic acid,

or R2 and R7 form a ring together with the nitrogen and oxygen atoms to which they are attached in such a way that the group formed in the products of formula (I):

[image]

represents a so-called natural or non-standard amino acid residue:

[image]

structures;

R3 represents -CH=N2 radical or -CH2-L-R4 radical, where L represents a single bond or a divalent radical selected from the group consisting of -O-, -O-C(O)-, -NH-, and -S-(CH2 )n-, where n represents an integer from 0 to 6,

and R4 represents a straight or branched alkyl radical containing at most 6 carbon atoms, a monocyclic or bicyclic carbocyclic or heterocyclic radical containing from 5 to 10 members, saturated or unsaturated, containing one or more identical or different heteroatoms selected from the group consisting of O, N, NH or S, where it may contain a -C(O) member,

carbocyclic and heterocyclic alkyl radicals, as defined above for R4, which are optionally substituted with one or more radicals selected from the group consisting of halogen atoms; hydroxyl radicals, free carboxyl radicals in the form of salts or esters; -C(O)-NH2, -C(O)-NH(alkyl), -C(O)-N(alkyl)(alkyl), -NH-C(O)-(alkyl), -N(alkyl) -C(O)-(alkyl); thienyl; phenyl; alkylphenyl; alkyl and alkoxyl radicals which are optionally substituted with one or more radicals selected from the group consisting of acyl radicals containing 7 carbon atoms, cyano, -NH2, -NH(alkyl), -N(alkyl)(alkyl) and phenyl radicals, where it is understood that the above-mentioned radicals are straight or branched alkyl and alkoxyl radicals, and that they contain a maximum of 4 carbon atoms,

the symbol * indicates a carbon atom that can be in S or R configuration,

and the mentioned products of formula (I) can be in all possible racemic, enantiomeric and diastereomeric isomeric forms, as well as in additional forms of salts of the mentioned products of formula (I) with mineral and organic acids, i.e. mineral and organic bases

With products of formula (I) and in the following situations:

◾ the term straight or branched alkyl radical means the radicals methyl, ethyl, propyl, isopropyl, hexyl, isohexyl, as well as heptyl, octyl, nonyl and decyl, as well as their straight and branched positional isomers: among these alkyl radicals, the most suitable radicals are which contain a maximum of 6 carbon atoms or those which contain a maximum of 4 carbon atoms;

◾ the term straight or branched alkoxy radical means methoxy, ethoxy, propoxy, isopropoxy straight, secondary or tertiary butoxy radicals, pentoxy or hexoxy radicals, as well as their straight and branched positional isomers: among these alkoxy radicals, the most suitable for selection are those radicals containing a maximum of 6 carbon atoms or those containing a maximum of 4 carbon atoms;

◾ the term halogen atom means chlorine, bromine, iodine or fluorine atoms, and preferably chlorine, bromine or iodine atoms;

◾ the term cycloalkyl radical denotes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl radicals, and especially cyclopentyl and cyclohexyl radicals;

◾ the term monocyclic heterocyclic radical means a saturated or unsaturated radical formed by 5 or 6 members such that one or more members represent an oxygen, sulfur or nitrogen atom: therefore such a monocyclic heterocyclic radical means a carbocyclic radical in which one or more heteroatoms selected from the group consist of oxygen, nitrogen or sulfur atoms, and it is understood that heterocyclic radicals can contain one or more atoms from the group consisting of oxygen, nitrogen or sulfur atoms, and if these heterocyclic radicals contain more than one heteroatom, the heteroatoms of these heterocyclic radicals can be the same or different. The following radicals may be specifically mentioned: dioxolane, dioxane, dithiolane, thiooxolane, thioxane, morpholinyl, piperazinyl, piperazinyl substituted with a straight or branched alkyl radical containing at most 4 carbon atoms, piperidyl, thienyl such as 2-thienyl and 3-thienyl, furyl such as 2-furyl, pyrimidinyl, pyridyl such as 2-pyridyl, 3-pyridyl and 4-pyridyl, pyrimidyl, pyrrolyl, thiazolyl, isothiozolyl, diazolyl, thiadiazolyl, triazolyl, tertrazolyl in base or salt form, thiadiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, 3- or 4-isoxazolyl. Morpholinyl, thienyl radicals such as 2-thienyl and 3-thienyl, furyl such as 2-furyl, tetrahydrofuryl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolinyl, pyridyl and pyrrolidinyl can also be highlighted.

◾ the term bicyclic heterocyclic radicals means saturated or unsaturated radicals that are composed of 8 to 12 members in such a way that one or more members represent an oxygen, sulfur or nitrogen atom, and in particular it means condensed heterocyclic groups that contain at least one heteroatom selected from the group consisting of sulfur, nitrogen and oxygen, for example benzothienyl, such as 3-benzothienyl, benzothiazolyl, quinolyl, tetralone, benzofuryl, benzopyrrolyl, benzimidazolyl, benzoxazolyl, thionaphthyl, indolyl or purinyl.

◾ the term carbocyclic or heterocyclic monocyclic or bicyclic radical having 5 to 10 members, saturated or unsaturated, containing one or more identical or different heteroatoms selected from the group consisting of O, N, NH or S, and which may contain -C( Article O) combines the definitions indicated in the above part on the one hand for the term - monocyclic heterocyclic radical and on the other hand for the term - bicyclic heterocyclic radical, whereby all these radicals are preferably substituted. It should be noted that a carbocyclic radical, as defined above, in particular represents a phenyl radical, and that a carbocyclic radical containing a -C(O) member is, for example, a tetralone radical.

◾ the term alkylphenyl means a phenyl radical substituted by one or more straight or branched alkyl radicals, as defined in the above section, and preferably containing a maximum of 4 carbon atoms,

◾ the term NH(alk) and N(alk)(alk) denotes an amino radical substituted with one or two alkyl radicals, whereby such an alkyl radical is straight or branched, and it is suitable to contain no more than 4 carbon atoms,

◾ the term acylamino means -C(O)-NH2, -C(O)-NH(alk) and -C(O)-N(alk)(alk) radicals, where NH(alk) and N(alk)(alk) ) radicals have the meaning indicated above,

◾ the term acyl denotes an R-C(O)-radical where R represents a radical selected from the group consisting of a hydrogen atom, straight or branched alkyl radicals containing at most 6 carbon atoms, a phenyl radical or a pyrrolidinyl radical: therefore the term acyl denotes especially formyl radicals, these radicals acetyl, propionyl, butanoyl, pentanoyl, hexanoyl, benzoyl and pyrrolidinylcarbonyl,

◾ the term alkenyl refers to straight or branched radicals containing at most 6 carbon atoms: the radicals vinyl, 1-propenyl, allyl, butenyl, 3-methyl-2-butenyl,

◾ the term alkylthio denotes straight or branched radicals containing a maximum of 6 carbon atoms, such as in particular the radicals methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, hexylthio or also isohexthio, as well as their straight or branched positional isomers: among these alkylthio radicals, it is convenient to select from among those mentioned in the above part those containing at most 4 carbon atoms.

So-called natural or non-standard amino acids are known to the skilled person and can be found in standard documents such as for example "Amino Acids" (1999), 16(3-4), 345-379.

The carboxyl radical(s) of the products of formula (I) can be converted into salt or ester form by means of various groups known to the person skilled in the art, among which may be mentioned, for example:

◾ among compounds that form salts, mineral bases, such as for example the equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium, or organic bases, such as for example methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N,N -dimethylethanolamine, tris(hydroxymethyl)aminomethane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine, N-methyl-glucamine,

◾ among compounds that form esters, alkyl radicals that form an alkoxy carbonyl group, such as, for example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, whereby these alkyl radicals can be substituted by radicals that are selected from the group consisting of, for example, halogen atoms , hydroxyl, alkoxy, acyl, acyloxy, alkylthio, amino or aryl radicals, such as for example a chloromethyl, hydroxypropyl, methoxymethyl, propionyloxymethyl, methylthiomethyl, dimethylaminoethyl, benzene or phenylethyl group.

Addition salts of products of formula (I) with mineral or organic acids can be, for example, salts that form chloride, bromide, iodide, nitrate, sulfate, phosphate, propane, acetic, trifluoroacetic, formic, benzoic maleic, fumaric, succinic, tartaric, oxalic , glyoxylic, aspartic, ascorbic acid, alkylsulfonic acids, such as for example methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, alkyldisulfonic acid, such as for example methanedisulfonic acid, alpha, beta-ethanedisulfonic acid, arylmonosulfonic acids, such as example of benzenesulfonic acid and aryldisulfonic acid. It should be remembered that stereoisomerism can be defined in its broadest sense as isomerism of compounds that have the same structural formulas, but different groups are differently distributed in space, as is the case in particular with monosubstituted cyclohexanes where the substituent can be in an axial or equatorial position, and with of different possible rotational configurations of ethane derivatives. However, there is a different type of stereoisomerism, which is caused by different spatial arrangements of fixed substituents, either on double bonds or on rings, which is often called geometric isomerism or cis-trans isomerism. The term stereoisomerism is used in this patent application in its broadest sense and therefore refers to all the compounds listed in the above section.

It must be emphasized that more suitable products of formula (I), as defined in the above section, in which carbon atoms are marked with the sign *, and which have the stereochemical configuration S. It should be noted that in products of formula (I), such as is defined above, the third carbon atom marked * in the formula of the product of formula (I) obviously does not have any particular R or S stereochemistry if R 2 represents a hydrogen atom.

Therefore, more specific objects of the invention are the products of formula (I), as defined in the above section, where R1 and R3 have the meaning as indicated in the above section, and R2 represents a so-called natural amino acid residue with the exception of aspartic acid,

the mentioned products of formula (I) are found in all possible racemic, enantiomeric and diastereomeric isomeric forms, as well as addition salts of the mentioned products of formula (I) with mineral and organic acids, i.e. mineral and organic bases.

Therefore, also specific objects of the present invention are products of formula (I), as defined in the above part, where R1 and R3 have the meaning as indicated in the above part, and R2 and R7 are such that:

or R7 represents a hydrogen atom, and R2 represents a hydrogen atom or a straight or branched alkyl radical containing at most 6 carbon atoms, preferably substituted with one or more radicals selected from the group consisting of amino; acylamino; NH=C(NH2)-NH-; mercapto; straight or branched alkylthio radicals containing at most 4 carbon atoms; straight or branched hydroxyl; alkyl radicals containing no more than 4 carbon atoms; imidazolyl, indolyl radicals; a phenyl radical that is itself substituted by one or more radicals selected from the group consisting of halogen atoms, a hydroxyl radical, a straight or branched alkoxy radical containing at most 4 carbon atoms, and a phenoxy radical that is itself substituted, if possible, by one or more radicals selected from groups consisting of iodine atoms and a hydroxyl radical; and -C(O)-O-R8 radical where R8 represents a hydrogen atom or a straight or branched alkyl or alkenyl radical containing no more than 6 carbon atoms,

or R2 and R7 form a ring together with the nitrogen and carbon atoms to which they are attached, and the ring includes from 5 to 7 members, and is preferably substituted by one or more hydroxyl or straight or branched alkyl radicals containing at most 4 carbon atoms, at wherefore the mentioned products of formula (I) are found in all possible racemic, enantiomeric and diastereomeric isomeric forms, as well as in the forms of addition salts of the mentioned products of formula (I) with mineral and organic acids, i.e. mineral and organic bases.

Specific objects of the present invention are products of formula (I), as defined above, where R1 and R3 have the meaning as indicated above, and R2 and R7 are such that:

or R 7 represents a hydrogen atom and R 2 has the meaning as indicated above

or R2 and R7 together with nitrogen and carbon atoms form a pyrrolidinyl ring, preferably substituted by one or more hydroxyl or straight or branched alkyl radicals containing at most 4 carbon atoms, whereby the mentioned products of formula (I) are found in all possible racemic, enantiomeric and diastereomeric isomeric forms, as well as in the form of addition salts of the mentioned products of formula (I) with mineral and organic acids, or mineral and organic bases.

Special mention may be made of the products of formula (I), as defined in the above section, in which R2 and R7 form a pyrrolidine ring together with the nitrogen and carbon atoms to which they are attached, whereby the amino acid residue is proline, or they form a substituted pyrrolidine ring preferably with a protective hydroxyl radical, in which case the amino acid residue is hydroxyproline.

