LT4535B - Tricyclic compounds having activity specific for integrins, particulary alpha-gama-beta-3 integrins, method for preparing same, intermediates therefor, use of said compounds as drugs, and pharmaceutical compositions containing same - Google Patents

Description

The present invention relates to novel tricyclic compounds, to processes for their preparation and to intermediates for use in the process, to their use in pharmaceuticals and to pharmaceutical compositions containing them.

The present invention relates to compounds of the general formula (I):

in which

R 1 represents -C = C- [A] - [B] -COR ₆ , -CH = CH- [A] - [B] -COR ₆₎ - (CH ₂ ) ₂ - [A] - [B] -COR ₆ , -O- [A] - [B] -COR ₆ , -CH ₂ CO- [A] - [B] -COR _s , in which [A] represents

- either a divalent linear or branched saturated or unsaturated hydrocarbon radical having from 1 to 12 carbon atoms and from 1 to 6 heteroatoms selected from oxygen, nitrogen or sulfur,

- or a bivalent linear or branched saturated or unsaturated acyclic hydrocarbon radical having from 1 to 12 carbon atoms [B] denotes phenyl, CH (Z) or singly bonded,

Z represents a hydrogen atom, (D) ₀ -6-NRaRb, (D) ₀ s-NH-SO ₂ -Rc, (D) ₀ -6-NH-CO ₂ R, (D) ₀ -6-NH- CO-R (b) ₀ -6-NH-SO ₂ -NH-Rc, (D) ₀ -6-NH-CO-NH-Rc, (D) _{the 0th 6} -CO ₂ Rc, (D) ₀ -6-SO ₂ -Rc, (D) og-CO-Rc, or (D) ₀ . _6- Rc groups wherein (D) ₀ -e contains a divalent linear or branched, saturated or unsaturated acyclic hydrocarbon radical having from 0 to 6 carbon atoms,

Ra, Rb and R represents a hydrogen atom, a (CH ₂₎ 3 O-Ar radical in which Ar represents a carbocyclic aryl group having 6-18 carbon atoms, (CH ₂₎ o-3-Het radical for which Het represents an aromatic or a non-aromatic, saturated or unsaturated heterocycle containing from 1 to 9 carbon atoms and from 1 to 5 heteroatoms selected from oxygen, nitrogen or sulfur, a (CH ₂ ) o-3-Alk radical in which Alk represents a non-aromatic, linear or branched or cyclic , a saturated or unsaturated hydrocarbon radical having from 1 to 12 carbon atoms, and Het, Ar and Alk may be unsubstituted or Ra and Rb together with the nitrogen atom to which they are attached denote aromatic or unsaturated, saturated or unsaturated nitrogen having a heterocycle which may contain one or more heteroatoms selected from oxygen, nitrogen or sulfur and which may or may not be substituted,

- R _s represents a hydroxyl radical, an O-Alk, Ο-Ar radical, NH _2, NH-Alk, N (Alk) _2, or L- or D-amino acid residue, wherein Ak and Ar are as defined above, and may whether or not substituted,

- R ₂ and R _3, identical or different, represent a hydrogen atom, a hydroxyl radical, OA! K radical or an O- (CH _{2) 0-3} -Ar radical, in which Alk and Ar are as defined above or _two R and R ₃ together form a -O- (CRdRe) _n -O- ring wherein n is an integer from 1 to 5, Rd and Re independently of one another represent a hydrogen atom, an alkyl radical having from 1 to 6 carbon atoms , or phenyl radical,

- R ₄ represents a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a nitro group, a cyano group, CF ₃ , an acyl or acyloxy group containing alkyl of 1 to 12 carbon atoms, alkenyl, alkynyl, alkylthio group, alkoxy group, alkylamino group, dialkylamino group containing from 1 to 6 carbon atoms in the alkyl moiety,

- R ₅ represents a hydrogen atom, a hydroxyl radical, a halogen atom, an O-Alk radical or an O- (CH ₂₎ 0- ₃ -Ar radical, Alk and Ar are as defined hereinbefore,

- G represents either a radical of formula G 1 - N - (Het ¹ )

Rh wherein Rh is a hydrogen atom or a (Alk) group as defined above and (Het ') is a heterocycle of the general formula;

C.

(H) wherein (H) forms with an N = C-NH- moiety an aromatic or non-aromatic, mono or bicyclic, saturated or unsaturated heterocycle containing from 1 to 9 carbon atoms and from 2 to 5 heteroatoms selected from oxygen, nitrogen or sulfur, and this radical may or may not be substituted,

- or a NRaRb radical (G2 radical) in which Ra and Rb are as defined above,

- or a (Het) radical (G3 radical) as defined above,

- or -NRh-C (= X) -NHRc (G4) where X is a sulfur atom, an oxygen atom or NH and Rh and Re are as defined above,

- or -NRh-SO ₂ Rc (G5) where Rh and Re are as defined above, the dotted line represents a possible second bond as well as their addition salts with acids and bases and esters.

R 1, R 2 and R ₃ may be in the 8, 9 or 10 position of the tricycle.

The compound of formula (I) encompasses all possible geometric isomers and stereoisomers, individually or in combination.

The group [A] denotes a divalent linear or branched saturated or unsaturated hydrocarbon radical having from 1 to 12 carbon atoms and from 1 to 6 heteroatoms selected from oxygen, nitrogen or sulfur, namely the radicals of alkanes containing some carbon atoms substituted with oxygen or sulfur atoms or C = O, SO, SO ₂ NH, N (Alk), NH-CO, N (Alk) -CO, CO-NH, CO-N (Alk), SO ₂ -NH, SO ₂ - N (Alk) groups in which (Alk) is as defined above. Such radicals can be mentioned in this case;

-CH ₂ -CH ₂ -O-CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -N (CH ₃ ) -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -C (O) -CH ₂ CH ₂ -, -CH ₂ -C (O) -C (Me) ₂ -CH ₂ -.

When - [A] - represents a bivalent linear or branched saturated or unsaturated acyclic hydrocarbon radical having 1 to 12 carbon atoms, it is meant in particular the alkylene radicals of the 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 alkenylene or alkynylene radicals such as -CH = CH-CH ₂ - or OC -CH ₂ -.

When these divalent radicals are branched, radicals such as -CH (CH ₃ ) -, -C (Me) ₂ -, -CH ₂ -C (Me ₂ ) -, -CH (Et) -, -CH may be mentioned. (CMCH) or -C (C = CH) (Et) -.

When [B] represents a divalent -Ph- radical, the COR ₆ group may be in the ortho, meta or para position. Preferably, this group is in a para-position.

When (D) o-6 is a divalent linear or branched saturated or unsaturated acyclic hydrocarbon radical having from 0 to 6 carbon atoms, (D) oe is selected from the values of [Aj] described above. (D) o means that there is no such radical, in other words, is a single covalent bond. Preferably, D is a single bond or a (CH ₂ ) _n group wherein n is an integer selected from 1,2 or 3.

When Ra, Rb and Rc represent a (CH ₂₎ o-3-Ar, (CH ₂₎ o-3-Het, (CH ₂₎ o-3-Alk group, a (CH ₂₎ o 3 represents either a single socket ( In the case of CH ₂ ) ₀ , or -CH ₂ -, - (CH ₂ ) ₂ - or - (CH ₂ ) ₃ - radicals. .

The symbol (Ar) for a carbocyclic aryl group having from 6 to 18 carbon atoms is understood to mean a cyclic aromatic hydrocarbon radical such as phenyl, naphthyl, phenanthrenyl, or a bicyclic or tricyclic fused hydrocarbon containing benzene ring such as indanyl, indenyl. , dihydronaphthyl, tetrahydronaphthyl or fluorenyl. The connector is to the benzene ring. The most suitable radical is phenyl,

The symbol (Het) for an aromatic or non-aromatic, saturated or unsaturated heterocycle having from 1 to 9 carbon atoms and from 1 to 5 heteroatoms selected from oxygen, nitrogen and sulfur means:

- monocyclic heterocyclic radicals such as thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazanyl, pyrolinyl, imidazolinyl, pyrazolinyl, thiazolinyl, triazolyl,

fused heterocyclic rings such as benzofuranyl, benzothienyl, benzothiazolyl, naphtho [2,3-b] thienyl, thiantrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, indolizinyl, isoindolyl, isoindolyl , isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, carbazolyl, beta-carbolinyl, acridinyl, phenazinyl, phenolazinyl, oindinyl, monocyclic heterocycles, such as furo [2,3-b] pyrrole or thieno [2,3-b] furan,

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

In addition, this symbol (Het) includes (Hetj) values as described above.

The symbol (Alk) denoting a non-aromatic, linear or branched chain or cyclic, saturated or unsaturated hydrocarbon, in the case of acyclic hydrocarbons, represents 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-dimethylheptyl or ndecyl, alkenyl radicals such as vinyl, propenyl, isopropenyl, allyl, 2-methylallyl, butenyl or isobutenyl, or alkynyl radicals such as 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 attached represent a nitrogen-containing heterocycle, these are saturated heterocycles such as morpholine, piperidine, piperazine, pyrrolidine, or unsaturated heteroaryls such as pyrimidine, pyridine or pyrazine.

When R ₂ , R _3i R 4 and R 5 represent an O- (Alk) radical having from 1 to 12 carbon atoms, these are primarily methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, alenyloxy or propargyloxy radicals. When R ₂ , R ₃ , R 4 and R 5 represent the radical O- (CH ₂ ) 0-3 -Ar, these are primarily phenylethoxy and phenylpropyloxy radicals.

When R ₂ and R ₃ together form a -O- (CRdRe) _n -O- ring in which n is an integer from 1 to 5, the term "-O-CH ₂ -O, OC (Me ₂ ) -O" OC (Ph ₂ ) -O. R ₂ and R ₃ must be ortho to each other.

When, R ₆ represents Ο-Alk or Ο-Ar, which are substituted or unsubstituted with Alk and Ar, these radicals are, in particular, the following: (C ₁ -C ₈ ) alkoxy, (C ₁ -C ₁₄ ) aryl-C ₁ -C ₆ alkoxy, (C ₆ -) C 1-4 aryloxy, (C ₁ -C ₈ ) alkylcarboxyloxy, (C ₁ -C ₈ ) dialkylaminocarbonylmethoxy, (C 6 -C ₁₄ ) aryl (C ₁ -C ₈ ) dialkylaminocarbonylmethoxy radicals.

When Re represents NH-Alk, NH (Alk) ₂ or NH-Ar, it is primarily C (C ₁ -C 6) alkylamino-, di- (C ₁ -C ₈ ) alkylamino-, (C 6 -C ₁₄ ) aryl- (C ₂ -C ₈ ) alkylamino, (C ₆ -C ₁₄ ) arylamino radicals.

When Re represents an amino acid residue, it may be L- or Daminic acid.

The L- or D-amino acids may be natural or non-natural. Preferred are α-amino acids. For example, such as those described in Houben-Weyl, Methoden der organizchen Chemie, Band XV / 1 and 2, Georg Thieme Verlag, Stuttgart, 1974:

Aad, Abu, yAbu, Abz, 2ABz, sAca, Ach, Acp, Adpd, Ahb, Aib, pAib, Ala, pAla, Aala, Alg, Ali, Ama, Amt, Ape, Apm, Apr, Arg, Asn, Asp, Asu, Aze, Azi, Bai, Bph, Can, Cit, Cys, (Cys) ₂ , Cyta, Daad, Dab, Dadd, Dap, Dapm, Dasu, Djen, Dpa, Dtc, Fel, Gln, Glu, Gly, Guv , hAla, hArg, hCys, hGIn, hGlu, His, hlle, hLeu, hLys, hMet, hPhe, hPro, hSer, hThr, hTrp, hTyr, Hyl, Hyp, 3Hyp, Ile, Ise, Iva, Kyn, Lant, Lcn , Leu, Lsg, Lys, pLys, Alys, Met, Mim, Min, nArg, Nle, Nva, Oly, Orn, Pan, Pec, Pen, Phe, Phg, Pic, Pro, APro, Pse, Pya, Pyr, Pza , Qin, Ros, Sar, Sec, Sem, Ser, Thi, pThi, Thr, Thy, Thx, Tia, Tie, Tly, Trp, Trta,

Tyr, Vai, tert-butylglycine (Tbg), neopentylglycine (Npg), cyclohexylglycine (Chg), cyclohexylalanine (Cha), 2-thienylalanine (Thia), 2,2-diphenylaminoacetic acid, 2- (p-toluyl) -2 -phenylaminoacetic acid, 2- (p-chlorophenyl) aminoacetic acid, as well as 2-pyrrolidineacetic acid, 1,2,3,4-tetrahydroisoquinoline-acetic acid, decahydroisoquinoline-3-acetic acid, octahydroisoquinoline-2-acetic acid, decahydroquinoline-2 -acetic acid, octah: drocyclopenta [b] pyrrole-2-carboxylic acid, 2-azabicyclo [2,2,2] octane-3-carboxylic acid, 2-azabicyclo [2,2,1] heptane-3-carboxylic acid, 2-azabicyclo [3 , 1,0] hexane-3-carboxylic acid, 2-azaspiro [4,4] nonane-3-carboxylic acid, 2azaspiro [4,5] decane-3-carboxylic acid, spiro (bicyclo [2,2,1] heptane) -2, 3pirolidin 5karboksirūgštis-spiro (bicyclo [2.2.2] octane-2,3-pyrrolidine-5karboksirūgštis, 2-tricyclo [4,3,0,1 ^{6 '9]} decane-3-carboxylic acid, decahydrocyclohepta [b ] pyrrole-2-carboxylic acid, decahydrocycloocta [c] pyrrole-2-carboxylic acid, octahydrocyclic clopenta [c] pyrrole-2-carboxylic acid, octahydroisoindole-1-carboxylic acid, 2,3,3a, 4,6a-hexahydrocyclopenta [b] pyrrole-2-carboxylic acid, 2,3,3a, 4,5,7a-hexahydroindole-2- carboxylic acid, tetrahydrothiazole-4-carboxylic acid, isoxazolidine-3-carboxylic acid, pyrazolidine-3-carboxylic acid, hydroxypyrrolidine-2-carboxylic acid, which may be optionally substituted (cf. the following formulas):

N

CO- '

N CO

COCON CON CO8

The residues of the above heterocycles are known, for example, from the following patents or patent applications:

US-A-4,334,949; US-A-4,374,847; US-A-4,350,704; EP-A-29,488; EP-A-31,741; EP-A-46,953; EP-A-49,605; EP-A-49,658; EP-A-50,800; EP-A-51,020; EP-A52.870; 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 amide, for example, methyl ester, ethyl ester, isopropyl ester, isobutyl ester, tert-butyl ester, benzyl ester, ethylamide, semicarbazide or co-amino (C ₂ -C ₈ ) alkylamide.

Finally, the functional groups of these amino acids may be blocked. Suitable protecting groups such as urethane protecting groups, carboxy protecting groups or side chain protecting groups are described in Hubbuch, Kontakte (Merck) 1979, no.3, p. 14-23 and Bullesbach, Kontakte (Merck) 1980, no.1, pp.23-35.

Mention may be made, for example, of Aloc, Pyoc, Fmoc, Tcboc, Z, Boc, Ddz, Bpoc, Adoc, Msc, Moc, Z (NO ₂ ), Z (Hal _n ), Bobz, Iboc, Adpoc, Mboc, Acm, tertbutyl. , Obzl, Onbzl, Ombzl, Bzl, Mob, Pic, Trt.

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

Rh

I (Het ') is a heterocycle having the general formula:

wherein (H) forms, with the N = C-NH- moiety, an aromatic or non-aromatic, mono or bicyclic, saturated or unsaturated heterocycle containing from 1 to 9 carbon atoms and from 2 to 5 heteroatoms selected from oxygen, nitrogen or sulfur, and whether or not substituted, G1 means in particular the following heterocycles:

-HN

-HN

-HN

N '/ where p is an integer from 1 to 4.

- When G is -NR a R b radical (called G2), Ra and Rb can be a hydrogen atom, (CH2) o-3-Ar, (CH ₂₎ o Het 3 or (CH ₂₎ 3 O-Alk radical. Ar, Het and Alk may be substituted by the groups indicated below.

Specifically, G2 may be NH _2, NH-Alk group such as NHMe, NHEt, N (Alk) ₂ group such as NMe _2, Net _2, NMeEt, NH- (CH ₂₎ oi -Ar group such as NHPh, NHCH ₂ Ph, or NHCH ₂ Het such as NHCH ₂ -pyrrol-2-yl.

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

When Ra and Rb, taken together with the nitrogen atom to which they are attached, form a nitrogen-containing heterocycle, the heterocyclic groups described above are primarily and may be unsubstituted.

When G is a (Het) radical (G3) and this radical may or may not be substituted, the above-mentioned heterocycles, in particular the heterocycles of the general formula (Het ') as described above, are intended. When this heterocycle is attached to its nitrogen atom, G2 values are obtained in which Ra and Rb together with the nitrogen atom therein form a heterocycle.

