ES2288795B1 - ANTITUMORAL COMPOUNDS. - Google Patents

Abstract

Compounds of general formula (I), their corresponding pharmaceutically acceptable salts, derivatives, prodrugs and stereoisomers, ** FIGURE ** useful for their cytotoxic activity and for their use as antitumor agents.

Description

Anti-tumor compounds

Field of the Invention

The present invention relates to new compounds, pharmaceutical compositions containing them and their use as antitumor agents.

Background of the invention

Several azafosfoles have been described as matrix metalloprotease inhibitors. These metalloproteases involved, along with other enzymes, in the destruction of the matrix extracellular Matrix metalloproteases are the components system key that dynamically controls the structure and the extracellular matrix function. Matrix metalloproteases are involved in the degeneration of the cornea, disease peridontal, dermatological diseases, arteriosclerosis, bone and joint disorders, vascular abnormalities and Cancer. The destruction of the extracellular matrix can lead to tumor invasion, followed by metastasis and angiogenesis.

In patent application WO2002083696, describes a series of cyclic azafosfoles as inhibitors of matrix metalloproteases.

         \ vskip1.000000 \ baselineskip
      

one

         \ vskip1.000000 \ baselineskip
      

The pIC 50 of these compounds in an assay Matrix metalloprotease inhibition varies in 5 and 9.

On the other hand, in US Patent 5,830,915 describe acyclic azafosfoles also as inhibitors of matrix metalloproteases.

Also, compound CK1-183 has been described as an inhibitor of proliferation induced by 17? -Estradiol (E2) in the tumor line of ER?-Positive breast cancer, showing minimal cytotoxicity against ER? negative at high micromolar concentrations. (Wipf et al , BioOrg. Med. Chem. 2005, 13 , 157-164).

         \ vskip1.000000 \ baselineskip
      

2

         \ vskip1.000000 \ baselineskip
      

In another area of the state of the art, it has been described the preparation and use of N, N'-bisphosphinamides as agents for heavy metal extraction (JP2004256470). The compounds synthesized in this work are shown below.

3

Also in another area of the state of the art, Irisli and Ayten have described the preparation and crystalline structure of an N, N'-bisphosfinamide (Irisli and Ayten, Acta Crystallographica, Section E: Structure Reports Online 2005, E61 (6), o1939-o1941).

4

In addition, several phosphinamides derived from polyamines have been described as synthetic intermediates in the preparation of 2-nitroimidazole conjugates. This work does not show any biological activity of these compounds (Cullis et al ., Org. BioOrg. Chem. 1999, 22 , 3243-3252).

         \ vskip1.000000 \ baselineskip
      

5

         \ vskip1.000000 \ baselineskip
      

Alibert et al have described the synthesis of a series of derivatives of 37-dihydroethaneanthracene and ethenoanthracene and its activity as inhibitors of drug transport in multiresistant tumor cells. Among the compounds tested is a bisphosphinamide that totally inhibits the transport of rhodamine in L5178 MDR tumor cells at a concentration of 2 µM (Alibert et al ., Eur. J. Med. Chem. 2003, 38 , 253-263).

         \ vskip1.000000 \ baselineskip
      

6

On the other hand Fernando López-Ortiz et al. Have described the synthesis of azaphospholes from phosphinamide through intramolecular nucleophilic addition reactions (Fernández de las Nieves, Doctoral Thesis, University of Almería, 2003; López Ortiz et al ., Chem. Commun. 2005, 43, 5408-5410; ARKIVOC 2005, 9, 375-393; Chem. Eur. J. 2005, 11, 3022-3031; J. Am. Chem. Soc. 2004, 126, 12551-12564; J. Org Chem. 2003, 68, 4472-4485; Synlett 2002, 5, 781-783; J. Org. Chem. 2002, 67, 11, 3852-3860; Org. Lett. 2001, 3, 1339-1342).

         \ vskip1.000000 \ baselineskip
      

7

         \ vskip1.000000 \ baselineskip
      

In this thesis the following are described compounds with cytotoxic activity at micromolar concentrations (Fernández de las Nieves, Doctoral Thesis, University of Almería 2003).

         \ vskip1.000000 \ baselineskip
      

8

         \ vskip1.000000 \ baselineskip
      

         \ vskip1.000000 \ baselineskip
      

9

         \ vskip1.000000 \ baselineskip
      

         \ vskip1.000000 \ baselineskip
      

10

         \ vskip1.000000 \ baselineskip
      

         \ vskip1.000000 \ baselineskip
      

eleven

         \ vskip1.000000 \ baselineskip
      

Cancer remains one of the main Causes of death between animal species and man. They have destined and continue to devote great efforts to find new safe and effective antitumor agents that contribute to increase the therapeutic arsenal necessary for treatment Effective of patients with this disease. In this sense, the The present invention tries to help solve this problem, providing new compounds useful in the treatment of Cancer.

Summary of the Invention

The present invention relates to compounds of general formula (I), as well as their corresponding salts pharmaceutically acceptable, derivatives, prodrugs and stereoisomers,

         \ vskip1.000000 \ baselineskip
      

12

in the which

R1 and R2 are groups independently selected from C 6 -C 18 aryl optionally substituted and C 3 -C 18 optionally substituted heterocycle;

A is a group C_ {1} -C_ {12} unsubstituted alkylene;

R 3 and R 5 are groups independently selected from C 1 -C 12 alkyl optionally substituted, C2-C12 alkenyl optionally substituted, C2-C12 optionally substituted alkynyl, C 7 -C 30 optionally substituted arylalkyl, C 8 {-C 30} arylalkenyl optionally substituted, C4-C30 heterocycloalkyl optionally substituted, C 5 -C 30 optionally substituted heterocycloalkenyl, C 3 -C 18 cycloalkyl optionally substituted, C4-C30 cycloalkylalkyl optionally substituted, C 5 -C 30 optionally substituted cycloalkylalkenyl, C 3 -C 18 cycloalkenyl optionally substituted, C 4 -C 30 cycloalkenyl alkyl optionally substituted and C 5 -C 30 optionally substituted cycloalkenyl alkenyl;

R 4 is a group selected from H and a radical of formula (II)

13

R 6 and R 7 are groups independently selected from C 6 -C 18 aryl optionally substituted and C 3 -C 18 optionally substituted heterocycle;

R 1 and R 3 and / or R 5 and R 6 can form, together with the adjacent P and N atoms, a heterocycle of according to formula (III) or (IV), respectively,

         \ vskip1.000000 \ baselineskip
      

14

where

Y 1, Y 2, Y 3 and Y 4 are groups independently selected from NR12 and CR 13 R 14;

Y 1 and Y 2, Y 2 and Y 3 and / or Y 3 and Y 4 can form a carbocyclic or heterocyclic ring additional condensate;

each dotted line represents the presence optional additional link;

R 8 and R 9 are groups independently selected from hydrogen, NO 2, CN, C (= O) R a, CO 2 R a, C (= O) NR a R b, (C = NR a) OR b, (C = NR a) R b, (C = NR a) NR a R b, (S = O) R a, SO 2 R a, SO 3 R a, SO 2 NR a R b, C 1 -C 12 optionally substituted alkyl, Optionally substituted C 6 -C 18 aryl, C 7 -C 30 arylalkyl optionally substituted, C 3 -C 18 heterocycle optionally substituted, C 4 -C 30 optionally substituted heterocycloalkyl, C 3 -C 18 cycloalkyl optionally substituted and C 4 -C 30 cycloalkylalkyl optionally substituted;

R 10 and R 11 are groups independently selected from hydrogen, OR a, OC (= O) R a, SR a, (S = O) R a, SO 2 R a, SO 3 R a, SO 2 NR a R b, NHR a, N (R a R b), NR a (OR b), NHCOR a, N (COR a) (COR b), NHCO 2 R a, NHC (= O) NR a R b, NHSO 2 R a, CN, halogen, C (= O) R a, CO 2 R a, C (= O) NR a R b, C 1 -C 12 optionally substituted alkyl, C 2 -C 12 alkenyl optionally substituted, C2-C12 alkynyl optionally substituted, C 6 -C 18 aryl optionally substituted, C 7 -C 30 arylalkyl optionally substituted, C 8 -C 30 optionally substituted arylalkenyl, C 3 -C 18 heterocycle optionally substituted, C4-C30 heterocycloalkyl optionally substituted, C 5 -C 30 optionally substituted heterocycloalkenyl, C 3 -C 18 cycloalkyl optionally substituted, C4-C30 cycloalkylalkyl optionally substituted, C 5 -C 30 optionally substituted cycloalkylalkenyl, C 3 -C 18 cycloalkenyl optionally substituted, C 4 -C 30 cycloalkenyl alkyl optionally substituted and C 5 -C 30 optionally substituted cycloalkenyl alkenyl, with the condition of  that R 11 will be absent if the carbon to which it is attached forms part of a double bond;

R 12, R 13 and R 14 are groups independently selected from hydrogen, OR a, OC (= O) R a, SR a, (S = O) R a, SO 2 R a, SO 3 R a, SO 2 NR a R b, NO 2,  NHR a, N (R a R b), NR a (OR b), NHCOR a, N (COR a) (COR b), NHCO 2 R a, NHC (= O) NR a R b, NHSO 2 R a, NH (C = NH) NH 2, CN, halogen, C (= O) R a, CO 2 R a, C (= O) NR a R b, C 1 -C 12 optionally substituted alkyl, C 2 -C 12 optionally substituted alkenyl, C 2 -C 12 alkynyl optionally substituted, C 6 -C 18 aryl optionally substituted, C 7 -C 30 arylalkyl optionally substituted, C 8 -C 30 optionally substituted arylalkenyl, C 3 -C 18 heterocycle optionally substituted, C4-C30 heterocycloalkyl optionally substituted, C 5 -C 30 optionally substituted heterocycloalkenyl, C 3 -C 18 cycloalkyl optionally substituted, C4-C30 cycloalkylalkyl optionally substituted, C 5 -C 30 optionally substituted cycloalkylalkenyl, C 3 -C 18 cycloalkenyl optionally substituted, C 4 -C 30 cycloalkenyl alkyl optionally substituted and C 5 -C 30 optionally substituted cycloalkenyl alkenyl, with the condition that one or more of these groups are absent if the Y group at that are attached is part of a double bond or a ring additional condensed carbocyclic or heterocyclic;

R a and R b are groups independently selected from hydrogen, C 1 -C 12 optionally substituted alkyl, C2-C12 optionally substituted alkenyl, C2-C12 optionally substituted alkynyl,  Optionally substituted C 6 -C 18 aryl, C 7 -C 30 arylalkyl optionally substituted, C 8 -C 30 arylalkenyl optionally substituted, C 3 -C 18 optionally substituted heterocycle, C 4 -C 30 heterocycloalkyl optionally substituted, C 5 -C 30 heterocycloalkenyl optionally substituted, C 3 -C 18 optionally substituted cycloalkyl, C 4 -C 30 cycloalkylalkyl optionally substituted, C 5 -C 30 cycloalkylalkenyl optionally substituted, C 3 -C 18 optionally substituted cycloalkenyl, C 4 -C 30 cycloalkenyl alkyl optionally substituted and C 5 -C 30 cycloalkenyl alkenyl optionally substituted;

with the exception of the compounds of formula:

fifteen

         \ vskip1.000000 \ baselineskip
      

16

17

         \ vskip1.000000 \ baselineskip
      

         \ vskip1.000000 \ baselineskip
      

18

         \ vskip1.000000 \ baselineskip
      

         \ vskip1.000000 \ baselineskip
      

         \ vskip1.000000 \ baselineskip
      

19

         \ vskip1.000000 \ baselineskip
      

         \ vskip1.000000 \ baselineskip
      

twenty

         \ vskip1.000000 \ baselineskip
      

         \ vskip1.000000 \ baselineskip
      

         \ vskip1.000000 \ baselineskip
      

twenty-one

The present invention also relates to Pharmaceutical compositions comprising a compound of formula (I), including those compounds previously excluded, and their corresponding pharmaceutically acceptable salts, derivatives, prodrugs or stereoisomers in admixture with an excipient or pharmaceutically acceptable diluent.

On the other hand, the present invention relates to the use of the compounds of formula (I), including those previously excluded compounds, as well as their corresponding pharmaceutically acceptable salts, derivatives, prodrugs or stereoisomers as medicines, especially in treatment of cancer, or in the preparation of a medicine for cancer treatment

Other aspects of the invention are methods of treatment and compounds for use in such treatments.

Detailed description of the invention

The present invention is related to compounds of general formula (I) as defined previously. In these compounds the groups or substituents can be selected according to the following criteria:

The term "alkyl" represents a straight or branched carbon chain having 1 to 12 carbon atoms. Alkyl groups of 1 to 6 carbon atoms are preferred, and particularly preferred are those consisting of 1, 2, 3 and 4 carbon atoms. Methyl, ethyl, propyl, isopropyl, butyl, sec- butyl, iso- butyl and tert-butyl groups are particularly preferred alkyl groups in the compounds of the present invention. The alkyl groups can be both substituted and unsubstituted.

The term "cycloalkyl" refers to a cyclic alkyl group, consisting of one or more fused rings, containing from 3 to 18 carbon atoms. Cycloalkyl groups having 5 to 10 carbon atoms are preferred, and particularly preferred are those consisting of 5 and 6 carbon atoms. Other preferred cycloalkyl groups are those having 10 to 14 carbon atoms. Cycloalkyl groups can be both substituted and unsubstituted. Also, the cycloalkyl groups may be linked to an alkyl or alkenyl group to form a cycloalkylalkyl or cycloalkylalkyl group, respectively. Cycloalkylalkyl groups contain from 4 to 30 carbon atoms. Preferably the cycloalkylalkyl groups consist of 7 to 20 carbon atoms, those consisting of 7 to 14 carbon atoms being particularly preferred. Cycloalkylalkenyl groups contain from 5 to 30 carbon atoms. Preferably the cycloalkylalkenyl groups consist of 8 to 20 carbon atoms, those consisting of 8 to 14 carbon atoms being particularly preferred
no.

The terms alkenyl and alkynyl represent linear or branched unsaturated alkyl chains containing from 2 to 12 carbon atoms and that include one or more unsaturations Alkenyl and alkynyl groups having 2 to 6 carbon atoms are preferred, and particularly preferred those consisting of 2, 3 and 4 carbon atoms. The groups alkenyl and alkynyl can be both substituted and non-substituted replaced.

The term cycloalkenyl represents a group cyclic alkenyl, formed by one or more fused rings, which they contain 3 to 18 carbon atoms and that includes one or more unsaturations Cycloalkenyl groups that have 5 to 10 carbon atoms are preferred, and particularly preferred constituted by 5 and 6 carbon atoms. Other groups Preferred cycloalkenyl are those with 10 to 14 carbon atoms Cycloalkenyl groups can be found both substituted as unsubstituted. Cycloalkenyl groups can be attached to an alkyl or alkenyl group to form a group cycloalkenyl alkyl or cycloalkenyl alkenyl, respectively. The cycloalkenyl alkyl groups contain from 4 to 30 carbon atoms. Preferably these groups consist of 7 to 20 atoms of carbon, and particularly preferred are those constituted by 7 to 14 carbon atoms. Cycloalkenyl alkenyl groups They contain 5 to 30 carbon atoms. Preferably the groups cycloalkenyl alkenyl consist of 8 to 20 atoms of carbon, and particularly preferred are those constituted by 8 to 14 carbon atoms.

