ES2370986A1 - Novel cxcr4 inhibitors as anti-hiv agents - Google Patents

Abstract

The invention relates to compounds having formula (I), and the pharmaceutically acceptable salts and hydrates and solvates of same, and to the use thereof as anti-HIV agents in the treatment of Acquired Immune Deficiency Syndrome (AIDS). The invention also relates to a method for obtaining same, to the synthesis intermediates used in said method, and to a method for the treatment of AIDS by means of the administration of said compounds.

Description

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New CXCR4 inhibitors as agents anti-HIV

Technical field

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

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State of the art

In the fight against the Syndrome of Acquired Immunodeficiency (AIDS) the main targets Therapeutics include all phases of the biological cycle of the Virus of Human Immunodeficiency (HIV), in order to block, decrease or cancel each of the key stages of the cycle HIV replicative. One of the main difficulties in the antiretroviral treatment is the great mutability linked to the great virus replication power, which allows it to become resistant to the drugs used to treat it. Another difficulty lies in side effects on the host, so that, for avoid them, drugs must be specific against enzymes or viral proteins

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

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

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 they are becoming the next generation of agents anti-HIV Among the compounds under study are they find BMS-488043 that joins the gp120 of the HIV-1 preventing you from recognizing the CD4 receptor, AMD070 that acts as a specific inhibitor of the CXCR4 correceptor, GW-873140, UK-427857 and SCH-D 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 receiving 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 Defic 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).

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

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

Object of the invention

The present invention relates to new compounds of formula (I) and their use as agents anti-HIV in the treatment of Acquired Immunodeficiency (AIDS), the process for obtaining it and the synthesis intermediates used in it.

The inventors have found that the compounds of formula (I) are potent inhibitors of the cytopathic effect HIV-induced while presenting an effect moderate cytotoxic so they have a good window therapy.

Description of the invention

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

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

G1 is selected from a) atoms of hydrogen, b) C 1 -C 12 alkyl groups optionally substituted with 1 to 3 halogen atoms and / or groups C 1 -C 6 alkoxy, c) groups C 6 -C 14 aryl optionally substituted with 1 to 4 halogen atoms, aryl groups and / or C 1 -C 6 alkoxy, d) groups C 1 -C 6 alkoxy and e) halogen atoms;

G 2 represents a pyrrolidinyl group or piperidinyl linked by its nitrogen atom to the chain of methylenes and that may or may not be substituted with an alkyl group C_ {1} -C_ {{}},

or pharmaceutically salts and / or solvates Acceptable of them.

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The term "C_ {6} -C_ {14} aryl "refers to aromatic cycles of between 6 and 14 members that do not include heteroatoms, optionally substituted and that they can be monocyclic or polycyclic such as phenyl, naphthyl, anthranyl and phenanthryl, with phenyl being especially preferred. From preferred mode aryl groups have up to 4 equal substituents or different. Preferred substituents of aryl groups are halogen atoms and alkoxy groups.

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

The term "halogen" means that means a substituent selected from fluorine, chlorine, bromine and iodine

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

For example, pharmaceutically salts Acceptable of the compounds previously described herein document are synthesized from the previously described compound which contains a basic or acid unit by chemical methods conventional. Such salts are generally prepared, for example, by reacting the acidic or basic forms free of these compounds with a stoichiometric amount of the base or acid suitable in water or in an organic solvent or in a mixture of both of them. Non-aqueous media, such as ether, are generally preferred. tetrahydrofuran, ethyl acetate, ethanol, isopropanol or acetonitrile 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 salts inorganic such as sodium, potassium, calcium, ammonium, magnesium, aluminum and lithium, for example, and organic alkaline salts such like ethylenediamine, ethanolamine, N, N-dialkylene ethanolamine, glucamine and salts of basic amino acids for example.

According to this invention, the term "solvate" It is understood to mean any form of a compound of the invention that has another molecule attached to it through linkage not covalent Examples of solvates include hydrates and alcoholates, for example methanolate or solvates with chloroform.

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

Salts and solvates can be prepared by of 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 salts, solvates or prodrugs pharmaceutically acceptable.

