ES2370986B1 - NEW CXCR4 INHIBITORS AS ANTI-HIV AGENTS - Google Patents

Abstract

Compounds of formula (I), and their pharmaceutically acceptable salts, hydrates and solvates, their use as anti-HIV agents in the treatment of Acquired Immunodeficiency Syndrome (AIDS), process for obtaining them and synthesis intermediates employed therein.

Description

New CXCR4 inhibitors as anti-HIV agents.

Technical field

The present invention relates to the compounds of formula (I), and their pharmaceutically acceptable salts, hydrates and solvates, to their use as anti-HIV agents in the treatment of Acquired Immune Deficiency Syndrome (AIDS), to the process for obtaining them and the synthesis intermediates used in it.

State of the art

In the fight against Acquired Immunodeficiency Syndrome (AIDS) the main therapeutic targets include all phases of the Human Immunodeficiency Virus (HIV) biological cycle, in order to block, decrease

or cancel each of the key stages of the HIV replicative cycle. One of the main difficulties in antiretroviral treatment is the great mutability coupled with the great replication power of the virus, which allows it to become resistant to the drugs used to treat it. Another difficulty lies in the side effects on the host, so that, to avoid them, drugs must be specific against viral enzymes or proteins.

Current antiretroviral therapy consists of combinations of two families of compounds: reverse transcriptase inhibitors (ITI) and protease inhibitors (IP), both targeting specific enzymes produced by HIV.

The stage of binding and fusion of the virus to the host cell is an interesting target in HIV chemotherapy. HIV needs a primary receptor (CD4) and chemokine receptors (CXCR4 or CCR5) as co-receptors to fuse with the cell. The CXCR4 chemokine receptor is a correceptor for the entry of tropic HIV T strains while CCR5 is for the Tropic M strains. Therefore, compounds that interact with the input co-receptors may be good drug candidates that prevent HIV from entering.

Small chemokine receptor inhibitor molecules have been identified (Moore et al., Nat Rev Mol Cell Biol, 2000, 1, 40). Agents that block CXCR4 include small peptides such as Allelix-40-4C, T22 and their analogs (Doranz et al., J Exp Med, 1997, 186, 13 95; Murakami et al., J Exp Med, 1997, 186 , 1389); peptoids such as CGP64222 and arginine conjugates (Cabrera et al., Antiviral Research, 2002, 53, 1; Cabrera et al., AIDS Res Hum Retroviruses, 2000, 16, 627; Daelemans et al., Mol Pharmacol, 2000, 57, 116); and bicycles (Bridger et al., J Med Chem, 1995, 38, 366; Este et al., Mol Pharmacol, 1999, 55, 67; Donzella et al., Nat Med, 1998, 4, 72; Schols et al. , J Exp Med, 1997, 186, 1383). Various compounds such as TAK-779, the derivative of spirodicetopiperazine E913 (Maeda et al., J Biol Chem, 2001, 13, 13), monoclonal antibodies such as 2D7 or PRO140 (Trkola et al., J Virol, 2001, 75 , 579) and low molecular weight compounds such as SCH-D have proven effective in blocking the function of CCR5 and HIV replication (Strizki et al., Proc Natl Acad Sci USA, 2001, 98, 12718). It has also been described that some gp41 inhibitor, such as the T-20 peptide, that inhibits HIV replication.

HIV fusion and entry inhibitors are becoming the next generation of anti-HIV agents. Among the compounds under study are BMS-488043 that binds to HIV-1 gp120 preventing it from recognizing the CD4 receptor, AMD070 that acts as a specific inhibitor of the CXCR4, GW-873140, UK427857 and SCH-D correceptor that are antagonists of the CCR5 correceptor.

A CXCR4 antagonist, AMD3100 reduced the viral load by 0.8-0.9 log10 in an individual infected with an X4 strain of HIV. The virus recovered from patients who received AMD3100 showed a change in the phenotype of X4 virus to R5 virus, suggesting that AMD3100 selectively blocked those viruses that used CXCR4 but was not effective in inhibiting CCR5-dependent HIV replication in vivo (Schols et al., 9th CROI, Seattle 2002). The development of AMD3100 was abandoned in 2001 due to possible cardiac toxicity (Hendrix et al., Antimicrob Agents Chemother, 2000, 44, 1667; Hendrix et al., J Acquir Immune De fi c Syndr, 2004, 37, 1253), in addition its lack of oral bioavailability related to its high positive charge in physiological medium could present long-term limitations for its application in anti-HIV therapy (Hatse et al., Biochem Pharmacol, 2005, 70, 752).

The current leads AMD3100, SCH-D and TAK-779, have aromatic or aliphatic spacers in polynitrogenated systems. Of all the compounds under study, bicycles in general, and AMD3100 in particular, appear to be the most active. However, compounds with a single unit of cyclam and with the 1,4-phenylene bismethylene spacer such as AMD3465 have proven to be up to 10 times more active than AMD3100 (Hatse et al., Biochem Pharmacol, 2005, 70, 752; Princen et al., J Virol, 2004, 78, 12996).

With this background, the authors of the present invention considered to obtain compounds in which both cyclic rings, too basic and possible causes of the toxicity observed in AMD3100, were replaced by other cyclic or heterocyclic nitrogen systems of lower basicity and, by therefore, of lower toxicity but maintaining its activity as inhibitors of the CXCR4 and CCR5 input correceptors.

In the international application WO 2008/049950 A1, the authors of the present invention proposed inhibitors of the CXCR4 and CCR5 input co-receptors derived from di (amino-methyl) benzene.

Object of the invention

The present invention refers to new compounds of formula (I) and their use as anti-HIV agents in the treatment of Acquired Immune Deficiency Syndrome (AIDS), the process for obtaining them and the synthesis intermediates employed therein.

The inventors have found that the compounds of formula (I) are potent inhibitors of the HIV-induced cytopathic effect while having a moderate cytotoxic effect, thus presenting a good therapeutic window.

Description of the invention

The compounds object of the present invention have the formula (I) described below.

in which m represents an integer selected from 2, 3, 4,5 and 6;

G1 is selected from a) hydrogen atoms, b) C1-C12 alkyl groups optionally substituted with 1 to 3 halogen atoms and / or C1-C6 alkoxy groups, c) C6-C14 aryl groups optionally substituted with 1 to 4 atoms of halogen, aryl and / or C1-C6 alkoxy groups, d) C1-C6 alkoxy groups and e) halogen atoms;

G2 represents a pyrrolidinyl or piperidinyl group attached by its nitrogen atom to the methylene chain and which may or may not be substituted with a C1-C4 alkyl group,

or pharmaceutically acceptable salts and / or solvates thereof.