The term alkylene represents a chain alkylenic, linear or branched having 1 to 12 atoms of carbon. The alkylene groups of 1 to 8 carbon atoms are preferred, and particularly preferred those constituted by 2, 3, 4, 5 and 6 carbon atoms. The ethylene, trimethylene, groups tetramethylene, pentamethylene, hexamethylene are alkylene groups particularly preferred in the compounds herein invention. Also, as used in the present invention, the "alkylene" refers to both a cyclic group and not cyclic, considering that cyclic groups are formed by one or several fused rings and comprise from 3 to 12 atoms of  carbon. Preferably the cyclic groups comprise from 5 to 8 carbon atoms Especially preferred are the groups cyclopentylene and cyclohexylene.

Among the aryl groups that may be present in the compounds of the invention we find those containing one or more rings, including multiple rings with aryl or heteroaryl groups separated or fused. Typically, aryl groups contain 1 to 3 rings and 6 to 18 atoms of carbon in the ring / s. Among the preferred aryl groups we find phenyl, naphthyl, biphenyl, phenanthryl and anthracil, all of them can be optionally substituted. The groups aryl can be attached to an alkyl or alkenyl group to forming an arylalkyl or arylalkyl group, respectively. The arylalkyl groups contain from 7 to 30 carbon atoms. Preferably these groups consist of 7 to 20 atoms carbon, and particularly preferred are those constituted for 7 to 14 carbon atoms. Phenylalkyl groups are especially preferred. The arylalkenyl groups contain from 8 to 30 carbon atoms Preferably these groups are consisting of 8 to 20 carbon atoms, and particularly Preferred are those consisting of 8 to 14 carbon atoms. Phenylalkenyl groups are especially preferred. The groups substituted or unsubstituted benzyl are most preferred.

The term carbocyclic ring refers to a cyclic alkyl group, which may be fully saturated or submit one or more unsaturations. Between the rings carbocyclics that may be present in the compounds of the invention include cycloalkyl, cycloalkenyl and aryl defined above. Carbocyclic rings can be both substituted and unsubstituted.

Among the heterocycle groups or rings that may be present in the compounds of the invention are both heteroaryl and heteroalicyclic groups. Typically these groups contain 1 to 3 rings and 3 to 18 carbon atoms in the ring / s. Preferably they contain 1 or 2 rings and 3 to 9 carbon atoms. The heteroaryl groups contain one, two or three heteroatoms selected from N, O and S and includes, for example, groups such as coumarinyl preferably 8-coumarinyl, quinolinyl preferably 8-quinolinyl, pyridyl, pyrazinyl, pyrimidyl, furyl, pyrrolyl, thienyl, thiazolyl, ozaxolyl, imidazolyl, indolyl, benzofuranyl and benzothiazolyl. Heteroalicyclic groups contain one, two or three heteroatoms selected from N, O, and S and includes, for example, groups such as tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholino and pyrrolidinyl. Heterocycle groups can be both substituted and unsubstituted. The heterocycle groups may be linked to an alkyl or alkenyl group to form a heterocycloalkyl or heterocycloalkenyl group, respectively. Heterocycloalkyl groups contain 4 to 30 carbon atoms. Preferably the heterocycloalkyl groups contain from 4 to 20 carbon atoms, those consisting of 4 to 14 carbon atoms being particularly preferred. Heterocycloalkenyl groups contain 5 to 30 carbon atoms. Preferably heterocycloalkenyl groups contain from 5 to 20 carbon atoms, those consisting of 5 to 14 atoms of particular preference being particularly preferred.
carbon.

The above mentioned groups can be optionally substituted in one or more of its positions available, independently, by one or more substituents suitable, such as OR ', = O, SR', SOR ', SO_ {2} R', NO_ {2}, NHR ', N (R') 2, = N-R ', NHCOR', N (COR ') 2, NHSO2 R', CN, halogen, C (= O) R ', COOR ', (C = NH) -R', (C = NR ') - R OC (= O) R ', C 6 -C 18 substituted aryl or unsubstituted and C 3 -C 18 heterocycle substituted or unsubstituted, where R 'is selected independently between hydrogen, OH, NO2, NH2, SH, CN, halogen, C (= O) H, C (= O) CH 3, COOH, C 1 -C 12 substituted or unsubstituted alkyl, C 2 -C 12 alkenyl substituted or not substituted, C2-C12 substituted alkynyl or unsubstituted and C 6 -C 18 substituted aryl or not replaced When these groups are in turn substituted, the substituents can be chosen from the list of substituents before mentioned.

Among the halogen substituents that can being present in the compounds of the present invention will includes F, Cl, Br and I.

The amino and hydroxyl groups can be found optionally protected. There is a large number of groups amino and hydroxyl protectors, and are well known for the skilled. As a guide, see Protecting groups, Kocienski, 2005, 3rd edition.

The term "pharmaceutically salts acceptable, derivatives, prodrugs "refers to any salt pharmaceutically acceptable ester, solvate, hydrate or any another compound that, after administration to the patient, is capable of provide (directly or indirectly) a compound of general formula (I). However, it should be noted that you leave non-pharmaceutically acceptable also fall within the scope of the invention since these may be useful in the preparation of pharmaceutically acceptable salts. The preparation of the salts, prodrugs and derivatives can be performed by known methods in the state of the art.

For example, pharmaceutically salts Acceptable of the compounds of the present invention are obtained at from the corresponding compounds that have acid units or basic, by conventional chemical methods. Usually, said salts are prepared, for example, by reaction of the corresponding basic or acid free form of said compound with a stoichiometric amount of the appropriate base or acid in water, in an organic solvent or in a mixture of both. Usually preferred non-aqueous media are ether, acetate ethyl, ethanol, isopropanol or acetonitrile. Among the salts of acid additions include mineral acid addition salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate and phosphate, and organic acid addition salts such as acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluenesulfonate. Basic addition salts include inorganic salts such as sodium, potassium, calcium and ammonium salts, and salts organic such as ethylenediamine, ethanolamine salts, N, N-dialkylene ethanolamine, triethanolamine and basic amino acids

The compounds of the present invention can be in crystalline form, both as free compounds as solvates (eg hydrates) leaving both forms included within of the scope of the present invention. Solvation methods are generally known in the state of the art.

Any compound that is a prodrug of a compound of general formula (I) is included within the scope of the present invention. The term "prodrug" is used in its broadest sense and encompasses all those derivatives likely to be transformed in vivo into any of the compounds of the invention. Any person skilled in the art knows what derivatives can be treated and includes, for example, compounds in which the free hydroxyl group is converted into an ester derivative, or an ester is modified by transesterification or a suitable amide is formed.

The compounds of the present invention represented by the general formula (I) may have more than one stereogenic center, whereby the invention also relates to each and every one of the possible enantiomers and diastereoisomers that can be formulated, as well as the possible Z and E stereoisomers that can be formed when there is a double bond in the molecule. Both pure isomers and mixtures of isomers of said Compounds are within the scope of this invention.

Among the preferred compounds herein invention we find those in which R 1 and R 2 are groups C 6 -C 18 aryl substituted or not substituted, those compounds in especially preferred being which R1 and R2 are phenyl groups substituted or not replaced.

Preferably R 4 is hydrogen or a radical of formula (II) where R 6 and R 7 are groups C 6 -C 18 aryl substituted or unsubstituted. Particularly preferred are those compounds in which R 4 is hydrogen or a radical of formula (II) where R 6 and R 7 are substituted or unsubstituted phenyl groups.

Preferably R 3 and R 5 are groups independently selected from C 1 -C 12 substituted or unsubstituted alkyl, C 7 -C 30 arylalkyl substituted or not substituted and C 4 -C 30 heterocycloalkyl substituted or unsubstituted, being particularly preferred those compounds with C 1 -C 6 groups optionally substituted alkyl, C 8 -C 14 substituted or unsubstituted arylalkyl and C4-C14 heterocycloalkyl substituted or not replaced. Especially preferred are the compounds with groups substituted or unsubstituted phenylalkyl.

Equally preferred are those compounds in which R 1 and R 3 and / or R 5 and R 6 together with the atoms of adjacent P and N form a heterocycle of formula (III) or (IV), respectively, where Y 1, Y 2, Y 3 and Y 4 are groups selected from NR 12 and CR 13 R 14. The presence of at least one additional link in any of the positions marked with dotted lines in formula (III) or (IV) is preferable. Particularly preferable is the presence of two double bonds giving rise to heterocycles of formula (V) at (VIII)

         \ vskip1.000000 \ baselineskip
      

         \ vskip1.000000 \ baselineskip
      

22

         \ vskip1.000000 \ baselineskip
      

         \ vskip1.000000 \ baselineskip
      

         \ vskip1.000000 \ baselineskip
      

         \ vskip1.000000 \ baselineskip
      

2. 3

         \ newpage
      

Preferably Y 1, Y 2, Y 3 e Y 4 are CR 13 groups R 14 where R 13 and R 14 are hydrogen or at least one of them is absent if the atom of carbon to which they are attached is part of a double bond or a additional condensed carbocyclic or heterocyclic ring.

Preferably R 8 and R 9 are groups independently selected from C 6 -C 18 substituted or unsubstituted aryl and C 3 -C 18 heterocycle substituted or not substituted, groups being particularly preferred C 6 -C 10 substituted or unsubstituted aryl and C 3 -C 9 heterocycle substituted or not replaced. Especially preferred are phenyl groups. substituted or unsubstituted.

Preferably R 10 and R 11 are groups independently selected from hydrogen, C 1 -C 12 substituted or unsubstituted alkyl, C 3 -C 18 cycloalkyl substituted or not substituted, C2-C12 substituted alkenyl or unsubstituted and C 3 -C 18 cycloalkenyl substituted or unsubstituted, with those being particularly preferred hydrogen groups, C 1 -C 6 alkyl substituted or unsubstituted, C 5 -C 10 substituted or unsubstituted cycloalkyl, C 2 -C 6 alkenyl substituted or not substituted, C 5 -C 10 cycloalkenyl substituted or unsubstituted. Groups are especially preferred hydrogen. Equally preferred is that the R 11 group be absent because the carbon to which it is attached is part of a double link.

The following compounds are particularly Preferred in the present invention:

         \ vskip1.000000 \ baselineskip
      

         \ vskip1.000000 \ baselineskip
      

24

         \ vskip1.000000 \ baselineskip
      

         \ vskip1.000000 \ baselineskip
      

         \ vskip1.000000 \ baselineskip
      

25

         \ vskip1.000000 \ baselineskip
      

         \ vskip1.000000 \ baselineskip
      

         \ vskip1.000000 \ baselineskip
      

26

         \ vskip1.000000 \ baselineskip
      

         \ vskip1.000000 \ baselineskip
      

         \ vskip1.000000 \ baselineskip
      

27

28

29

30

31

32

33

         \ vskip1.000000 \ baselineskip
      

         \ vskip1.000000 \ baselineskip
      

3. 4

         \ vskip1.000000 \ baselineskip
      

         \ vskip1.000000 \ baselineskip
      

35

         \ vskip1.000000 \ baselineskip
      

Some of the preferred methods for Obtaining the compounds of the present invention are described. in the following reaction schemes with examples of possible substitutions These examples do not limit the invention and the process It should be understood in the most general sense possible.

The preparation of the compounds where the pairs of groups formed by R 1 and R 3 and / or R 5 and R 6 no together with the adjacent P and N atoms form a heterocycle and A is A linear alkylene group is shown in Scheme I:

Scheme I

         \ vskip1.000000 \ baselineskip
      

36

         \ vskip1.000000 \ baselineskip
      

The preparation of the compounds where the pairs of groups formed by R 1 and R 3 and / or R 5 and R 6 no together with the adjacent P and N atoms form a heterocycle and A is A cyclic alkylene group is shown in Schemes II and III:

         \ newpage
      

Scheme II

37

         \ vskip1.000000 \ baselineskip
      

Scheme III

501

The preparation of the compounds where the pairs of groups formed by R 1 and R 3 and / or R 5 and R 6 form at least one adjacent to the adjacent P and N atoms heterocycle of formula (III) or (IV) and A is an ethylene group shown in Schemes IV and V:

Scheme IV

         \ vskip1.000000 \ baselineskip
      

38

Scheme V

         \ vskip1.000000 \ baselineskip
      

502

         \ vskip1.000000 \ baselineskip
      

How can the selectivity of the cyclization reaction increases by adding an intermediate stage in the that the anionic intermediate of the reaction is captured with a silylated electrophile.

The preparation of the compounds where the pairs of groups formed by R 1 and R 3 and / or R 5 and R 6 form at least one adjacent to the adjacent P and N atoms heterocycle of formula (III) or (IV) and A is a trimethylene group Sample in Scheme VI:

         \ vskip1.000000 \ baselineskip
      

Scheme SAW

         \ vskip1.000000 \ baselineskip
      

39

         \ vskip1.000000 \ baselineskip
      

The preparation of the compounds where the pairs of groups formed by R 1 and R 3 and / or R 5 and R 6 form at least one adjacent to the adjacent P and N atoms heterocycle of formula (III) or (IV) and A is a tetramethylene group It is shown in Schemes VII and VIII:

         \ newpage
      

Scheme VII

40

Scheme VIII

41

In this case, the improvement in the selectivity of the cyclization reaction by adding a step intermediate in which the anionic intermediate of the reaction with a silylated electrophile.

The preparation of the compounds where the pairs of groups formed by R 1 and R 3 and / or R 5 and R 6 form at least one adjacent to the adjacent P and N atoms heterocycle of formula (III) or (IV) and A is an alkylene group Cyclic is shown in Schemes IX and X:

Scheme IX

42

Scheme X

503

Alternatively, the preparation of compounds where the pairs of groups formed by R1 and R3 and / or R 5 and R 6 form together with the adjacent P and N atoms at least one substituted heterocycle of formula (III) or (IV) and A is a linear or cyclic alkylene can be made according to the Schemes XI to XIII:

Scheme XI

43

Scheme XII

44

Scheme XIII

Four. Five

On the other hand, it is possible to obtain analogues of said compounds by adapting previously described procedures for simpler compounds (López Ortiz et al ., Chem. Commun. 2005, 43, 5408-5410; ARKIVOC 2005, 9, 375-393; Chem. Eur. J. 2005, 11, 3022-3031; J. Am. Chem. Soc. 2004, 126, 12551-12564; J. Org. Chem. 2003, 68, 4472-4485; Synlett 2002, 5, 781 -783; J. Org. Chem. 2002, 67, 11, 3852-3860; Org. Lett. 2001, 3, 1339-1342).

An important aspect of the compounds of the The present invention is its bioactivity and in particular its activity cytotoxic Therefore, with the present invention we provide new pharmaceutical compositions of the compounds of formula general (I) that possess cytotoxic activity, as well as their use as antitumor agents. On the other hand, the present invention also provides pharmaceutical compositions comprising a compound of this invention, or a pharmaceutically acceptable salt, a derivative, a prodrug or a stereoisomer, in admixture with a pharmaceutically acceptable excipient or diluent.

