HRP970163A2 - Novel tricyclic compounds, process for the preparation and intermediates thereof, the application thereof as medicaments ans pharmaceutical preparations containing them - Google Patents

Description

The present invention relates to new tricyclic compounds, the process for their preparation and intermediates of this process, their use as medicines and pharmaceutical preparations containing them.

The object of the present invention is compounds of the general formula I:

[image]

in which R1 represents the group -C=C-/A/-/BACOR6, -CH=CH-/A/-/B/-COR6, -(CH2)2-/A/-/B/-COR6, -O -/A/-/B/-COR6, -CH2CO-/A/-/B/-COR6,

/A/ represents a hydrocarbon divalent radical derived from a linear or branched structure, saturated or unsaturated containing 1-12 carbon atoms and 1-6 heteroatoms selected from oxygen, nitrogen or sulfur atoms, a divalent radical derived from an acyclic hydrocarbon, linear or branched, saturated or unsaturated containing 1-12 carbon atoms,

/B/ represents a phenyl radical or a CH(Z) radical or a single bond,

Z represents a hydrogen atom or a group (D)0-6-NRaRb, (D)0-6-NH-SO2-Rc, (D)0-6-NH-C02-Rc, (D)0-6-NH- CO-Rc, (D)0-6-NH-SO2-NH-Rc, (D)0-6-NH-CO-NH-Rc, (D)0-6-C02-Rc, (D)0- 6-SO2-Rc, (D)0-6-CO-Rc or (D)0-6-Rc where (D)0-6 is a divalent radical derived from an acyclic hydrocarbon, linear or branched, saturated or unsaturated containing 0-6 carbon atoms,

Ra, Rb and Rc represent a hydrogen atom, the radical (CH2)0-3-Ar where Ar represents a carbocyclic aryl group containing 6-18 carbon atoms, the radical (CH2)0-3-Het where Het represents a radical derived from an aromatic or non-aromatic heterocycle, saturated or unsaturated containing 1-9 carbon atoms and 1-5 heteroatoms selected from oxygen, nitrogen or sulfur atoms, radical (CH2)0-3-Alk where Alk represents a radical derived from a non-aromatic hydrocarbon, branched or cyclic, saturated or unsaturated containing 1-12 carbon atoms, the Het, Ar and Alk radicals may be substituted or unsubstituted, or

Ra and Rb together with the nitrogen atom to which they are attached represent a nitrogen heterocycle, aromatic or non-aromatic, saturated or unsaturated, possibly containing one or more heteroatoms selected from oxygen, nitrogen or sulfur atoms, this radical can be substituted or unsubstituted,

R6 represents a hydroxyl radical, a radical 0-Alk, O-Ar, NH2, NH-Alk, N(Alk)2 or an amino acid residue L or D, Alk and Ar can be as defined above and can be substituted or unsubstituted ,

R2 and R3, identical or different, represent a hydrogen atom, a hydroxyl radical, an O-Alk radical or an O-(CH2)0-3-Ar radical, Alk and Ar are as defined above, or R2 and R3 together form a cycle of the type - O-(CRdRe)n-O-, n is a number between 1 and 5, Rd and Re each independently represents a hydrogen atom, an alkyl radical containing 1-6 carbon atoms or a phenyl radical,

R4 represents a hydrogen atom, a halogen atom, a hydroxyl, amino, nitro, cyano, CF3, acyl or acyloxy group having 1 to 12 carbon atoms, alkyl, alkenyl, alkynyl, alkylthio, alkoxy, alkylamino, dialkylamino, dialkylaminoalkyl, dialkylaminoalkyloxy where the alkyl part comprises 1 to 6 carbon atoms,

R5 represents a hydrogen atom, a hydroxyl radical, a halogen atom, an O-Alk radical or an O-(CH2)0-3-Ar radical, Alk and Ar are as defined above,

G represents:

- let's say the radical of the formula G 1

[image]

where Rh is a hydrogen atom or an Alk group as defined above and Het' is a heterocycle of the general formula:

[image]

where H builds with part N=C-NH- a heterocyclic residue aromatic or non-aromatic, mono or bicyclic, saturated or unsaturated comprising 1 to 9 carbon atoms and from 2 to 5 heteroatoms selected from oxygen, nitrogen and sulfur atoms, this radical can be substituted or unsubstituted,

- let's say the radical NRaRb (radical G2), Ra and Rb are as defined above,

-let's say the radical Het (radical G3) as defined above,

-let's say the radical -NRh-C(=X)-NHRc (radical G4), where X is a sulfur, oxygen or NH atom, Rh and Rc are as defined above,

-let's say the radical -NRh-SO2Rc (radical G5), where Rh and Rc are as defined previously,

arrows in dotted lines represent possible secondary bonds, their addition salts with acids and bases and esters,

R1, R2 and R3 can be in position 8, 9 or 10 of the tricycle.

The compound of formula I denotes all possible geometric and stereoisomeric isomers taken individually or in a mixture.

The group /A/ represents a derived bivalent radical of a linear or branched substructure, saturated or unsaturated, containing from 1 to 12 carbon atoms and from 1 to 6 heteroatoms selected from oxygen, nitrogen and sulfur atoms, and mainly denotes radicals derived from alkanes whose are certain carbons replaced with oxygen, sulfur or group atoms

C=O, SO, SO2, NH, N(Alk), NH-CO, N(ALk)-CO, CO-NH, CO-N(Alk), SO2-NH, SO2-N(Alk),

(Alk) is as defined above. So the following radicals can be listed

-CH2-CH2-O-CH2-CH2-, -CH2-CH2-N(CH3)-CH2-CH2-, CH2-CH2-C(O)-CH2-CH2, -CH2-C(O)-C( Me)2-CH2.

When /A/ represents a divalent radical derived from an acyclic, linear or branched, saturated or unsaturated hydrocarbon comprising from 1 to 12 carbon atoms, then it denotes mainly alkylene radicals of the formula -(CH2)n where n represents a number between 1 and 12 such as are -CH2-, -CH2CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2- or alkenylene or alkynylene radicals such as

-CH=CH-CH2- or -C=C-CH2-.

When these bivalent radicals are branched, they can represent radicals such as -CH(CH3), -C(Me)2, -CH2-C(Me)2-, CH(Et)-, -CH(C=CH)- or - C(C=CH)(Et)-.

When /B/ represents a divalent radical -Ph-, the COR6 group can be in ortho, meta or para position. It is preferably in the pair position.

When (D)0-6 is a divalent radical derived from an acyclic, linear or branched, saturated or unsaturated hydrocarbon comprising from 0 to 6 carbon atoms, (D)0-6 is selected from the values for /A/ cited above. (D)0 implies the absence of this radical, which confirms the existence of a simple covalent bond. (D) will preferably be a single bond or group (CH2)n, n being a number selected from 1, 2 or 3.

When Ra, Rb and Rc represent the group (CH2)0-3-Ar, (CH2)0-3-Het, (CH2)0-3-Alk; (CH2)0-3 represents, for example, a simple bond in the case of (CH2)0, for example radicals -CH2-, -(CH2)2- or -(CH2)3-.

The term Ar, which represents a carbocyclic aryl group that includes from 6 to 18 carbon atoms, means a radical derived from a cyclic aromatic hydrocarbon such as a phenyl, naphthyl, phenanthrenyl radical or a radical derived from a condensed bicyclic or tricyclic hydrocarbon that includes a benzene ring such as indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl or fluorenyl. Bonding is done at the level of the benzene ring. Preferably, phenyl is understood.

With the term Het representing a radical derived from an aromatic or non-aromatic heterocycle, saturated or unsaturated, comprising from 1 to 9 carbon atoms and from 1 to 5 heteroatoms selected from oxygen, nitrogen and sulfur atoms, the following are mainly indicated:

- heterocyclic monocyclic radicals, for example thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazanyl, pyrrolinyl, imidazolinyl, pyrazolinyl, thiazolinyl, triazolyl, tetrazolyl,

- heterocyclic fused rings, for example benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, naphtho/2,3-b/thienyl, thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, quinolizinyl . defined above, for example furo/2,3-b/pyrrole or thieno/2,3-b/furan,

- or saturated heterocycles such as pyrrolidine, piperidine, morpholine.

This term Het also includes the Het' values defined previously.

The term Alk, which represents a radical derived from hydrocarbons, non-aromatic, linear, branched or cyclic, saturated or unsaturated, denotes in the case of acyclic hydrocarbons alkyl radicals such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl , n-hexyl, 2-methyl pentyl, 2,3-dimethyl butyl, n-heptyl, 2-methylhexyl, 2,2-dimethylepntyl, 3,3-dimethyl pentyl, 3-ethylpentyl, n-octyl, 2,2- dimethylhexyl, 3,3-dimethylhexyl, 3-methyl-3-ethylpentyl, nonyl, 2,4-dimethylheptyl or n-decyl, alkenyl radicals such as vinyl, propenyl, isopropenyl, allyl, 2-methylallyl, butenyl or isobutenyl or alkynyl radicals such as ethynyl, propynyl, propargyl, butynyl or isobutynyl and in the case of cyclic radicals, cycloalkyl radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl.

When Ra and Rb represent together with the nitrogen atom to which the nitrogen heterocycle is attached, the following saturated heterocycles morpholine, piperidine, piperazine, pyrrolidine or unsaturated heterocycles such as pyrimidine, pyridine or pyrazine are meant.

When R2, R3, R4 and R5 represent the radical O-(Alk) comprising from 1 to 12 carbon atoms, the radicals methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, allenyloxy or propargyloxy are preferably understood. When R2, R3, R4 and R5 represent the radical O-(CH2)0-3-Ar, the radicals phenylethoxy and phenylpropyloxy are preferably understood.

When R2 and R3 form together a cycle of the type -O-(CRdRe)n-O-, n is an integer between 1 and 5, the radicals -O-CH2-O, O-C(Me2)-O, O-C(Ph2)-O are mainly understood . R2 and R3 must be in the position ortho to each other.

When R6 represents the radical O-Alk or O-Ar, Alk and Ar can be substituted or unsubstituted, the following radicals are mainly understood: (C1-8) alkoxy, (C1-14) aryl (C1-8) alkoxy, (C6- 14) aryloxy, (C1-8) alkylcarboxyloxy, (C1-8) dialkylaminocarbonylmethoxy, (C6-14) aryl (C1-8) diaminocarbonylmethoxy.

When R6 represents the radical NH-alk, NH(alk)2 or NH-Ar, it mainly means the radicals (C1-8) alkylamino, di-(C1-8) alkylamino, (C6-14) aryl (C2-8) alkylamino , (C6-14) arylamino.

When R6 represents an amino acid residue, it means acid L or D.

Amino acids L or D can be natural or non-natural. Preferably α-amino acids are understood. For example, those described in Houben-Weyl, Methoden der Organischen Chemie, Band XV/1 and 2, George Thieme Verlag, Stuttgart, 1974:

Aad, Abu, γAbu, Abz, 2Abz, εAca, Ach, Acp, Adpd, Ahb, Aib, βAib, Ala, βAla, ΔAla, Alg, All, Ama, Amt, Ape, Apm, Apr, Arg, Asn, Asu, Aze, Azi, Bai, Bph, Can, Cit, Cys, (Cys)2, Cyta, Daad, Dab, Dadd, Dap, Dapm, Dasu, Djen, Dpa, Dtc, Fel, Gln, Glu, Gly, Guv, hAla , hArg, hCys, hGln, hGlu, His, hLlee, hLeu, hLys, hMet, hPhe, hPro, hSer, hThr, hTrp, hTyr, Hyl, Hyp, 3Hyp, Ile, Ise, Iva, Kyn, Lant, Lcn, Leu , Lsg, Lys, βLys, ΔLys, Met, Mim, Min, nArg, Nle, Nva, Oly, Orn, Pan, Pec, Pen, Phe, Phg, Pic, Pro, ΔPro, Pse, Pya, Pyr, Pza, Qin , Ros, Sar, Sec, Sem, Ser, Thi, βThi, Thr, Thy, Thx, Tia, Tle, Tly, Trp, Trta, Tyr, Val, tert-butylglycine (Tbg), neopentylglycine (Npg), cyclohexylglycine (Chg ), cyclohexylalanine (Cha), 2-thienylalanine (Thia), 2,2-diphenylaminoacetic acid, 2-(p-tolyl) 2-phenylamino acetic acid, 2-(p-chlorophenyl) aminoacetic acid, or another 2-pyrrolidine acetic acid, 1,2,3,4-terahydroisoquinoline 3-acetic acid, decahydroisoquinoline 3-acetic acid, octahydroisoindole 2-oc tannic acid, decahydroquinoline 2-acetic acid, octahydrocyclopenta /b/ pyrrole 2-carboxylic acid, 2-azabicyclo /2.2.2/ octane-3-carboxylic acid, 2-azabicyclo /2.1.1/ heptane-3-carboxylic acid, 2 -azabicyclo /3.1.0/ hexane-3-carboxylic acid, 2-azaspiro /4.4/ nona-3-carboxylic acid, 2-azaspiro /4.5/ decane-3-carboxylic acid, spiro (bicyclo /2.2.1/ heptane) -2,3-pyrrolidine-5-carboxylic acid, spiro (bicyclo/2.2.2/ octane-2,3-pyrrolidine-5-carboxylic acid, 2-azatricyclo /4.3.0.16,9/ decane-3-carboxylic acid, decahydrocyclopenta /b/ pyrrole-2-carboxylic acid, decahydrocycloocta /c/ pyrrole-2-carboxylic acid, octahydrocyclopenta /c/ pyrrole-2-carboxylic acid, octahydroisoindole-1-carboxylic acid, 2,3,3a,4,6a- hexahydrocyclopenta /b/ pyrrole-2-carboxylic acid, 2,3,3a,4,5,7a-hexahydroindole-2-carboxylic acid, tetrahydrothiazole-4-carboxylic acid, isoxazolidine-3-carboxylic acid, pyrazolidine-3-carboxylic acid , hydroxypyrrolide in-2-carboxylic acid, which can be substituted in any case (see the following formulas):

[image]

Heterocyclic residues as described above are known for example from the following patents or patent applications:

US-A-344 949; US-A-4 374 847; US-A-4 350 704; EP-A-29 488; EP-A-31 741; EP-A-46 953; EP-A-49 605; EP-A-49 658; EP-A-50 800; EP-A-51 020; EP-A-52 870; EP-A-79 022; EP-A-84 164; EP-A-89 637; EP-A-90 341; EP-A-90 362; EP-A-105 102; EP-A-109 020; EP-A-111 873; EP-A-271 865 and EP-A-344 682.

Most amino acids can be in the form of esters or amides, such as methyl ester, ethyl ester, isopropyl ester, isobutyl ester, tert-butyl ester, benzyl ester, ethylamide, semicarbazide or omega-amino (C2-8)-alkylamide.

Finally, the functional groups of these amino acids can be protected. Suitable protecting groups, such as urethane, carboxyl or side chain protecting groups are described by Hubbuch, Kontakte (Merck) 1979, n° 3, p. 14 -23 and Bullesbach, Kontakte (Merck) 1980, n°, p. 23-35.

For example, Aloc, Pyoc, Emoc, Tcboc, Z, Boc, Ddz, Bpoc, Adoc, Msc, Moc, Z(NO2), Z(Haln), Bobz, Iboc, Adpoc, Mboc, Acm, tertbutyl may be cited. , Obzl, Onbzl, Bzl, Mob, Pic, Trt.

When G is a radical of formula G 1:

[image]

and Het' is a heterocycle of the general formula:

[image]

when H builds, with part N=C-NH-, a heterocycle aromatic or non-aromatic, mono or bicyclic, saturated or unsaturated, containing from 1 to 9 carbon atoms and from 2 to 5 heteroatoms selected from oxygen, nitrogen and sulfur atoms, this the radical can be substituted or unsubstituted, G 1 mainly represents the following heterocycles:

[image]

where p represents an integer between 1 and 4.

When G is the radical -NRaRb (called G2), Ra and Rb can be a hydrogen atom, the radical (CH2)0-3-Ar, (CH2)0-3-Het or (CH2)0-3-Alk. The groups Ar, Het and Alk may be equally substituted with groups as defined above.

G2 can mainly be the group NH2, NH-Alk such as NHMe, NHEt, N(Alk)2 such as NMe2, NEt2, NMeEt, NH-(CH2)0-1,-Ar such as NHPh, NHCH2Ph or else NHCH2Het such as NHCH2-pyrrol-2-yl.

When Ra is a hydrogen atom or an Alk group and when Rb is a Het' group, G1 values are obtained.

When Ra and Rb build together with the nitrogen atom to which the nitrogen heterocycle is attached, they mean mainly the heterocyclic groups described above which may be substituted or unsubstituted.

When G is a radical Het (radical G3), this radical can be substituted or unsubstituted and includes mainly heterocycles given above and especially heterocycles of the general formula Het' as defined above. When this heterocycle is bound at the level of its nitrogen atom, G2 values are obtained where Ra and Rb form a heterocycle with the nitrogen atom carrying them.

