Patent Application
20100022769
The present invention relates to compounds of formulae (1), (2) and (3) and to their pharmaceutically acceptable salts, hydrates, solvates, esters and metal complexes of said structures, to their use as anti-HIV agents in the treatment of Acquired Immune Deficiency Syndrome (AIDS), to the process for obtaining them and to the synthesis intermediates used therein.
In the fight against Acquired Immune Deficiency Syndrome (AIDS), the main therapeutic targets include all the phases of the biological cycle of the Human Immunodeficiency Virus (HIV) for the purpose of blocking, reducing or cancelling each of the key steps of the HIV reproductive cycle. One of the main difficulties in antiretroviral treatment is the fast evolution of the virus, which allows it to become resistant to the drugs which are used to treat it. Another difficulty lies in the side effects on the host, such that, to prevent them, the drugs must be specific against the viral proteins or enzymes and not against the reproduction mechanism.
Current antiretroviral therapy consists of combinations of two families of compounds: reverse transcriptase inhibitors (RTI) and protease inhibitors (PI), both aimed at specific enzymes produced by HIV.
The step of binding and fusing the virus to the host cell is an interesting target in chemotherapy against HIV. HIV needs a primary receptor (CD4) and chemokine receptors (CXCR4 or CCR5) as co-receptors to be fused to the cell. Chemokine receptor CXCR4 is a co-receptor for the entry of T-tropic HIV strains whereas CCR5 is a co-receptor for M-tropic strains. Therefore, the compounds which interact with the entry co-receptors could be good possible drugs against the entry of HIV.
Small chemokine receptor inhibitor molecules have been identified (Moore et al., Nat Rev Mol Cell Biol, 2000, 1, 40). The agents which block CXCR4 include small peptides such as Allelix-40-4C, T22 and analogs thereof (Doranz et al., J Exp Med, 1997, 186, 1395; 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 bicyclams (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). Several compounds such as Tak 779, the new derivative of spiro diketopiperazine 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 to be effective in blocking the function of CCR5 and the replication of HIV (Strizki et al., Proc Natl Acad Sci USA, 2001, 98, 12718). It has also been described that gp41 peptides, such as T-20, inhibit the replication of HIV.
HIV fusion inhibitors are becoming the next generation of anti-HIV agents. The compounds under study include BMS-488043 which binds to the gp120 of HIV-1 preventing it from recognizing the receptor CD4, AMD070 which acts as a specific inhibitor of the co-receptor CXCR4, GW-873140, UK-427857 and SCH-D which are antagonists of the co-receptor CCR5.
An antagonist of CXCR4, tAMD3100 reduces by 0.8-0.9 log 10 the viral load in a subject infected with a X4 strain of HIV. The virus recovered from patients who received AMD3100 showed a change in phenotype from X4 virus to R5 virus, suggesting that AMD3100 selectively blocked those viruses using CXCR4 but that it was not effective in inhibiting the in vivo CCR5-dependent replication of HIV (Schols et al., 9th CROI, Seattle 2002). The development of AMD3100 was abandoned in 2001 due to a possible cardiac toxicity (Hendrix et al., Antimicrob Agents Chemother, 2000, 44, 1667; Hendrix et al., J Acquir Immune Defic Syndr, 2004, 37, 1253), furthermore its lack of oral bioavailability related to its high positive charge in physiological medium could have 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, bicyclams in general and AMD3100 in particular seem to be the most active. Even so, compounds with a single cyclam unit and with the spacer 1,4-phenylenebismethylene 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 set out to obtain compounds in which both cyclam rings, too basic and possibly responsible for the toxicity observed in AMD3100, are substituted by other nitrogenated cyclic or heterocyclic systems with lower basicity and, therefore, with lower toxicity but maintaining their activity as inhibitors of the entry co-receptors CXCR4 and CCR5.
For the purpose of maintaining the benzyl nitrogen of both sides of the p-phenylene unit and the nitrogen of the selected nitrogenated heterocyclic systems at a distance similar to that existing in AMD3100, compounds containing a spacer —(CH2)n— (n=0, 2, 3, 4, 5, 6) between said benzyl nitrogens and the nitrogenated heterocyclic systems were designed. The latter could be bound to said spacer chain both by the nitrogen and by a ring carbon.
A literature search revealed that any system with these characteristics had been previously synthetized in a polymer chemistry environment as catalysts (Habaue et al. J. Polym. Sci., Part A: Polym. Chem. 2005, 43(8), 1635-1640) or as ligands for metal complexes (Habagami et al., Jpn. Kokai Tokkyo Koho JP 2005314274 (2005)).
