OA11603A - Tricyclic compounds having an activity with respect to integrins, in particular with respect to the ALPHAvBETA3 integrin, their process of preparation and the intermediates of this process, their application as medicaments and the pharmaceutical compositions containing them. - Google Patents

Description

011603

Novel tricyclic compounds, process for their preparation and intermediates thereof, their use as medicaments and pharmaceutical compositions containing them 5

The present invention relates to novel tricyclic compounds, process for their preparation and intermediates thereof, their use as medicaments and pharmaceutical compositions containing them. The subject of the present invention is the compounds of general formula (I):

in which R '^ represents a group -OC- [A] - [B] -CORg, -CH = CH- [A] - [B] -CORg, (CH2) 2- [A] - [B] -CORg , -O- [A] - [B] -CORg, -CH 2 CO- [A] - [B] -CORg, - [A] - representing - a divalent hydrocarbon radical derived from a linear or branched structure saturated or unsaturated, having from 1 to 12 carbon atoms and from 1 to 6 heteroatoms selected from oxygen, nitrogen or sulfur atoms, or a divalent radical derived from an acyclic, linear or branched hydrocarbon saturated or unsaturated, having from 1 to 12 carbon atoms, [B] representing a phenyl radical, a CH (Z) radical, or a single bond, Z represents a hydrogen atom, a (ü) Og-NRaRb group, (D) O-g-NH-SO2-Rc, (D) θ-g-NH-CO2-Rc, (D) O-g-NH-CO-Rc, (D) O-g-NH-SO2-NH-Rc, (D) O_g -NH-CO-NH-Rc, (D) og-CO2-Rc, (D) O-g-SO2-Rc, (D) O-g-CO-Rc or (D) O-g-Rc in which (D) is a bivalent radical derived from an acyclic, linear or branched, saturated or unsaturated hydrocarbon, t from 0 to 6 carbon atoms,

Ra, Rb and Rc represent a hydrogen atom, a (CH2) Q3-Ar radical in which Ar represents a carbocyclic aryl group containing from 6 to 18 carbon atoms, unradical (CH2) Q, 3-Het in which Het represents a radical derived from an aromatic or nonaromatic heterocycle, saturated or unsaturated, having from 1 to 9 carbon atoms and from 1 to 5 heteroatoms selected from oxygen, nitrogen or sulfur atoms, a radical (CH2) Q_2 Alk in which Alk represents a radical derived from a hydrocarbon, nonaromatic, linear, branched or cyclic, saturated or unsaturated, and comprising from 1 to 12 carbon atoms, the radicals Het, Ar and Alk being able to unsubstituted or substituted, or alternatively, Ra and Rb together with the nitrogen atom to which they are attached represent a nitrogenous, aromatic or non-aromatic, saturated or unsaturated heterocycle, optionally containing one or more heteroatoms selected from the group consisting of oxygen, nitrogen or of sulfur, this radical may be substituted or unsubstituted, - Rg represents a hydroxyl radical, an O-Alk, O-Ar, NH 2, NH-Alk, N (Alk) 2 radical or the residue of an L or D amino acid Since Alket Ar is as previously defined and may be substituted or unsubstituted, - R2 and R3, which may be the same or different, may be either a hydrogen atom, a hydroxyl group, an O-Alk group or an O- (CH2) O3 group. Ar, Alk and Ar being as defined above, or R2 and R3 together form a ring of the type -O- (CRdRe) nO-, where n is an integer of 1 to 5, Rd and Rependependently of each other represents a hydrogen atom, an alkyl radical containing 1 to 6 carbon atoms, or a phenyl radical; R 4 represents a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, nitro, cyano, CF 3, acyl or acyloxy containing 1 to 12 carbon atoms alkyl, alkenyl, alkynyl, alkylthio, alkoxy, alkylamino, dialkylamino, dialk ylaminoalkyl, dialkylaminoalkyloxy, in which the

C 1-6 alkyl represents 1 to 6 carbon atoms, R 5 represents a hydrogen atom, a hydroxyl radical, a halogen atom, an O-Alk radical or a radical O- (CH 2) g 3 -Ar, Alk and Ar being as defined above, 5 - G represents either a radical of formula G1 -N - (Het ')

I

Rh in which Rh is a hydrogen atom or a group (Alk) as defined above and (Het ') is a heterocycle of the general formula: N-x. Wherein (H), together with the N = C-NH- moiety, forms the residue of an aromatic or non-aromatic mono or bicyclic heterocycle, saturated or unsaturated, having from 1 to 9 carbon atoms and 2 to 5 heteroatoms selected from oxygen, nitrogen and sulfur atoms, which radical may be substituted or unsubstituted, or a radical NRaRb (radical G2), Ra and Rb being as defined more high, - either a radical (Het) (G3 radical) as defined above, or a radical -NRh-C (= X) -NHRc (G4 radical), in which X30 is a sulfur, oxygen or NH, Rh and Rc are as defined above, or a radical -NRh-SC ^ Rc, (G5 radical), in which Rh and Rc are as defined above, the dashed lines represent a possible second bond, as well as addition salts with acids and bases and esters,

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

By compound of formula (I) is meant all geometric isomers 011603 and possible stereoisomers taken individually or in mixture.

By group - [A] - representing a divalent radical derived from a linear or branched, saturated or unsaturated structure, having from 1 to 12 carbon atoms and from 1 to 6 heteroatom selected from oxygen atoms, nitrogen and sulfur, in particular, radicals derived from alkanes, some of which are replaced by oxygen, unsubstituted or C = O, SO, SO2, NH, N (Alk), NH-CO, 10N (Alk) -CO, CO-NH, CO-N (Alk), SO 2 -NH, SO 2 -N (Alk), (Alk) being as defined above. It can then be the following radicals -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 a linear or branched, saturated or unsaturated acyclic hydrocarbon containing from 1 to 12 carbon atoms, the alkylene radicals of formula - (CH 2) n - wherein n represents an integer from 1 to 12, such as -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 - or -CH 2 CH 2 CH 2 CH 2 -, or the alkenylene or alkynylene radicals such as -CH = CH-CH 2-or-OC- CH2.

When these bivalent radicals are branched, it is possible to act with radicals such as -CH (CH 3) -, -C (Me) 2, -CH 2 -C (Me) 2 -, -CH (Et) -, -CH (C = CH) - or -C (C = CH) (Et) -. When [B] represents a divalent radical -Ph-, the group CORg may be in the ortho, meta or para position. It is preferably in the para position.

When (D) g - g is a bivalent radical derived from a linear or branched, saturated or unsaturated, acyclic hydrocarbon having 0 to 6 carbon atoms, (D) g - g is selected from the values of [A] cited above. above. By (D) q is meant the absence of this radical, which amounts to having a single covalent bond. (D) will preferably be a simplelation or a group (CH2) n, where n is an integer selected from 1, 2 or 3.

When Ra, Rb and Rc represent a group (CH2) o-3-Ar, (CH2) 0.3-Het, (CH2) Q.3-Alk, (CH2) Q3 represents either a single bond in the case of (CH2) q, 011603 radicals -CH2-, - (CH2) 2- or - (ΟΗ2) β-.

By the term (Ar) representing a carbocyclic aryl group containing from 6 to 18 carbon atoms, is meant a radical derived from an aromatic cyclic hydrocarbon such as phenyl, naphthyl, phenanthreneyl or a radical derived from a hydrocarbon bicyclic or fused tricyclic ring having a benzene ring such as inda-nyl, indenyl, dihydronaphthyl, tetrahydronaphthyl or fluoroethyl. The junction takes place at the benzene ring level. It is preferably phenyl.

By the term (Het) representing a radical derived from an aromatic or nonaromatic heterocycle, saturated or unsaturated, having from 1 to 9 carbon atoms and from 1 to 5 heteroatoms selected from oxygen, nitrogen and nitrogen atoms. Sulfur is denoted in particular: heterocyclic monocyclic radicals, for example thienyl, furyl, pyranyl, pyrrolyl, imidazolylpyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinylthiazolyl, oxazolyl, furazanyl, pyrrolinyl, imidazolinyl, pyrazolinyl, thiazolinyl and triazolyl radicals, tetrazolyl; heterocyclic fused rings, for example benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, naphtho [2,3-b] thienyl, thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenyl N-octathiinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, nap htyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, lept eridinyl, carbazolyl, beta-carbolinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, indolinyl, isoindolinyl, imidazopyridyl, imidazo-pyrimidinyl or else the condensed polycyclic systems composed of heterocyclic monocyclics such as above-mentioned such as, for example, furo [2,3-b] pyrrole or thieno [2,3-b] furan, - or saturated heterocycles such as as pyrrolidine, piperidine, morpholine.

This term (Het) also encompasses the values of 011603 (Het ') as defined above.

By the term (Alk) representing a radical derived from a hydrocarbon, nonaromatic, linear, branched or cyclic, saturated or unsaturated, is meant in the case of acyclic hydrocarbons alkyl radicals such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, 2-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 3- ethylpentyl, n-octyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 3-methyl-3-ethylpentyl, nonyl, 2,4-dimethyl-thyl 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 together with the nitrogen atom to which they are bonded represent a nitrogen heterocycle, they are in particular the saturated heterocycles morpholine, piperidine, piperazine, pyrrolidine, or unsaturated heterocycles such as pyrimidine, pyridine or pyrazine.

When R2, R3, R4 and R5 represent an O- (Alk) radical containing from 1 to 12 carbon atoms, it is preferably methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, allenyloxy or propargyloxy radicals. . When R2, R3, R4 and R5 represent an O- (CH2) q3-Ar radical, the phenylethoxy and phenylpropyloxy radicals are preferably used.

When R2 and R3 together form a ring of the type -O- (CRdRe) nO-, where n is an integer of 1 to 5, it is in particular the radicals -O-CH 2 -O, OC (Me 2) - O, OC (Ph2) -O. R2 and R3 are imperatively in the ortho position one of the other.

When Rg represents an O-Alk or O-Ar radical, Alk and Ar being substituted or unsubstituted, these are especially the following radicals: (C 1 -C 4) alkoxy, (C 1 -C 14) -aryl (C 1 - C8) -alkoxy, (C1-C14) aryloxy, (C1-C8) alkylcarboxyloxy, (C1-C8) dialkylaminocarbonylmethoxy, (C1-C14) aryl (C1-C4) dialkyl-aminocarbonylmethoxy.

When Rg represents an NH-alk, NH (alk) 2 or NH-Ar radical, it is especially the radicals (CL-Cg) alkylamino, di- (CL-Cg) alkylamino, (Cg-C14) aryl (C2 -C8) alkylamino, C8-C14) arylamino.

When Rg represents the residue of an amino acid it can act as amino acid L or D.

The amino acids L or D can be natural or nonnaturals. Preferably it is a-amino acids. For example, those described in Houben-Weyl, Methoden der organischen Chemie, Band XV / 1 and 2, Georg Thieme Verlag, Stuttgart, 1974:

Aad, Abu, yAbu, Abz, 2ABz, eAca, Ach, Acp, Adpd, Ahb, Aib, jSAib, Ala, jSAla, Aala, Alg, Garlic, Ama, Amt, Ape, Apm, Apr, 15 Arg, Asn, Asp , Asu, Aze, Azi, 'Bai, Bph, Can, Cit, Cys, (Cys) 2, Cyta, Daad, Dab, Dadd, Dap, Dapm, Dasu, Djen, Dpa, Dtc, Fel, Gin, Glu, Gly , Guv, hAla, hArg, hCys, hGln, hGlu, His, hile, hLeu, hLys, hMet, hPhe, hPro, hSer, hThr, hTrp, hTyr, Hyl, Hyp, 3Hyp, Ile, Ise, Iva, Kyn, Lant , Lcn, Leu, Lsg, Lys, Lys, Alys, Met, Mim, Min, NArg, Nie, Nva, Oly,

Orn, Pan, Pec, Pen, Phe, Phg, Peak, Pro, Apro, Pse, Pya, Pyr, Pza, Qin, Ros, Sar, Sec, Sem, Ser, Thi, jtihi, 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, Acid 2- (p-tolyl) 2-phenylamino acetic acid, 2- (p-chlorophenyl) aminoacetic acid, or 2-pyrrolidine acetic acid, 1,2,3,4-tetrahydroisoquinoline acid; 3-acetic acid, 3-acetic acid decahydroisoquinoline, 2-acetic acid octahydroisoindol, 2-acetic acid deca-hydroquinoline, octahydrocyclopenta [b] pyrrol 2-carboxylic acid, 2-azabicyclo [2] acid 2,2-octan-3-carboxylic acid, 2-azabicyclo [2,2,1] heptan-3-carboxylic acid, 2-azabicyclo [3.1.0] hexan-3-yl carboxylic acid, 2-azaspiro [4,4] nonan-3-carboxylic acid, 2-azaspiro [4,5] decan-3-carboxylic acid, spiro acid (bicyclo [2,2,1] hept an) -2,3-pyrrolidin-5-carboxylic acid, spiro 8 011603 (bicyclo [2,2,2] octan-2,3-pyrrolidin-5-carboxylic acid, 2-azatricyclo [4.3, 0.1θ'θ] decan-3-carboxylic acid, acidecahydrocyclohepta [b] pyrrol-2-carboxylic acid, deca-hydrocycloocta [c] pyrrol-2-carboxylic acid, octahydro-cyclopenta [c] pyrrol acid -2-carboxylic acid, octahydro-isoindol-1-carboxylic acid, 2,3,3a, 4,6a-hexahydrocyclo-penta [b] pyrrol-2-carboxylic acid, 2,3,3a acid, 4,5,7a-hexahydroindol-2-carboxylic acid, tetrahydrothiazol-4-carboxylic acid, isoxazolidin-3-carboxylic acid, pyrazolidin-3-carboxylic acid, hydroxypyrrolidin-2-carboxylic acid, which if applicable, may be substituted (see following formulas): 0116G3

011603

The heterocycle residues as described above are known for example in the following patents or patent applications: US-A-4 344 949; US-A-4,374,847; US-A-4,350,704; EP-A-5 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. In addition, the amino acids may be in the form of an ester or an amide, such as, for example, methyl ester, ethyl ester, isopropyl ester, isobutyl ester, tert-butyl ester, benzyl ester, ethylamide, semicarbazide or ω- amino (C2-C8) -alkylamide. Finally, the functional groups of these amino acids can be protected. Suitable protecting groups, such as urethane protecting groups, protecting carboxyl groups or protecting side chain groups are described by Hubbuch, Kontakte (Merck) 1979, No. 3, p. 14-23 and by Bùllesbach, Kontakte (Merck) 1980, No. 1, p. 23-35.

There may be mentioned, for example, Aloc, Pyoc, Fmoc, Tcboc, Z, Boc, Ddz, Bpoc, Adoc, Msc, Moc, Z (NO2), Z (Haln), Bobz, Iboc,

Adpoc, Mboc, Acm, tert-butyl, Obzl, Onbzl, Ombzl, Bzl, Mob, Pic, Trt.

When G is a radical of formula G1 -N- (Het ')

Rh and (Het ') is a heterocycle of the general formula: -C (H) in which (H) forms, with the unit N = C-NH-, an aromatic or nonaromatic heterocycle, mono or bicyclic, saturated or unsaturated, having from 1 to 9 carbon atoms and from 2 to 5 heteroatoms selected from oxygen, nitrogen and sulfur, this radical may be substituted or unsubstituted, G1 represents in particular the following heterocycles:

In which p represents an integer from 1 to 4. - When G is a radical -NRaRb (named G2), Ra and Rb may be a hydrogen atom, a (CH2) O3-Ar radical, (CH2) O_3 -Het or (CH2) Q3-Alk. The groups Ar, Het and Alk may also be substituted by the groups as defined below. G 2 can be in particular a group NH 2, NH-Alk such that NHMe, NHEt, N (Alk) 2 such that NMe 2, NEt 2, NMeEt, NH- (CH 2) 0 1 ~ Artel NHPh, NHCH 2 Ph or NHCH 2 Het such as NHCH 2 -pyrrol- 2-yl. When Ra is a hydrogen atom or a group (Alk) and. when Rb is a grouping (Het ') we find the values of G1.