The compounds of formula (I) or their salts or solvates are preferably in pharmaceutically acceptable form or in substantially pure form. A form pharmaceutically acceptable is understood, among other things, as having a level of pharmaceutically acceptable purity, excluding additives normal pharmacists such as diluents and excipients and without include any material that is considered toxic at levels of normal dosage. 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, is greater than 95% of the compound of formula (I), or 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 centers chiral The enantiomers, individual diastereoisomers and mixtures thereof are within the scope of the present invention.

In an embodiment of the present invention G1 is selected from a) hydrogen atoms, b) groups C 1 -C 12 unsubstituted alkyl c) groups C 6 -C 14 aryl unsubstituted, d) groups C 1 -C 6 alkoxy and e) halogen atoms.

In another embodiment of the present invention G1 is hydrogen.

In an embodiment of the present invention m It has a value of 2 or 3, preferably 3.

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

Preferred compounds of formula (I) according to the The present invention is 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 described a process for the preparation of a compound of formula (I):

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in which m, G1 and G2 they have the meanings described above consisting of a) treat a dichloride derivative of Optionally substituted 1,4-benzenediacetyl of formula (III)

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with a primary amine of formula (IV)

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to get 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 such as shown in Schemes 1 to 3 where the variables G1, G 2 and m are selected so that the corresponding substituents do not include any combination that makes them inoperative the processes of Schemes 1 to 3. All starting products they are commercially available or can be obtained from Commercially affordable products by experienced staff. The compounds of general formula (I) can be prepared according to the Scheme 1:

Scheme one

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First the acid derivative 1,4-benzenediacetic (II) becomes derivative of benzenediacetyl dichloride (III) and this is condensed with a primary amine (IV) of formula G 2 - (CH 2) m -NH 2 to give the corresponding amide (V). In a final stage we proceed to the reduction of the carbonyl group of the amide (V) to provide the compounds of the invention (I).

The acid derivative conversion 1,4-benzenediacetic (II) dichloride derivative of benzenediacetyl (III) can be carried out by means of agents chlorants, preferably by the action of hexamethyldisilazane optionally in the presence of amounts trimethylchlorosilane catalysts in such an organic solvent such as 1,2-dichloroethane in a nitrogen atmosphere to give a trimethylsilylated intermediate that is reacted with oxalyl chloride in an organic solvent such as methylene

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

In a last stage the amide is reduced by a reducing agent such as the complex of dimethyl borane sulphide in an organic solvent such as tetrahydrofuran.

Pharmaceutically acceptable salts, hydrates and solvates of the compounds of formula (I) of the present invention they can be obtained by experienced personnel from products of Commercially available item.

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

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in which m, G1 and G2 they 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 the use of the compounds of formula (I) as medicaments, in particular in the treatment of immunodeficiency syndrome Acquired (AIDS).

It is also an aspect of the present invention the use of the compounds of formula (I) to prepare a medication, in particular a medication intended for treatment of Acquired Immunodeficiency 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 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 EC 50 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 The present invention generally has EC50 <0.6 \ mug / mL. Four of the compounds tested have presented a EC_50 = <0.1 µg / mL.

Without further elaboration, it is considered that a Experienced person can, using the preceding description, use the present invention to its full extent. Then, for a better understanding of the present invention, without having to be construed as limitations to it, the following examples:

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Examples

Example one

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

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An acid mixture was refluxed 1,4-benzenediacetic (2.0 g, 10.30 mmol), hexamethyldisilazane (HMDS) (2.86 ml, 20.60 mmol) and trimethylchlorosilane (12 drops) in 1,2-dichloroethane dry (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 CH 2 Cl 2 (20 ml) and anhydrous DMF (4 drops), was added dropwise oxalyl (1.86 ml, 21.86 mmol) at the solution at 0 ° C, the solution for 1 h at this temperature under N2 and for 1 h at room temperature before removing the solvent under pressure reduced The residual material was dichloride of 1,4-benzenediacetyl. CH 2 Cl 2 was added anhydrous (28 ml) to the flask and cooled to 0 ° C. They were added 1- (3-amino-propyl) pyrrolidine (2.68 ml, 20.60 mmol) and triethylamine (TEA) (3.20 ml, 22.96 mmol). Be stirred the solution for 16 hours at low room temperature N_ {2}. A solution of K2CO3 (25%) was added (40 ml) 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 dried concentrated. Purification of the residue by chromatography ultrafast (silica, 75: 25: 2, CH2Cl2 / MeOH / NH3) provided 2.43 g (5.84 mmol, 57%) of N, N'-bis (3-pyrrolidin-1-yl) propyl) -1,4-di (aminocarbonylmethyl) -benzene as a white solid, m.p. 160-161 ° C.

