ITBO20090236A1 - PROCEDURE FOR THE SYNTHESIS OF COMPOUNDS FOR THE TREATMENT OF TUMOR TO THE PROSTATE - Google Patents

Description

DESCRIPTION

of the patent for Industrial Invention entitled:

"PROCEDURE FOR THE SYNTHESIS OF COMPOUNDS FOR THE TREATMENT OF PROSTATE CANCER"

The present invention relates to a process for the synthesis of a compound.

The androgen receptor (RA), a member of the steroid receptor superfamily, is a cytosolic protein whose action, according to the most probable model, involves the diffusion of androgens across the plasma membrane resulting in the formation of an androgen-receptor complex in the cytosol. Once the androgen-receptor complex is formed, it is able to diffuse into the nucleus, where it undergoes conformational changes, exposing some steric sites that interact with nuclear chromatin and cause a change in DNA transcription and protein synthesis.

In case of mutation, genetic amplification or overexpression of co-activators, there is a hypersensitivity of the androgen receptor (Heinlein, C.A .; Chang, C. Endocr Rev 2004, 25, 276–308; Chen, C.D .; Welsbie. D. - S .; Tran, C., Baek, S.H .; Chen, R .; Vessella, R .; Rosenfeld, M. G .; Sawyers, C.L. Nat Med., 2004; 10, 33–9; Isaacs, J.T.; Isaacs, W. B. Nat. Med. 2004; 10, 26-7).

Many forms of prostate cancer increase thanks to the presence of testosterone (TS), the male hormone produced by the testicles and adrenal glands. Therefore, a reduction in hormone levels is one of the therapies used for the treatment of these pathologies. Reducing hormone levels (androgen deprivation) can be done in two different ways. For example through surgical castration or hormone therapy.

An alternative technique to those previously discussed and widely used today is the use of antiandrogenic drugs. These molecules bind to the receptor, inhibiting the action of endogenous hormones and ultimately inducing cellular apoptosis. Contrary to the hormone-receptor complex, the antiandrogen receptor complex is unstable and consequently genetic transcription and protein synthesis are inhibited (Gaillard-Moguilewsky, M. Urology 1991, 37 (Suppl), 5-12). Anti-androgens, based on their structure and nature, manifest their activity according to two different mechanisms: inhibition of ligand production (testosterone, TS and dihydrothesotsterone, DHT), or by blocking the receptor itself against the androgen.

Anti-androgens can be steroid or non-steroidal in nature. Cyproterone acetate, CPA, is a steroid antiandrogen used for the treatment of prostate cancer. Its use, however, is limited by the fact that this compound, in addition to blocking the activity of RA, inhibits the release of LH (lutenizing hormone), inducing a serious lowering of the levels of TS in the circulation, with consequent serious implications in the sexual sphere. of the individual (Furr, B.J.A .; Kaisary, A.V. Treatment: hormonal manipulation: Antiandrogens. In Kaisary, A.V .; Murphy, G.P .; Denis, L .; Griffiths, K. eds. Textbook of Prostate Cancer: Pathology, Diagnosis and Treatment. London : Martin Dunitz, 1999: 277–90).

Treatment with non-steroidal anti-androgens, on the other hand, is carried out with bicalutamide, flutamide or nilutamide (Tucker, H .; J. W. Crook, J. W .; Chesterson J. J. Med. Chem., 1988, 31, 954-959). These molecules are defined as "pure" anti-androgens because they compete with TS and DHT in interacting with the receptor, without altering the levels of TS circulating in the body. Pre-clinical data suggest that of the three molecules mentioned above, bicalutamide may be the most active in the treatment of prostate cancer. Bicalutamide, IUPAC name N- [4-cyano-3- (trifluoromethyl) phenyl] -3 - [(4-fluorophenyl) sulfonyl] -2-hydroxy-2-methyl-propanamide, is marketed by ASTRA ZENECA pharmaceuticals such as Casodex < ®> and acts by lowering TS levels in the prostate, without affecting the regulatory activity of the hypothalamus.

Bicalutamide (1) Flutamide Nilutamide Despite the good results obtained in the treatment of prostate cancer, thanks to the use of endocrine therapy based on non-steroidal anti-androgens and similar LHRH, clinical data show that this therapy is very effective initially, but that the its validity is limited in time. In fact, almost 50% of patients undergoing this therapy develop resistance to the treatment after a certain period (18-20 months). This resistance is likely linked to the development of hormone-independent cancer cells, or to the adrenal androgens having the ability to allow tumor growth themselves (Oh, W. K .; Kantoff, P. W. J Urol 1998, 160,1220–1229) .

It was also observed that for about 50% of patients with prostate cancer and treated with therapies that also include the use of anti-androgens, the tumor regresses when treatment is stopped. The name of “anti-androgen withdrawal response” (AAWR) has been associated with this phenomenon.

More recently, a new class of anti-androgens has been studied for which in vitro and pre-clinical studies have shown remarkable anti-androgenic activity, although their clinical activity is not yet known. Some examples of this class of molecules are: a) analogues of nilutamide; b) derivative of quinolone; c) RA antagonists containing a carbonic functionality and a hydrophobic skeleton. These molecules bind the androgen receptor and show anti-androgenic activity against SC-3 (Androgen dependent) cells, d) β-alklitium indole carbinols; e) phenothiazines derivatives.

Although these compounds have shown good affinity for RA and can be administered orally, they do not appear to possess tissue selectivity, thus also blocking androgen receptors in tissues other than the prostate, including skeletal muscles.

From the foregoing it is clear that there is still a considerable need to make available new compounds and in particular medicaments for the treatment of tumor pathologies, in particular of the prostate.

There is also a need to make new compounds available for the treatment of further pathologies such as osteoporosis, andropause, menopause, muscle wasting, cachexia, male infertility, Alzheimer's, arteriosclerosis, hypercholerestemia, prostatic hyperplasia, muscular dystrophy, osteopenia, osteoporosis induced by glucocorticoids, periodontal disease, bone fractures, bone damage following bone reconstruction surgery, sarcopenia, skin aging, male hypogonadism, postmenopausal symptoms in women, hyperlipidaemia, obesity, haematopoietic disorders (especially aplastic anemia), pancreatic cancer , inflammatory arthritis.

From the structural point of view, bicalutamide consists of a central core characterized by a substituted tetra carbon, therefore it exists in two enantiomeric forms, (US 2007149800 A1) even if the racemic mixture is currently marketed. However, it has been widely demonstrated that the most biologically active form is the (R) form, which appears to have an affinity for the receptor 30 times higher than the enantomeric form (S) (Tyagi, Om Dutt; Chauhan, Yogendra Kumar; Atmaram, Chavan Yuvraj; Dasdaji, Pawar Yogesh. An improved process for the purification of bicalutamide. Indian Pat. Appl. (2007), 15pp. CODEN: INXXBQ IN 2005KO00778 A 20070525 CAN 147: 433448 AN 2007: 607391). Furthermore, these compounds are metabolized by the liver (Tyagi, Om Dutt; Chauhan, Yogendra Kumar; Chavan, Yuvraj Atmaram; Pawar, Yogesh Dadaji. An improved process for the preparation of bicalutamide. Indian Pat. Appl. (2007), 21pp. CODEN : INXXBQ IN 2005KO00740 A 20070525 CAN 148: 426541 AN 2007: 607364) and in particular the (S) form is metabolized much faster than the (R) causing an overload of the liver itself. In addition to these aspects, it must be considered that the administration of pure enantiomenro would make it possible to significantly reduce the dosages. Therefore, the development of an industrially applicable enantioselective synthesis is desirable.

A chemical process for the enantioselective synthesis of Bicalutamide and its analogues has been reported in the Ekwuribe patent (US 6,583,306 B1).

It is important to note that the synthesis reported in this patent (US 6,583,306 B1) is carried out starting from (S) -citramallic acid, an economically not convenient starting compound. Another asymmetric synthesis to produce (R) -bicalutamide is performed starting from (R) -proline, (WO2006103689) which is also extremely expensive and therefore inaccessible from an industrial point of view. Another synthesis methodology of (R) -bicalutamide is based on an enzymatic hydrolysis reaction of the epoxide 2-methyl glycol benzyl ether (US 2006183934; EP1669347) followed by a complex series of synthetic steps which, on the whole, are expensive and of low surrender.

From an analysis of the state of the art, it is therefore evident that none of the processes known for the enantioselective synthesis of (R) -Bicalutamide is industrially applicable, either because of the high costs of the starting materials or because of the complexity of the process itself.

In consideration of this, there is also a considerable need to make available new processes for the synthesis of compounds (in particular, for the synthesis of Bicalutamide and its derivatives).

The purpose of the present invention is to provide a process for the synthesis of a compound, which allows to overcome, at least partially, the drawbacks of the known art and is, at the same time, easy and economical to produce.

According to the present invention there is provided a process for the synthesis of a compound according to what is disclosed in the following independent claims and, preferably, in any one of the claims directly or indirectly dependent on the independent claims.

Unless otherwise explicitly specified, the following terms have the meanings given below.

In this text, "pharmaceutically acceptable salt" means a salt which maintains the biological properties of the starting compound. Non-limiting examples of methodologies for the preparation of such salts include the following: addition of inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like) or organic acids (e.g. acetic acid, oxalic acid, maleic acid, methanesulfonic acid, salicylic acid, succinic acid, citric acid and the like) to a free base of the starting compound; replacement of an acid proton of the starting compound with a metal cation (for example a cation of an alkali metal or an aluminum or the like); transfer of an acid proton of the starting compound to an organic base (for example dimethylamine, triethylamine and the like) and coordination with this organic base. The compounds object of the present invention are to be understood, unless otherwise specified, as comprising their pharmaceutically acceptable salts.

In this text, “pro-drug” (“prodrug”) means an agent which is converted in vivo into a pharmacologically active substance. A pro-drug may have some advantages over the corresponding pharmacologically active substance. For example, it may be easier to administer to patients and / or have higher solubility and / or better ability to cross cell membranes. The compounds object of the present invention are to be understood as including their possible pro-drugs. The compounds object of the present invention can act as pro-drugs of further pharmacologically active substances.

Some compounds of this text may have one or more asymmetric centers; such compounds can, therefore, be produced as stereoisomers (R) - or (S) - or as mixtures thereof. The compounds identified in this text are to be understood, unless otherwise specified, as including both the isomers individually and their mixtures, racemic or otherwise. Methods for the determination of stereochemistry and separation of stereoisomers are known in the state of the art (see, for example, Chapter 4 of "Advanced Organic Chemistry", 4th edition L. March, John Wiley and Sons, New York, 1992 ).

The compounds identified in this text may exhibit tautomerism and / or geometric isomerism (ie cis-trans isomerism); such compounds are to be understood, unless otherwise specified, as comprising tautomeric and / or geometrically isomeric forms taken both individually and in mixtures. Therefore, in the present text "geometric isomers" means isomers that differ in the spatial arrangement of the groups bonded to a carbon of a carbon-carbon double bond (cis-trans isomers).

In particular, the groups linked to a carbon of a carbon-carbon double bond can be spatially arranged with respect to the double bond so as to define molecules with cis or trans isomerism. The compounds of the present text having a carbon-carbon double bond are to be understood as including the cis forms, the trans forms and their mixtures.

In this text, the term "treatment" of or "treating" a pathology means treating and / or prophylaxis and / or therapy for that pathology. By prophylaxis we mean, advantageously, at least partially preventing the development of a potential pathology and / or preventing the worsening of symptoms and / or the progression of a pathology. By therapy we mean partially or totally relieving the symptoms of a disease and / or reducing the extent of a disease. Advantageously, by "treatment" of or "treating" a pathology we mean therapy for that pathology.

In the present text, "Cx-Cy" refers to a group which is intended as having x to y carbon atoms.

In this text, "aliphatic" means a non-aromatic and unsubstituted hydrocarbon (unless otherwise specified), saturated or unsaturated, linear, branched and / or cyclic. Non-limiting examples of aliphatic groups are: t-butyl, ethenyl, 1- or 2-propenyl, cyclohexyl.

In the present text, "substituted aliphatic" means an aliphatic linked to from 1 to 9 substituents advantageously selected, each independently of the other, from the group consisting of: halogens, cyclic unsubstituted alkyls C3-C10 (in particular, C3-C6) cyclic unsubstituted heteroalkyls C2-C10 (in particular, C3-C6), -OH, alkoxy C1-C4, amino, acylamino, carboxy.

In the present text, "alkyl" means a saturated aliphatic (ie an aliphatic group devoid of double or triple carbon-carbon bonds). Non-limiting examples of alkyls are: methyl, n-propyl, t-butyl, cyclohexyl.