When G is the radical -NRh-C(=X)-NHRc (radical G4) or NRhSO2Rc (radical G5) where X is a sulfur, oxygen or NH atom; Rh and Rc are as defined above. They mainly mean the groups -NH-C(=NH)-NH2,

-NH-C(=O)-NH2, -NH-C(=O)-NH2 or -NH-C(=S)-NH2, -NH-C(=NH)-NHCH2-Ar such as -NH- C(=NH)-NHCH2Ph, -NH-C(=NH)-NHCH2-Het, -NH-C(=NH)-NHCH2-Het', -NH-C(=NH)-NH-Alk such as - NH-C(=NH)-NHCH3 or -NH-SO2Ph; the groups Ar, Het, Het' or Alk may be substituted or unsubstituted.

Possible substituents of the radicals Alk, Ar, Het, Het' or NRaRb that build the heterocycle are preferably the following radicals:

- halogen: fluorine, chlorine, bromine, iodine,

- alkyl, alkenyl, alkynyl containing from 1 to 12 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, vinyl or allenyl. These radicals may also be substituted with one or more halogen atoms, for example fluorine such as trifluoromethyl, oxo, cyano, nitro, formyl, carboxy and carboxyalkyl containing from 1 to 6 carbon atoms, carboxamide,

- Alkoxy containing from 1 to 12 carbon atoms, such as methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy,

- alkylthio containing from 1 to 12 carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio,

- amino, alkylamino containing from 1 to 12 carbon atoms such as methylamino or ethylamino, dialkylamino containing from 2 to 24 carbon atoms such as dimethylamino, diethylamino, methylethylamino, each of these dialkylamino radicals can possibly be in oxidized form,

- aminoalkyl containing from 1 to 12 carbon atoms, such as aminomethyl or aminoethyl,

- dialkylaminoalkyl containing from 3 to 25 carbon atoms, such as dimethylamino methyl or ethyl,

- dialkylaminoalkyloxy containing from 3 to 25 carbon atoms, such as dimethylaminoethyloxy,

- optionally acylated hydroxyl containing from 1 to 12 carbon atoms, for example, acetoxy,

- acyl containing from 1 to 12 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, succinyl, pivaloyl benzoyl possibly substituted for example by a chlorine, iodine or fluorine atom. Radicals chloroacetyl, dichloroacetyl, trichloroacetyl, bromoacetyl or trifluoroacetyl can be cited,

- aryl carbocyclic or heterocyclic such as phenyl, furyl, thienyl, pyridinyl or aralkyl such as benzyl, these radicals can also be substituted by radicals such as halogen, alkyl, alkoxy, alkylthio, amino alkyl or dialkylamino identically as above.

It is understood that one or more substituents, identical or different, may be present. In the case of Het, the substituents can be at the level of the NH group or the carbon atom.

These substituents illustrate equally the definition of R4.

It is understood that R 1 R 2 , R 3 , R 4 , R 5 , R 6 R a , R b , R c containing an alkyl, aryl or heterocycle group as defined above can be each independently identical or different.

The invention equally relates to salts of compounds of formula I, such as, for example, salts of compounds of formula I which contain an amino or amino guanidine function with hydrochloric, hydrobromic, nitric, sulfuric, phosphoric, acetic, trifluoroacetic, formic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkanesulfonic acids, such as methane or ethane sulfonic acid, arenesulfonic acids such as benzene or paratoluene sulfonic or arylcarboxylic acid or those compounds of formula I which have an acid function with possibly substituted with salts of alkali or alkaline earth metals or ammonia.

The invention equally relates to esters of compounds of formula I

In the first preferred group, the object of the invention is compounds of the general formula I as defined above which correspond to the general formula I':

[image]

where R1' represents the group:

-C=C-/A'/-/B'/-COR'6, -CH=CH-/A'/-/B'/-COR'6, -(CH2)-/A'/-/B '/-COR'6, -O-/A'/B'/-COR'6, -CH2CO-/A'/-/B'/-COR'6, -/A'/ represents the divalent radical alkylene, alkenylene or alkynylene containing from 1 to 6 carbon atoms, /B'/ represents the radical CH(Z') or a simple bond,

Z' represents a hydrogen atom, the group (CH2)0-6-NRaRb, (CH2)0-6-NH-SO2-Rc, (CH2)0-6-NH-CO2-Rc, (CH2)0-6-NH -CO-Rc, (CH2)0-6-NH-SO2-NH-Rc, (CH2)0-6-NH-CO-NH-Rc, (CH2)0-6-C02-Rc, (CH2)0 -6-SO2-Rc, (CH2)0-6-CO-Rc or (CH2)0-6-Rc; Ra, Rb and Rc are as defined above, R'6 represents the radical OH, amino or alkoxy containing from 1 to 8 carbon atoms, optionally substituted with one or more radicals selected from hydroxy, amino, phenyl, alkylamino or dialkylamino,

R'2 and R'3 represent a hydrogen atom or a methoxy radical and G is as defined previously, arrows in dotted lines represent a possible secondary bond, their addition salts with acids and bases and esters.

In another preferred group, the invention for object has compounds of the general formula I as defined above in which R6 represents the group -OH, -OCH3, -OCH2CH3, -O-(CH2)2-OH, -O-CH2-CH( OH)-(CH2)OH, -O-CH2-NH2, -O-(CH2)2-N-(CH3)2, -NH2 or -O-(CH2)-phenyl as well as their addition salts with acids and bases and esters.

In the third preferred group, the object of the invention is compounds of the general formula I as defined above where R1 represents the group O-(CH2)0-6CH(Z')-COOH or -(CH2)0-7CH(Z') -COOH as well as their addition salts with acids and bases and esters.

In the fourth preferred group, the object of the invention is compounds of the general formula I as defined above where Z' represents a hydrogen atom, as well as their addition salts with acids and bases and esters.

In the fifth preferred group, the object of the invention is compounds of the general formula I as defined above where Z' is the group (CH2)0-6-NH-CO2-Rc or (CH2)0-6-NH-Rb; Rb and Rc are as defined above, as well as their addition salts with acids and bases and esters.

In the sixth preferred group, the object of the invention is compounds of the general formula I as defined above, where Rb and Rc represent the group (CH2)0-3-Ar, where Ar is as defined above and can be substituted or unsubstituted, as well as their addition salts with acids and bases and esters.

In the seventh preferred group, the object of the invention is compounds of the general formula I as defined above, where G is a group G4 of the formula -NH-C-(=NH)-NHRc, where Rc is as defined above, as well as their addition salts with acids and bases and esters.

In the eighth preferred group, the object of the invention is compounds of the general formula I as defined above where G is the group G4 of the formula -NH-C-(=NH)-NH2, as well as their addition salts with acids and bases and esters.

In the ninth preferred group, the object of the invention is compounds of the general formula I as defined above, where G is a group of the formula -NH-(Het'), as defined above and mainly:

[image]

p is an integer equal to 2, 3 or 4, these heterocycles may be substituted or unsubstituted, as well as their addition salts with acids and bases and esters.

In the tenth preferred group, the object of the invention is compounds of the general formula I as defined above, where G is a group of the formula:

[image]

p is a number equal to 2, 3 or 4, as well as their addition salts with acids and bases and esters.

In the eleventh preferred group, the object of the invention is compounds of the general formula I as defined above, whose names follow:

4-((4-((aminoiminomethyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulen-yl)-butanoic acid,

5-((4-((aminoiminomethyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulen-yl)-pentanoic acid,

5-((4-((aminoiminomethyl)hydrazono)-8,10-dimethoxy-1,2,3,4,5,6-hexahydro-9-benz(e)azulen-yl)-pentanoic acid,

6-((4-((aminoiminomethyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)-hexanoic acid,

7-((4-((aminoiminomethyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)-heptanoic acid,

5-((9,10-dimethoxy-1,2,3,4,5,6-hexahydro-4-((4,5-dihydro-1H-imidazol-2-yl)hydrazono)-8-benz(e )azulenyl)oxy)-pentanoic acid,

ethyl 5-((4-((aminoiminomethyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)-pentanoate hydrochloride,

4-((4-((aminoiminomethyl)hydrazono)-8,9-dimethoxy-1,2,3,4,5,6-hexahydro-10-benz(e)azulenyl)-butanoic acid,

5-((4-((aminoiminomethyl)hydrazono)-8,9-dimethoxy-1,2,3,4,5,6-hexahydro-10-benz(e)azulenyl)oxy)-pentanoic acid,

5-((4-(((amino)carbonyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)-pentanoic acid,

5-((4-(((amino)thiocarbonyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)-pentanoic acid,

4-((4-((aminoiminomethyl)hydrazono)-8,10-dimethoxy-1,2,3,4,5,6-hexahydro-9-benz(e)azulen-yl)oxy)-butanoic acid,

6-((4-((4,5-dihydro-1H-imidazol-2-yl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e )azulenyl)oxy)-hexanoic acid,

5-((4-((aminoiminomethyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)-3,3-dimethyl- 4-oxo-pentanoic acid,

5-((4-((4,5-dihydro-1H-imidazol-2-yl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e )azulenyl)oxy)-3,3-dimethyl-4-oxo-pentanoic acid,

5-((4-((aminoiminomethyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro--benz(e) azulenyl)oxy)- pentanoic acid hydrochloride,

4-((4-((4,5-dihydro-1H-imidazol-2-yl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e )azulenyl)oxy)-butanoic acid,

5-((8-((aminoiminomethyl)hydrazono)-6,7,8,9,10,11-hexahydro-azuleno(5,6-d)-1,3-benzodioxol-4-yl)oxy)-pentanoic acid,

5-((8-((aminoiminomethyl)hydrazono)-2,2-diphenyl-6,7,8,9,10,11-hexahydro-azuleno(4,5-e)-1,3-benzodioxole-4- yl)oxy)-pentanoic acid,

4-((9,10-dimethoxy-4-((1,4,5,6-tetrahydro-2-pyrimidinyl)hydrazono)-1,2,3,4,5,6-hexahydro-8-benz(e )azulenyl)oxy)-butanoic acid,

2-((4-(4,5-dihydro-1H-imidazol-2-yl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e) azulenyl)oxy)-ethanoic acid,

3-((4-(4,5-dihydro-1H-imidazol-2-yl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e) azulenyl)oxy)-propanoic acid,

4-((4-(4,5-dihydro-1H-imidazol-2-yl)hydrazono)-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)-butanoic acid,

O/4-(4,5-dihydro-1H-imidazol-2-yl)hydrazono)-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl/-N-/( phenylmethoxy)carbonyl/-DL-homoserine,

O-(4-(1,2,3,4-tetrahydro 6-pyrimidyl)hydrazono)-9,10-dimethoxy 1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl/ N-/ (phenyl methoxy)carbonyl/-DL-homoserine,

2,3-dihydroxypropyl ester O-(9,10-dimethoxy-1,2,3,4,5,6-hexahydro-4-/(1,4,5,6-tetrahydro-2-pyrimidinyl) hydrazono/ - 8 – benz(e)azulenyl/-N-/(phenylmethoxy)carbonyl/-DL-homoserine,

O-/4-/(4,5-dihydro 1H-imidazol-2-yl)hydrazono) 9,10-dimethoxy 1,2,3,4,5,6-hexahydro -8-benz (e) azulenyl /N -/(8-quinoleinyl)sulfonyl/DL-homoserine,

O-/4-/(4,5-dihydro-1H-imidazol-2-yl)hydrazono) 9,10-dimethoxy 1,2,3,4,5,6-hexahydro 8-benz(e)azulenyl/ N -//3-/4-(3-pyridinyl) 1H-imidazol-1-yl/propoxy/carbonyl/DL-homoserine monohydrochloride,

5-//4-/(4,5-dihydro 4-oxo 1H-imidazol-2-yl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz (e) azulenyl)oxy)- pentanoic acid,

O-/9,10-dimethoxy 1,2,3,4,5,6-hexahydro 4-/(4,5,6,7-tetrahydro 1H-1,3-diazepin-2-yl) hydrazono/8- benz(e)azulenyl/ N-/ (phenylmethoxy)carbonyl/ DL-homoserine,

O-/9,10-dimethoxy 1,2,3,4,5,6-hexahydro 4-/(3a,4,5,6,7,7a-hexahydro 1H-benzimidazol-2-yl) hydrazono/ 8- benz(e)azulenyl/ N-/(phenylmethoxy)carbonyl/ DL-homoserine.

The invention equally has for its object a process for obtaining compounds of the general formula I, characterized by exposing the compound of formula II:

[image]

where R2, R3, R4 and R5 are as previously described with the exception of hydroxyl,

let's say the action of compounds of formula F1 in the presence of a base:

Hal-/A/-/B/-COR6 (F1)

or compounds of formula (F'1) in the presence of phosphine and ethyl azodicarboxylate:

HO-/A/-/B/-COR6 (F'1)

where Hal is a halogen atom, /A/, /B/ and R6 are as previously defined, /B/ can equally represent the group -C(NH-P)H-, P is the protecting group of the amine function to obtain compounds of the formula ( IIIa):

[image]

let's say the action of the activation group and then the compounds of formula (F2) in the presence of a catalyst:

[image]

to obtain the compound of formula (IIIb):

[image]

Compounds of formula (IIIa) or (IIIb) are subjected to the action of compounds of formula (F3):

H2N-G

(F3)

where G is as described above to obtain compounds of formulas (IVa) and (IVb) corresponding to certain products of formula I:

[image]

which undergo in that case, in the appropriate order, one or more of the following reactions:

- the action of a base or an acid to break up the ester and obtain the corresponding acid,

- action of a reducing agent capable of partially or completely reducing unsaturation,

- action of the triple bond hydration agent,

- action of the dealkylation agent,

- the action of an agent that deprotects the NH-P function as β-CO-R6 when /B/ represents the CH-NHP group,

- construction of the group NH-SO2Rc NH-CO2Rc, NHCORc, NH-SO2NH-Rc, NH-CO-NHRc starting from the corresponding amine as β-COR6 in order to obtain the corresponding compound of formula I, which is then subjected to the action of acid or base in order to obtain the corresponding salt or the action of an esterification agent in order to obtain the corresponding esters.

The action of the compounds of the formula Hal-/A/-/B/-COR6 (F1) is carried out preferably in the presence of a mineral base, such as potassium carbonate or sodium carbonate in the presence of an aprotic dipolar solvent such as dimethylformamide. Hal is preferably a chlorine or bromine atom.

The action of compounds of the formula HO-/A/-/B/-COR6 (F'1) is carried out in the presence of a phosphine such as triphenylphosphine and an agent such as diethyl azodicarboxylate (DEAD) in an aprotic solvent such as methylene chloride.

The action of compounds of the formula H-C=C-/A/-/B/-COR6 (F2) is carried out using an activation group such as an anhydride of the formula (CF3SO2)2O in the presence of a base such as pyridine to obtain the corresponding triflate of the formula (OSO2CF3) and then in the presence of a palladium derivative (Pd°) such as Pd(PPh3)4.

The action of NH2-G (F3) is carried out for example without a solvent, for example in an alcoholic solvent such as ethanol or butanol. Synton NH2-G is possibly used in the form of its salt such as hydrochloride or hydrobromide.

The saponification reaction of the ester function is carried out for example by the action of an alkaline base, such as sodium hydroxide (soda) or potassium hydroxide (potash) in tetrahydrofuran or in a lower alcohol such as methanol or ethanol. The ester can also be cleaved in an acidic medium according to procedures known to those skilled in the art.

The reduction of unsaturation can be carried out for example completely by the action of hydrogen in the presence of a catalyst such as palladium on carbon or a rhodium catalyst such as Wilkinson's reagent and for example partially (alkynylene to alkenylene) by the action of a poison catalyst such as palladium on barium sulfate poisoned with pyridine or triethylamine.

The hydration reaction that allows entry into the group -CH2CO-/A/-/B/-COR6 starting from -C=C-/A/-/B/-COR6 is carried out preferably in the presence of mercury sulfate.

The dealkylation reaction allowing entry into products of formula I with R 2 , R 3 , R 4 or R 5 representing hydroxyls is carried out in the presence of aluminum chloride or bromine tribromide.

Functionalization of NH2 in α-COR6, where B represents CH-NH2 or CH-NH2, Hcl, is carried out according to classic procedures known in organic chemistry.

The formation of NHSO2Rc starting from the corresponding amine is preferably carried out by the action of RcSO2Hal in the presence of a base, for example triethylamine.

The construction of NHCO2Rc starting from the corresponding amine is carried out preferably by the action of RcOH according to the procedure described in J. Org. Chem., 61, 3229 -3934 after mixing the previous triphosgene in the presence of sodium bicarbonate to obtain the intermediate isocyanate.

Solification reactions can be carried out under usual conditions. It is done, for example, to solify CO 2 H as the terminal group for R 1 in the presence of a sodium salt, such as sodium carbonate or acid carbonate of sodium or potassium.