Spectroscopic data

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

13 C-NMR (100.6 MHz, CDCl 3): 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 Csp 2 -H), 2962, 2874, 2791 (t Csp 3 -H), 1642 (t C = O), 1562 (δ NH).

MS (70 eV, EI): m / z (%) = 414.2 (16) [M] +, 330.1 (32) [M-C 5 H 10 N] +}, 274.0 (10) [M-C 8 H 16 N 2] +, 260.0 (43) [M-C 9 H 18 N 2 }] +, 97.9 (31) [C 6 H 12 N] +, 83.9 (100) [C 5 H 10 N] +, 69, 9 (29) [C 4 H 8 N] +.

HRMS (70 eV, EI): m / z calculated for C 24 H 38 N 4 O 2: 414.2995, [M] +; Found: 414.2992.

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

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The borane dimethyl sulphide complex was added (1.19 ml, 11.89 mmol) at 0 ° C at 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). He underwent reflux the solution for 6 h under N2, cooled to temperature ambient, diluted with 7.5 ml of 1.25 M MeOH / HCl solution and refluxed for 1 h. The solvent was removed in vacuo and diluted the crude material with a solution of 1 M NaOH (pH 14). Be extracted the aqueous solution twice with CH2Cl2, dried over MgSO4 and concentrated. The purification of the residue by flash chromatography (basic alumina, CH 2 Cl 2 -MeOH; from 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, m.p. 60-62 ° C.

Spectroscopic data

1 H-NMR (400 MHz, CDCl 3): δ (ppm) : 7.13 (s, 4H, C1-H), 2.87 (m, 4H, C4-H), 2 , 77 (m, 4H, C3-H), 2.68 (t, 3 J = 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, 3 J = 7.1 Hz, 4H, C6-H) .

13 C-NMR (100.6 MHz, CDCl 3): 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): nu (cm -1) : 32 63 (t NH), 2948, 2801 (t Csp 3 -H), 1697 (δ NH), 1458 (f Csp ^ 3} -H), 887 (δ NH).

MS (70 eV, EI): m / z (%) = 386.4 (2) [M] +, 302.2 (4) [M-C 5 H 10 N] ^ { +}, 274.2 (8) [M-C 7 H 14 N] +, 141.1 (47) [C 8 H 17
N 2] +, 112.1 (9) [C 7 H 14 N] +, 98.1 (11) [C 6 H 12 N] ^ {+}, 84.1 (100) [C 5 H 10 N] +, 70.1 (8) [C 4 H 8 N] +.

HRMS (70 eV, EI): m / z calculated for C 24 H 42 N 4: 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

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The procedure was the same as established previously for N, N'-bis (3-pyrrolidin-1-yl) propyl) -1,4-di (aminocarbonylmethyl) benzene, but it was carried out using acid 1,4-benzenediacetic (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 (ASD) (3.20 ml, 22.96 mmol). Behind the removal of the solvent, the residue was separated by flash chromatography (silica, 75: 25: 2, CH 2 Cl 2 / MeOH / NH 3) 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, m.p. 194-196 ° C.

Spectroscopic data

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

13 C-NMR (100.6 MHz, CDCl 3): 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 Csp 2 -H), 2964, 2939, 2872, 2800 (t Csp 3 -H ), 1648 (t C = O), 1549 (δ NH).

Anal. : calculated for C 22 H 34 N 4 O 2: 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-C 8 H 16 N 2] ] +, 84.1 (100) [C 5 H 10 N] +, 70.1 (2) [C 4 H 8 N] +.

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

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The procedure was the same as established formerly for N, N'-bis (3- (pyrrolidin-1-yl) propyl) -1,4-bis (2-aminoet-1-yl) benzene, but it was carried out using the borane dimethylsulfide 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), MeOH / 1.25 M HCl (9 ml). After removal of the solvent, the residue was separated by flash chromatography (basic alumina, CH 2 Cl 2 -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 Like a yellow oil

Spectroscopic data

1 H-NMR (400 MHz, CDCl 3): 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, 3 J = 6.5 Hz, 4H, C6-H), 2.49 (m, 8H, C7- H), 2.17 (sa, 2H, NH), 1.75 (m, 8H, C8-H).