Consequently, virtual chemical libraries of structures of formula (1), (2) and (3) were designed and constructed, and selected by means of an “in silico” test on suitably modeled receptors CXCR4 and CCR5.
Surprisingly, the tested and synthesized compounds generally have an EC50<10 μg/mL in an anti-HIV test in MT-4 cells, the CC50 values generally being greater than 25 μg/mL, proving the validity of the hypothesis.
The present invention relates to compounds of formulae (1), (2) and (3) and to the use thereof as anti-HIV agents in the treatment of Acquired Immune Deficiency Syndrome (AIDS), to the process for obtaining them and to the synthesis intermediates used therein.
The compounds object of the present invention are selected from the formulae (1), (2) and (3) described below.
The compounds of formula (1) have the following structure:
wherein:
The term “nitrogenated heterocyclic system” means an aromatic or non-aromatic monocyclic or polycyclic system containing between 5 and 24 atoms of which between 1 and 4 are nitrogen atoms and between 0 and 4 are oxygen atoms. Preferred compounds among the compounds of formula (1) of the present invention are those in which the nitrogenated heterocyclic system bonded by nitrogen or by one of the ring carbons is selected from among: pyrrolidine, piperazine, piperidine, morpholine, azacycloheptane, diazacycloheptane, azacyclotridecane, diazacyclooctane, pyrrole, imidazole, thiazole, prazole, pyridine, pyrimidine.
The term “substituted nitrogenated heterocyclic system” means any of the previous nitrogenated heterocyclic systems substituted by one or several C1-C12 alkyl chains in the ring carbons or in the ring nitrogens if these are not bound to the —(CH2)n— chain or to the —(CH2)m— chain. Preferred compounds among the compounds of formula (1) of the present invention are those in which the substituted nitrogenated heterocyclic system bonded by nitrogen or by one of the ring carbons is preferably selected from among: 2-methylpiperidine, 2,6-dimethylpiperidine and 4-methylpiperazine.
The term “C3-C12 aryl”, when it represents the R1 and R2 groups in NR1R2, means an aromatic monocyclic or polycyclic system containing between 3 and 12 atoms and optionally containing between one and three heteroatoms. Preferred compounds among the compounds of formula (1) of the present invention are those in which the C3-C12 aryl system is selected from among: phenyl, pyrrole, thiazole, pyrazole, imidazole, pyridine, pyrimidine.
The term “C1-C12 alkyl” and “substituted alkyl” means any linear or branched, saturated or unsaturated hydrocarbon chain containing between C1-C12 carbon atoms. Examples of alkyl substituents used herein are: —CH3, —CH2—CH3, —CH2—CH2—CH3, —CH(CH3)2, —C(CH3)3, —(CH2)3—CH3, —CH2—CH(CH3)2, —CH(CH3)—CH2—CH3 and —CH═CH2.
The term “cycloalkyl” means any saturated or unsaturated, monocyclic or polycyclic hydrocarbon system containing between C3-C12 carbon atoms. Examples of cycloalkyl and substituted cycloalkyl used herein are: cyclohexyl, cyclopentyl, 4-methylcyclohexyl, 4-methoxycyclohexyl, 4-carboxycyclohexyl.
The term “heteroatom” means oxygen, nitrogen or sulfur.
The term “halogen” means a substituent selected from among fluorine, chlorine, bromine and iodine.
The compounds of the formula (2) have the following structure:
wherein:
The compounds of formula (2) can be used as precursors of the compounds of formula (1).
The compounds of the formula (3) have the following structure:
wherein:
The compounds of formula (3) can be used as precursors of the compounds of formula (1).
Preferred compounds of formula (1) useful in the present invention are selected from the group including:
Preferred compounds of formula (2) useful in the present invention are selected from the group including:
Preferred compounds of formula (3) useful in the present invention are selected from the group including:
The compounds of formulae (1), (2) and (3) are prepared as shown in Schemes 1 to 3, wherein the variables Z, Y, n, m, and X are selected such that the corresponding substituents do not include any combination which renders the processes of Schemes 1 to 3 inoperative. All the starting products are commercially available or can be obtained from commercially available products by skilled personnel.