When Ra and Rb together with the nitrogen atom to which they are bonded a nitrogenous heterocycle, they are in particular heterocyclic groups as described above, which may be substituted or unsubstituted. When G is a radical (Het) (G3 radical), this radical may be substituted or unsubstituted, it is especially the heterocycles listed above and in particular the hetero rings of general formula (Het ') such than defined higher. When this heterocycle is connected at the level of the nitrogen sonatome, we find the values of G2 in which Ra and Rb form with the nitrogen atom which carries them a heterocycle. When G is a radical -NRh-C (= X) -NHRc (G4 radical), orNRhSO2Rc (G5 radical), in which X is a sulfur atom, oxygen atom or NH, Rh and Rc are such that defined previously. These include the groups -NH-C (= NH) -NH2 · -NH-C (= O) -NH2 or -NH-C (= S) -NH2, -NH-C (= NH) -NHCH2 -Ar such that -NH-C (= NH) -NHCH2Ph, -NH-C (= NH) -NHCH2-Het, -NH-C (= NH) -NHCH2-Het ', -NH-C (= NH) -NH-Alk such that -NH-C (= NH) -NHCH3, or -NH-SO2Ph, the Ar, Het, Het 'or Alk groups being substituted or unsubstituted.

The optional substituents of the radicals (Alk), (Ar), (Het), (Het ') or NRaRb forming a heterocycle are preferably the following radicals: - halogen: fluorine, chlorine, bromine, iodine, 25 - 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 are themselves even optionally substituted by one or more halogen atom, for example fluorine such as trifluoromethyl. Oxo, cyano, nitro, formyl, carboxy and carboxyalkyl containing 1 to 6 carbon atoms, carboxamide, alkoxy containing 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 optionally containing an oxidized form, - aminoalkyl containing from 1 to 12 atoms of carbon such as aminoethyl or aminoethyl, 5-dialkylaminoalkyl containing from 3 to 25 carbon atoms, dimethylamino methyl or ethyl, dialkylaminoalkyloxy containing from 3 to 25 carbon atoms, and dimethylaminoethyloxy, optionally acylated hydroxyl containing from 1 to 12 carbon atoms. for example acetoxy, acyl containing from 1 to 12 carbon atoms such asformyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, succinyl, pivaloyl benzoyl optionally substituted for example by a chlorine atom, iodine or fluorine. Mention may be made of chloroacetyl, dichloroacetyl, trichloroacetyl, bromoacetyltrifluoroacetyl, carbocyclic or heterocyclic aryl radicals such as phenyl, furyl, thienyl, pyridinyl or aralkyl radicals such as benzyl, these radicals themselves being optionally substituted with halogen, alkyl or alkoxy radicals. , alkylthio, amino alkyl or dialkylamino indicated above.

Of course, one or more substituents, identical or different, may be present. In the case of (Het) the substituents may be at the NH group or the carbon atom.

These substituents also illustrate the definition of R4.

It is understood that when R.sup.1 R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.1, R.sub.4, R.sub.4 contain an alkyl, aryl or hetero-ring group as defined above, they may be identical or different independently from each other. others. The invention extends naturally to the salts of the compounds of formula (I), such as, for example, the salts formed, when the compounds of formula (I) have an amino or amino guanidine function, with hydrochloric, hydrobromic, nitric or sulfuric acids. phosphoric acid, acetic acid, trifluoroacetic acid, formic acid, propionic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid, glyoxylic acid, aspartic acid, alkanesulfonic acid such as methane or ethanesulphonic acid and arsenic acid, such as benzene or para-toluenesulfonic acid and arylcarboxylic, or when the compounds of formula (I) have an acid function, with salts of alkali metals or alkaline earth or optionally substituted ammonium. The invention also extends to the esters of the compounds of Formula (I). In a first preferred group, the subject of the invention is the compounds of general formula (I) as defined above, corresponding to the general formula (I '):

wherein R 'represents a group-C = C- [A'] - [B '] -COR'g, -CH = CH- [A'] - [B '] -COR'g, 25 - (CH2 ) 2- [A '] - [B'] - COR'g, -O- [A *] - [B '] - COR'g, -CH2CO- [A'] - [B] -COR'g, - [A '] - representing a bivalentalkylene, alkylene or alkynylene radical containing from 1 to 6 carbon atoms, [B'] representing a radical CH (Z ') or a simpleling, Z' represents a hydrogen atom, a grouping (CH2) ng-NRaRb, (CH2) n -NH-SO2-Rc, (CH2) n.g-NH-CO2-Rc, (CH2) n -NH-CO-Rc, (CH2) n -NH-SO2 -NH-Rc, (CH2) n -NH-CO-NH-Rc, (CH2) O-6_CO2'Rc '(¾) O-6'SO2'Rc' (CH2) o_g-CO-Rc or (CH2) Wherein Ra, Rb and Rc being as previously defined, R1g represents an OH, amino or alkoxy radical containing from 1 to 8 carbon atoms, optionally substituted with one or more radicals chosen from hydroxyl, amino and phenyl radicals; , alkylamino or dialkylamino, R'2 and R'3 represent a hydrogen atom or a methoxy radical, and G is as defined above. The dashed lines represent a possible second bond, as well as the addition salts with acids and bases and esters.

In a second preferred group, the subject of the invention is the compounds of general formula (I) as defined above in which Rg represents a group -OH, -OCH3, -och2ch3, -O- (ch2) 2 -oh, - o-ch2-ch-ch2oh, -O- (ch2) 2-nh2,

OH-O- (CH 2) 2-N- (CH 3) 2, -NH 2 or -O- (CH 2) -phenyl, as well as addition salts with acids and bases and esters.

In a third preferred group, the subject of the invention is compounds of general formula (I) as defined above in which Rj. represents a group O- (CH2) O.OΟΗ (Z ') - COOH or - (CH2) O_7-CH (Z') - COOH, as well as addition salts with acids and bases and esters.

In a fourth preferred group, the subject of the invention is the compounds of general formula (I) as defined above, in which (Z ') is a hydrogen atom, as well as the addition salts with acids and bases and esters.

In a fifth preferred group, the subject of the invention is the compounds of general formula (I) as defined above, in which (Z ') is the group (CH 2) θ-g-NH-CO 2 -Rc or (CH 2) O -g- NHRb, Rb and Rc are as defined above, as well as the addition salts with acids and bases and esters. In a sixth preferred group, the subject of the invention is the compounds of general formula (I) as defined previously, in which Rb and Rc represent the group (CH2) o-3-Ar, Ar being as defined. previously and may be substituted or unsubstituted, as well as addition salts with acids and bases and esters.

In a seventh preferred group, the subject of the invention is the compounds of general formula (I) as defined above, in which G is a G4 group of formula ## STR1 ## where Rc is such that as defined above, as well as the addition salts with acids and bases and esters.

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

In a ninth preferred group, the subject of the invention is the compounds of general formula (I) as defined above, in which G is a group -NH- (Het ') as defined above and in particular

P being an integer equal to 2, 3 or 4, these heterocycles being substituted or unsubstituted, as well as the addition salts with acids and bases and esters.

In a tenth preferred group, the subject of the invention is the compounds of general formula (I) as defined above, in which G is the group

p being an integer equal to 2, 3 or 4, as well as the ad-ditioning salts with acids and bases and esters.

In a eleventh preferred group, the subject of the invention is the compounds of formula (I) as defined previously, the following names being given: - 4 - ((4 - ((aminoiminomethyl) hydrazono) -9,10-dimethoxy-1 acid , 2,3,4,5,6-hexahydro-8-benz (e) azulen-yl) oxy) butanoic acid, 5- ((4 - ((aminoiminomethyl) hydrazono) -9,10-dimethoxy-1, 15 2 -acetate, 3,4,5,6-hexahydro-8-benz (e) azulen-yl) oxy) pentanoic acid; 5 - ((4 - ((aminoiminomethyl) hydrazono) -8,10-dimethoxy-1, 2.3. 4.5.6-hexahydro-9-benz (e) azulen-yl) oxy) pentanoic acid, 6 - ((4- ((aminoiminomethyl) hydrazono) -9,10-dimethoxy-1, 2.3.4.5.6- hexahydro-8-benz (e) azulenyl) oxy) hexanoic acid, 20 - 7 - ((4 - ((aminoiminomethyl) hydrazono) -9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benzoic acid (e) azulenyl) oxy) heptanoic acid, - 5 - ((9,10-dimethoxy-1,2,3,4,5,6-hexahydro-4 - ((4,5-dihydro-1H-imidazole) 2-yl) hydrazono) -8-benz (e) azulenyl) oxy) -pentanoic acid, 5 - ((4 - ((aminoiminomethyl) hydrazono) -9,10-dimethoxy-1,2,3,4-hydrochloride , 5,6-hexahydro-8-b ethyl 4-((4 - ((aminoiminomethyl) hydrazono) -8,9-dimethoxy-1,2,3,4,5,6-hexahydro-10-benzohexyl-enz (e) azulenyl) oxy) pentanoate azulenyl) oxy) 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 acid ) -penta-noic acid, 4 - ((4 - ((aminoiminomethyl) hydrazono) -8,10-dimethoxy-1,2,3,4,5,6-hexahydro-9-benz (e) azulen-yl) oxy) - butanoic acid, 18 011 603 - 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-2,3,4,5,6-hexahydro-8-benzoic acid (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, 10-hydrochloride of the acid - ((4 - ((aminoiminomethyl) hydrazo-no) -9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz (e) azullyl) oxy) pentanoic acid, - 4 - ((4 - ((4,5-dihydro-1H-imidazol-2-yl) hydrazono) -9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benzoic acid azulenyl) oxy) butanoic acid, 5 - ((8 ((aminoiminomethyl) hydrazono) -6,7,8,9,10,11-hexahydroazuleno (5,6-d) -1,3-benzodioxol 4-yl) oxy) -pentanoyl, - 5 - ((8 ((aminoiminomethyl) hydrazono) -2,2-diphenyl-6,7,8,9,10,11-hexahydroazulenoic acid (4-yl) , 5-e) - (1,3) -benzodioxol-4-yl) oxy) -pentanoic acid, - 4 - ((9,10-dimethoxy-4 - ((1,4,5,6-tetrahydro-2) - acid 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) etha-noic acid. ((4 - ((4,5-dihydro-1H-imidazol-2-yl) hydrazono) -9,10diméthoxy-l, 2,3,4,5,6-he xahydro-8-benz (e) azulenyl) oxy) -pro- panoic 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, 4 - ((4 - ((4,5-dihydro-1H-imidazol-2-yl) hydrazono) - 1 2,3,4,5,6-hexahydro-8-benz (e) azulenyl) oxy) butanoic acid, 35-O- [4 [(4,5-dihydro-1H-imidazol-2-yl) hydrazono] 9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz [elazulenyl] -N - [(phenyl-methoxy) 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] Homoserine, 011603 - O- [4 - [(1,2,3,4-tetrahydro-6-pyrimidinyl) hydrazono] 9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benzoate [e] azulenyl] N- [(phenylmethoxy) carbonyl] DL-homoserine, -ester (2,3-dihydroxypropyl) ester of 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, 10-O- [4 - [(4 5-dihydro-1H-imidazol-2-yl) hydrazono] 9,10-dimethyl- 1,2,3,4,5,6-hexahydro-8-benz (e) azulenyl] N - [(8-quino-leinyl) sulfonyl] DL-homoserine, - O- [4 - [(4, monohydrochloride), 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, - 5 - [[4 - [(4,5-dihydro-4-oxo-1H-imidazol-2-yl) hydra-zono acid ] 9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz (e) azulenyl] oxy] pentanoic acid, 20-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 also relates to a process for the preparation of compounds of general formula (I), characterized in that a compound of formula (II) is subjected to:

wherein R2, R3, R4 and R5 are as previously described except for the hydroxyl value. Or to the action of a compound of formula (F1) in the presence of a base,

Hal- [A] - [B] -CORg (Fl) or a compound of formula (F '^) in the presence of a phosphine and diethyl azodicarboxylate: HO- [A] - [B] -CORg 10

(F'-J in which Hal is a halogen atom, [A], [B] and Rg are as previously described, [B] may also represent the group -CH-, P being a grouping

NH-P protecting the amine function, to obtain a deformula compound (Ilia):

(Ilia) either to the action of an activating group and then of a compound of formula (F2) in the presence of a catalyst:

O

IIH-C = C- [A] - [B] -C-Rg (F2) in order to obtain a compound of formula (IIIb):

011603 (IIIb) compounds of formula (Ilia) or (IIIb) which is subjected to the action of a compound of formula (F3): H2N-G (F3) in which G is as previously described, in order to Ob-hold the compounds of formula (IVa) and (IVb) corresponding to some products of formula (I):

O

II 25

Re-c- [b]

N-G (IVa) 30

* 6 ° - [B] - [A] -C = C

N-G (IVb) 35 22 01 1 6 G 3 which, if appropriate, is subjected, in an appropriate order, to the action of a base or an acid in order to cleave the ester and to obtain the corresponding acid, - to the action of a reducing agent capable of partially or completely reducing the unsaturations, - to the action of a hydrating agent of the triple bond, - to the action of an agent for dealkylation; - to the action of a deprotection agent of the NH-β-beta function of CO-Rg when [B] represents the CH-NHP group, 10 - to the formation of the NH-SO2RC group, NH-CO2Rc, NHCORc, NH-SO2-NH-Rc, NH-CO-NHRc from the corresponding amine CORP, to obtain the corresponding compounds of formula (I) which are subject, if appropriate, to action of an acid or a base to obtain the corresponding salts or to the action of an esterification agent to obtain the corresponding esters. The action of the compound of formula Hal- [A] - [B] -CORg (F1) is preferably effected 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 the compound of formula HO- [A] - [B] -CORg (F'p 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 the compound of formula H-CsC- [A] - [B] -CORg (F2) is preceded by that of an activating group such as triflic anhydride of formula (CF3SO2) 2O in the presence of a base such as pyridine to form the corresponding triflate of formula (OSO2CF3) then carried out in the presence of a palladium derivative (Pd °) such as Pd (PPh3) 4. The action of NH2 -G (F3) is carried out either without a solvent or in an alcoholic solvent such as ethanol or butanol The NH 2 -G synthon is optionally used in the form of a salt such as hydrochloride or hydrobromide .

The saponification reaction of the ester function 23 01 16G3 is carried out for example by the action of an alkaline base such as sodium hydroxide or potassium hydroxide in tetrahydrofuran or a lower alcohol such as ethanol or ethanol. The ester can also be cleaved in an acidic medium according to methods known to those skilled in the art.

The reduction of unsaturations can be carried out either completely by the action of hydrogen in the presence of a catalyst such as palladium on carbon or an aurhodium catalyst such as Wilkinson's reagent is partially (alkynylene becomes alkenylene). ) by the action of a poisoned catalyst such as palladium on debaryum sulfate poisoned by pyridine or triethylamine.

The hydration reaction allowing access to a -CH2CO- [A] - [B] -CORg group from -OC- [A] - [B] -CORg is preferably carried out by means of water action. presence of mercury sulphate.

The dealkylation reaction allowing access to the products of formula (I) with R2, R3, R4 or R5 representing hydroxyls is carried out in the presence of aluminum chloride or boron tribromide.

Functionalization of NH2 in alpha of CORg, [B] representing CH-NH2 or CH-NH2, Hcl, is carried out according to the known conventional methods in organic chemistry.

The formation of NHSO2RC from the corresponding amine is preferably carried out by the action of RcSO2Hal in the presence of a base, for example triethylamine.

The formation of NHCO2Rc from the corresponding amine is preferably carried out by the action of RCOH according to the method described in J. Org. Chem., 61, 3929-3934 after triphosgene has been previously activated in the presence of sodium bicarbonate in order to obtain the isocyanate intermediately.

Salification reactions can be carried out under customary conditions. For example, the terminal moiety CO2H of R1 # is salified in the presence of a sodium salt such as sodium carbonate or sodium or potassium hydrogen carbonate.

Likewise, the salification of the amine or amino-guanidine which G may represent by an acid is carried out under the usual conditions. For example, hydrochloric acid is used, for example in ethereal solution. The possible esterification of the products is carried out under the standard conditions known to those skilled in the art.

The reaction is generally carried out by reacting the acid of formula (I) or a functional derivative with a reagent capable of introducing the ester group, a non-exhaustive list of which appears in the definition of R 8. The products of general formula (Fl), (F 'I), (F2), (F3) are known or prepared according to methods known to those skilled in the art.

It is also possible to reverse the order of grafting of the various reagents, that is to say that the compound of formula (II) is subjected to the action of a compound of formula F3 in order to obtain intermediately the product of formula (IIIc):

(IIIc) that is subjected to the action of a compound of formula (Fl), (F'1) or (F2) to obtain the products of formulas (IVa) and (IVb) corresponding. In this case, it will be necessary, where appropriate, to provide protection for the group G of the product of formula (IIIc) and then, after the introduction of (F1), (F'1) or (F2), a deprotection according to methods known to those skilled in the art (TWGREENE Protective Groups in Organic Synthesis, John Wiley and 35 Sons Inc. 1991).