13 C-NMR (100.6 MHz, CDCl 3): 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): nu (cm -1) : 3305 (t NH), 2929, 2875, 2796 (t Csp 3 -H), 1673 (δ NH), 1458 (f Csp ^ {3} -H).

MS (FAB): m / z (%) = 359.3 (100) [M + H] +, 358.3 (14) [M] +, 288.3 (4) [M -C 4 H 8 N] +, 274.3 (12) [M-C 5 H 10 N] +, 231.1 (37) [M-C_ {7} H 15 N 2] +, 127.1 (15) [C 7 H 15 N 2] +.

HRMS (FAB): m / z calculated for C 22 H 39 N 4: 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

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The procedure was the same as established previously for N, N'-bis (3-pyrrolidin-1-yl) propyl) -1,4-di (aminocarbonylmethyl) benzene, but it was carried out using acid 1,4-benzenediacetic (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 mmoles). After removal of the solvent, the residue was separated by flash chromatography (silica, 75: 25: 2, CH 2 Cl 2 / MeOH / NH 3) 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, m.p. 119-120 ° C.

Spectroscopic data

1 H-NMR (400 MHz, CDCl 3): 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, 3 J = 6.3 Hz, 6H, C13-H).

13 C-NMR (100.6 MHz, CDCl 3): 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 Csp 2 -H), 2926, 2858, 2787, 2729 (t Csp 3 -H ), 1648 (t C = O), 1546 (δ NH).

\hbox{[C _{7} H _{14} N] ^{+} .}

MS (70 eV, EI): m / z (%) = 470.4 (6) [M] +, 455.4 (20) [M-CH 3] +, 358, 3 (8) [M-C 7 H 14 N] +, 112.1 (100)

 ? {[C 7 H 14 N] +.} 

HRMS (70 eV, EI): m / z calculated for C 28 H 46 N 4 O 2: 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

fifteen

The procedure was the same as established previously for N, N'-bis (3- (pyrrolidin-1-yl) propyl) -1,4-bis (2-aminoet-1-yl) benzene, but it was carried out using the borane dimethylsulfide 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), MeOH / HCl 1.25 M (7.5 ml) After removal of the solvent, the residue was separated by flash chromatography (basic alumina, CH 2 Cl 2 -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 Like an orange oil

Spectroscopic data

1 H-NMR (400 MHz, CDCl 3): 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, 3 J = 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, 3 J = 6.2 Hz, 6H, C13-H).

13 C-NMR (100.6 MHz, CDCl 3): 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): nu (cm -1) : 3280 (t NH), 2930, 2854, 2794 (t Csp 3 -H), 1655 (δ NH), 1449, 1372 (f Csp3 -H).

MS (70 eV, EI): m / z (%) = 442.4 (3) [M] +, 330.3 (9) [M-C 7 H 14 N] +}, 302.3 (18) [M-C 9 H 16 N] +, 169.2 (97) [C 10 H 21]
N 2] +, 140.1 (7) [C 9 H 18 N] +, 126.1 (13) [C 8 H 16 N] {+}, 112.1 (100) [C 7 H 14 N] +, 98.1 (28) [C 6 H 12 N] +.

HRMS (70 eV, EI): m / z calculated for C 28 H 50 N 4: 442.4035, [M] +; Found: 442.4027.

Example 4

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

16

The procedure was the same as established previously for N, N'-bis (3-pyrrolidin-1-yl) propyl) -1,4-di (aminocarbonylmethyl) benzene, but it was carried out using acid 1,4-benzenediacetic (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 (ASD) (3.20 ml, 22.96 mmol). Behind the removal of the solvent, the residue was separated by flash chromatography (silica, 75: 25: 2, CH 2 Cl 2 / MeOH / NH 3) 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, m.p. 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, 3 J = 6.0 Hz, 4H, C5-H), 2.36 (m, 12H, C7-H, C8-H) , 1.64 (quintuple, 3 J = 6.4 Hz, 4H, C6-H), 1.54 (quintuple, 3 J = 5.6 Hz, 8H, C9-H), 1 , 43 (m, 4H, C10-H).