Likewise, the solification of amine or amino-gunanidine, which can be represented as G, is realized with acid under usual conditions. It is done, for example, with hydrochloric acid, for example in an ethereal solution.

Any esterification of the product is carried out under classic conditions known to experts in this field.

It is usually done by reacting an acid of formula I or a functional derivative thereof with a reagent capable of introducing an ester group whose non-exclusive list is given above in the definition of R6.

Products of the general formulas (F1), (F'1), (F2), (F3) are known or are obtained by methods known to those skilled in the art.

It is also possible to polymerize different reactants in the inverse order, that is, to subject compounds of formula II to the action of compounds of formula F3 in order to obtain intermediate products of formula IIIc:

[image]

which is subjected to the action of compounds of formulas F1, F'1 or F2 in order to obtain the corresponding products of formulas IVa and IVb.

In this case, it is necessary to protect group G of the product of formula IIIc and then, after the introduction of F1, F'1 or F2, deprotection should be carried out according to procedures known to those skilled in the art (T. W. GREENE Protective Groups in Organic Synthesis. John Wiley and Sons Inc 1991).

The deprotection reaction of the NH-P group in β CO-R6 where /B/ represents the CH-NHP group is also carried out according to procedures known to experts in this field, mainly when P represents the CO2tBu group, by a decarboxylation reaction such as, for example, the action hydrochloric acid.

Bone is constantly undergoing a dynamic process that includes bone resorption and bone building. These processes are directed by specialized cells. Bone building is the result of the deposition of the mineral matrix by osteoclasts, and resorption is the result of the dissolution of this bone matrix by osteoclasts. Osteoporosis is characterized by the loss of strength of this bone matrix. A mature active osteoclast resorbs bone after adhesion to the bone matrix by secreting proteolytic enzymes and protons into the adhesion zone, which reaches the indentation or indentation of the bone surface that occur when the osteoclast touches the bone.

Compounds of formula I as well as their pharmaceutically acceptable addition salts possess interesting pharmacological properties. These compounds inhibit bone resorption, which is directed through osteoclasts.

The compounds of the invention are therefore applicable in the treatment of diseases caused by loss of bone matrix, mainly osteoporosis, malignant hypercalcemia, osteopenia of bone metastases, periodontitis, hyperparathyroidism, erosive periarticulars in rheumatoid arthritis, osteopenia caused by immobility, as well as diseases caused by glucocorticoid treatments or hormone deficiency treatments in both sexes , men and women.

They can also be used to treat inflammatory, cancerous and cardiovascular disorders, including atherosclerosis and restenosis.

They can further be used as inhibitors of angiogenesis and even in the treatment of tumors by inhibiting their neovasculature, diabetic retinopathies and nephropathies.

Recent studies have shown that fixation of osteoclasts to bone is conditioned by receptors: integrins.

Integrins are a superfamily of receptors that cause cell/cell and especially cell/matrix adhesion processes, including mainly α2bβ as a receptor for platelets (fibrinogen) and αvβ3 as a receptor for vitronectin, bone sialoproteins such as osteopontin and thrombospondin.

These receptors, which are heterodimers of protein compounds of two subunits α and β, have fixation sites for divalent ions such as Ca2+, mainly and a site for recognizing their ligand predefined by the quality of their subunits.

The αvβ3 receptor is a transmembrane glycoprotein that is expressed in a large number of cells, including endothelial cells, smooth muscle cells, osteoclasts and cancer cells, all of which highlight the multi-steric potency of the compounds according to the invention.

αvβ3 receptors expressed on the level of the osteoclast membrane are the basis of the adhesion/resorption process, contributing to the organization of the cytoskeletal cell and participating in osteoporosis (Ross et al., J. Biol. Chem. 1987, 262, 7703).

αvβ3 receptors expressed at the level of aortic smooth muscle cells stimulate migration through the neointima, which contributes to the formation of atherosclerosis and the appearance of post-angiplastin restenosis (Brown et al., cardiovascular Res. (1994), 28, 1815).

Endothelial cells secrete cross-linking factors that are mitogenic for the endothelium and can contribute to the formation of new blood vessels (angiogenesis). Angiogenic stimulation causes the formation of new blood vessels.

Antagonists of integrin αvβ3 can thus cause regression of cancerous tumors by inducing apoptosis of angiogenic blood vessels (Brook et al. cell (1994) 79, 1157).

The natural αvβ3 integrin ligands all contain an RGD moiety (Arg-Gly-Asp). Peptides containing this RGD as anti avp3 antibodies are known for their capacity to inhibit dentin resorption, preventing osteoclast adhesion to mineral matrices (Horton et al., exp. Cell. res. (1991), 195, 368).

The echistatin peptide isolated from snake venom also contains an RGD moiety described as an inhibitor of osteoclast adhesion to bone and thus a potent inhibitor of bone resorption in tissues in vitro culture (Sato et al. J. Cell. Biol. (1990), 111, 1713) and in vivo in rats (Fisher et al, Endocrinology (1993), 132, 1441).

Compounds of formula I as well as their pharmaceutically acceptable addition salts and pharmaceutically acceptable esters can have a significant affinity to the vitronectin receptor αvβ3 or to other integrins that have vitronectin as their ligand (αvβ1, αvβ5, α2bβ3 by inhibiting binding to its natural ligand.

This property thus makes the compounds of the invention applicable for the prevention or treatment of diseases whose sub-pathology is caused by ligands or cells that interact with the vitronectin receptor.

The compounds may also possess activity against other integrins that interact with their ligand through the tripeptide sequence RGD, which gives them properties pharmacologically applicable for the treatment of pathologies related to these receptors.

This activity towards integrins makes the compounds of the invention applicable in the treatment of numerous diseases such as those mentioned above or given in Dermot Cox DN&P Review 8(4) May 1995, 197-205 the integral text of which is incorporated in this application.

The object of the invention is therefore the compounds of formula I as medicaments, as well as their pharmaceutically acceptable addition salts or their esters.

Among the medicaments of the invention, the compounds described in the experimental part can be cited in particular.

Among these products, the invention particularly has for its object as medicaments the compounds of formula I enumerated above.

The dosage varies with the function of the treatment and the method of administration: it can vary, for example, from 1 mg to 1000 mg per day in adults for oral administration.

The invention relates to pharmaceutical preparations that include as an active principle at least one medication as defined above.

The compounds of formula I are used by the digestive, parenteral or topical route, for example, by application to the surface of the skin. They can be prescribed in the form of simple tablets or dragees, gels, granules, suppositories, ovules, injectable preparations, pomades, creams, gels, microspheres, nanospheres, implants, poultices, which are prepared according to usual procedures.

Active principles can be incorporated into excipients commonly used in these pharmaceutical preparations, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous carriers, fats of vegetable or animal origin, paraffin derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.

Products of formula II in which the hydroxyl radical is in position 10; R2 in position 8 and R3 in position 9 represent the group O-Alk or O-(CH2)0-3-Ar and R4 and R5 are hydrogen atoms are obtained according to the procedure described in European patent application n° 0729933 and in the experimental part below here ( preparation 2).

Two other positional isomers can be obtained as follows:

A compound of formula IIA undergoes:

[image]

to the action of a dealkylation reagent to obtain compounds of formula IIB:

[image]

a compound of formula IIB undergoes:

for example, the action of a protective reagent for diols in a basic medium to selectively obtain products of the formula IIC:

[image]

where P represents the residue of the diol protecting reagent, which is sequentially subjected to the action of a phenol protecting reagent, a diol deprotecting reagent, an alkylating agent and then a phenol deprotecting agent to obtain the compounds of formula IID corresponding to the product of formula II trisubstituted with OH at position 8 :

[image]

for example by the sequential action of a phenol protecting agent, an alkylating agent and then a deprotection agent to obtain a compound of formula IIE corresponding to a product of formula II trisubstituted with OH in position 9:

[image]

Alkylation reagent preferably means agents such as boron tribromide or aluminum chloride.

The protective reagent for diols which is reacted with the products of formula IIB can be a derivative of boron, such as boric acid, trialkyl borate, for example trimethyl or triethyl borate or even borax.

By protective agent for phenol is meant mainly a halide, such as mesyl or tosyl chloride or bromide, or further a benzyl derivative such as benzyl tosylate or mesylate.

The reagent for deprotection of the diol usually means a strong acid, such as hydrochloric acid, sulfuric acid, or paratoluene sulfonic acid, or an oxidant, for example hydrogen peroxide in the case of protection with a boron derivative.

By alkylating agent is meant any classical agent known to a person skilled in the art for the alkylation of phenol. For example, alkyl halides such as methyl or ethyl chloride, alkyl sulfates such as methyl or ethyl sulfate or diazomethane can be cited.

A deprotection agent is a base such as sodium hydroxide (soda), potassium hydroxide (potash) or even sodium or potassium carbonate.

Monosubstituted products of formula II, in which R2, R3, R4 and R5 represent a hydrogen atom, are obtained according to a procedure analogous to that described in European patent application n° 0729933:

(i) a compound of formula (a) is subjected to:

[image]

where O-Alk is in the meta or para position of the alkylcarboxyl group, Alk is, as defined above, the action of a halogenating agent to obtain the corresponding acyl halide:

(ii) subjected to the action of the reagent of formula (b):

[image]

where R(I) and R(II), identical or different, represent an alkyl group containing from 1 to 6 carbon atoms, or R(I) and R(II) together with the nitrogen atom to which they are attached represent a heterocycle of 5 or 6 members, saturated or unsaturated, possibly containing another heteroatom chosen between O and N, in order to obtain compounds of formula (c):

[image]

(iii) which is subjected to the action of a halogenating agent in order to obtain compounds of formula (d):

[image]

where Hal1, represents a halogen atom,

iv) which is subjected to the action of a Lewis acid in order to obtain compounds of formula (e):

[image]

v) which is subjected to the action of a dealkylation reagent in order to obtain

of the product of formula IIF corresponding to the expected monosubstituted product of the formula:

[image]

Disubstituted products of formula II in which R2 represents O-Alk or O-(CH2)0-3Ar; R3, R4 and R5 are hydrogen atoms and OH and R2 is in position 8, 9 or 10 are obtained according to the procedure as described above starting from the compound of formula (a'):

[image]

in which O-Alk and R2 are in the meta or para position of the carboxyl alkyl chain, R2 is the group O-Alk or -(CH2)0-3-Ar, which undergoes successive reactions (i), (ii), (iii) , (iv) and (v) to obtain products of formula IIG corresponding to the expected bisubstituted products of formula II:

[image]

The alkylating agent which reacts with the compound of formula (a) or (a') is for example thionyl chloride, oxalyl chloride or any other agent known to a person skilled in the art to obtain acid halides.

The reagent of formula (b) is obtained starting from cyclopentanone and a secondary amine, for example, diethylamine, piperidine, piperazine or preferably morpholine. It is done in the presence of a strong acid as a catalyst, for example, paratoluene sulfonic acid.

The action of the enamine of formula (b) on the acid halide is preferably carried out in the presence of a tertiary amine, such as triethylamine or pyridine. The halogenating agent which reacts with the compound of formula (c) or its disubstituted equivalent of formula (c') can be, for example, thionyl chloride, phosgene, phosphorus oxychloride or preferably oxalyl chloride.

The Lewis acid used for the cyclization of the compound of formula (d) or its disubstituted equivalent of formula (d') is for example aluminum chloride, titanium tetrachloride or preferably ferric chloride or ethane tetrachloride. The reaction, like those preceding, can be carried out, for example, in a halogen solvent such as methylene chloride, chloroform or dichloroethane.

The dealkylation reagent of the compound of formula (e) or its disubstituted equivalent of formula (e') to obtain the corresponding phenols is preferably aluminum chloride or boron tribromide.

Products of formula II in which R 4 is not a hydrogen atom are obtained by classical methods of substitution, electrophilic and nucleophilic, of aromatics which are known to those skilled in the art.

Products of formula II in which R5 is not a hydrogen atom are obtained according to procedures known to experts in this field and mainly according to the procedure described in European patent application n° 0729933, which means halogenation and then treatment with water or a suitable alcohol.

Products of formula II in which R5 is a hydrogen atom and in which there is a double bond in position 1-2 are obtained according to procedures known to the expert in this field and mainly according to the procedure described in European patent application n° 729933, that is to say by dehydration or deoxylation in the middle of anhydrous acid.

The products of formula II in which the bond between the cycle in 5 and the cycle in 7 is saturated are obtained according to classical methods of hydrogenation of the corresponding double bond mainly in the presence of palladium on carbon.

The introduction of R4 and R5 as a hydrogenation reaction is preferably carried out on compounds of formulas IIA, IID, IIR, IIF or IIG.

The products of formula II in which R2 and R3, in the position ortho to each other, form a cycle of the type -O-(CRdRe)n-O as defined above, are also obtained according to procedures known to those skilled in the art and mainly according to the procedure described hereafter in experimental part.

The invention also has for its object, as intermediate products, products of formulas IIIa, IIIb, IIIc; II as compounds of formula IIc and the following compounds:

-2,3,5,6-tetrahydro-9,10-dimethoxy-8-hydroxy-benz/e/azulen-4(1H)-one,

-2,3,5,6-tetrahydro-8,9-dimethoxy-10-hydroxy-benz/e/azulen-4(1H)-one

are turned off. The preparation of these two compounds is given later here in the experimental section.

The following examples illustrate the invention without any limitation.

Preparation 1: 2,3,5,6-tetrahydro-8,9,10-trihydroxy-benz/e/azulen-4(1H)-one

Grade A: 3,4,5-trimethoxy-benzenepropionic acid

6.8 g of potassium carbonate is added to a solution of 21.44 g of 3,4,5-trimethoxyphenyl-propenoic acid and 45 ml of water, after which it is hydrogenated for 1 hour under a pressure of 1200 to 1300 mbar in the presence of 1.8 g of 10% palladium on activated carbon, then 2.1 liters of hydrogen are absorbed. It is filtered, washed in water and acidified with 50 ml of hydrochloric acid (2N). It is filtered, washed in water and dried under reduced pressure at room temperature. This gives 19.8 g of the expected product (Tt = 102 to 103°C).

IR spectrum (CHC13)

Carbonyl /1712 cm-1 (max) aromatic /l592 cm-1

/l740 cm-1 (ep) /1510 cm'1

NMR spectrum (CDC13)

2.69(t) / =C-CH2-CH2-CO 3.83 (s) 7 3 H3CO-C-

3.85 (s)

6.43 (s) 2H aromatics

10,509m) lH movable

Grade B: 3,4,5-trimethoxy-benzenepropanoyl chloride

It is dried with 1.5 g of magnesium sulfate, a solution of 5 to 6 g of the product obtained in step A in 21 ml of methylene chloride, after filtering it is cooled to 5°C and 2.2 ml of thionyl chloride is added, then the solution is stirred for 20 hours at room temperature. temperature. Evaporate to dryness under reduced pressure repeating the procedure twice with cyclohexane to obtain 6.46 g of the desired product. (Tt = 60°C).

Grade C: 2-[3-(3,4,5-trimethoxyphenyl)-1-oxopropyl]-cyclopentanone

In a solution of 2.4 ml of 1-(N-morphonyl)cyclopentene, obtained as described above, 2.31 ml of triethylamine and 15 ml of methylene chloride, cooled to 5°C, were added during 1.5 hours at +5°C a solution of 4.27 g of the product obtained in step B in 15 ml of methylene chloride. It is stirred for 1 hour to raise the temperature again to +5°C, then 10 ml of hydrochloric acid 2 N is added, it is stirred for 1 hour at room temperature, decanted, washed with water, then with a saturated solution of sodium bicarbonate, dried, filtered and evaporated to dryness under reduced pressure, 5 g of the expected product is obtained. The crude product is purified by dissolving in 10 volumes of ethyl acetate, extracted with 1 N sodium hydroxide solution, the alkaline phase is washed with ethyl acetate, acidified to pH 1 with concentrated hydrochloric acid, extracted with methylene chloride, dried and evaporated to dryness under reduced pressure . 2.75 g of purified product is isolated.

IR spectrum (CHC13):

Carbonyl: /1741 cm-1 aromatic: /1592 cm-1

/1709 cm-1 /1509 cm-1

carbonyl: /1658 cm-1

+ C=C /about 1610 cm-1 with OH in the form of a chelate

NMR spectrum (CDC13)

6.41 (s) 2H arom. (integration base)

3.81(s)3.82(s)/9H in all

3.83 (s) 3.85 (s) /4 of the CH3O-C= type

1.86 (m) CH2-CH2 about 1.5H

1.95 to 2.95 (m) about 7.5H in all while =C-CH2 more types

3.27 (t) -0.4H CO-CH(CO)-CH2

11.2 (m large) H movable

Obtaining the 1-(N-morpholinyl)cyclopentene used in step C:

A solution of 100 ml of cyclohexane, 20 ml of cyclopentanone, 50 ml of morphline and 100 mg of paratoluene sulfonic acid is mixed for 4.5 hours at reflux while eliminating the accumulated water. After evaporating the solvent under reduced pressure, it is distilled under a pressure of 12 to 13 mbar and 27.44 g of the required product is isolated (Tklj = 83°C).