The deprotection reaction of the NH-P group in beta of CO-Rg, [B] representing the CH-NHP group, is also carried out according to the methods known to those skilled in the art, especially when P represents the CO2tBu group, by aaction decarboxylation such as for example by actionde hydrochloric acid. The bone is constantly undergoing a dynamic process that includes bone resorption and bone formation. These processes are mediated via specialized cells. Bone formation is the result of the deposition of a matricemineral by osteoblasts and bone resorption is the result of the dissolution of this bone matrix by osteoclasts. Osteoporosis is characterized by a loss of bone matrix. A mature osteoclast activates the bone after adhesion to the bone matrix via the secretion of proteolytic enzymes, and protons within the adhesion zone, resulting in depressions or excavations of the bone surface which appear at the moment when the osteoclast is detached from the bone.

The compounds of formula (I) and their pharmaceutically acceptable addition salts have interesting pharmacological properties. These compounds inhibit bone resorption that is mediated via osteoclasts.

The compounds of the invention are thus useful in the treatment of diseases caused by the loss of the bone matrix, in particular, osteoporosis, hypercalcemia of malignancy, osteopenia due to bone metastases, paroitesitis, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, paget's disease, immobilization-induced osteopenia, glucocorticoid treatments or male or female hormonal abnormalities.

They can also be used for the treatment of inflammatory, cancerous and cardiovascular disorders including atherosclerosis, restenosis.

They can finally be used as inhibitors of angiogenesis and therefore in the treatment of tumors, by inhibition of their neovascularization, diabetic retinopathies and nephropathies.

Recent studies have shown that osteoclast binding to bone is mediated by receptors: integrins.

Integrins are a receptor superfamily that mediates the cell / cell adhesion processes and more particularly cell / matrix, including a2b $ 3 as platelet receptor (fibrinogen) and ανβ3 as a vitronectin receptor, sialoproteinose as osteopontin and thrombospondin .

These receptors, which are protein heterodimerscomposed of two α and β subunits, have divalent ion binding sites such as Ca 2 + in particular and a recognition site of their ligand predefined by the quality of their subunits.

The ανβ3 receptor is a transmembrane glycoprotein which is expressed in a large number of cells including endothelial cells, smooth muscle cells, osteoclast and cancerous cells which thus leads to a pluripotentiality of the compounds according to the invention.

The av / 3 receptors expressed at the osteoclast membrane are the basis of the adhesion / resorption process, contribute to the organization of the cellular cyto-skeleton, and are involved in osteoporosis (Ross et al. J. Biol Chem., 1987, 262, 7703).

Αvβ3 receptors expressed at smooth aortic cell cells of the aorta stimulate their migration to the neointima, resulting in the formation of atherosclerosis and the occurrence of post-angioplasty restenosis (Brown et al, cardiovascular Res. (1994) , 28, 1815).

Endothelial cells secrete growth factors that are mitogenic to the endothelium and may contribute to the formation of new blood vessels (Angiogenesis). Angiogenic stimulation causes the formation of new blood vessels.

The integrin antagonists may result in a regression of cancerous tumors by inducing apoptosis of the angiogenic blood vessels. (Brook et al., Cell (1994) 79, 1157).

The natural ligands of the integrin ov / 33 all contain the motif RGD (Arg-Gly-Asp). Peptides containing this Q116G3 RGD motif as well as anti-β1ββ3 antibodies are known for their ability to inhibit dentin resorption, prevent adhesion of osteoclasts to the mineralized matrices (Horton et al., Exp Cell Res. (1991), 195, 368).

Echistatin peptide isolated from snake venom also containing an RGD motif is described as an inhibitor of osteoclast adhesion to bone, and is therefore a potent inhibitor of bone resorption in tissue in vitro culturing (Sato et al. J. Cell Biol (1990), 111, 1713) and in vivo in rats (Fisher et al., Endocrinology (1993), 132, 1441).

The compounds of formula (I) as well as their addition salts and their pharmaceutically acceptable esters may in particular have an affinity with respect to the α1ββ3 lavitronectin receptor or vis-à-vis other integrins having forligand vitronectin ( orv / 31, orv / 35, 012b / 33) by inhibiting the ligand to their natural ligand.

This property thus renders the compounds of the invention usable for the prevention or treatment of diseases in which the underlying pathology is caused by ligands or cells that interact with the lavitronectin receptor.

These compounds may also possess activity with respect to other integrins that interact with their ligand via the tripeptide sequence RGD, conferring pharmacological properties useful for treating the pathologies associated with these receptors.

This activity with respect to integrins thus makes the compounds of the invention usable in the treatment of many diseases such as those mentioned above or in the review by Dermot Cox DN & P (May 4, 1995, 197-205) whose content is integrated in this application. The subject of the invention is therefore the compounds of formula (I) as medicaments, as well as their addition salts or their pharmaceutically acceptable esters.

Among the medicaments of the invention, mention may be made particularly of the compounds described in the experimental part.

Among these products, the invention more particularly relates, as medicaments, the compounds of formula (I) listed above. The dosage varies according to the condition to be treated and the route of administration: it may vary, for example, from 1 mg to 1000 mg per day in the adult orally. The invention extends to pharmaceutical compositions containing as active ingredient at least one drug as defined above.

The compounds of formula (I) are used by the active, parenteral or local routes, for example by the intestinal route. They may be prescribed in the form of simple or coated tablets, capsules, granules, suppositories, ova, injectables, creams, creams, gels, microspheres, nanospheres, implants, patches, which are prepared according to the usual methods.

The active ingredient (s) can be incorporated into the excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, decaffeinated butter, aqueous vehicles or not, organic or vegetable fatty substances, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.

The products of formula (II), in which the hydroxy radical is in position 10, R2 in position 8 and R3 in position 9, represent a group O- (Alk) or O- (CH2) Q-2-Ar, R4 and R 5 are hydrogen atoms, are prepared according to the method described in European Patent Application No. 0729933 and in the experimental part hereinafter (Preparation 2).

The other two isomers of position can be prepared as follows: A compound of formula (IIA) is subjected: ΜθΟ

29 011603

MeO (ΙΙΑ)

OH to the action of a dealkylation reagent, to obtain the compound of formula (IIB):

compound of formula (IIB) which is subjected either to the action of a diol protecting reagent in a basic medium to selectively obtain the product of formula (IIC):

(IIC) wherein P represents the remainder of a diol protecting reagent, which is subjected successively to the action of a phenol protective reagent, a diol deprotection reagent, an alkylating agent and then a phenol deprotecting agent in order to obtain the compound of formula (IID) corresponding to the product of formula (II) trisubstituted with OH at position 8: 011603

(IID) either in the action successively of a phenol protecting agent, an alkylating agent and then a deprotecting agent in order to obtain the compound of formula (IIE) corresponding to the product of formula ( II) trisubstituted with OH in position 9

By dealkylation reagent is preferably meant agents such as boron tribromide or aluminum chloride.

The diol protecting reagent which is reacted with the products of formula (IIB) may be a boron derivative such as boric acid, a trialkyl borate, for example trimethyl or triethyl, or borax.

By phenol protection agent is meant in particular a halide such as mesyl or tosyl chloride or bromide or a benzyl derivative such as tosylate or benzyl mesylate.

By deprotection reagent of the diols is meant in particular a strong acid such as hydrochloric acid, sulfuric acid or para-toluenesulphonic acid or still oxidizing, for example hydrogen peroxide, in the case of a hydrogen peroxide. protection by a boron derivative.

By alkylating agent is meant any conventional agent known to those skilled in the art for alkylating the phenols. There may be mentioned, for example, an alkyl halide such as methyl chloride or ethyl chloride, an alkyl sulfate such as methyl or ethyl sulphate or diazomethane.

By deprotection agent is meant a base such as sodium hydroxide, potassium hydroxide or sodium carbonate or potassium.

Monosubstituted products of formula (II), in which R 2, R 3, R 4 and R 4 represent a hydrogen atom, are prepared by a method analogous to that described in European Patent Application No. 0729933: (i) compound of formula (a):

wherein O- (Alk) is in the meta or para position of the alkylcarboxylic group, (Alk) being as defined above, to the action of a halogenating agent to obtain the corresponding acyl halide, ( ii) that a reagent of formula (b) is subjected to the action of:

(b) R (II) / 30 in which R (I) and R (II), which are 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 which they are bonded represents a saturated or unsaturated 5- or 6-membered heterocycle, optionally containing another heteroatom selected from O and N, to obtain a compound of formula (c): 32

(Alk) O

(iii) submitting to obtain a compound

Cl 1603 (c) the action of a halogenating agent of formula (d):

in which Halj represents a halogen atom, (iv) which is subjected to the action of a Lewis acid, to obtain a compound of formula (e):

(e) (v) which is subjected to a dealkylation reagent to obtain the product of formula (IIF) corresponding to the product of the formula (II) monosubstituted expected:

(IIF)

The products of formula (II) disubstituted, wherein R 2 represents O- (Alk) or O- (CH 2) O 3 -Ar, R 3, R 4 and R 5 are hydrogen atoms and OH and R 2 being in the 8, 9 position. or 10, are prepared according to the method as described above from the compound of formula (a '):

in which O- (Alk) and R2 are in the meta or para position of the alkyl carboxylic chain, R2 being a group O- (Alk) or - (CH2) Q_3-Ar, in succession to the reactions (i), (ii), (iii), (iv) and (v) and the products of formula (IIG) corresponding to the products of formula (II) bisubstitutedare expected:

The halogenating agent which is acted on the compound of formula (a) or (a ') is, for example, thionyl chloride, oxalyl chloride or any other agent known to those skilled in the art for preparing a acid halide. The reagent of formula (b) is prepared from cyclopentanone and a secondary amine, for example diethylamine, piperidine, piperazine or, preferably, morpholine. The reaction is carried out in the presence of an acid catalyst, for example paratoluene sulphonic 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 is reacted with the compound of the formula (c), or its disubstituted equivalent of the formula (c '), may be, for example, thionyl chloride, phosgene, oxychloride and the like. phosphorus or, preferably, oxalyl chloride. The Lewis acid used to cyclize the compound of formula (d) or its disubstituted equivalent of formula (d ') is, for example, aluminum chloride, tetrachloride tetrahydrate, or preferably ferric chloride, or tetra -Chloride tin. The reaction, such as the foregoing, can be carried out, for example, in a halogenated solvent such as methylene chloride, chloroform or dichloroethane.

The dealkylation reagent of the compound of formula (e), or its disubstituted equivalent of formula (e ') in order to obtain the corresponding phenols is preferably alumi- nium chloride or boron tribromide.

The products of formula (II) in which R4 is different from the hydrogen atom, are prepared by conventional methods of electrophilic substitution and aromatic nucleophiles known to those skilled in the art.

The products of formula (II) in which R5 is different from the hydrogen atom are prepared according to the methods known to those skilled in the art and in particular according to the method described in European Patent Application No. 0729933, it is - ie by halogenation then action of water or an appropriate alcohol.

The products of formula (II) in which R 6 is a hydrogen atom and in which there is a double bond at position 1-2 are prepared according to the methods known to those skilled in the art and in particular according to the method described in the application for European Patent No. 0729933, that is to say by dehydration or dealkoxylation in anhydrous acid medium.

The products of formula (II) in which the junction between the 5-ring and the 7-ring is saturated are prepared by conventional hydrogenation methods, in particular in the presence of palladium on carbon of the corresponding double bond. The introduction of R 4, R 2 and the hydrogenation reaction is preferably carried out on compounds of formula (HA), (HD), (IIE), (IIF) or (IIG).

The products of formula (II) in which R 2 and R 3, which are ortho-positioned from each other, form a ring of the type -O-5 (CRdRe) n -O as defined above, are also prepared according to the methods known to those skilled in the art andnotamment according to the method described below in the experimental part. The subject of the invention is also, as intermediate products, the products of formula (Ilia), (IIIb), (IIIc) and (II), it being understood that the compounds of formula (IIc) and the following compounds: , 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. The preparation of these two compounds is shown below in the experimental part.

The following examples illustrate the invention without however limiting it. PREPARATION 1: 2,3,5,6-Tetrahydro-8,9,10-trihydroxybenz [e] azulen-4 (1H) -one

Stage A: 3,4,5-Trimethoxybenzenepropanoic acid

6.8 g of potassium carbonate are added to a solution of 21.44 g of 3,4,5-trimethoxyphenylpropenoic acid and 45 ml of water and then hydrogenated for one hour at a pressure of 1200-1300 mbar in the presence of 1.8 g of charcoal with 10% of palladium, thus absorbing 2.1 l of hydrogen. It is filtered, washed with water and acidified with 50 ml of hydrochloric acid (2N). It is drained, washed with water and dried under reduced pressure at room temperature. 19.8 g of the expected product are obtained (m.p. = 102-103 ° C.).

I.R. spectrum (CHCl 3) (1712 cm -1 (max) aromatic: {1592 cm -1 cm -1 1740 cm -1 (1510 cm -1))

Carbonyl {1740 cm -1 NMR (CDCl3) 2.69 (t)} = C-CH ~-CH, -CO2.91 (t)} 3.83 (s)} 3 H3CO-C-3.85 (m.p. s)} 36 011603 6,43 (s) 2H aromatics10,50 (m) 1H mobile

Stage B: 3,4,5-Trimethoxybenzenepropanoyl Chloride

A solution of 6 g of the product obtained in Stage A in 21 ml of methylene chloride is dried with 1.5 g of magnesium sulphate. After filtration, the mixture is cooled to 5 ° C. and 2,2 ml of thionyl chloride are added and the mixture is stirred. solution 20 hours at room temperature. It is evaporated to dryness under reduced pressure by carrying out two workups with cyclohexane, thereby collecting 6.46 g of the desired product. (Mp = 60 ° C) Step C: 2- [3- (3,4,5-trimethoxyphenyl) -1-oxopropyl] -cyclopentanone To a cooled solution at 5 ° C. of 2.4 ml of 1- ( N-mor-pholinyl) cyclopentene obtained as described below, 2.31 ml of triethylamine and 15 ml of methylene chloride are added in 1 hour 30 to + 5 ° C a solution of 4.27 g of the product obtained at the stage. B in 15 ml of methylene chloride. Stir 1 hour at + 5 ° C and then allowing the temperature to rise add 10 ml of 2 N hydrochloric acid, stir 1 hour at room temperature, decanted, washed with water and then with a saturated solution of sodium bicarbonate, dried, filter and evaporate to dryness under reduced pressure. 5 g of the expected product are obtained. The crude product is purified by dissolving in 10 volumes of ethyl acetate, extracting with N sodium hydroxide solution, washing the alkaline phase with ethyl acetate, acidifying to pH 1 with concentrated hydrochloric acid. extracted with methylene chloride, dried and evaporated under reduced pressure. 2.75 g of purified product are collected. I.R. spectrum (CHCl 3):

Carbonyl: {1741 cm -1 aromatic: {1592 cm -1 {1709 cm -1 (1509 cm -1

Carbonyl: {1658 cm -1 + C = C (-1610 cm -1) with OH in chelated form R.M.N. (CDCl3) 6.41 (s) 2H arom. (basis of integration) 3.8l (s) 3.82 (s)} 9H in all 3.83 (s) 3.85 (s)} 4 types of CH3O-C =

1.86 (m) CH2-CH2-CH2 ~ 1.5H 1.95 to 2.95 (m) ~ 7.5H in all of which = C-CH2 of several types 3.26 (t) ~ 0.4H CO -CH-CH2 37 011603

CO 11.2 (m wide) H mobile

Preparation of 1- (N-morpholinyl) -cyclopentene used in Stage C: A solution of 100 ml of cyclohexane, 20 ml of decyclopentanone, 50 ml of morpholine is stirred under reflux for 4 hours under reflux, removing the water formed. 100 mg of paratylenesulphonic acid. After evaporation of the solvent under reduced pressure, the mixture is distilled at 12-13 mbar pressure and 27.44 g of the desired product (bp = 83 ° C.) are collected.