As examples of pharmaceutical compositions, Includes any solid composition (tablets, pills, capsules, granules, etc.) or liquid (solutions, suspensions or emulsions) for oral, topical or parenteral administration. The pharmaceutical compositions containing the compounds of the The present invention can also be formulated in the form of liposomes or nanospheres, of sustained release formulations or of any other conventional release system.

The administration of the compounds or Compositions of the present invention can be made by any of the usual methods such as intravenous infusion, oral preparations and / or intraperitoneal administration and intravenous It is preferable that the infusion times used are not exceed 24 hours, preferably from 1 to 12 hours, and even more Preferable from 1 to 6 hours. Short infusion times are especially desired since they allow the treatment to take out without having to spend the night in the hospital. Without However, infusion times of 12 to 24 hours and even longer, they can be employed if these were necessary. The infusion can be carried out at convenient intervals, such as 1 to 4 weeks

The correct dosage of the compounds will vary according to the type of formulation used, the mode of application and the situs, host and tumor to be treated. They should also other factors such as age, body weight, sex, diet, administration time, excretion rate, guest health status, combination of active ingredients, sensitivities at the level of reactions and the severity of the disease. Administration can be carried out in a way continuous or periodic within the maximum tolerated dose.

The compounds and compositions herein invention can be used together with other active ingredients to combined therapy mode. The other active ingredients can be part of the same composition or they can be provided by a different composition, being administered at the same time or at different times.

Examples

All chiral compounds herein are describe with relative stereochemistry.

Example 1 Synthesis of bisphosphinamide 4-6

46

On a solution of amines 1, 2 (Niitsu and Keijiro, S. Chem. Pharm. Bull. 1986 , 34 , 1032) or 3 (Yabuta and Ikeda, JP 29003480) (8.60 mmol) in toluene (120 mL) in the presence of triethylamine (6.0 mL, 43.00 mmol) is added dropwise chlorodiphenylphosphine (3.24 mL, 18.06 mmol) at -80 ° C. The temperature is then allowed to rise slowly, maintaining stirring for 30 minutes. The toluene is then distilled off, CH2Cl2 (20-30 mL) is added and 77% MCPBA (3.85 g, 17.20 mmol) is added slowly at a temperature equal to or less than 0 ° C. Once the oxidation is complete (30 min), the reaction mixture is poured onto water, extracted with ethyl acetate (2 x 15 mL), washed with 1N NaOH (3 x 15 mL) and with water (1 x 15 mL) The organic extracts are dried over anhydrous Na2SO4 and concentrated in vacuo. Purification of 4 is achieved by precipitation in ethyl acetate, while that of compounds 5-6 is carried out with diethyl ether.

Compound 4

47

Purification: AcOEt precipitation; Yield: 83%; F. Empirical: C 40 H 38 N 2 O 2 P 2; Melting point: 171 ° C; IR (KBr, nu cm -1): 1186; MS ( m / z ): 641 (M + 1); 1 H NMR: 3.10 (m, 4H, 3 J PH 10.6 Hz, H-4), 3.83 (d, 4H, 3 J PH 9.9 Hz, H -3), 7.02 (m, 4H, ArH), 7.18-7.60 (m, 18H, ArH), 7.74 (m, 8H, 3 J PH 12.1 Hz, H-8); NMR - 13 C \ 1 H \: 44.02 (C-4), 49.73 (d, 2 J PC 3.7 Hz, C-3), 127.12 (C-12 ), 127.75 (C-10), 128.41 (d, 2 J PC 6.0 Hz, C-6), 128.62 (C-11), 130.31 (d, 1 J PC 128.6 Hz, C-5), 131.85 (d, 4 J PC 1.8 Hz, C-8), 132.20 (d, 3 J PC 9.6 Hz, C-7), 137.27 (d, 3 J PC 4.0 Hz, C-9); NMR - 31 P \ 1 H \: 31.00.

Compound 5

         \ vskip1.000000 \ baselineskip
      

48

         \ vskip1.000000 \ baselineskip
      

Purification: Precipitation in Et2O; Yield: 73%; F. Empirical: C 41 H 40 N 2 O 2 P 2; Melting point: 118 ° C; IR (KBr, nu cm -1): 1179, 1118; MS ( m / z ): 655 (M + 1); 1 H NMR: 1.72 (m, 2H, H-5), 2.53 (m, 4H, 3 J HH 7.9 Hz, 3 J PH 10.4 Hz, H -4), 4.03 (d, 4H, 3 J PH 9.7 Hz, H-3), 7.28 (m, 10H, H-11, H-12, H-13), 7.39-7.52 ( m, 6H, H-8, H-9), 7.83 (m, 4H, 3 J PH 11.5 Hz, H-7); NMR - 13 C \ 1 H \: 25.67 (t, 3 J PC 3.3 Hz, C-5), 42.45 (d, 2 J PC 3.0 Hz, C-4), 49.05 (d, 2 J PC 3.0 Hz, C-3), 127.31 (C-13), 128. 43 (C-12, C-13), 128.51 (d, 3 J PC 13.2 Hz, C-8), 131.75 (d, 1 J PC 129.2 Hz, C-6), 131.75 (d, 4 J PC 3.0 Hz, C-9), 132.31 (d, 2 J PC 9.0 Hz, C-7), 136.98 (d, 3 J PC 4.2 Hz, C-10); NMR - 31 P \ 1 H \: 30.83.

         \ vskip1.000000 \ baselineskip
      

Compound 6

         \ vskip1.000000 \ baselineskip
      

49

         \ vskip1.000000 \ baselineskip
      

Purification: Precipitation in Et2O; Yield: 81%; F. Empirical: C_ {42} H_ {42} N_ {2} P2 {2}; Melting point: 158 ° C; IR (KBr, nu cm -1): 1191, 1118; MS ( m / z ): 669 (M + 1); 1 H NMR: 1.16 (m, 4H, H-5), 2.61 (m, 4H, 3 J HH 7.0 Hz, 3 J PH 10.5 Hz, H -4), 4.08 (d, 4H, 3 J PH 9.8 Hz, H-3), 7.28 (m, 10H, H-11, H-12, H-13), 7.39-7.52 ( m, 12H, H-8, H-9), 7.84 (m, 8H, 3 J PH 11.7 Hz, H-7); NMR - 13 C \ 1 H \: 25.14 (d, 3 J PC 3.3 Hz, C-5), 42.90 (d, 2 J PC 3.0 Hz, C-4), 49.24 (d, 2 J PC 3.6 Hz, C-3), 127.23 (C-13), 128.24 (C-11), 128. 36 (C- 12), 128.44 (d, 3 J PC 12.9 Hz, C-8), 131.70 (d, 4 J PC 2.7 Hz, C-9), 131.91 (d, ^ 1 J PC 128.9 Hz, C-6), 132.30 (d, 2 J PC 9.3 Hz, C-7), 137.37 (d, 3 J PC) 4.8 Hz, C-10); NMR - 31 P \ 1 H \: 30.92.

         \ vskip1.000000 \ baselineskip
      

Example 2 Procedures for the dearomatization of 4 and characterization of the products obtained

Method one

On a solution of 4 (2.99 x 10-4 mol) in THF (20-35 mL) and HMPA (0.42 mL, 2.39 x 10-3 mol) a solution of LiBu s is added (1.15 mL, 1.3 M in cyclohexane, 1.50 x 10-3 mol) at -90 ° C and allowed to stir for 30 minutes at the same temperature. Subsequently, methanol (2 mL) or 2,6-di- tert- butyl-4-methylphenol (DTBMP) (8 equivalents) is added at -90 ° C and stirring is maintained for another 30 minutes. The reaction mixture is then poured into water and extracted with ethyl acetate (3 x 15 mL). The organic extracts are dried over Na2SO4, filtered and concentrated in vacuo. NMR spectra - 1 H, 1 H {31 P \, and 31 P \ {1 H}} were measured on the reaction crude in order to determine the stereoselectivity of the different processes. The purification of the generated compounds was performed, either by precipitation in diethyl ether, or by chromatographic column (silica gel, silica gel impregnated in 5% triethylamine or neutral alumina), using as eluent different mixtures of AcOEt / MeOH.

fifty

         \ vskip1.000000 \ baselineskip
      

The yields of the reactions are indicated in table I.

         \ vskip1.000000 \ baselineskip
      

TABLE I

         \ vskip1.000000 \ baselineskip
      

51

         \ newpage
      

Method 2

52

On a solution of 4 (2.99 x 10-4 mol) in THF (20-35 mL) and HMPA (0.42 mL, 2.39 x 10-3) mol) a solution of LiBu s (1.15 mL, 1.3 M in cyclohexane, 1.50 x 10-3 mol) at -90 ° C and allowed to stir for 0.5-2.0 h at the same temperature. Subsequently, a solution of TBDMSCl (180 mg, 1.2 x) is added 10-3 mol) in 1 mL of THF and stir for 30 min. Finally methanol (2 mL) is added at -90 ° C and stirring is maintained for Another 30 minutes The reaction mixture is then poured over water and extracted with ethyl acetate (3 x 15 mL). The organic extracts are dried over Na2SO4, filtered and They are concentrated in vacuo. The reaction crude was measured NMR spectra - 1 H, 1 H \ 31 P \ and 31 P \ {1 H \} in order to determine stereoselectivity of the different processes. The purification of the compounds generated was performed, either by precipitation in diethyl ether, either by chromatographic column (silica gel, silica gel impregnated in 5% triethylamine or neutral alumina), using as eluent different mixtures of AcOEt / MeOH.

The yields of the reactions are indicated in Table II

         \ vskip1.000000 \ baselineskip
      

TABLE II

53

         \ vskip1.000000 \ baselineskip
      

Compound 7

54

Purification: Crystallization from CH2Cl2 / CHCl3; F. Empirical: C 40 H 38 N 2 O 2 P 2; Melting point: 230 ° C; IR (KBr, nu cm -1): 1190; MS ( m / z ): 641 (M + 1); 1 H NMR: 2.58 (m, 2H, H-8), 2.81 (m, 2H, H-8 '), 2.89 (m, 2H, H-3a), 3.06 (tt, 2H, ^ 3 J HH 11.4 Hz, 3 J HH 3.0 Hz, 2 J PH 11.4 Hz, H-7a), 4.12 (d, 2H, 3 J 9.3 Hz, H-3), 5.29 (ddt, 2H, 3 J HH 9.5 Hz, 3 J HH 5.5 Hz, 4 J HH 0.8 Hz, H-4), 5.85 (dddt, 2H, 3 J HH 9.5 Hz, 3 J HH 3.0 Hz, 4 J HH 0.8 Hz , 3 J PH 9.5 Hz, H-7), 5.92 (ddc, 2H, 3 J HH 9.5 Hz, 3 J HH 5.5 Hz, 4 J HH 0.8 Hz, 5 J PH 0.8 Hz, H-5), 6.04 (m, 2H, 4 J PH 2.4 Hz, H-6), 7.09 (m, 4H, H-14), 7.31-7.55 (m, 12H, ArH), 7.62 (m, 4H, 3 J PH 12.2 Hz, H-10); NMR - 13 C \ 1 H \: 37.49 (d, 1 J PC 84.1 Hz, C-7a), 40.77 (d, 2 J PC 2.4 Hz, C-8), 43.44 (C-3a), 68.35 (d, 2 J PC 21.6 Hz, C-3), 119.40 (d, 2 J PC 8.4 Hz, C-7), 123.38 (d, 3 J PC 11.4, C-4), 124.27 (d, 3 J PC 5.4 Hz, C-6), 124.36 (d, 4 J PC 1.2 Hz, C-5), 127.54 (C-14), 128.23 (C-16), 128.42 (d, 3 J PC 12.7 Hz, C-11), 128.71 (C-15), 131.49 (d, 2 J PC 9.9 Hz, C-10), 131.61 (d, 4 J PC 2.9 2.9 Hz, C -12), 133.33 (d, 1 J PC 12.5 Hz, C-9), 138.91 (d, 3 J PC 9.6 Hz, C-13); NMR - 31 P \ 1 H \: 47.63.

Compound 8

55

Purification: AcOEt / MeOH flash chromatography, 25: 1; F. Empirical: C 40 H 38 N 2 O 2 P 2; Melting point: Oil; MS ( m / z ): 641 (M + 1); 1 H NMR: 2.67-2.94 (m, 6H, H-3a, H-8), 3.06 (m, 2H, 2 J PH 11.7 Hz, H-7a), 4.07 ( d, 2H, 3 J HH 9.2 Hz, H-3), 5.29 (ddc, 2H, 3 J HH 9.5 Hz, 3 J HH 5.4 Hz , H-4), 5.87 (m, 2H, 3 J PH 9.5 Hz, H-7), 5.94 (ddc, 2H, 3 J HH 9.5 Hz, 3 J HH 5.4 Hz, 5 J HH 0.8 Hz, H-5), 6.06 (m, 2H, H-6), 7.00 (m, 4H, H-14), 7.19- 7.40 (m, 6H, H-15, H-16), 7.40-7.59 (m, 6H, H-11, H-12), 7.72 (m, 4H, 3 J PH 12.4 Hz, H-10); NMR - 13 C \ 1 H \: 37.26 (d, 1 J PC 84.1 Hz, C-7a), 40.33 (C-8), 43.39 (C-3a ), 67.85 (d, 2 J PC 21.0 Hz, C-3), 119.43 (d, 2 J PC 8.4 Hz, C-7), 123.31 (d, ^ 3 J PC 11.4 Hz, C-4), 124.36 (C-5), 124.44 (d, 3 J PC 5.4 Hz, C-6), 127.70 (C-14), 128.36 (C-16), 128.44 (d, 3 J PC 13.2 Hz, C-11), 128.61 (C-15), 131.39 (d, 2 J PC 10.2 Hz , C-10), 131.61 (d, 4 J PC 2.5 Hz, C-12), 133.25 (d, 1 J PC 126.2 Hz, C-9), 139.24 ( d, 3 J PC 9.6 Hz, C-13); NMR - 31 P \ 1 H \: 49.17.

Compound 9

56

Purification: Precipitation in diethyl ether; F. Empirical: C 40 H 38 N 2 O 2 P 2; Melting point: 219 ° C; IR (KBr, nu cm -1): 1206; MS ( m / z ): 641 (M + 1); 1 H NMR: 2.64-2.87 (m, 8H, H-6, H-8), 3.12 (m, 2H, H-3a), 3.96 (d, 2H, 3 J HH 9.3 Hz, H-3), 5.43 (m, 2H, H-4), 5.69 (m, 2H, H-5), 6.59 (m, 2H, 3 J PH 16.6 Hz, H -7), 7.19 (m, 4H, H-14), 7.36-7.51 (m, 12H, ArH), 7.68 (m, 4H, 3 J PH 11.6 Hz, H-10); NMR - 13 C \ 1 H \: 27.63 (d, 3 J PC 12.6 Hz, C-6), 40.64 (d, 2 J PC 2.4 Hz, C-8), 46.62 (d, 2 J PC 13.8 Hz, C-3a), 67.19 (d, 2 J PC 12.0 Hz, C-3) , 122.82 (d, 3 J PC 6.6 Hz, C-4), 124.98 (d, 4 J PC 1.2 Hz, C-5), 127.90 (C-14), 128.28 (d, 3 J PC 13.2 Hz, C-11), 128.49 (C-16), 128.85 (C-15), 131.39 (d, 4 J PC 3.0 3.0 Hz , C-12), 131.53 (d, 2 J PC 10.8 Hz, C-10), 133.04 (d, 1 J PC 120.7 Hz, C-7a), 133.53 ( d, 1 J PC 132.8 Hz, C-9), 135.36 (d, 2 J PC 9.6 Hz, C-7), 138.19 (d, 3 J _ {PC} 8.4 Hz, C-13); NMR - 31 P \ 1 H \: 28.07.