Grade D: 1-(2-chloro-1-cyclopenten-1-yl)-3-(3,4,5-trimethoxyphenyl)-propan-1-one

13 ml of oxalyl chloride is added to the solution of 23 g of the product obtained in step C and 230 ml of chloroform at room temperature. It is stirred for 3 hours at room temperature, concentrated under reduced pressure twice in cyclohexane. 28 g of crude product is obtained, which is recrystallized in a mixture of 50 ml of cyclohexane and 50 ml of diisopropyl ether after partial concentration. It is filtered, washed with diisopropyl ether and dried under reduced pressure. 16.24 g of the expected product is obtained (Tt = 93°C).

IR spectrum (CHC13):

1659 cm-1: carbonyl

1599 cm-1

1586 cm-1: C=C + aromatic

1508 cm-1

NMR Spectrum of CDC13

1.93 (m) : CH2 central

2.69 (m) - 2.81 (m) : C-CH2-C= cyclopentene

2.85 (t, j=7.5) - 3.08 (t, j= 7.5) : others =C-CH2-C

2.44 : CH3-C=

3.68-3.81:OCH3

6.59 - 6.68 (d, j = 2): CH= aromatics meta bound

7.31 - 7.80 (d, j = 8): aromatics

Grade E: 2,3,5,6-tetrahydro-8,9,10-trimethoxy-benz/e/azulen-4(1H)-one

900 mg of the product obtained in step D, 9 ml of 1,2-dichloroethane and 0.9 ml of standard chloride are mixed for 20 hours at room temperature. Then 9 ml of water and ice are added and decanted, washed in water, re-extracted once with methylene chloride, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure to obtain 1 g of the expected product (crude) which is purified by chromatography on silica eluting with dicyclohexane in 10% ethyl acetate, then in 25% ethyl acetate. After concentration, 700 mg of the product is obtained, which crystallizes in 5 ml of n-hexane, then it is cooled to 0°C, washed with a minimum of n-hexane, dried under reduced pressure at room temperature to obtain 630 mg of the expected product. (Tt=101 to 102°C).

NMR spectrum (CDC13)

1.86 (m) CH2 central

2.65 (dd) 2H/ 3.847

2.72 (t) 2H/ other CH2 3.867 OMe

2.84 (dd) 2H/ 3.90/

3.06 2H/

6.59 (s) H aromatic

Grade F: 2,3,5,6-tetrahydro-8,9,10-trihydroxy-benz/e/azulen-4(1H)-one

It is done as in stage B of preparation 1 bis, in order to obtain the expected dimethylated product.

Preparation 1 bis: 2,3,5,6-tetrahydro-8,9,10-trihydroxy-benz/e/azulen-4(1H)-one

Grade A: 2,3,5,6-tetrahydro-8,9,10-trimethoxy-benz/e/azulen-4(1H)-one

60 g of the obtained preparation 2, 600 ml of 1,2-dichloroethane, 342 ml of soda 2 N, 1.2 g of tetrabutylammonium bromide and 33 ml of dimethyl sulfate are mixed for 2.5 hours at 20°C. Then 39 ml of trimethyl amine is introduced to remove excess dimethyl sulfate and mixed for 1 hour at 20°C + 2°C. Add 342 ml of demineralized water, mix for 15 minutes at 20°C + 2°C, decant, reextract the aqueous phase twice, each time with 120 ml of 1,2-dichloroethane. The 1,2-dichloroethane phases are combined and washed 4 times with 240 ml of demineralized water each, then with 300 ml of 1 N hydrochloric acid, then three times with 240 ml of demineralized water each (until neutral). The combined organic phases are dried over sodium sulfate, filtered and concentrated under normal pressure at 83°C to a volume of 480 ml.

Grade B: 2,3,5,6-tetrahydro-8,9,10-trihydroxy-benz/e/azulen-4(1H)-one

480 ml of the solution obtained in (A) with 102.3 g of aluminum chloride is heated at reflux for one hour. The reaction medium is cooled to 0°C + 2°C, then a mixture of 600 ml of demineralized water and 192 ml of pure sulfuric acid (concentrated) previously cooled to 0°C is added over the course of two hours while maintaining the temperature of the reaction medium below 20°C. In the course of 5 minutes, 300 ml of demineralized water is introduced at 20°C + 2°C and mixed for 16 hours at the same temperature, filtered, washed twice, each time with 60 ml of 1,2-dichloroethane, then with demineralized water , dried under reduced pressure to obtain 52.2 g of the desired product.

Preparation 2: 8,9-dimethoxy-10-hydroxy-2,3,5,6-tetrahydro-benz/e/azulen-4(1H)-one

Grade A: 3,4-dimethoxy 5'/(4-methylphenyl)-sulfonyl/oxy/-benzenepropanoic acid

It is carried out as in stage A of apparatus 1 using 29.76 g of 3,4-dimethoxy-5-///(4-

methylphenyl)sulfonyl/oxy/phenyl/-cinnamic acid, the preparation of which is given below, 43.5 g of potassium carbonate, 60 ml of methanol and 1.48 g of palladium (10%) activated carbon. This gives 28.23 g of the desired product in the form of colorless crystals (Tt = 148 to 149°C).

UV spectrum (EtOH)

For M = 380.4

max 226 nm ε = 22100

infl 263 nm ε = 2000

infl 269 nm ε = 2400

max 274 nm ε = 2800

infl 279 nm ε = 2500

infl 307 nm ε = 450

NMR spectrum (CDC13)

2.45 (s) CH3-

2.61 (m) =C-CH2-CH2-C= 3.68 (s) 2 CH3O-C=

2.86 (m) 3.81 (s)

6.61 (d, j = 2) 7.32 (dl)H3 H5

6.65 (d, j = 2) H4 H6 7.80 (dl) H2 H6

Grade B: 3,4-dimethoxy 5-//(4-methylphenyl)sulfonyl/oxy/-benzenepropanoyl chloride

It is carried out as in stage B of preparation 1 using 1.9 g of the product obtained in stage A, 9.5 ml of methylene chloride and 0.7 ml of thionyl chloride. 2.24 g of the desired product is obtained, which is used as such in the next step.

Grade C: 2-/3-/3.4-dimethoxy-5-//(4-methylphenyl)sulfonyl/oxy/phenyl/-1-oxopropyl/-cyclopentanone

Proceed as in step C of preparation 1 starting from 2.24 g of hydrochloric acid obtained in step B using 770 mg of 1-(N-morpholinyl)-cyclopentene (obtained in step C of preparation 1), 6 ml of methylene chloride and 0.77 ml triethylamine. After recrystallization in diisopropylene ether, 1.27 g of the desired product is obtained. (Tt = 84°C).

IR spectrum (CHC13)

carbonyl: /1742 cm-1 O-SO2/1374cm-'

/l709 cm-1 1178 cm-1 1658 cm-1

C=C + Aromatic /1608 cm-1 1599 cm-1 1586 cm-1 1508 cm-1

NMR spectrum (CDC13)

2.44 (s) CH3-O

3.67 (s) /2 OCH3

3.79 (s) 3.81 (s) /

6.59 to 6.65 (m) 2H arom. in ortho O.

7.32 (dl) H3 H5

7.89 (dl) H2 H6

13.58 (m large) OH builds enol

1.8 to 3.4 (m) 10 to 10 H other protons

UV spectrum

1 - EtOH (+ dioxane) for M = 446.52

max 225 nm ε = 23000

max 282 nm ε = 7900

infl 270, 277, 290, 300, 313 nm

2-EtOH (NaOH 0.1 N)

max 310 nm ε = 21600

infl. 268, 272, 276 nm

Step D: 1-(2-chloro-1-cyclopenten-1-yl)-3-(3,4-dimethoxy-5-//(4-methylphenyl)sulfonyl/oxy/phenyl/-propan-1-one

It is carried out as in step D, preparation 1 using 8.7 g of the product obtained in step C, 70 ml of chloroform and 3.5 ml of oxalyl chloride. After crystallization in diisopropyl ether, 7.75 g of the desired product is obtained (Tt = 73°C). This product is used as such for the next step.

The analytical sample is obtained by recrystallization in 2.5 ml of methylene chloride and 5 volumes of diisopropyl ether, followed by concentration to 3 volumes, straining, washing in diisopropyl ether and drying under reduced pressure at room temperature (Tt=77-78°C).

IR spectrum (CHCl3)

carbonyl: /1659 cm-1

C=C aromatic: /1599 cm-1 1586 cm-1 1508cm-

UV spectrum (EtOH)

max 227 nm ε = 26100

infl 248 nm E= 12800

infl 272 nm ε = 5300

infl 280 nm ε = 3200

infl 320 nm

NMR spectrum (CDCl3)

1.93 (m) -C-CH2-C- central/

2.69(m)/C-CH2-C= /

2.81(m)// /

2.85 (t, j = 7.5)/ others =C-CH2-C

3.08 (t, j = 7.5)/

2.44 CH2-C=

3,687 OCH3

3.81/

6.59 (d, j = 2) CH aromatic

6.68 (d, j = 2) target bound

7.31 (d, j = 8)/

7.80 (d, j = 8)/

Grade E: 8,9-dimethoxy-10-//(4-methylphenyl)sulfonyl/oxy/-2,3,5,6-tetrahydro-benz/e/azulen-4(1H)-one

By dissolving 2.32 g of the product obtained in step C in 50 ml of 1,2-dichloroethane, 1.65 g of ferric chloride (98%) is added at room temperature. It is stirred for 48 hours at room temperature, then added to a mixture of water and ice, stirred vigorously for 15 minutes and extracted with methylene chloride, washed in water, then with an aqueous saturated solution of sodium chloride. After drying and evaporation to dryness under reduced pressure, 2.15 g of crude product is obtained, which is chromatographed and eluted with cyclohexane 50% in ethyl acetate. 1.8 g of product is obtained, which is chromatographed again and recrystallized in a chloroform/diisopropyl ether mixture to obtain 720 mg of the desired product (Tt = 138°C).

IR spectrum (CHCl3)

carbonyl: /1650 cm-1

/1599 cm-1

C=C+ /1556 cm-1

aromatic /l512 - 1498 cm-1

UV spectrum (EtOH)

max 230 nm ε = 25300

infl 254 nm ε = 9400

max 323 nm ε = 10300

NMR spectrum (CDCl3)

-1.61 (m) (2H) CH2 central

-2.41 Ph-CH3

-2.50 to 2.80 CH2-C=

3.88 (s)/CH3

3.90 (s)/

6.74 H4

7.21 (d)/ C-Ph-SO2

7.64 (d)/

Grade F: 8,9-dimethoxy-10-hydroxy-2,3,5,6-tetrahydro-benz/e/azulen-4-(1H)-one

A mixture of 350 g of the product obtained in step E above, 1750 ml of methanol, 350 ml of demineralized water and 350 ml of pure sodium hydroxide solution (concentrated) is heated at reflux for 2 hours. The reaction medium is cooled to 2°C + 2°C and 467 ml of concentrated hydrochloric acid is introduced over 45 minutes while maintaining the temperature at the same value. Then 1645 ml of demineralized water is added over 10 minutes at 2°C + 2°C, after which the reaction medium is stirred for 30 minutes also at 2°C + 2°C. The formed crystals are filtered, washed 5 times with 700 ml of demineralized water at 20°C, then dried at 40°C under reduced pressure to obtain 199.1 g of the desired product.

Obtaining 3,4-dimethoxy 5-//(4-methylphenyl)sulfonyl/oxy/-cinnamic acid

(preparation 2 is used)

Grade A: Methyl 3,4-dimethoxy-5-//(4'methylphenyl)-sulfonyl/oxy/-benzoate

During 10 minutes at room temperature, 303 ml of triethylamine is added to the mixed mixture of 200 g of methyl gallate and 2 liters of methylene chloride. After dissolution, it is cooled to 0-5°C, then 130 ml of dichlorodimethyl-silane is added during 1 hour at this temperature, it is stirred for another 30 minutes at this temperature. Keeping the temperature at 0-5°C, 303.2 ml of triethylamine is added over 25 minutes, followed by 227.6 g of tosyl chloride over 15 minutes. Mix for another hour at 0-5°C and add 200 ml of acetic acid, then 500 ml of demineralized water over the course of 10 minutes while stirring and raising the temperature to 20-22°C. Methylene chloride is distilled off at a constant volume (3.31) which is maintained using demineralized water under reduced pressure, stirred for 2 hours at 20°C, washed with demineralized water to obtain 423 g (wet weight) of methyl 3,4-dihydroxy -5-//(4-methylphenyl)sulfonyl/oxy/-benzoate (methyl 3-tosyl gallate). The resulting moist product is taken up in 2.17 liters of sodium hydroxide (2N) and 2.17 liters of methylene chloride. It is mixed at 20°C until dissolved, then 18 g of tetrabutylammonium bromide is added at 20°C, then during 15 minutes at 20°C, 237 ml of dimethyl sulfate. The reaction medium is stirred for 1.5 hours at 20-22°C. At 20-22°C, 78 ml of triethylamine is added and stirred overnight at 20-22°C, then it is decanted and washed with 400 ml of demineralized water and 20 ml of pure acetic acid is added to the organic phase, which is stirred for 15 minutes. add 400 ml of demineralized water, then decant. The combined organic phase is concentrated to dryness first at atmospheric pressure and then under reduced pressure at 40 mm Hg and 60°C outside. It is extracted with 400 ml of methanol, then the dry extract obtained with 600 ml of methanol is heated at reflux until the product completely dissolves, then it is cooled to 0-5°C and stirred for 1 hour at this temperature. It is filtered and washed twice with 200 ml of methanol at -10°C and dried at 40°C under reduced pressure, thereby obtaining methyl 3,4-dimethoxy-5-//(4-methylphenyl)-sulfonyl/oxy /-benzoate. The crude product is purified by recrystallization in 330 ml of toluene. After stirring for 2 hours at -10°C, it is filtered, washed twice with 82 ml of toluene each, cooled to -15°C and dried under reduced pressure at 40°C to obtain 230.3 g of the purified desired product.

Grade B: 3,4-dimethoxy 5-//(4-methylphenyl)-sulfonyl/oxy/-cinnamic acid

a) Cool to 0°C, 600 ml of toluene and add 202 ml of 70% VitrideR solution in toluene at 0°C and add 67.6 ml of morpholine over 1 hour at 0-2°C, let the temperature reach 18°C. The solution thus obtained is used immediately for the next stage.

b) Mix 200 g of methyl 3,4-dimethoxy-5-//(4-methylphenyl)-sulfonyl/oxy/benzoate obtained in step A and 1400 ml of toluene for 10 minutes at 20-22°C until complete dissolution. During 1 hour at 10°C, the solution of the reagent obtained before is added. Stir for another hour and let the temperature reach 18°C.

200 ml of concentrated sulfuric acid and 1000 ml of demineralized water are introduced during 1 hour at 10°C, the solution cooled to 10°C. It is stirred for 16 hours at 20°C, then the organic phase is decanted, washed 5 times with 200 ml of demineralized water, dried, filtered and washed three times with 100 ml of methylene chloride. The intermediate aldehyde solution thus obtained is used as such in the next step.

c) The solution of intermediate aldehyde obtained above, 200 ml of 2-picoline, 120 g of malonic acid and 20 ml of piperidine is heated for 16 hours at 70°C 2+°C (while eliminating, at normal pressure, methylene chloride). It is cooled to 20-22°C and while maintaining this temperature for 15 minutes, a solution of 200 ml of concentrated hydrochloric acid and 400 ml of demineralized water is added. It is stirred for 2 hours at 20-22°C, then cooled to 0°C, the formed crystals are filtered off, washed in demineralized water, dried under reduced pressure at 40°C to obtain 171.7 g of the expected 3,4-dimethoxy 5 -//(4-methylphenyl)-sulfonyl/oxy/phenyl/-cinnamic acids.

Preparation 3: 9, 10-dimethoxy-8-hydroxy-2,3,5,6-tetrahydro-benz/e/azulen-4(1H)-one

Grade A: 9,10-dihydroxy-8-//(4-methylphenyl)sulfonyl/oxy/-2,3,5,6-tetrahydro-benz/e/azulen-4(1H)-one

30 g of 2,3,5,6-tetrahydro-8,9,10-trihydroxy-benz/e/azulen-4(1H)-one obtained as in preparation 1 or 1 bis, 300 ml of tetrahydrofuran, 60 ml of triethylamine and 12.9 ml of trimethylborate. 30 g of tosyl chloride is added and mixed for 16 hours at 20°C + 2°C, then during 10 minutes at 20°C + 2°C the reaction medium is added to the mixed mixture of 900 ml of demineralized water and 150 ml of concentrated hydrochloric acid, then 90 ml of tetrahydrofuran and 60 ml of methylene chloride are added. The resulting solution is stirred for 1 hour at 20°C, then 150 ml of methylene chloride is introduced and mixed for another 15 minutes, decanted and re-extracted twice with 75 ml of methylene chloride each. The combined organic phases are washed 4 times with 150 ml of demineralized water each and re-extracted with 75 ml of methylene chloride, then concentrated under reduced pressure of 20 mbar until the end of distillation at 50°C to obtain 47.6 g of the desired product.