Step D: 1- (2-chloro-1-cyclopenten-1-yl) -3- (3,4,5-trimethoxyphenyl) propan-1-one To a solution of 23 g of product obtained in Step C and 230 ml of chloroform, 13 ml of oxalyl chloride are added at room temperature. The mixture is stirred for three hours at ambient temperature and concentrated under reduced pressure using two cyclohexane procedures. 28 g of crude product are obtained and recrystallized from a mixture of 50 ml of cyclohexane and 50 ml of diisopropyl ether after partial concentration. It is drained, washed with diisopropyl ether and dried under reduced pressure. 16.24 g of the expected product are obtained. (M.p. = 93 ° C)

I.R. (CHCl 3): 1659 cm -1: Carbonyl 1599 cm -1 1586 cm -1 C = C + aromatic 1508 cm -1

Spectrum R.M.N. CDCl3 central CH2 1.93 (m) 2.69 (m) -2.81 (m): C-CH2-C = cyclopentene

2.85 (t, j = 7.5) - 3.08 (t, j = 7.5): the others = C-CH2-C 2.44: CH3-C = 3.68 - 3.81: OCH- = 6,59-6,68 (d, j = 2): CH = aromatics coupled meta7,31-7,80 (d, j = 8): aromatics.

Stage E: 2,3,5,6-tetrahydro-8,9,10-trimethoxy-benz [e] azulen-4 (1H) -one 900 mg of the product obtained at room temperature are stirred for 20 hours at room temperature D, 9 ml of 1,2-dichloroethane and 0.9 ml of stannic chloride. Then 9 ml of water and ice are added, washed with water, reextracted once with methylene chloride, dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure, to obtain 1 g of the expected product. (crude) which is purified by supersilution chromatography eluting with cyclohexane 10% ethyl acetate, then 25% ethyl acetate. After concentrating, 700 mg of product is collected which is crystallized from 5 ml of n-hexane, then cooled to 0 ° C., filtered, washed with n-hexane solution, dried under reduced pressure at room temperature to obtain 630 g. mg of expected product. (Mp 101 ° -102 ° C.). NMR Spectrum (CDCl3) 1.86 (m) Central CH2 2.65 (dd) 2H2.72 (t) 2H) Other 2.84 (dd) 2H + 3.06 2H + 6.59 (s) Romatic 3.84} CH2 3.86} OMe 3.90}

Stage F: 2,3,5,6-tetrahydro-8,9,10-trihydroxybenz [e] azulen-4 (1H) -one

Working as in Stage B of the preparation Ibis, the desired demethylated product is obtained. PREPARATION Ibis: 2,3,5,6-tetrahydro-8,9,10-trihydroxybenz [e] azulen-4 (1H) -one

Step A: 2,3,5,6-Tetrahydro-8,9,10-trimethoxybenz [e] azulen-4 (1H) -one

60 g of the product obtained in Preparation 2, 600 ml of 1,2-dichloroethane, 342 ml of 2N sodium hydroxide, 1.2 g of tetrabutylammonium bromide and 33 ml of the sulphate are stirred for 2 hours at 20 ° C. dimethyl. 39 ml of triethylamine are then introduced in order to destroy the excess dimethyl sulphate and stir for one hour at 20 ° C. ± 2 ° C. 342 ml of demineralized water are added, the mixture is stirred for 15 minutes at 20 ° C. ± 2 ° C., decanted, the aqueous phase is re-extracted twice with 120 ml of 1,2-dichloroethane each time. The 1,2-dichloroethane phases are combined and washed with 4 × 240 ml of demineralized water, then with 1 × 300 ml of N hydrochloric acid and then with 3 × 240 ml of demineralized water (until neutrality). The combined organic phases are dried over sodium sulphate, filtered and concentrated at ordinary pressure at 83 ° C. to a residual volume of 480 ml.

Stage B: 2,3,5,6-tetrahydro-8,9,10-trihydroxybenz [e] azulen-4 (1H) -one

480 ml of the solution obtained in (A) are refluxed for one hour with 102.3 g of anhydrous aluminum chloride. The medium is cooled to 0 ° C. ± 2 ° C. and then a mixture of 600 ml of demineralized water and 192 ml of pure sulfuric acid (concentrated), previously cooled to 0 ° C., is added for two hours while maintaining the reaction temperature below 20 ° C. C. 300 ml of demineralized water are introduced over 5 minutes at 20 ° C. ± 2 ° C. and the mixture is stirred for 16 hours at 20 ° C. ± 2 ° C., filtered, washed twice with 60 ml of 1,2-dichloroethane each time, and then with demineralised water, dried under reduced pressure and gives 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

Step A: 3,4-Dimethoxy-5 - [[(4-methylphenyl) -sulfonyl] oxy] benzenepropanoic acid

The procedure is as for Stage A of Preparation 1 using 29.76 g of 3,4-dimethoxy-5 - ([[(4-methylphenyl) -sulfonyl] oxy] phenyl] cinnamic acid whose preparation 43.5 g of potassium carbonate, 60 ml of ethanol and 1.48 g of 10% palladium-active carbon are obtained hereinafter, thus obtaining 28.23 g of the desired product in the form of colorless crystals (mp = 148 ° -149 ° C.). C).

U.V. spectrum (EtOH)

For M = 380.4 max 226nm ε = 22100 infl 263nm ε = 2000 10 15 20 25 40 011603 infl 269nm ε = 2400 max 274nm ε = 2800 infl 279nm ε = 2500 infl 307nm ε = 450

Spectrum R.Μ.N. (CDCl3) 2.45 (s) CH3-2.61 (m) = C-CH2-CH2-C = 2.86 (m) 6.61 (d, j = 2) 6.65 (d, j = 2) H4 Hg 3.68 (s) 2 CH3O-C = 3.81 (s) 7.32 (dl) H3 H57.80 (dl) H2 Hg

Stage B: 3,4-Dimethoxy-5 - [[(4-methylphenyl) -sulfonyl] oxy] benzenepropanoyl Chloride

The procedure is as in Stage B of Preparation 1 using 1.9 g of the product obtained in Step A, 9.5 ml of methylene chloride and 0.7 ml of thionyl chloride. Obtain 2.24 g of the desired product used as is for the next step.

Stage C: 2- [3- [3,4-Dimethoxy-5 - [[(4-methylphenyl) sulfonyl] oxy] phenyl] -1-oxopropyl] cyclopentanone

The reaction is carried out as in Stage C of Preparation 1 starting from 2.24 g of the acid chloride obtained in Stage B and using 770 mg of 1- (N-morpholinyl) -cyclopentene (prepared from C 1 of Preparation 1). ), 6 ml of methylene chloride and 0.77 ml of triethylamine. After recrystallization from diisopropyl ether, 1.27 g of the product (DMF = 84 ° C.) are obtained. I.R. spectrum (CHCl 3)

Carbonyl: {1742 cm -1 O-SO 2 (1374 cm -1) (1709 cm -1) 1178 cm -1 1658 cm -1 C = C + aromatic (1608 cm -1 1599 cm -1 1586 cm -1 1508 cm -1 1

NMR spectrum (CDCl13) 2.44 (s) CH3 -0.367 (s) 2CH3 3.79 (s) 3.81 (s)} 6.59-6.65 (m) 2H arom. in ortho of O.7,32 (dl) H3 H5 7.89 (dl) H2 Hg 41 13.58 (wide m) OH form enol 1.8 to 3.4 (m) 10 to 11 H other protonsSpectre UV 1 EtOH (+ dioxane) for M = 446.52 011603 max 225nm e = 23000 max 282nm e = 7900 infl 270, 277, 290, 3i 2 - EtOH (NaOH 0.1n) max 310 nm e = 21600 10 inflations 268, 272, 276 nm

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

The procedure is as in Step D of 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 from diisopropyl ether, 7.75 g of the desired product are obtained (mp = 73 ° C.). This product is used as is for the next step.

An analytical sample was obtained by recrystallizing from 2.5 volumes of methylene chloride and 5 volumes of diisopropyl ether followed by concentration at 3 volumes, spinning, washing with diisopropyl ether and drying under reduced pressure at room temperature (PF). = 77 - 78 ° C). IR spectrum (CHCl 3) Carbonyl: 1659 cm -1 C = aromatic C: C 1599 cm -1 - 1586 cm -1 - 1508 cm -1

U.V. Spectrum (EtOH) max 227nm e = 26100 infl 248nm e = 12800 30 infl 272nm e = 5300 infl 280nm e = 3200 infl 320nm

Spectrum R.M.N. (CDCl3) 1.93 (m) -C-CH2-C- middle} 2.69 (m)} C-CH2-C =} 2.81 (m}} 2.85 (t, j = 7.5)} the others = 0-0 ^ -03.08 (t, j = 7.5)} 0 3.30} 2.64 ch3-c = 3.68} the OCHs 3.81} 6.59 (d) , j = 2) 6.68 (d, j = 2) 7.31 (d, j = 8)} 7.80 (d, j = 8)} Stage E: 8.9 the methacrylated aromatic CH meta 8.9 dimethoxy-10 - [[(4-methylphenyl) sulfonyl] oxy] -

2,3,5,6-tetrahydro-benz [e] azulen-4 (1H) -one To a solution of 2.32 g of the product obtained in Stage C in 50 ml of 1,2-dichloroethane is added at room temperature 1 65 g of 98% ferric chloride. It is stirred for 48 hours at room temperature, then poured into a mixture of ice water and stirred vigorously for 15 minutes and extracted with methylene chloride, washed with water and then with a saturated aqueous solution of sodium chloride. After drying and evaporation to dryness under reduced pressure, 2.15 g of the crude product is obtained which is chromatographed eluting with cyclohexane at 50% ethyl acetate, 1.8 g of product are recovered and chromatographed again. and recrystallized from chloroform / diisopropyl ether to give 720 mg of the desired product (mp = 138 ° C.).

I.R. spectrum (CHCl 3)

Carbonyl: C = C + aromatic (1650 cm -1) 1599 cm -1 (1556 cm -1) 1512 cm -1 1498 cm -1

U.V. spectrum (EtOH) max 230 nm e = 25300 30 infl 254 nm e = 9400 max 323 nm e = 10300

Spectrum R.M.N. (CDCl3) ~ 1.61 (m) (2H) central CH2 ~ 2.41 Ph-CH3 35 -2.50 to 2.80 CH2-C = 3.88 (s)} OCH3 3.90 (s) } 43 011603 6.74 H4 7.21 (d)} C-Ph-SO2 7.64 (d)}

Stage F: 8,9-dimethoxy-10-hydroxy-2,3,5,6-tetrahydro-benzo [e] azulen-4 (1H) -one

A mixture of 350 g of the product obtained in Stage E above, 1750 ml of ethanol, 350 ml of demineralized water and 350 ml of pure laurate liquor (concentrated) is refluxed for 2 hours. The reaction medium is cooled to 2 ° C. ± 2 ° C. and 467 ml of concentrated hydrochloric acid are introduced over 45 minutes while maintaining the temperature at 2 ° C. ± 2 ° C. 1645 ml of deionized water are then added over 10 minutes and the temperature is maintained at 2 ° C. ± 2 ° C. and the reaction medium is then stirred for 30 minutes at 2 ° C. ± 2 ° C. The crystals formed were filtered off, washed with 5 times each with 700 ml of demineralized water at 20 ° C. with 40 ° C. under reduced pressure to obtain 199.1 g of the desired product.

Preparation of 3,4-dimethoxy-5 - [[(4-methylphenyl) -sulfonyl] oxy] -cinnamic acid used starting from Preparation 2.

Step A: Methyl 3,4-dimethoxy-5 - [[(4-methylphenyl) -sulfonyl] oxy] benzoate.

303 ml of triethylamine are added over a period of 10 minutes at room temperature to a stirred mixture of 200 g of methyl gallate and 2 liters of methylene chloride. After dissolving, the mixture is cooled to 0.degree.-5.degree. C. and 130 ml of dichlorodimethylsilane are then added thereto in the course of one hour, and this mixture is stirred for a further 30 minutes at this temperature. 303.2 ml of triethylamine are added in the course of 30 minutes at 30.degree.-5.degree. C. and 227.6 g of tosyl chloride are added in the course of 15 minutes. The mixture is stirred for 1 hour at 0.degree.-5.degree. C. and the mixture is stirred for 10 minutes and the temperature is allowed to rise to 20.degree.-22.degree. C., 200 ml of acetic acid, and then 500 ml of demineralized water are added. 15 minutes at 20 ° C. The methylene chloride is distilled at constant volume (3.3 l) under reduced pressure, replacing with demineralised water, the mixture is stirred for 2 hours at 20 ° C., drained, washed with demineralized water to obtain 44 ml. 011603 523 g (wet weight) of methyl 3,4-dihydroxy-5 - [[(4-methylphenyl) -sulfonyl] oxy] benzoate (3-tosylgallate demethyl). The wet product obtained is taken up in 2.17 l desoude (2N) and 2.17 l of methylene chloride. The mixture is stirred at 20.degree. C. until dissolution, then 18 g of tetrabutylammonium bromide are added at 20.degree. C. and 237 ml of dimethylsulfate are then added in the course of 15 minutes at 20.degree. The reaction medium is stirred for 1.5 hours at 20-22 ° C. 78 ml of triethylamine are added at 20 ° -22 ° C. and stirred overnight at 20.degree.-22.degree. C., then decanted and washed with 400 ml of demineralised water and 20 ml of acetic acid are added to the phase. organic stirred 15 minutes, add 400 ml of demineralized water, then decanted. The combined organic phases are concentrated to dryness, first at atmospheric pressure and then under reduced pressure at 40 mm Hg and 60 ° C. outside. The reaction mixture is stirred with 400 ml of methanol and then the dried extract is taken up with 600 ml of methanol, which is heated to reflux until the product has completely dissolved and then cooled to 0-5 ° C. for 1 hour at this temperature. The mixture is filtered and washed twice with 200 ml of methanol at -10 ° C. and dried at 40 ° C. under reduced pressure. 330.4 g of 3,4-dimethoxy-5 - [(4- Methylphenyl) -sulfonyl] oxy] benzoate. The crude product is purified by recrystallization from 330 ml of toluene. After stirring for 2 hours at -10 ° C., the mixture is filtered off, washed twice with 82 ml of toluene cooled to -15 ° C. and dried under reduced pressure at 40 ° C. to obtain 230.3 g of the desired purified product.

Step B: 3,4-dimethoxy-5 - [[(4-methylphenyl) -sulfonyl] oxy] cinnamic acid a) Cool to 0 ° C, 600 ml toluene and add 202 ml Vitride® solution 70% in toluene at 0 ° C and added in one hour 67.6 ml of morpholine at 0-2 ° C, let the temperature to18 ° C. The solution thus obtained is used immediately for the next step. b) stirring for 10 minutes at 20-22 ° C, 200 g of methyl 3,4-dimethoxy-5 [[(4-methylphenyl) -sulfonyl] oxy] benzoate obtained in Step A and 1400 ml of toluene until completely dissolved.

The solution of the reagent obtained above is added over one hour at 10 ° C. The mixture is stirred for an additional hour and the temperature is raised to 18 ° C.

A solution cooled at 10 ° C. of 200 ml of concentrated sulfuric acid and 1000 ml of demineralized water is introduced over one hour at 10 ° C. The mixture is stirred for 16 hours at 20 ° C. and the organic phase is decanted, washed with 5 × 200 ml of demineralized water, dried, filtered and washed with 3 × 100 ml of methylene chloride. The intermediate aldehyde solution thus obtained is used as it is in the next step. c) 16 hours at 70.degree. C. ± 2.degree. C. (by eliminating, on ordinary pressure, the methylene chloride), the intermediate aldehyde solution obtained above, 200 ml of 2-picoline, 120 g of malonic acid and 20 ml of piperidine.

It is cooled to 20.degree.-22.degree. C. and, maintaining this temperature, a solution of 200 ml of concentrated hydrochloric acid and 400 ml of demineralised water is added over a period of 15 minutes. The mixture is stirred for 2 hours at 20-22 ° C. and then cooled to 0 ° C., the crystals formed are filtered off, washed with demineralised water and dried under reduced pressure at 40 ° C. to obtain 171.7 g of 3,4-dimethoxy acid. 5 - [[(4-methylphenyl) -sulfonyl] oxy] phenyl] cinnamic expected. PREPARATION 3 s 9,10-dimethoxy-8-hydroxy-2,3,5,6-tetrahydro-benz [e] azulen-4 (1Ξ) -one

Step A: 9,10-Dihydroxy-8 - [[(4-methylphenyl) sulfonyl] oxy] -2,3,5,6-tetrahydro-benzene [e] azulen-4 (1H) -one

30 g of 2,3,5,6-tetrahydro-8,9,10-trihydroxy-benz [e] azulen-4 (1H) -oneobtenate are stirred for 1 hour at 20 ° C. ± 2 ° C. Preparation 1 or Ibis, 300 ml of tetrahydrofuran, 60 ml of triethylamine and 12.9 ml of trimethylbeat. 30 g of tosyl chloride are added and the mixture is stirred for 16 hours at 20 ° C. ± 2 ° C. and then, over 10 minutes at 20 ° C. ± 2 ° C., the reaction medium is poured onto a stirred 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 was stirred for one hour at 20 ° C, then 150 ml of methylene chloride was added, stirred for a further 15 minutes, decanted and reextracted with 2 x 75 ml of methylene chloride. The combined organic phases are washed with 4 x 150 ml of demineralized water and reextracted with 75 ml of methylene chloride, after concentration under a reduced pressure of 20 mbar until distillation is refused at 50 ° C to obtain 47, 6 g of the desired product.