13 C-NMR (100.6 MHz, CDCl 3): 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 Csp 2 -H), 2930, 2850, 2809, 2771 (t Csp 3 -H ), 1640 (t C = O), 1559 (δ
NH).

Anal. : calculated for C 26 H 42 N 4 O 2: 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-C 6 H 12 N] ^ +}, 274.1 (12) [M-C 10 H 20 N 2] +, 98.1 (100) [C 6 H 12 N] + }, 84.0 (5) [C 5 H 10 N] +.

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

17

The procedure was the same as established previously for N, N'-bis (3- (pyrrolidin-1-yl) propyl) -1,4-bis (2-aminoet-1-yl) benzene, but it was carried out using the borane dimethylsulfide 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), THF anhydrous (27 ml), MeOH / HCl 1.25 M (7.5 ml) After removal of the solvent, the residue was separated by flash chromatography (basic alumina, CH 2 Cl 2 -MeOH; from 100: 0 to 90:10 in 18 min.) producing 252.5 mg (0.61 mmol, 61%) of N, N'-bis (3- (piperidin-1-yl) propyl) -1,4-bis (2-aminoet-1-yl) benzene Like a yellow oil

Spectroscopic data

1 H-NMR (400 MHz, CDCl 3): δ (ppm) : 7.13 (s, 4H, C1-H), 2.86 (m, 4H, C4-H), 2 , 77 (m, 4H, C3-H), 2.65 (t, 3 J = 7.0 Hz, 4H, C7-H), 2.31 (m, 12H, C5-H, C8- H), 2.20 (sa, 2H, NH), 1.67 (quintuple, 3 J = 7.0 Hz, 4H, C6-H), 1.54 (m, 8H, C9-H) , 1.42 (m, 4H, C10-H).

13 C-NMR (100.6 MHz, CDCl 3): 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 NH), 2933, 2852, 2801 (t Csp 3 -H), 1676 (δ NH), 1443 (f Csp ^ {3} -H).

MS (70 eV, EI): m / z (%) = 414.4 (1) [M] +, 316.3 (3) [M-C 6 H 12 N] +}, 288.2 (4) [M-C 8 H 16 N] +, 155.2 (60) [C 9 H 19]
N 2] +, 126.1 (6) [C 8 H 16 N] +, 112.1 (9) [C 7 H 14 N] {+}, 98, 1 (100) [C 6 H 12 N] +, 84.1 (5) [C 5 H 10 N] +.

HRMS (70 eV, EI): m / z calculated for C 26 H 46 N 4: 414.3722, [M] +; Found: 414.3710.

Example 5

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

18

The procedure was the same as established previously for N, N'-bis (3-pyrrolidin-1-yl) propyl) -1,4-di (aminocarbonylmethyl) benzene, but it was carried out using acid 1,4-benzenediacetic (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 (ASD) (3.20 ml, 22.96 mmol). Behind the solvent removal, 4.27 g (10.3 mmol, quantitative) of N, N'-bis (2- (piperidin-1-yl) ethyl) -1, 4-di (aminocarbonylmethyl) benzene without further purification as a pale orange solid, m.p. 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, 3 J = 6.0 Hz, 4H, C5-H), 2.34 (t, 3 J = 6.1 Hz, 4H, C6-H), 2.27 (m, 8H, C7-H), 1.42 (m, 12H, C8-H, C9-H).

13 C-NMR (100.6 MHz, CDCl 3): 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 Csp 2 -H), 2924, 2849, 2779, 2751 (t Csp 3 -H ), 1642 (t C = O), 1556 (δ NH).

MS (70 eV, EI): m / z (%) = 414.3 (4) [M] +, 98.1 (100) [C 6 H 12 N] + .

HRMS (70 eV, EI): m / z calculated for C 24 H 38 N 4 O 2: 414.2995, [M] +; Found: 414.2987.

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

19

The procedure was the same as established previously for N, N'-bis (3- (pyrrolidin-1-yl) propyl) -1,4-bis (2-aminoet-1-yl) benzene, but it was carried out using the borane dimethylsulfide 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, CH 2 Cl 2 -MeOH; from 100: 0 to 90:10 in 18 min.) producing 320.4 mg (82.8 mmol, 83%) of N, N'-bis (2- (piperidin-1-yl) ethyl) -1,4-bis (2-aminoet-1-yl) benzene Like a yellow oil

Spectroscopic data

1 H-NMR (400 MHz, CDCl 3): δ (ppm) : 7.14 (s, 4H, C1-H), 2.87 (m, 4H, C4-H), 2 , 78 (m, 4H, C3-H), 2.72 (t, 4H, 3 J = 6.4 Hz, C5-H), 2.42 (t, 4H, 3 J = 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).