The term "C6-C14 aryl" refers to aromatic cycles of between 6 and 14 members which do not comprise heteroatoms, optionally substituted and which can be monocyclic or polycyclic such as phenyl, naphthyl, anthranyl and phenanthryl, with phenyl being especially preferred. Preferably, the aryl groups have up to 4 identical or different substituents. Preferred substituents of aryl groups are halogen atoms and alkoxy groups.

The term "alkyl" refers to optionally substituted linear or branched hydrocarbon chains having from 1-4 carbon atoms. Preferably, the alkyl groups have up to 4 identical or different substituents. Preferred substituents of the alkyl groups are halogen atoms. Examples of alkyl groups are methyl, ethyl, n-propyl, i-propyl n-butyl, sec-butyl and tert-butyl and tri-fluoromethyl.

The term "halogen" is understood to mean a substituent selected from fluorine, chlorine, bromine and iodine.

The expression "pharmaceutically acceptable salts, hydrates and solvates thereof" refers to salts, hydrates.

or solvates which, when administered to the recipient, can provide (directly or indirectly) a compound such as that described herein. However, it will be noted that pharmaceutically acceptable salts are also within the scope of the invention because they can be useful for preparing pharmaceutically acceptable salts. Salts and derivatives can be prepared by methods known in the state of the art. "Pharmaceutically acceptable" preferably refers to molecular entities and compositions that are physiologically tolerable and do not normally produce an allergic reaction or a similar unfavorable reaction, such as gastric disorders, dizziness and the like, when administered to a human or animal being. The term "pharmaceutically acceptable" means that it is approved by the regulatory agency of a state or federal government or is included in the US pharmacopoeia or other pharmacopoeia generally recognized for use in animals, and more particularly in humans.

For example, pharmaceutically acceptable salts of the compounds previously described herein are synthesized from the previously described compound that contains a basic or acidic unit by means of conventional chemical methods. Such salts are generally prepared, for example, by reacting the free acidic or basic forms of these compounds with a stoichiometric amount of the appropriate base or acid in water.

or in an organic solvent or in a mixture of both. Non-aqueous media, such as ether, tetrahydrofuran, ethyl acetate, ethanol, isopropanol or acetonitrile, are generally preferred. Examples of acid addition salts include mineral acid addition salts such as hydrochloride, hydrobromide, iodhydrate, sulfate, nitrate, phosphate, for example, and organic acid addition salts such as acetate, maleate, fumarate, citrate, oxalate , succinate, tartrate, malate, mandelate, methanesulfonate and p-toluenesulfonate, for example. Examples of alkaline addition salts include inorganic salts such as sodium, potassium, calcium, ammonium, magnesium, aluminum and lithium, for example, and organic alkaline salts such as ethylenediamine, ethanolamine, N, N-dialkylene ethanolamine, glucamine and amino acid salts Basic for example.

According to this invention, the term "solvate" is understood to mean any form of a compound of the invention that has another molecule attached to it through a non-covalent bond. Examples of solvates include hydrates and alcoholates, for example methanolate or solvates with chloroform.

The compounds used in the invention may be in crystalline form, that is as polymorphs, either as free compounds or as solvates (hydrates, for example) and it is understood that both forms are within the scope of the present invention. Solvation methods are generally known in the art. Suitable solvates are pharmaceutically acceptable solvates. In a particular embodiment, the solvate is a hydrate.

Salts and solvates can be prepared by methods known in the state of the art. It will be noted that pharmaceutically acceptable salts and solvates are also included within the scope of the invention because they can be useful in the preparation of pharmaceutically acceptable salts, solvates or prodrugs.

The compounds of formula (I) or their salts or solvates are preferably in pharmaceutically acceptable form or in substantially pure form. A pharmaceutically acceptable form is understood, inter alia, as having a pharmaceutically acceptable level of purity, excluding normal pharmaceutical additives such as diluents and excipients and not including any material that is considered toxic at normal dosage levels. The purity levels for the drug are preferably greater than 50%, more preferably greater than 70% and still more preferably greater than 90%. In a preferred embodiment, it is greater than 95% of the compound of formula (I), or of its salts or solvates.

The compounds used in the invention represented by the formula (I) described above may include enantiomers depending on the presence of chiral centers. The enantiomers, individual diastereoisomers and mixtures thereof are within the scope of the present invention.

In one embodiment of the present invention G1 is selected from a) hydrogen atoms, b) unsubstituted C1-C12 alkyl groups c) unsubstituted C6-C14 aryl groups, d) C1-C6 alkoxy groups and e) halogen atoms.

In another embodiment of the present invention G1 is hydrogen.

In one embodiment of the present invention m has a value of 2o3, preferably 3.

In another embodiment of the present invention G2 is selected from the group comprising the radicals 2-methylpiperidinyl (also designated 2-pipecolinyl), piperidinyl and pyrrolidinyl, preferably pyrrolidinyl and piperidinyl.

Preferred compounds of formula (I) according to the present invention are selected from the group that includes: N, N’-bis (3- (2-pipecolin-1-yl) propyl) -1,4-bis (2-aminoet-1-yl) benzene N, N’-bis (2- (pyrrolidin-1-yl) ethyl) -1,4-bis (2-aminoet-1-yl) benzene N, N’-bis (3- (pyrrolidin-1-yl) propyl) -l, 4-bis (2-aminoet-1-yl) benzene N, N’-bis (2- (piperidin-1-yl) ethyl) -1,4-bis (2-aminoet-1-yl) benzene N, N’-bis (3- (piperidin-1-yl) propyl) -1,4-bis (2-aminoet-1-yl) benzene.

It is an aspect of the present invention to describe a process for the preparation of a compound of formula (I):

wherein m, G1 and G2 have the meanings described above which consists of a) treating an optionally substituted 1,4-benzenediacetyl dichloride derivative of formula (III)

with a primary amine of formula (IV)

to obtain the corresponding amide of formula (V) and b) treat the amide of formula (V) with a reducing agent to obtain the compound of formula (I).

The compounds of formula (I) are prepared as shown in Schemes 1 to 3 where the variables G1, G2 and m are selected so that the corresponding substituents do not include any combination that renders the processes of Schemes1 to 3 inoperative. All products Starting are commercially available or can be obtained from commercially available products by experienced personnel. The compounds of general formula (I) can be prepared according to Scheme 1:

Scheme 1

First, the 1,4-benzenediacetic acid (II) derivative is converted into a benzenediacetyl dichloride (III) derivative and this is condensed with a primary amine (IV) of formula G2- (CH2) m-NH2 to give corresponding amide (V). In a final step, the carbonyl group of the amide (V) is reduced to provide the compounds of the invention (I).