Grade B: 9,10-dimethoxy-8-//(4-methylphenyl)sulfonyl/oxy/-2,3,5,6-tetrahydro-benz/e/azulen-4(1H)-one

47.6 of the product obtained above, 300 ml of methylene chloride, 300 ml of sodium hydroxide (2N), 0.6 g of tetrabutylammonium bromide and 30 ml of dimethyl sulfate are mixed for 16 hours at 20°C. Then 30 ml of triethylamine is introduced to remove excess dimethyl sulfate, the reaction medium is stirred for another 1 hour at 20°C + 2°C, then 150 ml of demineralized water is added and stirred for another 15 minutes and then decanted. The aqueous phase is re-extracted 2 times with 75 ml of methylene chloride each and the combined organic phases are washed 3 times with 120 ml of demineralized water each, then with 120 ml of hydrochloric acid (1N) and 3 times with 120 ml of demineralized water each, the organic phases are combined and dried on sodium sulfate, then 120 g of silicon gel (60 mix) is added during 1 hour at 20°C + 2°C with stirring and mixed for another 1 hour at 20°C, filtered, washed with methylene chloride and concentrated to dry under reduced pressure at 50°C to obtain 47.4 g of the desired product.

The crude product is purified by recrystallization in 390 ml of ethanol after distillation of 90 ml of ethanol, stirred for 3 hours at 0°C + 2°C, washed with 30 ml of ethanol at 0°C, then dried under reduced pressure at 40°C to obtain 41.1 g of the desired product (Tt = 129°C).

Grade C: 9,10-dimethoxy 8-hydroxy 2,3,5,6-tetrahydrobenz/e/azulen-4(1H)-one

Add 4.5 g of potassium hydroxide, then 10 ml of triethylamine to a suspension containing 10 g of 9,10-dimethoxy 8-(((4-methylphenyl)sulfonyl)oxy) 2,3,5,6-tetrahydro-benz/e /azulen-4(1H)-one obtained as in step B and 100 ml of methanol. It is heated for 1 hour at reflux, acidified by the addition of 20 ml of acetic acid, then 20 ml of water is added. It is extracted in dichloromethane, washed in water, the solvent is evaporated at 40°C under reduced pressure and 5.7 g of the expected product is obtained.

Preparation 4: 2,3,5,6-tetrahydro-8-hydroxy-9-methoxy-benz/e/azulen-4(1H)-one and 2,3,5,6-tetrahydro-9-hydroxy-8- methoxy-benz/e/azulen-4(1H)-one

It is carried out in a manner equivalent to that of preparation 2, steps B, C, D, E and F, but starting from 3-(3,4-dimethoxy-phenyl) propionic acid, and 1.08 g of crude product containing a mixture of monohydroxy product (8-OH/9-OMe and 9-OH/8-Ome) which is separated by chromatography on silica using a cyclohexane/ethyl acetate 7/3 mixture as eluent, so that the following two regioisomers are obtained:

8-OH/9-OMe 0.494 g Rf (cyclohexane/ethyl acetate 6/4) = 0.42

8-OMe/9-OH 0.041 g Rf (cyclohexane/ethyl acetate 6/4) = 0.33.

Preparation 5: 2,3,5,6-tetrahydro-8-hydroxy-10-methoxy-benz/e/azulen-4(1H)-one and 2,3,5,6-tetrahydro-10-hydroxy-8- methoxy-benz/e/azulen-4(1H)-one

It is carried out in a manner equivalent to that of preparation 2, steps B, C, D, E and F, but starting from 3-(3,5-dimethoxy-phenyl) propionic acid, and 1.428 g of product containing a mixture of monohydroxyls (8- Oh/10-OMe and 10-OH/8-OMe) and dihydroxyl (8-OH/10-OH) which is separated by means of chromatography on silica and using as eluent a mixture of cyclohexane/ethyl acetate 7/3.

Preparation 6: 2,3,5,6-tetrahydro-9-hydroxy-benz/e/azulen-4(1H)-one

It is done in a way equivalent to that in preparation 2, grades B, C, D, E and F, but starting from 3-(4-methoxy-phenyl) propionic acid. Demetallation is done with boron tribromide. (Rf = 0.15, cyclohexane/ethyl acetate 7/3)

Preparation 7: 2,5,5,6-tetrahydro-8-hydroxy-benz/e/azulen-4(1H)-one

It is carried out in a manner equivalent to that of preparation 2, steps B, C, D, E and F, but starting from 10.0 g of 3-(3-methoxyphenyl) propionic acid and 2.9 g of the expected product is obtained. Demetallation is done with boron tribromide. (Rf = 0.15, dichloromethane/ethyl acetate 95/5).

Preparation 8: Methyl ester (DL)-4-bromo-2-(phenylmethoxycarbonylamino)butanoic acid

Mix 25 g of 2-amino-4-butyrolactone hydrobromide in 200 ml of acetic acid with 24% gaseous hydrobromic acid for 18 hours at 120°C in a closed chamber. It is cooled to room temperature, atmospheric pressure is established, it is concentrated under reduced pressure, the residue is taken up in 200 ml of methanol, then hydrochloric acid is bubbled in for 2 hours while maintaining the temperature below 35°C. The solvent is evaporated under reduced pressure and methyl ester of 2-amino-4-bromo butanoic acid is obtained, which is taken in 250 ml of acetone and 100 ml of water, neutralized with sodium hydroxide 2N, then 35 ml of benzyl chloroformate is slowly added. It is stirred for 48 hours, filtered, extracted in ethyl acetate, the solvent is evaporated, the residue is chromatographed on silica (eluent: cyclohexane/ethyl acetate 7/3) and 27.9 g of the expected product is obtained. Tt = 90°C.

Preparation 9: Methyl ester of 4-bromo 2-(terbutoxycarbonylamino)butanoic acid

5.7 g of 2-amino 4-bromobutanoic acid methyl ester obtained as in preparation 8 is mixed for 48 hours at room temperature in 120 ml of methanol with 24 ml of triethylamine and 9 g of ditertbutyl dicarbonate. The solvents are evaporated, the residue is taken up in water and dichloromethane, filtered, extracted in dichloromethane, the solvents are evaporated, the residue is chromatographed on silica (eluent: cyclohexane-ACOEt-TEA 7-3-0.5) and 1.575 g of the expected product, Rf = 0.52.

Preparation 10: 4-(3-pyrimidinyl) 1H-imidazole 1-propanol

Mix 505 mg of sodium ethylate in 12.5 ml of dimethylformamide, add 1 g of 3-(1H-imidazol-4-yl) pyridine, then 0.64 ml of chloropropanol and mix for 16 hours at 55°C. The solvent is evaporated under reduced pressure, the residue is chromatographed (eluent: CH2Cl2-MeOH 98-2) and 1.015 g of the expected product is obtained.

IR spectrum (CHCl3)

OH 3626 cm-1 + assoc

heterocycle 1601, 1578, 1551, 1499 cm-1

Preparation 11: Hexahydro-2H-1,3-diazepin-2-one hydrazone

A suspension containing 3.3 g of nitroguanidine, 7 ml of water, 3.47 g of potassium hydroxide and 5 g of diamine dihydrochloride is heated to 65-70°C for 1 hour. Add 10.5 g of zinc, mix for 30 minutes at room temperature, then add 2 ml of acetic acid, heat for 1 hour at 40°C, filter, add 3 g of ammonium chloride, then add 4 g of sodium bicarbonate. It is extracted in dichloromethane, the solvent is evaporated under reduced pressure, the residue is chromatographed on silicon dioxide (eluent: CH2Cl2-MeOH-NH4OH 8-4-2) and 1.650 g of the expected product is obtained.

Preparation 12: 3a,4,5,6,7,7a-hexahydro 2-(propylthio) 1H-benzimidazole monohydrobromide

It is heated at reflux until complete dissolution of 1 g of octahydro 2H-benzimidazol-2-thione and 1.3 ml of bromopropane in 20 ml of ethanol. The solvent is evaporated under reduced pressure. The residue is taken up in a minimal amount of dichloromethane, isopropyl ether is added, the solvents are evaporated under reduced pressure, recrystallized in isopropyl ether, filtered and dried to give the expected product with a yield of 95%, Tt=136°C.

Example 1

7-((4-(((amino)iminomethyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydrobenz(e)azulen-8-yl)-heptanoic acid

Grade A: 7-(4-oxo)-9,10-dimethoxy-1,2,3,4,5,6-hexahydrobenz(e)azulen-8-yl)oxy)-heptanoic acid methyl ester

The suspension containing 0.684 g of 2,3,5,6-tetrahydro-8-hydroxy-9,10-dimethoxy-benz/e/azulen-4(1H)-one (preparation 3) is stirred at 40°C for 4 hours. ), 12 ml of dimethylformamide (DMF), 12 ml of tetrahydrofuran (THF), 0.7 g of potassium carbonate and 0.835 g of methyl 7-bromo oentate. After evaporation under reduced pressure, the crude product is chromatographed on silica eluting with a mixture of methylene chloride (CH2Cl2)/acetone 95/5. Thus, 1.00 g of the purified product is obtained in the form of a yellow oil. Rf = 0.5 (CH2Cl2/acetone 95/5).

IR (CHCl3)

C=O 1732 cm-1

OMe 1438 cm-1

conjugated ketone 1641 cm-1

C=C 1592, 1557, 1492 cm-1

+ aromatic

Step B: 7-((4-(((amino)iminomethyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydrobenz(e)azulen-8-yl)-methyl ester heptanoic acid

A suspension of 0.5 g of the product of the previous stage A, 5 ml of ethanol and 0.330 g of amino guanidine hydrochloride is mixed for 48 hours at room temperature, the solvent is evaporated under reduced pressure and the crude product is purified by chromatography on silica eluting with a mixture of CH2Cl2/methanol. (MeOH)/ammonia 80/20/4. Thus, 0.466 g of the purified product in the form of a white foam is obtained. Rf = 0.8 (CH2Cl2/methanol (MeOH)/ammonia 80/20/4).

IR (Nuzol)

NH/NH2 3495, 3155 cm-1 + assoc

C=C 1731 cm-1

C=N 1674 cm-1

C=C 1625 cm-1

aromatic 1595 cm-l(F)

NH/NH2 1534, 1491 cm-1.

Grade C: 7-((4-(((amino)iminomethyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydrobenz(e)azulen-8-yl)-heptanoic acid

A solution containing 0.44 g of the product obtained in the previous step, 5 ml of ethanol and 2 ml of sodium hydroxide 1N is mixed for 3 hours at room temperature. After evaporation under reduced pressure, the crude product is purified by chromatography eluting with CH2Cl2/methanol(MeOH)/ammonia 80/20/4. Thus, 0.192 g of the purified product recrystallized in methanol is obtained. Rf = 0.17 (CH2Cl2/methanol (MeOH)/ammonia 80/20/4).

NMR (D2O + 1 drop of sodium hydroxide 1 N)

3.92 tl 2H CH 2 -O

2.17 t 2H CH2-COOH

1.34 m 4H

1.55m 2H CH2 central + CH2-C=

1.70 m 4H

2.50 to 2.90 m 8H

6.62 with H7 aromatic

3.64 with 3H OCH3

3.73 with 3H OCH3

Microanalysis

% calculated C 62.86 H 7.47 N 12.21

% found C 62.9 H 7.5 N 12.1

It is carried out in a manner equivalent to that of Example 1, steps A, B and C starting from 2,3,5,6-tetrahydro-8-hydroxy-9,10-dimethoxy-benz/e/azulen-4(1H)-one (preparation 3), but with different alkylation groups and G-NH2, and the following products of formula I are obtained:

Example 2:

4-((4-(((amino)iminomethyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydrobenz(e)azulen-8-yl)oxy)-butanoic acid

Example 3:

4-((4-(((amino)iminomethyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydrobenz(e)azulen-8-yl)oxy)-pentanoic acid

Example 4:

5-((4-(((amino)carbonyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)-pentanoic acid

Example 5:

6-((4-(((amino)iminomethyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)-hexanoic acid

Example 6:

5-(9,10-dimethoxy-1,2,3,4,5,6-hexahydro-4-(4,5-dihydro-1H-imidazol-2-yl)hydrazono)-8-benz(e)azulenyl )oxy)-pentanoic acid

Example 7:

5-((4-(((amino)thiocarbonyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)-pentanoic acid

Example 8:

6-(4-((4,5-dihydro-1H-imidazol-2-yl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e) azulenyl)oxy)-hexanoic acid

Example 9:

5-((4-(((amino)iminomethyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)-3,3 -dimethyl-4-oxo-pentanoic acid

Example 10:

5-(4-((4,5-dihydro-1H-imidazol-2-yl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e) azulenyl)oxy)-3,3-dimethyl-4-oxo pentanoic acid

Example 11;

4-(4-((4,5-dihydro-1H-imidazol-2-yl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e) azulenyl)oxy)-butanoic acid

Example 12:

4-((9,10-dimethoxy-4-((1,4,5,6-tetrahydro-2-pyrimidinyl)hydrazono)-1, 2,3,4,5,6-hexahydro-8-benz(e ) azulenyl) oxy)- butanoic acid

Example 13:

2-(4-((4,5-dihydro-1H-imidazol-2-yl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e) azulenyl)oxy)-ethanoic acid

Example 14:

3-(4-((4,5-dihydro-1H-imidazol-2-yl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e) azulenyl)oxy)-propanoic acid

[image]

Example 15:

5-((4-(((amino)iminomethyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydrobenz(e)azulen-8-yl)oxy)-pentanoic acid hydrochloride

Mix 85 mg of the product of example 3 with 2 ml of water and 4 liters of hydrochloric acid (0.1 N), then after a few minutes the medium is lyophilized. 91 mg of the expected salt is obtained.

Example 16:

4-((4-(((amino)iminomethyl)hydrazono)-8,9-dimethoxy-1,2,3,4,5,6-hexahydro-10-benz(e)azulenyl)oxy)-butanoic acid

Example 17:

5-((4-(((amino)iminomethyl)hydrazono)-8,9-dimethoxy-1,2,3,4,5,6-hexahydro-10-benz(e)azulenyl)oxy)-pentanoic acid

It is done as in example 1, stages A, B and C, but starting from 2,3,5,6-tetrahydro-10-hydroxy-8,9-dimethoxy-benz/e/azulen-4(1H)-one (preparation 2).

[image]

Example 18:

4-((4-(((amino)iminomethyl)hydrazono)-8,10-dimethoxy-1,2,3,4,5,6-hexahydro-9-benz(e)azulenyl)oxy)-butanoic acid

Example 19:

5-((4-(((amino)iminomethyl)hydrazono)-8,10-dimethoxy-1,2,3,4,5,6-hexahydro-9-benz(e)azulenyl)oxy)-pentanoic acid

It is done as in example 1, stages A, B and C, but starting from 2,3,5,6-tetrahydro-9-hydroxy-8,10-dimethoxy-benz/e/azulen-4(1H)-one.

[image]

Example 20:

4-((4-((4,5-dihydro-1H-imidazol-2-yl)hydrazono)-1,2,3,4,5,6-hexahydro-9-benz(e)azulenyl)oxy)- butanoic acid

Grade A: 4-(4-oxo)-1,2,3,4,5,6-hexahydrobenz(e)azulen-9-yl)oxy)-butanoic acid ethyl ester

A suspension containing 0.6 g of 2,3,5,6-tetrahydro-9-hydroxy-benz/e/azulen-4(1H)-one (preparation 6), 12 ml of dimethylformamide is mixed at room temperature overnight. (DMF), 12 ml of tetrahydrofuran (THF), 0.7 g of potassium carbonate and 0.7 ml of ethyl bromobutyrate. After evaporation under reduced pressure, the crude product is chromatographed on silica eluting with a mixture of methylene chloride (dichloromethane/acetone 95/5). Thus, 0.609 g of the purified product is obtained in the form of a yellow oil.

IR (CHCl3)

C=O 1728 cm1-1

horse. ketone 1641 cm-1

C=C aromatics 1610, 1590, 1569, 1499 cm-1.

Grade B:

Ethyl ester 4-((4-((4,5-dihydro-1H-imidazolin-2-yl)hydrazono)-1,2,3,4,5,6-hexahydrobenz(e)azulen-9-yl)oxy )-butanoic acid

608 mg of the product of the previous step A, 10 ml of butanol and 600 mg of the following cyclic amino guanidine hydrobromide: (4,5-dihydro-1H-imidazolin-2-yl)hydrazine are mixed for 24 hours at reflux, the solvent is evaporated under reduced pressure and crude the product is purified by chromatography on silica eluting with a mixture of CH2Cl2/methanol (MeOH)/ammonia 80/20/4. Thus, 0.604 g of the expected product is obtained.