Compound 11

57

Purification: AcOEt / MeOH flash chromatography, 25: 1; F. Empirical: C 40 H 38 N 2 O 2 P 2; Melting point: Oil; IR (KBr, nu cm -1): 1261, 1113, 1021; MS ( m / z ): 641 (M + 1); 1 H NMR: 2.62-2.92 (m, 6H, H-3a ', H-6, H-8 and H-8'), 3.07 (m, 1H, 3 J PH 11.6 Hz, H-7a '), 3.09 (m, 1H, H-3a), 3.90 (d, 1H, 3 J HH 9.4 Hz, H-3), 4.18 (d, 1H, ^ {3} J {HH} 9.0 Hz, H-3 '), 5.31 (m, 1H, H-4'), 5.41 (m, 1H, H-4), 5.69 (m, 1H, H-5 ' ), 5.86 (m, 1H, H-7 '), 5.94 (m, 1H, H-5), 6.06 (m, 1H, H-6'), 6.60 (m, 1H, 3 J PH} 16.3 Hz, H-7), 7.11-7.14 (m, 4H, H-14, H-14 '), 7.35-7.56 (m, 12H, H-11, H-11', H-12, H -12 ', H-15, H-15', H-16, H-16 '), 7.65 (m, 2H, H-10), 7.68 (m, 2H, H-10'); NMR - 13 C \ 1 H \: 27.63 (d, 3 J PC 12.6 Hz, C-6), 37.49 (d, 1 J PC 84.7 Hz, C-7a '), 40.56 (d, 2 J PC 2.4 Hz, C-8), 40.85 (d, 2 J PC 2.4 Hz, C-8 '), 43.55 (C-3a'), 46.57 (d, 2 J PC 13.2 Hz, C-3a), 67.21 (d, 2 J PC 11.4 Hz, C- 3), 68.36 (d, 2 J PC 21.0 Hz, C-3 '), 119.47 (d, 2 J PC 8.4 Hz, C-7'), 122.73 (d , 3 J PC 6.6 Hz, C-4), 123.44 (d, 3 J PC 10.8 Hz, C-4 '), 124.29 (d, 3 J _ {PC} 4.2 Hz, C-6 '), 124.37 (d, 4 J PC 1.8 Hz, C-5'), 125.03 (d, 4 J PC 1.2 Hz, C-5), 127.65 (C-14), 127.83 (C-14 '), 128.25 (C-16), 128.33 (d, 3 J PC 13.2 Hz, C-11'), 128.43 (d, 3 J PC 12.6, C-11), 128.51 (C-16 '), 128.74 (C-15), 128.85 (C-15'), 131.47 (d, 4) J PC 3.0 Hz, C-12 '), 131.61 (d, 4 J PC 3.0 Hz, C-12), 132.93 (d, 1 J PC 121.3, C-7a), 133.27 (d, 1 J PC 125.5, C-9), 133.38 (d, 1 J PC 133.4 Hz, C-9 '), 135.45 (d , 2 J PC 9.6 Hz, C-7), 138.10 (d, 3 J PC 8.4 Hz, C-13 '), 138.92 (d, 3 J PC 9.6 Hz, C-13); NMR - 31 P \ 1 H \: 47.74 (P-1 '), 27.86 (P-1).

Compound 12

58

         \ vskip1.000000 \ baselineskip
      

Purification: AcOEt / MeOH flash chromatography, 25: 1; F. Empirical: C 40 H 38 N 2 O 2 P 2; Melting point: Oil; IR (KBr, nu cm -1): 1167, 1116; MS ( m / z ): 641 (M + 1); 1 H NMR: 2.63-2.92 (m, 5H, H6, H-8, H-8 '), 3.03-3.13 (m, 2H, H-7a', H-3a), 3.88 (d, 3 J HH 9.4 Hz, 1H, H-3), 4.10 (d, 1H, 3 J HH 9.4 Hz, H-3 '), 5.29 (m, 1H, H -4 '), 5.41 (m, 1H, H-4), 5.69 (m, 1H, H-5), 5.89 (dt, 1H, 3 J HH 9.9 Hz, 3 J HZ 2.6 Hz, 3 J PH 9.9 Hz, H-7 '), 5.95 (dd, 1H, 3 J HH 9.9 Hz, 3 J J HH} 5.5 Hz, H-5 '), 6.07 (m, 1H, H-6'), 6.60 (m, 1H, H-7), 7.02-7.07 (m, 4H, H-14, H-14 ' ), 7.29-7.33 (m, 6H, H-15, H-15 ', H-16, H-16'), 7.37-7.51 (m, 6H, H-11, H-11 ', H-12, H-12 '), 7.64-7.72 (m, 4H, H-10, H-10'); NMR - 13 C \ 1 H \: 27.57 (d, 3 J PC 12.6 Hz, C-6), 37.18 (d, 1 J PC } 84.1 Hz, C-7a '), 40.23 (m, C-8, C-8'), 46.14 (C-3a / C-3a '), 46.31 (C-3a / C-3a'), 67.09 ( d, 2 J PC 12.0 Hz, C-3), 67.74 (d, 2 J PC 21.6 Hz, C-3 '), 119.44 (d, 2 J PC 8.4 Hz, C-7 '), 122.66 (d, 3 J PC 6.6, C-4), 123.25 (d, 3 J PC 10.8 Hz, C -4 '), 124.35 (C-5'), 124.43 (d, 3 J PC 6.6 Hz, C-6 '), 124.99 (C-5), 127.44-128.74 (8CHAr), 131.29 -131.61 (4CHAr), 132.76 (d, 1 J PC 120.7 Hz, C-7a), 133.11 (d, 1 J PC 126.1 Hz, C-9), 133.28 ( d, 1 J PC 132.8 Hz, C-9 '), 135.32 (d, 2 J PC 9.6 Hz, C-7), 138.47 (d, 3 J PC 8.4 Hz, C-13 '), 139.13 (d, 3 J PC 9.0 Hz, C-13); NMR - 31 P \ 1 H \: 48.89 (P-1 '), 28.83 (P-1).

Mixture of compounds 13a and 13b

         \ vskip1.000000 \ baselineskip
      

59

         \ vskip1.000000 \ baselineskip
      

Purification: Flash chromatography on neutral alumina AcOEt / MeOH, 25: 1; Mix 41:59; F. Empirical: C_ {40} H_ {38} N_ {2}
O 2 P 2; Melting point: Oil; IR (KBr, nu cm -1): 1166, 1117; MS ( m / z ): 641 (M + 1); 1 H NMR: 2.07 (m, 4H, H-4), 2.68 (m, 2H, H-3a), 2.81 (m, 4H, H-6 '), 3.12 (m, 2H, H- 3a '), 3.93 (d, 1H, 3 J HH 9.6 Hz, H-3'), 3.96 (d, 1H, 3 J HH 9.5 Hz, H-3 ' ), 4.03 (d, 1H, 3 J HH 8.0 Hz, H-3), 4.06 (d, 3 J HH 8.1, H-3), 5.43 (m, 2H , H-4 '), 5.70 (m, 2H, H-5'), 5.95 (m, 2H, H-5), 6.03 (m, 2H, H-6), 6.52 (ddd, 2H, ^ 3 J HH 4.7 Hz, 4 J HH 2.9 Hz, 3 J PH 15.4 Hz, H-7), 6.60 (m, 2H, H-7 '), 7.09-7.17 (m, 8H, H-14, H-14 '), 7.35-7.56 (m, 24H, ArH), 7.65 (m, 4H, H-10), 7.70 (m, 4H, H-10'); NMR - 13 C \ 1 H \: 25.59 (d, 3 J PC 4.1 Hz, C-4), 27.64 (d, 3 J PC 13.2 Hz, C-6 '), 40.71 (C-8 / C-8'), 45.18 (d, 2 J PC 11.4 Hz, C3a), 46.64 (d, 2 J PC 13.2 hz, C-3a '), 67.12 (d, 2 J PC 12.0 Hz, C-3'), 67.19 (d, 2 J PC 12.0 Hz , C-3 '), 69.22 (d, 2 J PC 13.2 Hz, C-3), 69.31 (d, 2 J PC 12.6 Hz, C-3), 122.79 (d, 3 J PC 6.6 Hz, C-4 '), 124.69 (d, 3 J PC 15.0 Hz, C-6), 124.84 (3 J _ {PC} 15.6 Hz, C-6), 127.55-128.84 (8CHAr), 129.84 (4 J PC 2.4 Hz, C-5), 131.35-132.06 (4CHAr), 132.20-134.32 (4C- Ar), 135.46 (d, 2 J PC 9.6 Hz, C-7), 135.42 (d, 2 J PC 10.2 Hz, C-7 '), 138.21 (C- Ar), 138.69 (C-Ar); NMR -31 P \ 1H \: 13a or 13b 28.25, 30.66; 13a or 13b 28.32, 30.61.

Compound 15

         \ vskip1.000000 \ baselineskip
      

60

Purification: AcOEt / MeOH flash chromatography, 15: 1; F. Empirical: C 40 H 38 N 2 O 2 P 2; Melting point: White oil; MS ( m / z ): 641 (M + 1); 1 H NMR: 2.72-2.97 (m, 5H, H-3a, H-8, H-9), 3.04 (m, 1H, 3 J HH 11.0 Hz, 4 J HH 2.9 Hz, 2 J PH 11.0 Hz, H-7a), 3.86 (dd, 1H, 2 J HH 15.4 Hz, 3 J _ {PH 9.8 Hz, H-10), 4.07 (dd, 1H, 2 J HH 15.4 Hz, 3 J PH 10.3 Hz, H-10 '), 4.10 (d , 1H, 3 J HH 10.3 Hz, H-3), 5.27 (dddt, 1H, 3 J HH 9.5 Hz, 3 J HH 5.5 Hz, 4 J HH 1.1 Hz, 4 J PH 2.5 Hz, H-4), 5.88-5.98 (m, 2H, H-5, H-7), 6.09 (ddddt, 1H, 3 J HH 9.4 Hz, 3 J HH 5.3 Hz, 4 J HH 2.9 Hz, 4 J HH 0.9 Hz, 4 J J PH 0.9 Hz, H-6), 6.99 (ddd, 2H, 3 J HH 7.7 Hz, 4 J HH 1.3 Hz, 4 J HH 1.3 Hz, H-20), 7.09-7.19 (m, 5H, ArH), 7.23-7.55 (m, 12H, ArH), 7.65 (ddd, 2H, 3 J HH 7.0 Hz, 4 J HH 1.1 Hz, 3 J PH 12.5 Hz, H-12), 7.70 (ddd, 2H, 3 J HH 7.0 Hz , 4 J HH 1.5 Hz, 3 J PH 12.8 Hz, H-16), 7.75 (ddd, 2H, 3 J HH 6.8 Hz, 4 J HH 1.3 Hz, 3 J PH 11.9 Hz, H-16 '); NMR - 13 C \ 1 H \: 37.60 (d, 1 J PC 84.1 Hz, C-7a), 40.14 (dd, 2 J PC 2.4 Hz, 3 J PC 4.2 Hz, C-8), 43.46 (C-3a), 44.49 (d, 2 J PC 3.0 Hz, C-9), 49.82 (d, 2 J PC 3.0 Hz, C-10), 68.25 (d, 2 J PC 21.0 Hz, C-3), 119.32 (d, 2 J PC 8.4 Hz, C-7), 123.24 (d, 3 J PC 11.4 Hz, C-4), 124.42 (d, 4 J PC 3.6 Hz, C -5), 124.51 (d, 3 J PC 10.2 Hz, C-6), 127.01 (C-24), 127.40 (C-20), 128.30, (d, 3 J _ {PC} 11.4 Hz, CHAr), 128.37, (d, 3 J PC 9.6 Hz, CHAr), 128.25-128.61 (5CHAr), 131.43 (d, 2 J PC 10.2 Hz, C-12), 131.48 (d, 1 J PC 135.8 Hz, C-15), 131.55 (d, 1 J PC 131.6 Hz, C-15 '), 131.61 (d, 4 J PC 2.4 Hz, CHAr), 131.65 (d, 4 J PC 3.0 Hz, CHAr), 131.80 (d, 4 J PC 3.0 Hz, CHAr), 132.23 (d, 2 J PC 9.0 Hz, C-16), 132.25 (d, 2 J PC 9.0 Hz, C-16 '), 133.25 (d, 1 J PC 125.5 Hz, C-11), 137.50 (d, 3 J PC 4.2 Hz, C-23), 139.05 (d, 3 J PC 10.2 Hz, C-19); NMR - 31 P \ 1 H \: 30.92, 49.19.

         \ vskip1.000000 \ baselineskip
      

Compound 16

         \ vskip1.000000 \ baselineskip
      

61

         \ vskip1.000000 \ baselineskip
      

Purification: AcOEt / MeOH flash chromatography, 15: 1; F. Empirical: C 40 H 38 N 2 O 2 P 2; Melting point: White oil; IR (KBr, nu cm -1): 1197, 1123; MS ( m / z ): 641 (M + 1); 1 H NMR: 2.63-3.14 (m, 7H, H-3a, H-6, H-8, H-9), 3.88 (dd, 1H, 2 J HH 15.3 Hz , 3 J PH 7.4 Hz, H-10), 3.88 (d, 1H, 3 J HH 9.3 Hz, H-3), 4.09 (dd, 1H, 2 J HH 15.3 Hz, 3 J PH 10.0 Hz, H-10 '), 5.41 (m, 1H, H-4), 5.72 (m, 1H, H-5), 6.64 (m, 1H, H-7), 7.05 (m, 2H, H-20), 7.13 (m, 2H, H-24), 7.20 (m, 3H, ArH), 7.27-7.55 (m, 12H, ArH ), 7.65-7.81 (m, 6H, H-12, H-16, H-16 '); NMR - 13 C \ 1 H \: 27.65 (d, 3 J PC 12.8 Hz, C-6), 39.92 (dd, 2 J PC 2.8 Hz, 3 J PC 4.0 Hz, C-8), 44.52 (d, 2 J PC 3.0 Hz, C-9), 46.60 (C-3a), 49.68 (d, 2 J PC 3.3 Hz, C-10), 67.26 (d, 2 J PC 12.0 Hz, C-3), 122.60 (d, 3 J PC 6.6 Hz, C-4), 125.10 (d, 4 J PC 1.5 Hz, C-5), 127.03 (C-24), 127.67 (CHAr), 128.34 (CHAr), 128.35 (CHAr), 128.45, (d, 3 J PC 9.3 Hz, CHAr), 128.48 (d, 3 J PC 11.9 Hz, CHAr), 128.92 (CHAr), 131.46 (CHAr), 131.53 (d, 1 J PC 127.7 Hz, CAr), 131.61 (d, 4 J PC 1.7 Hz, CHAr), 131.65 (d, 4) J PC 2.0 Hz, CHAr), 131.63 (d, 1 J PC 128.4 Hz, CAr), 132.26 (d, 2 J PC 9.0 Hz, CHAr), 132.29 (d, 2 J PC 9.3 Hz, CHAr), 132.87 (d, 1 J PC 120.6 Hz, CAr), 133.23 (d, 1 J PC 132.6 Hz, CAr), 135.42 (d, 2 J PC 9.6 Hz, C-7), 137.63 (d, 3 J PC 4.4 Hz, C-23), 138.34 ( d, 3 J PC 8.4 Hz, C-19); NMR - 31 P \ 1 H \: 28.52, 30.89.