Specific objects of this invention are the products of formula (I), as defined in the above part, which correspond to formula (Ia):

[image]

where:

R1a represents -C(O)-R5a, -SO2-R5a or -C(O)-NR6aR5a radical

where R6a represents a hydrogen atom or a straight or branched alkyl radical containing a maximum of 4 carbon atoms, and R5a represents a radical selected from the group consisting of a straight or branched alkyl radical containing a maximum of 6 carbon atoms; cycloalkyl containing no more than 6 carbon atoms; phenyl, naphthyl, furyl, morpholinyl, thienyl, pyridyl,

whereby alkyl, phenyl, thienyl and pyridyl radicals are preferably substituted with one or more radicals selected from the group consisting of halogen atoms and straight or branched alkyl or alkoxyl radicals containing a maximum of 4 carbon atoms, hydroxyl, acyl containing a maximum of 7 carbon atoms , and phenoxy, trifluoromethyl, cyano, thienyl, phenyl and isoxazolyl radicals;

R2a has the meaning as indicated above when R7 represents a hydrogen atom,

R3a represents -CH=N2 radical or -CH2-La-R4a radical, where La represents a single bond or a divalent radical selected from the group consisting of -O-, -O-C(O)- and -S-(CH2)na, where on represents an integer from 0 to 3,

and R4a represents a radical selected from the group consisting of straight or branched alkyl radicals containing at most 6 carbon atoms; and phenyl radicals; tetrazolyl; piperazinyl; piperidyl; pyridyl; benzothiazolyl; quinolyl; thiadiazolyl; pyrimidinyl; tertralone;

alkyl, phenyl, tetrazolyl, piperazinyl and piperidyl radicals are as defined above for R4a, preferably substituted with one or more radicals selected from the group consisting of halogen atoms; and hydroxyl and carboxy radicals in the form of salts or esters;

-C(O)-NHH2; -C(O)-NH(alkyl); -C(O)-N(alkyl)(alkyl); -NH-C(O)-(alkyl); -N(alkyl)-C(O)-(alkyl); thienyl; phenyl; alkylphenyl; wherein the alkyl and alkoxyl radicals are themselves substituted with one or more radicals selected from the group consisting of acyl radicals containing a maximum of 7 carbon atoms, cyano, -NH2, -NH(alkyl), -N(alkyl)(alkyl) and phenyl radicals ,

whereby it is understood that with the above-mentioned radicals, alkyl and alkoxyl radicals are straight or branched, and that they contain a maximum of 4 carbon atoms,

whereby the mentioned products of formula (Ia) are found in all possible racemic, enantiomeric and diastereomeric isomeric forms, as well as in the forms of addition salts of the mentioned products of formula (Ia) with mineral and organic acids, i.e. mineral and organic bases.

Even more specific objects of the present invention are products of formula (I), as defined in the above section, corresponding to formula (Ib):

[image]

where:

R1b represents -C(O)-R5b, -SO2-R5b or -C(O)-NR6bR5b radical

where R6b represents a hydrogen atom or a methyl radical, and R5b represents a radical selected from the group consisting of straight or branched alkyl radicals containing at most 4 carbon atoms, and which are preferably substituted with thienyl radicals; cyclohexyl; phenyl, which is optionally substituted by a straight or branched alkyl radical containing at most 4 carbon atoms, or by radicals such as phenoxy or trifluoromethyl; naphthyl; furil; morpholinyl; thienyl, preferably substituted with an isoxazolyl radical; pyridyl preferably substituted with a trifluoromethyl radical,

R2b represents a hydrogen atom or a straight or branched alkyl radical containing a maximum of 6 carbon atoms, and which is preferably substituted either by a phenyl radical that is itself substituted by a hydroxyl or straight or branched alkyl radicals containing a maximum of 4 carbon atoms, or else by a radical -C( O)-O-R8b where R8b represents a straight or branched alkyl or alkenyl radical containing at most 6 carbon atoms,

R3b represents -CH=N2 radical or -CH2-Lb-R4b radical in which Lb represents a single bond or a divalent radical selected from the group consisting of -O-, -O-C(O)-, and -S-(CH2)nb-, where nb represents an integer from 0 to 1,

and R4b represents a radical selected from the group consisting of pyridyl; benzothiazolyl; quinolinyl; thiadiazolyl; pyrimidinyl; tetralone radical; straight or branched alkyl radicals containing at most 4 carbon atoms, preferably substituted with carboxy and thienyl radicals which are free or in the form of salts or esters; phenyl preferably substituted with one or more radicals selected from the group consisting of halogen atoms, and a carboxy radical that is free or in the form of a salt or ester, straight or branched alkyl and alkoxyl radicals that contain at most 4 carbon atoms, and cyanoalkyl, alkylphenyl radicals, -NH-C(O)-CH3, -C(O)-N(alkyl)(alkyl); tetrazolyl optionally substituted with a phenyl radical; piperazinyl preferably substituted on the second nitrogen atom with a phenyl radical or straight or branched alkyl containing at most 4 carbon atoms, which itself is preferably substituted with an acyl (pyrrolidinylcarbonyl) radical, with one or two phenyl radicals or with -NH2, -NH( alkyl) or -N(alkyl)(alkyl); piperidyl radical preferably substituted by benzyl or -C(O)-N(alkyl)(alkyl) radical, whereby it is understood that in the above-mentioned radicals, alkyl and alkoxyl radicals are straight or branched, and that they contain a maximum of 4 carbon atoms,

whereby the mentioned products of formula (Ib) are found in all possible racemic, enantiomeric and diastereomeric isomeric forms, as well as in the forms of addition salts of the mentioned products of formula (Ib) with mineral and organic acids, i.e. mineral and organic bases.

The subject of this invention are in particular products of formula (I), as defined in the above section, where R1 represents a radical selected from the group consisting of the following radicals:

[image]

R2, R3 and R7 have the values indicated above, and those where R7 represents a hydrogen atom and R2 represents a radical selected from the group consisting of the following radicals:

[image]

R1 and R3 have the values indicated above, and those where R3 represents a radical selected from the group consisting of the following radicals:

[image]

R1, R2 and R7 have the values indicated above,

whereby the mentioned products of formula (Ib) are found in all possible racemic, enantiomeric and diastereomeric isomeric forms, as well as in the forms of addition salts of the mentioned products of formula (Ib) with mineral and organic acids, i.e. mineral and organic bases.

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

A very specific subject of this invention are the products of formula (I), as defined in the above part, which correspond to the following formulas:

◾ 3-[9(S)-benzylamino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyridazino[1,2-a][1,2] diazepin-1(S)-carboxamide]-5-methyl-1-benzolyoxy-hexan-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]diazepin-1(S)-carboxamide]-5-methyl-1-(2,6-dichlorobenzolyoxy)-hexan-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]diazepin-1(S)-carboxamide]-4-(4-hydroxyphenyl)-1-(2,6-dichlorobenzolyoxy)-butan-2-one

The very specific objects of this invention are also the products of formula (I), as defined in the above part, which correspond to the following formulas:

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

◾ (2-propenyl)-(4S)-6-diazo-4-[[[(1S,9S)-9-[(3-methoxybenzoyl)-amino]-octahydro-6,10-dioxo-6H-pyridazino[ 1,2-a][1,2]diazepin-1-yl]-carbonyl]-amino]-5-oxo-hexanoate

◾ (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-oxo-hexanoate

◾ (2-propenyl)-(4S)-6-diazo-4-[[[(1S,9S)-9-[[(cyclohexylamino)-carbonyl]-amino]-octahydro-6,10-dioxo-6H- pyridazino[1,2-a][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-oxo-hexanoate

◾ (2-propenyl)-(4S)-6-diazo-4-[[[(1S,9S)-9-[[[[(2-p-2-yl)-ethyl]-amino]-carbonyl] -amino]-octahydro-6,10-dioxo-6H-pyridazino[1,2-a][1,2]diazepin-1-yl]-carbonyl]-amino]-5-oxo-hexanoate

◾ (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-oxo-hexanoate

◾ (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-oxo-hexanoate

◾ (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-oxo-hexanoate

◾ (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-oxo-hexanoate

◾ 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-6,10-dioxo-6H-pyridazino[1,2-a][1,2]diazepin-1-yl]-carbonyl]-amino]-5-oxo-hexanoate

◾ (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-oxo-hexanoate

◾ (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[1,2-a][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)-ethyl]-sulfonyl]-amino]-octahydro-6,10-dioxo-6H-pyridazino[1,2-a][1,2]diazepin-1-yl]- carbonyl]-amino]-5-oxo-hexanoate

◾ (2-propenyl)-(4S)-6-[4-[(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-oxo-hexanoate

◾ (2-propenyl)-(4S)-6-[(1-phenyl-1H-tertrazol-5-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- oxo-hexanoate

◾ (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-oxo-hexanoate

◾ (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-oxo-hexanoate

◾ (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-oxo-hexanoate

◾ (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-oxo-hexanoate

◾ (2-propenyl)-(4S)-6-acetyl-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-oxo-hexanoate

◾ (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- oxo-hexanoate

◾ (2-propenyl)-(4S)-6-[(1-phenyl-1H-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-oxo-hexanoate

◾ (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-oxo-hexanoate

◾ (2-propenyl)-(4S)-6-[(2,6-dichlorobenzoyl)-oxy]-4-[[[(1S,9S)-9-[(methylsulfonyl)-amino]-octahydro-6, 10-dioxo-6H-pyridazino[1,2-a][1,2]diazepin-1-yl]-carbonyl]-amino]-5-oxo-hexanoate

◾ 9-[(9S)-[[(4-phenoxyphenyl)-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-(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-naphthenyl)-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-6H-(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-(1S)-pyridazino[1,2-a][1,2]diazepine-1-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-[(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[(3S)-[[(4-phenoxyphenyl)-amino]-carbonyl]-amino]-octahydro-6,10-dioxo-6H-(1S) -pyridazino[1,2-a][1,2]diazepin-1-yl]-carbonyl]-amino]-butyl]-pentanedioate

◾ 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-oxo-ethyl]-piperazin-1-yl]]-3-oxo-2-butyl]-octahydro-6,10-dioxo-6H-(1S)-pyridazino[1, 2-a][1,2]diazepine-1-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-[(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-carboxamide

◾ 9-[(9S)-(2-methyl-1-oxo-propyl)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)-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

◾ 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-(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-(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-1-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-(1S)-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-carboxamide

◾ 9-[(9S)-(3-methoxybenzoyl)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-(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

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

The products of formula (I) according to this invention can be prepared according to the general synthetic scheme described in Figure 1 of this invention.

Therefore, the subject of this invention is also the process of preparing products of formula (I), as defined in the above part, which is characterized by the compound of formula (II):

[image]

participates in the reaction with the compound of formula (III):

R1'-X (III)

where X represents a halogen atom, and R1' has the meaning indicated in the above part for R1, where possible reactive functional groups are preferably protected by protective groups, in order to obtain the product of formula (IV):

[image]

where R1' has the meaning as indicated above, wherein the product of formula (IV) is subjected to a saponification reaction to obtain the product of formula (V):

[image]

where R1' has the meaning as indicated in the above part, wherein the product of formula (V) reacts with the product of formula (VI):

[image]

where R2' and R7' have the meaning as respectively indicated above for R2 and R7, where possible reactive functional groups are optionally protected by protecting groups, to obtain the product of formula (Ix):

[image]

where R1', R2' and R7' have the meaning as indicated in the above part, whereby the product of formula (Ix ) can be subjected to a bromination reaction to obtain the product of formula (VII):

[image]

where R1', R2' and R7' have the meaning as indicated in the above part, whereby the product of formula (VII) reacts with the product of formula (VIII):

H'-L-R4' (VIII)

where L has the meaning as indicated in the above part and R4' has the meaning as indicated in the above part for R4, where possible reactive functional groups are preferably protected by protecting groups, to obtain the product of formula (Iy):

[image]

where R1', R2', R4' and R7' have the meaning as indicated in the above part, whereby the products of formulas (Ix) and (Iy) can be products of formula (I), and which, if desired and necessary , can undergo one or more conversion reactions in any order to obtain other products of formula (I):

a) carboxyl group esterification reaction,

b) saponification reaction of the ester functional group into a carboxyl group,

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

d) conversion reaction of a keto functional group into an oxime functional group,

e) reduction reaction of a free or esterified carboxyl functional group into an alcohol functional group,

f) conversion reaction of an alkyl functional group into a hydroxyl functional group, or also a hydroxyl functional group into an hydroxy functional group

g) oxidation reaction of an alcohol functional group into an aldehyde, carboxyl or keto functional group,

h) conversion reaction of nitrile radical to tetrazolyl,

i) the reaction of removing the protective group that can be carried out with protected reactive functional groups,

j) the reaction of converting a mineral or organic acid or base into a salt in order to obtain the corresponding salt,

k) reaction of resolution of racemic forms to separated products of the mentioned products of formula (I) which are obtained in this way, and are found in all possible racemic, enantiomeric and diastereomeric isomeric forms.