Step B: 9,10-dimethoxy-8 - [[(4-methylphenyl) sulfonyl] oxy] -2,3,5,6-tetrahydro-benz [e] azulen-4 (1H) -one The mixture is stirred for 16 hours. at 20 ° C., 47.6 g 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 sulphate. 30 ml of triethylamine are then introduced in order to destroy the excess of dimethyl sulphate, the reaction mixture is stirred for another hour at 20 ° C. ± 2 ° C., then 150 ml of demineralized water are stirred for a further 15 minutes and then decanted. . The aqueous phase was reextracted with 2 × 75 ml of methylene chloride and the combined organic phases were washed with 3 × 120 ml of deionized water and then with 120 ml of N hydrochloric acid and 3 × 120 ml of demineralised water. the organic phases are combined and dried over sodium sulphate, then 120 g of silica gel (60 Mesh) are added at 20 ° C. ± 2 ° C. for 1 hour with stirring and the mixture is stirred for one hour at 20 ° C., filtered, washed with methylene chloride and concentrated to dryness under reduced pressure at 50 ° C to obtain 47.4 g of the desired product.

The crude product is purified by recrystallization from 390 ml of ethanol after distillation of 90 ml of ethanol and the mixture is stirred at 0 ° C. ± 2 ° C. for 3 hours. It is filtered off with suction, washed with 30 ml of ethanol at 0 ° C. and then dried under reduced pressure at 40 ° C. to obtain 41.1 g of the desired product (m.p. = 129 ° C.).

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

4.5 g of potassium hydroxide and then 10 ml of triethylamine are added to a suspension comprising 10 g of 9,10-dimethoxy-8 - (((4-methylphenyl) sulfonyl) oxy) 2,3,5,6-tetrahydro-benzine. [e] azu-en-4 (1H) -one obtained as in Stage B and 100 ml of methanol.On heated for 1 hour under reflux, acidified by adding 20 ml of acetic acid and then 20 ml of water. It is extracted with dichloromethane, washed with water, the solvent is evaporated at 40 ° C. under reduced pressure and 5.7 g of expected product is recovered. PREPARATION 4: 2,3,5,6-Tetrahydro-8-hydroxy-9-methoxybenz [e] azulen-4 (1H) -one and 2,3,5,6-tetrahydro-9-hydroxy- 8-methoxy-benz [e] azulen-4 (1H) -one

The procedure is equivalent to the preparation of 2 stages B, C, D, E and F but from 3- (3,4-dimethoxy-phenyl) propionic acid, and 1.08 g of crude product is obtained. a mixture of monohydroxylated product (8-OH / 9-OMe and 9-OH / 8-OMe) which is separated by supersite chromatography using 7/3 cyclohexane / ethyl acetate as eluent mixture. The following two regioisomers are thus obtained: 8-OH / 9-OMe 0.494 g Rf (cyclohexane / ethyl acetate 6/4) = 0.428-OMe / 9-OH 0.041 g Rf (cyclohexane / ethyl acetate 6 / 4) = 0.33PREPARATION 5: 2,3,5,6-Tetrahydro-8-hydroxy-10-methoxy-benz [e] azulen-4 (1H) -one and 2,3,5,6-tetrahydro-10 8-hydroxy-8-methoxy-benz [e] azulen-4 (1H) -one

The procedure is equivalent to Preparation 2, stages B, C, D, E and F, but from 3- (3,5-dimethoxyphenyl) propionic acid, and 1.428 g of a product containing a mixture of the monohydroxylated products (8-OH / 10-OMe and 10-OH / 8-OMe) and dihydroxylated (8-OH / 10-OH), which are separated by chromatography on silica using the mixture eluting the cyclohexane / ethyl acetate 7 / 3.PREPARATION 6: 2,3,5,6-Tetrahydro-9-hydroxy-benz [e] azulen-4 (1H) -one The procedure is equivalent to the preparation of 2 stages B, C, D, E and F but from 3- (4-methoxy-phenyl) propionic acid. Demethylation was carried out with borontribromide. (Rf = 0.15 cyclohexane / ethyl acetate 7/3). PREPARATION 7: 2,3,5,6-Tetrahydro-8-hydroxy-benz [e] azulen-4 (1H) -one

The procedure is equivalent to the preparation of 2 stages B, C, D, E and F but from 10.0 g of 3- (3-methoxyphenyl) propionic acid, and 2.9 g of the expected product are obtained. Demethylation was performed with debore tribromide. (Rf = 0.15 dichloromethane / ethyl acetate 95/5). PREPARATION 8: Methyl ester of (DL) -4-bromo-2- (phenylmethoxycarbonylamino) butanoic acid.

The mixture is stirred for 18 hours at 120 ° C. in a closed chamber of 2-amino-4-butyrolactone hydrobromide in 200 ml of 24% gaseous hydrobromic acid. It is cooled to room temperature, brought to atmospheric pressure, concentrated under reduced pressure, the residue is taken up in 200 ml of methanol and then a stream of hydrochloric acid is sparged for 2 hours while maintaining the temperature below 35 ° C. The solvent is evaporated under reduced pressure and the methyl ester of 2-amino-4-bromo-butanoic acid is obtained, which is taken up in 250 ml of acetone and 100 ml of water, neutralized using 2N sodium hydroxide then slowly add 35 ml of benzyl chloroformate. It is stirred for 48 hours, filtered, extracted with ethyl acetate, the solvent is evaporated off, the residue is chromatographed on silica (eluent: cyclohexane-ethyl acetate 7-3) and 27.9 g of expected product are recovered. Mp = 90 ° C. PREPARATION 9 4-bromo 2- (terbu-toxycarbonylamino) butanoic acid methyl ester. 5.7 g of the methyl ester of 2-amino-4-bromo-butanoic acid prepared as in Preparation 8 in 120 ml of methanol are stirred for 48 hours at room temperature with 24 ml of triethylamine and 9 g of diterbutyl dicarbonate. The solvents are evaporated, the residue is taken up in water and dichloromethane, filtered, extracted with dichloromethane, the solvents evaporated, the residue is chromatographed on silica (eluent: cyclohexane-ACOEt-TEA 7-3-0.5) and 1.575 g expected product of rf = 0.52. PREPARATION 10: 4- (3-Pyrimidinyl) ΙΗ-imidazol-1-propanol. 505 mg of sodium ethoxide are mixed in 12.5 ml of dimethylformamide, 1 g of 3- (1H-imidazol-4-yl) pyridine and then 0.64 ml of chloropropanol are added and the mixture is stirred at 55 ° C. for 16 hours. The solvent is evaporated off under reduced pressure, chromato-graphie the residue (eluent: Cl 2 C ^ -MeOH 98-2) and recovering 1.015 g of the expected product.

IR spectrum (CHCl 3) OH 3626 cm -1 + Heterocycle Associated 1601, 1578, 1551, 1499 cm -1 PREPARATION 11: Hexahydro-2H-1,3-diazepin-2-one hydrazone.

A suspension comprising 3.3 g of nitroguanidine, 7 ml of water, 3.47 g of potassium hydroxide and 5 g of diamine dihydrochloride is heated at 65 ° -70 ° C. for 1 hour; 10.5 g of zinc are added, the mixture is stirred for 30 minutes at room temperature, then 2 ml of acetic acid are added, the mixture is heated for 1 hour at 40 ° C., filtered, 3 g of ammonium chloride and then 4 g of sodium bicarbonate are added. It is extracted with dichloromethane, the solvent is evaporated off under reduced pressure, the residue is chromatographed on silica (eluent: CH 2 Cl 2 -MeOH-NH 4 OH 8-4-2) and 1.650 g of expected product is recovered. PREPARATION 12: 3a, 4,5,6,7,7a-hexahydro-2- (propylthio) 1H-benzixnidazole monohydrobromide.

Refluxed until completely dissolved 1 g deoctahydro 2H-benzimidazol-2-thione and 1.3 ml of bromopropan in 20 ml of ethanol. The solvent is evaporated under reduced pressure, the residue is taken up in a minimum amount of dichloromethane, isopropyl ether is added, the solvents are evaporated off under reduced pressure, recrystallized from isopropyl ether and the desired product is dried and dried in a yield of 95.degree. %. M.p. 136 ° C. EXAMPLE 1 7 - ((4 - ((((amino) iminomethyl) hydrazono) -9,10-dimethoxy-1,2,3,4,5,6-hexahydrobenz (e) azulen-8-yl) oxy) hepta acid noique

Step A: 7- (4-Oxo) -9,10-dimethoxy-1,2,3,4,5,6-hexahydrobenz (e) azulen-8-yl) oxy) methyl ester hepta-noique

A suspension containing 0.684 g of 2,3,5,6-tetrahydro-8-hydroxy-9,10-dimethoxy-benz [e] azulen-4 (1H) -one (0.684 g) is stirred at 40 ° C. for 4 hours ( Preparation 3), 12 ml of dimethylformamide (DMF), 12 ml of tetrahydrofuran (THF), 0.7 g of potassium decarbonate and 0.835 g of 7-bromo-enanthate-methyl. After evaporation under reduced pressure, the crude product is chromatographed on silica eluting with a mixture of methylene chloride (CH 2 Cl 2) / acetone 95/5. There is thus obtained 1.000 g of purified product in the form of a yellow oil.

Rf CH2Cl2 / acetone 95/5: 0.5 50 01 1 603 IR (CHCl 3) C = O 1732 cm -1OMe 1438 cm -1 conjugated ketone 1641 cm -1 C = C 1592 cm -1, 1557 cm -1, 1492 cm'1 + aromatic

Step B: 7 - ((4 - (((Amino) imino-methyl) hydrazono) -9,10-dimethoxy-1,2,3,4,5,6-hexahydro-benzyl methyl ester ) A suspension of 0.5 g of the product of Step A above, 5 ml of ethanol and 0.330 g of amino guanidine hydrochloride is stirred for 48 hours at room temperature and evaporated at room temperature for 48 hours. the solvent under reduced pressure, and purifies the crude product by chromatography on silica eluting with a mixture of CH 2 Cl 2 / methanol (MeOH) / 80/20/4 ammonia. 0.466 g of purified product is thus obtained in the form of a white foam.

Rf CH 2 Cl 2 / methanol (MeOH) / ammonia 80/20/4: 0.8IR (Nujol) 20 ΝΗ / ΝΗ 2 3495 cm -1, 3155 cm -1 associated C = O 1731 cm -1 C = N 1674 cm -1 C = C 1625 cm "1aromatic 1595 cm'1 (F) 25 ΝΗ / ΝΗ2 1534 cm-1, 1491 cm-1

Step C: 7 - ((4 - ((((amino) iminomethyl) hydrazono) -9,10-dimethoxy-1,2,3,4,5,6-hexahydrobenz (e) azulen-8-yl) oxy) hepta-noique

The solution containing 0.44 g of the product obtained in the above stage, 5 ml of ethanol and 2 ml of 1N sodium hydroxide is stirred for 3 hours at room temperature and then neutralized with 2 ml of 1N hydrochloric acid. After evaporation under reduced pressure, the crude product is purified by chromatography on silica eluting with a CH 2 Cl 2 / methanol (MeOH) / 80/20/4 ammonia mixture. 0.192 g of purified product recrystallized from methanol is thus obtained.

Rf CH2Cl2 / methanol (MeOH) / 80/20/4 ammonia: 0.17RMN (D2O + 1 drop of 1N sodium hydroxide) 51 10 3.92 tl. 2H ch2-o 2.17 t 2H CH2-COOH 1.34 m 4H 1.55 m 2H central CH2 + CH2-C 1.70 m 4H 2.50 to 2.90 m 8H 6.62 s 1H H7 aromatic 3 , 64 s 3H och3 3.73 s 3H och3

Mi croanalys e 01 1 60% calculated C 62.86 H 7.47 N 12.21% found C 62.9 H 7.5 N 12.1

By operating in a manner equivalent to Example 1, stages A, B and C, from 2,3,5,6-tetrahydro-8-hydroxy-9,10-dimethoxy-benz [e] azulen-4 (1H). -one (preparation 3), but with different alkyl groups and G-NH 2 groups, the following products of formula (I) were prepared: EXAMPLE 2: 4 - ((4 - (((amino) iminomethyl acid Hydrazono) -9,10-dimethoxy-1,2,3,4,5,6-hexahydrobenz (e) azulen-8-yl) oxy) -butanoic acid EXAMPLE 3 Acid 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) -hexanic acid EXAMPLE 6: 5- ( 9,10-dimethoxy-1,2,3,4,5,6-hexahydro-4- (4,5-dihydro-lH-imidazol-2-yl) hydrazono) -8-benz (e) azulenyl) oxy) -pentanoic EXAMPLE 7: 5- ((4 - (((am Ino) 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 EXAMPLE 9: 5 - ((4 - ((((amino) iminomethyl) hydrazono) -9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz (e) azulenyl) oxy) EXAMPLE 10 5- (4 ((4,5-Dihydro-ΙΗ-imidazol-2-yl) hydrazono) -9,10-dimethoxy-1,2-dihydroxybenzoyl 3,4,5,6-hexahydro-8-benz (e) azulenyl) oxy) -3,3-dimethyl-4-oxo-pentanoic EXAMPLE 11 4- (4 ((4,5-dihydro-ΙΗ-imidazol) -2-yl) hydrazono) -9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz (e) azulenyl) oxy) butanoic acid EXAMPLE 12: 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 EXAMPLE 13 2- (4 ((4,5-Dihydro-1H-imidazol-2-yl) hydrazono) -9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benzoic acid (e) azulenyl) oxy) ethanoic E EXAMPLE 14 3- (4 ((4,5-Dihydro-ΙΗ-imidazol-2-yl) hydrazono) -9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benzoic acid (e) azulenyl) oxy) -propanoic 53 011603

Example Pdt of starting product alkylating g-nh2 Rf. (1) 2 P3 Br- (CH2) 3-CO2Et H2N-NH-C (= NH) -NH2.HCl 0.112 3 P3 Br- (CH2) 4 -CO2tH2n-nh-c (= NH) -nh2 HCl 0.12 4 P3 Br- (CH2) 3-CO2Et H2N-NH-C (= O) -NH2.HCl 0.18 5 P3 Br- (CH2) 5-CO2Et H2N-NH-C (= NH) -NH 2 .HCl 0.17 6 P 3 Br- (CH 2) 4 -CO 2 EtN N H 2 N -NH- ## STR5 ## ## STR1 ## ## STR5 ## wherein R 2 is CH 2 Cl 2 HNH 3 NHCO 3 HCO 2 ## STR3 ## ## STR2 ## ## STR2 ## ## STR1 ## ## STR2 ## HBr HN 0.22 (1) dichloromethane / methanol / ammonia 80/20/4 EXAMPLE 15: 5- ((4 - (((amino) imino-methyl) hydrazono) -9,10-hydrochloride dimethoxy-l, 2,3,4,5,6-hexahydrobenz (e) azulen-8-yl) oxy) pentanoic acid

86 mg of the product of Example 3 are mixed with 2 ml of water and 4 l of 0.1 N hydrochloric acid and then, after a few minutes, lyophilizes the medium. 91 mg of salt are obtained. EXAMPLE 16 4 - ((4 - ((((amino) iminomethyl) hydrazono) -8,9-dimethoxy-1,2,3,4,5,6-hexahydro-10-benz (e) azulenyl) oxy) EXAMPLE 17: 5 - ((4 - ((((amino) iminomethyl) hydrazono) -8,9-dimethoxy-1,2,3,4,5,6-hexahydro-10-benz (e) azulenyl ) oxy) pentanoic acid

The procedure is as in Example 1, Steps 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).