The conversion of the 1,4-benzenediacetic acid (II) derivative into a benzenediacetyl dichloride derivative

(III) it can be carried out by means of chlorinating agents, preferably by the action of hexamethyldisilazane optionally in the presence of catalytic amounts of trimethylchlorosilane in an organic solvent such as 1,2-dichloroethane under a nitrogen atmosphere to give a trimethylsilylated intermediate which is reacted with chloride of oxalyl in an organic solvent such as methylene chloride.

The condensation of the benzenediacetyl dichloride derivative (III) with the amine of formula (IV) is carried out in an organic solvent such as methylene chloride in the presence of a base such as triethylamine to provide the amide of formula (V).

In a final step the amide is reduced by a reducing agent such as the borane-dimethyl sulfide complex in an organic solvent such as tetrahydrofuran.

The pharmaceutically acceptable salts, hydrates and solvates of the compounds of formula (I) of the present invention can be obtained by experienced personnel from commercially available starting products.

It is also an aspect of the present invention a compound of formula (V)

wherein m, G1 and G2 have the meanings defined above as intermediate in the synthesis of the compounds of formula (I).

It is also an aspect of the present invention to use the compounds of formula (I) as medicaments, in particular in the treatment of Acquired Immunodeficiency Syndrome (AIDS).

It is also an aspect of the present invention to use the compounds of formula (I) to prepare a medicament, in particular a medicament for the treatment of Acquired Immune Deficiency Syndrome (AIDS).

The biological activity as anti-HIV agents of the compounds of formula (I) object of the present invention has been demonstrated by the following in vitro test.

Protocol for the evaluation of the anti-HIV activity of compounds in MT-4 cells

The test of evaluation of the anti-HIV activity of compounds is based on the determination of cell viability by the method of reduction of meti 1-thiazol-tetrazolium (MTT). In vitro assays consist of culturing for 5 days MT-4 lymphoid cells in the presence of serial dilutions of the compounds to be tested in the presence or absence of the HIV-1 virus, strain NL4-3. The culture of cells and compound alone allows to determine the CC50 or 50 cytotoxic concentration, concentration at which the compound induces death in 50% of the cell culture. The culture of the cells and compound in the presence of virus, allows to evaluate the EC50 or effective concentration 50, concentration at which the compound inhibits 50% of the cytopathic effect induced by HIV. In each trial the anti-HIV activity of compounds of known activity is evaluated to validate the assay.

The compounds of formula (I) object of the present invention generally have EC50 <0.6 μg / mL. Four of the compounds tested have an EC50 = <0.1 μg / mL.

Without further elaboration, it is considered that an experienced person can, using the foregoing description, use the present invention to its fullest extent. Next, for a better understanding of the present invention, without being construed as limitations to it, the following examples are set forth:

Examples

Example 1

Synthesis of N, N’-bis (3- (pyrrolidin-1-yl) propyl) -1,4-di (amino carbonyl methyl) benzene

A mixture of 1,4-benzenediacetic acid (2.0 g, 10.30 mmol), hexamethyldisilazane (HMDS) (2.86 ml, 20.60 mmol) and trimethylchlorosilane (12 drops) in 1.2 was refluxed - Dry dichloroethane (60 ml) overnight under N2. The solution was evaporated under reduced pressure. The residual material was bis (trimethylsilyl) 1,4-benzenediacetate. This product thus obtained was dissolved in anhydrous CH2Cl2 (20 ml) and anhydrous DMF (4 drops), oxalyl chloride (1.86 ml, 21.86 mmol) was added dropwise to the solution at 0 ° C, the solution was stirred for 1 h at this temperature under N2 and for 1 h at room temperature before removing the solvent under reduced pressure. The residual material was 1,4-benzenediacetyl dichloride. Anhydrous CH2Cl2 (28 ml) was added to the flask and cooled to 0 ° C. 1- (3-Amino-propyl) pyrrolidine (2.68 ml, 20.60 mmol) and triethylamine (TEA) (3.20 ml, 22.96 mmol) were added. The solution was stirred for 16 hours at room temperature under N2. A solution of K2CO3 (25%) (40 ml) was added and the aqueous phase was separated and extracted with CH2Cl2 (3 x 40 ml). The combined organic extracts were washed with water (2 x 40 ml), brine (40 ml) and dried over MgSO4 and concentrated. Purification of the residue by flash chromatography (silica, 75: 25: 2, CH2Cl2 / MeOH / NH3) provided 2.43 g (5.84 mmol, 57%) of N, N'-bis (3-pyrrolidin-1- il) propyl) -1,4-di (aminocarbonylmethyl) -benzene as a white solid, mp 160-161 ° C.

Spectroscopic data

1H-NMR (400 MHz, CDCl3): δ (ppm): 7.23 (s, 4H, C1-H), 6.92 (sa, 2H, NH), 3.49 (s, 4H, C3-H ), 3.31 (q, 3J = 5.6 Hz, 4H, C5-H), 2.49 (t, 3J = 6.5 Hz, 4H, C7-H), 2.43 (m, 8H, C8-H), 1.71 (m, 8H, C9-H), 1.64 (quintuple, 3J = 6.5 Hz, 4H, C6-H).

13C-NMR (100.6 MHz, CDCl3): δ (ppm): 170.8 (C4), 134.1 (C2), 129.7 (C1), 54.9 (C7), 54.0 (C8 ), 43.6 (C3), 39.4 (C5), 27.1 (C6), 23.4 (C9).

IR (KBr): ν (cm − 1): 3264 (t NH), 3080 (t Csp2-H), 2962, 2874, 2791 (t Csp3-H), 1642 (t C = O), 1562 (δ NH ).

MS (70 eV, EI): m / z (%) = 414.2 (16) [M] +, 330.1 (32) [M-C5H10N] +, 274.0 (10) [M-C8H16N2] +, 260.0 (43) [M-C9H18N2] +, 97.9 (31) [C6H12N] +, 83.9 (100) [C5H10N] +, 69.9 (29) [C4H8N] +.

HRMS (70 eV, EI): m / z calculated for C24H38N4O2: 414.2995, [M] +; Found: 414.2992.