It should be noted that the reaction of conversion of substituents to other substituents can also be carried out on starting products, as well as on intermediates, as defined in the above section, before proceeding with the synthesis in accordance with the reactions specified in the procedure described above. The process described above, as shown in Figure 1, represents the process used to obtain all the products of formula (I) of this patent application, especially those described in Examples 1 to 3 in the experimental part of this patent application, as well as of those shown in the tables of Figure 4, which is described below.

Such a procedure shown in Figure 1 consists of the following four stages:

Stage 1 enables the product of formula (VI) to be obtained from the amino acid of formula (VIa),

Stage 2 enables the product of formula (V) to be obtained from the initial product of formula (II) in the reaction with the product of formula (III), i.e. R1-X which is selected from the values indicated in Table 1, Figure 2,

Stage 3 enables obtaining the product of formula (Ix) by peptide pairing of the product of formula (VI) obtained in Stage 1 with the product of formula (V) obtained in Stage 2.

Stage 4 enables the product of formula (Iy) to be obtained from the product of formula (Ix) obtained in Stage 3 by reaction with the compound of formula (VIII), i.e. H-L-R4' selected in particular from the values indicated in Table 2 shown in Figure 3: this stage 4 can can be carried out using two different procedures, one called "KF/DMF" (potassium fluoride in dimethylformamide) and the other called "supported amine".

By the term "supported amine" is meant an amine attached to a commercially available polystyrene support which is, for example, dimethylaminomethylpolystyrene resin, diethylaminomethyl or other commercially available tertiary amines.

In the following way, the process of this invention can be carried out, under suitable conditions of implementation of the invention, as shown below in Figure 1, and in 4 stages as defined above.

Step 1: preparation of diazo amino acid of formula (VI):

This level can be divided into 3 levels a1), b1) and c1).

a1) obtaining the product (VIb) from the amino acid (VIa)

Addition of fmoc to the N-terminal amino functional group of the starting amino acid: the conditions for this reaction are described in particular in the article related to the above: “Meuller, A.; Vogt, C.; Sewald, N.; Synthesis (1998), (6), 837-841”. Also, related to Fmoc-amino acids, the document: "Methods Enzymol. (1997), 289 (Solid-phase peptide synthesis), 44-67.

Such reaction conditions can be applied to so-called natural and non-standard amino acids.

b1) obtaining the diazo fmoc product of formula (Vic) starting from the product of formula (Vib), obtained above under a), in two reactions bi) and bii) which are described below:

bi) preparation of mixed anhydride

1.5 equivalents of 4-methyl morpholine are added, followed by dropwise addition of 1.03 equivalents of isobutyl chloroformate to a suspension of the product of formula (Vib), obtained in Step a) above, in dichloromethane (3 ml/mmol), under atmosphere nitrogen at -10 °C. The reaction is maintained for 1 hour at -10 °C, after which the mixture is quickly filtered.

bii) Diazotization

The filtrate is cooled to -10 °C, and then 2 equivalents of diazomethane in a dichloromethane solution (0.3 M) are added dropwise in a nitrogen atmosphere. The reaction medium is gradually returned to room temperature, after which it is stirred for 1 hour. The solution is poured into a saturated solution of sodium bicarbonate (10 ml/mmol). The organic phase is washed with water (10 ml/mmol), dried over magnesium sulfate and concentrated under vacuum. The crude product obtained is chromatographed on a silk gel column using a CH2Cl2/AcOEt mixture 95/5.

c1) obtaining the diazo amino acid of formula (VI) by removing the protecting group of fmoc-amino diazoketone, starting from the product of formula (Vic), obtained above in b)

A solution of the Fmoc-amino diazoketone compound of formula (VIc), obtained in Step b2) above, in dichloromethane (3.5 ml/mol) is treated at 0 °C under a nitrogen atmosphere with 2 equivalents of diazobicycloundecane (DBU) ( 2.1 eq.). The reaction takes place for half an hour, after which the solution is directly applied to the silica gel column. The amine is rapidly eluted with a CH2Cl2/MeOH 90/10 solution. The resulting crude amine reacts directly to couple the peptide, representing Step 3.

Stage 2: preparation of the bicycle frame of the formula (V):

This degree is divided into 2 degrees a2) and b2)

a2) Functionalization of amines, i.e. obtaining the product of formula (IV) from the product of formula (II) in the reaction with the product of formula (III).

The product of formula (II) is methyl ester 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)-carboxylic acids. In order to obtain the product (IV) from the product of formula (II), the product of formula (II) is reacted with the product R1-X of formula (III), as defined in the above part, selected for example from Table 1 described in Figure 2, and the procedure is carried out as follows:

1 equivalent of acid chloride, sulfonyl chloride, carbamoyl chloride or isocyanate, then 2 equivalents of diisopropylethylamine (DIEP) are added in turn to a solution of the amine of formula (II) in dichloromethane (6 ml/mmol) at 0 °C under nitrogen atmosphere. The reaction medium was poured into 1N HCl (3 ml/mmol). The organic solution is washed successively with a saturated solution of NaCl (3 ml/mmol), then with a saturated solution of sodium bicarbonate (3 ml/mmol). After drying on magnesium sulfate, the solution is concentrated under vacuum. The raw product is used directly in the next step of saponification of the ester functional group.

b2) Obtaining the product of formula (V) from the product of formula (IV) by saponification of the ester functional group

The methyl ester obtained in the above Step a) is treated with 2M lithium oxide dissolved in methanol (2 eq.). After the reaction is carried out overnight at room temperature, the mixture is concentrated to half its volume using a rotavapor, after which an equal volume of water is added. The pH of the solution is adjusted to 1 by adding concentrated acid. The mixture is extracted with ethyl acetate (2×5 ml/mol). The organic phase is washed with saturated sodium chloride solution. After drying on magnesium sulfate, the solution is concentrated to dryness. If necessary, the obtained product is purified on a silica gel column by elution using a mixture of CH2Cl2/MeOH/AcOH in the ratio 95/5/0.5.

Step 3: Peptide Pairing

Peptide pairing is carried out by reacting the product of formula (VI), obtained in Step 1, and the product of formula (V), obtained in Step 2, in order to obtain the product of formula (Ix).

1.1 equivalents of TBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3,-tetramethyluronium tetrafluoroborate) and 2 equivalents of DIEA are added respectively to a solution of the free amine and acid of formula (V) in CH2Cl2 ( 3.5 ml/mmol) in a nitrogen atmosphere at 0 °C. The reaction is left overnight at room temperature. The solution is poured into a saturated solution of NaHCO3 (20 ml/mmol), and extraction is carried out using ethyl acetate (2×10 ml/mmol). The combined organic phases are washed with water (20 ml/mmol), then with saturated KHSO3 solution, dried over MgSO4 and concentrated under vacuum.

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

This degree is divided into two Degrees a4) and b4).

a4) bromination of diazoketone product of formula (Ix). A solution of diazoketone in CH2Cl2 (6 ml/mmol) is treated with a solution of HBr (37%)/acetic acid in the ratio 30/70 (0.6 ml/mmol) at 0 °C under a nitrogen atmosphere. At the end of the reaction, the mixture is poured into a saturated solution of NaHCO3 (50 ml/mmol). The mixture is extracted with ethyl acetate (2×30 ml/mmol). The organic solution is washed with water (230 ml/mmol), dried over MgSO4 and concentrated to dryness. If necessary, the crude product is purified on a silica gel column by elution with CH2Cl2/MeOH in the ratio 95/5.

b4) Substitution using two possible procedures b4i) and li b4ii)

b4i) Procedure with KF

2 equivalents of potassium fluoride (KF) are added to a solution of bromoketone in DMF (6 ml/mmol) followed by 1.2 equivalents of the nucleophile of formula (VIII), i.e. R4'-L-H, which can be in acid, thiol or hydroxide form , as indicated in Table 2 Figure 3, which is described below. The reaction is stirred overnight, after which the mixture is poured into a saturated solution of NaHCO3 (100 ml/mmol) and extracted with ethyl acetate (2×50 ml/mmol). The combined organic phases are washed with water, dried over MgSO4 and concentrated to dryness. If necessary, perform chromatography eluting with CH2Cl2/MeOH.

b4ii) Process in which dimethylaminomethylpolystyrene resin is used.

2 equivalents of dimethylaminomethylpolystyrene resin (Fluka 3-4 mmol base/g) and nucleophile of formula (VIII) (1.1 equivalent) in DMF (15 ml/mmol) are added to the solution (1 equivalent) of bromoketone. The reaction is stirred slowly overnight. The reaction mixture is filtered and then evaporated under vacuum. If necessary, the products are purified on a silica gel column by elution using a MeOH/CH2Cl2 mixture.

For example, the preparation of the products from Examples 1, 2 and 3 of this patent application is described in the continuation of the experimental part of this patent application.

It should be noted that Step 1, described below for Example 1, applies to all products of formula (I) of this patent application where R2 represents the residue of the amino acid leucine, and therefore the starting amino acid of the formula (Via) is leucine (Leu): the same procedure can be apply in the case when the amino acid is different, i.e. especially when the initial amino acid of the formula (VIa) represents GLU-aloc, GLY, ALA, VAL, PHE, TYR(tBu). These amino acids are commercially available, as is the GLU-aloc compound.

Amino acids are also commercially available in the form of the fmoc-AA compound of the formula (Vib).

When the starting amino acid of formula (VIa) is tyrosine TYR, the process includes an additional step, as set forth in Example 3 below.

The reaction of a product of formula (II) with a product of formula (III) to produce a product of formula (IV) can be carried out in the presence of DIEA as well as in a solvent such as CH2Cl2 or also (DMF).

In the product of formula (III), the R1' radical represents the values indicated above for R1, if necessary in a protected form, and X represents a halogen atom such as chlorine or bromine.

The product of formula (IV) thus obtained is subjected to a saponification reaction, in order to produce the product of formula (V), under conditions known to the skilled person, such as in particular the presence of LiOH in an alcohol such as methanol as well as ethanol, in dioxane or dimethoxyethane , in the presence of sodium or potassium.

The product of formula (Vib) is obtained by coupling the fmoc radical to the terminal amino functional group of an amino acid of formula (VIa): such an amino acid of formula (VIa) can be any so-called natural or non-standard amino acid listed in the above section.

The product of formula (VIb) is subjected to a diazotization reaction, in two steps as indicated in the above section, to give the product of formula (VIc).

Then the product of formula (VIc) obtained in this way is released from the fmoc radical, in order to produce the product of formula (VI).

The coupling reaction of a product of formula (V) with a product of formula (VI) to produce a product of formula (Ix) is carried out for example in TBTU/DIEA in a solvent such as DMF or also dichloromethane.

Products of formula (Ix) represent products of formula (I), in which the reactive functional groups are preferably protected, and in which R3 represents the CH=N2 radical.

In order to obtain the products of formula (I) in which R 4 represents the radical -CH 2 -L-R 4 , the products of formula (Ix) are first subjected to bromination under the conditions described above to produce the products of formula (VII). Then the products of the formula (VII) are subjected to the action of the products of the formula (VIII) H-L-R4', in order to obtain the products of the formula (Iy), as defined in the above part: such a reaction can be carried out by means of two reaction procedures, as defined in the above part.

According to the values of R'1, R2', R4' and R7', products of formulas (Ix) and (Iy) constitute or do not constitute products of formula (I), and can produce products of formula (I) if subjected to one or more reactions of a) to k) which are indicated in the above part.

Therefore, different reactive functional groups can, if necessary, be converted into protected forms by means of certain compounds, in the reactions defined in the above section: this refers for example to radicals such as hydroxyl, acyl, free carboxyl group or also amino group or monoaminoalkyl , which can be protected by appropriate protecting groups.