Example Starting Pd alkylating product g-nh2 Rf. (II) A Br- (CH 2) 3 -CO 2 andH 2 N -NH-C (= NH) -NH 2 .HCl 0.07 17 (XX) A Br- (CH 2) 4 -CO 2 EtH 2 N -NH-C (= NH EXAMPLE 18: 4 - ((4 - ((((amino) iminomethyl) hydrazono) - 8,10-dimethoxy-1,2,3,4,5,6-hexahydro-9-benzoic acid (e) azulenyl) oxy) butanoic acid EXAMPLE 19: 5 - ((4 - ((((amino) iminomethyl) hydrazono) - 8,10-dimethoxy-1,2,3,4,5,6-hexahydro-9-benzoic acid (e) azulenyl) oxy) -30 pentanoic

The procedure is 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 . 35 011603 55

Example Starting Pd alkylating product g-nh2 Rf. (II) E1 Br- (CH2) 3-CO2Et h2n-nh-c (= nh) -nh2.HCl 0.10 19 (II) E1 Br- (CH2) 4-CO2Et H2N-NH-C (= NH 0.07 EXAMPLE 20: 4 - ((4 ((4,5-Dihydro-ΙΗ-imidazol-2-yl) hydrazono) -1,2,3,4,5,6-hexahydro acid 9-benz (e) azulenyl) oxy) butanoic

Step 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 toluene, is stirred at room temperature overnight. dimethylformamide (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 methylene chloride mixture (dichloromethane / acetone 95/5). 0.608 mg of purified product is thus obtained in the form of a yellow oil. IR (CHCI3) C = O 1728cm-1 aromatic ketone 1641 cm -1 aromatic C = C 1610 cm -1, 1590 cm -1, 1569 cm -1, 1499 cm -1 Assay B: Ethyl ester of acid 4 ((4 - ((4,5-dihydro-1H-imidazolin-2-yl) hydrazono) -1,2,3,4,5,6-hexahydrobenz (e) azulen-9-yl) oxy) - butanoic

Refluxed for 24 hours, 608 mg of the product of the preceding Step A, 10 ml of butanol and 600 mg of cyclic bromhydrated aminoguanidine were added as follows: (4,5-dihydro-1H-imidazolin-2-yl) -hydrazine, evaporated. the solvent under reduced pressure, and purifies the crude product by flash chromatography eluting with a mixture of C 2 -C 4 / methanol (MeOH) / ammo-nia 80/20/4. 0.604 g of the expected product is thus obtained .IR (CHCl 3) 35 = C-NH-3451 cm -1 C = O 1728 cm -1 (ester) C = N + C = C + aromatics: 1627 cm -1 ( F), 1568 cm -1, 1548 cm -1, 1497 cm -1, 1488 cm -1

Stage C: 7 - ((4,5-Dihydro-1H-imidazol-2-yl) hydrazono) -1,2,3,4,5,6-hexahydrobenz (e) azulen-9-yl) oxy) - butanoic. The solution containing 0.604 g of the product obtained in the preceding stage, 8 ml of ethanol, 5 ml of tetrahydrofuran and 2 ml of 2N is stirred for 4 hours at room temperature and then neutralized with 2 ml of hydrochloric acid. After evaporation under reduced pressure, the crude product is purified by chromatography on silica eluting with a dichloromethane (CH 2 Cl 2) / methanol (MeOH) / ammonia 80/20/4 mixture. 0.298 g of purified product recrystallized from methanol is thus obtained.

Rf (dichloromethane / methanol / 80/20/4 ammonia): 0.2 NMR (d 2 O + 1 drop of 1N sodium hydroxide) 1.71 (1) 2H o -CH 2 -CH 2 -CH 2 -CO 1.96 (m) 2H CH2 to 2 (cyclope 2.30 (t) 2H ch2-co 2.50 to 2.75 8H ch2-c = 20 3.45 (si) 4H ch2-n = 3.89 (tl) 2H Ph-O 6.70 (m) 2H H10 and H8 7.00 (d, J = 8) H7 EXAMPLE 21 4- (4 ((4,5-Dihydro-1H-imidazol-2-yl) acid Hydrazono) -1,2,3,4,5,6-hexahydro-8-benz (e) azulenyl) oxy) butadiene

The procedure is 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 expected product. Rf (dichloromethane / methanol / 80/20/4 ammonia): 0.27 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

Step A: 5 - (((4-Oxo) -9,10-dihydroxy-1,2,3,4,5,6-hexahydrobenz (e) azulen-9-yl) oxyethyl ester (1) protection To a 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 was added 4.42 ml of trimethoxyborate and 20.4 ml of triethylamine maintaining the temperature between 37 and 39 ° C and then stirring at room temperature for 3 hours. 2) alkylation and deprotection

9.7 ml of ethyl bromo-Svalerate, 100 ml of dimethylformamide and 8.4 g of potassium carbonate are then added and the mixture is stirred at 60 ° C. for 2 days. The reaction mixture is then treated with 120 ml of water and 50 ml of 36N concentrated hydrochloric acid, stirring for 1 hour addition of ethyl acetate, separating the organic and aqueous phases. Organic Laphase is then washed, dried and evaporated under reduced pressure. A crude product is obtained which is purified by chromatography on silica eluting with 70:30 cyclohexane / ethyl acetate. 5.2 g of pure expected product is obtained.

Rf (dichloromethane / methanol 95/5) = 0.82Rf (cyclohexane / ethyl acetate 70/30) = 0.23 Step B: Ethyl ester, 5 - (((8-oxo) -6 acid , 7,8,9,10,11-hexahydro-Azuleno (5,6-d) -1,3-benzodioxol-4-yl) oxy)) - pentanoic acid

2.5 g of the product obtained in the preceding stage, 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 filtration and rinsing with methanol, evaporated under reduced pressure and purified the crude product by chromatography on silica eluting with the 85/15 cyclohexane / ethyl acetate mixture. 1.73 g of expected pure product are obtained. (Mp = 118 ° C)

Rf (80/20 cyclohexane / ethyl acetate) = 0.25Stade C: 5 - ((8 - ((((amino) imino-methyl) hydrazono) -6,7,8,9 ethyl ester 10.11-hexahydro-azuleno (5,6-d) -1,3-benzodioxol-4-yl) oxy) -pentanoic 551 mg of the product obtained in the preceding stage are mixed overnight at 120 ° C. and 467 mg of aminoguanidine hydrochloride, then purified by chromatography eluting with a dichloromethane / methanol / 80/20/4 ammonia mixture. 58 Q11603 is obtained 174 mg of the expected product.

Rf (dichloromethane / methanol / ammonia 80/20/4) 0.98Stade D: 5 - ((8 - ((((amino) iminomethyl) hydrazono) - 6,7,8,9,10,11-hexahydroazuleno acid (5,6-d) -1,3-benzodioxol-4-yl) oxy) pentanoic

30.274 mg of the product obtained in the preceding stage and 1.86 ml of 1N, are then mixed at room temperature for 1 hour, then neutralized with 1N hydrochloric acid solution and evaporated under reduced pressure. The crude product is purified by chromatography eluting with 80/20/4 dichloromethane / methanol / ammonia. 141 mg of the expected product is obtained.

Rf (dichloromethane / methanol / ammonia 80/20/4) 0.23 NMR (DMSO)

1.55 to 1.9 (m) 4H1.55 to 1.9 (m) 2H

2.26 (t) 2H2.65 to 3.00 (m) 8H

4.07 (t) 2H 20 5.95 (s) 2H6.61 (m) 1HH mobile (m, wide)

O-CH2-CH2-CH2-CH2-COCH2 in 2 (Cyclopentene) CH2-COCH2-C = o-CH2-CH2 -O-CH2 -O H8 NH-C (= NH) -NH2 EXAMPLE 23 s Acid 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

The procedure is as in the preceding example, starting from 374 mg of the product obtained in Stage A of the preceding example and 0.19 ml of diphenyldichloromethane. 198 mg of expected product is obtained. Rf (dichloromethane / methanol / ammonia 80/20/4) = 0.17 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.

Step A: 0 - [(4-Oxo) -9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz (e) azulenyl] -N - [methyl ester phenylmethoxy) carbonyl] -DL-homoserine.

0.6 g of 2,3,5,6-tetrahydro-8-hydroxy-9,10-dimethoxybenz [e] azulen-4 (1H) -one (0.6%) are stirred overnight at room temperature (Preparation 3). 10 ml of dimethylformamide, 10 ml of tetrahydrofuran, 1 g of potassium carbonate and 0.867 g of (DL) -4-bromo-2- (phenylmethoxycarbonylamino) butanoic acid methyl ester prepared as in Preparation 8 After evaporation under reduced pressure, the crude product is chromatographed on silica eluting with a mixture of methylene chloride (CH 2 Cl 2) / acetone 95/5. In this way 1.166 g of purified product is obtained in the form of a yellow oil. IR (CHCl 3) C = O 1740 cm -1 (ep), 1721 cm -1 ketone, conj. 1642 cm -1 aromatic C = C 1593 cm -1, 1559 cm -1, 1508 cm -1, 1493 cm -1 Step B: Methyl ester of O- [4 - [(4,5-dihydro-1H-imidazole) 2-yl) hydrazono) -9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz (e) azulenyl] -N - [(phenylmethoxy) carbonyl] -DL-homoserine.

The mixture is stirred for 24 hours at 120 ° C., 539 mg of the product of the preceding stage, 15 ml of butanol and 600 mg of cyclic aminoguanidine hydrobromide according to (4,5-dihydro-1H-imidazol-2-yl). hydrazine, the solvent is evaporated under reduced pressure, and the crude product is purified by chromatography on silica eluting with a mixture CH 2 Cl 2 / methanol (MeOH) / ammonia 80/20/20. Thus 0.641 g of expected product is obtained. IR (CHCl 3) 25 = C-NH-3451 cm -1 combined C = O 1740 cm-1 (ep), 1720 cm -1 (max) C = N + C = C + aromatics + amide II: 1667 cm 1 (F), 1606 cm -1, 1508 cm -1, 1490 cm -1.

Step 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 above stage, 10 ml of ethanol and 2 ml of 2N sodium hydroxide is stirred for 2 hours at room temperature and then neutralized with 2 ml of hydrochloric acid. After evaporation under reduced pressure, the crude product is purified by chromatography on silica eluting with a CH 2 Cl 2 / methanol (MeOH) / 80/20/4 ammonia mixture. 0.349 g of purified product recrystallized from ethanol is thus obtained.

Rf CH2Cl2 / methanol (MeOH) / 80/20/4 ammonia: 0.37EXAMPLE 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.

The procedure is equivalent to Example 24 but from 0.428 g of 2,3,5,6-tetrahydro-9-hydroxy-benz [e] azulen-4 (1H) -one (Preparation 7). 245 mg of expected product is obtained. Rf CH2Cl2 / methanol (MeOH) / ammonia 80/20/4: 0.5 EXAMPLE 26: O- [4 - [(1,2,3,4-tetrahydro-6-pyrimidinyl) hydra-zono] 9,10- dimethoxy 1,2,3,4,5,6-hexahydro-8-benz [e] azulenyl] N - [(phenylmethoxy) carbonyl] DL-homoserine.

Step A: O- [9,10-15 dimethoxy 1,2,3,4,5,6-hexahydro-4 - [(1,4,5,6-tetrahydro-2-pyrimidinyl) hydrazono methyl ester monobromide ] 8-benz (e) azulenyl] N - [(phenylmethoxy) carbonyl] DL-homoserine.

The procedure is as in Example B, using, for example, 200 mg of the product obtained as in Example 24, Stage A in 2 ml of butanol and 74.5 mg of tetrahydro-2 hydra-zone monobromide ( 1H) -pyrimidinone and refluxed for 16 hours. Allowed to warm to room temperature, extracted with dichloromethane, dried, the solvent evaporated under reduced pressure and 152 mg of the expected product. Step 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.

The procedure is as in Example 24 Stage C using 131 mg of the product obtained in Step A above in solution in 1.3 ml of ethanol and 0.43 ml of N sodium hydroxide. Neutralized by addition of hydrochloric acid N evaporate the solvent, filter, dry 78 mg of expected product. Mp 172 ° C. NMR Spectrum (CDCl 3) 1.90 (m) (2H) CH 2 to 9 2.03 (m) Central CH 2 2.36 (m) (2H) 2.60 to 3.00 (8H) α = C-CH 2.48 (ml) (4H) = N-CH2 61

3.77 (s) 3.78 (s) (9H) = C-0Me 4.01 (m) (1H) 4.17 φ-ο-οη2 4.67 (P) = C-CH-NC = 5.14 (d) = C-NH-CH 6.49 (Si) H, 7.36 (m) (5H) Φ-C 011603 EXAMPLE 27 Ester (2) O- (9,10-dimethoxy-1,2,3,4,5,6-hexahydro-4- [(1,4,5,6-tetrahydro-2-pyrimidinyl) hydrazono] -8-dihydroxypropyl) -8- benzyl azulenyl] N - ((phenylmethoxy) carbonyl] DL-homoserine.

Step A: O- [9,10-dimethoxy-1,2,3,4,5,6-hexahydro-4- [1 (2,2-dimethyl-1,3-dioxolan-4-yl) methyl] ester 4,5,6-tetrahydro-2-pyrimidinyl) hydrazono] 8-benz (e) azulenyl] N- [(phenylmethoxy) carbonyl] DL-homoserine.

0.3 g of the product prepared as in Example 26 in 1 ml of dimethylformamide and 1 ml of dichloromethane, 96 mg of 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride and 68 mg of sodium are cooled to 0 ° C. hydroxy benzotriazole hydrate. Stirred 30 minutes at room temperature, intrudes 0.06 ml of solketal and continues stirring for 3.5 hours. The reaction medium is diluted with water and extracted with dichloromethane and 0.6 g of crude product is recovered, which is purified by chromatography on silica (eluent: CHCl 2 -MeOH 90-10). 0.352 g of expected product is obtained. IR (CHCl 3) 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

Step B: O- (9,10-dimethoxy) 1,2,3,4,5,6-hexahydro-4 ([(1,4,5,6-tetrahydro) -2- (2,3-dihydroxypropyl) ester pyrimidinyl) hydrazono] -8-benz (e) azulenyl] N - [(phenylmethoxy) carbonyl] DL-homoserine.

0.320 g of product obtained in Step A is stirred for 6 hours at room temperature in 3 ml of ethanol and 1 ml of 2N hydrochloric acid. After evaporation of the solvents and chromatography.

Silica graphs contain 0.112 g of NMR (CDCl3) 1.88 (m) (2H) (eluent product): CH2Cl2-MeOH-NH4OH 80-20-4), expected. Central 1.98} CH2 and CH2 at 9 2.36 2.60 at 3.10 (8H)} = c-CH2 3.43 (m) (4H) 3.79 (s)} = nn-ch2 3.81} Φ-OMe 3.60 to 3.90 o-ch2-ch-o "4.00 to 4.30} coo-ch2-ch} φ-ο-οη2-οη2 4.64 (m) ( 1H) = C-CH-NC = 5.13 (s) Coo'-ch2- $ 6.53 (s) h4 7.20-7.38 Φ-C EXAMPLE 28: Ο- [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-quinolinyl) sulfonyl] DL-homoserine.

Step A: O- (9,10-dimethoxy-1,2,3,4,5,6-hexahydro-4-oxo-8-benz (e) azulenyl) N - [(1,1-dimethylethoxy) carbonyl] methyl ester DL-homoserine.

4.1 g of the product prepared as in Preparation 3 and 5 g of the esterprepared as in Preparation 9 are stirred at room temperature for 65 hours in 50 ml of dimethylformamide and 50 ml of tetrahydrofuran in the presence of 5 g. potassium carbonate of potasium 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 are recovered.

IR (CHCl 3) = 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

Step B: O- (9,10-Dimethoxy-1,2,3,4,5,6-hexahydro-4-oxo-8-benz (e) azulenyl) methyl ester monohydrochloride DL-homoserine.

10 ml of hydrochloric acid in ethyl acetate are added 3 times to 6 g of the product of Step A in 5 ml of ethyl acetate and then stirred 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.

Stage C: O- (9,10-dimethoxy-1,2,3,4,5,6-hexahydro-4-oxo-8-10 benz (e) azulenyl) N - [(8-quinolinyl) sulfonyl] DL-homoserine.

0.656 g of the product obtained above is taken up in 5 ml of dichloromethane, 1 ml of triethylamine and 0.638 g of 8-chlorosulfonylquinoline are added and the mixture is stirred for 2 hours at room temperature. After evaporation of the solvents under reduced pressure and chromatography on silica (eluent: CHCl2-MeOH95-5), 0.956 g of expected product is recovered.