- g is -NRh-C (= X) -NHRc (radical G4), or HRhSO ₂ Rc radical (G5 radical), in which X is sulfur, nitrogen or NH, Rh and Re are as defined above. In particular, -NH-C (= NH) NH ₂ , -NH-C (= O) -NH ₂ or -NH-C (= S) -NH ₂ groups, -NH-C (= NH) -NHCH ₂ -Ar group such as -NH-C (= NH) -NHCH ₂ Ph, -NH-C (= NH) -NHCH ₂ -Het, -NHC (= NH) -NHCH ₂ -Het ', -NH- A C (= NH) -NH-Alk group such as -NHC (= NH) -NHCH ₃ , or a -NH-SO ₂ Ph group, and the Ar, Het, Het 'or Alk groups are substituted or unsubstituted.

Preferably, the substituents on (Alk), (Ar), (Het), (Het ') or on the NRaRb heterocycle are the following radicals:

- halogen: fluorine, chlorine, bromine, iodine,

alkyl, alkenyl, alkynyl containing from 1 to 12 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, vinyl or alenyl. These radicals, as well as substituents, may contain one or more halogens, for example fluorine atoms, e.g. trifluoromethyl.

oxo, cyano, nitro, formyl, carboxy and carboxyalkyl having 1 to 6 carbon atoms, carboxamide,

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

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

- an amino group, an alkylamino group having from 1 to 12 carbon atoms such as methylamino or ethylamino, a dialklamino group having from 2 to 24 carbon atoms such as dimethylamino, diethylamino, methylethylamino and each of these dialkylamino radicals may be in oxidized form,

- aminoalkyl containing from 1 to 12 carbon atoms such as aminomethyl or aminoethyl, dialkylaminoalkyl having from 3 to 25 carbon atoms such as dimethylaminomethyl or ethyl,

- a dialkylaminoalkoxy group having from 3 to 25 carbon atoms, such as dimethylaminoethyloxy group,

- hydroxyl, which may be acylated and then has 1 to 12 carbon atoms, such as acetoxy,

- acyl containing from 1 to 12 carbon atoms such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, succinyl, pivaloyl, benzoyl which may be substituted, for example, by chlorine, iodine or fluorine. Mention may be made of the chloroacetyl, dichloroacetyl, trichloroacetyl, bromoacetyl or trifluoroacetyl radicals,

- a carbocyclic or heterocyclic aryl such as phenyl, furyl, thienyl, pyridinyl, or aralkyl such as benzyl; and the aforementioned halogen, alkyl, alkoxy, alkylthio, aminoalkyl or dialkylamino radicals may also be substituted as substituents.

It is understood that there may be one or more identical or different substituents. In the case of (Het) the substituents may be on the NH group or on the carbon atom.

These substituents also illustrate the description of R ₄ .

It is understood that when R _b R ₂ , R 3, R 4, R ₅ , R ₈ , R a, R b, R e have the alkyl, aryl or heterocycle groups described above, they may be the same or different independently of one another.

The invention also encompasses salts of the compounds of formula (I), such as those formed when the compounds of formula (I) contain an amino group or an aminoguanidine group with hydrogen chloride, hydrogen bromide, nitrate, sulfate, phosphate, vinegar, trifluoroacetate, ants, propane, benzoic acid, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkanesulfonic acids such as methane or ethanesulfonic acids, arenesulfonic acids such as benzene and para-toluenesulfonic acids, and arylcarboxylic acids, The compounds of formula I contain an acidic group, salts of alkali or earth alkaline metals and of ammonium, which may be substituted.

The invention also encompasses esters of compounds of formula (I).

In a first preferred group of compounds, the present invention relates to compounds of general formula (I) as described above, which correspond to general formula (I '):

in which

Rb represents -C = C- [A '] - [B'] - COR'6, -CH = CH- [A '] - [B'] - COR ' ₆₎

- (CH ₂ ) ₂ - [A '] - [B'] - COR ' ₆ , -O- [A ^! ] - [B '] - COR' _6i -CH ₂ CO- [A '] - [B'] - COR ' ₆ groups, - [A'] - denote bivalent alkylene, alkenylene or alkynylene having from 1 to 6 carbon atoms , [B'j represents a CH (Z ') radical or a single bond,

Z 'represents a hydrogen atom, (CH ₂ ) o-6-NR a R b, (CH ₂ ) o-6-NH-SO ₂ -R c, (CH ₂ ) o-6-NH-CO ₂ -R c, (CH ₂ ) ₀ -6-NH-CO-Rc, (CH _{2) 0-6} -NH-SO ₂ -NH-R c,

I (CH ₂₎ o-6-NH-CO-NH-Rc, (CH _{2) 0} -6-CO ₂ -Rc, (CH _{2) 0-6} -SO ₂ -Rc, (CH _{2) 0th} -CO-R ₆ or (CH _{2) 0} -6-R group in which R a, R b and R e are as defined above, _R's are OH radical, amino or alkoxy having 1-8 carbon atoms, optionally substituted with may be one or more radicals selected from hydroxy, amino, phenyl, alkylamino or dialkylamino,

R ' ₂ and R' ₃ represent a hydrogen atom or a methoxy group, o

G is as described above, the dotted lines represent the possible second linkage, as well as their addition salts with acids and bases and their esters.

In a second preferred group of compounds, the present invention relates to compounds of the general formula (i) described above, wherein R e represents -OH, -OCH ₃ , -OCH ₂ CH ₃ , -O- (CH ₂ ) ₂ -OH, -O- CH ₂ -CH (OH) -CH ₂ OH, -O- (CH ₂ ) ₂ NH ₂ , -O- (OH ₂ ) ₂ -N (CH ₃ ) _{2 i} -NH _2, or -O- (CH ₂ ) - phenyl groups, as well as their addition salts with acids and bases and their esters.

The third group of compounds which is preferred, the invention is of general formula (I) compounds of general formula where R represents -O- (CH _{2) 0} -6CH (Z ') - COOH or - (CH _{2) 0} .7-CH (Z ') - COOH groups, as well as their addition salts with acids and bases and their esters.

In a fourth preferred group of compounds, the present invention relates to compounds of general formula (I) as described above wherein (Z ') is a hydrogen atom, as well as their addition salts with acids and bases and their esters.

In a fifth preferred group of compounds, the present invention relates to compounds of general formula (I) as described above wherein (Z ') is (CH ₂ ) ₀ -6-NH-CO ₂ -R c or (CH ₂ ) ₀ -NHR b. , wherein Rb and Re are as described above, as well as their addition salts with acids and bases and their esters.

In a sixth preferred group of compounds, the present invention relates to compounds of general formula (I) as described above wherein

Rb and Re represent (CH ₂ ) q. A _3- A group wherein Ar is as defined above and may or may not be substituted, as well as their addition salts with acids and bases and their esters.

In a seventh preferred group of compounds, the present invention relates to compounds of the general formula (I) as described above, wherein G is a group G 4 of the formula -NH-C (= NH) -NHRc and Re is as described above, and their addition salts with acids and bases and their esters.

In an eighth preferred group of compounds, the present invention relates to compounds of the general formula (I) as described above, wherein G is a group G4 of the formula -NH-C (= NH) -NH 2, and addition salts thereof with acids and bases. their esters.

In a ninth preferred group of compounds, the present invention relates to compounds of the general formula (I) above, wherein G is -NH- (Het ') as defined above, namely;

O

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

In a tenth preferred group of compounds, the present invention relates to compounds of general formula (I) above wherein G is;

- c (CH ₂ ) P

An NH ⁷ group wherein p is an integer equal to 2, 3 or 4 as well as their addition salts with acids and bases and their esters.

Within the eleventh preferred group of compounds, the present invention relates to compounds of the general formula (I) as described above, which are as follows:

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

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

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

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

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

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

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

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

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

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

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

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

6 - ((4 - ((4,5-Dihydro-1H-imidazol-2-yl) hydrazono) -9,10-dimethoxy-1,2.3.4.5.6-hexahydro-8-benz (e) azijlenyl) oxy) hexane acid,

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

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

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

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

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

4 - ((9,10-dimethoxy-4 - ((1,4,5,6-tetrahydro-2-pyrimidinyl) hydrazone) 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 ) acetic acid,

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

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

O- [4 - [(4,5-dihydro-1H-imidazol-2-yl) hydrazono] -9,10-dimetoksi1,2,3,4 _r 5,6-hexahydro-8-benz [e] azulenyl] -N - [(phenylmethoxy) carbonyl] -DL · homoserine,

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

O- [4 - [(1,2,3,4-Tetrahydro-6-pyrimidinyl) hydrazono] -9,10-dimethoxy-1,2,3,4,4,5,6-hexahydro-8-benz [e] azulenyl] -N- [ (phenylmethoxy) carbonyl] -DLhomoserine,

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] -DLhomoserine 2,3-dihydroxypropyl ester,

O- [4 - [(4,5-Dihydro-1H-imidazol-2-yl) hydrazono] -9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz (e) azenyl] -N - [(8-quinolinyl) sulfonyl] -DL · homoserine,

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

5 - [[4 - [(4,5-Dihydro-4-oxo-1H-imidazol-2-yl) hydrazono] -9,10-dimethoxy-1,2,3,4,4,5,6-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) hydrazone] - 8-benz (e) azuenyl] -N - [(phenylmethoxy) carbonyl] -DL-homoserine,

O- [9,10-Dimethoxy-1,2,3,4,5,6-hexahydro-4 - [(3a, 4,5,6,7,7a-hexahydro-1 H -benzimidazol-2-yl) hydrazone] - 8-Benz (e) azulenyl] -N - [(phenylmethoxy) carbonyl] DL-homoserine.

The present invention also relates to a process for the preparation of compounds of the general formula (I) characterized in that the compound of the formula (II):

wherein R ₂ , R 3, R ₄ and R 5 are as defined above, except for hydroxyl, either in the action of a compound of formula (F 1)

Hal- [A] - [B] -COR ₆ (F1) in the presence of a base or a compound of the formula (FR):

HO- [A] - [B] -COR ₆ (F'i) in the presence of phosphine and diethyl azodicarboxylate, where Hal is a halogen atom, [A], [Bj and R _s are as described above,

- CH -

I [B] can also be an ^NH_P group, wherein P is an amino protecting group to form a compound of formula (IIaa):

or activates a group, then acts with a compound of formula (F2):

O

H - C = C - [A] - [B] - C - R ₆ (F 2) in the presence of a catalyst to form a compound of formula (IIIb):

then, reacting the compounds of formulas (IIIa) and (IIIb) with a compound of formula (F3): H ₂ NG (F3), wherein G is as described above, to give compounds of formulas (IVa) and (IVb) certain formulas (I)

(IVa),

(IVb) then optionally treated with a base or an acid, if necessary, to reduce an ester and to obtain the corresponding acid, a reducing agent suitable for partial or total reduction of unsaturated bonds, a triple hydration agent, a dealkylation agent, acts as a deprotecting agent for the NH-P group in the beta position relative to the CO-R ₆ group, where [B] represents CH-NHP, introduces NH-SO ₂ Rc, NH-CO ₂ Rc, NHCORc, NH-SO ₂ -NH -R c, NH-CO-NHRc group starting from the corresponding amino group of a beta position of CO-R ₆ in the group, and receives the corresponding formula (I) compounds which, if appropriate, an acid or base to give the corresponding salts, or acts as an esterification agent to obtain the corresponding esters.

The reaction of the compound of formula Hal- [A] - [B] -COR ₆ (F1) is preferably carried out in the presence of a mineral base such as potassium carbonate or sodium carbonate in a dipolar aprotic solvent such as dimethylformamide. Preferably, Hal is a chlorine or bromine atom.

The reaction of the compound of formula HO- [A] - [B] -COR _S (F'i) 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.

Prior to treatment with a compound of formula HC = C- [Aj- [B] -COR ₆ (F2), group activation such as by treatment with (CF ₃ SO ₂ ) ₂ O triflic anhydride in the presence of a base such as pyridine to give the corresponding (OSO ₂₎ CF ₃ ), followed by reaction with a palladium (Pd °) derivative such as Pd (PPh ₃ ) 4.

The NH ₂ -G (F3) reaction is carried out either in the absence of a solvent or in an alcohol such as ethanol or butanol. Sinton NH2-G can also be used in the form of a salt such as its hydrochloride or hydrobromide.

The saponification reaction of the ester group is carried out, for example, with an alkali such as sodium or potassium alkali, in tetrahydrofuran, or in a lower alcohol such as methanol or ethanol. The ester may also be cleaved in acidic media by methods known to those skilled in the art.

The reduction of unsaturated bonds may be accomplished either completely by hydrogen in the presence of a catalyst such as palladium on carbon or by a rhodium catalyst such as Wilkinson's reagent or partially (alkynylene is converted to alkenylene) by treatment with a poisoned catalyst such as palladium on barium sulfate, poisoned with pyridine or triethylamine.

The hydration reaction affording the -CH ₂ CO- [A] - [B] -COR ₆ group leaving the -C = C- [A] - [B] -COR ₆ group is preferably carried out with water in the presence of mercury sulfate.

The dealkylation reaction to give compounds of formula (I) with R 2, R 3, R ₄ or R ₅ hydroxyls is carried out in the presence of aluminum chloride or boron tribromide.

The introduction of functional groups into the NH ₂ group at the alpha position relative to the COR ₆ group, when [B] represents CH-NH ₂ or CH-NH ₂ .HCl, is accomplished by conventional methods known in organic chemistry.

The Rc group of the NHSO ₂ R ₂ leaving the corresponding amine is preferably obtained by the action of RcSO ₂ Hal in the presence of a base such as triethylamine.

The Rc group of NHCO ₂ leaving the corresponding amine is preferably obtained by treatment with RcOH according to J. Org. Chem., 61, 3929-3934, by first treating the triiosgene with sodium bicarbonate to prepare the intermediate isocyanate.

Salts can be reacted under normal conditions. For example, the reaction is carried out in the presence of a sodium salt, such as sodium carbonate or acidic sodium or potassium carbonate, to provide the terminal H ₂ salt of Ri.

Similarly, acid addition of amino or aminoguanidine groups which may be present on the G moiety is carried out under conventional conditions. For example, the reaction with hydrochloric acid is carried out, for example, in an ethereal solution.

Possible product esterification is carried out under conditions known to those skilled in the art.

The reaction is usually carried out using an acid of formula (I) or a functional derivative thereof with a reagent capable of introducing ester groups, which are not exhaustively listed above for R ₆ .

The compounds of the general formulas (F1), (F'1), (F2) and (F3) are known or may be prepared by methods known to those skilled in the art.

Alternatively, the order of attachment of the various reagents may be interchanged, namely to act on the compound of formula (II) with the compound of formula F3 to afford the intermediate of formula (IIIc):

which is then treated with a compound of formula (F1), (F'1) or (F2) to give the corresponding products of formulas (IVa) and (IVb).

In this case, it will be necessary to provide for the blocking of group G of the product of formula (IIIc), if necessary, followed by deprotection of (F1), (F'1) or (F2) by methods known to those skilled in the art (TW Greene, Protective Groups in Organic Synthesis .John Wiley and Sons Ine. 1991).

The deprotection of the NH-P group in the beta position relative to CO-R ₆ , where [B] represents a CH-NHP group, is known to those skilled in the art, namely, when P is CO ₂ tBu, a decarboxylation reaction, for example, with hydrochloric acid.

Bones are all the time in a dynamic process that involves bone resorption and bone formation. These processes are mediated by specialized cells. Bone formation is the result of the formation of a mineral matrix deposited by osteoblasts, and bone resorption is the result of the dissolution of this bone matrix by osteoclasts. Osteoporosis is characterized by dry decay of this bone matrix. When attached to the bone matrix, mature activated osteoclasts through the secretion of proteolytic enzymes and protons in the adherent zone cause bone surface depressions or protrusions that occur when the osteoclast detaches from the bone.

The compounds of formula (I) and their pharmaceutically acceptable addition salts possess interesting pharmacological properties. These compounds inhibit bone resorption mediated by osteoclasts.

Thus, the compounds of the present invention are useful in the treatment of diseases associated with bone matrix loss, namely osteoporosis, malignant hypercalcaemia, osteopenia due to bone metastases, periodontitis, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, Paget's disease, osteoporosis, or female hormone deficiency.

They can also be used to treat inflammatory diseases, cancers and cardiovascular diseases including atherosclerosis, relapse of stenosis.

In addition, they may be used as inhibitors of angiogenesis; thus, they are useful in the treatment of tumors by inhibiting the formation of their new blood vessels, in the treatment of diabetic retinopathy and nephropathy.

Recent studies have shown that osteoclast fixation is mediated by receptors, the integrins.

Integrins are a family of receptors that mediate cell / cell, or more specifically, cell / matrix, adhesion processes that include a2bp3 as a platelet receptor (fibrinogen) and ανβ3 as a vitronectin receptor, bone sialoproteins such as osteopontin and thrombospondin.