The following non-exhaustive list of protective reactive functional groups can be provided:

◾ hydroxyl groups can be protected by alkyl radicals such as tert-butyl, trimethylsilyl, tert-butyldimethylsilyl, methoxymethyl, tetrahydropyranyl, benzene or acetyl,

◾ amino groups can be protected, for example, by radicals such as acetyl, trityl, benzene, tert-butoxycarbonyl, benzyloxycarbonyl, phthalimido or other radicals known in peptide chemistry,

◾ acyl groups such as the formyl group can be protected for example in the form of cyclic or non-cyclic ketals or thioketals such as dimethyl or diethylketal or ethylene dioxyketal, or diethylthioketal or ethylenedithioketal,

◾ the acidic functional groups of the products described above can, if desired, be converted into the amide form using a primary or secondary amine, for example methylene chloride, in the presence of, for example, 1-ethyl-3-(dimethylamino-propyl) carbodiimide hydrochloride at room temperature:

◾ acid functional groups can be protected, for example, in the form of easily removable esters such as benzyl or tetrabutyl esters or esters known in peptide chemistry.

The reactions to which the products of formulas (Ix) and (Iy) can be subjected, as defined in the above section, can, if desired or necessary, be carried out, for example, in the manner indicated below.

a) The products described in the above section, if desired, can be subject to esterification reactions on possible carboxyl functional groups, which can be carried out according to usual procedures known to experts.

b) The possible conversion of the ester functional group into the carboxyl functional group of the products described above can be carried out, if desired, according to the usual procedures known to those skilled in the art, in particular by acid or basic hydrolysis, for example using sodium or potassium in an alcoholic medium such as for example methanol, or also using hydrochloric or sulfuric acid.

c) Possible alkylthio functional groups of the products described above can, if desired, be converted into corresponding sulfoxide or sulfonic functional groups, under the usual conditions known to those skilled in the art, such as for example a peracid such as for example peracetic acid or metachloroperbenzoic acid or also ozone, oxone, sodium periodate in a solvent such as methylene chloride or dioxane at room temperature.

Obtaining the sulfoxide functional group can be supported by an equimolar mixture of a product containing an alkylthio group and a reagent such as, in particular, a peracid.

Obtaining the sulfoxide functional group can be supported by an equimolar mixture of the product containing the alkylthio group with an excess of reagents such as, in particular, peracid.

d) The conversion reaction of the keto functional group into the oxamine functional group can be carried out under the usual conditions known to those skilled in the art, such as in particular the reaction in the presence of an optionally O-substituted hydroxylamine in an alcohol, such as for example ethanol, at room temperature or during heating.

e) Possible free or esterified carboxyl functional groups of the products described above can be reduced to alcohols, if desired, using methods known to those skilled in the art: possible esterified carboxyl functional groups can be reduced to alcohols, if desired, using methods known to those skilled in the art , and in particular by means of lithium aluminum hydride in a solvent such as, for example, tetrahydrofuran, as well as dioxane or ethyl ether.

f) Possible alkoxy functional groups of the products described above, such as in particular the methoxy group, can be converted into a hydroxyl functional group, if desired, under the usual conditions known to those skilled in the art, using boron tribromide and a solvent such as, for example, methylene chloride, using pyridine hydrobromide or hydrochloride, as well as bromic or hydrochloric acid in water or trifluoroacetic acid with reflux.

g) Possible alcohol functional groups of the products described above can be converted into an aldehyde or carboxyl functional group, if desired, under the usual conditions known to skilled persons, such as for example the action of magnesium oxide to obtain aldehydes, or with Jones's reagent to obtain acid.

h) Possible nitrile functional groups of the products described above can be converted to tetrazolyl, if desired, under usual conditions known to those skilled in the art, such as for example cycloaddition of metal azides, such as for example sodium azide or trialkyltin azide, to nitrile functional group, as indicated in the procedure described in the article with the following reference:

J Organometallic Chemistry, 33, 337 (1971) KOZIMA S. & coll. It should be noted that the conversion reaction of carbamate to urea, and especially sulfonylcarbamate to sulfonylurea, can be carried out, for example, with the return of a suitable solvent such as, for example, toluene in the presence of a suitable amine.

It is understood that the reactions described above are carried out as indicated or also, if appropriate, according to procedures known to those skilled in the art.

i) The elimination of protective groups, such as for example those indicated in the above section, can be carried out under the usual conditions known to skilled persons, in particular by means of acid hydrolysis which is carried out using an acid such as hydrochloric, benzenesulfonic, para-toluenesulfonic, formic or trifluoroacetic acid acid or also by means of catalytic hydrogenation.

The phthalamido group can be eliminated using hydrazine.

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

j) The products described in the above section can be subjected to a reaction of translation into salt form, if desired, for example using mineral or organic acids, or mineral or organic bases in accordance with usual procedures known to skilled persons. The conversion reaction to the salt form can, for example, be carried out in the presence of hydrochloric acid or also tartaric, citric or methanesulfonic acid, in an alcohol such as, for example, methanol or ethanol.

k) Possible optically active forms of the products described above can be prepared by resolving racemic mixtures according to usual procedures known to skilled persons.

Illustrations of the reactions defined in the above section are shown in the section of examples where the preparations are described, and follow below.

The products of formula (I), as defined above, as well as their acid addition salts have useful pharmacological properties.

The products of the present invention may therefore possess the properties of inhibiting one or more metabolic enzymes, as defined above, and in particular kinases or proteases. Certain products of formula (I) of the present invention, as defined above, may therefore have certain protein kinase or lipase inhibitory properties.

Several kinase inhibitors have been described, such as butyrolactone, flavopiridol, and 2-(2-hydroxyethylamino)-6-benzylamino-9-methylpurine, also called olomoucine.

Several kinase inhibitors are described in "Journal of Medicinal Chemistry, vol. 43-no. 3 (D. Leung, G. Abbenante and D.P. Fairlie). According to a non-exhaustive list, aragatroban, napsagatran, inogatran, efegatran, CVS-1123, as well as melagatran can be mentioned as thrombin inhibitors.

As potent inhibitors of factor Xa, Dx-9065a, YM-60828 and ZK 807191 or FX 2212 can also be mentioned.

ICI-200800, MR 889, L-658, 758, MDL 101,146, ZD 8321 or also various heterocyclic derivatives such as penicillins, penems, β-lactams, isocoumarins, benzisothiazolones and alkylazetidinones can be mentioned as elastase inhibitors.

APC-366 can be mentioned as a tryptase inhibitor, and sepimostat mesilate (FUT-187) or nafamostat mesilate (FUT 175) can be mentioned as "complement convertase" inhibitors.

Cbz-Leu-Leu-CHO, 1,3-bis(acylamino)-2-propanone or 1,5-diacylcarbohydrazide derivatives can be mentioned as potent cathepsin K inhibitors; as caspase inhibitors, 5-aminopyrimidin-6-one derivatives, phenyl ketomethyl ether or amino methylene ketone derivatives can be mentioned; peptide aldehydes such as Cbz-Val-Phe-CHO and calpeptin can be mentioned as calpain inhibitors.

The levels, regulation and activity of a number of protein kinases or proteases play a role in some pathological changes in humans. Protein kinase or protease activity can be particularly associated with receptors that have transmembrane domains or intracellular proteins.

Certain kinases or proteases may play a role in the initiation, development or termination of cell cycle processes, and therefore inhibitory molecules of such kinases or proteases may limit unwanted cell proliferation encountered in cancer, psoriasis, fungal growth, parasites (animals, protozoa): such inhibitory molecules of these kinases or proteases are also able to play a role in the regulation of neurodegenerative diseases such as Alzheimer's disease. Certain products of formula (I) of the present invention may therefore have antimitotic properties. Certain products of formula (I), as defined above, may, as kinase or protease inhibitors, have the property of inhibiting osteoclast-driven bone resorption. They can therefore be suitable for the therapeutic or prophylactic treatment of diseases that are at least partially caused by an unwanted increase in bone resorption, such as for example osteoporosis.

Certain products of formula (I) of the present invention can therefore, for example, inhibit the adhesion of osteoclasts to the bone surface and thus the resorption of bone by osteoclasts.

Bone diseases, the treatment or prevention of which require the use of compounds of formula (I) or their prodrugs, are especially osteoporosis, hypercalcemia, osteopenia, which is for example caused by bone metastases, dental disorders, for example periodontitis, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, Paget's disease, osteopenia caused by immobilization. Furthermore, the compounds of formula (I) can be used to alleviate, prevent or treat bone diseases caused by treatment with glucocorticoids, therapies associated with taking steroids or corticosteroids, or male or female sex hormone deficiency.

All these disorders are characterized by bone mass loss, which is caused by an error in the balance between bone formation and bone destruction, and which can be influenced in a convenient way by inhibiting bone resorption through osteoclasts.

Certain products of formula (I) of this invention may possess, in addition to their specific properties of kinase or protease inhibition, beneficial effects on the cell, such as antiproliferative properties, and especially effects on apoptosis.

From works described in the literature, such as WO 97/20842, it is known that there is a connection between the cell cycle and apoptosis. Some of the pathways leading to apoptosis are kinase or protease dependent.

The products of this invention are particularly suitable for tumor therapy.

Therefore, the objects of the present invention can also enhance the therapeutic effects of currently used anti-tumor agents. Therefore, the products of formula (I) of this invention have particularly antimitotic and antineurodegenerative properties.

Certain products of this invention can be inhibitors of vasoconstrictive and hypertensive effects, and thus cause an anti-ischemic effect, and also act against stimulant effects at the level of certain cell types, especially smooth muscle cells, fibroblasts, neuronal cells and bone cells.

Therefore, the products according to this invention can be used for the treatment of diseases such as proliferative diseases, cancer, return of stenosis, inflammation; allergies, cardiovascular diseases or certain infectious diseases.

The products of this invention can also be used for the treatment of certain gastrointestinal diseases, gynecological disorders, and especially for the effect of relaxing the uterus.

The products of formula (I) of this patent application may therefore have suitable pharmacological properties justifying their therapeutic use.

As medicaments, the products of formula (I) which are found in all racemic, enantiomeric and diastereomeric isomeric forms, as well as in the form of addition salts of said products of formula (I) with pharmacologically acceptable mineral and organic acids or mineral and organic bases, are therefore a special subject of this invention.

As medicaments, the products defined by formula (Ia) or (Ib) are therefore an even more specific subject of the invention, whereby the said products of formula (Ia) or (Ib) are found in all racemic, enantiomeric and diastereomeric isomeric forms, as well as in addition forms salts of the mentioned products of formula (Ia) or (Ib) with pharmacologically acceptable mineral and organic acids or mineral and organic bases.

As medications, the products described below in the examples are a very special subject of the invention, and in particular the products of 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-pyradazino[1,2-a][1,2] diazepin-1(S)-carboxamide]-5-methyl-1-benzoyloxy-hexan-2-one

◾ 3-[9(S)-(2-furanoyl)amino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyradazino[1,2-a] [1,2]diazepin-1(S)-carboxamide]-5-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-pyradazino[1,2 -a][1,2]diazepin-1(S)-carboxamide]-4-(4-hydroxyphenyl)-1-(2,6-dichlorobenzoyloxy)-butan-2-one

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

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

◾ (2-propenyl)-(4S)-6-diazo-4-[[[(1S,9S)-9-[(3-methoxybenzoyl)-amino]-octahydro-6,10-dioxo-6H-pyridazino[ 1,2-a][1,2]diazepin-1-yl]-carbonyl]-amino]-5-oxo-hexanoate

◾ (2-propenyl)-(4S)-6-diazo-4-[[[(1S,9S)-9-[[(2-furanoyl)-carbonyl]-amino]-octahydro-6,10-dioxo- 6H-Pyridazino[1,2-a][1,2]diazepin-1-yl]-carbonyl]-amino]-5-oxo-hexanoate

◾ (2-propenyl)-(4S)-6-diazo-4-[[[(1S,9S)-9-[[(cyclohexylamino)-carbonyl]-amino]-octahydro-6,10-dioxo-6H- pyridazino[1,2-a][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-oxo-hexanoate

◾ (2-propenyl)-(4S)-6-diazo-4-[[[(1S,9S)-9-[[[(2-(p-2-yl)ethyl]amino]-carbonyl]-amino ]-octahydro-6,10-dioxo-6H-pyridazino[1,2-a][1,2]diazepin-1-yl]carbonyl]-amino]-5-oxo-hexanoate

◾ (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-oxo-hexanoate

◾ (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-oxo-hexanoate

◾ (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-oxo-hexanoate

◾ (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-oxo-hexanoate

◾ 9-[9(S)-[[(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-furanoyl)-carbonyl]-amino] -octahydro-6,10-dioxo-6H-pyridazino[1,2-a][1,2]diazepin-1-yl]-carbonyl]-amino]-5-oxo-hexanoate