IR (CHCl3)

=C-NH-3451 cm-1

C=O 1728 cm-1 (ester)

C=N + C=C + aromatics: 1627 cm-1 (F), 1568, 1548, 1497, 1488 cm-1

Grade C:

7-((4,5-dihydro-1H-imidazol-2-yl)hydrazono)-1,2,3,4,5,6-hexahydrobenz(e)azulen-9-yl)oxy)-butanoic acid

The solution containing 0.604 g of the product obtained in the previous stage, 8 ml of ethanol, 5 ml of tetrahydrofuran and 2 ml of sodium hydroxide 2N is mixed for 4 hours at room temperature, then neutralized with 2 ml of hydrochloric acid. After evaporation under reduced pressure, the crude product is purified by chromatography on silica eluting with CH2Cl2/methanol (MeOH)/ammonia 80/20/4. Thus, 0.298 g of the purified product recrystallized in methanol is obtained.

Rf - 0.2 (CH2Cl2/methanol (MeOH)/ammonia 80/20/4).

NMR (D2O + 1 drop of sodium hydroxide 1 N)

1.71 (1) 2H O-CH2-CH2-CH2-CO

1.96 (m) 2H CH2 in 2 (cyclopentene)

2.30 (t) 2H CH2-CO

2.50 to 2.75 8H CH2-C-

3.45 (sl) 4H CH2-N=

3.89 (tl) 2H Ph-OCH2-C

6.70(m)2H HI0 and H8

7.00 (d, J = 8) H7

Example 21;

4-((4-((4,5-dihydro-1H-imidazol-2-yl)hydrazono)-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)- butanoic acid

It is done as in example 20, but starting from 0.856 g of 2,3,5,6-tetrahydro-8-hydroxy-benz/e/azulen-4(1H)-one (preparation 7) and 0.299 g of the expected product is obtained.

Rf = 0.27 (CH2Cl2/methanol (MeOH)/ammonia 80/20/4).

Example 22:

5-((8-(((amino)iminomethyl)hydrazono)-6,7,8,9,10,11-hexahydro-azuleno (5,6-d)-1,3-benzodioxol-4-yl)oxy - pentanoic acid

Grade A:

5-(((4-oxo)-9,10-dihydroxy-1,2,3,4,5,6-hexahydrobenz(e)azulen-9-yl)oxy) pentanoic acid ethyl ester 1) protection

In the solution, under an inert atmosphere, 10 g of 2,3,5,6-tetrahydro-8,9,10-trihydroxy-benz/e/azulen-4(1H)-one (preparation 1) in 100 ml of tetrahydrofuran is added 4.42 ml of trimethoxyborate and 20.4 ml of triethylamine while maintaining the temperature between 37 and 39°C, then it is mixed at room temperature for 3 hours.

2) alkylation and deprotection

9.7 ml of ethyl bromo-5-valerate, 100 ml of dimethylformamide and 8.4 g of potassium carbonate were then added and mixed for 2 days at 60°C. The reaction mixture is then treated with 120 ml of water and 50 ml of concentrated hydrochloric acid (36N), stirred for 1 hour, ethyl acetate is added and the organic and inorganic phases are separated. The organic phase is then washed, dried and evaporated under reduced pressure. A crude product is obtained which is purified by means of chromatography on silica eluting with a mixture of cyclohexane/ethyl acetate 70/30. 5.2 g of pure expected product is obtained. Rf = 0.82 (dichloromethane/methanol 95/5) Rf = 0.23 (cyclohexane/ethyl acetate 70/30)

Grade B:

5-(((8-oxo)-6,7,8,9,10,11-hexahydro-azuleno(5,6-d)-1,3-benzodioxol-4-yl)oxy))-pentanoic acid ethyl ester acid

2.5 g of the product obtained in the previous step, 17 ml of dimethylformamide, 3.6 g of CsF and 1.4 ml of dibromomethane are mixed under an inert atmosphere at 60°C for 1 hour. After filtering and washing in methanol, it is evaporated under reduced pressure and the crude product is purified by chromatography on silica eluting with a mixture of cyclohexane/ethyl acetate 85/15. 1.73 of the expected pure product is obtained (Tt = 118°C). Rf = 0.25 (cyclohexane/ethyl acetate 80/20).

Grade C:

Ethyl ester 5-((8-(((amino)iminomethyl)hydrazono)-6,7,8,9,10,11-hexahydro-azuleno(5,6-d)-1, 3-benzodioxol-4-yl ) oxy) - pentanoic acid

551 mg of the product obtained in the previous step and 467 mg of aminoguanidine hydrochloride are mixed overnight at 120°C, then purified by chromatography, eluting with a mixture of dichloromethane/methanol/ammonia 80/20/4. 174 mg of the expected product is obtained. Rf = 0.98 (dichloromethane/methanol/ammonia 80/20/4)

Grade D:

5-((8-(((amino)iminomethyl)hydrazono)-6,7,8,9,10,11-hexahydro-azuleno(5,6-d)-1, 3-benzodioxol-4-yl)oxy ) – pentanoic acid

274 mg of the product obtained in the previous step and 1.86 ml of sodium hydroxide (1N) are mixed at room temperature for 1.5 hours, then neutralized with (1N) hydrochloric acid solution and evaporated under reduced pressure. The crude product is purified by chromatography eluting with a mixture of dichloromethane/methanol/ammonia 80/20/4. 141 mg of the expected product is obtained.

Rf = 0.23 (dichloromethane/methanol/ammonia 80/20/4)

NMR (DMSO)

1.55 to 1.9 (m) 4H O-CH2-CH2-CH2-CO

1.55 to 1.9 (m) 2H CH2 in 2 (cyclopentene)

2.26 (t) 2H CH2-CO

2.65 to 3.00 (m) 8H CH 2 -O

4.07 (t) 2H O-CH2-CH2-

5.95 (s) 2H-O-CH2-O

6.61 (m) 1H H8

H mobile (m, large) NH-C(=NH)-NH2

Example 23:

5-((8-(((amino)iminomethyl)hydrazono)-2,2-diphenyl-6,7,8,9,10,11-hexahydro-azuleno(4,5-e)-1, 3-benzo -dioxol-4-yl)oxy)-pentanoic acid

It is carried out as in the previous example, starting from 374 mg of the product obtained in stage A of the previous example and 0.19 ml of diphenyldichloromethane. 198 mg of the expected product is obtained. Rf = 0.17 (dichloromethane/methanol/ammonia 80/20/4)

Example 24:

O-(4-(4,5-dihydro-1H-imidazol-2-yl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e) azulenyl/-N-/(phenylmethoxy)carbonyl/-DL-homoserine

Grade A:

Methyl ester O-/(4-oxo)-9,10-dimethoxy-1,2,3,4,5,6- hexahydro-8-benz(e)azulenyl/- N-/(phenylmethoxy)carbonyl/- DL - homoserine

It is mixed for 1 night at room temperature 0.6 g of 2,3,5,6-tetrahydro-8-hydroxy-9,10-dimethoxy-benz/e/azulen-4(1H)-one (preparation 3), 10 ml dimethylformamide, 10 ml of tetrahydrofuran, 1 g of potassium carbonate and 0.867 g of DL-4-bromo-2-(phenylmethoxycarbonylamino) butanoic acid methyl ester obtained as in preparation 8. After evaporation under reduced pressure, the crude product is chromatographed on silica eluting with a mixture methylene chloride (CH2Cl2)/acetone 95/5. Thus, 1.166 g of the purified product is obtained in the form of a yellow oil.

IR(CHC13)

C=O 1740 cm-1 (ep), 1721 cm-1

conjug. ketone 1642 cm-1.

C=C aromatics 1593, 1559, 1508, 1493 cm-1.

Grade B:

Methyl ester O-/4-/(4,5-dihydro-1H-imidazol-2-yl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz( e) azulenyl/- N-/(phenylmethoxy)carbonyl/-DL-homoserine

539 mg of the product of the previous stage A, 15 ml of butanol and 600 mg of the following cyclic amino guanidine hydrobromide: (4,5-dihydro-1H-imidazol-2-yl)hydrazine are mixed for 24 hours at 120 °C, the solvent is evaporated under reduced pressure and the crude product is purified by chromatography on silica eluting with a mixture of CH2Cl2/methanol (MeOH)/ammonia 80/20/4. Thus, 0.641 g of the expected product is obtained.

IR(CHCl3)

=C-NH-3451 cm-1 + associates

C=O 1740 cm-1 (ep), 1720 cm-1 (max)

C=N + C=C + aromatics + amide II: 1667 cm-1 (F), 1601, 1508, 1490 cm-1.

Grade C:

O-(4-(4,5-dihydro-1H-imidazol-2-yl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e) azulenyl/-N-/(phenylmethoxy)carbonyl/-DL-homoserine

The solution containing 0.6 g of the product obtained in the previous step, 10 ml of ethanol and 2 ml (2N) sodium hydroxide is mixed for 2 hours at room temperature, then neutralized with 2 ml of hydrochloric acid. After evaporation under reduced pressure, the crude product is purified by chromatography on silica and eluted with a mixture of CH2Cl2/methanol (MeOH)/ammonia 80/20/4. Thus, 0.349 g of the purified product recrystallized in methanol is obtained. Rf = 0.37 (CH2Cl2/methanol (MeOH)/ammonia 80/20/4).

Example 25:

O-/4-/(4,5-dihydro-1H-imidazol-2-yl)hydrazono)-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl/-N-/ (phenylmethoxy)carbonyl/-DL-homoserine

It is carried out in a manner equivalent to that in example 24, but starting from 0.428 g of 2,3,5,6-tetrahydro-9-hydroxy-benz/e/azulen-4(1H)-ane (preparation 7). 245 mg of the expected product is obtained. Rf = 0.5 (CH2Cl2/methanol (MeOH)/ammonia 80/20/4).

Example 26:

O-/4-/(1,2,3,4-tetrahydro 6-pyrimidinyl)hydrazono/-9,10-dimethoxy 1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl/ -N-(phenylmethoxy)carbonyl/-DL-homoserine

Grade A:

Methyl ester O-/9,10-dimethoxy 1,2,3,4,5,6-hexahydro4-/(1,4,5,6-tetrahydro 2-pyrimidinyl)hydrazono/8-benz(e) azulenyl/- N-/(phenylmethoxy)carbonyl/ DL-homoserine

It is carried out as in Example 24, stage B using initially 200 mg of the product obtained as in Example 24, stage A in 2 ml of butanol and 74.5 mg of tetrahydro-2(1H)-pyrimidinone hydrazone monohydrobromide and heated at reflux for 16 hours . Allow to reach room temperature, extract into dichloromethane, dry and evaporate the solvent under reduced pressure to give 152 mg of the expected product.

Grade B:

O-/4-/(1,2,3,4-tetrahydro 6-pyrimidinyl)hydrazono/9,10-dimethoxy 1,2,3,4,5,6-hexahydro 8-benz(e)azulenyl/ -N - /(phenylmethoxy)carbonyl/ DL-homoserine

Proceed as in Example 24, Step C using a solution of 131 mg of the product obtained in Step A above in 1.3 ml ethanol and 0.43 ml (1N) sodium hydroxide. It is neutralized by the addition of (1N) hydrochloric acid, the solvent is evaporated, filtered and dried to obtain 78 mg of the expected product. Tt = 172°C.

NMR (CDCl3)

1.90(m)2H CH2 in 9

2.03 (m) CH2 central

2.36 (m) 2H

2.60 to 3.00 8H =C-CH2

3.48 (ml) 4H =N-CH2

3.77 (s) 3.78 (s) 9H =C-OMe

4.01 (m) 1H 4.17 φ-O-CH2

4.67 (p) =C-CH-N-C=

5.14 (sl) COO-CH2-φ

6.13 (d) =C-NH-CH

6.49 (fig.) H4

7.36 (m) 5H φ-C

Example 27:

2,3-dihydroxypropyl ester O-(9,10-dimethoxy 1,2,3,4,5,6-hexahydro 4-/(1,4,5,6-tetrahydro 2-pyrimidinyl) hydrazono/-8-benz (e)azulinyl/ N-/(phenylmethoxy)carbonyl/ DL-homeserine

Grade A:

/(2,2-dimethyl 1,3-dioxolan-4-yl)methyl/ester O-(9,10-dimethoxy 1,2,3,4,5,6-hexahydro 4-/(1,4,5,6 -tetrahydro 2-pyrimidinyl) hydrazono/8-benz(e)azulinyl/N-/(phenylmethoxy)carbonyl/ DL-homeserine

Cool to 0°C 0.3 g of the product obtained as in example 26 in 1 ml of dimethylformamide and 1 ml of dichloromethane, 96 mg of 1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride and 68 mg of 1-hydroxy benzotriazole hydrate. It is stirred for 30 minutes at room temperature, 0.06 ml of solketal is introduced and then stirred for 3.5 hours. The reaction medium is diluted with water, extracted in dichloromethane and 0.6 g of crude product is obtained, which is purified by chromatography on silica (eluent: CH2Cl2-MeOH 90-10). 0.352 g of the expected product is obtained.

IR spectrum (CHCl3)

NH 3400 cm-1

C=O 1745 (ep), 1719 cm-1

C=N,C=C/

aromatic, amide II/ 1672 (F), 1645, 1597, 1565 (f), 1507, 1492 cm-1.

Grade B:

/(2.3-dihydroxypropyl/ester O-(9,10-dimethoxy 1,2,3,4,5,6-hexahydro 4-/(1,4,5,6-tetrahydro 2-pyrimidinyl) hydrazono/ 8-benz (e)azulinyl/ N-/(phenylmethoxy)carbonyl/ DL-homeserine

0.320 g of the product obtained in a step of 3 ml of ethanol and 1 ml of 2 N hydrochloric acid is mixed for 6 hours at room temperature. After evaporation of the solvent and chromatography on silica (eluent: CH2Cl2-MeOH-NH4OH 80-20-4), 0.112 g of the expected product is obtained.

NMR spectrum (CDCl3)

1.88(m)2H /

1.98 / CH2 central and CH2 in 9

2.36 /

2.60 to 3.10 8H =C-CH2

3.43 (m) 4H =N-N-CH2

3.79 (s) /

3.81 / φ-OMe

3.60 to 3.90 O-CH2-CH-O

4.00 to 4.30 / COO-CH2-CH

/ φ-O-CH2-CH2

4.64 (m) 1H =C-CH-NC=

5.13 (s) COO-CH2-φ

6.53 (s) H4

7.20 to 7.38 φ-C

Example 28:

O-/4-/(4,5-dihydro 1H-imidazol-2-yl/hydrazono/9,10-dimethoxy-1, 2,3,4,5,6-hexahydro 8-benz(e)azulinyl/N -/(8-quinoleinyl) sulfonyl/ DL-homeserine

Grade A:

Methyl ester O-(9,10-dimethoxy 1,2,3,4,5,6-hexahydro 4-oxo 8-benz(e)azulinyl/N-/(1,1-dimethylethoxy)carbonyl/DL-homeserine

4.1 g of the product obtained as in preparation 3 and 5 g of the ester obtained as in preparation 9 are mixed at room temperature for 65 hours in 50 ml of dimethylformamide and 50 ml of tetrahydrofuran in the presence of 5 g of potassium carbonate and dimethylaminopyridine. The solvent is evaporated under reduced pressure, the residue is purified by chromatography on silica (eluent: CH2Cl2-acetone 95-5) and 7.3 g of the expected product is obtained.

IR spectrum (CHCl3)

=C-NH 3430 cm-1

C=O 1744 cm-1 (methyl ester)

1710 cm-1 (NH-BOC)

1648 cm-1 (conjugated ketone)

aromatic + amide II 1593, 1559, 1493 cm-1.

Grade B:

Monohydrochloride methyl ester O-(9,10-dimethoxy 1,2,3,4,5,6-hexahydro 4-oxo 8-benz(e)azulinyl/N-(1,1-dimethylethoxy)carbonyl/ DL-homeserine

Add three times 10 ml of hydrochloric acid to 6 g of the product obtained in step A in 10 ml of ethyl acetate, then mix for 16 hours at room temperature. The solvent is evaporated under reduced pressure and 0.656 g of the expected product is obtained, which is used as such in the next step.

Grade C:

O-(9,10-dimethoxy 1,2,3,4,5,6-hexahydro 4-oxo 8-benz(e)azulinyl/N-/(8-quinoleinyl)sulfonyl/ DL-homeserine

0.656 g of the product obtained above is taken in 5 ml of dichloromethane, 1 ml of triethylamine and 0.638 g of 8-chlorosulfonyl quinoline are added and stirred for 2 hours at room temperature. After evaporation of the solvent under reduced pressure and chromatography on silica (eluent: CHCl2-MeOH 95-5), 0.956 g of the expected product is obtained.