The compounds of general formula (1) can be prepared according to Scheme 1:
The reductive amination of a dialkoxymethylbenzaldehyde of general structure (4), wherein the term “alkoxy” means -Oalkyl such as the alkyl which has been defined previously, with an amino derivative of general structure NH2—(CH2)n—Y (n≧2 if the system Y is bonded by nitrogen) in the presence of a reducing agent, preferably sodium borohydride or sodium cyanoborohydride, to yield, through the monoimine (5), the intermediate acetal of formula (6). Alternatively, it is possible to isolate the monoimine (5) upon treating the compound (4) with the amine NH2—(CH2)n—Y in the presence of a dehydrating agent, preferably molecular sieves. The deprotection of the acetal of (6), for example in aqueous acid medium with 2 M hydrochloric acid, yields the aldehyde (7). The treatment of (7) with the corresponding amino derivative of general formula NH2—(CH2)m-Z (m≧2 if the system Z is bonded by nitrogen) in the presence of a reducing agent, preferably sodium borohydride or sodium cyanoborohydride, leads to the final symmetrical (if Z=Y and m=n) or asymmetric diamine system (1). Alternatively, it is possible to obtain by treatment of (7) with the corresponding amino derivative NH2—(CH2)m-Z, in the presence of a dehydrating agent, the monoimines (2), compounds which are also object of the present invention, which, if desired, can subsequently be reduced to the corresponding compound of formula (1). It is also possible to obtain the aldehyde (8) starting from the monoimine (5), by the deprotection of the acetal group, which aldehyde treated with an amino derivative of general structure NH2—(CH2)m-Z in the presence of a dehydrating agent, preferably molecular sieves, yields the diimines (3), compounds which are also object the present invention, which, if desired, can subsequently be reduced to the corresponding compound of formula (1).
In the specific case of compounds (1a), (1) wherein X═H and the substituents —CH2—NH—(CH2)m-Z and —CH2—NH—(CH2)n—Y are para to one another, the starting compound 4 could correspond to the commercial product 4-(diethoxymethyl)benzaldehyde (4a).
The compounds of formula (1b), (1) wherein Y=Z and m=n, can be prepared by methods similar to those described in Scheme 1 or in Scheme 2.
Thus, the treatment of a dialdehyde of general structure (9) with an amino derivative of general structure NH2—(CH2)m-Z in the presence of a reducing agent, preferably sodium borohydride or sodium cyanoborohydride, yields a symmetrical compound of formula (1b). Said compound (1b) is also accessible by treatment of (9) with an amino derivative of general structure NH2—(CH2)m-Z in the presence of a dehydrating agent, preferably molecular sieves, to yield the symmetrical diimine (3b), which is reduced to the diamine (1b) with the same type of reducing agent.
In the specific case of compounds (1c), (1) wherein X═H, Y=Z, m=n and the substituents —CH2—NH—(CH2)m-Z are para to one another, the starting compound (9) could correspond to the commercial product terephthaldehyde (9a).
The compounds of general formula (2), which can also be obtained according to Scheme 1, are also an object of the present invention. In the specific case of compounds (2a), (2) wherein X═H and the substituents —CH2—NH—(CH2)m-Z and —CH2—NH—(CH2)n—Y are para to one another, the starting compound (4) could correspond to the commercial product 4-(diethoxymethyl)benzaldehyde (4a).
The compounds of general formula (3), which can also be obtained according to Scheme 1, are also an object of the present invention. In the specific case of compounds (3b), (3) wherein m=n and Z=Y, these compounds can be obtained according to Scheme 1 or Scheme 2.
In the specific case of compounds (3c), (3) wherein X═H, Y=Z, m=n and the substituents —CH2—NH—(CH2)m-Z are para to one another, the starting compound (9) could correspond to the commercial product terephthaldehyde (9a).
In the specific case of compounds (3d), (3) wherein n=0 and Y is bonded by nitrogen, these compounds can also be obtained according to Scheme 3 by treatment of a dialdehyde (9) with a hydrazine NH2—Y in the presence of a dehydrating agent to yield the aldehyde (10). The treatment of (10) with an amino derivative of formula NH2—(CH2)m-Z in the presence of a dehydrating agent yields (3d).
In the specific case of compounds (3d) in which the system NH2—(CH2)m-Z used has not been a hydrazine (m≧2 if Z is bonded by nitrogen), the subsequent treatment with a reducing agent yields compounds (2d). It should be emphasized that (2d) can be obtained from (10) in situ without isolating (3d) by treatment with the amino derivative of general structure NH2—(CH2)m-Z in the presence of a reducing agent.
In the specific case of compounds (3e), (3) wherein n=0, X═H and the substituents are para to one another, the starting compound (9) would correspond to terephthaldehyde (9a).