◾ (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-oxo-hexanoate

◾ (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[1,2-a][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-oxo-hexanoate

◾ (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-oxo-hexanoate

◾ (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-oxo-hexanoate

◾ (2-propenyl)-(4S)-6-[(1-phenyl-1H-tertrazol-5-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- oxo-hexanoate

◾ (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-oxo-hexanoate

◾ (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-oxo-hexanoate

◾ (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-oxo-hexanoate

◾ (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-oxo-hexanoate

◾ (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-oxo-hexanoate

◾ (2-propenyl)-(4S)-6-acetyl-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-oxo-hexanoate

◾ (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- oxo-hexanoate

◾ (2-propenyl)-(4S)-6-[(1-phenyl-1H-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-oxo-hexanoate

◾ (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-oxo-hexanoate

◾ (2-propenyl)-(4S)-6-[(2,6-dichlorobenzoyl)-oxy]-4-[[[(1S,9S)-9-[(methylsulfonyl)-amino]-octahydro-6, 10-dioxo-6H-pyridazino[1,2-a][1,2]diazepin-1-yl]-carbonyl]-amino]-5-oxo-hexanoate

◾ 9-[(9S)-[[(4-phenoxyphenyl)-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-(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-naphthenyl)-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-6H-(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-(1S)-pyridazino[1,2-a][1,2]diazepine-1-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-[(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[(3S)-[[(4-phenoxyphenyl)-amino]-carbonyl]-amino]-octahydro-6,10-dioxo-6H-(1S) -pyridazino[1,2-a][1,2]diazepin-1-yl]-carbonyl]-amino]-butyl]-pentanedioate

◾ 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-oxo-ethyl]-piperazin-1-yl]]-3-oxo-2-butyl]-octahydro-6,10-dioxo-6H-(1S)-pyridazino[1, 2-a][1,2]diazepine-1-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-[(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-carboxamide

◾ 9-[(9S)-(2-methyl-1-oxo-propyl)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)-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

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

The products of formula (I) of this invention can therefore be used in particular in the form of medicaments that inhibit an unwanted mechanism that provokes the emergence of a pathological change under the influence of one or more proteases or kinases: therefore, the procedure can consist of administering an inhibitory amount of such a medicament according to this invention to a patient whose treatment requires inhibiting the effect of such protease or kinase.

The medicinal products that are the subject of the invention can therefore be used for the treatment and prevention of cardiovascular diseases associated with changes in vasomotor or volemia, myocardial infarction and its consequences, heart failure, renal insufficiency, angina pectoris, hyperaldosteronism, arterial hypertension and its consequences; for the treatment and prevention of complications, especially cardiac and vascular hypertrophy, as well as the development of fibrosis at the level of target organs, for the prevention and treatment of hypertension, metabolic, endocrinological and neurological disorders, endotoxic shock, "suparachnoid" hemorrhage, arrhythmia, asthma, acute renal failure, preeclampsia and diabetes.

The medicinal products that are the subject of the invention are therefore used for the treatment of vascular spasms, for the treatment of the consequences of cerebral hemorrhage, for the treatment of coronary spasms, and peripheral vascular spasms. In particular, these medications can be used for the treatment of heart failure, in the prevention of post-angioplasty recurrence of stenosis, in the prevention of cardiac and vascular fibrosis, for the treatment of atherosclerosis and certain forms of hypertension such as pulmonary hypertension, as well as for the treatment of asthma.

These medicaments which are the subject of the invention can also be used for the treatment of glaucoma and various types of visceral spasms, as well as neuronal protective substances or also in the prevention of post-angioplasty recurrence of stenosis.

the medications that are the subject of the invention can be especially used due to their antihypertrophic and antifibrotic effects at the cardiac and vascular level. More specifically, they can be used to treat and prevent diabetes-related cardiovascular disorders.

Medicinal products that are the subject of the invention can also be used for the treatment of osteoporosis and as neuroprotection.

The medicinal products that are the subject of the invention can also be used to treat memory disorders and cognitive function disorders, as well as anxiety.

The medicinal products that are the subject of the invention can also be used as antimitotics, in cancer chemotherapy, as well as for the treatment of psoriasis, parasitosis caused by protozoa or fungi, and for the treatment of Alzheimer's disease, or for the treatment of neuronal apoptosis.

A very special subject of the invention are pharmaceutical preparations that contain at least one medication as an active substance, which is defined in the above section.

A very special subject of the invention are the pharmaceutical preparations that are defined in the above section, and which are characteristically used as medications, as defined in the above section.

The pharmaceutical compositions of the present invention, as defined above, can be administered buccally, parenterally, or topically in the form of topical application to the skin and mucous membrane, or by intravenous or intramuscular injection.

These preparations can be solids or liquids, and can be present in all pharmaceutical forms that are commonly used in human medicine, such as, for example, flat tablets or dragees, pills, tablets, gelatin capsules, drops, granules, injectable preparations, ointments, creams or gels; they are prepared according to the usual procedures. The active ingredient can be incorporated together with excipients commonly used in these pharmaceutical preparations, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous solvents, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various humectants, dispersants, emulsifiers, and preservatives.

The usual dose, which is variable depending on the product where it is used, on the treated subject, and on the disease in question, can be for example from 0.1 to 2 g per day.

A special subject of the invention are pharmaceutical preparations, as defined in the above section, which are characteristically used as antimitotics, then especially in cancer chemotherapy, and also for the treatment of psoriasis, and parasitosis such as those caused by fungi or protozoa, i.e. Alzheimer's disease .

Pharmaceutical preparations, as defined in the above section, which are characteristically used as antineurodegenerative medications, especially as neuronal antiapoptotic medications, are a very special subject of the invention.

A special subject of the invention is the use of products of formula (I), as defined in the above section, in the preparation of pharmaceutical preparations used for the treatment or prevention of diseases that require inhibition of one or more metabolic enzymes, as defined in the above section.

A special subject of the invention is therefore the use of products of formula (I), as defined in the above part, in the preparation of pharmaceutical preparations used for the treatment of diseases caused by anomalies at the level of regulation or activity of a certain number of metabolic enzymes. Such anomalies play a role in certain pathological changes in humans, which represent the special interest of this invention.

Therefore, this invention particularly relates to the use of products of formula (I) of this invention which are protease or kinase inhibitors. This invention therefore relates to the inhibition of one of these protease or kinase enzymes, and requires the use of the products of this invention as inhibitors in the event that inhibition of such protease or kinase is indicated.

A very special object of the invention is therefore the use of products of formula (I), as defined in the above section, or pharmaceutically acceptable salts of said products of formula (I) for the preparation of medications intended for the prevention or treatment of diseases in which metabolic enzymes are involved, such as are proteases or kinases.

An even more specific object of the invention is the use of products of formula (I), as defined in the above section, or pharmaceutically acceptable salts of said products of formula (I), which are characterized by preventing or treating diseases selected from the following group consisting of: cardiovascular diseases, cancers, diseases of the central nervous system, inflammatory diseases, infectious diseases, as well as bone diseases.

A very specific object of the invention is the use of products of formula (I), as defined in the above section, or pharmaceutically acceptable salts of said products of formula (I), which are characterized by preventing or treating diseases of the central nervous system or bone diseases such as osteoporosis .

The subject of this invention is therefore the use of products of formula (I), as defined in the above section, or pharmaceutically acceptable salts of said products of formula (I) in the preparation of medications that are particularly intended for the prevention and treatment of bone metabolism diseases.

A very specific subject of the invention is therefore the use of products of formula (I), as defined in the above section, in the preparation of pharmaceutical mixtures intended for the treatment of arterial hypertension, cardiac insufficiency, post-angioplasty recurrence of stenosis, vascular spasms, consequences of cerebral hemorrhage and renal insufficiency.

A very specific subject of the invention is therefore the use of the products of formula (I), as defined in the above part, in the preparation of pharmaceutical mixtures intended for the treatment of myocardial infarction, for the prevention of post-angioplasty recurrence of stenosis and for the prevention of cardiac and vascular fibrosis.

A very specific subject of the invention is therefore the use of the products of formula (I), as defined in the above section, in the preparation of pharmaceutical mixtures intended for the treatment of renal insufficiency.

A very specific subject of the invention is therefore the use of the products of formula (I), as defined in the above section, in the preparation of pharmaceutical mixtures intended for the treatment and prevention of cardiovascular disorders associated with diabetes.

The specific subject of the invention is therefore the use of the products of formula (I), as defined in the above part, in the preparation of medicines intended for cancer chemotherapy, for the treatment of psoriasis, and parasitosis such as those caused by fungi or protozoa, for the treatment of Alzheimer's disease or for the treatment of neurodegenerative changes , and especially neuronal apoptosis.

The starting products of formula (VIa), which represent natural or non-standard amino acids, are commercially available, that is, they can be prepared according to the usual procedures known to skilled persons.

In particular, the following products of the formula (Via): Glu, Gly, Ala, Val, Phe or Tyr can be mentioned, and these amino acids can preferably be protected, for example with an alloc or tert-butyl group.

Products of the formula (Vib) can be prepared from the so-called natural or non-standard amino acids of the formula (Via), as indicated in the above section, by coupling the Fmoc radical with the N-terminal amino functional group of a certain amino acid: such a reaction is particularly described in the article with the following reference : "Mueller, A.; Vogt, C.; Sewald, N; Synthesis (1998), (6), 837-841”.

A large number of products of formula (VIa) are also commercially available, wherein the amino acids are in their fmoc protected form, and thus can be an integral part of the starting products for the process in this patent application, described in Figure 1.

In particular, the following products of formula (VIb) can be mentioned: Fmoc-Leu, Fmoc-L-Glu(aloc); Fmoc-Gly; Fmoc-Ala; Fmoc-Val; Fmoc-Phe, as well as Fmoc-Zyr(OtBu).

The product of formula (II) is methyl ester 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)-carboxylic acids. Such an initial product of formula (II) can be prepared according to the usual procedures known to skilled persons, as well as in the manner indicated in the patent application EP 94095, i.e. in the following publications:

◾ Attwood M. et al., J. Chem. Soc., Perkin trans, 1, (1986), (6), 1011-19;

◾ Thomas W. et al., J. Chem. Soc., Perkin trans, 2, (1986), (5), 747-55;

The initial product of formula (III), i.e. R1X where X represents a hydrogen atom, can be selected in particular from Table 1, described in Figure 2 of this invention: in that table, X represents a chlorine atom, but it can also represent a bromine atom. Such a product of formula (III) is commercially available, i.e. it can be prepared according to the usual procedures known to those skilled in the art.

As an example, the following products of formula (III) can be mentioned: benzoyl chloride, isopropanoic acid chloride, cyclohexyl isocyanate, methanesulfonyl chloride, as well as benzenesulfonyl chloride.

The starting product of formula (VIII), i.e. R4'-L-H in which R4' and L have the meaning indicated above, can be selected in particular from Table 2 described in Figure 3 of this invention. Such a product of formula (VIII) is commercially available, that is, it can be prepared according to the usual procedures known to those skilled in the art.

In particular, the following product of formula (VIII) can be mentioned: mercaptobenzimidazole, benzoic acid, 1-phenylpiperazine, 4-fluorophenol, piperidine.

The experimental section that follows below provides examples of such starting products.

Finally, the subject of this invention are new industrial products, compounds of formula (VII), as defined in the process of this invention.

The tables from Figure 4, which are given further on pages 69 to 182, represent the products that are obtained according to the process described in the above part according to this invention: these products represent examples of the products of formula (I) of this invention, and are characterized in the following tables below using their molecular weights shown as Mm (Mw) in those tables. Such Mm values listed in these tables are determined as follows.

The products presented in the tables of Figures 4 were prepared and characterized using our own HPLC-MS spectra, i.e. by high-pressure liquid chromatography connected to a mass spectrograph: this chromatography was carried out on an ODS-AQ column with an acetonitrile/water mixture as an eluent in variable proportions that are a function of the compounds . Electron spray in positive mode was used to determine molecular masses. The mass of each individual product is determined using the mass of the H+ molecular ion, i.e. in the form of sodium or acetonitrile adduct.

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

For the other examples of this patent application, indicated in the tables of Figure 4, in which the corresponding amino acid is Leu, Stage 1 of the synthesis of these products is carried out in the same way as in Example 1, described below in the experimental part.