In the present text, "substituted alkyl" means an alkyl linked to from 1 to 9 substituents advantageously selected, each independently of the other, from the group consisting of: halogens, cyclic unsubstituted alkyls C3-C6, cyclic unsubstituted heteroalkyls C3-C6 , -OH, C1-C4 alkoxy, amino, acylamino, carboxy. When the term "Cx-Cy" is associated with the term substituted alkyl, the latter term refers to the total number of carbon atoms including the carbon atoms of the substituent (s).

In the present text, "alkylthio" means a -SR <m> group, in which R <m> is an alkyl.

In the present text, "alkylsulfinyl" means a -SOR <m> group, where R <m> is an alkyl.

In the present text, by "alkylsulfonyl" is meant a -SO2R <m> group, in which R <m> is an alkyl.

In the present text, by "carbamoyl methyl" is meant the group having the formula -CH2-CONH2.

In the present text, a group indicated with the prefix "per-fluorine" is a group in which the alkyl moiety is completely replaced by fluorine atoms. For example: per-fluoro methyl has the formula -CF3; per-fluoroethylthio has the formula -S-CF2-CF3.

In the present text, the term "electron-withdrawing group" means a group capable of exerting an electron-withdrawing effect on phenyl due to an inductive and / or resonance effect.

In the present text, "alkenyl" means an aliphatic having at least one carbon-carbon double bond.

In the present text, by "aromatic group" or "aromatic" is meant an unsubstituted group having at least one aromatic ring, in particular containing from 5 to 12 members and a substantially conjugated π electronic system. In particular, the aromatic group consists of a monocyclic ring or several fused rings (i.e. rings that share at least one pair of adjacent and bonded atoms). Each aromatic ring can be aryl (i.e., where all the members of the ring are carbon atoms) or heteroaromatic (i.e., where one, two or three of the ring members are chosen from N, O, S, NO, SO2; the remaining members of the ring are carbon atoms). Non-limiting examples of aromatic groups are: phenyl, naphthalene, anthracene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, purine and carbazole.

The term "aryl" or "aryl", as used in this text, indicates a C6-C10 aromatic group, comprising at least one aromatic ring, all members of which are carbon atoms. An “aryl” or “aryl” group can have multiple fused rings (for example naphthalene) or polycyclic (for example a biphenyl). All the carbon atoms of an "aryl" or "aryl" group are members of a ring. Examples of aryls are: phenyl, naphthalene and biphenyl.

By "substituted aryl" or "substituted aryl" group we mean a group consisting of an aryl bound to from one to three substituents selected, each independently from the others, in the group consisting of: halogen, hydroxy, -CN, -NO2, C1 alkyl -C4, alkoxy C1-C4, carboxy, carbamoyl methyl (-CONH2), amino, acylamino, trifluoromethyl, silane, -NCS, -N-succinimide, - (N (SO2) R <19>), wherein R <19 > is selected from the group consisting of: C1-C4 alkyl, aryl, aryl substituted with a C0-C4 substituent. According to advantageous embodiments of the present invention, the "substituted aryl" or "substituted aryl" group is linked to a single substituent selected between -NCS and -N-succinimide.

In the present text, "alkylaryl" means an alkyl bonded to an aryl or a substituted aryl. The alkyl portion is bonded to the remaining part of the molecule. When the term "alkylaryl" is followed by the term "Cx-Cy", the latter term refers only to the alkyl portion and not to the substituted aryl or aryl. Therefore, for example, -CH2CH2Ph falls within the definition of C2-C3 alkylaryl. According to some embodiments, the alkylaryl comprises an aryl and not a substituted aryl.

In the present text, "alkoxy" means an aliphatic (advantageously an alkyl) bound to the remaining part of the molecule through an oxygen atom. Non-limiting examples of alkoxy groups are: methoxy, ethoxy.

In the present text, "amino" means a group having the formula -NR <b> R <c> in which R <b> and R <c> are chosen, each independently from the other, from the group consisting of: -H, C1-C4 alkyl. Optionally, R <b> and R <c> are linked together to form a cycle.

In the present text by "acylamino" is meant a group having the formula -NCOR <h> in which R <h> is selected from the group consisting of: -H, C1-C4 alkyl.

The term "alkanoyl", as used in this text, represents an aliphatic group or a substituted aliphatic group bonded to the remaining part of the molecule through a carbonyl group.

The term "carboxy", as used in this text, represents a -COOR <a> group, wherein R <a> is chosen from the group consisting of: -H, C1-C4 alkyl. According to some embodiments, R <a> is a C1-C4 alkyl.

In the present text, "silane" means a group having the formula -SiR <d> R <e> R <f>, in which R <d>, R <e> and R <f> are chosen, each independently of the other in the group consisting of: -H, phenyl, C1-C4 alkyl.

In the present text, by "cyclic alkyl" is meant an alkyl consisting of a non-aromatic monocyclic ring or of several fused rings (ie rings that share at least one pair of adjacent and bonded atoms) that are non-aromatic. Advantageously, a cyclic alkyl consists of only one ring (i.e. no more than one). In particular, the ring or rings have from three to six members. Advantageously, the ring or rings have five or six members. Non-limiting examples of cyclic alkyls are: cyclopentyl, cyclohexyl.

In the present text, "heteroalkyl" means an alkyl in which instead of one of the carbon atoms there is a hetero radical chosen from the group consisting of: -N-, -O-, -S -, - NR <g> - , -SO2-, wherein R <g> is selected from the group consisting of: H, C1-C4 alkyl.

In the present text, "substituted heteroalkyl" means a heteroalkyl bonded to from 1 to 9 substituents advantageously selected, each independently of the other, from the group consisting of: halogens, cyclic unsubstituted alkyls C3-C6, cyclic unsubstituted heteroalkyls C3-C6 , -OH, C1-C4 alkoxy, amino, acylamino, carboxy. When the term "Cx-Cy" is associated with the term substituted alkyl, the latter term refers to the total number of carbon atoms including the carbon atoms of the substituent (s).

In the present text, "cyclic heteroalkyl" means a heteroalkyl consisting of a non-aromatic monocyclic ring or of several fused rings (ie rings that share at least one pair of adjacent and bonded atoms) that are non-aromatic; the members of at least one first ring are carbon atoms except from one to three members of the ring which are selected from N, O, S, NO, NR <g>, SO2, where R <g> is selected from the group consisting di: H, C1-C4 alkyl; the further rings are defined as the first ring or are cyclic alkyls. Advantageously, a cyclic heteroalkyl comprises only one ring (i.e. no more than one). In particular, the ring or rings have from three to six members. Advantageously, the ring or rings have five or six members. Non-limiting examples of cyclic heteroalkyls are: tetrahydrofuran, tetrahydrothiophene.

In the present text, "aromatic heterocycle" means a C4-C10 aromatic group in which at least one aromatic ring is heteroaromatic, that is, in which the members of the ring are carbon atoms except one to three members of the ring which they are chosen from N, O, S, NO, SO2. Examples of aromatic heterocycle substituents are: pyridine, pyrrole, pyrazole, imidazole, thienyl, furan, indocyl, indolizinyl, aza-indolizinyl, quinoline, pyrazine, pyrimidine, pyridazine, oxazole, iso-oxazole, benzooxazole, benzookinazole, benzo-thiazole , benzotriazole, benzofuran, benzothienyl, benzopyran, isoquinoline, benzo-imidazolol, benzo-triazolol, benzofuran, benzo-thienyl, benzo-pyran, imidazo [2,1-b] thiazole, imidazo [1,2-a] pyridine, imidazo [1,2-a] pyrimidine, pyrazole [1,5, a] pyridine, imidazole, triazole, thia-diazole, oxadiazole, thiazole, triazolopyrimidinine, pyrazolopyrimidine, thieno pyrimidinine, pyrrolpyridinyl 4,5,6,7-tetrahydrobenzisoxazole , 4,5,6,7-tetrahydroindazole and 4,5,6,7-tetrahydrobenzo thienyl.

By "substituted aromatic heterocycle" group we mean a group consisting of an aromatic heterocycle bound to from one to three substituents selected, each independently from the others, in the group consisting of: halogen, hydroxy, -CN, -NO2, C1-C4 alkyl, alkoxy C1-C4, carboxy, carbamoyl methyl (-CONH2), amino, trifluoromethyl, silane, -NCS, -N-succinimide, - (N (SO2) R <19>), wherein R <19> is selected in the group consisting of: C1-C4 alkyl, aryl, aryl substituted with a C0-C4 substituent. According to advantageous embodiments of the present invention, the "substituted aromatic heterocycle" group is linked to a single substituent selected between -NCS and -N-succinimide.

In the present text, "heteroaromatic alkyl" means an alkyl bonded to an aromatic heterocycle or a substituted aromatic heterocycle; this alkyl is bound to the remaining part of the molecule. When the term "heteroaromatic alkyl" is followed by the term "Cx-Cy", the latter term refers only to this alkyl and not to the aromatic heterocycle or substituted aromatic heterocycle. Therefore, for example, an ethyl furan falls within the definition of C2-C3 heteroaromatic alkyl. According to some embodiments, the heteroaromatic alkyl comprises an aromatic neterocycle and not a substituted aromatic heterocycle.

The invention will now be described with reference to the attached drawings, which illustrate some non-limiting examples of implementation, in which:

- Figure 1 illustrates the cytotoxic activity of (R) -Bicalutamide (graph on the right), of compound I-2 (graph in the center), of compound I-3 (graph on the right); the ordinate indicates the net percentage growth (% netgrowth); the concentration (μM) is indicated on the abscissa;

- Figure 2 illustrates the activity of Bicalutamide () and compound I-3 (U) at steady state concentration - 20 μM - on the LNCaP cell line in ordinate the net percentage growth (% netgrowth) is indicated; the time (hours) is indicated on the abscissa.

According to a first aspect of the present invention, a compound is provided having the eneral formula I

or its geometric isomers or its optically active forms or diastereomers or its racemic forms or its pharmaceutically acceptable salts or its pro-drugs.

According to some embodiments, R is selected from the group consisting of: aryl, substituted aryl, C1-C4 alkylaryl, C1-C4 heteroaromatic alkyl, aromatic heterocycle, substituted aromatic heterocycle, C2-C12 substituted alkyl, C2-C10 alkyl, heteroalkyl C2-C10, C2-C10 substituted heteroalkyl.

According to some embodiments, R is selected from the group consisting of: aryl, substituted aryl, C1-C4 alkylaryl, C1-C4 heteroaromatic alkyl, aromatic heterocycle, substituted aromatic heterocycle, C2-C12 substituted alkyl, C2-C10 alkyl, heteroalkyl C2-C10.

According to some embodiments, R is selected from the group consisting of: aryl, substituted aryl, C1-C4 alkylaryl, C1-C4 heteroaromatic alkyl, aromatic heterocycle, substituted aromatic heterocycle, substituted C2-C12 alkyl, branchified C3-C10 alkyl, heteroalkyl C2-C10.

According to some embodiments, R is selected from the group consisting of: aryl, substituted aryl, C1-C4 alkylaryl, C1-C4 heteroaromatic alkyl, aromatic heterocycle, substituted aromatic heterocycle, C3-C12 substituted alkyl, branchified C3-C10 alkyl, heteroalkyl C3-C10.

According to some embodiments, R is selected from the group consisting of: aryl, substituted aryl, C1-C4 alkylaryl, C1-C4 heteroaromatic alkyl, aromatic heterocycle, substituted aromatic heterocycle, C3-C10 substituted alkyl, C3-C10 alkyl.

Advantageously, with reference to the definition of R, the alkyl is C5-C8.

According to some embodiments, R is chosen from the group consisting of: C1-C4 alkylaryl; C1-C4 heteroaromatic alkyl; substituted C4-C10 alkyl, which comprises at least one substituent selected from the group consisting of: a C3-C6 unsubstituted cyclic alkyl and C3-C6 unsubstituted cyclic heteroalkyl; C4-C10 alkyl.

According to some embodiments, R is chosen from the group consisting of: C1-C4 alkylaryl; C4-C10 substituted alkyl; branched C4-C10 alkyl.

According to some embodiments, R is chosen from the group consisting of: C1-C4 alkylaryl; substituted C4-C10 alkyl, which comprises at least one substituent selected from the group consisting of: a C3-C6 unsubstituted cyclic alkyl and C3-C6 unsubstituted cyclic heteroalkyl; branched C4-C10 alkyl.