Grade D:

Methyl ester O-/4-/(4,5-dihydro 1H-imidazol-2-yl)hydrazono/9,10-dimethoxy 1,2,3,4,5,6-hexahydro 8-benz(e)azulinyl/ N-/(8-quinoleinyl)sulfonyl/ DL-homeserine

0.9 g of the product of the previous step A, 5 ml of butanol and 0.6 g of the following cyclic amino-gunanidine hydrobromide are mixed for 16 hours at 120°C: (4,5-dihydro 1H-imidazol-2-yl)hydrazine, dissolved evaporate under reduced pressure and obtain 0.786 g of the expected product, which is used as such for the next step.

Grade E:

O-/4-/(4,5-dihydro 1H-imidazol-2-yl) hydrazono/9,10-dimethoxy 1,2,3,4,5,6-hexahydro 8-benz(e)azulinyl/ N - / (8-quinoleinyl)sulfonyl/ DL-homeserine

The solution containing 0.786 g of the product obtained in the previous step, 5 ml of methanol and 2 ml of 2 N sodium hydroxide is mixed for 2 hours at room temperature, then neutralized with 2 ml of 2 N hydrochloric acid and mixed for 10 minutes. After evaporation under reduced pressure, the crude product is purified by chromatography on silica and eluted with a mixture of CH2Cl2-methanol-ammonia 80-20-4. 0.438 g of the expected product is obtained after recrystallization in methanol.

Rf = 0.40 (CH2Cl2-methanol-ammonia 80-20-4).

NMR spectrum (DMSO)

1.81 (sl) CH2 in 9

2.40 to 3.20 =C-CH2

3.35 (1) = N-CH2

3.55 (sl) C-OMe

6.63 (fig) H2

7.58 (dd) H'3

7.67 (t) H'6

8.19(d), 8.29(d) H'5 and H'7

8.45 (d) H4

8.90 (d) H2

7.31 (si) /

7.97 / H movable

10.40 (f) /

12.62 /

Example 29:

Monohydrochloride O-/4-/(4,5-dihydro 1H-imidazol-2-yl) hydrazono/9,10-dimethoxy 1,2,3,4,5,6-hexahydro 8-benz (e)azulinyl/ N -//3-/4-(3-pyridinyl) 1H-imidazol-yl/propoxy/carbonyl/ DL-homeserine

Grade A:

Methyl 4-//9,10-dimethoxy 1,2,3,4,5,6-hexahydro 4-oxo 8-benz(e)-azulinyl/oxy/ 2-isocyanato butanoate

450 mg of the amine obtained in step B of Example 28 was mixed for 10 minutes at 0°C in 10.2 ml of saturated aqueous sodium bicarbonate solution and 10.2 ml of dichloromethane. 204 mg of a solution of triphyosgene in 2 ml of dichloromethane is added to the organic phase of the reaction medium, mixed for 10 minutes, extracted into dichloromethane, dried, the solvent is evaporated under reduced pressure and 430 mg of the expected product is obtained, which is used as such in the next step.

Grade B:

O-//9,10-dimethoxy 1,2,3,4,5,6-hexahydro 4-oxo 8-benz(e)azulinyl/N-//3-/4-(3-pyridinyl) 1H-imidazole -1-yl/ propoxy / carbonyl/ DL-homoserine

Cool to 0°C 430 mg of the product obtained in step A in 20 ml of dichloromethane and add 414 mg of alcohol obtained as in preparation 10 in 10 ml of dichloromethane. It is allowed to reach room temperature, kept under stirring for 48 hours, the solvent is evaporated under reduced pressure, the residue is chromatographed on aluminum trioxide (eluent: CH2Cl2-MeOH) and 298 mg of the expected product is obtained.

Grade C:

Monohydrobromide O-/4-/(4,5-dihydro 1H-imidazol-2-yl)hydrazono/9,10-dimethoxy 1,2,3,4,5,6-hexahydro 8-benz (e)azulinyl/N -//3-/4-(3-pyridinyl) 1H-imidazol-1-yl/propoxy/carbonyl/ DL-homoserine

It is carried out as in example 24, stage B starting from 277 mg of the product obtained above and 164 mg of cyclic aminoguanidine hydrobromide in 13 ml of butanol. After chromatography on aluminum trioxide (eluent: CH2Cl2-MeOH 95-5), 289 mg of the expected product is obtained.

IR spectrum (CHCl3)

C=O 1746 (ep) 1723 (max) cm-1

conjug. system/

+aromatic /1668, 1625 (F), 1599 (ep), 1551, 1509, 1489 cm-1

+amide II /

OH 3618 cm-1

Grade D:

Monohydrochloride O-/4-/(4,5-dihydro 1H-imidazol-2-yl)hydrazono/9,10-dimethoxy 1,2,3,4,5,6-hexahydro 8-benz(e)azulinyl/N -//3-/4-(3-pyridinyl) 1H-imidazol-1-yl/propoxy/carbonyl/DL-homoserine

Add 0.3 ml of 1N sodium hydroxide to 277 mg of the product obtained in step C above in 10 ml of ethanol, stir for 30 minutes, add 10 ml of water, acidify the reaction medium to pH = 2.5 using 1N hydrochloric acid, solvent is evaporated under reduced pressure, the residue is chromatographed on silicon dioxide (eluent: CH2Cl2-MeOH-NH4OH 40-10-2), the filtrate is evaporated under reduced pressure, the residue is taken up in isopropyl ether, the precipitate is filtered, dried and 126 is obtained mg of expected product.

NMR spectrum (DMSO)

l,78(m)2H /

l.90 to 2.30 (m) 5H /

1.90 to 2.30 (m) 5H/3-CH2

1.60 to 2.90 (m) 8H CH2-C=

3.53 (sl) 4H N-CH2-CH2-N

3.69 (s), 3.71 (s) CH3O-C=

3.90 to 4.20 (m) (7 - 8H) CH2 and CH

6.73 (s) H4

7.20 (d, large) CO-NH-CH-

7.35 (dd) H'5

8.04 (d) H'4

8.37 (dl) H'6

8.94 (sl) H'2

7.72 (s), 7.80 (s) CH-imidazole

Example 30:

5-//4-/(4,5-dihydro oxo 1H-imidazol-2-yl)hydrazono/9,10-dimethoxy 1,2,3,4,5,6-hexahydro 8-benz(e)azulinyl/ oxy/ pentanoic acid

Place at room temperature 300 mg of the product obtained in step A of example 3 in 6 ml of ethanol with 61 mg of sodium carbonate and 0.7 ml of ethyl bromoacetate. The solvents are removed, the residue is chromatographed on silica (eluent: CH2Cl2-MeOH 95-5) and 139 mg of intermediate ethyl ester is obtained. Mix 110 mg of this ester in 1 ml of ethanol in the presence of 0.5 ml of 2N sodium hydroxide for 2 hours at room temperature. After neutralizing the reaction medium with 2N hydrochloric acid, the formed precipitate is filtered, dried and 44 mg of the expected product is obtained.

NMR spectrum (DMSO)

1.73 (m) 6H CH2 central and CH2 in 9

2.30 (t) 2H =C-CH2 (chain)

2.30 to 3.20 =C-CH2

3.73 (s), 3.75 (s) φ-OMe

3.83 (sl) =C-N-CH2-C=

4.02 (t) φ-O-CH2

6.76 (s) H4

7.20 (sl) 1H/

8.28 (sl) 1H/H mobile

12.04 1H /

Example 31

O-/9,10-dimethoxy 1,2,3,4,5,6-hexahydro 4-/(4,5,6,7-tetrahydro 1H-1,3-diazepin-2-yl) hydrazono) 8- benz (e)-azulinyl/-N-/(phenylmethoxy)carbonyl/DL-homoserine

The compound obtained in example 24, stage A is mixed for 16 hours at 130°C in 5 ml of butanol and 0.9 g of cyclic aminoguanidine obtained in preparation 11. The solvent is removed under reduced pressure, the residue is chromatographed on silica (eluent: CH2Cl2 -MeOH 90-10) and 0.8 g of the intermediate ester is obtained, which is mixed at room temperature for 1.5 hours in 3 ml of methanol with 2 ml of 2N sodium hydroxide. After neutralizing the reaction medium with 2N hydrochloric acid and evaporating the solvent under reduced pressure, the residue is chromatographed on silica (eluent: CH2Cl2-MeOH-NH4OH 90-15-2) and 0.22 g of the expected product is obtained.

Example 32

O-/9,10-dimethoxy 1,2,3,4,5,6-hexahydro 4-/(3a,4,5,6,7,7a-hexahydro 1H-benzimidazol-2-yl) hydrazono) 8- benz (e)-azulinyl/N-/(phenylmethoxy)carbonyl/DL-homoserine

It is done as in stages B and C of example 24 starting from 200 mg of the compound obtained in example 24, stage A and 176 mg of cyclic amino guanidine obtained as in preparation 12. 102 mg of intermediate ester is obtained, 100 mg of which is used for the saponification reaction. 59 mg of the expected product is obtained.

Rf-0.24 (CH2Cl2-MeOH-NH4OH 85-15-3).

Pharmaceutical preparations

Tablets corresponding to the following formula are prepared:

Product of example 1 50 mg

Excipient (talc, starch, magnesium stearate)

QS for final tablets up to 120 mg

Pharmacological testing of the product of the invention

1) Testing the products of the invention to move the link:

Vitronectin/Vitronectin receptor (αvβ3)

Protocol:

96-well MaxiSorp plates were coated overnight at 4°C with 100 μl of human Vitronectin at 2 μ/ml (dilution in coating buffer) (see Yatohgo et al. Cell., Structure and fraction 13 :281-292 (1988 )).

The next day, the wells are emptied and the ligands (vitronectin) are then fixed (using fixation buffer) for 1 hour at room temperature with gentle agitation.

The loops are washed six times (using the washing buffer), then they are added to the loops in the following order:

-40 μl incubation buffer

-10 μl diluent of the test product (the products are diluted in a 50/50 DMSO-H2O mixture)

-50 μl of human receptor αVβ3 (see Pytels et al. Methods Enzymol (1987) 144:475 (dilution in incubation buffer is adjusted according to the proportions of receptor and ligand).

The ligand, the human receptor αvβ3 and the products to be tested are incubated for 3 hours at room temperature with gentle mixing.

The cells are washed again six times, then they are incubated for two hours at room temperature with gentle mixing in the presence of 100 μl of the antibody 4B12-HRP, an anti-receptor bound to peroxidase (the antibody 4B12-HRP is diluted in the incubation buffer. The dilution is adjusted according to the proportion receptors).

The wells are then washed six times before measuring ligand-receptor binding using a peroxidase intermediate assay (TMB Microwell Peroxidase Substrate System Kirkegaard: Ref. cat. 50-76-00).

This trial contains vial A of substrate (3,3',5,5'-tetramethylbenzidine at 0.4 g/l) and vial B (H2O2 at 0.02% in citrate/citric acid buffer). Immediately, one volume of A is mixed with one volume of B, then the reaction mixture is dispensed at 100 μl/well. The enzymatic reaction takes place during 12 minutes for Vitronectin/αvβ3, then it is stopped by the addition of 100 μl of 1 M phosphoric acid. The optical density is measured at 450 nm.

Buffers:

-coating buffer: Carbonate 0.05 M, NaOH pH 9.6

-fixing buffer: PBS containing 0.5% BSA (pH 7.4)

-washing buffer: PBS containing 0.05% Tween 2o (pH 7.4)

- buffer for incubation: 50 mM TRIS pH 7.4; 0.5% BSA; 0.05% Tween

20; 1mM MnCl2; 50 μM CaCl2; 50 μM MgCl2; 100 mM NaCl.

Expression of results:

The following curve is drawn: the percentage of binding of human vitronectin as a function of the logarithm of the change in the concentration of the tested product.

[image]

For each product, the IC50 is determined according to the following formula:

BO = Maximum binding in the absence of all products

Bmin = Minimum binding in the presence of the best product concentration

2. Testing mouse calvaria

Principle

One dose of 45Ca marker (CaCl2) is injected into female mice for the purpose of examining bone resorption by measuring the release of 45Ca from the pups' skulls.

Goal

Determination of the activity of molecules on bone resorption, study in vivo.

Products

1) The product being tested;

Carrier: DMSO, H20/BSA (0.1%)

Dose: Variable (10 μM in trial)

2) Reference products:

Echistatin (ref. H-9010-BACHEM)

Carrier: H20/BSA

Dose: 10 μM

3) Radioactive marker:

45Ca in the form of an aqueous solution of CaCl2 -ref-CES3 AMERSHAM or NEZ-

NEZ- 013 NEN.

Carrier: Physiological serum

Dose: 25 μCi/mouse/0.4 ml

Culture medium: CMRL 1066 with red phenol (ref. 041-01535

M/GIBCO) supplemented with 0.1% BSA and

penicillin/streptomycin.

Method

1) 45Ca is injected into cattle mice (OF1, breed: Swiss)

a) Preparation of labeled solution:

190 μl of maternal calcium solution at 2 mci/ml is added to 6 ml of physiological serum.

b) Injection:

On the seventeenth day of pregnancy, mice receive 400 μl of this solution intravenously, say 25 μCi/mouse.

2) Taking tissue (ball of the skull (calvarium))

Six days after birth, newborn mice are decapitated, the head is removed and the skin is cut on the back of the head. The calvarium (skull) is separated by cutting with a chisel and using a punch and both completely identical half-skulls (one left and one right) are separated as individual bones. One will serve as a reference and the other will be used to test the tested product.

3) The "rinse" phase

Each half of the calvaria is placed in a 24-well plate containing 1 ml of medium, on a 100 μm polyethylene and nylon support, to avoid any contact with the bottom of the well.

After 24 hours, the polyethylene supports bearing the calvaria are transferred to new 24-well plates containing 1 ml of fresh medium and the test products or their solvates. 200 μl of the middle of the first plates is separated into each well and the first reading of radioactivity (A value) is performed.

This change of environment allows the elimination of all previous mechanical stresses.

4) The "resorption" phase

48 hours after tissue contact with the studied products, 200 μl of the medium is taken in each eye and the radioactivity (value B) is read to determine the amount of 45Ca released in the medium during the phase called resorption.

The calvaria is then completely demineralized in 1 ml of 5% trichloroacetic acid and after destruction, 200 μl of the solution is separated and the radioactivity is read to determine the amount of calcium remaining in the bone (C value).

Expression of results

The percentage of bone resorption is calculated for each half of the calvaria (each

[image]

okce) in the following way:

The sum of A + B + C represents the amount of 45Ca incorporated into each piece of bone the previous day.

In order to measure the effect of the product of the invention, the ratio of the percentage of bone resorption of the treated eye and the corresponding reference eye is given for each point. The value found, called the resorption index, is between 0 and 1 if the product inhibits bone resorption and is greater than 1 if the product supports it. Then the mean value of the 6 indices (since there are 6 points/group) of each product is found, which is given as an index/product. If the value index 1 is omitted, the possibility of inhibition of the product is obtained, which can be expressed as a percentage.

In addition to this, a statistical test (subject T-test) was performed, which includes point/point indices of individual resorptions.