         \ vskip1.000000 \ baselineskip
      

Example 3 Procedures for the dearomatization of 5 and characterization of the products obtained

Method one

On a solution of 5 (2.99 x 10-4 mol) in THF (20-35 mL) and HMPA (0.42 mL, 2.39 x 10-3 mol) a solution of LiBu s is added (1.15 mL, 1.3 M in cyclohexane, 1.50 x 10-3 mol) at -90 ° C and allowed to stir for 30 minutes at the same temperature. Subsequently, methanol (2 mL) or 2,6-di- tert- butyl-4-methylphenol (DTBMP) (8 equivalents) is added at -90 ° C and stirring is maintained for another 30 minutes. The reaction mixture is then poured into water and extracted with ethyl acetate (3 x 15 mL). The organic extracts are dried over Na2SO4, filtered and concentrated in vacuo. Purification of the generated compounds was carried out, either by precipitation in diethyl ether, or by chromatographic column (SiO2, SiO2 impregnated in 5% Et3N or neutral alumina), using different mixtures as eluent of AcOEt / MeOH.

62

         \ vskip1.000000 \ baselineskip
      

The test results are summarized in the table III.

         \ vskip1.000000 \ baselineskip
      

TABLE III

63

         \ vskip1.000000 \ baselineskip
      

Method 2

On a solution of 5 (2.99 x 10-4 mol) in THF (20-35 mL) and HMPA (0.42 mL, 2.39 x 10-3) mol) a solution of LiBu s (1.15 mL, 1.3 M in cyclohexane, 1.50 x 10-3 mol) at -90 ° C and allowed to stir for 0.5-2.0 h at the same temperature. Subsequently, a solution of TBDMSCl (180 mg, 1.2 x) is added 10-3 mol) in 1 mL of THF and stir for 30 min. Finally methanol (2 mL) is added at -90 ° C and stirring is maintained for Another 30 minutes The reaction mixture is then poured over water and extracted with ethyl acetate (3 x 15 mL). The organic extracts are dried over Na2SO4, filtered and They are concentrated in vacuo. The reaction crude was measured NMR spectra - 1 H, 1 H \ 31 P \ and 31 P \ {1 H \} in order to determine stereoselectivity of the different processes. The purification of the compounds generated was performed, either by precipitation in diethyl ether, either by chromatographic column (silica gel, silica gel impregnated in 5% triethylamine or neutral alumina), using as eluent different mixtures of AcOEt / MeOH.

The yields of the reaction are indicated in the table IV.

         \ vskip1.000000 \ baselineskip
      

TABLE IV

64

Compound 17

         \ vskip1.000000 \ baselineskip
      

65

         \ vskip1.000000 \ baselineskip
      

Purification: Cromat. AcOEt / MeOH flash, 60: 1 to 30: 1; F. Empirical: C 41 H 40 N 2 O 2 P 2; Melting point: Oil; IR (KBr, nu cm -1): 1168, 1114; MS ( m / z ): 655 (M + 1); 1 H NMR: 1.50 (m, 2H, H-9), 2.59-2.86 (m, 6H, H-3a, H-8), 3.01 (m, 2H, 2 J PH 11.4 Hz, H-7a), 4.10 (d, 2H, 3 J HH 9.2 Hz, H-3), 5.32 (m, 2H, H-4), 5.91 (m, 2H, ^ {3 J HH 9.5 Hz, 4 J HH 2.6 Hz, 3 J PH 9.5 Hz, H-7), 5.99 (dd, 2H, 3 J HH 9.5 Hz, 3 J HH 5.3 Hz, H-5), 6.09 (m, 2H, H-6), H-5), 6.09 (m, 2H, H-6 ), 7.23 (dd, 4H, 3 J HH 7.8 Hz, 4 J HH 2.8 Hz, H-15), 7.33-7.56 (m, 12H, ArH), 7.84 ( ddd, 4H, 3 J HH 7.3 Hz, 4 J HH 1.8 Hz, 3 J PH 12.7 Hz, H-10); NMR - 13 C \ 1 H \: 25.99 (C-9), 37.52 (d, 1 J PC 84.7 Hz, C-7a), 39.63 (d, ^ {2 J PC 3.0 Hz, C-8), 43.26 (C-3a), 66.58 (d, 2 J PC 21.6 Hz, C-3), 119.36 (d, ^ 2 J PC 8.1 Hz, C-7), 123.39 (d, 3 J PC 11.4 Hz, C-4), 124.46 (d, 4 J PC 3.0) Hz, C-5), 124.54 (d, 3 J PC 9.6 Hz, C-6), 127.59 (C-15), 128.06 (C-17), 128.46 (d, 3) J PC 12.3 Hz, C-12), 128.65 (C-16), 131.58, (d, 2 J PC 9.9 Hz, C-11), 131.66 (d, 4) J PC 2.4 Hz, C-13), 133.90 (d, 1 J PC 126.1 Hz, C-10), 139.32 (d, 3 J PC 9.6 Hz, C-14); NMR - 31 P \ 1 H \: 48.83.

Compound 19

66

Purification: Flash chromatography on silica gel impregnated in a solution of Et3N in 5% hexane AcOEt / MeOH, 40: 1; F. Empirical: C 41 H 40 N 2 O 2 P 2; Melting point: White oil; IR (KBr, nu cm -1): 1170, 1113; MS ( m / z ): 655 (M + l); 1 H NMR: 1.40-1.74 (m, 2H, H-9), 2.43 (m, 2H, H-8), 2.71-2.95 (m, 6H, H-6, H-8 '), 3.15 (m, 2H, H-3a), 4.18 (d, 2H, {3} J {HH} 9.4 Hz, H-3), 5.57 (m, 2H, H-4), 5.79 (m, 2H , H-5), 6.65 (m, 2H, 3 J PH 16.0 Hz, H-7), 7.30-7.55 (m, 16H, ArH), 7.86 (m, 4H, 3 J PH 13.1 Hz, H-10); NMR - 13 C \ 1 H \: 26.23 (C-9), 27.66 (d, 3 J PC 12.6 Hz, C-6), 39.01 (d, ^ {2 J PC 3.0 Hz, C-8), 46.34 (d, 2 J PC 14.4 Hz, C-3a), 66.00 (d, 2 J PC} 12.0 Hz, C-3), 123.08 (d, 3 J PC 6.6 Hz, C-4), 124.90 (d, 4 J PC 1.2 Hz, C-5), 127.97 (C-15), 128.12 (C-17), 128.39 (d, 3 J PC 13.1 Hz, C-12), 128.80 (C-16), 131.46 (d, 4) J PC 3.0 Hz, C-13), 131.60 (d, 2 J PC 10.2 Hz, C-11), 133.04 (d, 1 J PC 121.3 Hz, C-7a), 133.91 (d, 1 J PC 133.3 Hz, C-10), 134.94 (d, 2 J PC 9.6 Hz, C-7), 138.75 (d , 3 J PC 8.4 Hz, C-14); NMR - 31 P \ 1 H \: 28.67.

Compound 21

67

Purification: Flash chromatography on silica gel impregnated with Et 3 N AcOEt / MeOH, 40: 1; F. Empirical: C 40 H 38 N 2 O 2 P 2; Melting point: White oil; IR (KBr, nu cm -1): 1173, 1112, 1071, 1020 cm -1; MS ( m / z ): 655 (M + 1); NMR - 1 H: 2.33-2.98 (m, 8H, H-6, H-8, H-9, H-10), 3.18 (m, H-3a), 3.97 (dd, 1H, ^ 2 J HH 15.3 Hz, 3 J PH 11.3 Hz, H-11), 4.04 (dd, 1H, 2 J HH 15.3 Hz, 3 J PH 10.9 Hz, H-10 '), 4.06 (d, 1H, 3 J HH 9.3 Hz, H-3), 5.53 (m, 1H, H-4), 5.79 (m , 1H, H-5), 6.70 (m, 1H, H-7), 7.15-7.62 (m, 19H, ArH), 7.71-7.95 (m, 6H, H-13, H-17, H-17 '); NMR - 13 C \ 1 H \: 26.25 (d, 3 J PC 3.6 Hz, C-9), 27.71 (d, 3 J PC 12.6 Hz, C-6), 39.48 (d, 2 J PC 3.0 Hz, C-8), 42.26 (d, 2 J PC 3.6 Hz, C-10) , 46.43 (d, 2 J PC 13.2 Hz, C-3a), 48.82 (d, 2 J PC 3.0 Hz, C-11), 66.55 (d, 2 J PC 12.0 Hz, C-3), 122.78 (d, 3 J PC 6.0 Hz, C-4), 125.16 (d, 4 J PC 1.2 Hz , C-5), 127.11 (CHAr), 127.94 (CHAr), 128.33 (CHAr), 128. 39 (CHAr), 128.49 (CHAr), 128.51 (d, 3 J PC 10.8 Hz, CHAr ), 128.55, (d, 3 J PC 9.0 Hz, CHAr), 128.58 (CHAr), 128.91 (CHAr), 131.56 (d, 4 J PC 2.4 2.4 Hz, CHAr) , 131.58 (d, 4 J PC 1.8 Hz, CAr), 131.65 (d, 2 J PC 10.8 Hz, CHAr), 131.75 (d, 2 J PC 10.2 Hz, CHAr), 131.93 (d, 1 J PC 129.2 Hz, CAr), 131.99 (d, 1 J PC 129.2 Hz, CAr), 132.30 (d, 2 J PC 9.0 Hz, CHAr), 132.40 (d, 2 J PC 9.0 Hz, CHAr), 132.91 (d, 1 J PC 120.2 Hz, CAr), 133.68 (d, 1 J PC 133.4 Hz, CAr), 135.24 (d, 2 J PC 9.6 Hz, C-7), 137.04 (d, 3 } J _ {PC} 3.6 Hz, C-23), 138.50 (d, 3 J PC 8.4 Hz, C-19); NMR - 31 P \ 1 H \: 28.66, 31.27.

         \ vskip1.000000 \ baselineskip
      

Example 4 Procedure for the dearomatization of 6 and characterization of the products obtained

Method one

On a solution of 6 (2.99 x 10-4 mol) in THF (20-35 mL) and HMPA (0.42 mL, 2.39 x 10-3 mol) a solution of LiBu s is added (1.15 mL, 1.3 M in cyclohexane, 1.50 x 10-3 mol) at -90 ° C and allowed to stir for 30 minutes at the same temperature. Subsequently, methanol (2 mL) or 2,6-di- tert- butyl-4-methylphenol (DTBMP) (8 equivalents) is added at -90 ° C and stirring is maintained for another 30 minutes. The reaction mixture is then poured into water and extracted with ethyl acetate (3 x 15 mL). The organic extracts are dried over Na2SO4, filtered and concentrated in vacuo. Purification of the generated compounds was carried out, either by precipitation in diethyl ether, or by chromatographic column (SiO2, SiO2 impregnated in 5% Et3N or neutral alumina), using different mixtures as eluent of AcOEt / McOH.

68

         \ vskip1.000000 \ baselineskip
      

Table V summarizes the tests of Cycling done. The tests were performed at concentrations between 8.4 and 10.0 mM.

         \ vskip1.000000 \ baselineskip
      

TABLE V

69

         \ newpage
      

Method 2

         \ vskip1.000000 \ baselineskip
      

70

On a solution of 6 (2.99 x 10-4 mol) in THF (20-35 mL) and HMPA (0.42 mL, 2.39 x 10-3) mol) a solution of LiBu s (1.15 mL, 1.3 M in cyclohexane, 1.50 x 10-3 mol) at -90 ° C and allowed to stir for 0.5-2.0 h at the same temperature. Subsequently, a solution of TBDMCSl (180 mg, 1.2 x) is added 10-3 mol) in 1 mL of THF and stir for 30 min. Finally methanol (2 mL) is added at -90 ° C and stirring is maintained for Another 30 minutes The reaction mixture is then poured over water and extracted with ethyl acetate (3 x 15 mL). The organic extracts are dried over Na2SO4, filtered and They are concentrated in vacuo. The reaction crude was measured NMR spectra - 1 H, 1 H \ 31 P \ and 31 P \ {1 H \} in order to determine stereoselectivity of the different processes. The purification of the compounds generated was performed, either by precipitation in diethyl ether, either by chromatographic column (silica gel, silica gel impregnated in 5% triethylamine or neutral alumina), using as eluent different mixtures of AcOEt / MeOH.

Compound 23

71

Purification: AcOEt / MeOH flash chromatography, 49: 1; F. Empirical: C_ {42} H_ {42} N_ {2} P2 {2}; Melting point: Oil; IR (KBr, nu cm -1): 1164, 1113; MS ( m / z ): 669 (M + 1); 1 H NMR: 1.03-1.18 (m, 4H, H-9), 2.45-2.64 (m, 4H, H-8), 2.84 (dddd, 1H, 3 J HH 10.7 Hz, 3 J HH 9.7 Hz, 3 J HH 5.9 Hz, 3 J PH 2.9 Hz, H-3a), 3.04 (m, 1H, ^ {3 J HH 10.7 Hz, 3 J HH 3.7 Hz, 4 J HH 2.9 Hz, 2 J PH 10.7 Hz, H-7a ), 4.26 (d, 1H, 3 J HH 9.7 Hz, H-3), 5.34 (ddddd, 1H, 3 J HH 9.5 Hz, 3 J J HH 5.9 Hz, 4 J HH 2.9 Hz, 4 J HH 0.9 Hz, 4 J PH 2.3 Hz, H-4), 5.92-6.01 ( m, 2H, H-5, H-7), 6.11 (ddddd, 1H, 3 J HH 9.5 Hz, 3 J HH 5.3 Hz, 4 J J HH 2.9 Hz, 4 J HH 0.9 Hz, 4 J PH 0.9 Hz, H-6), 7.21-7.55 (m, 16H, ArH), 7.88 (ddd, 4H , 3 J HH 7.7 Hz, 4 J HH 1.7 Hz, 3 J PH 12.3 Hz, H-11); NMR - 13 C \ 1 H \: 25.84 (C-9), 33.77 (d, 1 J PC 84.7 Hz, C-7a), 41.85 (d, ^ {2 J PC} 2.4 Hz, C-8), 43.06 (C-3a), 67.32 (d, 2 J PC 20.1 Hz, C-3), 119.51 (d, ^ 2 J PC 8.3 Hz, C-7), 123.50 (d, 3 J PC 11.4 Hz, C-4), 124.40 (d, 4 J PC 3.0 Hz, C-5), 124.51 (d, 3 J PC 10.2 Hz, C-6), 127.55 (C-15), 128.11-128.66 (3CHAr), 131.62, (d, 2 J PC 9.6 Hz, C-11), 131.74 (d, 4 J PC 2.4 Hz, C-13), 134.01 (d, 1 J PC 126.2 Hz , C-10), 139.37 (d, 3 J PC 10.2 Hz, C-14); NMR - 31 P \ 1 H \: 49.48.