According to some embodiments, R is chosen from the group consisting of: C1-C4 alkylaryl; substituted C4-C10 alkyl, which comprises at least one substituent selected from the group consisting of: a C3-C6 unsubstituted cyclic alkyl and C3-C6 unsubstituted cyclic heteroalkyl.

According to some embodiments, R is chosen from the group consisting of: C1-C4 alkylaryl; C1-C4 heteroaromatic alkyl; C5-C10 substituted alkyl, which comprises at least one substituent selected from the group consisting of: a C4-C6 unsubstituted cyclic alkyl and C4-C6 unsubstituted cyclic heteroalkyl; C6-C10 alkyl.

According to some embodiments, R is chosen from the group consisting of: C1-C4 alkylaryl; C1-C4 heteroaromatic alkyl.

According to some embodiments, R is a C1-C4 alkylaryl.

According to some embodiments, R is a C1-C2 alkylaryl. According to specific forms of implementation, R is a benzyl (-CH2Ph).

Advantageously, with reference to the definition of R, aryl is a phenyl or a naphthyl.

Advantageously, with reference to the definition of R, the alkylaryl has the formula -R <q> Ph, in which R <q> is an alkyl (advantageously, C1-C4).

Advantageously, with reference to the definition of R, the alkylaryl comprises an aryl (not a substituted aryl), in particular a phenyl or a naphthyl (in particular, a phenyl).

Advantageously, with reference to the definition of R, the aromatic heterocycle is chosen from the group consisting of: thiophene, furan, pyridine, pyrrole.

Advantageously, the heteroaromatic alkyl comprises an aromatic heterocycle (not a substituted aromatic heterocycle).

Advantageously, with reference to the definition of R, the aromatic heterocycle of the heteroaromatic alkyl is selected from the group consisting of: thiophene, furan, pyridine, pyrrole.

Advantageously, with reference to the definition of R, the alkyl is a C3-C10 alkyl.

Advantageously, with reference to the definition of R, the alkyl is a branched alkyl.

Advantageously, with reference to the definition of R, the heteroalkyl is C3-C10.

Advantageously, with reference to the definition of R, the heteroalkyl is branched.

Advantageously, with reference to the definition of R, the substituted alkyl comprises at least one (in particular, only one) group selected from a cyclic unsubstituted C3-C6 alkyl and a cyclic unsubstituted heteroalkyl C3-C6. In particular, the substituted alkyl comprises a cyclic unsubstituted alkyl.

Advantageously, with reference to the definition of R, the substituted heteroalkyl comprises at least one (in particular, only one) group selected from a cyclic unsubstituted C3-C6 alkyl and a cyclic unsubstituted C3-C6 heteroalkyl. According to specific forms of implementation, cyclic unsubstituted alkyl is a slender.

According to some forms of implementation, X is chosen from the group consisting of: -S-, -SO2-, -SO-, -O-, -NR <n> -, -Se-, -PR <n> -.

R <n> is selected from the group consisting of: H, C1-C4 alkyl. Advantageously, R <n> is selected from the group consisting of: H, C1-C2 alkyl.

According to some forms of implementation, X is chosen from the group consisting of: -S-, -SO2-, -SO-, -O-.

According to some forms of implementation, X is chosen from the group consisting of: -S-, -SO2-, -SO-.

According to some forms of implementation, X is chosen from the group consisting of: -S-, -SO2-.

According to specific forms of implementation, X is -S-.

According to specific forms of implementation, X is -SO2-.

According to specific forms of implementation, X is -O-.

R <1> is selected from the group consisting of: H, C1C4 alkyl, electron withdrawing group. Advantageously, R <1> is an electron withdrawing group.

According to some embodiments, as regards R <1>, the electron-withdrawing group is chosen from the group consisting of: halogen, -NO2, -CN, -SiR <i> 3, -NHCOCF3, -NHCOR <i>, -NHCONHR <i>, -NHCOOR <i>, -OCONHR <i>, -CONHR <i>, -NHCSCF3, -NHCSR <i>, -NHSO2R <i>, -NCS, -OR <i>, -COR <i>, -COOR <i>, -OSO2R <i>, -SO2R <i>, -S-R <i>, -OH, -R <ii>, -R <iii>. Advantageously, R <1> is selected from the group consisting of: halogen, -NO2, -CN, -SiR <i> 3, -NHCOCF3, -NHCOR <i>, -NHCONHR <i>, -NHCOOR <i>, - OCONHR <i>, -CONHR <i>, -NHCSCF3, -NHCSR <i>, -NHSO2R <i>, -OR <i>, -COR <i>, -COOR <i>, -OSO2R <i>, -SO2R <i>, -S-R <i>, -OH, -R <ii>, -R <iii>. Advantageously, R <1> (and / or the electron attractor group) is selected from the group consisting of: halogen, -NO2, -CN, -OR <i>, -COR <i>, -COOR <i>, -OSO2R <i>, -SO2R <i>, -S-R <i>, -OH, -R <iii>. Advantageously, R <1> (and / or the electron attrotor group) is selected from the group consisting of: halogen, -NO2, -CN, -OR <i>, -S-R <i>, -OH, -R <iii> . Advantageously, R <1> is selected from the group consisting of: halogen, -NO2, -CN, -R <iii>. Advantageously, R <1> is selected from the group consisting of: halogen, -NO2, -CN. Advantageously, R <1> is a halogen. According to specific forms of implementation, R <1> is an F.

R <i> is selected from the group consisting of: H, C1-C4 alkyl, C1-C4 halo-alkyl, C1-C4 dihalo-alkyl, C1-C4 trialo-alkyl, C1-C4 per-fluoro alkyl, aryl, halogen , C1-C4 alkenyl. Advantageously, R <i> is selected from the group consisting of: H, C1-C4 alkyl, C1-C4 halo-alkyl, C1-C4 dihalo-alkyl, C1-C4 trialo-alkyl, -CF2CF3, aryl, halogen, C1 alkenyl -C4. Advantageously, R <i> is selected from the group consisting of: H, C1-C4 alkyl, C1-C4 fluoro-alkyl, C1-C4 difluoro-alkyl, C1-C4 trifluoro-alkyl, -CF2CF3, phenyl, halogen, C1- alkenyl C4. Advantageously, R 1 is selected from the group consisting of: H, C1-C4 alkyl, C1-C4 fluoro-alkyl, C1-C4 difluoro-alkyl, C1-C4 trifluoro-alkyl. Advantageously, R 1 is selected from the group consisting of: H, C1-C4 alkyl.

R <ii> is a ring fused with the phenyl of the remaining part of the molecule to which and is bound selected from the group consisting of:

X <5> is selected from the group consisting of: S, SO2, SO, O. Advantageously, X <5> is selected from the group consisting of: S, O. Advantageously, R <ii> is linked in meta and para position with respect to X.

R <iii> is selected from the group consisting of: C1-C4 halo-alkyl, C1-C4 dihalo-alkyl, C1-C4 trialo-alkyl, C1-C4 per-fluoro alkyl. Advantageously, R <iii> is selected from the group consisting of: C1-C4 halo-alkyl, C1-C4 dihalo-alkyl, C1-C4 trialo-alkyl, -CF2CF3. Advantageously, R <iii> is selected from the group consisting of: C1-C4 fluoro-alkyl, C1-C4 difluofo-alkyl, C1-C4 trifluoro-alkyl, -CF2CF3.

According to some forms of implementation, E is chosen from the group consisting of: H, bond with R <5>. Advantageously, E is H.

According to some embodiments, R <5> is selected from the group consisting of: H, C1-C4 alkyl, -CO-, -CS-, -SO-, -SO2-, -R <p> CO-, - R <p> CS-, -R <p> SO-, -R <p> SO2-; with the condition that when R <5> is chosen from the group consisting of: -CO-, -CS-, -SO-, -SO2-, -R <p> CO-, -R <p> CS-, -R <p> SO-, -R <p> SO2-, R <5> is linked to E in order to define a cycle.

According to some embodiments, R <5> is chosen from the group consisting of: H, C1-C4 alkyl, -CO-, -CS-, -SO-, -SO2-; with the condition that, when R <5> is chosen from the group consisting of: -CO-, -CS-, -SO- and -SO2-, R <5> is connected to E so as to define a cycle; optionally, when R <5> is an alkyl, R <5> is linked to E in order to define a cycle.

Advantageously, R <5> is selected from the group consisting of: H, C1-C4 alkyl. Advantageously, R <5> is selected from the group consisting of: H, C1-C2 alkyl. According to specific forms of implementation, R <5> is an H.

R <p> is a C1-C3 alkyl. Advantageously, R <p> is CH2.

Optionally, when R <5> is an alkyl, R <5> is linked to E to define a cycle. According to some forms of implementation, R <5> is not connected to E in order to define a cycle.

According to some embodiments, R <4> is chosen from the group consisting of: H and halogen. Advantageously, R <4> is an H.

R <2> is selected from the group consisting of: -H, C1-C4 alkyl, electron withdrawing group.

According to some embodiments, R <2> is selected from the group consisting of: -CN, carbamoyl methyl, -NO2, halogen, -H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkanoyl, C1 alkylthio- C4, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 per-fluoro alkyl, C1-C4 per-fluoro alkylthio, C1-C4 per-fluoro alkyl sulfinyl, and C1-C4 per-fluoro alkyl sulfonyl. Advantageously, R <2> is selected from the group consisting of: -CN, carbamoyl methyl, -NO2, halogen, alkoxy C1-C4, alkanoyl C1-C4, alkylthio C1-C4, alkylsulfinyl C1-C4, alkylsulfonyl C1-C4, for -fluoro alkyl C1-C4, per-fluoro alkylthio C1-C4, per-fluoro alkyl sulfinyl C1-C4 and per-fluoro alkyl sulfonyl C1-C4.

According to some embodiments, R <2> is selected from the group consisting of: -CN, -NO2, halogen, C1-C4 alkylthio, C1-C4 alkylthio, C1-C4 per-fluoro alkyl. Advantageously, R <2> is selected from the group consisting of: -CN, -NO2, halogen, C1-C2 per-fluoro alkyl. According to particular forms of implementation, R <2> is chosen from the group consisting of: -CN, -NO2, halogen. Advantageously, R <2> is selected from the group consisting of: -CN, -NO2.

According to some embodiments, R <2> is chosen from the group consisting of: -CN, halogen, per-fluoro alkyl C1-C2.

According to specific forms of implementation, R <2> is -CN.

With reference to the definition of R <2>, according to some embodiments, optionally, the alkyl C1-C4, the alkoxy C1-C4, the alkanoyl C1-C4, the alkylthio C1-C4, the achylsulfinyl C1-C4, C1-C4 alkylsulfonyl, C1-C4 perfluoro alkyl, C1-C4 per-fluoro alkyl thio, C1-C4 per-fluoro alkylsulfinyl and C1-C4 per-fluoro alkylsulfonyl are each bonded to a C1-C4 alkyl, a phenyl, a phenylthio (-SPh), a phenylsulfinyl (-SOPh), a phenylsulfonyl (-SO2Ph).

R <3> is selected from the group consisting of: -H, C1-C4 alkyl, electron withdrawing group.

According to some embodiments, R <3> is selected from the group consisting of: -CN, carbamoyl methyl, -NO2, halogen, -H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkanoyl, C1 alkylthio- C4, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 per-fluoro alkyl, C1-C4 per-fluoro alkyl thio, C1-C4 per-fluoro alkyl sulfinyl, and C1-C4 per-fluoro alkyl sulfonyl. Advantageously, R <3> is selected from the group consisting of: -CN, carbamoyl methyl, -NO2, halogen, alkoxy C1-C4, alkanoyl C1-C4, alkylthio C1-C4, alkylsulfinyl C1-C4, alkylsulfonyl C1-C4, for -fluoro alkyl C1-C4, per-fluoro alkyl thio C1-C4, per-fluoro alkyl sulfinyl C1-C4 and per-fluoro alkyl sulfonyl C1-C4.

According to some embodiments, R <3> is selected from the group consisting of: -CN, -NO2, halogen, alkoxy C1-C4, alkylthio C1-C4, per-fluoro alkyl C1-C4. Advantageously, R <3> is selected from the group consisting of: -CN, -NO2, halogen, C1-C4 per-fluoro alkyl. According to some embodiments, R <3> is selected from the group consisting of: -CN, -NO2, halogen, per-fluoro alkyl C1-C2.