These receptors, which are protein heterodimers composed of two subunits a and β, have sites for attachment of divalent ions such as Ca ²⁺ and their ligand recognition site, which is determined by the qualitative composition of their subunits.

The σ.νβ3 receptor is a transmembrane glycoprotein that is expressed in a variety of cells, including endothelial cells, smooth muscle cells, osteoclasts, and cancer cells, and enables the compounds of this invention to be used for a variety of purposes.

ανβ3 receptors, which occur on osteoclast membranes, are at the core of the adhesion / resorption process, contribute to the cellular cytoskeleton organization, and are involved in osteoporosis (Ross.et et al., J. Biol. Chem., 1987, 262, 7703).

ανβ3 receptors, which occur in aortic smooth muscle cells, stimulate their migration to the new inner vascular sheath; it causes atherosclerosis and the occurrence of relapses of stenosis after angioplasty. (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.

Thus, ανβ3 integrin antagonists may induce regression of cancerous tumors by inducing angiogenic vascular apoptosis (Brook et al. Cell (1994) 79, 1157).

All natural α.νβ3 integrin ligands contain an RGD (Arg-Gly-Asp) moiety. Peptides containing this fragment of RGD and antibodies to ανβ3 are known for their ability to inhibit dentin resorption by preventing the adhesion of osteoclasts to mineralized matrices (Horton et al., Exp. Cell. Res. (1991) 195, 368).

The peptide echistatin isolated from snake venom, also containing an RGD fragment, has been described as an inhibitor of osteoclast adhesion to bone and is therefore a potent inhibitor of bone resorption in tissue cultures in vitro (Shato et al., J. Cell. Biol. (1990), 111). , 1713) and in in vivo rat studies (Fisher et al., Endocrinology (1993) 132, 1441).

Compounds of formula (I), their addition salts and their pharmaceutically acceptable esters may exhibit affinity for the vitronectin ανβ3 receptor or other integrins containing vitronectin (ανβ1, ανβ5, α2bβ3) by inhibiting binding to their natural ligand.

This property makes the compounds of the invention useful for the prophylaxis or treatment of diseases in which pathology is caused by ligands or cells interacting with the vitronectin receptor.

These compounds may also exhibit activity against other integrins by interacting with their ligand via the tripeptide RGD sequence, which provides these compounds with useful pharmacological properties and renders them useful in the treatment of pathologies associated with these receptors.

This activity against integrins makes the compounds of the present invention useful in the treatment of many diseases such as those described above or in the review of Dermot Cox DN&P 8 (4) May 1995, 197-205, which is appended to this application.

Thus, the present invention relates to the use of compounds of formula (I), their addition salts and their pharmaceutically acceptable esters for use in medicine.

Among the compounds of the present invention as medicaments, particular mention should be made of the compounds described in the experimental part.

Among these products for pharmaceutical use, the present invention relates in particular to the compounds of formula (I) listed above.

The dose of the compound will vary depending on the disease being treated and the route of administration: for example, oral administration in adults may vary from 1 mg to 1000 mg per day.

The invention also encompasses pharmaceutical compositions containing as active ingredient at least one of the above described pharmaceutical compounds.

The compounds of formula (I) are administered orally, parenterally or topically, for example percutaneously. They may be administered in the form of plain tablets, dragees, gelatin capsules, granules, suppositories, beads, injectables, ointments, creams, gels, microparticles, nanoparticles, implants, patches in conventional dosage forms,

The active ingredients in these pharmaceutical compositions may be formulated with conventional excipients such as talc, gum arabic, lactose, amidone, magnesium stearate, cocoa butter, aqueous or non-aqueous diluents, animal or vegetable fats, paraffin derivatives, glycols, various dispersants or emulsifiers, preservatives.

Formula (II) products in which a hydroxyl radical is in position 10, R _{2-8-position,} and R _3-9-position denoting -O- (Alk) or O (CH _{2) 0-3} -Ar groups R ₄ and R ₅ are hydrogen atoms, were prepared according to the procedure described in European Patent Application Ser. 0729933 and Experimental Part 2 (Preparation 2).

The other two position isomers can be prepared as follows:

Compound of Formula (HA):

(HA) treated with a dealkylation reagent to give a compound of formula (IIB):

which is affected:

or a diol blocking agent in an alkaline medium to selectively form a product of formula (IIC):

I

wherein P is the residue of a diol blocking reagent, which is then treated successively with a phenol blocking reagent, a diol deprotecting agent, an alkylating agent and then a phenol deprotecting reagent to give a compound of formula (IID) corresponding to the triple product of formula (II) in position:

or by treatment successively with a phenol blocking agent, an alkylating agent, followed by a deprotecting agent to give a compound of formula (HE) corresponding to the tri-substituted product of formula (II) with an OH group at position 9:

Of alkylation reagents, agents such as boron tribromide or aluminum chloride are preferred.

By the diol blocking reagent acting on the products of formula (II) is meant a boron derivative such as boric acid, a trialkylborate such as trimethyl or triethylborate, as well as borax.

By phenol blocking agent is meant in particular a halide such as methanesulfonyl- or 4-methylbenzenesulfonyl chloride or bromide and a benzyl derivative such as benzyl 4-methylbenzenesulfonate or methanesulfonate.

By diol deprotecting agent is meant in particular a strong acid such as hydrochloric, sulfate or p-toluenesulfonic acid, or an oxidizing agent such as hydrogen peroxide if blocked with a boron derivative.

The alkylating agent is understood to mean any classical agent known to those skilled in the art for alkylation of phenols. Examples include alkyl halide such as methyl or ethyl chloride, alkyl sulfate such as methyl or ethyl sulfate, and diazomethane.

The unblocking agent is understood to mean a base such as sodium hydroxide, potassium hydroxide as well as sodium or potassium carbonate.

The monosubstituted products of formula (II) wherein R ₂ , R 3, R 4 and R 5 represent hydrogen are prepared according to a procedure analogous to that described in European patent application no. 0729933:

Compound (I) of Formula (a):

wherein O- (Alk) is in the meta or para position with respect to the alkyl carboxy group, (Alk) is as defined above, treated with a halogenating agent to form the corresponding acyl halide, (ii) which is treated with a reagent of formula (b):

R {0 \ z · / ^N A

R (II) ^zv (b), wherein R (II) and R (II), the same or different, represent an alkyl group having from 1 to 6 carbon atoms, or R (II) and R (II) together with a nitrogen atom, to which they are attached represents a 5- or 6-membered, saturated or unsaturated heterocycle which may contain another heteroatom selected from O and N to form a compound of formula (c):

(Alk) O

(iii) which is treated with a halogenating agent to form a compound of formula (d):

wherein Hali represents a halogen atom (iv) which is treated with Lewis acid to form a compound of formula (e):

(v) subjecting to the dealkylation reagent and finally obtaining the product of formula (IIF) corresponding to the expected mono-substituted product of formula (II):

Substituted formula (II) wherein R ₂ represents O- (Alk) or O- (CH ₂ ) ₀ -3 -Ar, R ₃ , R 4 and R 5 are hydrogen and OH, and R ₂ is 8-, 9- or At position 10, the products were prepared according to the procedure described above, starting from a compound of the formula (aj:

wherein O- (Alk) and R ₂ are in the meta or para position with respect to the carboxyalkyl chain, R ₂ is O- (Alk) or O- (CH ₂ ) ₀ -3 -Ar in the sequence (i), (ii) ), (iii), (iv) and (v) to give products of formula (IIG) which correspond to the expected disubstituted products of formula (II):

The halogenating agent which acts 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 to obtain acid anhydrides.

The reagent of formula (b) is prepared from cyclopentanone and a secondary amine such as diethylamine, ptperidine, piperazine or preferably morpholine. The reaction is carried out in the presence of a strong acid such as para-toluenesulfonic acid as a catalyst.

The reaction of the enamine of formula (b) with an acid halide anhydride is preferably carried out in the presence of a tertiary amine such as triethylamine or pyridine.

The halogenating agent acting on the compound of formula (c) or a substituted equivalent of formula (c ') may be, for example, thionyl chloride, phosgene, phosphorus oxychloride or preferably oxalyl chloride.

The lysic acid used to cyclize the compound of formula (d) or its substituted equivalent of formula (d ') is, for example, aluminum chloride, titanium tetrachloride, or preferably ferric chloride, or tin tetrachloride. This reaction, as well as the above, may be carried out, for example, in a halogenated solvent such as methylene chloride, chloroform or dichloroethane.

The preferred dealkylation reagent for a compound of formula (e) or a disubstituted equivalent of formula (e ¹ ) to give the corresponding phenols is aluminum chloride or boron tribromide.

The products of formula (II) wherein R ₄ is not a hydrogen atom have been prepared by classical methods of electrophilic and nucleophilic substitution in the aromatic ring known to those skilled in the art.

The products of formula (II) wherein R ₅ is not a hydrogen atom have been prepared by methods known to those skilled in the art, in particular in European Patent Application Ser. 0729933, by halogenation followed by treatment with water or the corresponding alcohol.

The products of formula (II) wherein R ₅ is a hydrogen atom and the double bond is in the 1-2 position have been prepared by methods known to those skilled in the art, in particular in European patent application no. 0729933, dehydration or dealkoxylation in anhydrous acidic medium.

The products of formula (II) in which the bond between the 5-membered ring and the 7-membered ring are saturated were prepared by classical hydrogenation techniques, namely by hydrogenation of the corresponding double bond palladium on carbon.

It is desirable to carry out the R ₄ , R ₅ introduction and hydrogenation reactions with compounds of formula (HA), (IID), (HE), (IIF) or (IIG).

The products of formula (II) wherein R ₂ and R ₃ , which are ortho to each other, form a -0- (CRdRe) _n -0 ring as described above are also prepared by methods known to those skilled in the art, in particular in the experimental section below. way.

It is also an object of the invention to use as intermediates compounds of formulas (IIIa), (IIIb), (IIIc) and (II), it being understood that the compounds of formula (IIc) and the following compounds:

2,3,5,6-tetrahydro-9,10-dimethoxy-8-hydroxy-benz [e] azulen-4 (1H) -one and 2,3,5,6-tetrahydro-8,9-dimethoxy-10- hydroxybenz [e] azulene-4 (1H) -one is illegible. The synthesis of these two compounds is given in the experimental section below.

The following examples illustrate the invention without limiting it.

PREPARATIVE EXAMPLE: 2,3,5,6-Tetrahydro-8,9,10-trihydroxybenz [e] azulen-4- (1H) -one

A: 3,4,5-trimethoxybenzenepropanoic acid To a solution of 21.44 g of 3,4,5-trimethoxyphenylpropenoic acid in 45 ml of water is added 6.8 g of potassium carbonate, and the solution is kept at 1200 to 1300 mbar for one hour, in 1.8 g of 10% palladium on activated carbon until absorption of 2.1 L of hydrogen. Filter, wash with water and acidify with 50 ml of hydrochloric acid (2N). Suction, rinse with water and dry under reduced pressure at room temperature. 19.8 g of the expected product are obtained (m.p. 102-103 ° C).

IR (CHCl _3):

Carbonyl: {1712 cm ' ¹ (max) aromatic: {1592 cm {1740 cm' ¹ (fold)

NMR (CDCl _3):

2.69 (t)} = C-CH ₂ -CH ₂ -CO 2.91 (t)} |

6.43 (s) 2H aromatic 10.50 (m) 1H mobile {1510 cm

3.83 (s)} 3 H ₃ CO-C = 3.85 (s)} I

Step B: 3,4,5-trimethoxybenzenpropanoyl chloride

A solution of 6 g of the product of Step A in 21 ml of methylene chloride is dried over 1.5 g of magnesium sulfate, filtered and after cooling to 5 ° C, 2.2 ml of thionyl chloride is added, followed by stirring for 20 hours. at room temperature. It is evaporated to dryness under reduced pressure, twice treated with cyclohexane to give 6.46 g of the desired product (m.p. 60 ° C).

Stage C and 2- [3- (3,4,5-trimethoxyphenH) -1-oxopropH] -cyclopentanone

A solution of 2.4 ml of 1- (N-morpholinyl) cyclopentene obtained according to the procedure described below, 2.31 ml of triethylamine and 15 ml of methylene chloride was cooled to 5 ° C over 1 hour. 30 min Add a solution of 4.27 g of the product obtained in Step B in 15 ml of methylene chloride at + 5 ° C. Stir for 1 h at + 5 ° C, then allow to rise, add 10 ml of 2N hydrochloric acid and stir for 1 h. at room temperature, decant, wash with water and then with saturated sodium bicarbonate solution, dry, filter and evaporate to dryness under reduced pressure. 5 g of the expected product are obtained. The crude product is purified by dissolving 10 volumes of ethyl acetate, extracting with 1N sodium hydroxide solution, washing the alkaline phase with ethyl acetate, acidifying to pH 1 with concentrated hydrochloric acid, extracting with methylene chloride, drying and evaporating to dryness under reduced pressure. 2.75 g of purified product are obtained.

IR spectrum (CHCl3):

Carboniferous; {1741 cm ' ¹ aromatic: {1592 cm' ¹ {1709 cm ' ¹ {1509 cm' ¹

Carboniferous: {1658 cm ' ¹ {-1610 cm' ^{1 in} chelate with OH form.

NMR Spectrum (CDCl ₃ );

6.41 (s) 2H arom. (integration reference point)

3.81 (s) 3.82 (s)} total 9H

3.83 (s) 3.85 (s)} 4 types of CH ₃ OC =

1.86 (m) CH ₂ -CH ₂ -CH ₂ ~ 1.5H

I, 95-2.95 (m) total ~ 7.5H, various types = C-CH ₂

3.26 (t) -0,4H, CO-CH-CH ₂

CO

II, 2 (wide m), H, agile

Preparation of 1- (N-morpholine H) cyclopenten used in Step C

A solution of 100 ml of cyclohexane, 20 ml of cyclopentanone, 50 ml of morpholine and 100 mg of para-toluenesulfonic acid was stirred and refluxed for 4 hours. 30 minutes to remove water. Evaporation of the solvent under reduced pressure gave a distillation of 12-13 mbar to give 27.44 g of the desired product (boiling point 83 ° C).

Step D: 1- (2-Chloro-1-cyclopenten-1-yl) -3- (3,4,5-trimethoxyphenyl) -propan-1-one J To a solution of 23 g of the product of Step C in 230 ml of chloroform is added at room temperature. 13 ml of oxalyl chloride. Stir in 3 or. at room temperature, concentrated under reduced pressure with two cyclohexane treatments. 28 g of a crude product are obtained which is recrystallized from 50 ml of a mixture of cyclohexane and 50 ml of diisopropyl ether by partial concentration. Vacuum, wash with diisopropyl ether and dry under reduced pressure to give 16.24 g of the expected product (mp 93 ° C).

IR (CHCl _3):

1659 cm ^-1 : carbonyl

1599 cm ^-1

1586 cm ^-1 ; C = C + aromatic

1508 cm ^-1

NMR (CDCl _3):

1.93 (m): Central CH ₂

2.69 (m) -2.81 (m): C-CH ₂ -C = cyclopentene

2.85 (t, J = 7.5) - 3.08 (t, J = 7.5): others = C-CH ₂ -C

2.44: CH ₃ -C =

3.68-3.81: OCH ₃

6.59-6.68 (d, J = 2): CH = aromatic interacting with meta 7.31-7.80 (d, J = 8): aromatic

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

900 mg of the product of Step D, 9 ml of 1,2-dichloroethane and 0.9 ml of tin chloride are stirred at room temperature for 20 hours. 9 ml of water and ice are then added, rinsed off, washed with water, extracted once with methylene chloride, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure to give 1 g of the crude product which is purified by chromatography on silica eluting with cyclohexane. 10% ethyl acetate followed by 25% ethyl acetate. Concentration gives 700 mg of product which crystallizes from 5 ml of n-hexane; The mixture is cooled to 0 ° C, suctioned, the crystals are washed with a minimum amount of n-hexane, dried under reduced pressure at room temperature to give 630 mg of the desired product (mp 101-102 ° C).

NMR (CDCl _3):

1.86 (m) Central CH ₂ 2.65 (dd) 2H}

2.72 (t) 2H} others CH ₂

2.84 (dd) 2H}

3.06 2H}

6.59 (s) aromatic H

3.84}

3.86} OMe 3.90}

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

The reaction is carried out as described in Preparation Example Ibis, Step B, to afford the expected demethylated product.