Compound 25

72

Purification: Precipitation in diethyl ether; F. Empirical: C_ {42} H_ {42} N_ {2} P2 {2}; IR (KBr, nu cm -1): 1195, 1115; MS ( m / z ): 669 (M + 1); 1 H NMR: 1.12 (m, 4H, H-9), 2.38-2.58 (m, 4H, H-8), 2.72-2.94 (m, 4H, H-6), 3.14 (m, 2H , H-3a), 4.05 (d, 2H, 3 J HH 9.5 Hz, H-3), 5.50 (m, 2H, H-4), 5.74 (m, 2H, H-5) , 6.66 (m, 2H, 3 J PH 16.2 Hz, H-7), 7.26-7.39 (m, 10H, ArH), 7.46-7.53 (m, 6H, H-12, H-13 ), 7.91 (m, 4H, 3 J PH 12.8 Hz, H-10); NMR - 13 C \ 1 H \: 25.76 (C-9), 27.65 (d, 3 J PC 12.6 Hz, C-6), 41.70 (d, ^ {2 J PC 2.4 Hz, C-8), 46.25 (d, 2 J PC 13.8 Hz, C-3a), 66.72 (d, 2 J PC} 12.0 Hz, C-3), 122.86 (d, 3 J PC 6.0 Hz, C-4), 125.03 (C-5), 127.83 (C-15), 128.26 (C-17), 128.46 (d, 3 J PC 13.2 Hz, C-12), 128.80 (C-16), 131.57 (d, 4 J PC 2.4 Hz, C-13), 131.75 (d, 2 J PC 10.8 Hz, C-11), 133.32 (d, 1 J PC 120.7 Hz, C-7a), 133.85 (d, 1 J PC 133.4 Hz, C-10), 134.88 (d, 2 J PC 9.6 Hz, C-7), 138.65 (d, 3 J PC 9.0 Hz, C - 14); NMR - 31 P \ 1 H \: 28.76.

Compound 26

         \ vskip1.000000 \ baselineskip
      

73

         \ vskip1.000000 \ baselineskip
      

Purification: Flash chromatography on neutral alumina AcOEt / MeOH, 30: 1. Mix 26:25, 52:48; F. Empirical: C_ {42} H_ {42} N_ {2} P2 {2}; Melting point: Colorless oil; MS ( m / z ): 669 (M + 1); 1 H NMR: 1.14 (m, 4H, H-9), 2.37-2.57 (m, 4H, H-8), 2.73-2.95 (m, 4H, H-6), 3.15 (m, 2H , H-3a), 4.05 (d, 2H, 3 J HH 9.3 Hz, H-3), 5.50 (m, 2H, H-4), 5.75 (m, 2H, H-5) , 6.66 (m, 2H, 3 J PH 16.5 Hz, H-7), 7.25-7.40 (m, 10H, ArH), 7.47-7.52 (m, 6H, H-12, H-13 ), 7.88 (m, 4H, 3 J PH 12.8 Hz, H-10); NMR - 13 C \ 1 H \: 25.68 (C-9), 27.64 (d, 3 J PC 12.0 Hz, C-6), 41.91 (d, ^ {2 J PC 2.4 Hz, C-8), 46.16 (d, 2 J PC 13.8 Hz, C-3a), 67.11 (d, 2 J PC} 12.0 Hz, C-3), 122.83 (d, 3 J PC 6.6 Hz, C-4), 125.07 (d, 4 J PC 1.2 Hz, C-5), 127.84 (C-15), 128.26 (C-17), 128.44 (d, 3 J PC 13.2 Hz, C-12), 128.77 (C-16), 131.54 (d, 4) J PC 3.0 Hz, C-13), 131.65 (d, 2 J PC 10.2 Hz, C-11), 133.33 (d, 1 J PC 120.7 Hz, C-7a), 133.99 (d, 1 J PC 134.0 Hz, C-10), 134.88 (d, 2 J PC 9.6 Hz, C-7), 138.75 (d , 3 J PC 9.0 Hz, C-14); NMR - 31 P \ 1 H \: 28.84.

         \ vskip1.000000 \ baselineskip
      

Example 5 Synthesis compounds 29, 30 and 31

         \ vskip1.000000 \ baselineskip
      

74

         \ vskip1.000000 \ baselineskip
      

On a solution of 6 (2.99 x 10-4 mol) in THF (20-35 mL) and HMPA (0.42 mL, 2.39 x 10-3) mol) a solution of LiBu s (1.15 mL, 1.3 M in cyclohexane, 1.50 x 10-3 mol) at -90 ° C and allowed to stir for 2.0 h at the same temperature. Subsequently, a solution of benzaldehyde (127 mg, 1.2 x 10-3 mol) in 1 mL of THF and stir for 2 h. Finally, methanol (2 mL) is added to -90 ° C and stirring is maintained for another 5 minutes. The reaction mixture is then poured into water and extracted with ethyl acetate (3 x 15 mL). The organic extracts are dried over Na 2 SO 4, they are filtered and concentrated in vacuo. On the reaction crude spectra were measured from NMR - 1 H, 1 H \ 31 P \ and 31 P \ {1 H \} in order to determine stereoselectivity of the different processes. The purification of the compounds generated was performed, either by precipitation in diethyl ether, either by chromatographic column (silica gel, silica gel impregnated in 5% triethylamine or neutral alumina), using as eluent different mixtures of AcOEt / MeOH.

Compound 29

         \ vskip1.000000 \ baselineskip
      

75

         \ vskip1.000000 \ baselineskip
      

Purification: AcOEt / MeOH flash chromatography, 15: 1; F. Empirical: C_ {56} H_ {54} N_ {2} O4 {P2}; Melting point: Oil; IR (KBr, nu cm -1): 3270, 1183, 1156; MS ( m / z ): 881 (M + 1); 1 H NMR: 1.14 (m, 4H, H-9), 2.49 (m, 2H, 3 J PH 14.1 Hz, H-8), 3.00 (m, 2H, H- 8 '), 3.17-3.28 (m, 4H, H-3a, H-6), 3.15 (m, 2H, H-3a), 4.30 (d, 2H, 3 J HH 8.5 Hz, H-3), 5.25 (sa, H-10), 5.53 (m, 2H, 3 J HH 10.6 Hz, H-5), 5.72 (dd, 2H, 3 J J HH 10.6 Hz, 4 J PH 4.0 Hz, H-4), 6.34 (sa, 1H, H-11, OH), 6.85 (m, 2H, 3 J PH) 17.3 Hz, H-7), 7.19-7.58 (m, 26H, ArH), 7.99 (ddd, 4H, 3 J HH 7.6 Hz, 4 J HH 1.8 Hz, ^ 3 J PH 12.9 Hz, H-13); NMR - 13 C \ 1 H \: 24.50 (C-9), 40.74 (C-8), 45.74 (d, 3 J PC 12.0 Hz, C-6 ), 46.99 (d, 2 J PC 14.4 Hz, C-3a), 65.82 (d, 2 J PC 12.0 Hz, C-3), 74.31 (C-10) , 124.37 (d, 3 J PC 7.2 Hz, C-4), 124.68 (C-5), 125.87 (C-21), 126.59 (C-23), 127.92 (C-22), 128.11-128.78 (CHAr), 131.88 (d, 4 J PC 3.6 Hz, C-15), 131.92 (d, 2 J PC 10.2 Hz, C-13), 133.02 (d, 1 J PC 116.7 Hz, C-12), 133.78 (d, 1 J PC 119.5 Hz, C-7a), 138.44 (d, 3 J PC 8.4 Hz, C-16), 139.64 (d, 2 J PC 8.4 Hz, C-7), 142.83 (C-20); NMR - 31 P \ 1 H \: 28.67.

         \ vskip1.000000 \ baselineskip
      

Example 6 Composite Synthesis 33 Compound 33

76

On a solution of trans -1,2-N, N'-dibenzylcyclohexylamine (32) (Denmark et al , J. Org. Chem. 1991, 56, 5063), (8.30 mmol) in the presence of triethylamine (2.90 mL, 20.75 mmol) and in toluene (120 mL), chlorodiphenylphosphine (1.49 mL, 8.30 mmol) is added dropwise at -80 ° C. Stirring is maintained for 30 minutes. The solvent and excess triethylamine are then vacuum distilled off and 30 mL of THF are added. Next, 30% v / v hydrogen peroxide (0.85 mL, 8.30 mmol) is added at a temperature between -20 ° C and 0 ° C. Stirring is maintained for 30 minutes. After the oxidation is complete, the reaction mixture is poured into water, extracted with ethyl acetate (3 x 15 mL), washed with 1N NaOH (2 x 15 mL) and with water (1 x 15 mL). The organic extracts are dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Subsequent purification by precipitation in cold diethyl ether provides diphenylphosphinamide 33 as a white solid; F. Empirical: C 32 H 35 N 35 OP; Melting point: 94 ° C; IR (KBr, nu cm -1): 3321, 1183, 1116; MS ( m / z ): 495 (M + 1); 1 H NMR (60 ° C): 0.79-1.08 (m, 3H), 1.45-1.61 (m, 3H), 1.87 (m, 1H), 2.08 (m, 1H), 2.45 (dt, 1H, ^ 3 J HH 10.4, 3 J HH 3.7 Hz, H-2), 2.97 (sa, 1H, NH, H-9), 3.17 (dc, 1H, 3 J HH 10.4, 3 J HH 3.7 Hz, 3 J PH 3.7 Hz, H-1), 3.32 (d, 1H, 2 J HH 13.4 Hz, H-11), 3.79 (d, 1H, 2 J HH 13.4 Hz, H-11 '), 4.10 (dd, 1H, 2 J HH 15.8 Hz , 3 J PH 11.2 Hz, H-10), 4.17 (dd, 1H, 2 J HH 15.8 Hz, 3 J PH 11.0 Hz, H- 10 '), 7.17 (m, 3H, ArH), 7.28 (m, 3H, ArH), 7.36-7.49 (m, 10H, ArH), 7.97 (m, 4H, H-13); NMR - 13 C \ 1H \ (60 ° C): 24.40 (CH2), 25.99 (CH2), 32.28 (CH2), 32.32 (CH2) ), 47.34 (da, 2 J PC 4.5 Hz, C-10), 50.44 (C-11), 57.91 (d, 3 J PC 3.2 Hz, C-2) , 61.86 (d, 2 J PC 2.8 Hz, C-1), 126.52 (CHAr), 126.90 (CHAr), 128.10 (d, 3 J PC 12.0 Hz, C- 14), 128.11 (CHAr), 128.18 (d, 3 J PC 13.0 Hz, C-14 '), 128.20 (CHAr), 128.28 (CHAr), 131.33 (d, 4 J _ {PC} 2.8 Hz, C-15), 131.40 (d, 4 J PC 2.6 Hz, C-15 '), 132.55 (d, 1 J PC 126.8 Hz, C -12), 132.63 (d, 2 J PC 9.3 Hz, C-13), 132.69 (d, 2 J PC 9.1 Hz, C-13 '), 132.72 (d , 1 J PC 128.3 Hz, C-12 '), 139.92 (d, 3 J PC 3.9 Hz, C-16), 141.10 (C-10); NMR -31 P \ 1H \ (60 ° C): 32.45.

Example 7 Procedure for the dearomatization of 33 and characterization of the products obtained

Method one

77

On a solution of 33 (2.99 x 10-4) mol) in THF (20-35 mL) and HMPA (0.42 mL, 1.79 x 10 <3> mol) a solution of LiBu s (0.81 mL, 1.3 M in C 6 H 12, 1.05 x 10 -3 mol) at -90 ° C and left stirring for 30 min at that temperature. Subsequently, it is added methanol at -90 ° C and stirring is maintained for another 30 minutes The reaction mixture is poured onto water and extracted with ethyl acetate (3 x 15 mL). The organic extracts are dried over Na 2 SO 4, they are filtered and concentrated in vacuo. On the reaction crude spectra were measured from NMR - 1 H, 1 H \ 31 P \ and 31 P \ {1 H \} in order to determine stereoselectivity of the different processes. The purification of the compounds generated was performed by chromatographic column using as eluent different mixtures of AcOEt / MeOH.

Method 2

78

On a solution of 33 (2.99 x 10-4) mol) in THF (20-35 mL) and HMPA (0.42 mL, 1.79 x 10 <3> mol) a solution of LiBu s (0.81 mL, 1.3 M in C 6 H 12, 1.05 x 10 -3 mol) at -90 ° C and left stirring for 30 min at that temperature. One is added TBDMSiCl solution (150 mg, 1.05 x 10-3 mol) in 1 mL of THF and stir for 30 min. Subsequently, methanol is added to -90 ° C and stirring is maintained for another 30 minutes. The reaction mixture is poured onto water and extracted with acetate ethyl (3 x 15 mL). The organic extracts are dried over Na 2 SO 4, are filtered and concentrated in vacuo. About him reaction crude spectra were measured from NMR - 1 H, 1 H \ 31 P \ and 31 P \ {1 H \} in order to determine stereoselectivity of the different processes. The purification of the compounds generated was performed by chromatographic column using as eluent different mixtures of AcOEt / MeOH.

Compound 34

         \ vskip1.000000 \ baselineskip
      

79

Purification: AcOEt / MeOH flash chromatography, 20: 1; F. Empirical: C 32 H 35 N 35 OP; Melting point: Oil; IR (KBr, nu cm -1): 3429, 1114; MS ( m / z ): 495 (M + 1); 1 H NMR (60 ° C): 0.72-1.18 (m, 3H), 1.48-2.08 (m, 6H), 2.67-2.94 (m, 5H, H-6, H-8, H-13, H -15), 2.77 (cc, 1H, 3 J HH 9.6 Hz, 4.5 J HH 2.5 Hz, H-3a), 3.54 (da, 1H, 2 } J {HH} 13.8 Hz, H-15 '), 4.34 (d, 1H, {3} J {HH} 9.6 Hz, H-3), 5.51 (m, 1H, H-4), 5.78 (m, 1H, H-5), 6.63 (m, 1H, 3 J PH 16.5 Hz, H-7), 7.12 (da, 2H, 3 J HH 7.1 Hz , H-25), 7.18-7.28 (m, 3H, H-26, H-27), 7.34-7.41 (m, 8H, ArH), 8.00 (ddd, 2H, 3 J HH 7.8 Hz, 4 J HH 1.6 Hz, 3 J PH 12.9 Hz, H-17); NMR - 13 C \ 1 H \ (60 ° C): 24.17 (CH 2), 25.72 (CH 2), 27.45 (d, 3 J PC 12.6 Hz, C-6), 30.84 (CH 2), 32.15 (CH 2), 45.64 (d, 2 J PC 14.4 Hz, C-3a), 48.92 (C-15) , 56.78 (C-13), 59.86 (C-8), 66.78 (d, 2 J PC 10.8 Hz, C-3), 122.97 (d, 3 J PC 6.5 Hz, C-4), 124.88 (C-5), 125.30-131.27 (CHAr), 133.78 (d, 1 J PC 118.9 Hz, C-7a), 133.87 (d, 2) J PC 9.6 Hz, C-7), 135.64 (d, 1 J PC 131.6 Hz, C-16), 140.74 (d, 3 J PC 7.8 Hz, C-20), 141.70 (C-24); NMR -31 P \ 1H \ (60 ° C): 27.97.