With reference to the definition of R <3>, the C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkanoyl, C1-C4 alkylthio, C1-C4 achylsulfinyl, C1- alkylsulfonyl C4, perfluoro alkyl C1-C4, per-fluoro alkyl thio C1-C4, per-fluoro alkyl sulfinyl C1-C4 and per-fluoro alkyl sulfonyl C1-C4 are each optionally bonded to a C1-C4 alkyl, a phenyl, a phenylthio, a phenylsulfinyl, a phenylsulfonyl.

Alternatively or in addition to what is indicated above for R <3>, R <3> is selected from a group consisting of: C1-C4 halo-alkyl, C1-C4 dihalo-alkyl, C1-C4 trialo-alkyl. Advantageously, R <3> is selected from a group consisting of: C1-C2 halo-alkyl, C1-C2 dihalo-alkyl, C1-C2 trialo-alkyl.

According to some embodiments, R <3> is a C1-C4 per-fluoro alkyl, in particular a C1-C2 per-fluoro alkyl. According to specific forms of implementation, R <3> is a -CF3.

Advantageously, R <1> is arranged in para position with respect to the remaining part of the molecule.

According to specific forms of implementation, the compound has the following formula:

According to advantageous forms of implementation, the compound has the following geometric configuration (i.e. absolute configuration):

According to a specific form of implementation, the compound has the following formula:

According to a further aspect of the present invention, a process is provided for the synthesis of a compound having the eneral formula I

o its geometric isomers, its optically active forms, its diastereomers, its racemic forms,

wherein R is selected from the group consisting of: aryl, substituted aryl, C1-C4 alkylaryl, C1-C4 heteroaromatic alkyl, aromatic heterocycle, substituted aromatic heterocycle, C1-C12 substituted alkyl, C1-C10 alkyl, C1-C10 heteroalkyl, heteroalkyl substituted C1-C10;

X is chosen from the group consisting of: -S-, -SO2-, -SO-, -O-, -NR <n> -, -Se-, -PR <n> -,

wherein R <n> is selected from the group consisting of: H, C1-C4 alkyl;

R <1> is selected from the group consisting of: H, C1-C4 alkyl, electron withdrawing group;

E is selected from the group consisting of: H, bond with R <5>; R <5> is selected from the group consisting of: H, C1-C4 alkyl, -CO-, -CS-, -SO-, -SO2-, -R <p> CO-, -R <p> CS-, -R <p> SO-, -R <p> SO2-; with the condition that when R <5> is chosen from the group consisting of: -CO-, -CS-, -SO-, -SO2-, -R <p> CO-, -R <p> CS-, -R <p> SO-, -R <p> SO2-, R <5> is connected to E in order to define a cycle; optionally, when R <5> is an alkyl, R <5> is connected to E in order to define a cycle; R <p> is a C1-C3 alkyl;

R <4> is selected from the group consisting of: H and halogen;

R <2> is selected from the group consisting of: -H, C1-C4 alkyl, electron withdrawing group;

R <3> is selected from the group consisting of: -H, C1-C4 alkyl, electron withdrawing group;

According to some forms of implementation, the procedure includes a protection phase, during which a starting compound XXXV

wherein R <35> is selected from the group consisting of: R, -CH2COOH, is reacted with an aldehyde XXXVI

in which R <6> and R <7> are different from each other and are chosen, each independently of the other, from the group consisting of: H, C1-C6 alkyl, in order to obtain a first protected intermediate XXXVII

and an electrophilic substitution step, during which the first protected intermediate XXXVII is reacted under basic conditions with a reagent, the synthetic equivalent of which has formula XXXVIII

in order to obtain a second IXC protected intermediate

where R <36> is chosen from the group consisting of: R, CH2-X <3>,

where X <3> is chosen from the group consisting of: halogen, -OH, -OR <iv>,

wherein R <iv> is suitably selected from the group consisting of: mesyl, tosyl, C1-C4 alkyl, C1-C4 alkylaryl, -COR <V>, -COOR <V>,

wherein R <V> is a C1-C4 alkyl

According to some forms of implementation, when R <35> is R, R <36> is CH2-X <3> and therefore the second protected intermediate has the formula of a cyclic intermediate VIII

According to some forms of implementation, when R <35> is -CH2COOH, R <36> is R, and the second protected intermediate IXC is subjected to a decarboxylative halogenation in order to obtain the cyclic intermediate VIII

According to some embodiments, X <3> is a halogen, in particular a bromine.

According to some forms of implementation, the procedure also includes a deprotection phase, during which aldehyde XXXVI is removed;

a nucleophilic substitution phase, during which -X <3> is substituted with the portion in which X <4> is chosen from the group consisting of: -S-, -SO2-, -SO-, -O-, -NR <n> -, -If-, -PR <n> -.

and a coupling phase with an amine, which is subsequent to the deprotection phase and during which an XC amine

is made to react so that the hydroxide

carboxyl is substituted with the moiety

According to some forms of implementation X <4> is chosen from the group consisting of: -S-, -O-. According to specific forms of implementation, X <4> is -S-.

Optionally, when X is S, the process comprises an oxidation step to oxidize said sulfur so as to obtain an X selected from the group consisting of: -SO2-, -SO-.

It is important to underline that when R <35> is -CH2COOH, the starting compound XXXV is malic acid, which is available at very low cost both in an enantiomerically pure form (in particular the (S) enantiomer is present in nature ) than in racemic form.

Similarly, when R <35> is R the starting compound XXXV is an α-hydroxy acid which is commercially available or can be synthesized in an enantiomerically pure form or in a low cost racemic form.

Note that when using an enantiomerically pure starting compound XXXV it is possible to obtain

a cyclic intermediate VIII (VIII), in which the stereocenter indicated with * substantially has a single absolute geometric configuration, as the electrophilic substitution reaction (thanks to the presence of the asymmetric protecting group - R <6> different from R <7>) it is generally stereospecific. However, if the reaction was not completely stereospecific, two diastereoisomers would be obtained, easily separable by simple traditional methods, such as silica gel chromatographic column separation. As a consequence of this also the compound I ;; (I) is produced as regards; the stereocenter * in substantially pure enantiomerically form with great simplicity and without the need for particular purifications (the particular and complex techniques that must be used to separate enantiomers are not necessary). In particular, when the (S) enantiomer of malic acid is used, it is possible to obtain compound I with the following

absolute geometric configuration

When a starting compound XXXV is used in racemic form, the cyclic intermediate VIII has two stereocenters and can therefore exist in diastreoisomeric forms separable from each other by simple traditional methodologies (the particular and more complex techniques that must be used to separate enantiomers).

According to some embodiments R is selected from the group consisting of: aryl, substituted aryl, C1-C4 alkylaryl, C1-C4 heteroaromatic alkyl, aromatic heterocycle, substituted aromatic heterocycle, C1-C12 substituted alkyl, C1-C10 alkyl, C1 heteroalkyl -C10.

According to some embodiments, R is selected from the group consisting of: aryl, substituted aryl, C1-C4 alkylaryl, C1-C4 heteroaromatic alkyl, aromatic heterocycle, substituted aromatic heterocycle, C1-C10 substituted alkyl, C1-C10 alkyl.

According to some embodiments, R is chosen from the group consisting of: C1-C4 alkylaryl; C1-C4 heteroaromatic alkyl; C1-C8 alkyl; C1-C10 substituted alkyl, which comprises at least one substituent selected from the group consisting of: a C3-C6 unsubstituted cyclic alkyl and C3-C6 unsubstituted cyclic heteroalkyl.

According to some embodiments, R is chosen from the group consisting of: C1-C4 alkylaryl; C1-C4 heteroaromatic alkyl.

According to some embodiments, R is a C1-C4 alkyl. According to specific forms of implementation, R is a methyl.

According to some embodiments, R <1> is defined in accordance with the first aspect of the present invention.

According to some embodiments, R <2> is defined in accordance with the first aspect of the present invention.

According to some embodiments, R <3> is defined in accordance with the first aspect of the present invention.

According to some embodiments, R <4> is defined in accordance with the first aspect of the present invention.

According to some embodiments, R <5> is defined in accordance with the first aspect of the present invention.

According to some embodiments, X is defined in accordance with the first aspect of the present invention.

According to some embodiments, E is defined in accordance with the first aspect of the present invention.

According to some forms of implementation, R <35> is -CH2COOH, R <36> is R, and the second IXC protected intermediate is subjected to a decarboxylation halogenation.

According to some forms of implementation, R <35> is R, R <36> is CH2-X <3>. The electrophilic substitution phase leading directly to the cyclic intermediate VIII. X <3> is a halogen. According to some forms of implementation, the protection phase takes place in acid catalysis.

According to some embodiments, R <6> is H and R <7> is a C1-C4 alkyl. Advantageously, R <6> is H and R <7> is selected from the group consisting of: tert-butyl, iso-butyl.

According to some forms of implementation, the reagent whose synthetic equivalent has formula XXXVIII, has formula LG-R <36> in which LG indicates a leaving group. Advantageously, LG is selected from the group consisting of: halogen, -OR <vi>, wherein R <vi> is selected from the group consisting of: mesyl, tosyl.

According to some forms of implementation, the deprotection phase occurs in the presence of water in acidic conditions.

According to some forms of implementation, the compound is reacted during the nucleophilic substitution phase

(XXI). Advantageously, the

Nucleophilic substitution occurs in a basic environment, particularly in the presence of NaH.

According to some forms of implementation, the deprotection phase takes place in the presence of water and an alcohol in basic conditions. Advantageously, the alcohol is isopropanol. In particular, the deprotection phase takes place in the presence of (XXI) to give, in a single step, the intermediate (XVI) (for example, see step (b) of diagram 1 below). According to some embodiments, the coupling phase with an amine includes an activation sub-phase, which is at least partially prior to the addition of the amine XC and during which the substrate is reacted with SOCl2. Alternatively, during the activation step, the substrate is transformed into the corresponding compound:

X <6> is a leaving group. According to some forms of implementation, X <6> is chosen from the group consisting of: N (CH3) (OCH3), -OR <x>. R <x> is a C1-C4 alkyl.

According to some forms of implementation, the deprotection phase at least partially precedes the nucleophilic substitution phase. In particular, in this case, the cyclic intermediate VIII is converted into an intermediate

open

According to some embodiments, the coupling phase with an amine at least partially precedes the nucleophilic substitution phase. In particular, in this case, the open intermediate XIX is modified in order to obtain the XX molecule

According to specific forms of implementation, the compound described above can be obtained using one of the synthetic schemes listed below:

Scheme 1

In which the molecules of formula VIII can be obtained (if they are not commercially available) by means of the synthetic methods schematically illustrated below:

Scheme 2

in which R <6> and R <7> are selected, each independently of the other, in the group consisting of: H, C1-C6 alkyl (advantageously, C1-C4). According to some embodiments, R <6> is H and R <7> is tert-Butyl. According to some embodiments, R <6> is H, and R <7> is iso-Butyl.

X <3> is a leaving group. According to some embodiments, X <3> is chosen from the group consisting of: halogen, -OH, -OR <iv>. R <iv> is suitably selected from the group consisting of: mesyl, tosyl, C1-C4 alkyl, C1-C4 alkylaryl, -COR <V>, -COOR <V>. R <V> is a C1-C4 alkyl.

In scheme 2, phases i and iv are insertions of chiral protecting groups and / or inductors; phases ii and v are alkylations; phase iii is a decarboxylation halogenation.

LG indicates a leaving group. According to some forms of implementation, LG is chosen from the group consisting of: halogen, -OR <vi>. R <vi> is suitably chosen from the group consisting of: mesyl, tosyl.

According to a further aspect of the present invention, the compound as defined above is provided for use as a medicament. Advantageously, the compound as defined above is provided for an antitumor treatment, in particular for the treatment of prostate cancer. According to some forms of implementation, the compound as defined above with X chosen between O and S is provided for the treatment of a further pathology chosen from the group consisting of: osteoporosis, andropause, menopause, muscle wasting, cachexia, male infertility, Alzheimer's, arteriosclerosis, hypercholesterolemia, prostatic hyperplasia, muscular dystrophy, osteopenia, glucocorticoid-induced osteoporosis, periodontal disease, bone fractures, bone damage following bone reconstruction surgery, sarcopenia, skin aging, male hypogonadism, postmenopausal symptoms in women, hyperlipidemia, obesity, haematopoietic disorders (in particular, aplastic anemia), pancreatic cancer, inflammatory arthritis. Advantageously, the aforementioned further pathology is selected from the group consisting of: osteoporosis, andropause, menopause, muscle wasting, cachecsia, male infertility, Alzheimer's, arteriosclerosis, hypercholerestemia, prostatic hyperplasia, muscular dystrophy. According to a specific form of implementation, the further pathology is osteoporosis.