For other examples of this patent application, indicated in the tables of Figure 4, where the corresponding amino acid is not Leu, Stage 1 of the synthesis of these products is carried out in the same way as in Example 1, described in the continuation of the experimental part, where instead of Fmoc-Leu, a compound of the formula is used (Vib) corresponding to a specific amino acid of interest, ie the following Fmoc amino acids: Fmoc-L-Glu(Aloc); Fmoc-Gly; Fmoc-Ala; Fmoc-Val; Fmoc-Phe and Fmoc-Tyr(OtBu): in this way the final products are obtained in which the amino acid residue is Glu or Glu(Aloc), Gly, Ala, Val, Phe or Tyr(OtBu) residue.

For other examples of this patent application, indicated in the tables of Figure 4, where the corresponding amino acid is

tyrosine, the preparation from Example 3 listed below is carried out, using the product of formula (VI) Fmoc-Tyr(OtBu), in order to obtain the corresponding final product of formula (I) in which the hydroxyl radical is converted to tert- butoxy form: the hydroxyl functional group is then free in the product of formula (I) thus obtained, to give a new product of formula (I), in which the amino acid residue is then tyrosine. Deprotection of such a derivative of formula (I) where R 2 is (tBuO)PhCH 2 can be carried out for example by standard procedures with trifluoroacetic acid in a 50/50 mixture with dichloromethane. The diagram of such a reaction is shown below.

[image]

The examples given in Figure 4, described below, illustrate the process described above, but do not limit the present invention in any way.

The examples described in the experimental part of this patent application, which are therefore Examples 1 to 3 of the tables of Figures 4, show examples of application of the present invention that illustrate the invention without limiting it in any way.

Experimental part

Example 1: 3-[9(S)-benzylamino-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-benzolioxy-hexan-2-one

Step 1: N-Fmoc-3-amino-1-diazo-5-methyl-hexan-2-one

[image]

To a suspension of 3.52 g of Fmoc-leucine (11.3 mmol) in 35 ml of dichloromethane, 1.3 ml of 4-methyl-morpholine (11.9 mmol; 1.05 eq.) and 1.5 ml of isobutyl chloroformate are added in order (11.6 mmol; 1.03 equiv.) at -10 °C under nitrogen atmosphere. The reaction mixture becomes clear, after which a precipitate of 4-methyl-morpholine hydrochloride appears. After stirring for 1 hour at 10 °C, the precipitate is filtered off.

The resulting solution was cooled to -10 °C, and then 75 ml (19.1 mmol. 2 equiv.) of a 0.3 M solution of diazomethane in CH2Cl2 was added under a nitrogen atmosphere. The temperature is progressively raised to room temperature. After the reaction for one hour at room temperature, the mixture is poured into 100 ml of saturated sodium bicarbonate solution. The organic phase is washed with water (100 ml), dried over magnesium sulfate, and then concentrated to dryness. The crude product is directly chromatographed on 500 g of silica gel using CH2Cl2/AcOEt in the ratio 95/5. 2.6 g (yield = 65%) of a yellowish solid was isolated.

MS: MH+378

NMR H1 (CDCl3) (250 MHz) 0.95 (6H; d; 2CH3), 1.40 to 1.85 (3H; 2m; 1CH and 1CH2) 4.18 (1H, t, CH Fmoc) 4.4 to 4.55 (2H; bd, CH2 Fmoc), 5.12 (1H; bs; CH2N2), 5.28 (1H, bd, NHCO), 4.42 (2H; bd; CH2 Fmoc), 5.12 (1H; bs; CH2N2), 6.90 to 7.45 (9H; m; aromatic Hs), 7.55 (2H; bt, aromatic Hs), 7.77 (2H; bd, aromatic Hs -s).

Stage 2:

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

[image]

To a solution of 500 mg of amine (1) (1.96 mmol) in 12 ml of CH2Cl2, 0.68 ml of diisopropylethylamine (2 mmol; 2 eq.) and 0.26 ml of benzoyl chloride (2.16 mmol; 1.1 eq.) at 0 °C in a nitrogen atmosphere. The temperature rises to room temperature. After stirring for 1 hour, 12 ml of 1 N HCl was added. The mixture is decanted, and the organic solution is washed with saturated NaCl solution and with 12 ml of saturated sodium bicarbonate solution. The organic solution is dried over magnesium sulfate and then concentrated to dryness. 0.424 g (yield = 54%) of methyl benzoylaminopyrazepate was 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]diazepine-1(S)- carboxylic acid

[image]

In a solution of 424 mg (1.18 mmol) methyl ester 9(S)-benzoylamino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyridazino[1,2 -a]diazepine-1(S)-carboxylic acid in 10 ml of methanol at 0 °C is added 99 mg of lithium hydroxide (2.36 mmol; 2 eq.). The temperature is raised to room temperature, and then the reaction is maintained overnight. The solution is concentrated to 5 ml using a rotavapor. Add 5 ml of water and adjust the pH of the solution to 1 by adding a few drops of concentrated HCl. The mixture is extracted with 2 x 5 ml of ethyl acetate. The organic phase is washed with 5 ml of saturated NaCl solution, dried over magnesium sulfate and concentrated to dryness. 305 mg of 9(S)-benzoylamino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyridazino[1,2-a]diazepine-1(S )-carboxylic acids (yield = 75%).

MS: [MH]- 344; MH+346; MNa+ 368

NMR-H1 (CDCl3) (300 MHz): 1.76 (2H; m; CH2), 1.96 and 2.35 (2H; 2m; CH2), 1.97 and 2.84 (2H; 2m; CH2 ), 2.41 and 3.48 (2H; m; CH2), 4.96 and 4.68 (2H; m and bd; CH2), 5.17 (1H; m; HN), 5.47 (1H, dd. CHCO2H), 7.26 (1H; d; CONH), 7.38 to 7.53 (3H; m; aromatic Hs), 7.81 (2H,; bd; aromatic Hs).

Step 3: 3-[9(S)-benzoylamino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyradazino[1,2-a][1, 2]diazepin-1(S)-carboxamide]-5-methyl-1-diazo-hexan-2-one

[image]

A solution of 378 mg (1 mmol) of N-Fmoc-3-amino-1-diazo-5-methyl-hexan-2-one in 3.5 ml of CH2Cl2 was treated with DBU (2.1 mmol; 2.1 eq.) at 0 °C in a nitrogen atmosphere. After one hour of the reaction, the solution is placed on a silica gel column (40 g) and quickly eluted with a CH2Cl2/methanol solution in the ratio 90/10. The resulting yellow oil (198 mg, yield = 100%) is translated into the salt form in 3.5 ml of CH2Cl2, after which 0.35 g (1 mmol) of the acid obtained in Step 2 is added. 625 mg of TBTU (1 .1 mmol; 1.1 equiv.) and 0.35 ml of DIEA (2 mmol; 2 equiv.) in a nitrogen atmosphere at 0 °C. The reaction is maintained at room temperature overnight, after which the reaction medium is poured into 20 ml of saturated NaHCO3 solution and extracted with 2 x 10 ml of ethyl acetate. The combined organic phases are washed with water (20 ml) and then with saturated KHSO3 solution. The solution is dried over MgSO4 and concentrated to dryness. 244 mg of foam was isolated (yield = 50%).

MS: [M+Na]+ 505; MH+ -N2 455; MH+ 483

NMR-H1 (CDCl3) (300 MHz): 0.95 (6H; dd; 2CH3), 1.56 (2H m; CH2), 1.69 (1H; m; CH), 4.53 (2H; m ; CH2), 6.40 (1H; bd; NH), 1.66 (2H; m; CH2), 1.92 (2H; m; CH2), 1.90 and 2.90 (2H; 2m; CH2 ), 2.39 and 3.24 (2H; 1dd; and 1dt; CH2); 3.01 and 4.66 (2H; 1dt; and 1m; CH2), 4.66 (1H; td; CH), 5.17 (1H; m; CH), 7.02 (1H; d; NH) , 5.40 (1H; bs; CHN2), 7.46 (2H; dd; aromatic 2Hs in the meta position), 7.51 (1H, m; aromatic Hs in the para position), 7.81 ( 2H; dd; aromatic Hs in the ortho position).

Step 4: 3-[9(S)-benzoylamino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyradazino[1,2-a][1, 2]diazepin-1(S)-carboxamide]-5-methyl-1-benzoyloxo-hexan-2-one

a) 3-[9(S)-benzoylamino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyradazino[1,2-a][1,2 ]diazepin-1(S)-carboxamide]-5-methyl-1-bromo-hexan-2-one

[image]

A solution of 219 mg of the compound (0.38 mmol) in 2 ml of CH2Cl2 is treated at 0 °C with 0.2 ml of a 30/70 HBr (37%)/AcOH solution. After the reaction is carried out for half an hour at 0 °C, the reaction mixture is poured into 20 ml of saturated NaHCO3 solution. The mixture was extracted with 2 x 10 ml of AcOEt. The organic phases are washed with water (20 ml), dried over MgSO4 and concentrated under vacuum. 203 mg (yield = 94%) of bromoketone was isolated in the form of a yellow foam.

MS: M+H+ 535

NMR H1 (CDCl3) (300 MHz): 0.97 (6H; d; 2CH3), 1.67 (1H; m; CH), 1.51-1.69 (2H; 2m; 2H), 1, 66 (2H; m; CH2), 1.94 (2H; m; CH2), 1.88 to 1.98 and 2.12 to 2.90 (2H; 2m; CH2), 2.40 and 3.16 to 3.47 (2H; dd and m; CH2), 3.01-4.61 (2H; 2m; CH2) 4.57 (1H; t; CH), 5.16 (1H; m; CH); 7.00 (1H; d; NH), 4.05 (2H; AB, CH2), 7.47 (2H, td; aromatic 2Hs in the meta position), 7.53 (1H; m; aromatic 2H- these in the para position), 7.82 (2H; dd; aromatic 2Hs in the para position).

b) 3-[9(S)-benzoylamino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyradazino[1,2-a][1,2 ]diazepin-1(S)-carboxamide]-5-methyl-1-benzoyloxy-hexan-2-one

[image]

11 mg of KF (0.186 mmol; 2 eq.) and then 13.7 mg of benzoic acid are added to a solution of 50 mg of previously obtained bromoketone (0.093 mmol) in 0.6 ml of DMF. The reaction is left overnight with vigorous stirring at room temperature. The reaction mixture is poured into 10 ml of saturated NaHCO3 solution, and the extraction is carried out with 2 x 5 ml of ethyl acetate. The combined organic phases are washed with water (10 ml), dried over MgSO4 and concentrated under reduced pressure. 42 mg of light yellow resin was obtained (yield = 78%).

MS: MH+577; MNa+ 599

NMR-H1: 0.97 (6H; d; 2CH3), 1.71 (1H; m; CH), 1.52-1.75 (2H; 2m; CH2), 4.82 (1H; m; CHNH ), 6.27 (1H; d; CHNH), 2.40-3.19 (2H; 2m; CH2), 3.02-4.60 (2H; 2m; CH2), 1.50 to 2.20 (2H; m; CH2), 5.03 (2H; AB J = 17 Hz); COCH2O), 5.17 (2H, m; 2CH), 7.00 (1H; d; CONHCH), 7.40 to 7.65 (6H; m; aromatic 6Hs), 7.81 and 8.09 (4H; dd; aromatic 2 × 2Hs in ortho position from 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]diazepin-1(S)-carboxamide]-5-methyl-1-(2,6-dichlorobenzolyoxy)-hexan-2-one

[image]

The procedure is carried out starting with the product obtained in Stage b) Stage 3 from Example 1 as follows:

In the solution 11.6 mg (0.022 mmol) 3-[9(S)-(2-furanoyl)amino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H 11 mg of dimethylaminomethylpolystyrene resin (0.044 mmol; 2 eq.). The reaction is left overnight with stirring. The mixture is filtered through a sinter funnel, and the resin is washed twice with 2 ml of CH2Cl2. After intensive evaporation under vacuum, 9 mg of the expected product was isolated (yield = 82%).

LC-MS (purity >80%)

MH+ 636

Example 3: 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]diazepin-1(S)-carboxamide]-4-(hydroxyphenyl)-1-(2,6-dichlorobenzolyoxy)-butan-2-one

Step 1: 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]diazepin-1(S)-carboxamide]-4-(4-tert-butylphenoxy)-1-(2,6-dichlorobenzolyoxy)-butan-2-one

[image]

The procedure is carried out as in Step 1 of Example 1 with the use of another compound of the formula (VI): fmoc-TYR(OtBu) instead of the compound of the formula (VI): Leu-fmoc in the same amount. After that, the procedure is carried out under the same reaction conditions as for Steps 2 to 4 from Example 1, and in this way the expected product is obtained.