PREPARATIVE EXAMPLE 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-trimethoxy-benz [e] azulen-4 (1H) -one in Preparation 2, 600 ml 1,2-dichloroethane, 342 ml 2N sodium of alkali, 1.2 g of tetrabutylammonium and 33 ml of dimethyl sulphate are stirred for 2 hours. 30 min At 20 ° C. Thereafter, 39 ml of triethylamine are added to destroy the excess dimethyl sulphate and the mixture is stirred for one hour at 20 ± 2 ° C. Add 342 ml demineralized water, stir for 15 min. At 20 ± 2 ° C, discard and extract the aqueous phase twice with 120 ml of 1,2-dichloroethane. The 1,2-dichloroethane phases are mixed and washed with 4 x 240 mL of demineralized water followed by 1 x 300 mL of 1N hydrochloric acid followed by 3 x 240 mL of demineralized water (until neutral). The combined organic phases are dried over sodium sulfate, filtered and concentrated under normal pressure at 83 ° C to 480 ml.

Step B: 2 _L 3,5,6-Tetrahydro-8,9,10-trihydroxy-benz [e] azulen-4 (1H) -one

480 ml of the solution obtained in Step A and 102.3 g of anhydrous aluminum chloride are refluxed for one hour. The mixture is cooled to 0 ± 2 [deg.] C. and then, after two hours, the mixture is cooled to about 0 [deg.] C. with 600 ml of demineralized water and 192 ml of pure (concentrated) sulfuric acid, maintaining the reaction temperature below 20 [deg.] C. Within 5 minutes Add 300 ml of demineralized water at 20 ± 2 ° C and mix for 16 hours. At 20 ± 2 ° C, suction, wash twice with 60 ml of 1,2-dichloroethane followed by demineralized water, dry under reduced pressure to give 52.2 g of the desired product.

PREPARATIVE EXAMPLE: 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 reaction is carried out as in Preparation 1, Step A, using 29.76 g of 43.5 g of 3,4-dimethoxy-5 - [[[(4-methylphenyl) sulfonyl] oxy] phenyl] cinnamic acid, the synthesis of which is given below. potassium carbonate, 60 ml methanol and 1.48 g 10% palladium on activated carbon. 28.23 g of the expected product are obtained in the form of colorless crystals (m.p. 148-149 ° C).

UV spectrum (EtOH):

For M = 380.4 maximum 226 nm ε = 22100 curvature 263 nm ε = 2000 curvature 269 nm ε = 2400 maximum 274 nm ε = 2800 curvature 279 nm ε = 2500 curvature 307 nm ε = 450

NMR Spectrum (CDCl ₃ ): 2.45 (s) CH ₃ 2.61 (m) = C-CH ₂ -CH ₂ -C =

2.86 (m)

6.61 (d, J = 2)

6.65 (d, J = 2) H ₄ H _s

3.68 (s) 2 CH ₃ OC 3.81 (s)

7.32 (d1) H ₃ Hs 7.80 (d1) H ₂ H ₆

Stage B and: 3,4-Dimethoxy-5 - [[(4-methylphenyl) sulfone] oxy] benzenepropanoic chloride

The reaction is carried out as in Preparation 1, Step B, using 1.9 g of the product of Step A, 9.5 ml of methylene chloride and 0.7 ml of thionyl chloride. 2.24 g of the expected product are obtained, which product is used as is in the following stage.

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

The reaction is carried out as in Preparation 1, Step C, starting from 2.24 g of the chloro-anhydride obtained in Preparation B and using 770 mg of 1- (N-morpholinyl) -cyclopentene (prepared in Preparation 1, Step C), 6 ml . Recrystallization from diisopropyl ether gives 1.27 g of the desired product (m.p. 84 ° C).

IR (CHCl _3):

Carbonyl: {1742 cm ' ¹ O-SO ₂ {1374 cm' ¹ 1178 cm ' ¹ {1709 cm' ¹

C = C + Aromatic {1658 cm ' ¹ 1608 cm' ¹ 1599 cm ' ¹ 1586 cm' ¹ 1508 cm ' ¹

NMR (CDCl _3):

2.44 (s) CH ₃ -O

3.67 (s)} 2 OCH ₃

3.79 (s) 3.81 (s)}

6.59-6.65 (m) 2H aromatic at ortho position to O. 7.32 (d1) H ₃ H ₅ 7.89 (dl) H ₂ H ₆

13.58 (m, broad) OH in enol form

1.8-3.4 (m) 10-11 H other protons

UV spectrum:

- EtOH (+ dioxane) for M = 446.52 peak at 225 nm ε - 23000 peak at 282 nm ε = 7900 curves, 270, 277, 290, 300, 313 nm.

- EtOH (NaOH, 0.1 N) peak at 310 nm ε = 21600 curves at 268, 272, 276 nm

Step D: 1- (2-Chloro-1-cyclopenten-1-yl) -3- [3,4-dimethoxy-5-N - [(4-methylphenyl) sulfonyl] oxy] phenyl] -propan-1-one > as

The reaction is carried out as in Preparation 1, Step D, using 8.7 g of the product of Step C, 70 ml of chloroform and 3.5 ml of oxalyl chloride. Recrystallization from diisopropyl ether gives 7.75 g of the desired product (m.p. 73 ° C). Such a product is also used at a later stage.

The analytical sample is obtained by crystallization from 2.5 volumes of methylene chloride and 5 volumes of diisopropyl ether, followed by concentration to 3 volumes, suction, washing with diisopropyl ether and drying under reduced pressure at room temperature (m.p. 77-78 ° C).

IR (CHCl _3):

Carbonyl: {1659 cm ' ¹ aromatic C = C: {1599 cm' ¹ 1586 cm ' ¹ 1508 cm' ¹

UV spectrum (EtOH):

maximum curvature curvature curvature curvature

227 nm ε = 26100 248 nm ε = 12800 272 nm ε = 5300 280 nm ε = 3200 320 nm

NMR (CDCl _3):

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

2.69 (m)} C-CH ₂ -C =}

2.81 (m)}}

2.85 (t, J = 7.5)} others = C-CH ₂ -C 3.08 (t, J = 7.5)}

2.44 CH ₃ -C =

3.68} OCH ₃

3.81}

6.59 (d, J = 2) aromatic CH 6.68 (d, J = 2) interacts with meta 7.31 (d, J = 8)}

7.80 (d, J = 8)}

Step E: 8,9-Dimethoxy-10 - [[(4-methylphenyl) sulfonyl] oxy] -2,3,5,6-tetrahydrobenz [e] azulene-4 (1H) -one 1 2.32 g C 1.65 g (98%) of ferric chloride is added at room temperature in 50 ml of 1,2-dichloroethane. After stirring at room temperature for 48 hours, it is poured into a water / ice mixture, stirred vigorously for 15 minutes, extracted with methylene chloride, washed with water and then with a saturated aqueous sodium chloride solution. After drying and evaporation under reduced pressure, 2.15 g of crude is obtained. the product to be chromatographed using 50% ethyl acetate in cyclohexane; 1.8 g of product are obtained, which is recrystallized and recrystallized from a mixture of chloroform and diisopropyl ether to give 720 mg of the desired product (m.p. 138 ° C).

IR (CHCl _3):

Carbonyl: {1650 cm ' ¹ {1599 cm' ¹

C = C + Aromatic {1556 cm ' ¹ {1512 cm' ¹ - 1498 cm ' ¹

UV spectrum (EtOH):

max 230 nm ε = 25300 infl 254 nm ε = 9400 max 323 nm, ε = 10,300 NMR spectrum (CDCl _3):

-1.61 (m) (2H) central CH ₂ -2.41 Ph-CH ₃

-2.50-2.80 CH ₂ -C =

3.83 (s)} OCH ₃

3.90 (s)}

6.74 H4

7.21 (d)} C-Ph-SO ₂

7.64 (d)}

Stage F: 8,9-Dimethoxy-10-hydroxy-2,3,5,6-tetrahydro-benz [e] azulene-4 (1H) -one

350 g of the product obtained in Step E above, 1750 ml of methanol, 350 ml of demineralized water and 350 ml of concentrated caustic soda are refluxed for 2 hours. The reaction mixture was cooled to 2 ± 2 ° C and within 45 min. 467 ml of concentrated hydrochloric acid are added thereto at a temperature of 2 ± 2 ° C. After that, within 10 minutes. 1645 ml demineralized water was added at 2 ± 2 ° C and the reaction mixture was stirred for 30 min. At 2 ± 2 ° C. The resulting crystals are suctioned off, washed five times with 700 ml of demineralized water at 20 ° C, then dried at 40 ° G under reduced pressure to give 199.1 g of the desired product,

Preparation of 3,4-dimethoxy-5-ii (4-methylphenyl) sulfonyloxylcinnamic acid, used as starting material in Preparation 2

Step A: Methyl 3,4-dimethoxy-5 - [[(4-methylphenyl) sulfonyl] oxy] benzoate to a stirred mixture of 200 g of methyl gallate and 2 L of methylene chloride at room temperature for 10 min. 303 ml of triethylamine are added. When the materials are dissolved, cool to 0-5 ° C, then within 1 hour. 130 ml of dichlorodimethylsilane are added at the same temperature and stirred at this temperature for another 30 minutes. Maintaining a temperature of 0-5 ° C, within 25 min. 303.2 ml of triethylamine was added followed by 15 min. 227.6 g 4-methylbenzenesulfonyl chloride. Stir for 1 more hour. 0-5 ° C and stirring and allowing the temperature to rise to 20-22 ° C over 10 min. 200 ml of acetic acid are added followed by 500 ml of demineralized water and stirring is continued for 15 minutes. At 20 ° C. Methylene chloride is distilled off under reduced pressure and replaced with demineralized water to constant volume (3.3 L) for 2 hours. At 20 ° C, suction, wash with demineralized water to give 523 g (wet weight) of methyl 3,4-dihydroxy 5 - [[(4-methylphenyl) sulfonyl] oxy] benzoate (methyl 3-tosyl gallate). The resulting wet product was dissolved in 2.17 L sodium hydroxide (2N) and 2.17 L methylene chloride. Stir at 20 ° C until dissolved, then add 18 g of tetrabutylammonium bromide at 20 ° C, then at 20 ° C for 15 min. 237 mL of dimethyl sulfate was added. The reaction mixture was stirred for 1.5 h. At 20-22 ° C. At this temperature, 78 ml of triethylamine are added and stirred overnight at 20-22 ° C, the layers are separated, washed with 400 ml of demineralized water, 20 ml of pure acetic acid are added to the organic phase, stirred for 15 minutes, 400 ml of demineralized water are added and the layers are separated. The combined organic phases are concentrated to dryness, first at atmospheric pressure and then under reduced pressure (40 mm Hg, external temp. 60 ° C). Treatment with 400 ml of methanol, followed by dissolution of the dry extract in 600 ml by refluxing until complete dissolution, followed by cooling to 0-5 ° C and stirring at this temperature for 1 hour. Vacuum and wash twice with 200 ml of methanol at -10 ° C and dry at 40 ° C under reduced pressure to give 330.4 g of methyl 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, suction, wash twice with 82 ml of chilled to -15 ° C toluene and drying at 40 ° C under reduced pressure to give 230.3 g of the purified desired product.

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

(a) Cool 600 ml of toluene to 0 ° C and add at 0 ° C

202 ml of 70% Vitride® solution in toluene, over 1 hour. At 0-2 ° C, 67.6 ml of morpholine are added and the temperature is allowed to rise to 18 ° C. The solution thus obtained is used immediately in the next step.

b) 200 g of the methyl 3,4-dimethoxy-5 - [[(4-methylphenyl) sulfonyl] oxybenzoate obtained in Step A and 1400 ml of toluene are stirred for 10 min. 20-22 ° C until complete dissolution. Within 1 or. At 10 ° C, add the reagent solution obtained above. Stir for another 1 hour, allowing the temperature to rise to 18 ° C. Within 1 or. A solution of 200 ml of concentrated sulfuric acid and 1000 ml of demineralized water is added at 10 ° C, cooled to 10 ° C. Mix for 16 or. At 20 ° C, the organic phase is separated off, washed with 5 x 200 ml of demineralized water, dried, filtered and washed with 3 x 100 ml of methylene chloride. The intermediate aldehyde solution thus obtained is used in the next step.

(c) A solution of the above aldehyde intermediate, 200 ml of 2-picoline, 120 g of malonic acid and 20 ml of piperidine is heated at 70 ± 2 ° C (with removal of methylene chloride at normal pressure) for 16 hours. Cool to 20-22 ° C and maintain this temperature for 15 minutes. pour 200 ml machine. solution of hydrochloric acid and 400 ml of demineralized water. Stir in 2 or. The crystals formed are suctioned off, washed with demineralized water, dried under reduced pressure at 40 ° C to give 171.7 g of the expected 3,4-dimethoxy-5 [[(4-methylphenyl) sulfonyl] oxy} phenyl] cinnamic acid.

PREPARATIVE EXAMPLE: 9,10-Dimethoxy-8-hydroxy-2,3,5,6-tetrahydro-benz [e] azulen-4 (1H) -one

Step A: 9,10-Dihydroxy-8 - [[(4-methylphenyl) sulfonyl] oxy] -2,3,5,6-tetrahydrobenz [e] azulene-4 (1H) -one g 2,3,5 6-Tetrahydro-8,9,10-trihydroxy-benz [e] azulen-4 (1H) -one obtained according to Preparation 1 or Ibis, 300 ml of tetrahydrofuran, 60 ml of triethylamine and 12.9 ml of trimethylborate are stirred for 1 hour. or. 30 min At 20 ± 2 ° C. 30 g of 4-methylbenzenesulfonyl chloride are added and the mixture is stirred for 16 hours. 20 ± 2 ° C, followed by the reaction mixture for 10 min. It is poured into a stirred mixture of 900 ml of demineralized water and 150 ml of concentrated hydrochloric acid at 20 ± 2 ° C, followed by the addition of 90 ml of tetrahydrofuran and 60 ml of methylene chloride. The resulting solution was stirred for 1 h. At 20 ° C, 150 ml of methylene chloride are added and the mixture is stirred for another 15 minutes, the layers are separated and extracted with 2 x 75 ml of methylene chloride. The combined organic phases are washed with 4 x 150 ml demineralized water, re-extracted with 75 ml methylene chloride and concentrated under reduced pressure at 20 mbar to 50 ° C to give 47.6 g of the desired product.

Stage B: 9,10-Dimethoxy-8 - [[(4-methylphenyl) sulfonyl] oxy] -2,3,5,6-tetrahydrobenz [e] azulen-4 (1H) -one

47.6 g of the product obtained above, 300 ml of methylene chloride, 300 ml of caustic soda (2N), 0.6 g of tetrabutylammonium bromide and 30 ml of dimethyl sulphate are stirred for 16 hours. At 20 ° C. Then 30 ml of triethylamine are added to destroy the excess dimethyl sulfate, and the reaction mixture is stirred for a further 1 hour. At 20 ± 2 ° C, 150 ml of demineralized water is added and the mixture is stirred for another 15 minutes. and separating layers. The aqueous phase is extracted with 2 x 75 ml of methylene chloride, the combined organic phases are washed with 3 x 120 ml of demineralized water followed by 120 ml of 1N hydrochloric acid and 3 x 120 ml of demineralized water, the organic phases are dried and dried over sodium sulfate. . 120 g of silica gel (60 mesh) are added with stirring at 20 ± 2 [deg.] C., the mixture is stirred for a further 1 hour, filtered, washed with methylene chloride and concentrated to dryness under reduced pressure at 50 [deg.] C. to give 47.4 g of the desired product. The crude product is purified by crystallization from 390 ml of ethanol; after removing 90 ml of ethanol, stir for 3 hours. At 0 ± 2 ° C, suction, wash with 30 ml of ethanol at 0 ° C, followed by drying under reduced pressure at 40 ° C, afforded 41.1 g of the desired product (mp 129 ° C).

Step C: 9,10-d / Methoxy / -8-hydroxy-2,3,5,6-tetrahydrobenz [e] azulene-4 (1H) -one | 10 g of 9,10-dimethoxy-8 - [[(4-methylphenyl) sulfonyl] oxy] 2,3,5,6-tetrahydro-benz [e] azulen-4 (1H) -one from Step B and 100 mL of methanol 4.5 g of potassium alkali are added to the suspension followed by 10 ml of triethylamine. Boil for 1 hour. reflux, acidify by adding 20 ml of acetic acid, followed by addition of 20 ml of water. Extract with dichloromethane, wash with water and evaporate the solvent at 40 ° C under reduced pressure to give 5.7 g of the expected product.

PREPARATIVE EXAMPLE: 2,3,5,6-Tetrahydro-8-hydroxy-9-methoxybenz [e] azulen-4 (1H) -one and 2,3,5,6-tetrahydro-9-hydroxy-8-methoxybenz [e] azulen-4 (1H) -one

The reaction is carried out according to the procedures described in Preparative Example 2, Steps B, C, D, E and F, with the exception of 3- (3,4-dimethoxyphenyl) propanoic acid, to give 1.08 g of crude product which is a mixture of monohydroxylated products (8). -OH / 9-OMe and 9-OH / 8-OMe); these products are separated by chromatography on silica eluting with a cyclohexane / ethyl acetate (7/3) mixture. The following two regioisomers are obtained: 8-OH / 9-OMe 0.494 g Rf (cyclohexane / ethyl acetate 6/4) = 0.42, 8-OMe / 9-OH 0.041 g Rf (cyclohexane / ethyl acetate, 6/4) = 0.33.