According to a further aspect of the present invention, a use of a compound as defined above is provided for the preparation of a drug for the treatment of a pathology.

According to some forms of implementation, a use of a compound as defined above is provided for the preparation of a drug for the treatment of a tumor. Advantageously, a use of a compound as defined above is provided for the preparation of a drug for the treatment of prostate cancer (and / or its metastases).

According to some forms of implementation, a use of a compound as defined above is provided for the preparation of a drug for the treatment of the aforementioned further pathology.

In particular, the foregoing refers to the treatment of a pathology (tumor or tumor of the prostate or of the aforementioned further pathology) in mammals.

According to a further aspect of the present invention, a pharmaceutical preparation is provided comprising a compound as defined above and a pharmaceutically acceptable excipient.

The compounds falling within the general formula (I) can be formulated, in a known way, for parenteral administration by injection or continuous administration. Injection formulations can be in unit dose form, for example in ampoules or multidose containers containing preservatives. The composition may be in suspension form, in aqueous or oily liquids, and may contain formulation elements such as dispersing and stabilizing agents. Alternatively, the active compound can be in powder form to be dissolved just before use in a liquid for this purpose, for example sterilized water.

The compounds falling within the general formula (I) can be formulated for rectal administration as suppositories or enemas, for example by containing excipients for known type suppositories such as cocoa butter or other glycerides.

The compounds falling within the general formula (I) can also be formulated, in a known way, as extended release compositions. These prolonged-release compositions can be administered by means of an implant (for example subcutaneous, or intramuscular) or by an intramuscular injection. Therefore, for example, the compounds included within the general formula (I) can be formulated with suitable polymeric or hydrophobic materials (e.g. an emulsion or an oil) or ion exchange resins, or relatively poorly soluble derivatives, such as relatively salts. slightly soluble.

For intranasal administration, the compounds included within the general formula (I) can be formulated for administration through a (known) device, for example in powder form with a suitable carrier.

The dosages of the compounds falling within the general formula (I) will depend on the age and condition of the patient, therefore the precise dosage should be decided on a case by case basis by the doctor. The dosage will also depend on the method of administration and the particular compound selected. Usable doses can for example be comprised between 0.1 mg / kg and 400 mg / kg with respect to the body weight per day.

The compounds falling within the general formula (I), can be administered in combination with one or more suitable therapeutic agents and formulated in any known usable way.

Further characteristics of the present invention will emerge from the following description of some merely illustrative and non-limiting examples.

Example 1

XXV-1

The reaction was carried out starting from (D) -malic acid as reported in the literature: Y. Huang, Y.-B. Zhang, Z.-C. Chen, P.-F. Xu Tetrahedron Asymm. 2006, 17, 3152-3157. To a solution of pivalaldehyde (1.55 eq.) In pentane (1.3 mL x mmol), p-toluene sulfonic acid (0.013 g x mmol of acid), a few drops of concentrated sulfuric acid and finally D-malic acid (1 eq.). The reaction mixture was then stirred under reflux for 36 hours. After cooling it to room temperature, filtration was carried out and the solid was dissolved with dichloromethane and washed with an aqueous solution of 8% phosphoric acid (2 times). The organic phase was then dried over anhydrous sodium sulfate and the solvent removed under reduced pressure. Yield = 98%. M.p. = 104-106 ° C;

[α] D = 2.2 (c, 1-2, CHCl3).

IR (cm <-1>): 3292 (br), 2968 (br), 1786 (s), 1741 (s);

<1> H NMR (400 MHz, CDCl3): δ 4.67 (1H, ot, J = 1.5, 3.5, 7.5 Hz), 3.02 (1H, dd, J = 3.5, 17 Hz), 2.84 (1H, dd, J = 7.5, 17 Hz), 0.99 (s, 9H);

<13> C NMR (125 MHz, CDCl3): d 174.90, 172.11, 109.88, 71.40, 34.23, 23.40.

GENERAL PROCEDURE FOR THE REACTION OF ALKYLATION OF XXV-1 General scheme:

XXV-1 XXVI-a

The reactions were carried out according to Y. Huang, Y.-B. Zhang, Z.-C. Chen, P.-F. Xu Tetrahedron Asymm. 2006, 17, 3152-3157.

To a solution of XXV-1 (1 eq.) In anhydrous tetrahydrofuran (THF, 1 mL x mmol of XXV-1) cooled to -78 ° C and in an atmosphere of inert gas, a solution of lithium was added by dripping it hexamethyl bis-disilyl amide (LHMDS; 2 eq.) in anhydrous THF (1 mL x mmol of LHMDS). After 5 minutes at -78 ° C the appropriate alkylating agent (1.5 eq.) Dissolved in THF (3 mL x mmol) was added. The reaction was stirred for 30 minutes, then the temperature was made to rise up to the ambient value and then quenched with 1M HCl. The organic phase was extracted with ether and the reaction crude was purified by a silica gel chromatographic column.

Example 2

Alkylating agent. CH3I, Yield: 80%;

<1> HNMR (400 MHz, CDCl3): δ 5.73–5.82 (m, 1H), 5.19–5.24 (m, 3H), 2.82 (s, 2H), 2.54 (d, J = XXVI-1

6.3 Hz, 2H), 0.91 (s, 9H); <13> CNMR (100 MHz, CDCl3): δ 174.4, 173.4, 129.9, 121.2, 108.3, 79.7, 39.4, 38.0, 34.2, 23.5.

Example 3

Alkylating agent. CH3CH2I, Yield: 63%;

<1> HNMR (400 MHz, CDCl3): δ 5.20 (s, 1H), 2.89 (d,

1H, J = 16 Hz), 2.85 (d 1H, J = 16 Hz), 1.90 (q,

XXVI-2 2H, J = 7.5 Hz), 1.07 (t, 3H, J = 7.5 Hz), 0.98 (s, 9H). <13> CNMR (100 MHz, CDCl3): δ 174.62, 173.90, 108.29, 80.37, 38.90, 34.36, 26.69, 23.55, 7.73.

Example 4

Alkylating agent. C6H5Br, Yield: 81%;

<1> HNMR (400 MHz, CDCl3): δ 7.24–7.34 (m, 5H), 4.61

(s, 1H), 3.21 (d, 1H, J = 14 Hz), 3.03 (d, 1H, J

= 14 Hz), 2.91 (q, 1H, J = 16 Hz), 2.77 (d, 1H, J XXVI-3

= 16 Hz), 0.89 (s, 9H).

<13> CNMR (100 MHz, CDCl3): δ 174.31, 133.70, 130.37, 128.67, 127.67, 108.73, 80.78, 40.13, 40.02, 34.24, 23.47.

Example 5

Alkylating agent. p-F-C6H5Br, Yield: 52%;

<1> HNMR (400 MHz, CDCl3): δ 7.20-7.24 (m, 2H), 7.01-7-05 (m, 2H), 4.61 (s, 1H), 3.18 (d, 1H, J =

14Hz), 3.07 (d, 1H, J = 14.4Hz), 2.88 (d, 1H, J =

XXVI-4 16.4Hz), 2.76 (d, 1H, J = 16Hz), 0.90 (s, 9H). <13> CNMR (100 MHz, CDCl3): δ207.4, 173.8, 173.3, 162.5 (d, J = 245.3 Hz), 132.2 (d, J = 8.1Hz), 129.7 (d, J = 3.4Hz), 115.8 (d, 21.2Hz), 109.1, 80.9, 40.3, 39.5, 34.6, 31.123.7.

Example 6

Alkylating agent. C4H3SCH2Br, Yield: 83%;

<1> HNMR (400 MHz, CDCl3): δ 6.95-7.00 (m, 3H), 4.82

(s, 1H), 3.41 (d, 1H, J = 15.2Hz), 3.30 (d, 1H,

J = 15.2Hz), 2.89 (d, 1H, J = 16.4Hz), 2.83 (d, XXVI-7

1H, J = 16Hz), 0.95 (s, 9H).

<13> CNMR (100 MHz, CDCl3): δ173.4, 134.7, 128.2, 126.0, 108.8, 80.3, 39.5, 34.3, 33.8, 23.5.

Examples 7-9

Following the same general procedure described above, the compounds can also be obtained:

GENERAL PROCEDURE FOR THE SYNTHESIS VIII-a

General scheme:

XXVI-a VIII-a

A solution of di-kylohexyl carbodimide (DCC) in CBrCl3 ( 2.4 eq.) At reflux. At the end of the addition (about 3 mL every 0.5h), it was allowed to react under reflux for a further 2 hours, then it was cooled and concentrated at reduced pressure. The reaction crude was purified by a silica chromatographic column.

Example 10

Synthesis of (R) -VIII-1

Eluent: cHex / Et2O: 7/3; Yield = 75%.

<1> H NMR (400 MHz), CDCl3): 5.18 (s, 1H), 3.57 (d,

J = 11.6 Hz, 1H), 3.55 (d, J = 11.6 Hz, 1H) 1.51 (s,

VIII-1 3H), 1.03 (s, 9H). <13> C NMR (100 MHz CDCl3): 172.7, 108.0, 79.3, 34.9, 24.0, 19.1.

Example 11

Synthesis of (R) -VIII-2

Eluent: cHex / Et2O: 8/2; Yield = 73%.

<1> H NMR (400 MHz, CDCl3): 5.22 (s, 1H), 3.61 (d,

J = 14Hz, 1H), 3.59 (d, J = 14Hz, 1H), 1.94 (m,

VIII-2 2H), 1.02 (m, 3H), 1.01 (s, 9H).

Example 12

Synthesis of (R) -VIII-3

Eluent: cHex / Et2O: 9/1; Yield 75%.

<1> H NMR (400 MHz, CDCl3): 7.20-7.39 (m, 5H), 4.44

VIII-3

(s, 1H), 3.61 (d, J = 11.2Hz, 1H), 3.54 (d, J = 11.2Hz, 1H), 3.19 (d, J = 14Hz, 1H), 3 , 13 (d, J = 14Hz, 1H), 0.91 (s, 9H).

<13> C NMR (100 MHz, CDCl3): 172.3, 133.7, 130.5, 129.0, 128.0, 109.3, 82.6, 40.3, 34.8, 34.7, 29.8.

Example 13

Synthesis of (R) -VIII-4

Eluent: cHex / Et2O: 9/1; Yield 88%.

[α] <20>

D + 28.2 (c 0.17, CHCl3);

<1> H NMR (400 MHz, CDCl3): δ 7.21-7.24 (m, 2H),

6.99-7.03 (m, 2H), 4.47 (s, 1H), 3.58 (d, 1H,

VIII-4

J = 11.6 Hz), 3.53 (d, 1H, J = 11.2 Hz), 3.14 (s, 2H), 0.91 (s, 9H). <13> C NMR (100 MHz, CDCl3) δ: 172.1, 162.5 (d , J = 24.3Hz), 132.0 (d, J = 8.1Hz), 129.4 (d, J = 3.0Hz), 115.9 (d, J = 21.4Hz), 109.5, 82.5, 39.5, 34.9, 34.6, 23.8.

Example 14

Synthesis of (R) -VIII-7

Eluent: cHex / Et2O: 9/1; Yield 73%.

[α] <20>

D + 49.7 (c 0.865, CHCl3);

<1> H NMR (400 MHz, CDCl3): δ 7.26-7.24 (m, 1H),

6.98-6.94 (m, 2H), 4.71 (s, 1H), 3.60 (d, 1H, J =

VIII-7

11.2Hz), 3.55 (d, 1H, J = 11.6Hz), 3.41 (d, 1H, J = 15.2Hz), 3.37 (d, 1H, J = 15.2Hz), 0.96 (s, 9H). <13> C NMR (100 MHz, CDCl3) δ: 172.0, 134.6, 128.4, 127.5, 126.3, 109.5, 82.2, 34.9, 34.2, 34.1, 23.8.

Examples 15-17. Following the same general procedure described above, the compounds can also be obtained:

(i): the reaction was carried out starting from (R) - (-) - mandelic acid as reported in the literature: D. Seebach, R. Naef, G. Calderari Tetrahedron 1984, 40, 1313-1324.