Step 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]diazepin-1(S)-carboxamide]-4-(4-hydroxyphenyl)-1-(2,6-dichlorobenzolyoxy)-butan-2-one

[image]

A solution of 16 mg (0.22 mmol) of the product obtained in Step 1 above in 0.25 ml of CH 2 Cl 2 is treated with 0.25 ml of trifluoroacetic acid. The reaction is allowed to stir for 1 hour at room temperature. The solvent is evaporated to dryness. 14.4 mg of the expected product was isolated (yield = 95%).

LC-MS (purity >80%) MH+ 686

The products of Examples 4 to 609 were prepared by the procedure indicated above, and their structures are indicated in the Tables of Figure 4.

Example 610: pharmaceutical preparation

The tablets are prepared according to the following formula:

[image]

(excipients listed in detail: lactose, talc, starch, magnesium stearate).

Pharmacological testing

Cathepsin K inhibition test:

The tested products (10 mM) are diluted up to 1 MW in DMSO, and placed in Nunc polystyrene wells in an amount of 2 μl per well. Column 12 on the plate is reserved for control samples, and 1 μl of DMSO (without product) per well is placed in them. The plates are stored at -80 °C and thawed on the day of the experiment.

The products are diluted to 50 μM by adding 38 μl of reaction buffer: sodium acetate 100 mM, EDTA 5 mM, DTT 1 MW, pH 5.5. Addition, as well as all other pipetting operations, are performed using a CybiWell pipette type 96. After mixing the solutions, each product is transferred to 2 wells (duplicates) on a Grainer black plate with wells in an amount of 10 μl per well. Therefore, two 96-well plates can be assayed in a 384-well plate.

A 50 μM substrate solution, Z-Val-Arg-AMC (Calbiochem), was prepared in the reaction buffer. After that, the substrate was distributed in all the wells of the 384-well plate (20 μl per well).

A cathepsin K solution at a concentration of 12.5 ng/ml was prepared in the reaction buffer and distributed in all wells of the 384-well plate (20 μl per well), except for 16 wells that serve as 100% inhibition control (columns 23 and 24, rows I and P) into which 20 μl buffer without enzymes is placed. 100% inhibition controls are placed in columns 23 and 24, rows A through H containing no products.

The plates are then incubated for 2 h at room temperature, after which they are read on a fluoroscan (Labsystems): excitation 390 nm; emission 460 nm.

The final concentrations of each individual reagent are:

products 10 μM; substrate 20 μM, enzyme 5 ng/ml.

The % inhibition for each product is calculated by using the points at 0 and 100% inhibition of each plate as references. Products exhibiting significant inhibition in the concentration range of 50 to 0.5 μM are then retested to determine the IC50.

Cathepsin B inhibition test:

The protocol is identical to that for cathepsin K except for:

- Z-arg-arg-AMC substrate (Calbiochem), 50 μM solution, final concentration 20 μM

- cathepsin B (Calbiochem), solution of 40 ng/ml, final concentration 16 ng/ml

- incubation for 1 hour at room temperature

Papain inhibition assay

The protocol is identical to that for cathepsin K except for:

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

- incubation for 30 minutes at room temperature

the results

The IC50's obtained for the products of the examples are shown in Table I below, in micromoles.

TABLE I

[image] [image] [image] [image]

Claims (22)