13 C-NMR (100.6 MHz, CDCl 3): 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): nu (cm -1) : 3300 (t NH), 2933, 2851, 2801 (t Csp 3 -H), 1678 (δ NH), 1442 (f Csp ^ {3} -H).

MS (FAB): m / z (%) = 387.4 (100) [M + H] +, 386.3 (11) [M] +, 288.3 (11) [M -C 6 H 12 N] +, 141.1 (9) [C 8 H 17 N 2] +, 112.1 (89) [C_ { 7} H 14 N] +.

HRMS (FAB): m / z calculated for C 24 H 38 N 4 O 2: 387.3488, [M + H] +; Found: 387.3496.

Example 6

Evaluation of the inhibition of the cytopathic effect induced by HIV (EC50) and the cytotoxic effect of the compounds of examples 1 to 5

twenty

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) to it time presenting a moderate cytotoxic effect (CC50) per what present a good therapeutic window (CC_ {50} / EC_ {50}).

Claims (13)

1. A compound of formula (I)

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twenty-one

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in which m represents a number integer selected from 2, 3, 4, 5 and 6; G1 is selected from a) atoms of hydrogen, b) C 1 -C 12 alkyl groups optionally substituted with 1 to 3 halogen atoms and / or groups C 1 -C 6 alkoxy, c) groups C 6 -C 14 aryl optionally substituted with 1 to 4 halogen atoms, aryl groups and / or C 1 -C 6 alkoxy, d) groups C 1 -C 6 alkoxy and e) halogen atoms; G 2 represents a pyrrolidinyl group or piperidinyl linked by its nitrogen atom to the chain of methylenes and that may or may not be substituted with an alkyl group C_ {1} -C_ {{}}, or a salt and / or a solvate pharmaceutically acceptable of it.

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2. A compound according to claim 1 in the that G 1 is selected from a) hydrogen atoms, b) groups C 1 -C 12 unsubstituted alkyl c) groups C 6 -C 14 aryl unsubstituted, d) groups C 1 -C 6 alkoxy and e) halogen atoms; 3. A compound according to claim 2 in the that G1 is a hydrogen atom. 4. A compound according to any of the claims 1 to 3 wherein m has the value of 2 or 3. 5. A compound according to claim 4 in the that m has the value of 3. 6. A compound according to any of the claims 1 to 5 wherein G 2 is selected from the group comprising radicals 2-methylpiperidinyl, piperidinyl and pyrrolidinyl 7. A compound according to claim 6 in the that G 2 are 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
from:

to)

treat a dichloride derivative of Optionally substituted 1,4-benzenediacetyl of formula (III)

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22

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with an amine primary formula (IV)

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2. 3

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To obtain the corresponding amide of formula (V)

24

b)

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

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9. A compound of formula (V) 25 in which m represents a number integer selected from 2, 3, 4, 5 and 6; G1 is selected from a) atoms of hydrogen, b) C 1 -C 12 alkyl groups optionally substituted with 1 to 3 halogen atoms and / or groups C 1 -C 6 alkoxy, c) groups C 6 -C 14 aryl optionally substituted with 1 to 4 halogen atoms, aryl groups and / or C 1 -C 6 alkoxy, d) groups C 1 -C 6 alkoxy and e) halogen atoms; G 2 represents a pyrrolidinyl group or piperidinyl linked by its nitrogen atom to the chain of methylenes and that may or may not be substituted with an alkyl group C_ {1} -C_ {{}}, or a salt and / or a solvate thereof.

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10. Compound according to any of the claims 1 to 7 for use as a medicine. 11. Compound according to any of the claims 1 to 7 for use in the treatment of Acquired Immunodeficiency (AIDS). 12. Use of a compound according to any of claims 1 to 7 for preparing a medicament. 13. Use of a compound according to any of claims 1 to 7 for preparing a medicament intended for Acquired Immune Deficiency Syndrome (AIDS) treatment.