[image]

Claims (22)

1. Compounds of general formula I: [image] characterized by: R represents the group -C=C-/A/-/B/-COR6, -CH=CH-/A/-/B/-COR6, -(CH2)2-/A/-/B/-COR6, - O-/A/-/B/-COR6, -CH2CO-/A/-/BACOR6, /A/ represents -hydrocarbon divalent radical derived from a linear or branched structure, saturated or unsaturated, containing 1-12 carbon atoms and 1-6 heteroatoms selected from oxygen, nitrogen or sulfur atoms, - a divalent radical derived from an acyclic hydrocarbon, linear or branched, saturated or unsaturated, containing 1-12 carbon atoms, /B/ represents a phenyl radical or a CH(Z) radical or a single bond, Z represents a hydrogen atom or a group (D)0-6-NRaRb, (D)0-6-NH-SO2-Rc, (D)0-6-NH-CO2-Rc, (D)0-6-NH- CO-Rc, (D)0-6-NH-SO2-NH-Rc, (D)0-6-NH-CO-NH-Rc, (D)0-6-CO2-Rc, (D)0- 6-SO2-Rc, (D)0-6-CO-Rc or (D)0-6-Rc indicated that (D)0-6 is a divalent radical derived from an acyclic hydrocarbon, linear or branched, saturated or unsaturated containing 0-6 carbon atoms, Ra, Rb and Rc represent a hydrogen atom, the radical (CH2)0-3-Ar indicated that Ar represents a carbocyclic aryl group containing 6-18 carbon atoms, the radical (CH2)0-3-Het indicated that Het represents a radical derived from an aromatic or non-aromatic heterocycle, saturated or unsaturated containing 1-9 carbon atoms and 1-5 heteroatoms selected from oxygen, nitrogen or sulfur atoms, the (CH2)0-3-Alk radical indicated by the fact that Alk represents a radical derived from a non-aromatic hydrocarbon, branched or cyclic, saturated or unsaturated containing 1-12 carbon atoms, the radicals Het, Ar and Alk may be substituted or unsubstituted, or Ra and Rb together with the nitrogen atom to which they are attached represent a nitrogen heterocycle, aromatic or non-aromatic, saturated or unsaturated, possibly containing one or more heteroatoms selected from oxygen, nitrogen or sulfur atoms, this radical can be substituted or unsubstituted, R6 represents a hydroxyl radical, a radical 0-Alk, O-Ar, NH2, NH-Alk, N(Alk)2 or an amino acid residue L or D, Alk and Ar can be as defined above and can be substituted or unsubstituted , R2 and R3, identical or different, represent a hydrogen atom, a hydroxyl radical, an O-Alk radical or an O-(CH2)0-3-Ar radical, Alk and Ar are as defined above, or R2 and R3 together form a ring of the type -O-(CRdRe)n-O-, n is an integer between 1 and 5, Rd and Re each independently represents a hydrogen atom, an alkyl radical containing 1-6 carbon atoms or a phenyl radical, R4 represents a hydrogen atom, a halogen atom, a hydroxyl, amino, nitro, cyano, CF3, acyl or acyloxy group having 1 to 12 carbon atoms, alkyl, alkenyl, alkynyl, alkylthio, alkoxy, alkylamino, dialkylamino, dialkylaminoalkyl, dialkylaminoalkyloxy, indicated by the alkyl part comprises 1 to 6 carbon atoms, R5 represents a hydrogen atom, a hydroxyl radical, a halogen atom, an O-Alk radical or an O-(CH2)0-3-Ar radical, Alk and Ar are as defined above, G represents: - let's say the radical of the formula G 1 [image] where Rh is a hydrogen atom or an Alk group as defined above and Het' is a heterocycle of the general formula: [image] where H forms with part N=C-NH- a heterocyclic residue aromatic or non-aromatic, mono or bicyclic, saturated or unsaturated comprising 1 to 9 carbon atoms and from 2 to 5 heteroatoms selected from oxygen, nitrogen and sulfur atoms, this radical can be substituted or unsubstituted, - let's say the radical NRaRb (radical G2), Ra and Rb are as defined above, -let's say the radical Het (radical G3) as defined above, - let's say the radical -NRh-C(=X)-NHRc (radical G4), indicated by the fact that X is a sulfur atom, oxygen or NH, Rh and Rc are as defined previously, -let's say the radical -NRh-SO2Rc (radical G5), indicated by the fact that Rh and Rc are as defined previously, arrows in dotted lines represent a possible secondary bond, as well as their addition salts with acids and bases and esters, R1 R2 and R3 can be in position 8, 9 or 10 tricycles. 2. Compounds of the general formula I as defined in claim 1, to which the general formula I' corresponds: [image] indicated by what R', represents the group: -C=C-/A'/-/B'/-COR'6, -CH=CH-/A'/-/B/-COR'6, -(CH2)-/A'/-/B' /-COR'6, -O-/A'/-/B'/-COR'6, -CH2CO-/A'/-/B/-COR'6, -/A'/ represents a divalent radical alkylene, alkenylene or alkynylene containing from 1 to 6 carbon atoms, /B'/ represents the radical CH(Z') or a simple bond, Z' represents a hydrogen atom, the group (CH2)0-6-NRaRb, (CH2)0-6-NH-SO2-Rc, (CH2)0-6-NH-CO2-Rc, (CH2)0-6-NH -CO-Rc, (CH2)0-6-NH-SO2-NH-Rc, (CH2)0-6-NH-CO-NH-Rc, (CH2)0-6-CO2-Rc, (CH2)0 -6-SO2-Rc, (CH2)0-6-CO-Rc or (CH2)0-6-Rc; Ra, Rb and Rc are as defined above, R'6 represents the radical OH, amino or alkoxy containing from 1 to 8 carbon atoms, optionally substituted with one or more radicals selected from hydroxy, amino, phenyl, alkylamino or dialkylamino, R'2 and R'3 represent a hydrogen atom or a methoxy radical and G is as defined previously, arrows in dotted lines represent a possible secondary bond, as well as their addition salts with acids and bases and esters. 3. Compounds of the general formula I as defined in claim 1 or 2 characterized in that R6 represents the group -OH, -OCH3, -OCH2CH3, -O-(CH2)2-OH, -O-CH2-CH(OH) -(CH2)OH, -O-CH2-NH2, -O-(CH2)2-N-(CH3)2, -NH2 or -O-(CH2)-phenyl as well as their addition salts with acids and bases and esters . 4. Compounds of the general formula I as defined in claim 1, 2 or 3, characterized in that R1 represents the group O-(CH2)0-6CH(Z')-COOH or -(CH2)0-7CH(Z ')-COOH as well as their addition salts with acids and bases and esters. 5. Compounds of the general formula I such as defined in one of the previous claims indicated by the fact that Z' represents a hydrogen atom, as well as their addition salts with acids and bases and esters. 6. Compounds of the general formula I as defined in any of the preceding claims 1-4, characterized in that Z' is the group (CH2)0-6-NH-CO2-Rc or (CH2)0-6-NH-Rb , Rb and Rc are as defined in claim 1, as well as their addition salts with acids and bases and esters. 7. Compounds of the general formula I as defined in claim 6, characterized in that Rb and Rc represent the groups (CH2)0-3-Ar or (CH2)0-3-Alk, characterized in that Ar and Alk are as is defined in claim 1 and can be substituted or unsubstituted, as well as their addition salts with acids and bases and esters. 8. Compounds of the general formula I as defined in any of the preceding claims 1-7, characterized in that G is a group G4 of the general formula -NH-C-(=NH)-NHRc, characterized in that Rc is as defined in claim 1, as well as their addition salts with acids and bases and esters. 9. Compounds of the general formula I as defined in claim 8, characterized in that Rc is a hydrogen atom, as well as their addition salts with acids and bases and esters. 10. Compounds of the general formula I as defined in any of the preceding claims 1-7, characterized in that G is -NH-(Het'), as defined in claim 1. 11. Compounds of the general formula I, as defined in claim 10, characterized in that G represents the following heterocycles: [image] where p is an integer of 2, 3 or 4, these heterocycles are substituted or unsubstituted, as well as their addition salts with acids and esters. 12. Compounds of the general formula I as defined in claim 10 or 11, characterized in that G is a group of the formula: [image] p is a number equal to 2, 3 or 4, as well as their addition salts with acids and bases and esters. 13. Compounds of formula I as defined in claim 1 characterized by comprising 4-((4-((aminoiminomethyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulen-yl)-butanoic acid, 5-((4-((aminoiminomethyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulen-yl)-pentanoic acid, 5-((4-((aminoiminomethyl)hydrazono)-8,10-dimethoxy-1,2,3,4,5,6-hexahydro-9-benz(e)azulen-yl)-pentanoic acid, 6-((4-((aminoiminomethyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)-hexanoic acid, 7-((4-((aminoiminomethyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro- 8-Benz(e)azulenyl)-heptanoic acid, 5-((9,10-dimethoxy-1,2,3,4,5,6-hexahydro-4-((4,5-dihydro-1H-imidazol-2-yl)hydrazono)-8-benz(e )azulenyl)oxy)-pentanoic acid, ethyl 5-((4-((aminoiminomethyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)-pentanoate hydrochloride, 4-((4-((aminoiminomethyl)hydrazono)-8,9-dimethoxy-1,2,3,4,5,6-hexahydro-10-benz(e)azulenyl)-butanoic acid, 5-((4-((aminoiminomethyl)hydrazono)-8,9-dimethoxy-1,2,3,4,5,6-hexahydro-10-benz(e)azulenyl)oxy)-pentanoic acid, 5-((4-(((amino)carbonyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)-pentanoic acid, 5-((4-(((amino)thiocarbonyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)-pentanoic acid, 4-((4-((aminoiminomethyl)hydrazono)-8,10-dimethoxy-1,2,3,4,5,6-hexahydro-9-benz(e)azulen-yl)oxy)-butanoic acid, 6-((4-((4,5-dihydro-1H-imidazol-2-yl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e )azulenyl)oxy)-hexanoic acid, 5-((4-((aminoiminomethyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)-3,3-dimethyl- 4-oxo-pentanoic acid, 5-((4-((4,5-dihydro-1H-imidazol-2-yl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e )azulenyl)oxy)-3,3-dimethyl-4-oxo-pentanoic acid, 5-((4-((aminoiminomethyl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)-pentanoic acid hydrochloride, 4-((4-((4,5-dihydro-1H-imidazol-2-yl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e )azulenyl)oxy)-butanoic acid, 5-((8-((aminoiminomethyl)hydrazono)-6,7,8,9,10,11-hexahydro-azuleno(5,6-d)-1,3-benzodioxol-4-yl)oxy)-pentanoic acid, 5-((8-((aminoiminomethyl)hydrazono)-2,2-diphenyl-6,7,8,9,10,11-hexahydro-azuleno(4,5-e)-1,3-benzodioxole-4- yl)oxy)-pentanoic acid, 4-((9,10-dimethoxy-4-((1,4,5,6-tetrahydro-2-pyrimidinyl)hydrazono)-1,2,3,4,5,6-hexahydro-8-benz(e )azulenyl)oxy)-butanoic acid, 2-((4-(4,5-dihydro-1H-imidazol-2-yl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e) azulenyl)oxy)-ethanoic acid, 3-((4-(4,5-dihydro-1H-imidazol-2-yl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e) azulenyl)oxy)-propanoic acid, 4-((4-(4,5-dihydro-1H-imidazol-2-yl)hydrazono)-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl)oxy)-butanoic acid, O-(4-(4,5-dihydro-1H-imidazol-2-yl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e) azulenyl/-N-/(phenylmethoxy)carbonyl/DL-homoserine, O-/4-/(4,5-dihydro-1H-imidazol-2-yl)hydrazono)-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl/-N-/ (phenylmethoxy)carbonyl/-DL-homoserine, O-/4-/(1,2,3,4-tetrahydro 6-pyrimidinyl) hydrazono/9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e)azulenyl/ N- /(phenylmethoxy)carbonyl/ DL-homoserine, 2,3-dihydroxypropylene ester O-(9,10-dimethoxy-1,2,3,4,5,6-hexahydro-4-/(1,4,5,6-tetrahydro-2-pyrimidinyl)hydrazone/- 8 -benz(e)azulenyl/N-/(phenylmethoxy)carbonyl/DL-homoserine, O-(4-(4,5-dihydro-1H-imidazol-2-yl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e) azulenyl/-N-/(8-quinoleinyl)sulfonyl/DL-homoserine, O-(4-(4,5-dihydro-1H-imidazol-2-yl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz(e) azulenyl/-N-//3-/4-(3-pyridinyl) 1H-imidazol-1-yl/propoxy/carbonyl/-DL-homoserine monohydrochloride, 5-//4-/(4,5-dihydro 4-oxo 1H-imidazol-2-yl)hydrazono)-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz (e) azulenyl)oxy)-pentanoic acid, O-/9,10-dimethoxy 1,2,3,4,5,6-hexahydro 4-/(4,5,6,7-tetrahydro 1H-1,3-diazepin-2-yl) hydrazono/ 8- benz(e)azulenyl/N-/(phenylmethoxy)carbonyl/ DL-homoserine, O-/9,10-dimethoxy 1,2,3,4,5,6-hexahydro 4-/(3a,4,5,6,7,7a-hexahydro 1H-benzimidazol-2-yl)hydrazono/8- b enz(e)azulenyl/N-/(phenylmethoxy)carbonyl/DL-homoserine. 14. Process for obtaining compounds of general formula I such as defined in claim 1, characterized in that the compound of formula II is subjected to: [image] where R2, R3, R4 and R5 are as defined in claim 1 with the exception of the meaning hydroxyl, let's say the action of the compound/s of formula F 1 in the presence of a base: Hal-/A/-/B/-COR6 (F1) or compounds of formula (F'1) in the presence of phosphine and ethyl azodicarboxylate: HO-/A/-/B/-COR6 (F'1) where Hal is a halogen atom, /A/, /B/ and R6 are as defined above, /B/ can equally represent the group -(P-NH)-C-H-, P is the protecting group of the amine function to obtain compounds of the formula ( IIIa): [image] let's say the action of the activation group and then the compounds of formula (F2) in the presence of a catalyst: [image] to obtain the compound of formula (IIIb): [image] compounds of formula (IIIa) or (IIIb) are subjected to the action of compounds of formula (F3): H2N-G where G is as defined in claim 1, in order to obtain compounds of formulas (IVa) and (IVb) corresponding to certain products of formula I: [image] [image] which undergo in that case, in the appropriate order, one or more of the following reactions: - the action of a base or an acid to break up the ester and obtain the corresponding acid, - action of a reducing agent capable of reducing partial or complete unsaturation, - action of the triple bond hydration agent, - action of the dealkylation agent, - the action of an agent that deprotects the NH-P function as β-CO-R6 when /B/ represents the CH-NHP group, - forming the group NH-SO2Rc, NH-CO2Rc, NHCORc, NH-SO2-NH-Rc, NH-CO-NHRc starting from the corresponding amine as β-COR6 in order to obtain the corresponding compound of formula I, which is then subjected to the action of an acid or a base to obtain appropriate salts or to the action of an esterification agent to obtain appropriate esters. 15. Process for obtaining compounds of formula I as defined in claim 1, characterized in that the compound of formula II is previously subjected to the action of compounds of formula F3 in order to obtain intermediate products of formula IIIc: [image] which, in the case of protection of group G, is then subjected to the action of compounds of formulas F1, F'1 or F2 and, if necessary, to the deprotection reaction of group G, in order to obtain the corresponding products of formulas IVa and IVb, which are then, if necessary, subjected to various reactions such as is defined in claim 14, the compounds of formula II, F1, F'1, F2, F3, IVa and IVb are as defined in claim 14. 16. Process for obtaining products of formula II as defined in claim 14, where R2, R3, R4 and R5 represent hydrogen atoms and OH is in position 8, 9 or 10, indicated by the fact that (i) a compound of formula (a) is subjected to: [image] where O-Alk is in the meta or para alkylcarboxyl group position, Alk is as defined in claim 1, to the action of a halogenating agent to obtain the corresponding acyl halide: (ii) subjected to the action of the reagent of formula (b): [image] where R(I) and R(II), identical or different, represent an alkyl group containing from 1 to 6 carbon atoms, or R(I) and R(II) together with the nitrogen atom to which they are attached represent a heterocycle of 5 or 6 members, saturated or unsaturated, possibly containing another heteroatom chosen between O and N, in order to obtain compounds of formula (c): [image] (iii) which is subjected to the action of a halogenating agent in order to obtain compounds of formula (d): [image] where Hal1 represents a halogen atom, iv) which is subjected to the action of a Lewis acid in order to obtain compounds of formula (e): [image] v) which is subjected to the action of a dealkylation reagent to obtain a product of formula IIF corresponding to the expected monosubstituted product of formula II: [image] 17. Process for obtaining compounds of the general formula II as defined in claim 14 where R2 represents for example the group O-Alk, O-(CH2)0-3Ar and R3, R4 and R5 are hydrogen atoms and OH and R2 is in the position 8, 9 or 10, characterized in that it subjects the compound of formula (a'): [image] in which O-AlK and R2 are in the meta or para position of the alkylcarboxylic group, by successive reactions (i), (ii), (iii), (iv) and (v) to obtain products of formula IIG corresponding to the expected bisubstituted products of formula II: [image] 18. Process for obtaining compounds of the general formula II, as defined in claim 14 and where R2 and R3 represent the group O-Alk or O-(CH2)0-3-Ar, R4 and R5 are hydrogen atoms, OH in the position 9, characterized in that the compound of formula IIA undergoes: [image] to the action of a dealkylation reagent to obtain compounds of formula IIB: [image] a compound of formula IIB undergoes: - let's say the action of a protective reagent for diols in a basic environment in order to selectively obtain products of the formula HC: [image] where P represents the residue of the diol protecting reagent, which is sequentially treated with a phenol protecting reagent, a diol deprotecting reagent, an alkylating agent and then a phenol deprotecting agent to give the compound of formula IID corresponding to the product of formula II trisubstituted with OH at the 8 position : [image] - say the sequential action of a phenol protecting agent, an alkylating agent, then a deprotecting agent to obtain a compound of formula IIE which corresponds to a product of formula II trisubstituted with OH in position 9: [image] 19. Compounds of formula I as defined in any of claims 1-12, as well as their pharmaceutically acceptable addition salts and esters, indicated by the fact that they are used as medications. 20. Compounds of formula I as defined in claim 13, characterized in that they are used as medications. 21. Pharmaceutical preparations characterized by the fact that they include as an active principle at least one of the medicines defined in claim 19 or 20, 22. New intermediate products, compounds of general formulas IIIa, IIIb, IIIc and II as defined in any of claims 14-18, characterized in that the expected compounds of formula IIc are compounds: 2,3,5,6-tetrahydro-9,10-dimethoxy-8-hydroxy-benz/e/azulen-4(1H)-one and 2,3,5,6-tetrahydro-8,9-dimethoxy-10-hydroxy-benz/e/azulen-4(1H)-one are excluded.