PREPARATIVE EXAMPLE: 2,3,5,6-Tetrahydro-8-hydroxy-10-methoxybenz [e] azulen-4 (1H) -one and 2,3,5,6-tetrahydro-10-hydroxy-8-methoxybenz [ e] azulen-4 (1H) -one

The reaction is carried out according to the procedures described in Preparative Example 2, Steps B, C, D, E and F, with the exception of 3- (3,5-dimethoxyphenyl) propanoic acid, to give 1.428 g of the product which is monohydroxylated (8-OH). / 10OMe and 10-OH / 8-OMe) and dihydroxylated (8-OH / 10-OH) products; these products are separated by chromatography on silica eluting with a cyclohexane / ethyl acetate (7/3) mixture.

PREPARATIVE EXAMPLE: 2,3,5,6-Tetrahydro-9-hydroxybenz [e] azulen-4 (1H) -one

The reaction is carried out according to the procedures described in Preparative Example 2, Steps B, C, D, E and F, except for 3- (4-methoxyphenyl) propanoic acid. Demethylation with boron tribromide.

(Rf = 0.15 cyclohexane / ethyl acetate, 7/3).

PREPARATIVE EXAMPLE: 2,3,5,6-Tetrahydro-8-hydroxybenz [e] azulen-4 (1H) -one

The reaction is carried out according to the procedures described in Preparative Example 2, Steps B, C, D, E and F, leaving only 10.0 g of 3- (3-methoxyphenyl) propanoic acid to give 2.9 g of the expected product. Demethylation with boron tribromide.

(R f = 0.15 cyclohexane / ethyl acetate, 95/5).

PREPARATIVE EXAMPLE: (DL) -4-Bromo-2- (phenylmethoxycarbonylamino) butanoic acid methyl ester

25 g of 2-amino-4-butyrolactone hydrobromide in 200 ml of acetic acid containing 24% hydrobromic acid gas are stirred at 120 ° C for 18 hours. Cool to room temperature, reduce to atmospheric pressure, concentrate under reduced pressure, dissolve the residue in 200 ml methanol, then for 2 hours. a stream of hydrogen chloride gas is allowed while maintaining the temperature of the reaction mixture at 35 ° C. The solvent was evaporated under reduced pressure to give 2 amino-4-bromobutanoic acid methyl ester, which was dissolved in 250 mL of acetone and 100 mL of water, neutralized by the addition of 2N sodium hydroxide, followed by the slow addition of 35 mL of benzyl chloroformate. After stirring for 48 hours, filter, extract with ethyl acetate, evaporate the solvent, and chromatograph the residue over silica (eluent: cyclohexane / ethyl acetate = 7: 3). 27.9 g of the expected product are obtained (m.p. 90 ° C).

PREPARATIVE EXAMPLE: 4-Bromo-2- (tert-butoxycarbonylamino) butanoic acid methyl ester

5.7 g of 2-amino-4-bromobutanoic acid prepared according to the procedure described in Preparative Example 8 are mixed with 120 ml of methanol for 48 hours at room temperature with 24 ml of triethylamine and 9 g of ditret.butyl dicarbonate. Solvents were evaporated and the residue was dissolved in water and dichloromethane, filtered, extracted with dichloromethane, the solvents were evaporated and the residue was chromatographed on silica (eluant: cyclohexane - -TEA AcOEt, 7: 3: 0.5) to give 1.575 g of the expected product with R _f = 0.52.

PREPARATIVE EXAMPLE: 4- (3-Pyrimidinyl) -1H-imidazole-1-propanol To a mixture of 505 mg of sodium ethylate and 12.5 ml of dimethylformamide is added 1 g of 3- (1H-imidazol-4-yl) pyridine, followed by 0.64 ml of chloropropanol and stir for 16 hours. At 55 ° C. The solvent was evaporated under reduced pressure and the residue was chromatographed (eluent: CH ₂ Cl ₂ - MeOH, 98: 1) to give 1.015 g of the expected product.

IR (CHCl _3):

OH 3626 cm ' ¹ + associate heterocycle 1601, 1578, 1551, 1499 cm' ¹ .

PREPARATIVE EXAMPLE: Hexahydro-2H-1,3-diazepin-2-one hydrazone

A suspension of 3.3 g of nitroguanidine, 7 ml of water, 3.47 g of potassium alkali and 5 g of diamine dihydrochloride is heated at 65-70 ° C for 1 hour. Added

10.5 g of zinc, stir for 30 min. at room temperature, followed by addition of ml of acetic acid, warmed to reflux. At 40 ° C, filter, add 3 g of ammonium chloride followed by 4 g of acidic sodium carbonate. Extracted with dichloromethane and the solvent removed under reduced pressure and the residue is chromatographed on silica gel (eluent: CH ₂ Cl ₂ -MeOHNH ₄ OH, 8: 4: 2) to afford 1.650 g of expected product.

PREPARATIVE EXAMPLE: 3a, 4,5,6,7 ₍ 7a-Hexahydro-2-propylthio-1H-benzimidazole monohydrobromide g octahydro-2H-benzimidazol-2-thione and 1.3 ml of bromopropane in 20 ml of ethanol are refluxed until The solvent is evaporated under reduced pressure, the residue is dissolved in a minimum amount of dichloromethane, isopropyl ether is added, the solvents are evaporated under reduced pressure, crystallized from isopropyl ether, filtered off and dried to give the expected product in 95% yield.

EXAMPLE 7 - ((4 - (((Amino) iminomethyl) hydrazono) -9,10-dimethoxy-1,2,3,4.5.6-hexahydrobenz (e) azulen-8-yl) oxy) heptanoic acid

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

A suspension of 0.684 g of 2,3,5,6-tetrahydro-8-hydroxy-9,10-dimethoxybenzo [ejazulen-4 (1H) -one (Preparation 3), 12 ml of dimethylformamide (DMF), 12 ml of tetrahydrofuran ( THF), 0.7 g of potassium carbonate and 0.835 g of methyl 7-bromenanthate are stirred for 4 hours. At 40 ° C. After evaporation under reduced pressure, the crude product is chromatographed on silica, eluting with methylene chloride. (CH ₂ Cl ₂ ) / acetone (95/5). 1.000 g of a purified product are obtained which is a yellow oil.

R f (CH 2 Cl 2, acetone, 95/5): 0.5.

IR (CHCl _3):

C = O 1732 cm ^-1

OMe 1438 cm ' ¹ Conjugated Ketone 1641 cm' ¹

C = C + aromatic 1592 cm ' ¹ , 1557 cm' ¹ , 1492 cm ' ¹

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

A suspension of 0.5 g of the product of Step A described above, 5 ml of ethanol and 0.330 g of aminoguanidine hydrochloride is stirred for 48 hours. at room temperature under reduced pressure, the solvent was evaporated, and the crude product was chromatographed over silica eluting with a mixture of CH2Cl2 / methanol (MeOH) / ammonia (80/20/4). 0.466 g of purified product is obtained which is a white foam.

R f (CH ₂ Cl ₂ / MeOH / ammonia, 80/20/4): 0.8.

IR spectrum (Nujoie):

NH / NH ₂ 3495 cm ' ¹ , 3155 cm' ¹ + assoc

C = O 1731 cm ^-1

C = N 1674 cm ^-1

C = C 1625 cm ' ¹ aromatic 1595 cm' ¹ (st)

NH / NH ₂ 1534 cm ^-1 , 1491 cm ^-1

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

A solution of 0.44 g of the product from the previous step, 5 ml of ethanol and 2 ml of 1N sodium hydroxide solution is stirred for 3 hours. at room temperature, 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 mixture of CH 2 Cl 2: methanol (MeOH) / ammonia (80/20/4). Recrystallization from methanol gives 0.192 g of the purified product.

R <(CH2Cl2 / MeOH / ammonia, 80/20/4): 0.17.

NMR (D ₂ O + 1 drop 1N sodium hydroxide):

3.92 t1 2H CH ₂ -O

2.171 2H CH ₂ -COOH 1.34 m 4H

1.55 m, 2H central CH ₂

1.70 m 4H + ch ₂ -c =

2.50-2.90 m 6.62 s 1H 3.64 s 3H

8H aromatic H ₇ OCH ₃

3.73 S 3 H OCHs

Microanalysis:

Calculated,%: C, 62.86; H, 7.47; N, 12.21;

Reactions were carried out according to the procedures described in Example 1, Steps A, B and C, starting from 2,3,5,6-tetrahydro-8-hydroxy-9,10-dimethoxybenz [e] azulen-4 (1H) -one (Preparation 3). ), with only other alkylating groups and G-NH ₂ groups, the following products of formula (I) are obtained:

EXAMPLE 4 - ((4 - (((Amino) iminomethyl) hydrazone) -9,10-dimethoxy-1,2.3.4.5.6- hexahydrobenz (e) azuylene-8-yl) oxy) butanoic acid

EXAMPLE: 4 - ((4 - (((amino) iminomethyl) hydrazone) -9,10-dimethoxy-1,2.3.4.5.6- hexahydrobenz (e) azulen-8-yl) oxy) pentanoic acid

EXAMPLE 5 - ((4 - (((Amino) carbonyl) hydrazone) -9,10-dimethoxy-1,2.3.4.5.6-hexahydro-8-benz (e) azulenyl) oxy) pentanoic acid

EXAMPLE: 6 - ((4 - (((Amino) iminomethyl) hydrazone) -9,10-dimethoxy-1,2.3.4.5.6-hexahydro-8-benz (e) azulenyl) oxy) hexanoic acid

EXAMPLE: 5- (9,10-Dimethoxy-1,2,3,4,5,6-hexahydro-4- (4,5-dihydro-1 Himidazol-2-yl) hydrazone-8-benz (e) azuylene) ) oxy) pentanoic acid

EXAMPLE: 5 - ((4 - (((amino) thiocarbonyl) hydrazone) -9,10-dimethoxy-1,2.3.4.5.6-hexahydro-8-benz (e) azulenyl) oxy) pentanoic acid

EXAMPLE: 6- (4 - ((4,5-Dihydro-1H-imidazol-2-yl) hydrazone) -9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz (e) azulenii) oxy) hexanoic acid

EXAMPLE 5 - ((4 - (((amino) iminomethyl) hydrazone) -9,10-dimethoxy-1,2,3,4,4,5,6-hexahydro-8-benz (e) azulenyl) oxy) -3,3-dimethyl-4 -oxopentanoic acid

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

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

EXAMPLE 4 - ((9,10-Dimethoxy-4 - ((1,4,5,6-tetrahydro-2-pyrimidinyl) hydrazone) -1,2,3,4,5,6-hexahydro-8-benz (e. ) azulenyl) oxy) butanoic acid

EXAMPLE: 2- (4 - ((4,5-Dihydro-1H-imidazol-2-yl) hydrazone) -9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz (e) azulenyl) oxy) -acetic acid

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

For example, Home product it Alkylating product g-nh ₂ Rf (D 2 P3 Br- (CH ₂ ) ₃ -CO ₂ Et H ₂ N-NH-C (= NH) -NH ₂ -HCl 0.12 3 P3 Br- (CH ₂ ) ₄ -CO ₂ Et H ₂ N-NH-C (= NH) -NH ₂ -HCl 0.12 4 P3 Br- (CH ₂ ) ₃ -CO ₂ Et H ₂ N-NH-C (= O) -NH ₂ -HCl 0.18 5 P3 Br- (CH ₂ ) ₅ -CO ₂ Et H ₂ N-NH-C (= NH) -NH ₂ -HCl 0.17 6th P3 Br- (CH ₂ ) ₄ -CO ₂ Et z ^N > H ₂ N-NH- C ^ J · HBr HN ^ 0.27 7th P3 Br- (CH ₂ ) ₄ -CO ₂ Et H ₂ N-NH-C (= S) -NH ₂ -HCl 0.25 8th P3 Br- (CH ₂ ) ₅ -CO ₂ Et z ^N > H ₂ N-NH-J · HBr HN ^ 0.6 9th P3 BrCH ₂ C (O) C (Me) ₂ - CH ₂ CO ₂ Et H ₂ N-NH-C (= NH) -NH ₂ -HCl 0.3 10th P3 BrCH ₂ C (O) C (Me) ₂ - CH ₂ CO ₂ Et z ^N > H ₂ N-NH-C <^ J HBr H LT 0.5 11th P3 Br- (CH ₂ ) ₃ -CO ₂ Et z ^N > H ₂ N-NH-C <^ J HBr Hhr 0.3 12th P3 Br- (CH ₂ ) ₃ -CO ₂ Et _{/ N} H ₂ N-NH-J · HBr 0.63

13th P3 Br- (CH ₂ ) -CO ₂ Et H ₂ N-NH-C ^ J · HBr Hbr 0.3 14th P3 Br- (CH ₂ ) ₂ -CO ₂ Et H ₂ N-NH-C <^ J · HBr HN ^ 0.22

(1) Dichloromethane / Metariol / Ammonia 80/20/4

EXAMPLE: 5 - ((4 - (((Amino) iminomethyl) hydrazone) -9,10-dimethoxy-1,2,3,4,5,6-hexahydrobenz (e) azulen-8-yl) oxy) pentanoic acid hydrochloride

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 the mixture is lyophilized after a few minutes. 91 mg of the expected salt is obtained.

EXAMPLE: 4 - ((4 - (((Amino) iminomethyl) hydrazone) -8,9-dimethoxy-N, N '-> - hexahydro-10-benzyl azulenyl-oxy] butanoic acid

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

The reaction is carried out according to the procedure described in Example 1, Steps A, B and C, but leaving 2,3,5,6-tetrahydro-10-hydroxy-8,9-dimethoxybenz [e] azulen-4 (1H) -one (Preparation 2). example).

For example, Home product Alkylating product ; G-NH ₂ Rf 16th (H) a Br- (CH ₂ ) ₃ -CO ₂ Et H ₂ N-NH-C (= NH) -NH ₂ -HGI 0.07 17th (H) a Br- (CH ₂ ) ₄ -CO ₂ Et H ₂ N-NH-C (= NH) -NH ₂ -HCl 0.07

EXAMPLE 4 - ((4 - (((amino) iminomethyl) hydrazono) _{-8,10-dimetoksi1!} 2,3,4,5,6-hexahydro-9-benz (e) azulenyl) oxy) butanoic acid

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

The reaction is carried out according to the procedure described in Example 1, Steps A, B and C, but leaving 2,3,5,6-tetrahydro-9-hydroxy-8,10-dimethoxybenz [e] azulen-4 (1H) -one.

For example, Home product Alkylating product G-NH ₂ Rf 18th (H) no Br- (CH ₂ ) ₃ -CO ₂ Et H ₂ N-NH-C (= NH) -NH ₂ HCl 0.10 19th (II) _E1 Br- (CH ₂ ) ₄ -CO ₂ Et H ₂ N-NH-C (= NH) -NH ₂ -HCl 0.07

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

Step A: Ethyl 4- (4-oxo) -1,2,3,4,5,6-hexahydrobenz (e) azulene-9-ii) oxy) butanoic acid

A suspension of 0.6 g of 2,3,5,6-tetrahydro-9-hydroxybenz [e] azulen-4 (1H) -one (Preparation 6), 12 ml of dimethylformamide (DMF), 12 ml of tetrahydrofuran (THF) ), 0.7 g of potassium carbonate and 0.7 ml of ethyl bromobutyrate are stirred at room temperature overnight. After evaporation under reduced pressure, the crude product is chromatographed over silica eluting with a mixture of methylene chloride and acetone (dichloromethane / acetone 95/5). 0.608 g of purified product is obtained which is a yellow oil.

IR (CHCl _3):

C = O 1728 cm ' ¹ Conjugated Ketone 1641 cm' ¹ Aromatic C = C 1610 cm ' ¹ , 1590 cm' ¹ , 1569 cm ' ¹ , 1499 cm' ¹

Step B: 4 - ((4 - ((4,5-Dihydro-1H-imidazolin-2-yl) hydrazone) -1,2,3,4,5,6hexahydrobenz (e) azulen-9-yl) oxy ) ethyl ester of butanoic acid

608 mg of the product of Step A described above, 10 ml of butanol and 600 mg of cyclic aminoguanidine hydrobromide, ie (4,5-dihydro-1H-imidazolin-2-yl) -hydrazine, are refluxed for 24 hours, the solvent is evaporated under reduced pressure and the product is purified by chromatography on silica eluting with a 80/20/4 mixture of CH ₂ Cl ₂ / methanol (MeOH) / ammonia. 0.604 g of the expected product is obtained.