Synthesis of N, N’-bis (3- (pyrrolidin-1-yl) propyl) -1,4-bis (2-aminoet-1-yl) -benzene

The borane dimethyl sulphide complex (1.19 ml, 11.89 mmol) was added at 0 ° C to a solution of N, N'-bis (3- (pyrrolidin-1-yl) propyl) -1,4-di (aminocarbonylmethyl) ) benzene (414.58 mg, 1.0 mmol) in anhydrous THF (27 ml). The solution was refluxed for 6 h under N2, cooled to room temperature, diluted with 7.5 ml of 1.25M MeOH / HCl solution and refluxed for 1 h. The solvent was removed in vacuo and the crude material was diluted with a solution of 1 M NaOH (pH 14). The aqueous solution was extracted twice with CH2Cl2, dried over MgSO4 and concentrated. Purification of the residue by flash chromatography (basic alumina, CH2Cl2-MeOH; 100: 0 to 90:10 in 18 min.) Produced 296 mg (0.77 mmol, 77%) of N, N'-bis (3- (pyrrolidin-1-yl) propyl) -1,4-bis (2-aminoet-1-yl) benzene as a white solid, mp 60-62 ° C.

Spectroscopic data

1H-NMR (400 MHz, CDCl3): δ (ppm): 7.13 (s, 4H, C1-H), 2.87 (m, 4H, C4-H), 2.77 (m, 4H, C3 -H), 2.68 (t, 3J = 7.1 Hz, 4H, C5-H), 2.46 (m, 12H, C7-H, C8-H), 1.91 (sa, 2H, NH ), 1.75 (m, 8H, C9-H), 1.69 (quintuple, 3J = 7.1 Hz, 4H, C6-H).

13C-NMR (100.6 MHz, CDCl3): δ (ppm): 137.9 (C2), 128.9 (C1), 54.9 (C7), 54.4 (C8), 51.3 (C4 ), 48.6 (C5), 36.0 (C3), 29.4 (C6), 23.5 (C9).

IR (KBr): ν (cm − 1): 32 63 (t N-H), 2948, 2801 (t Csp3-H), 1697 (δ NH), 1458 (f Csp3-H), 887 (δ NH).

MS (70 eV, EI): m / z (%) = 386.4 (2) [M] +, 302.2 (4) [M-C5H10N] +, 274.2 (8) [M-C7H14N] +, 141.1 (47) [C8H17 N2] +, 112.1 (9) [C7H14N] +, 98.1 (11) [C6H12N] +, 84.1 (100) [C5H10N] +, 70.1 (8) [C4H8N] +.

HRMS (70 eV, EI): m / z calculated for C24H42N4: 386.3409, [M] +; Found: 386.3405. Example 2

Synthesis of N, N’-bis (2- (pyrrolidin-1-yl) ethyl) -1,4-di (amino carbonyl methyl) benzene

The procedure was the same as set out above for N, N'-bis (3-pyrrolidin-1-yl) propyl) -1,4-di (aminocarbonylmethyl) benzene, but was carried out using 1,4-benzenediacetic acid (2.0 g, 10.30 mmol), hexamethyldisilazane (HMDS) (2.86 ml, 20.60 mmol), trimethylchlorosilane (12 drops), DMF (4 drops), oxalyl chloride (1.86 ml, 21 , 86 mmol), 1- (2-aminoethyl) pyrrolidine (2.65 ml, 20.60 mmol) and triethylamine (TEA) (3.20 ml, 22.96 mmol). After removal of the solvent, the residue was separated by flash chromatography (silica, 75: 25: 2, CH2Cl2 / MeOH / NH3) yielding 3.06 g (7.82 mmol, 76%) of N, N'-bis ( 2- (pyrrolidin-1-yl) ethyl) -1,4-di (aminocarbonylmethyl) benzene as a white solid, mp 194-196 ° C.

Spectroscopic data

1H-NMR (400 MHz, CDCl3): δ (ppm): 7.24 (s, 4H, C1-H), 6.16 (sa, 2H, NH), 3.53 (s, 4H, C3-H ), 3.32 (q, 3J = 6.1 Hz, 4H, C5-H), 2.54 (t, 3J = 6.2 Hz, 4H, C6-H), 2.45 (m, 8H, C7-H), 1.72 (m, 8H, C8-H).

13C-NMR (100.6 MHz, CDCl3): δ (ppm): 170.8 (C4), 134.0 (C2), 129.6 (C1), 54.3 (C6), 53.7 (C7 ), 43.3 (C3), 38.2 (C5), 23.4 (C8).

IR (KBr): ν (cm − 1): 3288 (t NH), 3083 (t Csp2-H), 2964, 2939, 2872, 2800 (t Csp3-H), 1648 (t C = O), 1549 ( δ NH).

Anal .: calculated for C22H34N4O2: C: 68.36%, H: 8.87%, N: 14.49%, O: 8.28%; Found: C: 68.11%, H: 8.75%,

N: 14.69%.

MS (70 eV, EI): m / z (%) = 386.3 (2) [M] +, 246.2 (2) [M-C8H16N2] +, 84.1 (100) [C5H10N] +, 70.1 (2) [C4H8N] +.

Synthesis of N, N’-bis (2- (pyrrolidin-1-yl) ethyl) -1,4-bis (2-aminoet-1-yl) -benzene

The procedure was the same as set out above for N, N'-bis (3- (pyrrolidin-1-yl) propyl) -1,4-bis (2 aminoet-1-yl) benzene, but was carried out using the borane dimethyl sulphide complex (0.58 ml, 6.15 mmol), N, N'-bis (2- (pyrrolidin-1-yl) ethyl) -1,4-di (aminocarbonylmethyl) benzene (466.2 mg, 1.21 mmol), anhydrous THF (4 ml), 1.25 M MeOH / HCl (9 ml). After removal of the solvent, the residue was separated by flash chromatography (basic alumina, CH2Cl2-MeOH; from 100: 0 to 90:10 in 18 min.) Yielding 267.0 mg (74.5 mmol, 75%) of N , N'bis (2- (pyrrolidin-1-yl) ethyl) -1,4-bis (2-aminoet-1-yl) benzene as a yellow oil.

Spectroscopic data

1H-NMR (400 MHz, CDCl3): δ (ppm): 7.13 (s, 4H, C1-H), 2.88 (m, 4H, C4-H), 2.78 (m, 8H, C3 -H, C5-H), 2.59 (t, 3J = 6.5 Hz, 4H, C6-H), 2.49 (m, 8H, C7-H), 2.17 (sa, 2H, NH ), 1.75 (m, 8H, C8-H).