Stage D: O- [4 - [(4,5-dihydro-1H-imidazol-2-yl) hydrazono] 9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benzyl methyl ester e) azulenyl] N - [(8-quinolinyl) sulfonyl] DL-homoserine.

16 g are stirred at 120 ° C., 0.9 g of the product of Step A above, 5 ml of butanol and 0.6 g of cyclic amino guanidine hydrobromide according to (4,5-dihydro-1H-imidazole). -2-yl) hydrazine, the solvent is evaporated off under reduced pressure and 0.786 g of the expected product is obtained, used as such for the following stage.

Step E: O- [4 - [(4,5-dihydro-1H-imidazol-2-yl) hydrazono] 9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz (e) azulenyl ] Ν-ΕΟ -quinolinyl) sulfonyl] DL-homoserine.

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

Rf = 0.40 (CHCl2-MeOH-NH4OH 80-20-4). 64 011603

NMR Spectrum (DMSO) 1.81 (Si) CH 2 in 9 2.40-3.20 α = c-CH 2 3.35 (1) = n-CH 2 3.55 (Si) = C-OMe 6 63 (si) h4 7.58 (dd) h'3 7.67 (t) H'6 8.19 (d), 8.29 (d) H5 and H '? 8.45 (d) H4 8.90 (d) H2 7.31 (si) 7.97} H m <□ biles 10.40 (f)} 12.62} EXAMPLE 29 O-Monohydrochloride 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. Step A: Methyl 4- [[9,10-dimethoxy-1,2,3,4,5,6-hexahydro-4-oxo-8-benz (e) azylenyl] oxy] -2-isocyanato-butanoate.

450 mg of the amine obtained austad B of Example 28 are stirred for 10 minutes at 0 ° C. in 10.2 ml of an aqueous solution of sodium bicarbonate and 10.2 ml of dichloromethane. 204 mg of triphosgene dissolved in 2 ml of dichloromethane are added to the organic phase of the reaction medium, the mixture is stirred for 10 minutes, extracted with dichloromethane, dried, the solvent is evaporated off under reduced pressure and 430 mg of expected product is obtained which is used which at the next stage.

Stage B: O- [9,10-dimethoxy-1,2,3,4,5,6-hexahydro-4-oxo-8-benz (e) azulenyl] N - [[3- [4- (3-pyridinyl)] - imidazol-1-yl] propoxy] carbonyl] DL-homoserine.

430 mg of the product of Step A in 20 ml of dichloromethane are cooled to 0 ° C. and 414 mg of the alcohol prepared as in Preparation 10 are added to 10 ml of dichloromethane. Allowed to warm to room temperature, stirred for 48 hours, the solvent evaporated under reduced pressure, chromatography residue on alumina (eluent: CH2Cl2-MeOH) and recovered 298 mg of expected product.

Stage C: O- [4 [(4,5-dihydro-1H-imidazol-2-yl) hydrazono] 9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benzo-5-monobromhydrate ( e) azulenyl] N - [[3- [4- (3-pyridinyl) 1H-imidazol-1-yl] propoxy] carbonyl] DL-homoserine.

The procedure is as in Example 24, Stage B, using 277 mg of the product obtained in Stage B above and 164 mg of cyclic aminoguanidine hydrobromide in 13 ml of butanol. After chromatography on alumina (eluent: CH2Cl2-MeOH 95-5), 289 mg of expected product is obtained.

IR spectrum (CHC13)

C = O 15

system. conjugate + aromatic + amide II 1746 (ep) 1723 (max) cm-1} 1668, 1625 (F), 1599 (ep), 1551, 1509, 1489 cm-1) 20 OH 3618 cm-1

Step D: O- [4 - [(4,5-dihydro-1H-imidazol-2-yl) hydrazono] 9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benzohydrochloride ) azulenyl] N - [[3- [4- (3-pyridinyl) 1H-imidazol-1-yl] propoxy] carbonyl] DL-homoserine.

0.3 ml of N sodium hydroxide solution is added to 277 mg of the product obtained in Step C above in 10 ml of ethanol, the mixture is stirred for 30 minutes, 10 ml of water are added, the reaction medium is acidified to pH = 25. 2.5 with N hydrochloric acid, the solvents are evaporated off under reduced pressure, the supersilica residue is chromatographed (eluent: CH 2 Cl 2 -MeOH-NH 4 OH 40-10-2), the filtrate evaporated under reduced pressure, the residue is taken up in ether-isopropyl, filtered the precipitate, dried and collected 126 mg of expected product.

NMR Spectrum (DMSO) 1.78 (m) (2H)} 1.90 to 2.30 (m) (5H)} the 3-CH 2 1.60 to 2.90 (m) (8H) CH 2 - C = 3.53 (si) ("4H) n-ch2-ch2-n 3.69 (s), 3.71 (S) ch3o-c = 3.90 to 4.20 (m) (7 to 8H) ) CH2 and <6.73 (s). h4 011603 66 5 7.20 (d, broad) CO-NH-CH- 7.35 (dd) Hs 8.04 (d) h'4 8.37 (dl) H'6 8.94 (si) H2 7.72 (s), 7.80 (s) CH = imidazole. EXAMPLE 30: 5- [[4- [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. 300 mg of the product of Step A of Example 3 are mixed at room temperature in 6 ml of ethanol with 61 mg of sodium bicarbonate and 0.7 ml of ethyl bromoacetate. The solvents are evaporated, the residue is chromatographed on silica (eluent: CH 2 Cl 2 -MeOH 95-5) and 139 mg of the intermediate ethyl ester are obtained. 110 mg of this ester are mixed for 2 hours at room temperature in 1 ml of ethanol in the presence of 0.5 ml of 2N sodium hydroxide. After neutralizing the reaction medium with 2N hydrochloric acid, filter the precipitate formed, dry and recover 44 mg of the expected product.

NMR Spectrum (DMSO) δ 1.73 (m) (6H) central CH 2 and 2.30 (t) (2H) = C-CH 2 (chain) 2.30 to 3.20 = c-CH 2 δ 3.73 ( s), 3.75 (s) Φ-OMe 3.83 (si) = cn-ch2-c = 4.02 (t) 4> -O-CH2 6.76 (s) h4 30 7.20 (if) ) (1H)} 8.28 (si) (1H)} mobile H 12.04 (1H)} EXAMPLE 31: O- [9,10-dimethoxy 1,2,3,4,5,6 [(4, 5,6,7-tetrahydro-1H-1,3-diazepin-2-yl) benz (e) -azulenyl] N - [(phenylmethoxy) carbonyl] DL-homoserine.

1 g of the compound prepared in Example 24, Stage A, in 5 ml of butanol and 0.9 g of cyclic aminoguanidine prepared as in Preparation 11 are mixed for 16 hours at 130 ° C. 67 011603

The solvent is evaporated off under reduced pressure, the residue is chromatographed on silica (eluent: CH 2 Cl 2 -MeOH 90-10) and 0.8 g of intermediate ester are obtained which is stirred at ambient temperature for 1.5 hours in 3 ml of methanol with 2N sodium hydroxide 2N. After neutralization of the reaction medium with 2N hydrochloric acid and evaporation of the solvents under reduced pressure, the supersilica residue is chromatographed (eluent: CH2Cl2-MeOH-NH4OH 90-15-2) and 0.22 g of the expected product is recovered. EXAMPLE 32 O- [9,10-dimethoxy-1,2,3,4,5,6-hexahydro-4- [(3α, 4,5,6,7,7a-hexahydro-1H-benzimidazol-2-yl) hydrazono] 8-benz (e) azulenyl] N - [(phenylmethoxy) carbonyl] DL-homoserine.

The procedure is as for Steps B and C of Example 24, starting with 200 mg of the compound prepared in Example 24, Stage A, and 176 mg of cyclic amino guanidine prepared as in Preparation 12. 102 mg of the title compound are recovered. intermediate ester is used 100 mg for the saponification reaction. 59 mg of expected product is obtained.

Rf = 0.24 (CH2Cl2-MeOH-NH4OH 85-15-3). 20 Pharmaceutical compositions

Tablets having the following formula were prepared: - product of Example 1 50 mg - Excipient (talc, starch, magnesium stearate) QS for a 120 mg tablet

Pharmacological study of the products of the invention 1 - Study by the products of the invention of the displacement of the link: Vitronectin / Vitronectin Receptor (a ^ j)

Protocol:

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

The next day, the wells are emptied and the ligands (Vitronectine) are then fixed (see fixing buffer) for 1H at room temperature with gentle stirring. 68 01160 3

The wells are washed six times (see washing buffer), and then are added per well and in this order: 40 μl of incubation buffer, 10 μl of the dilution of the product to be tested, the products are diluted in a 50/50 mixture of DMSO-H2O) - 50 μl of human β3 receptor (cf Pytela et al., MethodsEnzymol (1987) 144: 475) (dilution in incubation buffer, to be adapted according to the receptor batch and according to the ligand).

The ligand, the human β3 receptor and the products to be studied are incubated for 3 hours at room temperature with gentle agitation.

The wells are again washed six times, then incubated for 2 hours at room temperature with gentle shaking, in the presence of 100 μl of antibody 4B12-HRP, anti-peroxidase-coupled receptor (antibody 4B12-HRP is diluted entampon). The dilution is to be adapted according to the lot of receptor).

The wells are then washed six times prior to the ligand-receptor determination made through a peroxidase developer kit (TMB Microwell Peroxidase Substrate System Kirkegaard: Cat.No. 50-76-00).

This kit contains a vial A of substrate (3,3 ', 5,5'-tetramethylbenzidine at 0.4 g / l) and a vial B (0.02% H 2 O 2 in citrate / citric acid buffer). Extemporaneously, a volume of A is mixed with a volume of B, then the reaction mixture is dispensed at 100 μΐ / well. The enzymatic reaction develops in 12 'for Vitronectin / 0 ^ 3, evolution is stopped by the addition of 100 μΐ of phosphoric acid IM. The optical density is measured at 450 nm.

Buffers: - coating buffer: 0.05 M carbonate, NaOH pH 9.6 - fixing buffer: PBS containing 0.5% BSA (pH 7.4) - washing buffer: PBS containing 0.05% Tween (PH 7.4) - incubation buffer: 50 mM TRIS pH 7.4

. 0.5% BSA 69 011603. 0.05% Tween 20. 1 mM MnCl 2. 50 μΜ CaCl2. 50 μM MgCl25. 100 mM NaCl.

Expression of results:

The following curve is plotted: the percentage of binding to human vitronectin as a function of the logarithm of concentration of each product tested. For each product, the IC 50 is determined according to the following formula: IC 50 = (BO + B min) / 2 BO = Maximum binding in the absence of any product

Bmin = Minimum binding in the presence of the highest concentration of product. 2 - Mouse calvarium test

Principle

Injection of a tracer dose of 45Ca (CaCl 2) to pregnant females in order to study bone resorption by measuring the release of 45Ca from cranial tissues of newborns.

Purpose Determination of the activity of a molecule on bone resorption, ex-vivo study. 25 Products 1) Test product: Vehicle: DMSO, H20 / BSA (0.1%)

Dose: Variables (10 μΜ in screening). 2) Reference products: Echistatin (Ref H-9010-BACHEM) Vehicle: H20 / BSADose: 10 μΜ. 3) Radioactive tracer: 4 Ca in the form of an aqueous CaCl 2 solution-ref. CES3 35 AMERSHAM or NEZ-013 NEN. Vehicle: Physiological serum

Dose: 25 μ € ί / 3θηΓΪ3 / 0.4 ml. Culture medium 70 011603 CMRL 1066 with phenol red (ref 041-01535 M / GIBCO) supplemented with 0.1% BSA and penicillin / streptomycin.Method 1) Injection of 45Ca to pregnant mice (OF1, strain: 5 Swiss) a) Preparation of the marked solution: 190 μl of the calcium stock solution at 2 mcf / ml is added to 6 ml of physiological saline. b) Injection: At the 17th day of gestation, the mice receive 400 μ of this solution intravenously, ie 25 μCi / mouse. 2) Removal of the tissue (cranial cap (calvarium))

Six days after their birth the newborns are empty, then the head is recovered, and the skin incised from the nape of the neck to the forehead. The cranial cap is removed by scissors cutting and with a cookie cutter, two exactly identical half-calvaria (one on the left and one on the right) are cut in the parietal bones. One serves as a control, the other will be used to test the product to be tested. 3) "Rinse" phase

Each half calvarium is deposited in a well of a plate 24 wells, containing 1 ml of medium, on a support of polyethylene and nylex 100 / xm, to avoid contact with the bottom of the well.

After 24 hours, the polyethylene carriers carrying calva-ria are transferred to new 24-well plates containing 1 ml of fresh medium and the test products or their solvents. 200 μl of medium of the first plates are taken from each well and a first count of the radioactivity is performed (A value).

This change of environment eliminates all the mechanical stress associated with the sample. 4) "Resorption" Phase 48 hours after the tissues were brought into contact with the products studied, 200 μl of medium are taken from each well and counted (B value), so as to determine the amount of 45Ca released into the wells. the medium during the so-called resorption phase.

The calvarium is then completely demineralized in 1 ml of 5% trichloroacetic acid and after digestion, 200 μl are also taken and counted so as to determine the amount of calcium remaining in the bone (C value).

Expression of results

A% bone resorption is calculated for each half-calvarium (each well) as follows:% bone resorption = dpm B / dpm (A + B + C) x 100 10

The sum of the dpm A + B + C represents the amount of 45C incorporated in each bone part on the day of sampling.

To measure the effect of a product, the percentage of bone resorption of the treated well and the corresponding control well is made for each point. The value called the resorption index is between 0 and 1 if the product inhibits bone resorption and is produced by potentiation. The indexes are then averaged (since there are 6 points / group) of each product giving a clue / product. If we subtract this index from value 1, we obtain the power of inhibition of the product, which can be expressed as a percentage.

Moreover, a statistical test (Student T-test) is performed by comparing point / point the individual resorption indices. 72 011603 RESULTS:

Examples Competition test binding Vn / VR ((0 ^ 3) ICc; n in μΜ Calvarian of mouse% inhibition at ΙΟμΜ EX 2 0.45 19 EX 3 2.1 - EX 6 0.11 7.5 EX 8.79 - EX 10 0.8 8 EX 11 0.05 7 EX 22 2.36 - EX 12 0.35 12 EX 14 0.75 14 EX 24 0.03 18 EX 0.079 11 EX 21 0.037 - EX 25 0.013 26 EX 26 0.006 30 EX 27 0.170 39 EX 28 0.015 27 EX 29 0.028 18 EX 31 0.055 20 EX 32 0.035 - 25

Claims (8)