1. Products of formula (I), [image] indicated that: R1 represents -C(O)-R5, -SO2-R5 or -C(O)-NR6R5 radical, where R6 represents a hydrogen atom or a straight or branched alkyl radical containing at most 4 carbon atoms, and R5 represents a straight or branched alkyl radical containing at most 6 carbon atoms, a cycloalkyl radical containing at most 6 carbon atoms, phenyl, naphthyl, or a 5- or 6-membered monocyclic heterocyclic saturated or unsaturated radical containing one or more identical or different heteroatoms selected from the group consisting of O, N or WITH, alkyl, phenyl and heterocyclic radicals, as defined above for R1, which are preferably substituted with one or more radicals selected from the group consisting of halogen atoms, and straight or branched alkyl or alkoxyl radicals containing at most 4 carbon atoms, hydroxyl, acyl radicals containing a maximum of 7 carbon atoms, trifluoromethyl, cyano, thienyl, phenyl phenoxy and isoxazolyl radicals; R2 and R7 are such that or R7 represents a hydrogen atom, and R2 is such that [image] group in the product of formula (I) represents a so-called natural or non-standard amino acid residue [image] structures with the exception of aspartic acid, or R2 and R7 form a ring together with the nitrogen and oxygen atoms to which they are attached in such a way that the group formed in the products of formula (I): [image] represents a so-called natural or non-standard amino acid residue: [image] structures; R3 represents -CH=N2 radical or -CH2-L-R4 radical, where L represents a single bond or a divalent radical selected from the group consisting of -O-, -O-C(O)-, -NH-, and -S-(CH2 )n-, where n represents an integer from 0 to 6, and R4 represents a straight or branched alkyl radical containing at most 6 carbon atoms, a monocyclic or bicyclic carbocyclic or heterocyclic radical containing from 5 to 10 members, saturated or unsaturated, containing one or more identical or different heteroatoms selected from the group consisting of O, N, NH or S, where it may contain a -C(O) member, carbocyclic and heterocyclic alkyl radicals, as defined above for R4, which are optionally substituted with one or more radicals selected from the group consisting of halogen atoms; hydroxyl radicals, free carboxyl radicals in the form of salts or esters; -C(O)-NH2, -C(O)-NH(alkyl), -C(O)-N(alkyl)(alkyl), -NH-C(O)-(alkyl), -N(alkyl) -C(O)-(alkyl); thienyl; phenyl; alkylphenyl; alkyl and alkoxyl radicals which are optionally substituted with one or more radicals selected from the group consisting of acyl radicals containing 7 carbon atoms, cyano, -NH2, -NH(alkyl), -N(alkyl)(alkyl) and phenyl radicals, where it is understood that the above-mentioned radicals are straight or branched alkyl and alkoxyl radicals, and that they contain a maximum of 4 carbon atoms, the symbol * indicates a carbon atom that can be in S or R configuration, and the mentioned products of formula (I) can be in all possible racemic, enantiomeric and diastereomeric isomeric forms, as well as in additional forms of salts of the mentioned products of formula (I) with mineral and organic acids, or mineral and organic bases. 2. Products of formula (I), as defined in claim 1, characterized in that R1 and R3 have the meaning as indicated in the above part, and R2 represents a so-called natural amino acid residue with the exception of aspartic acid, said products of formula (I) are found in all possible racemic, enantiomeric and diastereomeric isomeric forms, as well as addition salts of the mentioned products of formula (I) with mineral and organic acids, i.e. mineral and organic bases. 3. Products of formula (I), as defined in any of claims 1 and 2, characterized in that R1 and R3 have the meaning as defined in claims 1 and 2, and R2 and R7 are such that: or R7 represents a hydrogen atom, and R2 represents a hydrogen atom or a straight or branched alkyl radical containing at most 6 carbon atoms, preferably substituted with one or more radicals selected from the group consisting of amino; acylamino; NH=C(NH2)-NH-; mercapto; straight or branched alkylthio radicals containing at most 4 carbon atoms; straight or branched hydroxyl; alkyl radicals containing no more than 4 carbon atoms; imidazolyl, indolyl radicals; a phenyl radical that is itself substituted by one or more radicals selected from the group consisting of halogen atoms, a hydroxyl radical, a straight or branched alkoxy radical containing at most 4 carbon atoms, and a phenoxy radical that is itself substituted, if possible, by one or more radicals selected from groups consisting of iodine atoms and a hydroxyl radical; and -C(O)-O-R8 radical where R8 represents a hydrogen atom or a straight or branched alkyl or alkenyl radical containing no more than 6 carbon atoms, or R2 and R7 form a ring together with the nitrogen and carbon atoms to which they are attached, and the ring includes from 5 to 7 members, and is preferably substituted by one or more hydroxyl or straight or branched alkyl radicals containing at most 4 carbon atoms, whereby the mentioned products of formula (I) are found in all possible racemic, enantiomeric and diastereomeric isomeric forms, as well as in the forms of addition salts of the mentioned products of formula (I) with mineral and organic acids, i.e. mineral and organic bases. 4. Products of formula (I), as defined in any of claims 1 to 3, characterized in that R1 and R3 have the meaning as defined in claims 1 and 3, and R2 and R7 are such that: or R7 represents a hydrogen atom and R2 has the meaning as indicated in claim 3, or R2 and R7 together with nitrogen and carbon atoms form a pyrrolidinyl ring, preferably substituted by one or more hydroxyl or straight or branched alkyl radicals containing at most 4 carbon atoms, whereby the mentioned products of formula (I) are found in all possible racemic, enantiomeric and diastereomeric isomeric forms, as well as in the form of addition salts of the mentioned products of formula (I) with mineral and organic acids, or mineral and organic bases. 5. Products of formula (I), as defined in any of claims 1 to 3, characterized in that they correspond to formula (Ia): [image] where: R1a represents -C(O)-R5a, -SO2-R5a or -C(O)-NR6aR5a radical where R6a represents a hydrogen atom or a straight or branched alkyl radical containing a maximum of 4 carbon atoms, and R5a represents a radical selected from the group consisting of a straight or branched alkyl radical containing a maximum of 6 carbon atoms; cycloalkyl containing no more than 6 carbon atoms; phenyl, naphthyl, furyl, morpholinyl, thienyl, pyridyl, whereby alkyl, phenyl, thienyl and pyridyl radicals are preferably substituted with one or more radicals selected from the group consisting of halogen atoms and straight or branched alkyl or alkoxyl radicals containing a maximum of 4 carbon atoms, hydroxyl, acyl containing a maximum of 7 carbon atoms , and phenoxy, trifluoromethyl, cyano, thienyl, phenyl and isoxazolyl radicals; R2a has the meaning as indicated above when R7 represents a hydrogen atom, R3a represents -CH=N2 radical or -CH2-La-R4a radical, where La represents a single bond or a divalent radical selected from the group consisting of -O-, -O-C(O)- and -S-(CH2)na, where on represents an integer from 0 to 3, and R4a represents a radical selected from the group consisting of straight or branched alkyl radicals containing at most 6 carbon atoms; and phenyl radicals; tetrazolyl; piperazinyl; piperidyl; pyridyl; benzothiazolyl; quinolyl; thiadiazolyl; pyrimidinyl; tertralone; alkyl, phenyl, tetrazolyl, piperazinyl and piperidyl radicals are as defined above for R4a, preferably substituted with one or more radicals selected from the group consisting of halogen atoms; and hydroxyl and carboxy radicals in the form of salts or esters; -C(O)-NHH2; -C(O)-NH(alkyl); -C(O)-N(alkyl)(alkyl); -NH-C(O)-(alkyl); -N(alkyl)-C(O)-(alkyl); thienyl; phenyl; alkylphenyl; wherein the alkyl and alkoxyl radicals are themselves substituted with one or more radicals selected from the group consisting of acyl radicals containing a maximum of 7 carbon atoms, cyano, -NH2, -NH(alkyl), -N(alkyl)(alkyl) and phenyl radicals , whereby it is understood that with the above-mentioned radicals, alkyl and alkoxyl radicals are straight or branched, and that they contain a maximum of 4 carbon atoms, whereby the mentioned products of formula (Ia) are found in all possible racemic, enantiomeric and diastereomeric isomeric forms, as well as in the forms of addition salts of the mentioned products of formula (Ia) with mineral and organic acids, i.e. mineral and organic bases. 6. Products of formula (I), as defined in any of claims 1 to 5, characterized in that they correspond to formula (Ib): [image] where: R1b represents -C(O)-R5b, -SO2-R5b or -C(O)-NR6bR5b radical where R6b represents a hydrogen atom or a methyl radical, and R5b represents a radical selected from the group consisting of straight or branched alkyl radicals containing at most 4 carbon atoms, and which are preferably substituted with thienyl radicals; cyclohexyl; phenyl, which is optionally substituted by a straight or branched alkyl radical containing at most 4 carbon atoms, or by radicals such as phenoxy or trifluoromethyl; naphthyl; furil; morpholinyl; thienyl, preferably substituted with an isoxazolyl radical; pyridyl preferably substituted with a trifluoromethyl radical, R2b represents a hydrogen atom or a straight or branched alkyl radical containing no more than 6 carbon atoms, and which is preferably substituted either by a phenyl radical which is itself substituted by hydroxyl or straight or branched alkyl radicals containing no more than 4 carbon atoms, or by the radical -C( O)-O-R8b where R8b represents a straight or branched alkyl or alkenyl radical containing at most 6 carbon atoms, R3b represents -CH=N2 radical or -CH2-Lb-R4b radical in which Lb represents a single bond or a divalent radical selected from the group consisting of -O-, -O-C(O)-, and -S-(CH2)nb-, where nb represents an integer from 0 to 1, and R4b represents a radical selected from the group consisting of pyridyl; benzothiazolyl; quinolinyl, thiadiazolyl; pyrimidinyl; tetralone radical; straight or branched alkyl radicals containing at most 4 carbon atoms, preferably substituted with carboxy and thienyl radicals which are free or in the form of salts or esters; phenyl preferably substituted with one or more radicals selected from the group consisting of halogen atoms, and a carboxy radical that is free or in the form of a salt or ester, straight or branched alkyl and alkoxyl radicals that contain at most 4 carbon atoms, and cyanoalkyl, alkylphenyl radicals, -NH-C(O)-CH3, -C(O)-N(alkyl)(alkyl); tetrazolyl optionally substituted with a phenyl radical; piperazinyl preferably substituted on the second nitrogen atom with a phenyl radical or straight or branched alkyl containing at most 4 carbon atoms, which itself is preferably substituted with an acyl (pyrrolidinylcarbonyl) radical, with one or two phenyl radicals or with -NH2, -NH( alkyl) or -N(alkyl)(alkyl); piperidyl radical preferably substituted by benzyl or -C(O)-N(alkyl)(alkyl) radical, whereby it is understood that in the above-mentioned radicals, alkyl and alkoxyl radicals are straight or branched, and that they contain a maximum of 4 carbon atoms, whereby the mentioned products of formula (Ib) are found in all possible racemic, enantiomeric and diastereomeric isomeric forms, as well as in the forms of addition salts of the mentioned products of formula (Ib) with mineral and organic acids, i.e. mineral and organic bases. 7. Products of formula (I), as defined in any of claims 1 to 6, characterized in that R1 represents a radical selected from the group consisting of the following radicals: [image] and R2, R3 and R7 have the values indicated in claim 1. 8. Products of formula (I), as defined in any of claims 1 to 7, characterized in that R7 represents a hydrogen atom and R2 represents a radical selected from the group consisting of the following radicals: [image] R1 and R3 have the values indicated in claim 1. 9. Products of formula (I), as defined in any of claims 1 to 8, characterized in that R3 represents a radical selected from the group consisting of the following radicals: [image] and R1, R2 and R7 have the values indicated in claim 1. 10. Products of formula (I), indicated by the fact that they are as follows: ◾ 3-[9(S)-benzylamino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyridazino[1,2-a][1,2] diazepin-1(S)-carboxamide]-5-methyl-1-benzolyoxy-hexan-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]diazepin-1(S)-carboxamide]-5-methyl-1-(2,6-dichlorobenzolyoxy)-hexan-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]diazepin-1(S)-carboxamide]-4-(4-hydroxyphenyl)-1-(2,6-dichlorobenzolyoxy)-butan-2-one 11. Products of formula (I), indicated by the fact that they are as follows: ◾ (2-propenyl)-(4S)-6-diazo-4-[[[(1S,9S)-9-[(2-methyl-1-oxo-propyl)-amino]-octahydro-6,10- dioxo-6H-pyridazino[1,2-a][1,2]diazepin-1-yl]-carbonyl]-amino]-5-oxo-hexanoate ◾ (2-propenyl)-(4S)-6-diazo-4-[[[(1S,9S)-9-[(3-methoxybenzoyl)-amino]-octahydro-6,10-dioxo-6H-pyridazino[ 1,2-a][1,2]diazepin-1-yl]-carbonyl]-amino]-5-oxo-hexanoate ◾ (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-oxo-hexanoate ◾ (2-propenyl)-(4S)-6-diazo-4-[[[(1S,9S)-9-[[(cyclohexylamino)-carbonyl]-amino]-octahydro-6,10-dioxo-6H- pyridazino[1,2-a][1,2]diazepin-1-yl]-carbonyl]-amino]-5-oxo-hexanoate ◾ (2-propenyl)-(4S)-6-diazo-4-[[[(1S,9S)-9-[[[(4-phenoxyphenyl)-anino]-carbonyl]-amino]-octahydro-6, 10-dioxo-6H-pyridazino[1,2-a][1,2]diazepin-1-yl]-carbonyl]-amino]-5-oxo-hexanoate ◾ (2-propenyl)-(4S)-6-diazo-4-[[[(1S,9S)-9-[[[[(2-p-2-yl)-ethyl]-amino]-carbonyl] -amino]-octahydro-6,10-dioxo-6H-pyridazino[1,2-a][1,2]diazepin-1-yl]-carbonyl]-amino]-5-oxo-hexanoate ◾ (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-oxo-hexanoate ◾ (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-oxo-hexanoate ◾ (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-oxo-hexanoate ◾ (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-oxo-hexanoate ◾ 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-dchlorobenzoyl)-oxy]-4-[[[(1S,9S)-9-[[(2-furanylnyl)-carbonyl]-amino] -octahydro-6,10-dioxo-6H-pyridazino[1,2-a][1,2]diazepin-1-yl]-carbonyl]-amino]-5-oxo-hexanoate ◾ (2-propenyl)-(4S)-6-[2,6-dchlorobenzoyl)-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-oxo-hexanoate ◾ (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[1,2-a][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)-ethyl]-sulfonyl]-amino]-octahydro-6,10-dioxo-6H-pyridazino[1,2-a][1,2]diazepin-1-yl]- carbonyl]-amino]-5-oxo-hexanoate ◾ (2-propenyl)-(4S)-6-[4-[(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-oxo-hexanoate ◾ (2-propenyl)-(4S)-6-[(1-phenyl-1H-tertrazol-5-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- oxo-hexanoate ◾ (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-oxo-hexanoate ◾ (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-oxo-hexanoate ◾ (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-oxo-hexanoate ◾ (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-oxo-hexanoate ◾ (2-propenyl)-(4S)-6-acetyl-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-oxo-hexanoate ◾ (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- oxo-hexanoate ◾ (2-propenyl)-(4S)-6-[(1-phenyl-1H-tertazol-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-oxo-hexanoate ◾ (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-oxo-hexanoate ◾ (2-propenyl)-(4S)-6-[(2,6-dichlorobenzoyl)-oxy]-4-[[[(1S,9S)-9-[(methylsulfonyl)-amino]-octahydro-6, 10-dioxo-6H-pyridazino[1,2-a][1,2]diazepin-1-yl]-carbonyl]-amino]-5-oxo-hexanoate ◾ 9-[(9S)-[[(4-phenoxyphenyl)-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-(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-naphthenyl)-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-6H-(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-(1S)-pyridazino[1,2-a][1,2]diazepine-1-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-[(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[(3S)-[[(4-phenoxyphenyl)-amino]-carbonyl]-amino]-octahydro-6,10-dioxo-6H-(1S) -pyridazino[1,2-a][1,2]diazepin-1-yl]-carbonyl]-amino]-butyl]-pentanedioate ◾ 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-oxo-ethyl]-piperazin-1-yl]]-3-oxo-2-butyl]-octahydro-6,10-dioxo-6H-(1S)-pyridazino[1, 2-a][1,2]diazepine-1-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-[(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-carboxamide ◾ 9-[(9S)-(2-methyl-1-oxo-propyl)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)-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 ◾ 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-(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-(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-1-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-(1S)-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-carboxamide ◾ 9-[(9S)-(3-methoxybenzoyl)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-(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 ◾ 9-[(9S)-[(cyclohexylamino)-carbonyl]-amino]-N-[(2S)-4-[(benzothiazol-2-yl)-thio]-1-[(1,1-dimethyl) -ethoxy]-phenyl]-3-oxo-2-butyl]-6H-(1S)-pyridazino[1,2-a][1,2]diazepine-1-carboxamide 12. Process for preparing products of formula (I), as defined in claim 1, characterized by the fact that the compound of formula (II): [image] participates in the reaction with the compound of formula (III): R1'-X (III) where X represents a halogen atom, and R1' has the meaning indicated in claim 1 for R1, in which the possible reactive functional groups are preferably protected by protective groups, in order to obtain the product of formula (IV): [image] where R1' has the meaning as indicated above, wherein the product of formula (IV) is subjected to a saponification reaction to obtain the product of formula (V): [image] where R1' has the meaning as indicated in the above part, wherein the product of formula (V) reacts with the product of formula (VI): [image] where R2' and R7' have the meaning as respectively indicated in claim 1 for R2 and R7, where possible reactive functional groups are optionally protected by protecting groups, in order to obtain a product of formula (Ix): [image] where R1', R2' and R7' have the meaning as indicated in the above part, whereby the product of formula (Ix ) can be subjected to a bromination reaction to obtain the product of formula (VII): [image] where R1', R2' and R7' have the meaning as indicated in the above part, whereby the product of formula (VII) reacts with the product of formula (VIII): H'-L-R4' (VIII) where L has the meaning as indicated in claim 1, and R4' has the meaning as indicated in the above part for R4, where possible reactive functional groups are preferably protected by protecting groups, to obtain the product of formula (Iy): [image] where R1', R2', R4' and R7' have the meaning as indicated in the above part, whereby the products of formula (Ix) and (Iy) can be products of formula (I), and which, if desired and necessary , can undergo one or more conversion reactions in any order to obtain other products of formula (I): a) carboxyl group esterification reaction, b) saponification reaction of the ester functional group into a carboxyl group, c) the oxidation reaction of the alkylthio functional group into the corresponding sulfoxide or sulfone, d) conversion reaction of a keto functional group into an oxime functional group, e) reduction reaction of a free or esterified carboxyl functional group into an alcohol functional group, f) conversion reaction of an alkyl functional group into a hydroxyl functional group, or also a hydroxyl functional group into an hydroxy functional group g) oxidation reaction of an alcohol functional group into an aldehyde, carboxyl or keto functional group, h) conversion reaction of nitrile radical to tetrazolyl, i) the reaction of removing the protective group that can be carried out with protected reactive functional groups, j) the reaction of converting a mineral or organic acid or base into a salt in order to obtain the corresponding salt, k) reaction of resolution of racemic forms to separated products of the mentioned products of formula (I) which are obtained in this way, and are found in all possible racemic, enantiomeric and diastereomeric isomeric forms. 13. Medicinal products, characterized in that they are products of formula (I), as defined in claims 1 to 4, as well as addition salts with pharmaceutically acceptable mineral or organic acids, or mineral or organic bases of said products of formula (I). 14. Medicinal products, indicated by the fact that they are products of formulas (Ia) and (Ib), as defined in claims 5 or 6, as well as addition salts with pharmaceutically acceptable mineral or organic acids or mineral or organic bases of said products of formula (Ia) and (Ib). 15. Medicinal products, characterized in that they are products of formula (I), as defined in claims 7 to 9, as well as addition salts with pharmaceutically acceptable mineral or organic acids, or mineral or organic bases of said products of formula (I). 16. Medicinal products, characterized in that they are products of formula (I), as defined in claims 10 or 11, as well as addition salts with pharmaceutically acceptable mineral or organic acids, or mineral or organic bases of said products of formula (I). 17. Pharmaceutical preparations, characterized by the fact that they contain at least one of the medicines as defined in claims 13 to 16 as an active substance. 18. Use of products according to one of claims 1 to 11 or pharmaceutically acceptable salts of said products, indicated by the fact that it is intended for the preparation of medicines intended for the prevention or treatment of diseases in which cathepsin K, cathepsin B or papain are involved. 19. Use according to claim 18, characterized in that it is intended for the preparation of medicines intended for the prevention or treatment of diseases in which cathepsin K, cathepsin B or papain are included. 20. Use according to claim 18, characterized in that it is intended for the prevention or treatment of diseases selected from the following group consisting of: cardiovascular diseases, cancers, diseases of the central nervous system, inflammatory diseases, infectious diseases, as well as bone diseases. 21. Use according to claim 18, characterized in that it is intended for the prevention or treatment of diseases of the central nervous system or bone diseases, especially osteoporosis. 22. Compounds of formula (VII), characterized by the fact that they are industrial products.