13C-NMR (100.6 MHz, CDCl3): δ (ppm): 137.4 (C2), 128.7 (C1), 55.9 (C6), 54.2 (C7), 51.4 (C4 ), 48.4 (C5), 35.9 (C3), 23.4 (C8).

IR (KBr): ν (cm − 1): 3305 (t N-H), 2929, 2875, 2796 (t Csp3-H), 1673 (δ NH), 1458 (f Csp3-H).

MS (FAB): m / z (%) = 359.3 (100) [M + H] +, 358.3 (14) [M] +, 288.3 (4) [M-C4H8N] +, 274 , 3 (12) [M-C5H10N] +, 231.1 (37) [M-C7H15N2] +, 127.1 (15) [C7H15N2] +. HRMS (FAB): m / z calculated for C22H39N4: 359.3175, [M] +; Found: 359.3159. Example 3

Synthesis of N, N’-bis (3- (2-pipecolin-1-yl) propyl) -1,4-di (amino carbonyl methyl) benzene

The procedure was the same as set out above for N, N'-bis (3-pyrrolidin-1-yl) propyl) -1,4-di (aminocarbonylmethyl) benzene, but was carried out using 1,4-benzenediacetic acid (2.0 g, 10.30 mmol), hexamethyldisilazane (HMDS) (2.86 ml, 20.60 mmol), trimethylchlorosilane (12 drops), DMF (4 drops), oxalyl chloride (1.86 ml, 21 , 86 mmol), 1- (3-aminopropyl) -2-pipecoline (3.77 ml, 20.60 mmol) and triethylamine (TEA) (3.20 ml, 22.96 mmol). After removal of the solvent, the residue was separated by flash chromatography (silica, 75: 25: 2, CH2Cl2 / MeOH / NH3) yielding 3.46 g (7.35 mmol, 71%) of N, N'-bis ( 3- (2-pipecolin-1-yl) propyl) -1,4-di (aminocarbonylmethyl) -benzene as off-white solid, mp 119-120 ° C.

Spectroscopic data

1H-NMR (400 MHz, CDCl3): δ (ppm): 7.24 (s, 4H, C1-H), 7.09 (sa, 2H, NH), 3.50 (s, 4H, C3-H ), 3.37 (m, 2H, C5-H), 3.21 (m, 2H, C5-H), 2.83 (m, 2H, C8-H), 2.75 (m, 2H, C7 -H), 2.24 (m, 4H, C7-H, C12-H), 2.03 (m, 2H, C8-H), 1.61 (m, 10H, C6-H, C9-H, C10-H, C11-H), 1.42 (m, 2H, C9-H), 1.26 (m, 2H, C10-H, C11-H), 1.00 (d, 3J = 6.3 Hz, 6H, C13-H).

13C-NMR (100.6 MHz, CDCl3): δ (ppm): 170.5 (C4), 134.1 (C2), 129.7 (C1), 56.3 (C12), 52.6 (C7 ), 51.7 (C8), 43.6 (C3), 39.7 (C5), 34.5 (C11), 26.0 (C9), 24.9 (C6), 23.5 (C10) , 18.6 (C13).

IR (KBr): ν (cm − 1): 3292 (t NH), 3074 (t Csp2-H), 2926, 2858, 2787, 2729 (t Csp3-H), 1648 (t C = O), 1546 ( δ NH).

MS (70 eV, EI): m / z (%) = 470.4 (6) [M] +, 455.4 (20) [M-CH3] +, 358, 3 (8) [M-C7H14N] +, 112.1 (100) [C7H14N] +.

HRMS (70 eV, EI): m / z calculated for C28H46N4O2: 470.3621, [M] +; Found: 470.3615.

Synthesis of N, N’-bis (3- (2-pipecolin-1-yl) propyl) -1,4-bis (2-aminoet-1-yl) benzene

The procedure was the same as set out above for N, N'-bis (3- (pyrrolidin-1-yl) propyl) -1,4-bis (2 aminoet-1-yl) benzene, but was carried out using the borane dimethyl sulphide complex (1.19 ml, 11.89 mmol), N, N'-bis (3- (2-pipecolin-1-yl) propyl) -1,4-di (aminocarbonylmethyl) -benzene (470, 7 mg, 1.0 mmol), anhydrous THF (27 ml), 1.25 M MeOH / HCl (7.5 ml). After removal of the solvent, the residue was separated by flash chromatography (basic alumina, CH2Cl2-MeOH; from 100: 0 to 90:10 in 18 min.) Yielding 237.0 mg (0.53 mmol, 53%) of N , N'-bis (3- (2-pipecolin-1-yl) propyl) -1,4-bis (2-aminoet-1-yl) benzene as an orange oil.

Spectroscopic data

1H-NMR (400 MHz, CDCl3): δ (ppm): 7.13 (s, 4H, C1-H), 2.84 (m, 6H, C4-H, C8-H), 2.77 (m , 4H, C3-H), 2.68 (m, 2H, C7-H), 2.62 (t, 3J = 7.0 Hz, 4H, C5-H), 2.32 (m, 2H, C7 -H), 2.23 (m, 2H, C12-H), 2.09 (m, 2H, C8-H), 1.92 (sa, 2H, NH), 1.63 (m, 6H, C6 -H, C10-H), 1.57 (m, 4H, C9-H, C11-H), 1.48 (m, 2H, C9-H), 1.26 (m, 4H, C10-H, C11-H), 1.02 (d, 3J = 6.2 Hz, 6H, C13-H).

13C-NMR (100.6 MHz, CDCl3): δ (ppm): 138.0 (C2), 129.0 (C1), 56.1 (C12), 52.4 (C7), 52.3 (C8 ), 51.4 (C4), 49.0 (C5), 36.2 (C3), 34.8 (C11), 26.3 (C9), 26.0 (C6), 24.2 (C10) , 19.3 (C13).

IR (KBr): ν (cm − 1): 3280 (t N-H), 2930, 2854, 2794 (t Csp3-H), 1655 (δ NH), 1449, 1372 (f Csp3-H).

MS (70 eV, EI): m / z (%) = 442.4 (3) [M] +, 330.3 (9) [M-C7H14N] +, 302.3 (18) [M-C9H16N] +, 169.2 (97) [C10H21 N2] +, 140.1 (7) [C9H18N] +, 126.1 (13) [C8H16N] +, 112.1 (100) [C7H14N] +, 98.1 (28) [C6H12N] +.