Compound 35

         \ vskip1.000000 \ baselineskip
      

80

         \ vskip1.000000 \ baselineskip
      

Purification: AcOEt flash chromatography; F. Empirical: C 32 H 35 N 35 OP; Melting point: Colorless oil; IR (KBr, nu cm -1): 3431, 1195, 1113; MS ( m / z ): 495 (M + 1); 1 H NMR (60 ° C): 0.76-1.89 (m, 8H), 2.08 (m, 1H), 2.75 (dt, 1H, 3 J HH 10.3 Hz, 3 J 4.2 Hz, H8), 2.84-3.14 (m, 4H, H-3a, H-7a, H-13, H-15), 3.63 (da, 1H, 2 J HH) 13.6 Hz, H-15 '), 4.60 (d, 1H, 3 J HH 8.8 Hz, H-3), 5.39 (m, 1H, H-4), 6.01-6.16 (m, 3H , H-5, H-6, H-7), 7.17 (m, 2H, ArH), 7.23-7.40 (m, 16 H, ArH), 8.03 (m, 2H, 3 J PH 12.9 Hz, H-17); NMR - 13 C \ 1H \ (60 ° C): 24.19 (CH2), 25.71 (CH2), 31.05 (ma, CH2), 32.30 (CH_ { 2)), 38.59 (d, 1H, 1 J PC 83.7 Hz, C-7a), 42.56 (C-3a), 49.25 (C-15), 56.95 (C-13), 59.48 ( C-8), 67.02 (d, 2 J PC 20.4 Hz, C-3), 119.72 (d, 2 J PC 8.1 Hz, C-7), 123.78 (d , 3 J PC 12.0 Hz, C-4), 124.34 (d, 3 J PC 5.5 Hz, C-6), 124.43 (d, 4 J PC 1.2 1.2, C-5), 126.08-128.61 (7CHAr), 131.16 (d, 2 J PC 9.6 Hz, C-17), 131.39 (d, 4 J PC 3.0 Hz, C-19), 135.76 (d, 1 J PC 124.8 Hz, C-16), 141.58 (C-24), 141.62 (d, 3 J PC) 14.3 Hz, C-20); NMR -31 P \ 1H \ (60 ° C): 49.06.

Example 8 Synthesis compounds 37 and 38

         \ vskip1.000000 \ baselineskip
      

81

         \ vskip1.000000 \ baselineskip
      

On a solution of 33 (2.99 x 10-4) mol) in THF (20-35 mL) and HMPA (0.42 mL, 1.79 x 10 <3> mol) a solution of LiBu s (0.8 mL, 1.3 M in C 6 H 12, 1.05 x 10 -3 mol) at -90 ° C and left stirring for 0.5 h at that temperature. Subsequently, it is added benzyl bromide (132 mg, 1.05 x 10-3 mol) at -90 ° C and be keep stirring at -90 ° C for 2 more hours. The mixture of reaction is poured into water and extracted with ethyl acetate (3 x 15 mL) The organic extracts are dried over Na2SO4, dried filter and concentrate in vacuo. On the reaction crude is measured 1 H NMR spectra, 1 H \ {31 P \ and 31 P \ {1 H \} in order to determine the stereoselectivity of the different processes. Purification of The generated compounds were performed by chromatographic column  using different mixtures of AcOEt / MeOH as eluent or AcOEt / hexane.

Compound 37

82

Purification: AcOEt flash chromatography; F. Empirical: C_ {39} H_ {41} N_ {OP}; Melting point: White oil; IR (KBr, nu cm -1): 3440, 1200, 1114; MS ( m / z ): 585 (M + 1); 1 H NMR (60 ° C): 0.77-1.85 (m, 8H), 2.07 (ma, 1H), 2.67-2.96 (m, 6H, H-3a, H-8, H-13, H-18 , H-20), 3.29 (m, 1H, H-6), 3.55 (da, 1H, 2 J HH 13.8 Hz, H-20 '), 4.25 (d, 1H, 3 J HH 9.7 Hz, H-3), 5.52 (dddd, 1H, 3 J HH 9.9 Hz, 3 J HH 2.2 Hz, 4 J _ {HH 1.1 Hz, 4 J PH 3.5 Hz, H-4), 5.77 (ddt, 1H, 3 J HH 9.9 Hz, 3 J HH) 2.6 Hz, 4 J HH 1.5 Hz, 5 J PH 1.5 Hz, H-5), 6.63 (dddd, 1H, 3 J HH 4.6 Hz, 4 J HH 3.0 Hz, 5 J HH 1.5 Hz, 3 J PH 16.4 Hz, H-7), 6.95 (m, 2H, H-10 ), 7.11-7.35 (m, 13H, ArH), 7.37-7.50 (m, 3H, H-23, H-24), 7.89 (m, 2H, 3 J PH 12.9 Hz; H- 22); NMR - 13 C \ 1H \ (60 ° C): 24.19 (CH2), 25.73 (CH2), 29.51 (CH2), 32.17 (CH2) ), 39.20 (d, 3 J PC 12.1 Hz, C-6), 41.05 (d, 4 J PC 2.0 Hz, C-8), 45.95 (d, ^ 2 J PC 14.9 Hz, C-3a), 48.90 (C-20), 56.73 (C-18), 59.82 (C-13), 66.58 (d, 2 J PC 11.2 Hz, C-3), 123.99 (d, 3 J PC 6.6 Hz, C-4), 125.91 (CHAr), 126.02 (CHAr), 127.63-128.46 (7CHAr), 129.28 (C-5 , C-10), 131.15 (d, 4 J PC 3.2 Hz, C-24), 131.20 (d, 2 J PC 10.6 Hz, C-22), 134.56 ( d, 1 J PC 118.5 Hz, C-7a), 135.63 (d, 1 J PC 131.8 Hz, C-21), 137.47 (d, 2 J _ {PC 8.9 Hz, C-7), 138.02 (C-9), 140.80 (d, 3 J PC 9.2 Hz, C-25), 141.76 (C-29); NMR -31 P \ 1H \ (60 ° C): 28.87.

Example 9 Synthesis Compounds 39 and 40

83

On a solution of 33 (2.99 x 10-4) mol) in THF (20-35 mL) and HMPA (0.42 mL, 1.79 x 10 <3> mol) a solution of LiBu s (0.8 mL, 1.3 M in C 6 H 12, 1.05 x 10 -3 mol) at -90 ° C and left stirring for 0.5 h at that temperature. Subsequently, it is added a solution of benzaldehyde (110 mg, 1.05 x 10-3 mol) in 1 mL of THF at -90 ° C and stirring is maintained at -90 ° C for 2 more hours The reaction mixture is treated with MeOH at -90 ° C for 5 min and pour over water and extract with ethyl acetate (3 x 15 mL) The organic extracts are dried over Na2SO4, dried filter and concentrate in vacuo. On the reaction crude is measured 1 H NMR spectra, 1 H \ {31 P \ and 31 P \ {1 H \} in order to determine the stereoselectivity of the different processes. Purification of the generated compounds was performed by column chromatographic using as eluent different mixtures of AcOEt / MeOH or AcOEt / hexane.

Compound 39

84

Purification: AcOEt flash chromatography; F. Empirical: C_ {39} H_ {41} N_ {2} P2; Melting point: White oil; MS ( m / z ): 601 (M + 1); 1 H NMR (60 ° C): 0.72-2.06 (m, 8H), 2.63-2.77 (m, 4H, H-14, H-19, H-20, H-21), 3.20-3.52 (m , 2H, H-3a, H-6), 3.50 (da, 1H, 2 J HH 11.9 Hz, H-21 '), 4.16 (d, 1H, 3 J HH 9.4 Hz, H-3), 4.91 (d, 1H, 3 J HH 4.6 Hz, H-8), 5.56 (m, 1H, H-4), 5.84 (da, 1H, ^ 3 J HH 10.1 Hz, H-5), 6.58 (m, 1H, 3 J PH 16.8 Hz, H-7), 7.11 (da, 2H, 3 J 7.0 Hz, H-31), 7.17-7.45 (m, 16H, ArH), 7.95 (m, 2H, 3 J PH 12.9 Hz; H-23); NMR - 13 C \ 1H \ (60 ° C): 24.10 (CH2), 25.64 (CH2), 29.52 (CH2), 32.02 (CH2) ), 44.79 (d, 2 J PC 12.5 Hz, C-3a), 46.66 (d, 3 J PC 14.4 Hz, C-6), 56.53 (C-19) , 59.88 (C-14), 66.52 (ma, C-3), 75.47 (C-8), 123.95 (d, 3 J PC 7.2 Hz, C-4), 125.88 (C-5 ), 126.06-128.54 (CHAr), 131.28 (d, 2 J PC 10.3 Hz, C-23), 131.40 (d, 4 J PC 3.0 3.0, C-25) , 132.56-135.61 (C-7a, C-22), 136.02 (d, 2 J PC 9.6 Hz, C-7), 140.45 (d, 3 J PC 7.8 7.8 Hz , C-26), 141.56 (C-30), 142.18 (C-10). NMR -31 P \ 1H \ (60 ° C): 27.70.

Compound 40

85

Purification: AcOEt flash chromatography; F. Empirical: C_ {39} H_ {41} N_ {2} P2; Melting point: White oil; MS ( m / z ): 601 (M + 1); 1 H NMR (60 ° C): 0.72-2.06 (m, 8H), 2.63-2.77 (m, 4H, H-14, H-19, H-20, H-21), 3.20-3.52 (m , 2H, H-3a, H-6), 3.50 (da, 1H, 2 J HH 11.9 Hz, H-21 '), 4.16 (d, 1H, 3 J HH 9.4 Hz, H-3), 4.77 (d, 1H, 3 J HH 6.6 Hz, H-8), 5.51-5.61 (m, 2H, H-4, H-5), 6.83 (m, 1H, 3 J PH 16.6 Hz, H-7), 7.11 (da, 2H, 3 J HH 7.0 Hz, H-31), 7.17-7.45 (m , 16H, ArH), 7.95 (m, 2H, 3 J PH 12.9 Hz; H-23); NMR - 13 C \ 1H \ (60 ° C): 24.10 (CH2), 25.64 (CH2), 29.52 (CH2), 32.02 (CH2) ), 44.84 (d, 2 J PC 11.7 Hz, C-3a), 46.66 (d, 3 J PC 14.4 Hz, C-6), 56.70 (C-19) , 59.88 (C-14), 66.52 (ma, C-3), 76.14 (C-8), 124.28 (d, 3 J PC 6.6 Hz, C-4), 126.06-128.54 (CHAr ), 131.30 (d, 2 J PC 10.7 Hz, C-23), 131.40 (d, 4 J PC 3.0 Hz, C-25), 132.56-135.61 (C- 7a, C-22), 135.16 (d, 2 J PC 9.6 Hz, C-7), 140.76 (d, 3 J PC 9.0 Hz, C-26), 141.65 (C-30), 142.48 (C-10); NMR -31 P \ 1H \ (60 ° C): 27.70.

Example 10 Composite Synthesis 43

86

rac -42 was prepared from rac -41 using the procedure described for the synthesis of (R, R) -42 (Shi and Sui, Tetrahedron Asymmetry 1999, 10 , 3319).

In a suitably dried and evacuated schlenk, 8.0 g of rac -42 (15.56 mmol) are introduced and treated at room temperature with NaH (4.98 g, 124.46 mmol) in THF for 30 minutes. The addition of benzyl bromide (3.78 mL, 31.12 mmol) at the same temperature and subsequent reflux of the solution for 2 hours, makes it possible to obtain diphosphinamide 43. Rend 87%. MP 146-147 ° C. 1 H-NMR: (CDCl 3, 20 ° C) 0.72 (bs, 2H, H-3), 0.99 (bs, 2H, H-2), 1.28 (bs, 2H, H-3 '), 1.90 (bs, 2H, H-2 '), 3.94 (bs, 2H, H-6), 4.19 (d, 2H, 3 J PH 16.6, H-1), 4.25 (d, 2H , 3 J PH 15.4 Hz, H-1), 4.51 (bs, 2H, H-6), 7.66-6.93 (m, 22H, ArH), 7.97 (m, 4H, H-8) , 8.09 (m, 4H, H-8). (DMSO- d 6, 100 ° C) 0.62 (m, 2H, H-3), 1.03 (m, 2H, H-2), 1.24 (m, 2H, H-3 '), 1.82 (m, 2H , H-2 '), 3.88 (m, 2H, H-1), 4.20 (dd, 2H, 3 J PH 15.9 Hz, 2 J HH 16.1 Hz, H- 6), 4.42 (dd, 2H, 3 J PH 10.3, JHH 16.1 Hz, H-6 '), 7.69-6.91 (m, 22H, ArH), 7.95 (m, 4H, H-8 ), 8.05 (m, 4H, H-8). 13 C-NMR: (CDCl 3, 20 ° C) 25.53 (C-3), 35.87 (C-2), 47.81 (C-6), 56.83 (C-1), 126.93 (C-14) , 127.85 (C-12), 128.40 (d, 3 J PC 12.6 Hz, C-9), 128.49 (d, 3 J PC 12.6 Hz, C-9), 129.45 (C-13), 131.46 (d, 4 J PC 1.8 Hz, C-10), 131.87 (d, 4 J PC 1.8 Hz, C-10), 132.56 (d, 2 J PC 9.6 Hz, C-8), 133.24 (d, 2 J PC 9.0 Hz, C-8), 139.74 (C-11). (DMSO- d 6, 100 ° C) 25.67 (C-3), 35.84 (C-2), 48.63 (C-6), 58.22 (C-1), 127.26 (C-14), 128.03 (C- 12), 128.69 (d, 3 J PC 12.0 Hz, C-9), 128.89 (d, 3 J PC 12.0 Hz, C-9), 129.31 (C-13 ), 131.83 (d, 4 J PC 2.4 Hz, C-10), 132.21 (d, 4 J PC 2.4 Hz, C-10), 132.64 (d, ^ 2 J PC 9.6 Hz, C-8), 133.05 (d, 2 J PC 9.6 Hz, C-8), 133.35 (d, 1 J PC 124.9 Hz, C-7), 134.15 (d, 1 J PC 124.4 Hz, C-7), 140.09 (C-11). 31 P-NMR: (CDCl 3, 20 ° C) 31.49. (DMSO- d 6, 100 ° C) 29.69).

Example 11 Bioassays of antitumor activity

The purpose of these assays is to interrupt the growth of a tumor cell culture in vitro through continued exposure of the cells to the agent tested.