(ii): a solution cooled to -78 ° C of THF (5.0 mL x mmol of XXVIII-1), hexamethyl phosphorodamide (HMPA, 0.8 mL x mmol of XXVIII-1) and LHMDS (1.05 eq.) was added draining it, a solution of XXVIII-1 (1 eq.) in THF (1.4 mL x mmol). The reaction mixture was stirred at this temperature for 30 minutes, then a solution of di-iodomethane (CH2I, 3 eq.) In THF (0.20 mL x mmol of CH2I) was added by dropping it. After 90 minutes at -78 ° C a few mL of a saturated NH4Cl solution were added and the organic phase was extracted with EtOAc. The reaction crude was purified by a chromatographic column of silica gel eluting hexane / ether = 4/1. PROCEDURE FOR ACID HYDROLYSIS REACTION (Scheme 1, (a)) General scheme:

General procedure:

The bromide of general formula VIII-a was dissolved with a 6N HCl solution (large excess) and then refluxed for 4 hours. Once the reflux was over, the solution was cooled to room temperature, brine was added and extracted with ethyl acetate (3 times). The combined organic phases were washed with a saturated solution of NaHCO3. The aqueous phase thus obtained was acidified with HCl and extracted with ethyl acetate. The organic phase was then dried with Na2SO4, filtered and concentrated under reduced pressure. The acids thus obtained did not require further purification.

Example 19

For the spectroscopic characterization of XIX-1

see Tucker, H .; Chesterson, G. J. J. Med.

Chem. 1988, 31, 885-887.

XIX-1

Example 20

Spectroscopic characterization:

XIX-2

<1> H NMR (400 MHz, CDCl3): 10.9 (broad, 1H) 3.74 (d, J = 10.4, 1H), 3.52 (d, J = 10.4.1H), 1.73-1.99 (m, 2H), 1.03 (t, 3H).

Example 21

Spectroscopic characterization:

<1> H NMR (400 MHz, CDCl3): 10.9 (broad, 1H) 3.83 (d, J = 10.4, 1H), 3.54 (d, J = 10.4.1H), 3.18 XIX-3

(d, J = 13.6, 1H), 3.06 (d, J = 13.6, 1H). <13> C NMR (100 MHz, CDCl3): 177.8, 134.3, 130.4, 128.7, 127.8, 77.9 , 43.6, 38.6.

GENERAL PROCEDURE FOR THE COUPLING REACTION WITH THE AMINE (Procedure A)

Energy scheme:

General procedure:

1.3 eq of SOCl2 in an inert atmosphere were added to a solution of XIX-a acid in DMA (dimethyl acetamide) (0.55M) at -10 ° C. The solution was reacted at this temperature for about 3 hours, then a solution of XVII-1 (1.2 eq in 1.5 mL of DMA) was added drop by drop. After the addition, it was brought to room temperature and left to react for 16 hours under nitrogen.

The reaction crude was then concentrated under reduced pressure, then a saturated solution of NaHCO3 was added extracting with ethyl acetate. The organic phase was dried then filtered and the solvent was removed with the rotavapor. The purification of the raw reaction product was carried out by means of a silica gel chromatographic column.

Example 22

Known product. Eluent CH2Cl2 / Et2O = 20/1; Yield 84%

Eluent CH2Cl2 / Et2O = 20/1; Yield 78%

<1> H NMR (400 MHz, CDCl3): 9.03 (broad s, 1H) 8.10 (s, 1H), 7.96 (m, 1H), 7.80 (m, 1H), 3.99 (d, J = 10.8, 1H), 3.58 (d, J = 10.8, 1H), 3.07 (bs, 1H), 1.76-2.15 (m, 2H), 1.00 (t, 3H). <13> C NMR (100 MHz, CDCl3): 171.6, 141.4, 136.1, 134.6, 134.1 (q, J = 32.5 Hz), 122.2, 117.5 (q, J = 20 Hz), 115.7, 105.0, 78.7, 40.6, 31.3, 8.3.

Example 24

Eluent CH2Cl2 / Et2O = 20 / 0.1; Yield 30%

<1> H-NMR (400 MHz, CDCl3): 8.55 (broad s,

1H) 7.85 (s, 1H), 7.95-7.82 (m, 2H),

7.17-7.39 (m, 6H), 4.13 (d, J = 10.4, 1H) 3.57 (d, J = 10.4, 1H), 3.30 (d, J = 13.6, 1H), 3.06 (d, J = 13.6, 1H ), 2.93 (bs, 1H).

<13> C-NMR (100 MHz, CDCl3) relevant peaks: 171.1, 141.0,136.0, 134.0, 130.4, 129.0, 128.0, 122.3, 117.6 (q, J = 5 Hz), 115.6, 105.0, 78.5, 43.8, 40.1 .

COUPLING REACTION WITH p-fluorine thiophenol

General scheme:

General procedure:

To a suspension of NaH (60% dispersed in mineral oil, 1.3 eq) in THF under nitrogen and cooled to 0-5 ° C, a solution of XIV-1 (1 eq.) In THF was added by dropping. It was allowed to react at this temperature for 10 min, then the temperature was brought to room value for 0.5 hours. After this period, the reaction mixture was cooled again to 0-5 ° C and the XX-a anilide dissolved in THF was added. It was left to react at room temperature for 3-5 hours, then H2O and a saturated solution of NH4Cl were added. The organic phase was extracted several times with ethyl acetate, then dried, filtered and concentrated under reduced pressure. The reaction crude was purified by a silica gel chromatographic column.

Example 25

Known product. Eluent EtOAC / cHex = 9/11; Yield 88%

Example 26

Eluent EtOAC / cHex = 9/11; Yield 85%

<1> H NMR (400 MHz, CDCl3): 8.97 (broad

s, 1H) 7.90 (s, 1H), 7.74 (s, 2H),

7.37 (dd, J = 8.4 2H), 6.85 (dd, J = 8.4, 2H), 3.74 (d, J = 14.0 Hz, 1H), 3.45 (b s, 1H), 3.08 (d, J = 14.0 Hz, 1H ) 1.86-2.00 (m, 1H), 1.63-1.76 (m, 1H), 0.93 (t, 3H). <13> C-NMR (100 MHz, CDCl3) relevant peaks: 172.8, 161.5 (d, J = 256 Hz), 141.3, 135.9, 134.8 (q, J = 35Hz) 134.0, 128.7, 121.8, 117.3 (q, J = 5Hz), 116.4 (d, J = 22.1Hz) 115.7, 104.7, 78.2, 45.1, 32.7, 8.0 .

Example 27

Eluent EtOAC / cHex = 5/15; Yield 78%

<1> H NMR (400 MHz, CDCl3): 8.53 (broad

s, 1H) 7.63-7.72 (m, 2H), .7.50-

7.55 (m, 1H), 7.34-7.40 (m, 2H), 7.15-7.19 (m, 5H), 6.87 (dd, J = 8.8 Hz, 1H) 3.87 (d, J = 14.4 Hz, 1H), 3.45 ( s, 1H). 3.22 (d, J = 13.6Hz, 1H), 3.11 (d, J = 13.6Hz, 1H), 2.95 (d, J = 14.4Hz, 1H).

<13> C-NMR (100 MHz, CDCl3) relevant peaks: 172.1, 161.8 (d, J = 248 Hz) 141.0,135.8, 134.5, 134.2 (d, J = 8.5 Hz), 130.5, 128.8, 127.7, 122.6 ( q), 122.0, 117.6 (q, J = 5 Hz), 116.5 (d, J = 22.1Hz) 115.6, 105.0.

GENERAL PROCEDURE OF BASIC HYDROLYSIS AND "ONE-POT" REACTION

The reaction was carried out according to: Tetrahedron 2002, 58, 5905-5908.

VIII-a (1 eq.) Is treated, at room temperature, with a 1: 1 mixture (30 mL total per mmol of VIII-a) of NaOH (1M in H2O) and isopropanol. The mixture thus obtained was stirred for 3 hours and XIV-1 (1.6 eq.) Was added dropwise. After 13 hours of stirring at room temperature, the pH of the reaction mixture with HCl was brought to 8 and the organic phase was extracted with CH2Cl2. The aqueous phase was then acidified (pH = 1) with HCl, concentrated and extracted several times with CH2Cl2. The organic phase thus obtained was therefore anhydrified, filtered, concentrated under reduced pressure and the product was crystallized from CHCl3 / pentane.

Example 28

Yield: 95%.

<1> H NMR (400 MHz, CDCl3): 7.42-7.46 (m, 2H),

7.18-7.20 (m, 2H), 6.95-7.02 (m, 4H), 3.47 (d, 1H, J = 14Hz), 3.25 (d, 1H, J = 13.6Hz), 3.10 (d, 1H, J = 13.6 Hz), 2.99 (d, 1H, J = 13.6Hz).

<13> C-NMR (100 MHz, CDCl3) δ: 174, 164, 133.9 (d, J = 8.1Hz), 131.7 (d, J = 7.6Hz), 116.2 (d, J = 21.7Hz), 115.3 ( d, J = 21.2Hz), 76.7, 45.2, 44.1.

Example 29

Yield: 89%.

<1> H NMR (400 MHz, CDCl3): 6.86 (d, 1H, J =

3.6Hz), 6.93-6.99 (m, 3H), 7.19 (dd, 1H, J =

5.2; 1.2Hz), 7.42-7.45 (m, 2H), 3.22-3.42 (m, 4H).

<13> C-NMR (100 MHz, CDCl3) δ: 177.7, 163.7, 161.3, 135.8, 133.9 (d, J = 8.1Hz), 130.4 (d, J = 3.9Hz), 127.9, 127.0, 125.7, 116.3 ( d, J = 21.6Hz), 78.3, 44.5, 39.2.

Example 30-33

By following the same procedure reported for examples 28 and 29, the derivatives can also be obtained:

GENERAL PROCEDURE FOR THE COUPLING REACTION WITH THE AMINE (Procedure B)

General scheme:

(i) To a solution of XVI-a (1 eq.) in MeOH (5.4 ml x mmol) and toluene (5.4 ml x mmol), 1.5 eq. of a 2M solution in trimethylsyl azide ether. After one hour at room temperature the reaction was complete. Then a few drops of acetic acid were added and the organic phase with EtOAc was dried, filtered and concentrated under reduced pressure obtaining the methyl ester of XVI-a in a quantitative way.

(ii) To a solution of XVII-1 (1.6 eq.) in anhydrous THF (9 mL x mmol) cooled to -10 ° C, 4.5 eq. by LHMDS. The reaction mixture was stirred at this temperature for 40 minutes, then HMPA (0.9 mL x mmol of XVII-1) and a solution of methyl ester of XVI-a (1 eq.) In THF (7 mL x mmol) are been added. The solution was stirred at room temperature for 15 hours, then quenched with a few mL of a 0.1 M solution of HCl in water and extracted with ethyl acetate. The reaction crude was purified by a silica gel chromatographic column, eluent C-Hex / EtOAc = 2/1.

Example 34

Yield on 2 passes: 50%

<1> H NMR (400 MHz, CDCl3): 8.53 (s, 1H), 7.68-7.72 (m, 2H), 7.51 (dd, 1H, J = 8.4; 2.0Hz), 7.36-7.40 (m, 2H) , 7.14-7.17 (m, 2H), 6.94 (t, 2H, J = 8.4Hz), 6.87 (t, 2H, J = 8.4Hz), 3.89 (d, 1H, J = 14.4Hz), 3.55 (s, 1H), 3.20 (d, 1H, J = 14.0Hz), 3.08 (d, 1H, J = 14.0Hz), 2.91 (d, 1H, J = 13.6Hz).

<13> C NMR (100 MHz, CDCl3): 172.1, 163.7 (d, J = 27.6 Hz), 161.3 (d, J = 24.6Hz) ,, 140.8, 135.9, 134.2 (d, J = 8.1 Hz), 134.0 , 132.0 (d, J = 8.1Hz), 130.3 (d, J = 3.0Hz), 128.0 (d, J = 3.4Hz), 123.6, 121.8, 120.8, 117.3 (d, J = 4.7Hz), 116.5 (d , J = 22.1Hz), 115.6, 115.5 (d, J = 21.3Hz), 105.1, 77.9, 44.7, 44.3.

Example 35

Yield on 2 passes: 58%

<1> H NMR (400 MHz, CDCl3): 8.69 (s, 1H),

7.71-7-73 (m, 2H), 7.61 (dd, 1H, J =

8.8; 2.4Hz), 7.36-7.39 (m, 2H), 7.18 (d, 1H, J = 5.2Hz), 6.85-6.93 (m, 4H), 3.81 (d, 1H, J = 14.0Hz), 3.54 (s, 1H), 3.45 (d, 1H, J = 14.8Hz), 3.20 (d, 1H, J = 15.2Hz), 3.13 (d, 1H, J = 14.4Hz).

<13> C NMR (100 MHz, CDCl3) δ: 172.0, 163.9, 161.4, 141.0, 135.7 (d, J = 28.9Hz), 134.1 (d, J = 8.1Hz), 128.4, 127.3, 126.1, 122.0, 117.4 (d, J = 4.7Hz), 116.5 (d, J = 21.7Hz), 115.6, 105.1, 77.7, 66.1, 44.2, 39.4, 29.9, 15.5.