HRMS (70 eV, EI): m / z calculated for C28H50N4: 442.4035, [M] +; Found: 442.4027. Example 4

Synthesis of N, N’-bis (3- (piperidin-1-yl) propyl) -1,4-di (amino carbonylmethyl) -benzene

The procedure was the same as set out above for N, N'-bis (3-pyrrolidin-1-yl) propyl) -1,4-di (aminocarbonylmethyl) benzene, but was carried out using 1,4-benzenediacetic acid (2.0 g, 10.30 mmol), hexamethyldisilazane (HMDS) (2.86 ml, 20.60 mmol), trimethylchlorosilane (12 drops), DMF (4 drops), oxalyl chloride (1.86 ml, 21 , 86 mmol), 1- (3-aminopropyl) piperidine (3.38 ml, 20.60 mmol) and triethylamine (TEA) (3.20 ml, 22.96 mmol). After removal of the solvent, the residue was separated by flash chromatography (silica, 75: 25: 2, CH2Cl2 / MeOH / NH3) yielding 3.45 g (7.79 mmol, 76%) of N, N'-bis ( 3- (piperidin-1-yl) propyl) -1,4-di (aminocarbonylmethyl) -benzene as a white solid, mp 151-153 ° C.

Spectroscopic data

1 H-NMR (400 MHz, CDCl 3): δ (ppm): 7.24 (s, 4H, C1-H), 7.17 (sa, 2H, NH), 3.49 (s, 4H, C3-H ), 3.30 (q, 3J = 6.0 Hz, 4H, C5-H), 2.36 (m, 12H, C7-H, C8-H), 1.64 (quintuplet, 3J = 6.4 Hz, 4H, C6-H), 1.54 (quintuple, 3J = 5.6 Hz, 8H, C9-H), 1.43 (m, 4H, C10-H).

13C-NMR (100.6 MHz, CDCl3): δ (ppm): 170.7 (C4), 134.1 (C2), 129.6 (C1), 57.8 (C7), 54.5 (C8 ), 43.5 (C3), 39.5 (C5), 25.9 (C9), 24.9 (C6), 24.2 (C10).

IR (KBr): ν (cm − 1): 3289 (t NH), 3089 (t Csp2-H), 2930, 2850, 2809, 2771 (t Csp3-H), 1640 (t C = O), 1559 ( δ NH).

Anal .: calculated for C26H42N4O2: C: 70.55%, H: 9.56%, N: 12.66%, O: 7.23%; Found: C: 70.40%, H: 9.42%,

N: 12.50%.

MS (70 eV, EI): m / z (%) = 442.3 (9) [M] +, 344.2 (18) [M-C6H12N] +, 274.1 (12) [M-C10H20N2] +, 98.1 (100) [C6H12N] +, 84.0 (5) [C5H10N] +.

Synthesis of N, N’-bis (3- (piperidin-1-yl) propyl) -1,4-bis (2-aminoet-1-yl) -benzene

The procedure was the same as set out above for N, N'-bis (3- (pyrrolidin-1-yl) propyl) -1,4-bis (2 aminoet-1-yl) benzene, but was carried out using the borane dimethyl sulphide complex (1.19 ml, 11.89 mmol), N, N'-bis (3- (piperidin-1-yl) propyl) -1,4-di (aminocarbonylmethyl) benzene (442.6 mg, 1.0 mmol), anhydrous THF (27 ml), 1.25 M MeOH / HCl (7.5 ml). After removal of the solvent, the residue was separated by flash chromatography (basic alumina, CH2Cl2-MeOH; from 100: 0 to 90:10 in 18 min.) Yielding 252.5 mg (0.61 mmol, 61%) of N , N'-bis (3- (piperidin-1-yl) propyl) -1,4-bis (2-aminoet-1-yl) benzene as a yellow oil.

Spectroscopic data

1H-NMR (400 MHz, CDCl3): δ (ppm): 7.13 (s, 4H, C1-H), 2.86 (m, 4H, C4-H), 2.77 (m, 4H, C3 -H), 2.65 (t, 3J = 7.0 Hz, 4H, C7-H), 2.31 (m, 12H, C5-H, C8-H), 2.20 (sa, 2H, NH ), 1.67 (quintuple, 3J = 7.0 Hz, 4H, C6-H), 1.54 (m, 8H, C9-H), 1.42 (m, 4H, C10-H).

13C-NMR (100.6 MHz, CDCl3): δ (ppm): 137.9 (C2), 129.0 (C1), 57.9 (C5), 54.8 (C8), 51.3 (C4 ), 48.8 (C7), 36.0 (C3), 27.1 (C6), 26.1 (C9), 24.6 (C10).

IR (KBr): ν (cm − 1): 3283 (t N-H), 2933, 2852, 2801 (t Csp3-H), 1676 (δ NH), 1443 (f Csp3-H).

MS (70 eV, EI): m / z (%) = 414.4 (1) [M] +, 316.3 (3) [M-C6H12N] +, 288.2 (4) [M-C8H16N] +, 155.2 (60) [C9H19 N2] +, 126.1 (6) [C8H16N] +, 112.1 (9) [C7H14N] +, 98, 1 (100) [C6H12N] +, 84.1 (5) [C5H10N] +.

HRMS (70 eV, EI): m / z calculated for C26H46N4: 414.3722, [M] +; Found: 414.3710. Example 5

Synthesis of N, N’-bis (2- (piperidin-1-yl) ethyl) -1,4-di (amino carbonylmethyl) -benzene

The procedure was the same as set out above for N, N'-bis (3-pyrrolidin-1-yl) propyl) -1,4-di (aminocarbonylmethyl) benzene, but was carried out using 1,4-benzenediacetic acid (2.0 g, 10.30 mmol), hexamethyldisilazane (HMDS) (2.86 ml, 20.60 mmol), trimethylchlorosilane (12 drops), DMF (4 drops), oxalyl chloride (1.86 ml, 21 , 86 mmol), 1- (2-aminoethyl) piperidine (2.99 ml, 20.60 mmol) and triethylamine (TEA) (3.20 ml, 22.96 mmol). After removal of the solvent, 4.27 g (10.3 mmol, quantitative) of N, N'-bis (2- (piperidin-1-yl) ethyl) -1,4-di (aminocarbonylmethyl) benzene without additional puri fi cation as a pale orange solid, mp 174-176 ° C.

Spectroscopic data

1 H-NMR (400 MHz, CDCl 3): δ (ppm): 7.26 (s, 4H, C1-H), 6.16 (sa, 2 H, NH), 3.55 (s, 4H, C3- H), 3.27 (q, 3J = 6.0 Hz, 4H, C5-H), 2.34 (t, 3J = 6.1 Hz, 4H, C6-H), 2.27 (m, 8H , C7-H), 1.42 (m, 12H, C8-H, C9-H).