1) Compounds of general formula (I): in which R-j represents a group -C = C- [A] - [B] -CORg, -CH = CH- [A] - [B] -CORg, - (CH2) 2- [A] - [B] -CORg, -O- [A] - [B] -CORg, -CH2CO- [A] ] - [B] -CORg, - [A] - representing - a divalent hydrocarbon radical derived from a linear or branched, saturated or unsaturated structure, having del to 12 carbon atoms and from 1 to 6 selected heteroatoms among the oxygen, nitrogen or sulfur atoms, - either a divalent radical derived from a linear or branched, saturated or unsaturated, acyclic hydrocarbon having from 1 to 12 carbon atoms, [B] representing a radical phenyl, a radical CH (Z), or a single bond, Z represents a hydrogen atom, a group (D) Qg-NRaRb, (D) O_g-NH-SO2-Rc, (D) θ-g-NH- CO2-Rc, (D) θ-g-NH-CO-RC, (D) O-g-NH-SO2-NH-Rc, (D) θ. g-NH-CO-NH-Rc, (D) 0-6 "co2'Rg '(d> 0-6" SO2 "Rc' (D) q.6-CO-Rc or (D) O_g-Rc in Where (D) 0 - g is a divalent radical derived from a linear or branched, saturated or unsaturated acyclic hydrocarbon containing from 0 to 6 carbon atoms, Ra, Rb and Rc represent a hydrogen atom, a radical In which Ar represents a carbocyclic aryl group containing from 6 to 18 carbon atoms, a (CH 2) Q 3 Het radical in which Het represents a radical derived from an aromatic or nonaromatic heterocycle, saturated or unsaturated, having from 1 to 9 carbon atoms and from 1 to 160 3 to 5 heteroatoms selected from oxygen, nitrogen or sulfur, a radical (CH2) Q3-Alk in which Alk represents radical derived; of a linear, branched or cyclic, saturated or unsaturated, nonaromatic, hydrocarbon containing from 1 to 12 carbon atoms, the radicals Het, Ar and Alk may be unsubstituted or substituted, or alternatively Ra and Rb; together with the nitrogen atom to which they are bonded represent a saturated or unsaturated, aromatic or nonaromatic nitrogenous heterocycle, optionally containing one or more heteroatoms chosen from oxygen, nitrogen or sulfur atoms, this radical possibly being substituted or unsubstituted, -Rg represents a hydroxyl radical, an O-Alk, O-Ar, NH2, NH-Alk, N (Alk) 2 radical or the residue of an L or D amino acid, Alk and Ar being as defined above and which may be substituted or unsubstituted, - R 2 and R 3, which may be identical or different, represent either a hydrogen atom, a hydroxyl radical, an O-Alk radical or an O- (CH 2) Q 3 -Ar, Alk and Ar radical; being as defined above, or R2 and R3 together form a -O- (CRdRe) nO- ring, n being an integer of 1 to 5, Rd and Reindependently of each other represent an atom of hydrogen, an alkyl radical containing from 1 to 6 carbon atoms, or a phenyl radical, R 4 represents a hydrogen atom, a halogen atom, a hydroxyl, amino, nitro, cyano, CF 3, acyl or acyloxy group containing from 1 to 12 carbon atoms alkyl, alkenyl, alkynyl, alkylthio, alkoxy, alkylamino, dialkylamino, dialkylaminoalkyl, dialkylaminoalkyloxy, in which the term alkyl contains from 1 to 6 carbon atoms, - R5 represents a hydrogen atom, a hydroxyl radical, a halogen atom, an O-Alk radical or a radical O- (CH 2) Q 2 -Ar, Alk and Ar being as previously defined, - G represents either a radical of the formula ## STR1 ## wherein Rh is a hydrogen atom or a hydrogen atom; Alktel group as defined above and (Het ') is a heterocycle of general formula: 10 c (H) in which (H) forms, with the unit N = C-NH-, the remainder of an aromatic or nonaromatic heterocycle, mono or bicyclic, saturated or unsaturated, having 1 to 9 carbon atoms and 2 to 5 heteroatoms selected by the oxygen, nitrogen and sulfur atoms, which radical may be substituted or unsubstituted, ie NRaRb radical (G2 radical), Ra and Rb being as defined above, or a radical (Het) ( radical G3) as defined above, - or a radical -NRh-C (= X) -NHRc (G4 radical), in which X25 is a sulfur, oxygen atom or NH, Rh and Rc are as defined above or - a radical -NRh-SO2Rc, (G5 radical), in which Rh and Rc are as defined above, the dotted lines represent a possible second bond, as well as the addition salts with the acids and the bases and the esters. Rx, r2 and r3 May be in position 8, 9 or 10 of the tricycle, 2) Compounds of general formula (I) as defined in claim 1, having the general formula (! '): 76 011603 In which R '- | _ represents a group -OC- [A'] - [B '] -COR'g, -CH = CH- [A'] - [B '] -COR'g, - (CH2 ) 2- [A '] - [B'] - COR'g, -O- [A '] - [B'] - COR'g, -CH2CO- [A '] - [B'] - COR'g - [A '] - representing an alkylene, alkenylene or alkynylene radical containing from 1 to 6 carbon atoms, [B'] representing a radical CH (Z ') or a single bond, Z' represents a hydrogen atom, a (CH 2) O-6-NRaRb group, (CH 2) O 8 -NH-SO 2 -Rc, (CH 2) O -g-NH-CO2-Rc, (CH 2) O -g-NH-CO-Rc, (CH 2) O -g-NH -SO 2 -NH-Rc, (CH 2) q-g -NH-CO-NH-Rc, (CH 2) O -g-CO2-Rc, (CH 2) θ-g-SO 2 -Rc, (CH 2) O -g-CO-Rc or (CH 2) wherein R, Rb and Rc are as defined in claim 1, R'g represents an OH, amino or alkoxy radical containing from 1 to 8 carbon atoms, optionally substituted with one or more radicals selected from radicals; hydroxy, amino, phenylalkylamino or dialkylamino, R'2 and R'3 represent a hydrogen atom or a methoxy radical, and G is as defined in the claim-tion 1, dotted lines represent a possible second bond, as well as addition salts with acids and bases and esters. 3) Compounds of general formula (I) as defined in claim 1 or 2 wherein Rg represents a group-ment -oh, -och3, -och2ch3, -o- (ch2) 2-oh, -o-ch2-ch ## STR5 ## wherein acids and bases and esters. 4) Compounds of the general formula (I) as defined in claim 1, 2 or 3, wherein R 1 represents a group O- (CH 2) θ g-CH (Z ') -COOH or - (CH 2) ## STR5 ## and addition salts with acids and bases and esters. 5) Compounds of general formula (I) as defined in any one of claims 1 to 4, wherein (Z ') is a hydrogen atom, as well as the addition salts with acids and bases and esters. 6) Compounds of general formula (I) as defined in any one of claims 1 to 4, wherein (Z ') is (CH 2) O-g-NH-CO2-Rc or (CH 2) O-g-NH-Rb , Rb and Rcétant as defined in claim 1, as well as addition salts with acids and bases and esters. 7) Compounds of general formula (I) as defined in claim 6, wherein Rb and Rc are (CH2) 0.3-Ar or (CH2) O3-Alk groups, Ar and Alk being as defined in claim 1 and may be substituted or unsubstituted, as well as addition salts with acids and bases and esters. 8) Compounds of general formula (I) as defined in one of claims 1 to 7, wherein G is a group G4 of general formula -NH-C (= NH) -NHRc, Rc being as defined in claim 1, as well as addition salts with acids and bases and esters. 9) Compounds of general formula (I) as defined in claim 8, wherein Rc is a hydrogen atom, as well as addition salts with acids and bases and esters. 10) Compounds of general formula (I) as defined in one of claims 1 to 7, wherein G is a group NH- (Het '), (Het') being as defined in the claim tion l. 11) Compounds of general formula (I) as defined in claim 10, wherein G represents the following heterocycles: -HN 15 N -HN- N p being an integer of 2, 3 or 4, these heterocycles being substituted or unsubstituted, as well as the addition salts with acids and bases and esters. 12) Compounds of general formula (I) as defined in claim 10 or 11, wherein G is the grouping p being an integer of 2, 3 or 4, as well as addition salts with acids and bases and esters. 13) Compounds of formula (I) as defined in claim 1-tion whose names follow: - 4 - ((4- ((aminoiminomethyl) hydrazono) -9,10-dimethoxy-1, 2.3.4.5.6 acid hexahydro-8-benz (e) azulen-yl) oxy) butanoic acid, 5 - ((4- ((aminoiminomethyl) hydrazono) -9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz (e) azulen-yl) oxy) pentanoic acid 5 - ((4- ((aminoiminomethyl) hydrazono) -8,10-dimethoxy-1, 2,3,4,5,6-hexahydro-9-benz (e) azulen-yl) oxy) pentanoic acid, 79 G11603 - 6- ((4 - ((aminoiminomethyl) hydrazono) -9,10-dimethoxy-1, 2,3,4,5,6-hexahydro-8-benz (e) azulenyl) oxy) hexanoic acid, 7 - ((4 - ((aminoiminomethyl) hydrazono) -9,10-dimethoxy-1, 2,3,4,5,6-hexahydro-8-benz (e) azulenyl) oxy) heptanoic, 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, 5 - ((4 - ((aminoiminomethyl) hydrazono) -9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benzohydrochloride (e) ethyl azulenyl) oxy) pentanoate, - 4 - ((4 - ((aminoiminomethyl) hydrazono) -8,9-dimethoxy-1,2,3,4,5,6-hexahydro-10-benzoic acid ) azulenyl) oxy) butanoic acid, 5 - ((4 - ((aminoiminomethyl) hydrazono) -8,9-dimethoxy-1, 2,3,4,5,6-hexahydro-10-benz (e) azulenyl) oxy) - pentanoic, 5 - ((4 - ((((amino) carbonyl) hydrazono) -9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz (e) azulenyl) oxy) pentanoic acid, - Acid 5 - ((4 - (((amino) thiocarbonyl) hydrazono) -9,10-dimethoxy-1,2,4,4,5,6-hexahydro-8-benz (e) azulenyl) oxy) penta -noique, 4- ((4 - ((aminoiminomethyl) hydrazono) -8,10-dimethoxy-1,2,3,4,5,6-hexahydro-9-benz (e) azulen-yl) oxy) butanoic acid, - 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 hydrochloride, 5 - ((4 - ((aminoiminomethyl) hydrazo-no) -9,10 1,2,3,4,5,6-hexahydro-8-benz (e) azulenyl) oxy) pentanoic acid, - 4 - ((4 - ((4,5-dihydro-1H) -acetate imidazol-2-yl) hydrazono) -9,10-35 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-hexahydroazuleno (5,6-d) -1,3-benzodioxol-4-yl) oxy) pentanoic acid; - ((8 ((Aminomiminomethyl) hydrazono) -2,2-diphenyl-6,7,8,9,10,11-hexahydroazuleno (4,5-e) - (1,3) -benzodioxol-4- yl) oxy) pentanoic acid, 5 - 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-acid, 3,4,5,6 -hexahydro-8-benz (e) azulenyl) oxy) ethanol, - 3 - ((4 - ((4,5-dihydro-1H-imidazol-2-yl) acid hydrazono) -9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz (e) azulenyl) oxy) -pro-panoic 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, 4 - ((4 - ((4,5-Dihydro-1H-imidazol-2-yl) hydrazono) 1,2,3,4,5,6-hexahydro-8-benz (e) azulenyl) oxy) butanoic acid, [4 [(4,5-dihydro-1H-imidazol-2-yl) hydrazono] -9,10-dime-methoxy-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-β-pyrimidinyl) hydrazono] ] 9,10 Dimethoxy-1,2,3,4,5,6-hexahydro-8-benz [e] azulenyl] N - [(phenylmethoxy) carbonyl] DL-homoserine, - (2,3-dihydroxypropyl) ester of 0- (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-quino-leinyl) sulfonyl] DL-homoserine, - O- [4 - [(4,5-dihydro-1H-imidazol-2-yl) monochlorohydrate) 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, - 5 - [(4 - [(4,5-dihydro-4-oxo-1H-imidazol-2-yl) hydra-zona] 9,10-dimethoxy-1,2 acid, 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-Sun 1,2,3,4,5,6-hexahydroxy-4 - [(3a, 4,5,6,7,7a-hexahydro-1H-benzimidazol-2-yl) hydrazono] 8-benz (e) azulenyl] N - [(phenylmethoxy) carbonyl] DL-homoserine. 14) Process for the preparation of the compounds of formula (I) as defined in claim 1, characterized in that a compound of formula (II) is subjected to: Wherein R 2, R 3, R 4 and R 4 are as defined in claim 1 with the exception of hydroxyl or the action of a compound of formula (II) in the presence of a base, Hal- [A] ] - [B] -CORg (Fl) or a compound of formula (F '^) in the presence of a phosphine and diethyl azodicarboxylate: OH- [A] - [B] -CORg (F'-jJ in which Hal is a halogen atom, [A], [B] and Rg are as previously described, [B] may also represent the group -CH-, P being a NH-P group protecting the amine function to obtain a compound of formula (Ilia): (Ilia) either to the action of an activating group and then of a compound of formula (F2) in the presence of a catalyst: ## STR2 ## to obtain a compound of formula (IIIb): (Hib) compounds of formula (Ilia) or (IIIb) which are subjected to the action of a compound of formula (F3): h2n-g (F3) in which G is as defined in claim 1, in order to obtain the compounds of formula (IVa) and (IVb) corresponding to certain products of formula (I): (iva) (IVb) which is optionally, in appropriate order, subjected to one or more of the following reactions: - action of a base or an acid in order to cleave the ester and obtain the corresponding acid, - action of a reducing agent capable of partially reducing all unsaturations, - the action of a hydrating agent of the triple bond, - the action of a dealkylation reagent, - to the action of an agent of deprotection of the NH-P function beta of CO-Rg when [B] represents the group CH-NHP, - to the formation of the group NH-SO2RC, NH-CO2Rc, NHCORc, NH-SO2 -NH-RC, NH-CO-NHRc from the corresponding beta-amine of CORg, to obtain the corresponding compounds of formula (I) which, if appropriate, are subjected to the action of an acid or of a base in order to obtain the corresponding salts or to the action of an esterification agent in order to obtain the corresponding esters. 15) A process for forming the compounds of formula (I) as defined in claim 1, characterized in that ontoumet previously a compound of formula (II) to the action 5 of a compound of formula (F3) in order to obtain a compound of formula (IIIc): compound of formula (IIIc) which is subjected, after the protective case of G, to the action of a compound of formula (Fl), (F'1) or (F2) and, if appropriate, to a reaction of 20 deprotection of G, in order to obtain the corresponding compounds of formula (IVa) and (IVb) which are then subjected, if necessary, to the various reactions as defined in claim 14, the compounds of formulas (II), ), (F'j), (F2), (F3), (IVa) and (IVb) being as defined in claim 14. 16) Process for the preparation of the products of formula (II) as defined in claim 14, wherein R2, R3, R4 and R8 are hydrogen and OH is at the 8, 9 or 10 position, wherein (i) subjecting a compound of formula (a): (Alk) O 85 wherein O- (Alk) is in the meta or para position of the alkylcarboxylic group, (Alk) being as defined in claim 1, to the action of a halogenating agent to obtain the corresponding acyl halide, (ii) which is reacted with a reagent of formula (b): Feel an alkyl group containing 1 to 6 carbon atoms, or R (j) and r (h) together with the nitrogen atom which they are bonded to, represent a 5- or 6-membered saturated or unsaturated heterocyclic ring, optionally containing another heteroatom selected from O and N, to obtain a compound of formula (c): (Iii) subjecting a halogenating agent to a compound of formula (d): (d) wherein Hal represents a halogen atom. (Iv) which is subjected to the action of a Lewis acid, to obtain a compound of formula (e): 011603 86 (Alk) O Ο (e) (v) which is subjected to a dealkylation reagent in order to obtain the product of formula (IIF) corresponding to the product of formula (II) monosubstituted expected: 17) Process for the preparation of the compounds of general formula (II) as defined in claim 14 and wherein R2 is either an OAlk group or a group O- (CH2) Q3-Ar and R2, R4 and R5 are atoms of hydrogen, OH and R2 being in position 8, 9 or 10, characterized in that onsoumet the compound of general formula (a '): In which R2 and O- (Alk) are in the meta or para position of the alkylcarboxylic group, successively to reactions (i), (ii), (iii), (iv) and (v) in order to obtain the product of 87 011603 formula (IIG) corresponding to the product of formula (II) bisubstituted expected: (IIG) 18) Process for the preparation of the compounds of general formula (II) as defined in claim 14 and in which R 2 and R 3 represent a group O- (Alk) or O- (CH 2) q 3 - (Ar), R 4 and R5 are hydrogen atoms, OH being in the 9-position, wherein the compound of Formula (IIA) is subjected to: (HA) 25 to the actioncomposed of a dealkylation reagent, to obtain the formula (IIB): (IIB) compound of formula (IIB) which is subjected either to the action of a diol protecting reagent in basic medium, in order to selectively obtain the product of formula (IIC): (IIC) wherein P represents the remainder of a diol protecting reagent, which is subjected successively to the action of a phenol protection reagent, a diol deprotection reagent, an alkylating agent and then a phenol deprotection agent in order to obtain the compound of formula (IID) corresponding to the product of formula (II) trisubstituted with OH at position 8:20 (IID) or successively a phenol protecting agent, an alkylating agent and then a deprotecting agent in order to obtain the compound of formula (IIE) corresponding to the product of formula ( II) trisubstituted with OH in position 9 19) As a medicament, the compounds of formula (I) as defined in any one of claims 1 to 12, as well as their addition salts and their pharmaceutically acceptable esters. 20) As a medicament, the compounds of formula (I) as defined in claim 13. 21) Pharmaceutical compositions containing as active principle at least one of the drugs defined in claim 19 or 20. 22) As new intermediate products, the compounds of general formulas (Ilia), (IIIb), (IIIc) and (II) as defined in one of Claims 14 to 18 being understood that the compounds of formula (IIc) and the compounds: 10-2,3,5,6-tetrahydro-9,10-dimethoxy-8-hydroxy-benz [e] azul-4-yl (1H) -one, and 2, 3, 5, 6-Tetrahydro-8,9-dimethoxy-10-hydroxy-benz- [e] azulen-4 (1H) -one are excluded. 15