By following the same procedure reported for examples 30 and 31, the derivatives can also be obtained:

REACTION OF OXIDATION: GENERAL PROCEDURE

General scheme:

General procedure:

To a solution of sulphide II in CH2Cl2 (about 0.1 mM)

3 eqs of mCPBA have been added. After stirring a

room temperature for 1 night the solution was

diluted with ethyl acetate. The organic phase was

washed with a Na2SO3 solution followed by washing

with NaHCO3. The organic phase was then dried,

filtered and concentrated at reduced pressure. The raw of

reaction was purified by chromatographic column

of silica gel.

Example 36

Example 37

Eluent EtOAC / cHex = 3/1; Yield 90%

[α] <20>

D-57 (c 0.4, EtOH);

<1> H NMR (400 MHz, CDCl3): 9.05 (broad

s, 1H) 7.97 (s, 1H), 7.85-7.91 (m, 2H), 7.79-7.90 (m, 2H), 7.12-7.19 (m, 2H), 4.94 (s, 1H) 3.95 (d, J = 14.4Hz, 1H), 3.45 (d, J = 14.4Hz), 1.78-2.00 (m, 2H) 0.95 (t, 3H).

<13> C NMR (100 MHz, CDCl3) Relevant: 171.2, 166.5 (d, J = 257 Hz), 141.1, 136.1, 135.2, 134.8 (q, J = 35Hz) 131.1 (d, J = 37.2Hz), 122.0 (q), 121.9, 117.3 (q, J = 5 Hz), 117.0 (d, J = 22.1Hz) 115.5, 104.8, 77.1, 60.8, 33.9, 7.5.

Example 38

Eluent EtOAC / cHex = 2/1; Yield 90% [α] <20>

D + 132 (c 0.4, CHCl3);

<1> H NMR (400 MHz, CDCl3): 8.65 (broad s, 1H) 8.1 (s, 1H), 7.97-8.01 (m, 1H), 7.84-7.91 (m, 2H), 7.70-7.75 ( m, 2H), 7.51-7.63 (m, 2H), 7.40-7.46 (m, 1H) 7.12-7.26 (m, 3H), 5.0 (s, 1H).

4.12 (d, J = 14.0 Hz, 1H), 3.44 (d, J = 14.0Hz, 1H), 3.11 (d, J = 13.6 Hz, 1H), 3.03 (d, J = 13.6 Hz, 1H).

<13> C NMR (100 MHz, CDCl3) Relevant: 170.8, 166.4 (d, J = 248 Hz), 140.0, 135.9, 135.1, 134.4 (q, J = 35 Hz), 134.1, 133.3, 131.1 (d, J = 37.2Hz), 130.7, 130.5, 130.1, 128.8, 128.5, 128.1, 122.3, 117.6 (q, J = 5 Hz), 117.0 (d, J = 22.1Hz) 115.5, 105.4, 77.0, 60.7, 46.5.

Example 39

Eluent EtOAC / cHex = 2/1; Yield> 95%;

[α] <20>

D + 64.4 (c 0.29, CHCl3);

<1> H NMR (400 MHz, CDCl3): 8.64 (s, 1H), 7.86-7.89 (m, 2H), 7.74-7.76 (m, 2H), 7.54 (dd, 1H, J = 8.8; 3.6Hz) , 7.13-7.17 (m, 4H), 6.94 (t, 1H, J = 8.4Hz), 5.11 (s, 1H), 4.05 (d, 1H, J = 14.4Hz), 3.40 (d, 1H, J = 14.4 Hz), 3.10 (d, 1H, J = 13.6Hz), 3.01 (d, 1H, J = 14.0Hz).

<13> C NMR (100 MHz, CDCl3) δ: 170.4, 140.6, 135.7, 132.0 (d, J = 8.1Hz), 130.9 (d, J = 9.8Hz), 128.9, 121.9, 117.3 (d, J = 5.1 Hz), 116.7 (d, J = 22.5Hz), 115.3 (d, J = 20.8Hz), 77.2, 60.3, 45.3.

Example 40

Eluent EtOAC / cHex = 2/1; Yield> 95% [α] <20>

D + 87 (c 0.28, CHCl3);

<1> H NMR (400 MHz, CDCl3): 8.84 (s,

1H), 7.86-7.90 (m, 2H), 7.80 (d, H,

J = 1.6Hz), 7.75 (d, 1H, J = 8.4Hz), 7.63 (dd, 1H, J = 8.4; 2.0Hz), 7.21 (dd, 1H, J = 5.2; 1.2Hz), 7.15 (t, 2H, J = 8.4Hz), 6.92 (t, 1H, J = 3.6Hz), 6.85 (d, 1H, J = 3.2Hz), 5.10 (s, 1H), 4.04 (d, 1H, J = 14.8Hz) , 3.44 (d, 1H, J = 14.4Hz), 3.34 (d, 1H, J = 14.4Hz), 3.27 (d, 1H, J = 14.8Hz).

<13> C NMR (100 MHz, CDCl3) δ: 170.3, 167.6, 165.0, 140.6, 135.7, 134.8 (d, J = 3.4Hz), 134.1 (d, J = 18.3Hz), 133.9, 131.0 (d, J = 9.8Hz), 128.6, 127.0, 126.3, 123.3, 122.0, 120.6, 117.4 (d, J = 4.7Hz), 117.3, 116.8 (d, J = 23.0Hz), 115.3, 105.2, 76.3, 59.7, 40.5.

Examples 41-44

Through the same general oxidation procedure, the following compounds can also be obtained:

Example 45

The synthesis of compound I-10 can be traced back to the procedures previously reported for the synthesis of the other derivatives. In particular, the synthesis of XX-9 was described in example 21, while for step (iv) the general procedure of the coupling reaction with p-F-thiophenol (examples 10-12) is followed, replacing the p-F-thiophenol reagent with the p-CN-phenol reagent.

Example 46

The synthesis of compound I-11 is attributable to the procedures previously reported for the synthesis of the other derivatives. In particular, the synthesis of XX-6 was described in example 18, while for step (iv) the general procedure of the coupling reaction with p-F-thiophenol (examples 10-12) is followed, replacing the p-F-thiophenol reagent with the p-CN-phenol reagent.

Example 47

The synthesis of compound I-12 is attributable to the procedures previously reported for the synthesis of the other derivatives. In particular, the synthesis of XX-3 was described in example 9, while for step (iv) the general procedure of the coupling reaction with p-F-thiophenol (examples 10-12) is followed, replacing the p-F-thiophenol reagent with the p-CN-phenol reagent.

Example 48

The synthesis of compound I-13 is attributable to the procedures previously reported for the synthesis of the other derivatives. In particular, the synthesis of XX-4 was described in example 16, while for step (iv) the general procedure of the coupling reaction with p-F-thiophenol (examples 10-12) is followed, replacing the p-F-thiophenol reagent with the p-CN-phenol reagent.

Example 49

The synthesis of compound I-14 is attributable to the procedures previously reported for the synthesis of the other derivatives. In particular, the synthesis of XX-5 was described in example 17, while for step (iv) the general procedure of the coupling reaction with p-F-thiophenol (examples 10-12) is followed, replacing the p-F-thiophenol reagent with the p-CN-phenol reagent.

Example 50

BIOLOGICAL ACTIVITY STUDIES

Objective:

Comparative evaluation of the cytotoxic activity of Bicalutamide and derivatives in the human prostate tumor line of hormone sensitive LNCaP.

MATERIALS AND METHODS

Cellular Lines

1. Hormone-sensitive prostate cancer:

LNCaP, stabilized cell line derived from a metastatic lymph node lesion commercially available and marketed by the American Type Culture Collection (ATCC). The cell lines are cultured in a medium consisting of DMEM and Ham's F12 in equal parts, supplemented with fetal calf serum (10%), L-glutamine (2 mM), non-essential amino acids (1%) (Mascia Brunelli s.p.a.) and insulin (10 μg / ml) (Sigma). Cells in the exponential growth phase were used in all experiments.

Medicines

Bicalutamide and compounds I-2 and I-3 were solubilized in acetone (ATIES company) at a concentration of 10 mM, divided into aliquots and stored at - 20 ° C. Medium containing acetone at the highest concentration used in the experiments was used as a control.

In vitro chemosensitivity assays.

Cytotoxicity test

The activity of the individual compounds was tested using the SRB colorimetric test in accordance with the method described by Skehan et al. (JNCI, 1991).

In summary, the cells were detached by trypsin, counted and seeded in 96-well flat-bottom plates, at a density of 10,000 cells per well (100 μl of cell suspension per well). Each chemosensitivity assay was conducted in triplicate and each experiment repeated at least three times. At the end of exposure to drugs, the plates were fixed, stained with Sulforodamine B and the optical density was evaluated by reading on the spectrophotometer at a wavelength of 490 nm. The drugs were used in the experiments, at concentrations not exceeding the mean peak plasma values of the respective parental compounds.

Cytotoxic activity. The antiproliferative activity and the cytocidal effect of the drugs were calculated by applying the processing method reported by Monks et al. (JNCI, 1991) based on the formula: [(ODtrattato-ODzero) / (ODcontrol-ODzero)] x 100, in case ODtrattatis ≥ ODzero. If ODtractor is <of ODzer, it means that cell death has occurred. ODzerorrepresents the number of cells at the time of dispensing the drug, ODcontrol the number of cells present at the end of the experiment in the wells in which the drug was not dispensed and ODtractor represents the number of surviving cells at the end of the drug exposure.

RESULTS AND CONCLUSIONS

Activity of bicalutamide derivatives in the hormone-sensitive prostate tumor line (LNCaP)

Bicalutamide and compounds I-2 and I-3 (all obtained as described above in substantially enantiomerically pure form) were tested at different times (24, 48 and 72 hours) and at different concentrations (0.02, 0.2, 2 and 20 μM ) (Figure 1). The ethylated derivative (I-2) showed little activity, regardless of the time and concentration used. The benzyl derivative (I-3) has shown an antiproliferative activity superior to bicalutamide, time and concentration dependent. In particular, with the same concentration (20 μM) and exposure time, the most active compound was found to be derivative I-3 (figure 2). It is important to emphasize that compound I-2, although in the tests described above it showed a low activity, it instead has a more than relevant agonist activity.

Tests carried out on compounds falling within the general formula I in which X is O show that these compounds have more than relevant agonist activities.

The compounds with agonist activity are useful for the treatment of a further pathology chosen from the group consisting of: osteoporosis, andropause, menopause, muscle wasting, cachecsia, male infertility, Alzheimer's, arteriosclerosis, hypercholerestemia, prostatic hyperplasia, muscular dystrophy, osteopenia, induced osteoporosis from glucocorticoids, periodontal disease, bone fractures, bone damage following bone reconstruction surgery, sarcopenia, skin aging, male hypogonadism, postmenopausal symptoms in women, hyperlipidaemia, obesity, haematopoietic disorders (in particular, aplastic anemia), cancer of the pancreas, inflammatory arthritis. Advantageously, the aforementioned further pathology is selected from the group consisting of: osteoporosis, andropause, menopause, muscle wasting, cachecsia, male infertility, Alzheimer's, arteriosclerosis, hypercholerestemia, prostatic hyperplasia, muscular dystrophy (in particular osteoporosis).