Finally, the compounds (1), (2) and (3) in which X represents hydrogen and both substituents are meta to one another, can be prepared by skilled personnel from isophthaldehyde (11) and from 3-(diethoxymethyl)benzaldehyde (12), both compounds being commercially available, by means of processes similar to those described in Schemes 1 to 3.
The pharmaceutically acceptable salts, hydrates, solvates, esters and metal complexes of the compounds of formula (1), (2) and (3) object of the present invention can be obtained from skilled personnel from commercially available starting products.
The biological activity as anti-HIV agents of the compounds of formula (1), (2) and (3) object of the present invention has been demonstrated by means of the following in vitro test.
The assay for evaluating the anti-HIV activity of compounds is based on determining cell viability by the methyl-thiazole-tetrazolium (MTT) reduction method. The in vitro assays consist of culturing for MT-4 lymphoid cells for 5 days in the presence of serial dilutions of the compounds to be tested in the presence or absence of virus. The culture of cells and compound alone allows determining the CC50 or cytotoxic concentration 50, the 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 evaluating the EC50 or effective concentration 50, the concentration at which the compound inhibits 50% of the cytopathic effect induced by HIV. The anti-HIV activity of compounds with known activity is evaluated in each assay to validate the assay.
The compounds of formula (1), (2) and (3) object of the present invention generally have an EC50<10 μg/mL. Three of the assayed compounds have shown an EC50<0.05 μg/mL. The CC50 values are generally greater than 25 μg/mL.
Without going into further detail, it is considered that a skilled person can, using the previous description, use the present invention in its entire depth. The following examples are set forth below in order to better understand the invention, but must not be considered as limitations thereto:
The amino derivatives of general formulae NH2—(CH2)n—Y and NH2—(CH2)m-Z used are shown in FIG. 1. The numbering of the compounds (1), (2) and (3) follows the format 1{amino derivative Z, amino derivative Y}.
0.61 g (4.5 mmol) of terephthaldehyde (9a) and 1.04 g (9.0 mmol) of 2-(pyrrolidin-1-yl)ethylamine 5{1} (m=2, Z=pyrrolidin-1-yl) are dissolved in 30 mL of anhydrous MeOH. Molecular sieve (4 Å) is added and it is stirred at reflux temperature under a nitrogen atmosphere for 24 h. The molecular sieve is filtered and 0.34 g (9.0 mmol) of NaBH4 are added. It is allowed to react at room temperature for 16 h. After this time water is added and it is extracted with CH2Cl2. The organic phase is washed with brine and dried on anhydrous MgSO4. The solvent is eliminated under reduced pressure and 1.32 g (4.0 mmol, 89%) of a yellow oil 1{1,1} are obtained. IR (film): ν (cm−1) 3310, 2962, 2928, 2874, 2794, 1485, 1444, 775. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.27 (s, 4H, Ph), 3.79 (s, 4H, CH2-Ph), 2.73 (t, 4H, J=6.0 Hz, CH2—N), 2.59 (t, 4H, J=6.0 Hz, CH2—N), 2.47 (m, 8H, CH2—N), 2.20 (bs, 2H, NH), 1.75 (m, 8H, J=3.3 Hz, CH2). 13C-NMR (75 MHz, CDCl3): δ (ppm) 138.8, 128.0, 55.9, 54.2, 53.8, 47.8, 23.5. MS (FAB): m/z 331.3 [M+1H]+, 330.3, 84.0. HRMS: Calculated for C20H35N4: 331.2862 [M+1H]+. Obtained: 331.2867.
As for 1{1,1}, but using 0.75 g (5.5 mmol) of terephthaldehyde (9a), 1.47 g (11.1 mmol) of 3-(pyrrolidin-1-yl)propan-1-amine {2} and 0.43 g (11.1 mmol) of NaBH4. 1.98 g (5.5 mmol, 99%) of a yellow oil 1{2,2} are obtained. IR (CHCl3 evaporated film): □ ν(cm−1) 3282, 2936, 2789, 1458. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.26 (s, 4H, Ph), 3.77 (s, 4H, CH2-Ph), 2.69 (t, 4H, J=7.0 Hz, CH2—N), 2.49 (m, 12H, CH2—N), 2.08 (bs, 2H, NH), 1.75 (m, 12H, CH2). 13C-NMR (75 MHz, CDCl3): δ (ppm) 138.5, 128.0, 54.6, 54.1, 53.5, 47.9, 28.8, 23.4. MS (IE): m/z 359.2 [M+1H]+, 231.0, 230.0, 127.0, 98.0, 84.0. HRMS: Calculated for C22H39N4: 359.3175. Obtained: 359.3169.