13C-NMR (100.6 MHz, CDCl3): δ (ppm): 170.7 (C4), 134.1 (C2), 129.8 (C1), 56.7 (C6), 54.0 (C7 ), 43.3 (C3), 36.1 (C5), 25.9 (C8), 24.3 (C9).

IR (KBr): ν (cm − 1): 3298 (t NH), 3091 (t Csp2-H), 2924, 2849, 2779, 2751 (t Csp3-H), 1642 (t C = O), 1556 ( δ NH).

MS (70 eV, EI): m / z (%) = 414.3 (4) [M] +, 98.1 (100) [C6H12N] +.

HRMS (70 eV, EI): m / z calculated for C24H38N4O2: 414.2995, [M] +; Found: 414.2987.

Synthesis of N, N’-bis (2- (piperidin-1-yl) ethyl) -1,4-bis (2-aminoet-1-yl) benzene

The procedure was the same as set out above for N, N'-bis (3- (pyrrolidin-1-yl) propyl) -1,4-bis (2 aminoet-1-yl) benzene, but was carried out using the borane dimethyl sulphide complex (1.19 ml, 11.89 mmol), N, N'-bis (2- (piperidin-1-yl) ethyl) -1,4-di (aminocarbonylmethyl) benzene (414.6 mg, mmol), anhydrous THF (27 ml), 1.25 M MeOH / HCl (7.5 ml). After removal of the solvent, the residue was separated by flash chromatography (basic alumina, CH2Cl2-MeOH; from 100: 0 to 90:10 in 18 min.) Yielding 320.4 mg (82.8 mmol, 83%) of N , N'-bis (2- (piperidin-1-yl) ethyl) -1,4-bis (2-aminoet-1-yl) benzene as a yellow oil.

Spectroscopic data

1H-NMR (400 MHz, CDCl3): δ (ppm): 7.14 (s, 4H, C1-H), 2.87 (m, 4H, C4-H), 2.78 (m, 4H, C3 -H), 2.72 (t, 4H, 3J = 6.4 Hz, C5-H), 2.42 (t, 4H, 3J = 6.4 Hz, C6-H), 2.34 (m, 8H, C7-H), 1.91 (sa, 2H, NH), 1.51 (m, 8H, C8-H), 1.40 (m, 4H, C9-H).

13C-NMR (100.6 MHz, CDCl3): δ (ppm): 137.8 (C2), 128.7 (C1), 58.5 (C6), 54.7 (C7), 51.4 (C4 ), 46.6 (C5), 35.9 (C3), 26.0 (C8), 24.4 (C9).

IR (KBr): ν (cm − 1): 3300 (t N-H), 2933, 2851, 2801 (t Csp3-H), 1678 (δ NH), 1442 (f Csp3-H).

MS (FAB): m / z (%) = 387.4 (100) [M + H] +, 386.3 (11) [M] +, 288.3 (11) [M-C6H12N] +, 141 , 1 (9) [C8H17N2] +, 112.1 (89) [C7H14N] +.

HRMS (FAB): m / z calculated for C24H38N4O2: 387.3488, [M + H] +; Found: 387.3496. Example 6

Evaluation of the inhibition of the HIV-induced cytopathic effect (EC50) and the cytotoxic effect of the compounds of examples1 to 5

The results in Table I show that the compounds of formula (I) of the invention are potent inhibitors of the HIV-induced cytopathic effect (EC50) while having a moderate cytotoxic effect (CC50) so they have a good window therapeutic (CC50 / EC50).

Claims (14)

1. A compound of formula (I) in which m represents an integer selected from 2, 3, 4,5 and 6; G1 is selected from a) hydrogen atoms, b) C1-C12 alkyl groups optionally substituted with 1 to 3 halogen atoms and / or C1-C6 alkoxy groups, c) C6-C14 aryl groups optionally substituted with 1 to 4 atoms of halogen, aryl and / or C1-C6 alkoxy groups, d) C1-C6 alkoxy groups and e) halogen atoms; G2 represents a pyrrolidinyl or piperidinyl group attached by its nitrogen atom to the methylene chain and which may or may not be substituted with a C1-C4 alkyl group, or a pharmaceutically acceptable salt and / or solvate thereof.

2.

A compound according to claim 1 wherein G1 is selected from a) hydrogen atoms, b) unsubstituted C1-C12 alkyl groups c) unsubstituted aryl C6-C14 groups, d) C1-C6 alkoxy groups and e) halogen atoms ;

3.

A compound according to claim 2 wherein G1 is a hydrogen atom.

Four.

A compound according to any one of claims 1 to 3 have a value of 2 to 3.

5.

A compound according to claim 4 wherein m has the value of 3.

6.

A compound according to any one of claims 1 to 5 wherein G2 is selected from the group comprising the 2-methylpiperidinyl, piperidinyl and pyrrolidinyl radicals.

7.

A compound according to claim 6 wherein G2 is selected from the group comprising the piperidinyl and pyrrolidinyl radicals.

8.

A process for the preparation of the compounds defined in claims 1 to 7 comprising:

a) treating an optionally substituted 1,4-benzenediacetyl dichloride derivative of formula (III) with a primary amine of formula (IV) to obtain the corresponding amide of formula (V) b) treating the amide of formula (V) with a reducing agent to obtain the compound of formula (I). 9. A compound of formula (V) in which m represents an integer selected from 2, 3, 4,5 and 6; G1 is selected from a) hydrogen atoms, b) C1-C12 alkyl groups optionally substituted with 1 to 3 halogen atoms and / or C1-C6 alkoxy groups, c) C6-C14 aryl groups optionally substituted with 1 to 4 atoms of halogen, aryl and / or C1-C6 alkoxy groups, d) C1-C6 alkoxy groups and e) halogen atoms; G2 represents a pyrrolidinyl or piperidinyl group attached by its nitrogen atom to the methylene chain and which may or may not be substituted with a C1-C4 alkyl group, or a salt and / or a solvate thereof. 10. Compound according to any of claims 1-7 for use as a medicament.

eleven.

Compound according to any of claims 1-7 for use in the treatment of Acquired Immune Deficiency Syndrome (AIDS).

12. Use of a compound according to any of claims 1-7 to prepare a medicament.

13.

Use of a compound according to any one of claims 1 to 7 to prepare a medicament for the treatment of Acquired Immune Deficiency Syndrome (AIDS).