Claims (1)

R I V E N D I C A Z I O N I 1.- Process for the synthesis of a compound having general formula I o its geometric isomers, its optically active forms, its diastereomers, its racemic forms, wherein R is selected from the group consisting of: aryl, substituted aryl, C1-C4 alkylaryl, C1-C4 heteroaromatic alkyl, aromatic heterocycle, substituted aromatic heterocycle, C1-C12 substituted alkyl, C1-C10 alkyl, C1-C10 heteroalkyl, heteroalkyl substituted C1-C10; X is chosen from the group consisting of: -S-, -SO2-, -SO-, -O-, -NR <n> -, -Se-, -PR <n> -, wherein R <n> is selected from the group consisting of: H, C1-C4 alkyl; R <1> is selected from the group consisting of: H, C1-C4 alkyl, electron withdrawing group; E is selected from the group consisting of: H, bond with R <5>; R <5> is selected from the group consisting of: H, C1-C4 alkyl, -CO-, -CS-, -SO-, -SO2-, -R <p> CO-, -R <p> CS-, -R <p> SO-, -R <p> SO2-; with the condition that when R <5> is chosen from the group consisting of: -CO-, -CS-, -SO-, -SO2-, -R <p> CO-, -R <p> CS-, -R <p> SO-, -R <p> SO2-, R <5> is connected to E in order to define a cycle; optionally, when R <5> is an alkyl, R <5> is connected to E in order to define a cycle; R <p> is a C1-C3 alkyl; R <4> is selected from the group consisting of: H and halogen; R <2> is selected from the group consisting of: -H, C1-C4 alkyl, electron withdrawing group; R <3> is selected from the group consisting of: -H, C1-C4 alkyl, electron withdrawing group; the process comprises a protection step, during which a starting compound XXXV wherein R <35> is selected from the group consisting of: R, -CH2COOH, is reacted with an aldehyde XXXVI in which R <6> and R <7> are different from each other and are selected from the group consisting of: H, C1-C6 alkyl, so as to obtain a first protected intermediate XXXVII an electrophilic substitution step, during which the first protected intermediate XXXVII is reacted under basic conditions with a reagent, whose synthetic equivalent has formula XXXVIII R <36⊕> (XXXVIII) in order to obtain a second IXC protected intermediate where R <36> is selected from the group consisting of: R, CH2-X <3>, where X <3> is selected from the group consisting of: halogen, -OH, -OR <iv>, wherein R <iv> is selected from the group consisting of: mesyl, tosyl, C1-C4 alkyl, C1-C4 alkylaryl, -COR <V>, -COOR <V>, where R <V> is a C1- alkyl C4 with the conditions that when R <35> is R, R <36> is CH2-X <3> and when R <35> is -CH2COOH, R <36> is R, and the second IXC protected intermediate is subjected to a decarboxylation halogenation in order to obtain, both when R <35> is R and when R <35> is - CH2COOH, a cyclic intermediate VIII the procedure also includes a deprotection phase, during which the aldehyde XXXVI is removed; a nucleophilic substitution phase, during which -X <3> is replaced with the portion, X <4> is chosen from the group consisting of: -S-, -SO2-, -SO-, -O-, -NR <n> -, Se-, -PR <n> -; and a coupling phase with an amine, which is subsequent to the deprotection phase and during which an XC amine is made to react so that carboxyl is substituted with the moiety optionally, when X <4> is S, the process comprises an oxidation step for oxidizing said sulfur so as to obtain an X selected from the group consisting of: -SO2-, -SO-. 2. Process according to claim 1, wherein R <35> is -CH2COOH, R <36> is R, and the second protected intermediate IXC is subjected to a decarboxylation halogenation; X <3> is a halogen. 3. Process according to claim 1, wherein R <35> is R, R <36> is CH2-X <3>; the electrophilic substitution phase leading directly to the cyclic intermediate VIII. 4.- Process according to one of the preceding claims, in which the protection step takes place in acid catalysis; R <6> is -H and R <7> is a C1-C4 alkyl; the reagent whose synthetic equivalent has formula XXXVIII has formula LG-R <36> in which LG indicates a leaving group; the deprotection phase occurs in the presence of water under acidic conditions; during the nucleophilic substitution step the compound XXI is reacted the coupling phase with an amine includes an activation sub-phase, which is at least partially prior to the addition of the amine XC and during which the substrate is reacted with SOCl2; X <3> is a halogen. 5. A process according to claim 4, wherein R <6> is H and R <7> is selected from the group consisting of: tert-butyl, iso-butyl; LG is chosen from the group consisting of: halogen, -OR <vi>, wherein R <vi> is chosen from the group consisting of: mesyl, tosyl; the nucleophilic substitution phase occurs in a basic environment. 6.- Process according to one of the preceding claims, wherein R is selected from the group consisting of: aryl, substituted aryl, C1-C4 alkylaryl, C1-C4 heteroaromatic alkyl, aromatic heterocycle, substituted aromatic heterocycle, C1-C12 substituted alkyl, alkyl C1-C10, C1-C10 heteroalkyl; X is chosen from the group consisting of: -S-, -SO2-, -SO-, -O-, -NR <n> -, -Se-, -PR <n> -, wherein R <n> is selected from the group consisting of: H, C1-C4 alkyl; R <1> is selected from the group consisting of: H, C1-C4 alkyl, halogen, -NO2, -CN, -SiR <i> 3, -NHCOCF3, -NHCOR <i>, -NHCONHR <i>, -NHCOOR <i>, -OCONHR <i>, -CONHR <i>, -NHCSCF3, -NHCSR <i>, -NHSO2R <i>, -NCS -OR <i>, -COR <i>, -COOR <i>, -OSO2R <i>, -SO2R <i>, -S-R <i>, -R <ii>, -R <iii>, where R <i> is selected from the group consisting of: H, C1-C4 alkyl, C1-C4 halo-alkyl, C1-C4 dihalo-alkyl, C1-C4 trialo-alkyl, C1-C4 per-fluoro alkyl, aryl, halogen, C1-C4 alkenyl; R <ii> is a ring fused with the phenyl of the remaining part of the molecule to which it is bound chosen from the group consisting of: X <5> is selected from the group consisting of: S, SO2, SO, O; R <iii> is selected from the group consisting of: C1-C4 halo-alkyl, C1-C4 dihalo-alkyl, C1-C4 trialo-alkyl, C1-C4 per-fluoro alkyl; E is selected from the group consisting of: H, bond with R <5>; R <5> is selected from the group consisting of: H, C1C4 alkyl, -CO-, -CS-, -SO-, -SO2-; with the condition that, when R <5> is chosen from the group consisting of: -CO-, -CS-, -SO- and -SO2-, R <5> is connected to E so as to define a cycle; optionally, when R <5> is an alkyl, R <5> is connected to E in order to define a cycle; R <2> is selected from the group consisting of: -CN, carbamoyl methyl, -NO2, halogen, -H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkanoyl, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 per-fluoro alkyl, C1-C4 per-fluoro alkylthio, C1-C4 per-fluoro alkyl sulfinyl and C1-C4 perfluoro alkyl sulfonyl; optionally, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkanoyl, C1-C4 alkylthio, C1-C4 achylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 perfluoro alkyl , the per-fluoro alkyl thio C1-C4, the per-fluoro alkylsulfinyl C1-C4 and the per-fluoro alkylsulfonyl C1-C4 are each bonded to a C1-C4 alkyl, a phenyl, a phenylthio (-SPh), a phenylsulfinyl (-SOPh), a phenylsulfonyl (-SO2Ph); R <3> is selected from the group consisting of: -CN, carbamoyl methyl, -NO2, halogen, -H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkanoyl, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 per-fluoro alkyl, C1-C4 per-fluoro alkyl thio, C1-C4 per-fluoro alkyl sulfinyl and C1-C4 perfluoro alkyl sulfonyl; with the proviso that C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkanoyl, C1-C4 alkylthio, C1-C4 achylsulfinyl, C1-C4 alkylsulfonyl, per-fluorine C1-C4 alkyl, C1-C4 per-fluoro alkyl thio C1-C4, C1-C4 per-fluoro alkyl sulfinyl and C1-C4 per-fluoro alkyl sulfonyl are, optionally, each bonded to a C1-C4 alkyl, a phenyl, a phenylthio, a phenylsulfinyl, a phenylsulfonyl. 7.- Process according to claim 6, wherein R is selected from the group consisting of: aryl, substituted aryl, C1-C4 alkylaryl, C1-C4 heteroaromatic alkyl, aromatic heterocycle, substituted aromatic heterocycle, C1-C10 substituted alkyl, C1 alkyl -C10; X is chosen from the group consisting of: -S-, -SO2-, -SO-, -O-; R <1> is selected from the group consisting of: halogen, -NO2, -CN, -SiR <i> 3, -NHCOCF3, -NHCOR <i>, -NHCONHR <i>, -NHCOOR <i>, -OCONHR <i>, -CONHR <i>, -NCS, -NHCSCF3, -NHCSR <i>, -NHSO2R < i>, -OR <i>, -COR <i>, -COOR <i>, -OSO2R <i>, -SO2R <i>, -S-R <i>, -R <ii>, -R <iii> , where R <i> is selected from the group consisting of: H, C1-C4 alkyl, C1-C4 halo-alkyl, C1-C4 dihalo-alkyl, C1-C4 trialo-alkyl, -CF2CF3, aryl, halogen, C1- alkenyl C4; R <ii> is a ring fused with the phenyl of the remaining part of the molecule to which it is bound chosen from the group consisting of: X <5> is selected from the group consisting of: S, SO2, SO, O; R <iii> is selected from the group consisting of: C1-C4 halo-alkyl, C1-C4 dihalo-alkyl, C1-C4 trialo-alkyl, -CF2CF3. 8. A process according to claim 7, wherein R is selected from the group consisting of: C1-C4 alkylaryl; C1-C4 heteroaromatic alkyl; C1-C8 alkyl; C1-C10 substituted alkyl, which comprises at least one substituent selected from the group consisting of: a C3-C6 unsubstituted cyclic alkyl and C3-C6 unsubstituted cyclic heteroalkyl; X is chosen from the group consisting of: -S-, -SO2-, -SO-; R <1> is selected from the group consisting of: halogen, -NO2, -CN, -SiR <i> 3, -NCS, -NHCOCF3, -NHCOR <i>, -NHCONHR <i>, -NHCOOR <i>, -OCONHR <i>, -CONHR <i>, -NHCSCF3, -NHCSR <i>, -NHSO2R < i>, -OR <i>, -COR <i>, -COOR <i>, -OSO2R <i>, -SO2R <i>, -S-R <i>, -R <ii>, -R <iii> , where R <i> is selected from the group consisting of: H, C1-C4 alkyl, C1-C4 fluoro-alkyl, C1-C4 difluoro-alkyl, C1-C4 trifluoro-alkyl, -CF2CF3, phenyl, halogen, C1-C4 alkenyl ; R <ii> is a ring fused with the phenyl of the remaining part of the molecule to which it is bound chosen from the group consisting of: X <5> is selected from the group consisting of: S, SO2, SO, O; R <iii> is selected from the group consisting of: C1-C4 fluoro alkyl, C1-C4 difluofo-alkyl, C1-C4 trifluoro-alkyl, -CF2CF3; R <2> is selected from the group consisting of: -CN, carbamoyl methyl, -NO2, halogen, alkoxy C1-C4, alkanoyl C1-C4, alkylthio C1-C4, alkylsulfinyl C1-C4, alkylsulfonyl C1-C4, per-fluoro C1-C4 alkyl, C1-C4 per-fluoro alkylthio, C1-C4 per-fluoro alkyl sulfinyl, and C1-C4 per-fluoro alkyl sulfonyl; R <3> is selected from the group consisting of: -CN, carbamoyl methyl, -NO2, halogen, alkoxy C1-C4, alkanoyl C1-C4, alkylthio C1-C4, alkylsulfinyl C1-C4, alkylsulfonyl C1-C4, per-fluoro C1-C4 alkyl, C1-C4 per-fluoro alkyl thio C1-C4, C1-C4 per-fluoro alkyl sulfinyl and C1-C4 per-fluoro alkyl sulfonyl. 9. Process according to one of claims 1 to 8, wherein R is selected from the group consisting of: C1-C4 alkylaryl; C1-C4 heteroaromatic alkyl; R <1> is selected from the group consisting of: halogen, -NO2, -CN, -R <iii>; R <iii> is selected from the group consisting of: C1-C4 halo-alkyl, C1-C4 dihalo-alkyl, C1-C4 trialo-alkyl, -CF2CF3; E is an H. 10.- Process according to one of the preceding claims, in which R <1> is selected from the group consisting of: halogen, -NO2, -CN; E is an H; R <5> is selected from the group consisting of: H, C1-C2 alkyl; R <2> is selected from the group consisting of: -CN, -NO2, halogen, C1-C2 per-fluoro alkyl; R <3> is selected from the group consisting of: -CN, -NO2, halogen, C1-C2 per-fluoro alkyl. 11. A process according to claim 10, wherein X is selected from the group consisting of: -S-, -SO2-; R <1> is a halogen; E is an H; R <5> is an H; R <4> is an H; R <2> is selected from the group consisting of: -CN, halogen, C1-C2 per-fluoro alkyl; R <3> is selected from the group consisting of: -CN, halogen, C1-C2 per-fluoro alkyl. 12.- Process according to one of the preceding claims, in which R <1> is in para position with respect to X; R <2> is selected from the group consisting of: -CN, -NO2; R <3> is selected from the group consisting of: halogen, perfluoro alkyl C1-C2. 13.- Process according to one of the preceding claims, in which the coupling step with an amine at least partially precedes the nucleophilic substitution step.