IR (CHCl _3):

= C-NH-3451 cm ^-1

C = O 1728 cm ^-1 (ester)

C = N + C = C + aromatic: 1627 ^cm-1 (st), 1568 ^cm-1, 1548 ^cm-1, 1497 cm ^1, 1488 ^cm-first

Step C: 7 - ((4 - ((4,5-Dihydro-1H-imidazol-2-yl) hydrazone) -1,2,3,4,5,6hexahydrobenz (e) azulen-9-yl) oxy ) butanoic acid

A solution of 0.604 g of product from the above step, 8 ml of ethanol, 5 ml of tetrahydrofuran and 2 ml of 2N sodium hydroxide solution is stirred for 4 hours. at room temperature, then neutralized with 2 ml of hydrochloric acid. After evaporation under reduced pressure, the crude product is purified by chromatography on silica eluting with a 80/20/4 mixture of dichloromethane (CH ₂ Cl ₂ ) / methanol (MeOH) / ammonia. Recrystallization from methanol gives 0.298 g of the purified product.

Rt (dichloromethane / methanol / ammonia 80/20/4): 0.2

NMR Spectrum (D ₂ O + 1 drop 1N sodium hydroxide):

1.71 (1) 2H -O-CH ₂ -CH ₂ -CH ₂ -CO 1.96 (m) 2H GH _{2 at} position 2 (cyclopentene) 2.30 (t) 2H ch ₂ -co 2.50-2.75 8H ch ₂ -g = 3.45 (s1) 4H ch ₂ -n = 3.89 (t1) 2H Ph-O-CH ₂ -C 6.70 (m) 2H H10 and Hg 7.00 (d, J = 8) h ₇

EXAMPLE 4 - ((4 - ((4,5-Dihydro-1H-imidazol-2-yl) hydrazone) -1,2,3,4,5,6hexahydro-8-benz (e) azu); enil) oxy) butanoic acid

The reaction was carried out as in Example 20, except that 0.856 g of 2,3,5,6-tetrahydro-8-hydroxy-benz [e] azulen-4 (1H) -one (Preparation 7) was obtained, yielding 0.299 of the expected product.

Rf (dichloromethane / methanol / ammonia 80/20/4): 0.27.

EXAMPLE: 5 - ((8 - (((amino) iminomethyl) hydrazono) -6,7,8,9,10,11hexahydro-azulene (5,6-d) -1,3-benzodloxol-4-yl) oxy ) pentanoic acid

Step A: 5 - (((4-Oxo) -9,10-dihydroxy / -1,2,3,4,5,6-hexahydrobenz (e) azulen-9-yl) oxy) -pentanoic acid ethyl ester

1) Blocking To a solution of 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 under an inert atmosphere is added 4, 42 ml of trimethoxyborate and 20.4 ml of triethylamine were maintained at a temperature between 37 and 39 ° C, followed by stirring at room temperature for 3 hours.

2) Alkylation and debugging

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

R f (dichloromethane / methanol 95/5) = 0.82.

R f (cyclohexane / ethyl acetate 70/30) = 0.23.

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

2.5 g of the product obtained in the preceding step, 17 ml of dimethylformamide, 3.6 g of CsF and 1.4 ml of dibromomethane are stirred under inert atmosphere at 60 ° C for 1 hour. After filtration and washing with methanol, the solvent is evaporated off under reduced pressure and the crude product is purified by chromatography on silica eluting with a 85/15 mixture of cyclohexane / ethyl acetate. 1.73 g of pure expected product are obtained. (Mp 118 ° C).

R f (cyclohexane / ethyl acetate 80/20) = 0.25.

Step C: 5 - ((8 - (((Amino) iminomethyl) hydrazorio) -6,7,8,9,10,11-hexahydroazulene (5,6-d) -1,3-benzodioxol-4-yl) oxy) -pentanoic acid ethyl ester

551 mg of the product obtained in the previous step and 467 mg of aminoguanidine hydrochloride are stirred overnight at 120 ° C, followed by purification by chromatography eluting with 80/20/4 dichloromethane / methanol / ammonia. 174 mg of the expected product is obtained.

Rt (dichloromethane / methanol / ammonia 80/20/4) = 0.98.

Step D: 5 - ((8 - (((Amino) iminomethyl) hydrazono) -6,7,8,9,10,11-hexahydroazulene (5,6-d) -1,3-benzodioxol-4-yl) oxy) -pentanoic acid

274 mg of the product obtained in the previous step and 1.86 ml of 1N sodium hydroxide are stirred at room temperature for 1 hour. 30 min, then neutralized with 1N hydrochloric acid 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 are obtained.

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

NMR Spectrum (DMSO):

1.55-1.9 (m) 4H O-CH ₂ -CH ₂ -CH ₂ -CH ₂ -CO 1.55-1.9 (m) 2H CH _{2 at} position 2 (cyclopentene) 2.26 (t) 2H ch ₂ -co 2.65-3.00 (m) 8H ch ₂ -c = 4.04 t 2H o-ch ₂ -ch ₂ - 5.95 (S) 2H -o-ch ₂ -o 6.61 (m) 1H h ₈ H agile (m, wide) NH-C (= NH) -NH ₂

EXAMPLE 5 - ((8 - (((amino) iminomethyl) hydrazono) -2,2-diphenyl-6,7,8,9,10,11-hexahydro-azulene (4,5-e) -1,3-benzodioxole -4il) oxy) pentanoic acid

The reaction is carried out as described in the previous example, using 374 mg of the product obtained in Step A of the previous example and 0.19 ml of diphenyl dichloromethane. 198 mg of the expected product are obtained.

Rf (dichloromethane / methanol / ammonia 80/20/4) = 0.17.

EXAMPLE: O- [4 - [(4,5-Dihydro-1H-imidazol-2-yl) hydrazono) -9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz (e) azuenyl] -N - [(phenylmethoxy) carbonyl] -DL-homoserine

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

0.6 g of 2,3,5,6-tetrahydro-8-hydroxy-9,10-dimethoxy-benz [e] azulene-4 (1H) -one (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 according to Preparation 8 are stirred at room temperature overnight. After evaporation under reduced pressure, the crude product is chromatographed on silica, eluting with a mixture of methylene chloride (CHEC 3 / Acetone 95/5), to give 1.166 g of a purified product which is a yellow oil.

IR (CHCl _3):

C = O 1740 cm ' ¹ (m.p.), 1721 cm' ¹ Conjugated ketone 1642 cm ' ¹ Aromatic C = C 1593. cm' ¹ , 1559 cm ' ¹ , 1508 cm' ¹ , 1493 cm ' ¹

Stage B and: O- [4 - [(4,5-Dihydro-1H-imidazol-2-yl) hydrazono-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz (e) ) azuenyl] -N - [(phenylmethoxy) carbonyl] -DLhomoserine methyl ester

539 mg of the product of Step A described above, 15 ml of butanol and 600 mg of cyclic aminoguanidine hydrobromide, m.p. (4,5-Dihydro-1H-imidazolin-2-yl) -hydrazine is stirred for 24 hours. At 120 ° C, the solvent is evaporated off under reduced pressure and the crude product is purified by chromatography on silica eluting with a 80/20/4 mixture of CH 2 Cl 2 / methanol (MeOH) / ammonia. 0.641 g of the expected product is obtained.

IR (CHCl _3):

= C-NH- 3451 cm ' ¹ + associated

C = O 1740 cm @ ^-1 (cm @ ^-1 ), 1720 cm @ ^-1 (max.)

C = N + C = C + aromatic + amide ii: 1667 cm ^-1 (st), 1606 cm ^-1 , 1508 cm ^-1 , 1490 cm ^-1 .

Step C and: 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] -DLhomoserine

A solution of 0.6 g of the product obtained in the above step, 10 ml of ethanol and 2 ml of 2N sodium hydroxide solution is stirred for 2 hours. at room temperature, then neutralized with 2 ml of hydrochloric acid. After evaporation under reduced pressure, the crude product is purified by chromatography on silica eluting with 80/20/4 CH ₂ Cl ₂ / methanol (MeOH) / ammonia. Recrystallization from methanol gives 0.349 g of the purified product.

R f CH ₂ Cl ₂ / methanol (MeOH) / ammonia 80/20/4: 0.37

EXAMPLE: O- [4 - [(4,5-Dihydro-1H-imidazole-2 H -hydrazonoyl) -1H-hexahydro-8-benz (e) azulenyl] -N - [(phenylmethoxy) carbonyl] -DLhomoserine

The reaction was carried out as in Example 24, except that 0.428 g of 2,3,5,6-tetrahydro-9-hydroxy-benz [e] azulen-4 (1H) -one was obtained (Preparation 7).

245 mg of the expected product is obtained.

R f Ch ^ Cl ^ methanol (MeOH) / ammonia 80/20/4: 0.5.

EXAMPLE: O- [4 - [(1,2,3,4-Tetrahydro-6-Pyrimidinyl) Hydrazone) -9,10-Dimethoxy-1,2,3,4,5,6-Hexahydro-8-Benz (e) azulenyl] -N [(phenylmethoxy) carbonyl] -DL-homoserine

Step A and: 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] -DLhomoserine methyl ester monohydrobromide

The reaction is carried out as in Example 24, Step B, using 200 mg of the product of Example 24, Step A, 2 ml of butanol and 74.5 mg of tetrahydro-2 (1H) -pyrimidone hydrazone monohydrobromide under reflux for 16 hours. The mixture was allowed to cool to room temperature, extracted with dichloromethane, dried and the solvent evaporated under reduced pressure to give 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) ) azulene H] -N - [(phenylmethoxy) carbonyl] -DLhomoserine

The reaction is carried out as in Example 24, Step C, using a solution of 131 mg of the product obtained in Step A above in 1.3 ml of ethanol and 0.43 ml of 1N sodium hydroxide. Neutralize with 1N hydrochloric acid, evaporate the solvent, filter, dry to give 78 mg of the expected product. Lyd. temp. 172 ° C.

NMR (CDCl _3):

1.90 (m) (2H) CH _{2 at} position 9 2.03 (m) CH2 central 2.36 (m) (2H) 2.60-3.00 (8H) = c-ch ₂ 3.48 (ml) (4H) = n-ch ₂ 3.77 (s) 3.78 (s) (9H) = C-OMe 4.01 (m) (1H) 4.17 Ph-O-CH ₂ 4.67 (p) = C-CH-N-C = 5.14 (si) COO-CH ₂ -Ph 6.13 (d) = C-NH-CH 6.49 (si) h ₄ 7 7.36 (m) (5H) Ph-C

EXAMPLE: O- (9,10-Dimethoxy-1,2,3,4,5,6-hexahydro-4 - [(1,4,5,6-tetrahydro-2-pyrimidinyl) hydrazone] -8-benz (e) azulenyl] -N - [(phenylmethoxy) carbonyl] -DL-homoserine 2,3-dihydroxypropyl ester

Step A: 0- (9,10-Dimethoxy-1,2,3,4,5,6-hexahydro-4 - [(1,4,5,6-tetrahydro-2-pyrimidinyl) hydrazone] -8-benz (e) ) azulenyl] -N - [(phenylmethoxy) carbonyl] -DLhomoserine (2,2-dimethyl-1,3-dioxolan-4-yl) methyl ester

0.3 g of the product prepared in Example 26 are cooled to 0 ° C with 1 ml of dimethylformamide and 1 ml of dichloromethane, and 96 mg of 1- (3dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 68 mg of 1-hydroxybenzotriazole hydrate are added. Stir for 30 minutes. at room temperature, add 0.06 ml of zolketal and stir for a further 3.5 hours. The reaction mixture is diluted with water, extracted with dichloromethane and 0.6 g of crude product is isolated, which is purified by chromatography on silica (eluent; CH ₂ Cl ₂ -MeOH 90:10). 0.352 g of the expected product is obtained.

IR (CHCl _3):

NH 3400 cm ^-1

C = O 1745 (ref.), 1719 cm @ ^-1

C = N, C = C, aromatic, amide II: 1672 (st), 1645, 1597, 1565 (st),

1507, 1492 cm ^-1

Step B: 0- (9,1 O-Dimethoxy-1,2,3,4,5,6-hexahydro-4 - [(1,4,5,6-tetrahydro-2-pyrimidinyl) hydrazone] -8-benz ( e) Azulene H] -N - [(phenylmethoxy) carbonyl] -DLhomoserine 2,3-dihydroxypropyl ester

A solution of 0.320 g of the product of Step A in 3 ml of ethanol and 1 ml of 2N hydrochloric acid was stirred at room temperature for 6 hours. Evaporation of the solvent and chromatography on silica (eluant: ₂ ΟΗ ΟΙ -ΜβΟΗ _2-ΝΗ ΟΗ ₄ 80: 20: 4) to give 0.112 g of expected product.

NMR (CDCl _3): 1.88 (m) (2H) } 1.98 } CH ₂ central and CH _{2 at} position 9 2.36 } 2.60-3.10 (8H) = c-ch ₂ 3.43 (m) (4H) = nn-ch ₂ 3.79 (s) } Φ-OMe

3.81

3.60-3.90 ^ 4.00-4.17

4.64 (m) (1H) 5.13 (s)

6.53 (s) 7.20-7.38}

O-CH ₂ -CH-O} COO-CH a-CH} <PO-CH ₂ -CH ₂ = C-CH-NC =

COO-CH ₂ -Ph

H ₄ ··· Φ-C

EXAMPLE: O- [4 - [(4,5-Dihydro-1H-imidazol-2-yl) hydrazone] - [9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz ( e) Azulenyl] -N - [(8quinolinyl) sulfonyl] -DL-homoserine

Stage A and: O- (9,10-Dimethoxy-1,2,3,4,5,6-hexahydro-4-oxo-8-benz (e) azulenyl) - N - [(1,1-dimethylethoxy) carbonyl] ] -DL-Homosein methyl ester

A solution of 4.1 g of the product of Preparation 3 and 5 g of the ester of Preparation 9 in 50 ml of dimethylformamide and 50 ml of tetrahydrofuran in 5 g of potassium carbonate and dimethylpyridine is stirred at room temperature for 65 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: CH ₂ Cl ₂ -acetone 95: 5) to give 7.3 g of the expected product.

IR (CHCl _3):

= C-NH

C = O aromatic + amide II

3430 cm ^-1

1744 cm ^-1 (methyl ester)

1710 cm ^-1 (NH-BOC)

1648 cm ^-1 (conjugated ketone) 1593, 1559, 1493 cm ^-1

Step B: O- (9,10-Dimethoxy-1,2,3,4,5,6-hexahydro-4-oxo-8-benz (e) azulenyl) - N - [(1,1-dimethoxyethoxy) carbonyl] ] -DL-homosenno methyl ester monohydrochloride To a solution of 6 g of the product of Step A in 10 ml of ethyl acetate is added 3 times 10 ml of a solution of hydrochloric acid in ethyl acetate, followed by stirring for 16 hours. at room temperature. The solvent is evaporated under reduced pressure to give 0.656 g of the expected product which is used in the next step.

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

Dissolve 0.656 g of the product obtained above in 5 ml of dichloromethane, add 1 ml of triethylamine and 0.638 g of 8-chlorosulfonylquinoline and stir for 2 hours. at room temperature. After evaporation of the solvents under reduced pressure and chromatography over silica (eluent: CH ₂ Cl ₂ -MeOH 95: 5), 0.956 g of the expected product is isolated.

Step D: 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-quinolinyl) sulfonyl] -DLhomoserine methyl ester

0.9 g of the product of Step A, 5 ml of butanol and 0.6 g of cyclic aminoguanidine, m.p. (4,5-Dihydro-1H-imidazol-2-yl) hydrazine, stirred for 16 h. The solvent is evaporated under reduced pressure at 120 [deg.] C. to give 0.789 g of the expected product which is used in the next step.

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) -N - [(8-quinolinyl) sulfonyl] -DLhomoserine

A solution of 0.786 g of the product obtained in the previous step, 5 ml of methanol and 2 ml of 2N sodium hydroxide solution is stirred at room temperature for 2 hours, then neutralized with 2N hydrochloric acid and stirred for 10 minutes. After evaporation under reduced pressure, the crude product is purified by chromatography on silica, eluting with a 80: 20: 4 mixture of CH ₂ Cl _{2 -} methanol: ammonia. Recrystallization from methanol gives 0.438 g of the expected product.

R _f = 0.40 (CH ₂ Cl ₂ -MeOH-NH ₄ OH 80: 20: 4)

NMR Spectrum (DMSO):

1.81 (si) CH _{2 at the} 9-position

2.40-3.20 3.35 (I) 3.55 (si) 6.63 (si) 7.58 (dd) 7.67 (t) = C-CH ₂ = N-CH ₂ = C- OMe

8.19 (d), 8.29 (d)

H ₄ h ₂

8.45 (d) 8.90 (d) 7.31 (si) 7.97

10.40 (f) 12.62}

}}

} agile H

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

Stage A: Methyl 4 - [[9,10-dimethoxy-1,2,3,4,5,6-hexahydro-4-oxo-8β-bis (e) azulenyl] oxy-2-isocyanato-butanoate

450 mg of the amine from Example 28, Step B, dissolved in 10.2 mL of saturated aqueous sodium bicarbonate solution and 10.2 mL of dichloromethane are stirred for 10 min. At 0 ° C, 204 mg of triphosgene, dissolved in 2 ml of dichloromethane, are added to the organic phase of the reaction mixture, stirred for 10 minutes, extracted with dichloromethane, dried, evaporated under reduced pressure to give 430 mg of the expected product.