         \ vskip1.000000 \ baselineskip
      

Inhibition of cell growth by assay colorimetric

Lines cell phones

         \ vskip1.000000 \ baselineskip
      

87

         \ vskip1.000000 \ baselineskip
      

         \ vskip1.000000 \ baselineskip
      

A colorimetric assay that uses the sulphordamine B (SRB) reaction has been adapted for the quantitative measurement of cell growth and viability [following the technique described by Philip Skehan et al . (1990), New colorimetric cytotoxicity assay for anticancer drug screening, J. Natl. Cancer Inst. , 82: 1107-1112].

This test uses 96 culture microplates 9 mm diameter wells (Faircloth, 1988; Mosmann, 1983). The most cell lines have been obtained from the American Type Culture Collection (ATCC) and derived from different types of human cancers

The cells are kept in RPMI 1640 10% FBS, supplemented with 0.1 g / L of penicillin and 0.1 g / L of streptomycin sulfate and incubated at 37 ° C, 5% CO2 and 98% humidity. For the experiments, the cells of subconfluent cultures are collected using trypsin and resuspended in fresh medium before being introduced into the cells.
plates.

         \ newpage
      

Cells are seeded in 96 plates wells, with 5 x 10 3 cells per well in 195 aliquots µL of medium, and are allowed to anchor to the surface of the plate for 18 h in a free medium of the tested compound. Subsequently dissolved samples are added in 5 µL of DMSO: EtOH: PBS (0.5: 0.5: 99) at concentrations between 10 to 10-8 \ mug / mL. After 48 h of exposure, the antitumor effect is measured by the SRB method: the cells are fixed by adding 50 µL of a 50% cold solution (weight / vol) of trichloroacetic acid and incubate at 4 ° C for 60 min. The plates are washed with water deionized and dried. 100 µL of SRB solution (0.4% is added weight / vol in 1% acetic acid) to each well and incubate for 10 min at room temperature. Unbound SRB is deleted by washing with 1% acetic acid. The plates are dried with air and the cultures are solubilized using Tris buffer. They read optical densities with a spectrophotomic plate reader at a single wavelength of 490 nm.

The mean values +/- the deviation are calculated standard of the data obtained in triplicate. It can be calculated Some parameters of cellular response: GI = inhibition of growth, TGI = total growth inhibition (effect cytostatic) and LC = cell death (cytotoxic effect).

Table VI provides data on the biological activity in this test of the compounds of the
invention.

         \ vskip1.000000 \ baselineskip
      

         \ vskip1.000000 \ baselineskip
      

TABLE VI Cytotoxicity tests - Activity data (Cool)

         \ vskip1.000000 \ baselineskip
      

89

90

         \ vskip1.000000 \ baselineskip
      

Example 12 Bioassays of antitumor activity

The objective of this test is to evaluate in vitro cytostatic activity (ability to slow or stop tumor cell growth) or cytotoxic (ability to kill tumor cells) in the samples tested.

         \ newpage
      

Inhibition of cell growth by assay colorimetry

Lines cell phones

         \ vskip1.000000 \ baselineskip
      

91

         \ vskip1.000000 \ baselineskip
      

A colorimetric type assay is adapted using sulphordamine B (SBR) as a colorimetric reagent for the measurement of cell growth and viability (following the technique described by Skehan P et al . J. Natl. Cancer Inst. 1990, 82, 1107-1112) .

This assay employs standard SBS 96-well cell culture microplates (Faircloth et al . Methods in Cell Science, 1988, 11 (4), 201-205; Mosmann et al . Journal of. Immunological Methods, 1983, 65 (1- 2), 55-63). All cell lines used in this study, derived from different types of human cancer, were obtained from the American Type Culture Collection (ATCC).

The cell culture medium used was DMEM (Dulbecco's Modified Eagle Medium), supplemented with 10% FBS (fetal bovine serum), 2 mL of L-glutamine, 100 U / mL of penicillin and 100 U / mL of streptomycin at 37 ° C, 5% CO2 and 98% humidity For experiments the cells are collected from subconfluent cultures by trypsinization and resuspended in Freshly prepared medium before counting and plating.

Cells are seeded in 96-well microtiter plates with 5 x 10 3 cells per well in 150 µL aliquots, and adhesion to the surface is allowed for 18 hours in free medium of the tested compound. A control plate (untreated) is fixed for each cell line (as described below) and is used as a reference value for zero time. Subsequently, the test samples are added to the cultures in decimatured solutions, in 50 pL aliquots, in ranges from 10 to 0.00262 µg / mL. After 48 hours of exposure, the antitumor effect is estimated by the SRB method: briefly, the cells are washed in duplicate with PBS, fixed for 15 min in 1% glutaraldehyde solution, rinsed in duplicate in PBS, and stained in 0.4% SRB solution for 30 min at room temperature. The cells are rinsed at different times with 1% acetic acid and air dried. The SRB is extracted in 10 mM base trizm solution and the absorbance is measured in an automatic spectrophotometric reader at 490 nm. Cellular survival is expressed as a percentage of control cell growth. The final effect of the tested sample is estimated by applying the NCI algorithm (Boyd MR and Paull KD. Drug Dev. Res. 1995, 34,
91-104).

Using the mean +/- the standard triplicate deviation of the crops automatically generates a dose-response curve using non-linear regression analysis. Three reference parameters (NCI algorithm) are calculated by automatic interpolation: GI 50 = concentration that produces a 50% growth inhibition; TGI = total growth inhibition (cytostatic effect) and LC50 = concentration that produces 50% net cell death (cytotoxic effect).

Table VII provides data on the biological activity in this test of the compounds of the invention.
tion.

TABLE VII Cytotoxicity tests - Activity data (Cool)

         \ vskip1.000000 \ baselineskip
      

92

Claims (22)

1. A compound according to the general formula (I):

           \ vskip1.000000 \ baselineskip
        

93 in the which R1 and R2 are groups independently selected from C 6 -C 18 aryl optionally substituted and C 3 -C 18 optionally substituted heterocycle; A is a group C_ {1} -C_ {12} unsubstituted alkylene; R 3 and R 5 are groups independently selected from C 1 -C 12 alkyl optionally substituted, C2-C12 alkenyl optionally substituted, C2-C12 optionally substituted alkynyl, C 7 -C 30 optionally substituted arylalkyl, C 8 {-C 30} arylalkenyl optionally substituted, C4-C30 heterocycloalkyl optionally substituted, C 5 -C 30 optionally substituted heterocycloalkenyl, C 3 -C 18 cycloalkyl optionally substituted, C4-C30 cycloalkylalkyl optionally substituted, C 5 -C 30 optionally substituted cycloalkylalkenyl, C 3 -C 18 cycloalkenyl optionally substituted, C 4 -C 30 cycloalkenyl alkyl optionally substituted and C 5 -C 30 optionally substituted cycloalkenyl alkenyl; R 4 is a group selected from hydrogen and a radical of formula (II) 94 R 6 and R 7 are groups independently selected from C 6 -C 18 aryl optionally substituted and C 3 -C 18 optionally substituted heterocycle; R 1 and R 3 and / or R 5 and R 6 can form, together with the adjacent P and N atoms, a heterocycle of according to formula (III) or (IV), respectively,

           \ vskip1.000000 \ baselineskip
        

95 where Y 1, Y 2, Y 3 and Y 4 are groups independently selected from NR12 and CR 13 R 14; Y 1 and Y 2, Y 2 and Y 3 and / or Y 3 and Y 4 can form a carbocyclic or heterocyclic ring additional condensate; each dotted line represents the presence optional additional link; R 8 and R 9 are groups independently selected from hydrogen, NO 2, CN, C (= O) R a, CO 2 R a, C (= O) NR a R b, (C = NR a) OR b, (C = NR a) R b, (C = NR a) NR a R b, (S = O) R a, SO 2 R a, SO 3 R a, SO 2 NR a R b, C 1 -C 12 optionally substituted alkyl, Optionally substituted C 6 -C 18 aryl, C 7 -C 30 arylalkyl optionally substituted, C 3 -C 18 heterocycle optionally substituted, C 4 -C 30 optionally substituted heterocycloalkyl, C 3 -C 18 cycloalkyl optionally substituted and C 4 -C 30 cycloalkylalkyl optionally substituted; R 10 and R 11 are groups independently selected from hydrogen, OR a, OC (= O) R a, SR a, (S = O) R a, SO 2 R a, SO 3 R a, SO 2 NR a R b, NHR a, N (R a R b), NR a (OR b), NHCOR a, N (COR a) (COR b), NHCO 2 R a, NHC (= O) NR a R b, NHSO 2 R a, CN, halogen, C (= O) R a, CO 2 R a, C (= O) NR a R b, C 1 -C 12 optionally substituted alkyl, C 2 -C 12 alkenyl optionally substituted, C2-C12 alkynyl optionally substituted, C 6 -C 18 aryl optionally substituted, C 7 -C 30 arylalkyl optionally substituted, C 8 -C 30 optionally substituted arylalkenyl, C 3 -C 18 heterocycle optionally substituted, C4-C30 heterocycloalkyl optionally substituted, C 5 -C 30 optionally substituted heterocycloalkenyl, C 3 -C 18 cycloalkyl optionally substituted, C4-C30 cycloalkylalkyl optionally substituted, C 5 -C 30 optionally substituted cycloalkylalkenyl, C 3 -C 18 cycloalkenyl optionally substituted, C 4 -C 30 cycloalkenyl alkyl optionally substituted and C 5 -C 30 optionally substituted cycloalkenyl alkenyl, with the condition of  that R 11 will be absent if the carbon to which it is attached forms part of a double bond; R 12, R 13 and R 14 are groups independently selected from hydrogen, OR a, OC (= O) R a, SR a, (S = O) R a, SO 2 R a, SO 3 R a, SO 2 NR a R b, NO 2,  NHR a, N (R a R b), NR a (OR b), NHCOR a, N (COR a) (COR b), NHCO 2 R a, NHC (= O) NR a R b, NHSO 2 R a, NH (C = NH) NH 2, CN, halogen, C (= O) R a, CO 2 R a, C (= O) NR a R b, C 1 -C 12 optionally substituted alkyl, C 2 -C 12 alkenyl optionally substituted, C2-C12 alkynyl optionally  substituted, C 6 -C 18 aryl optionally substituted, C 7 -C 30 arylalkyl optionally substituted, C 8 -C 30 optionally substituted arylalkenyl, C 3 -C 18 heterocycle optionally substituted, C4-C30 heterocycloalkyl optionally substituted, C 5 -C 30 optionally substituted heterocycloalkenyl, C 3 -C 18 cycloalkyl optionally substituted, C4-C30 cycloalkylalkyl optionally substituted, C 5 -C 30 optionally substituted cycloalkylalkenyl, C 3 -C 18 cycloalkenyl optionally substituted, C 4 -C 30 cycloalkenyl alkyl optionally substituted and C 5 -C 30 optionally substituted cycloalkenyl alkenyl, with the condition that one or more of these groups are absent if the Y group at that are attached is part of a double bond or a ring additional condensed carbocyclic or heterocyclic; R a and R b are groups independently selected from hydrogen, C 1 -C 12 optionally substituted alkyl, C2-C12 optionally substituted alkenyl, C2-C12 optionally substituted alkynyl,  Optionally substituted C 6 -C 18 aryl, C 7 -C 30 arylalkyl optionally substituted, C 8 -C 30 arylalkenyl optionally substituted, C 3 -C 18 optionally substituted heterocycle, C 4 -C 30 heterocycloalkyl optionally substituted, C 5 -C 30 heterocycloalkenyl optionally substituted, C 3 -C 18 optionally substituted cycloalkyl, C 4 -C 30 cycloalkylalkyl optionally substituted, C 5 -C 30 cycloalkylalkenyl optionally substituted, C 3 -C 18 optionally substituted cycloalkenyl, C 4 -C 30 cycloalkenyl alkyl optionally substituted and C 5 -C 30 cycloalkenyl alkenyl optionally substituted; or a pharmaceutically acceptable salt, derivative, prodrug or stereoisomer thereof; with the exception of the compounds of formula: 96

           \ vskip1.000000 \ baselineskip
        

97 98

           \ vskip1.000000 \ baselineskip
        

99

           \ vskip1.000000 \ baselineskip
        

100

           \ vskip1.000000 \ baselineskip
        

101

           \ vskip1.000000 \ baselineskip
        

102 2. A compound according to claim 1 in the that R 4 is a radical of formula (II). 3. A compound according to claim 2 in the that R 6 and R 7 are C 6 -C 18 groups substituted or unsubstituted aryl. 4. A compound according to any one of the claims 2 or 3 wherein R 6 and R 7 are groups substituted or unsubstituted phenyl. 5. A compound according to claim 1 in the that R 4 is hydrogen. 6. A compound according to any one of the claims 1 to 5 wherein R 1 and R 2 are groups C 6 -C 18 aryl substituted or not replaced. 7. A compound according to claim 6 in the that R1 and R2 are phenyl groups substituted or not replaced. 8. A compound according to any one of the claims 1, 2 or 5 wherein the groups R1 and R3 and / or R 5 and R 6 form, together with the atoms of P and N adjacent, a heterocycle according to formulas (III) or (IV), respectively. 9. A compound according to claim 8 in the that the heterocycles of formulas (III) and (IV) have two doubles bonds giving rise to heterocycles of formula (V) to (VIII) 103

           \ vskip1.000000 \ baselineskip
        

104 10. A compound according to any one of the claims 8 or 9 wherein the groups Y1, Y2, Y 3 and Y 4 are CR 13 groups R 14 where R 13 and R 14 are hydrogen or at least one of them is absent if the carbon atom to which they are attached is part of a double bond or of a condensed carbocyclic or heterocyclic ring additional. 11. A compound according to any one of the claims 8 to 10 wherein the group R 10 is hydrogen. 12. A compound according to any one of the claims 8 to 11 wherein R 11 is hydrogen or is absent when the carbon atom to which it is attached is part of a double bond 13. A compound according to any one of the claims claims 1 to 7 wherein R 3 and R 5 are groups selected from C_ {1} -C_ {12} substituted or unsubstituted alkyl, C 7 -C 30 substituted or unsubstituted arylalkyl and C4-C30 heterocycloalkyl substituted or not replaced. 14. A compound according to claim 13 in which R 3 and R 5 are groups C 8 -C 14 arylalkyl substituted or not replaced. 15. A compound according to claim 14 in which R 3 and R 5 are substituted or unsubstituted phenylalkyl groups replaced. 16. A compound according to claim 15 in which R 3 and R 5 are substituted or unsubstituted benzyl groups replaced. 17. A compound according to claims 8 a 12 in which R 8 and R 9 are groups selected from hydrogen and substituted or unsubstituted phenyl. 18. A compound according to any one of the claims 1 to 17, including compounds A to L, or a salt pharmaceutically acceptable, a derivative, a prodrug or a stereoisomer thereof, for use as a medicine. 19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17, including compounds A to L, or a pharmaceutically salt acceptable, a derivative, a prodrug or a stereoisomer of same, in admixture with a pharmaceutically excipient or diluent acceptable. 20. A compound according to claim 18 for Use as a medicine to treat cancer. 21. Use of a compound according to any one of claims 1 to 17, including compounds A to L, or a pharmaceutically acceptable salt, a derivative, a prodrug or a stereoisomer thereof, in the preparation of a medicament. 22. Use of a compound according to claim 21 in the preparation of a medicament for the treatment of Cancer.