SPANISH OFFICE OF THE PATENTS AND BRAND Application no .: 201030884 SPAIN Date of submission of the application: 08.06.2010 Priority Date: REPORT ON THE STATE OF THE TECHNIQUE 51 Int. Cl.: See Additional Sheet RELEVANT DOCUMENTS

Category

Documents cited Claims Affected

TO

WO 2008049950 A1 (INSTITUT QUIMIC DE SARRIA CETS) 02.05.2008, page 1, lines 5-10; page 5, lines 1-28. 1-13

TO

BIG, F. et al. "Small Molecules Anti-HIV Therapeutics Targeting CXCR4". Current Pharmaceutical Design, 2008, Volume 14, pages 385-404. See page 385, summary; page 396, figure 12; page 397, figure 13; page 391, figure 7; page 392, figure 8, compounds 16-22 and formula III. 1-13

TO

SHOLS, D. "HIV co-receptor inhibitors as novel class of anti-HIV drugs". Antiviral Research, 2006, Volume 71, pages 216-226. See page 216, summary; page 218, figure 1; page 220, figure 2. 1-13

TO

WO 2008019371 A1 (GENZYME CORPORATION) 02.02.2008, page 6, lines 30-31; page 38, line 17 - page 39, line 9; page 43, lines 24-33. 1-13

TO

EP 0645370 A1 (LILLY INDUSTRIES LIMITED) 29.03.1995, page 3, lines 1-53; formula (I). 1-13

Category of the documents cited X: of particular relevance Y: of particular relevance combined with other / s of the same category A: reflects the state of the art O: refers to unwritten disclosure P: published between the priority date and the date of priority submission of the application E: previous document, but published after the date of submission of the application

This report has been prepared • for all claims • for claims no:

Date of realization of the report 04.10.2011

Examiner G. Esteban García Page 1/4

REPORT OF THE STATE OF THE TECHNIQUE Application number: 201030884 CLASSIFICATION OBJECT OF THE APPLICATION  C07D295 / 135 (2006.01) C07D295 / 023 (2006.01) A61K31 / 401 (2006.01) A61K31 / 4453 (2006.01) A61K31 / 454 (2006.01) A61P31 / 18 (2006.01) Minimum documentation sought (classification system followed by classification symbols) C07D, A61K, A61P Electronic databases consulted during the search (name of the database and, if possible, search terms used) EPODOC, WPI, INVENES, REGISTRY, CAPLUS, BIOSIS, MEDLINE, XPESP, EMBASE, NPL, PUBMED State of the Art Report Page 2/4  WRITTEN OPINION Application number: 201030884 Date of Completion of Written Opinion: 04.10.2011 Statement

Novelty (Art. 6.1 LP 11/1986)

Claims Claims 1-13 IF NOT

Inventive activity (Art. 8.1 LP11 / 1986)

Claims Claims 1-13 IF NOT

The application is considered to comply with the industrial application requirement. This requirement was evaluated during the formal and technical examination phase of the application (Article 31.2 Law 11/1986).  Opinion Base.- This opinion has been made on the basis of the patent application as published. State of the Art Report Page 3/4  WRITTEN OPINION Application number: 201030884 1. Documents considered.- The documents belonging to the state of the art taken into consideration for the realization of this opinion are listed below.

Document

Publication or Identification Number publication date

D01

WO 2008049950 A1 05.02.2008

D02

BIG, F. et al. Current Pharmaceutical Design, 2008, Vol. 14, pp. 385-404. 2008

D03

SHOLS, D. Antiviral Research, 2006, Vol. 71, pp. 216-226. 2006

D04

WO 2008019371 A1 02/14/2008

2. Statement motivated according to articles 29.6 and 29.7 of the Regulations for the execution of Law 11/1986, of March 20, on Patents on novelty and inventive activity; quotes and explanations in support of this statement The object of the invention is a compound of the general formula (I) with a 1,4-phenylenebisethylene structure comprising two pyrrolidinyl and / or piperidinyl groups; a process for the preparation thereof which uses the bisamide of the general formula (V) as an intermediate; said compound of formula (V); and the use of (I) for the preparation of a medicament for the treatment of Acquired Immunodeficiency Syndrome (AIDS). Document D01 discloses compounds of formula (1) with a bisphenylenemethylene spacer, useful as anti-HIV agents in the treatment of Acquired Immune Deficiency Syndrome (AIDS) (see page 1, lines 5-10) comprising heterocyclic-derived radicals nitrogen, such as pyrrolidine or piperidine (see page 5, lines 1-28). These compounds differ from the compounds of the invention of formula (I) in that the spacer comprises methylene groups, rather than ethylene. Document D02 discloses a series of antagonist molecules of the CXC-chemokine 4 (CXCR4) receptor with anti-HIV activity (see page 385, summary), among which are various monoamides of benzoic acid of general formula IX, which have its structure different amine groups, some of them cyclic, such as compounds 39-53 (see page 396, figure 12; page 397, figure 13). This document also discloses other CXCR4 representative antagonists, such as monocyclams and polyamines (compounds 16-22) and tetrahydroquinolines derivatives of general formula III (see page 391, figure 7; page 392, figure 8). Document D03 also discloses HIV co-receptor inhibitors useful for the treatment of type 1 immunodeficiency virus (see page 216, summary), with varied structures, some of which possess cyclic amines as substituents (see page 218, figure one). The document also discloses CXCR4 antagonists of the bicyclic type, such as AMD3100, which contains a phenylenedimethylene spacer (see page 220, figure 2). Document D04 discloses CXCR4 antagonist compounds that are used in effective combinations in chemotherapy (see page 6, lines 30-31), with 1,4-bisphenylenemethylene structure substituted by different amine groups and nitrogen heterocycles, such as the compounds of formula general 1A (see page 38, lines 17-page 39, line 9) and 1E (see page 43, lines 24-33). The cited documents show only the state of the art of the field to which the invention belongs. None of them, taken alone or in combination with the others, disclose or contain any suggestion that could direct the person skilled in the art towards the compounds of the invention (I), which has a bisphenylenethylene group and two pyrrolidinyl or piperidinyl substituents (independent claim 1) and (V), bisamide precursor to (I) (independent claim 9); and therefore, neither towards a procedure for obtaining (I) that passes through (V) (independent claim 8); nor to the use of (I) for the preparation of a medicament for the treatment of AIDS (independent claim 12). Therefore, it is considered that the object of claims 1-13 meets the requirements of novelty and inventive activity set forth in Articles 6.1 and 8.1 of the Patent Law. State of the Art Report Page 4/4