Step B: O- [9,10-Dimethoxy-1,2,3,4,5,6-hexahydro-4-oxo-8-benz (e) azulenyl] - N - [[3- [4- (3- pyridinyl) -1H-imidazole-1-H] propoxy] carbonyl-DL-homoserine

A solution of 430 mg of the product of Step A in 20 ml of dichloromethane is cooled to 0 ° C and 414 mg of the alcohol solution of Preparation 10 in 10 ml of dichloromethane are added. The temperature is allowed to rise to room temperature, the solvent is evaporated off under reduced pressure, and the residue is chromatographed on alumina (eluent: CH ₂ Cl ₂ -MeOH) to give 298 mg of the expected product.

Step C and: O- [4 - [(4,5-Dihydro-1H-imidazol-2-yl) hydrazono] -9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz ( e) Azulenyl] -N - [[3- [4- (3-pyridinyl) -1H-imidazol-1-yl] propoxy] carbonyl-DL-homoserine monohydrobromide

The reaction was carried out as in Example 24, Step B, using 277 mg of the product of Step B above and 164 mg of cyclic aminoguanidine hydrobromide in 13 ml of butanol. Chromatography over alumina (eluent: CH ₂ Cl ₂ -MeOH 95: 5) gives 289 mg of the expected product.

IR (CHCl _3):

C = O-conjugated system} + aromatic group} + amide ii}

OH

1746 (fold) 1723 (max) cm

1668, 1625 (st), 1599 (ref.), 1551, 1509, 1489 cm

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-benz (e) ) azulenyl] -N - [[3- [4- (3-pyridinyl) -1H-imidazol-1-yl] propoxy] carbonyl-DL-homosene monohydrochloride

A solution of 277 mg of the product obtained in the above-mentioned step C in 10 ml of ethanol is added 0.3 ml of 1N sodium hydroxide solution, stirred for 30 minutes, 10 ml of water are added, the reaction medium is acidified with 1N hydrochloric acid to pH = 2.5, the solvents are evaporated The residue is chromatographed on silica (eluent: CH ₂ Cl ₂ -MeOH-NH ₄ OH 40: 10: 2), the filtrate is evaporated under reduced pressure, to the residue isopropyl ether is added, the precipitate is filtered off, dried to give 126 mg of the expected product.

NMR Spectrum (DMSO):

1.78 (m) (2H)}

1.90-2.30 (m) (5H)} 1.60-2.90 (m) (8H) 3.53 (pl.s) («4Η)

3.69 (s), 3.71 (s)

3.90-4.20 (m) (7-8H) 6.73 (s)

7.20 (d, wide)

3-CH ₂ CH ₂ -C = n-ch ₂ -ch ₂ -n ch ₃ oc = CH ₂ and CH H ₄

CO-NH-CH62

H ' ₅

H'4

Hey

H ' ₂

CH = imidazole.

7.35 (dd)

8.04 (d)

8.37 (dl)

8.94 (si)

7.72 (s), 7.80 (s)

EXAMPLE: 5 - [[4 - [(4,5-Dihydro-4-oxo-1H-imidazol-2-yl) hydrazone] 9,10-dimethoxy-1,2,3,4,5,6-hexahydro- 8-benz (e) azulenyl] oxo] pentanoic acid

A solution of 300 mg of the product prepared in Example 3, Step A at room temperature is mixed with 6 ml of ethanol with 61 mg of acid sodium carbonate and 0.7 ml of ethyl bromoacetate. The solvents were evaporated and the residue was chromatographed on silica (eluent: CH ₂ Cl ₂ -MeOH 95: 5) to give 139 mg of the intermediate ethyl ester. A solution of 110 mg of this ester in 1 ml of ethanol is added for 2 hours with the addition of 0.5 ml of 2N sodium hydroxide. at room temperature. Neutralization of the reaction mixture with 2N hydrochloric acid gave a precipitate of the expected product.

NMR Spectrum (DMSO) δ 1.73 (m) (6H)

2.30 (t) (2H)

2.30-3.20 3.73 (s), 3.75 (s)

3.83 (si)

4.02 t

6.76 (s)

7.20 (si) (1H)}

8.28 (si) (1H)}

12.04 (1H)} are filtered off, dried, and 44 mg of central CH ₂ and CH ₂ are isolated at position 9 = C-CH ₂ (chain) = C-CH ₂ Φ-OMe = CN-CH ₂ -C = = -ο-οη ₂ h ₄ agile H

EXAMPLE: O- [9,10-Dimethoxy-1,2,3,4,5,6-hexahydro-4 - [(4,5,6,7-tetrahydro-1 H -1,3-diazepin-2-yl) hydrazone ] -8-Benz (e) azulenyl] -N - [(phenylmethoxy) carbonyl] -DL-homoserine A solution of the compound prepared in Example 24, Step A, in 5 ml of butanol and 0.9 g of the cyclic aminoguanidine prepared according to the procedure described in Preparation 11 is stirred. 16 or. At 130 ° C. The solvent was evaporated under reduced pressure, and the residue was chromatographed on silica (eluent: CH ₂ Cl ₂ -MeOH 90:10) to give 0.8 g of the intermediate ester, which was stirred in 3 ml of methanol for 1.5 hours. with 2 ml of 2N sodium hydroxide. After neutralization of the reaction mixture with 2N hydrochloric acid and evaporation of the solvents under reduced pressure, the residue was chromatographed on silica (eluent: CH ₂ Cl ₂ -MeOH-NH ₄ OH 90: 15: 2) to give 0.22 g of the expected product.

EXAMPLE: O- [9,10-Dimethoxy-1-ASAZ] -hexahydro-4 H -axaza [a] hexahydro-1 H -benzimidazol-2-yl) hydrazono] -8-benz (e) azulenyl] -N [(phenylmethoxy) carbonyl] -DL- homoserine

The reaction is carried out as in Example 24, Steps B and C, using 200 mg of the product of Example 24, Step A and 176 mg of the cyclic aminoguanidine prepared according to the procedure described in Preparation 12. 102 mg of the intermediate ester are isolated; 100 mg of this ester is used in the saponification reaction. 59 mg of the expected product are obtained.

R t = 0.24 (CH ₂ Cl ₂ -MeOH-NH ₄ OH 85: 15: 3).

Pharmaceutical compositions

The tablets are made according to the following recipe:

-1 Product of Example 50 mg

- base (talc, amidone, magnesium stearate)

O.S. for tablets up to 120 mg

Pharmacological examination of the products of the invention

1. Investigation of the ability of compounds of the invention to cleave vitronectin / vitronectin receptor (α _ν β ₃ )

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

The next day, the wells are drained and ligands (vitronectin) are fixed (see fixation buffer) for 1 hour. at room temperature with gentle stirring.

Wash the wells six times (see washing buffer), then add successively to each well:

- 40 μΙ incubation buffer,

- 10 μΙ of the specific dilution of the test product (diluted with DMSO-H ₂ O 50/50),

- 50 μΙ of human α _ν β ₃ receptor (see Pytela et al., Methods Enzymol. (1987) 144: 475) (diluted in incubation buffer, dilution adjusted to receptor volume and ligand volume).

The ligand, human α _ν β ₃ receptor, and test products are incubated for 3 hours at room temperature with gentle agitation.

The wells are washed again six times, then 2 hours. incubate at room temperature with gentle mixing with 100 μΙ of antibody 4B12-HRP anti-receptor conjugated with peroxidase (antibody 4B12-HRP diluted in incubation buffer. Dilution adjusted to receptor volume).

The wells are again washed six times before measuring ligand-receptor binding using the Peroxidase Enhancement Kit (TMB Microwell Peroxidase Substrats. System Kirkegaard: Cat. # 50-76-00).

This kit contains substrate vial A (0.4 g / l 3.3 ', 5.5'tetramethylbenzidine) and vial B (0.02% H2O2 in citrate / citric acid buffer). Immediately before the test, volume A is mixed with volume B, and the reaction mixture is then poured into 100 μΙ / well. Enzymatic reaction to vitronectin / a. _v p ₃ develops within 12 min, then stopped by addition of 100 μΙ 1M phosphate acid.

Optical density is measured at 450 nm.

Buffers

- Coating buffer: 0.05M carbonate, NaOH pH 9.6

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

- Wash Buffer: PBS containing 0.05% Tween 20 (pH 7.4)

- incubation buffer:

. 50 mM TRIS pH 7.4. 0.5% BSA. 0.05% Tween 20. 1 mM MnCl ₂ , 50 μΜ CaCl ₂ . 50 μΜ MgCl ₂ . 100 mM NaCl.

Expression of results

Plot the following: Plot of human vitronectin binding versus log concentration for each product tested.

For each product the IC ₅ o shall be determined according to the formula:

IC ₅₀ = (BO - Bmin) / 2

BO = maximum binding in the absence of a product,

Bmin = minimum binding at maximum product concentration.

2. Mouse Skull Test

Principle Injection of ⁴⁵ Ca (CaCl ₂ ) dose into pregnant female mice followed by bone resorption assay, measuring ⁴⁵ Ca release in the neonatal cranial vault.

Purpose

Determination of the effect of the molecule on bone resorption by ex-v! Vo. Products

(1) Product under investigation

Solvent: DMSO, H 2 O / BSA (0.1%).

Dose: Variable (10 μΜ for screening).

(2) Control products:

Echistatin (Cat. No. H-9010-BACHEM)

Thinner: H20 / BSA

Dose: 10μΜ.

3) Radioactive label:

⁴⁵ Ca in the form of aqueous CaCl ₂ (Cat. No. CES3 AMERSHAM or NEZ-013 NEN).

Solvent: physiological serum

Dose: 25 pCi / mouse / 0.4 ml

Cultural medium

CMLR 1066 with phenol red (cat. No. 041-01535 M / GIBCO) to which 0.1% BSA and penicillin / streptomycin were added.

Methodology

1) Injection of ⁴⁵ Ca into pregnant mice (OF1, line: Swiss)

(a) Preparation of the labeled solution:

Add 190 μΙ of stock calcium solution containing 2 mCi / ml to 6 ml of physiological serum.

(b) injection:

On day 17 of pregnancy, mice receive 400 μ 400 of this solution at 25 pCi / ml / mouse.

2) Sampling of tissue (skull vault (skull))

Six days after birth, newborns are given a fresh cut, followed by a head recuperation and a cut from the occiput to the forehead. Skull vault specimens are obtained by dividing the skull with scissors and buttocks into two completely identical skull halves (one left and one right) in the maxillary bone. One part will be devoted to control and the other part will be used to test the product of the invention.

3) Wash ”phase

Each side of the skull is placed in a 24-well plate containing 1 ml of medium on a polyethylene and 100 µm nilex tray to avoid contact with the bottom of the well.

After 24 or. transfer polyethylene trays with skulls into new wells of 24-well plate containing 1 ml of fresh medium and test products or solvents, adding 200 μΙ of the first plate medium to each well and calculating the first radioactivity (value A).

This change of medium eliminates all mechanical stress associated with sampling.

4) “Absorption” phase

48 hours later after tissue contact with test products, add 200 μΙ of sample to each well and calculate (B value) to determine the amount of ⁴⁵ Ca released in the medium during said resorption phase.

The skull is then completely demineralized with 1 ml of 5% trichloroacetic acid and, after destruction, taken again with 200 μΙ of the sample and counted to determine the amount of calcium remaining in the bone (C value).

Expression of results

Calculate% bone resorption for each half of the skull (per well) as follows:

bone resorption% = ipm B / ipm (A + B + C) x 100.

The sum imp A + B + C represents the amount of ⁴⁵ Ca that was incorporated into each bone piece on the day of sampling.

To measure the effect of the product, the percentage of bone resorption of each well with the product and the corresponding control well is calculated for each point. The value obtained is called the resorption index and is between 0 and 1 if the product inhibits bone resorption and is> 1 if the product promotes bone resorption. Then the average of the 6 indicators of each product (since there are 6 points per group) is taken, which gives the product indicator. Subtracting this from 1 gives the product's inhibitory capacity, which can be expressed as a percentage.

In addition, a statistical test (Student's T-test) was performed comparing the points of individual resorption rates.

RESULTS:

Pay-outs

Of Vn / VR (α _ν β ₃ ) binding

% Inhibition of mouse skull,

competition test IC50, μΜ at 10 μΜ 2 0.45 19th 3 2.1 - 6th 0.11 7.5 8th 2.79 - 10th 0.8 8th 11th ··. 0.05 7th 22nd 2.36 - 12th 0.35 12th 14th 0.75 14th 24th 0.03 18th 20th 0.079 11th 21st 0.037 - 25th 0.013 26th 26th 0.006 30th 27th 0.170 39 28th 0.015 27th 29th 0.028 18th 31st 0.055 20th 32 0.035 -

DEFINITION OF INVENTION

Claims (22)

DEFINITION OF INVENTION 1. Compounds of general formula (I): in which Rt represents -C ^ C- [A] - [B] -COR _S , -CH = CH- [A] - [Bj-COR ₆ , - (CH ₂ ) ₂ - [A] - [B] -COR ₆ , -O- [A] - [B] -COR ₆ , -CH ₂ CO- [Aj- [B] -COR ₆ , wherein [A] represents - either a divalent linear or branched, saturated or unsaturated hydrocarbon radical having from 1 to 12 carbon atoms and from 1 to 6 heteroatoms selected from oxygen, nitrogen or sulfur, - or a bivalent linear or branched, saturated or unsaturated acyclic hydrocarbon radical having from 1 to 12 carbon atoms, [B] denoting phenyl, CH (Z) or singly bonded, Z represents a hydrogen atom, (D) ₀ -6-NRaRb, (D) o. ₆ -NH-SO ₂ -Rc, (D) o. ₆ -NH-CO ₂ Rc, (D) ₀ . ₆ -NH-CO-R c, (D) ₀ . ₆ -NH-SO ₂ -NH-R c, (D) ₀ . ₆ -NH-CO-NH-Rc, (D) ₀ .e-CO ₂ Rc, (D) ₀ -6-SO ₂ -Rc, (D) ₀ -6-CO-Rc or (D) oe-Rc groups in which (D) ₀ . ₆ is a divalent linear or branched, saturated or unsaturated acyclic hydrocarbon radical having from 0 to 6 carbon atoms, Ra, Rb and Rc represent a hydrogen atom, a (CH ₂ ) ₀ -3-Ar radical in which Ar represents a carbocyclic aryl group having 6-18 carbon atoms, a (CH ₂ ) ₀ -3-Het radical in which Het represents an aromatic or a non-aromatic, saturated or unsaturated heterocycle containing from 1 to 9 carbon atoms and from 1 to 5 heteroatoms selected from oxygen, nitrogen or sulfur, a (CH ₂ ) o-3-A (k radical in which Alk represents a non-aromatic, linear or branched chain) or a cyclic, saturated or unsaturated hydrocarbon radical having from 1 to 12 carbon atoms, and Het, Ar and Alk may or may not be substituted, or Ra and Rb together with the nitrogen atom to which they are attached represent an aromatic or non-aromatic, saturated or unsaturated nitrogen-containing heterocycle containing one or more heteroatoms selected from oxygen, nitrogen or sulfur, which may or may not be substituted, - R _s represents a hydroxyl radical, an O-Alk, Ο-Ar, NH _2, NH-Alk, N (Alk) ₂ radical or a L- or D-amino acid residue, wherein Ak and Ar are as defined above, and may whether or not substituted, - R ₂ and R _3, identical or different, represent a hydrogen atom, a hydroxyl radical, an O-Alk radical or an O- (CH _{2) 0-3} -Ar radical, Alk and Ar are as defined above or _two R and R ₃ together form a -O- (CRdRe) _n -O- ring wherein n is an integer from 1 to 5, Rd and Re independently of one another represent a hydrogen atom, an alkyl radical having from 1 to 6 carbon atoms , or phenyl radical, - R ₄ represents a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a nitro group, a cyano group, CF ₃ , an acyl or acyloxy group having 1-12 carbon atoms alkyl, alkenyl, alkynyl, alkylthio group, alkoxy group, alkylamino group, dialkylamino group, dialkylamino group; containing from 1 to 6 carbon atoms in the alkyl moiety, - R ₅ represents a hydrogen atom, a hydroxyl radical, a halogen atom, an O-Alk radical or an O- (CH ₂ ) ₀ -3-Ar radical where Alk and Ar are as defined above, - G represents either a radical of formula G1 N- (Het ') Rh wherein Rh is a hydrogen atom or (Alk) as defined above and (Het ') is a heterocycle of the general formula: (H) C. N in which (H) forms with an N = C-NH- moiety an aromatic or non-aromatic, mono or bicyclic, saturated or unsaturated heterocycle having from 1 to 9 carbon atoms and from 2 to 5 heteroatoms selected from oxygen, nitrogen or sulfur and in this radical may or may not be substituted, - or a NRaRb radical (G2 radical) in which Ra and Rb are as defined above, - or a (Het) radical (G3 radical) as defined above, - or -NRh-C (= X) -NHRc (G4) where X is a sulfur atom, an oxygen atom or NH and Rh and Re are as defined above, - or -NRh-SO ₂ Rc (G5), where Rh and Re are as defined above, the dotted line represents a possible second bond, R ₁ , R ₂ and R ₃ may be in the 8-, 9- or 10-position of the tricyclic, as well as their addition salts with acids and bases and esters. 2. Compounds of general formula (I) according to claim 1, characterized in that their general formula (Γ): in which Rh represents -C = C- [A '] - [B'] - C0R'6, -CH = CH- [A '] - [B'] - COR ' ₆ , - (CH ₂ ) 2- [A '] - [B'] - COR ' ₆ , -O- [A'] - [B '] - COR' ₆ , -CH ₂ CO- [A '] - [B '] -COR' ₆ groups, - [A '] - denotes bivalent alkylene, alkenylene or alkynylene having from 1 to 6 carbon atoms, [B'] denotes a CH (Z ') radical or a single bond, Z 'represents a hydrogen atom, (CH ₂ ) o. ₆ -NR a R b, (CH ₂ ) ₀ -6-NH-SO ₂ -R c, (CH ₂ ) o-6-NH-CO ₂ -R c, (CH ₂ ) ₀ -6-NH-CO-R c, (CH _{2) 0} -6-NH-SO ₂ -NH-Rc, (CH ₂₎ o- ₆ -NH-CO-NH-Rc, (CH ₂₎ o- ₆ -C0 ₂ -Rc, (CH ₂₎ o 6-S0 ₂ -R c (CH _{2) 0-6} -CO-Rc or (CH ₂₎ o- ₆ -R c group in which R a, R b and R e are as defined in claim 1, R _'6 OH radical an amino or alkoxy group having from 1 to 8 carbon atoms which may be substituted by one or more radicals selected from hydroxy, amino, phenylalkylamino or dialkylamino, R ' ₂ and R' ₃ represent a hydrogen atom or a methoxy group, o G is as defined in claim 1, the dotted line represents the optional second, as well as their addition salts with acids and bases, and their esters. 3 (I) as defined in claim 1 or claim 2, characterized in that they _are R represents -OH, -OCH _3, -OCH ₂ CH _3, -O- (CH _{2) 2} OH, -O-CH ₂ -CH (OH) -CH ₂ OH, -O- (CH ₂ ) ₂ NH ₂ , -O- (CH ₂ ) ₂ -N (CH ₃ ) ₂ , -nh ₂ or -O- (CH ₂ ) ₂ -phenyl groups as well as their addition salts with acids and bases and their esters. Compounds of general formula (I) according to claim 1, 2 or 3, wherein Rf represents O- (CH ₂ ) ₀ -6-CH (Z ') - COOH or - (OH ₂ ) o. ₇ -CH (Z ') - COOH groups, as well as their addition salts with acids and bases and their esters. Compounds of general formula (I) according to any one of Claims 1 to 4, characterized in that they contain (Z ') a hydrogen atom as well as their addition salts with acids and bases and their esters. Compounds of general formula (I) according to any one of Claims 1 to 4, characterized in that (Z ') contains (CH ₂ ) o -6-NH-CO ₂ -R c or (CH ₂ ) ₀ -6-. NHRb groups wherein Rb and Re are as defined in claim 1, as well as their acid and base addition salts and their esters. 7. (I) as defined in claim 6, characterized in that they contain Rb and R is (CH ₂₎ o-3-Ar or (CH _{2) 0} -3-Alk group in which Ar and Alk are as defined 1, and may or may not be substituted, as well as their addition salts with acids and bases and their esters. Compounds of general formula (I) according to any one of Claims 1 to 7, characterized in that G contains a group G4 of the general formula -NHC (= NH) -NHRc, and Re is as defined in Claim 1, and also their addition salts with acids and bases and their esters. Compounds of general formula (I) according to claim 8, characterized in that they contain a hydrogen atom as well as their addition salts with acids and bases and their esters. Compounds of general formula (I) according to any one of Claims 1 to 7, characterized in that G contains a -NH- (Het ') group in which (Hetj) is as defined in Claim 1. Compounds of general formula (I) according to claim 10, characterized in that G represents the following heterocycles: wherein p is an integer equal to 2, 3 or 4; these heterocycles are substituted or unsubstituted as well as their addition salts with acids and bases and their esters. 12. Compounds of general formula (I) according to claim 10 or 11, characterized in that G contains: - a group C (CH ₂ ) p ^ NH ' ⁷ wherein p is an integer equal to 2, 3 or 4 as well as their addition salts with acids and bases and their esters. 13. Compounds of general formula (I) according to Claim 1, characterized in that they have the following names: 4 - ((4 - ((aminoiminomethyl) hydrazono) -9,10-dimethoxy-1,2,3,4,5,6hexahydro-8-benz (e) azulenyl) oxy) butanoic acid, 5 - ((4 - ((aminoimidomethyl) hydrazorio) -9,10-dimethoxy-1,2,3,4,5,6hexahydro-8-benz (e) azulenyl) oxy) pentanoic acid, 5 - ((4 - ((aminoiminomethyl) hydrazono) -8,10-dimethoxy-1,2,3,4,5,6hexahydro-9-benz (e) azulenyl) oxy) pentanoic acid, 6 - ((4 - ((aminoiminomethyl) hydrazono) -9,10-dimethoxy-1,2,3,4,5,6hexahydro-8-benz (e) azulenyl) oxy) hexanoic acid, 7 - ((4 - ((aminoiminomethyl) hydrazono) -9,10-dimethoxy-1,2,3,4,5,6hexahydro-8-benz (e) azulenyl) oxy) heptanoic acid, 5 - ((9,10-dimethoxy-1,2,3,4,5,6-hexahydro-4 - ((4,5-dihydro-1 H -imidazol-2-yl) hydrazone-8-benz (e) azulenyl)) oxy) pentanoic acid, 5 - ((4 - ((aminoiminomethyl) hydrazone) -9,10-dimethoxy-1,2,3,4,5,6hexahydro-8-benz (e) azulenyl) oxy) pentanoic acid ethyl ester hydrochloride, 4 - ((4 - ((aminoiminomethyl) hydrazono) -8,9-dimethoxy-1,2,3,4,5,6hexahydro-10-benz (e) azulenyl) oxy) butanoic acid, 5 - ((4 - ((aminoiminomethyl) hydrazono) -8,9-dimethoxy-1,2,3,4,5,6hexahydro-10-benz (e) azulenyl) oxy) pentanoic acid, 5 - ((4 - (((amino) carbonyl) hydrazono) -9,10-dimethoxy-1,2,3,4,5,6hexahydro-8-benz (e) azulenyl) oxy) pentanoic acid, 5 - ((4 - (((amino) thiocarbonyl) hydrazono) -9,10-dimethoxy-1,2,3,4,5,6hexahydro-8-benz (e) azulenyl) oxy) pentanoic acid, 4 - ((4 - ((aminoiminomethyl) hydrazono) -8,10-dimethoxy-1,2,3,4,5,6hexahydro-9-benz (e) azulenyl) oxy) butanoic acid, 6 - ((4 - ((4,5-dihydro-1H-imidazol-2-yl) hydrazono) -9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz (e) azulenyl) oxy) hexanoic acid, 5 - ((4 - ((aminoiminomethyl) hydrazono) -9,10-dimethoxy-1,2,3,4,5,6hexahydro-8-benz (e) azulenyl) oxy) -3,3-dimethyl-4- oxopentanoic acid, 5 - ((4 - ((4,5-Dihydro-1 H -imidazol-2-yl) hydrazorio) -9,10-dimethoxy-1,2.3.4.5.6-hexahydro-8-benz (e) azulenyl) oxy) - 3,3-dimethyl-4-oxopentanoic acid, 5 - ((4 - ((aminoiminomethyl) hydrazone) -9,10-dimethoxy-1,2,3,4,5,6hexahydro-8-benz (e) azulenyl) oxy) pentanoic acid hydrochloride, 4 - ((4 - ((4,5-Dihydro-1H-imidazol-2-yl) hydrazono) -9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz (e) azulenyl) oxy) butanoic acid, 5 - ((8 - ((aminoiminomethyl) hydrazono) -6,7,8,9,10,11-hexahydroazulene (5,6-d) -1,3-benzodioxol-4-yl) oxy) pentanoic acid, 5 - ((8 - ((aminoiminomethyl) hydrazono) -2,2-diphenyl-6,7,8,9,10,11hexahydro-azulene (4,5-e) - (1,3) -benzodioxo-4 -il) oxy) pentanoic acid, 4 - ((9,10-dimethoxy-4 - ((1,4,5,6-tetrahydro-2-pyrimidinyl) hydrazone) 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 ) acetic acid, 3 - ((4 - ((4,5-Dihydro-1H-imidazol-2-yl) hydrazono) -9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz (e) azulenyl) oxy) propane acid, 4 - ((4 - ((4,5-dihydro-1H-imidazol-2-yl) hydrazone) -1,2,3,4,5,6-hexahydro-8-benz (e) azulenyl) oxy) butanoic acid, O- [4 - [(4,5-Dihydro-1H-imidazol-2-yl) hydrazono] -9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz [e] azulenyl] -N- [ (phenylmethoxy) carbonyl] -DLhomoserine, 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-homoseririas, O- [4 - [(1,2,3,4-Tetrahydro-6-pyrimidinyl) hydrazono] -9,10-dimethoxy-1,2,3,4,4,5,6-hexahydro-8-benz [e] azulenyl] -N- [ (phenylmethoxy) carbonyl] -DL · homoserine, 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] -DLhomoserine 2,3-dihydroxypropio ester, O- [4 - [(4,5-Dihydro-1H-imidazol-2-yl) hydrazono] -9,10-dimethoxy-1,2.3.4.5.6-hexahydro _: 8-benz (e) azulenyl] -N- [ (8-quinolinyl) sulfonyl] -DL · homoserine, O- [4 - [(4,5-Dihydro-1H-imidazol-2-yl) hydrazono] -9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz (e) azulenyl] -N- [ [3- [4- (3-Pyridinyl) -1H-imidazol-1yl] propoxy] carbonyl] -DL-homoserine monohydrochloride, 5 - [[4 - [(4,5-Dihydro-4-oxo-1H-imidazol-2-yl) hydrazono] -9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz (e) azulenyl] oxy] pentanoic acid, O- [9,10-Dimethoxy-1,2,3,4,5,6-hexahydro-4 - [(4,5,6,7-tetrahydro-1H-1,3-diazepin-2-ii) hydrazone] -8-benz (e) azulenyl] -N - [(phenylmethoxy) carbonyl] -DLhomoserine, O- [9,10-Dimethoxy-1,2,3,4,5,6-hexahydro-4 - [(3a, 4,5,6,7,7a-hexahydro-1 H -benzimidazol-2-yl) hydrazone] - 8-Benz (e) azulenyl] -N - [(phenylmethoxy) carbonyl] DL-homoserine. 14. A process for the preparation of compounds of the general formula (I) as defined in claim 1, characterized in that the compound of the formula (II): wherein R ₂ , R ₃ , R ₄ and R ₅ are as defined in claim 1 with the exception of hydroxyl, either acting on a compound of formula (F 1) Hal- [A] - [B] -COR ₆ (F1) in the presence of a base or a compound of the formula (FU): HO- [A] - [B] -COR ₆ (F 'in the presence of phosphine and diethyl azodicarboxylate, where Hal is a halogen atom, [A], [B] and Re are as described above, -CHI [B] may also be ^NH -P _ς Γυ ρθ, py _no amino protecting group to form a compound of formula (IIIa): or activates a group, then acts with a compound of formula (F2): O H - C = C - [Aj - [B] -CR ₆ (F 2) in the presence of a catalyst to form a compound of formula (IIIb): (Hlb) followed by treating the compounds of formulas (IIIa) and (IIIb) with a compound of formula (F3): H ₂ NG (F3) wherein G is as defined in claim 1 to give compounds of formulas (IVa) and (IVb) corresponding to certain products of formula (I): (IVa), II R ₆ -C - [B] - [A] - (= N - G (IVb)) which are then reacted, as appropriate, with one or more of the following reagents: with a base or acid to cleave the ester and obtain the corresponding acid, a reducing agent suitable for partial or total reduction of unsaturated bonds, an agent for triple hydration, a dealkylation agent, The NH-P group in the beta position relative to the CO-R ₀ group, when [B] represents CH-NHP, as a deprotecting agent, introduces NH-SO ₂ Rc, NH-CO ₂ Rc, NHCORc, NH-SO ₂ -NHR _C , NH-CO-NHRc groups, leaving the corresponding amino group at the beta position relative to the CO-R ₀ group and obtaining the corresponding compounds of formula (I) which are optionally treated with an acid or a base to give the corresponding salts, or an esterification agent to give the corresponding esters. 15. A process for the preparation of compounds of the general formula (I) as defined in claim 1, wherein the compound of the formula (II) initially acts as a compound of the formula (F3) to form a compound of the formula (Ule): followed by G-blocking (where appropriate) with a compound of formula (F1), (F'1) or (F2), followed by G-deprotection (if necessary) to yield the corresponding products of formulas IVa and IVb and, if necessary, performing various reactions such as those described in paragraph 14; Compounds of formulas (II), (F1), (F'1), (F2), (F3), IVa) and (IVb) are as described in claim 14. 16. A process for the preparation of compounds of general formula (II) as defined in claim 14 wherein R ₂₁ , R 3, R ₄ and R ₈ are hydrogen atoms and OH is in the 8-, 9- or 10-position, wherein (i) Compound of Formula (a): wherein O- (Alk) is in the meta- or para-position with respect to the alkylcarboxy group, (Alk) being as defined in claim 1, acting as a halogenating agent to form the corresponding acyl halide, (ii) acting as a reagent of formula (b): R (l) \ r R (II / (b)). wherein R (l) and R (II), the same or different, represent an alkyl group having from 1 to 6 carbon atoms, or R (l) and R (II) together with the nitrogen atom to which they are attached represent 5- or a 6-membered, saturated or unsaturated heterocycle which may have another heteroatom selected from O and N to give a compound of formula (c): (iii) acting as a halogenating agent to form a compound of formula (d): wherein Hali represents a halogen atom (iv) which is reacted with Lewis acid to form a compound of formula (e): (v) acting as a deacylation reagent and finally obtaining a product of formula (IIF) corresponding to the expected mono-substituted product of formula (II): 17, Compounds of general formula (II) as defined in claim 14, wherein R ₂ is either O- (Alk) or O- (CH ₂ ) o-3-Ar and R ₃ , R ₄ and R ₅ are hydrogen. atoms, OH and R ₂ are in the 8-, 9- or 10-position, wherein the compound of formula (a '): wherein R ₂ and O- (Alk) .- are in the meta or para position with respect to the alkyl carboxy group, carrying out the reactions of (i), (ii), (iii), (iv) and (v) to give the product of formula (IIG) corresponding to] the expected disubstituted product of formula (II): Compounds of the general formula (II) as defined in claim 14, wherein R ₂ and R ₃ represent O- (Alk) 'or O- (CH ₂ ) ₀ -3-Ar groups, R ₄ and R ₅ are hydrogen atoms and OH is in the 9-position, except that the compound of formula (HA): acts as a deacylation reagent to give a compound of formula (IIB): powered by: or a diol blocking reagent in an alkaline medium to selectively form a product of formula (liC): (UC), wherein P is the residue of a diol blocking reagent, which is then treated successively with a phenol blocking reagent, a diol deprotection reagent, an alkylating agent and then a phenol deprotecting reagent to give a compound of formula (IID) corresponding to the triple product of formula OH group at position 8: ΗΓ O (IID) or acts sequentially with a phenol blocking agent, an alkylating agent, followed by a deprotecting agent to give a compound of formula (IIE) corresponding to the tri-substituted product of formula (II) with an OH group at position 9: O (E). Compounds of formula (I) according to any one of claims 1 to 12, and pharmaceutically acceptable addition salts and esters thereof as medicaments. Compounds of formula (I) according to claim 13 as medicaments. 21. Pharmaceutical compositions, characterized in that they contain, as an active ingredient, at least one of the medicaments according to claim 19 or 20. Compounds of general formulas (IIIa), (IIIb), (IIIc) and (II), except those of (III), 2,3,5,6-tetrahydro-9,10-dimethoxy- 8-hydroxy-benz (e) azulen-4 (1H) -one and 2,3,5,6-tetrahydro-8,9-dimethoxy-10-hydroxy-benz (e) azulen-4 (1H) -one as new intermediates products.