As for 1{1,1}, but using 0.54 g (3.9 mmol) of terephthaldehyde (9a), 1.00 g (7.8 mmol) of 3-(1H-imidazol-1-yl)propan-1-amine {3} and 0.30 g (7.8 mmol) of NaBH4. 1.38 g (3.9 mmol, 100%) of a yellow oil 1{3,3} are obtained. IR (CHCl3 evaporated film): □ ν (cm−1) 3277, 3103, 2935, 2815, 1508, 1453. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.41 (s, 2H, N═CH), 7.26 (s, 4H, Ph), 7.02 (s, 2H, CH), 6.88 (s, 2H, CH), 4.04 (t, 4H, J=6.9 Hz, CH2—N), 3.74 (s, 4H, CH2-Ph), 2.60 (t, 4H, J=6.9 Hz, CH2—N), 2.05 (s, 2H, NH), 1.92 (m, 4H, 6.9 Hz, CH2). 13C-NMR (75 MHz, CDCl3): δ (ppm) 138.8, 137.1, 129.2, 128.2, 118.7, 53.6, 45.6, 44.6, 31.3. MS (IE): m/z 353.0 [M+1H]+, 260.0, 228.9, 138.0, 81.0. HRMS: Calculated for C20H28N6: 352.2454 [M+1H]+. Obtained: 353.2448.
As for 1{1,1}, but using 0.29 g (2.1 mmol) of terephthaldehyde (9a), 0.56 g (4.3 mmol) of 2-(piperidin-1-yl)ethylamine {4} and 0.16 g (4.3 mmol) of NaBH4. 0.76 g (2.1 mmol, 100%) of a yellow oil 1{4,4} are obtained. IR (CHCl3 evaporated film (cm−1) 3310. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.32 (s, 4H, Ph), 3.75 (s, 4H, CH2-Ph), 2.69 (t, J=7.0 Hz, 4H, CH2—N), 2.47 (t, J=7.0 Hz, 4H, CH2—N), 2.39 (m, 8H, CH2—N), 1.62-1.39 (m, 12H, CH2). 13C-NMR (75.5 MHz, CDCl3): δ (ppm) 139.4, 129.6, 55.7, 59.0, 54.1, 46.1, 26.7, 25.2. Anal. Calculated for C22H38N4: C, 73.69%, H, 10.68%, N, 15.63%. Obtained: C, 73.78%, H, 10.56%, N, 15.45%.
As for 1{1,1}, but using 0.43 g (3.2 mmol) of terephthaldehyde (9a), 1.04 g (6.4 mmol) of 3-(2-methylpiperidin-1-yl)propan-1-amine {5} and 0.25 g (6.4 mmol) of NaBH4. 1.33 g (3.2 mmol, 100%) of a pale brown oil 1{5,5} are obtained. IR (CHCl3 evaporated film): ν (□cm−1) 3282, 2929, 2854, 2793, 1449, 1372. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.27 (s, 4H, Ph), 3.77 (s, 4H, CH2-Ph), 2.87 (m, 2H, CH), 2.73 (m, 2H, CH2), 2.63 (t, 4H, J=6.8 Hz, CH2), 2.36 (m, 2H, CH2), 2.26 (m, 2H, CH2), 2.14 (bs, 2H, NH), 2.11 (m, 2H, CH2), 1.73-1.44 (m, 12H, CH2), 1.27 (m, 4H, CH2), 1.05 (d, 6H, J=6.3 Hz, CH3). 13C-NMR (75 MHz, CDCl3): δ (ppm) 138.8, 128.0, 55.9, 53.7, 52.3, 52.1, 48.3, 34.7, 26.2, 25.7, 24.0, 19.1. MS (IE): m/z 415.4 [M+1H]+, 112.1. Anal. Calculated for C26H46N4: C, 75.31%, H, 11.18%, N, 13.51%. Obtained: C, 75.21%, H, 10.92%, N, 13.48%.
As for 1{1,1}, but using 0.48 g (3.5 mmol) of terephthaldehyde (9a), 1.14 g (7.0 mmol) of 3-(4-methylpiperazin-1-yl)propan-1-amine {6} and 0.27 g (7.0 mmol) of NaBH4. 1.28 g (3.1 mmol, 87%) of a brown oil 1{6,6} are obtained. IR (CHCl3 evaporated film): ν (□cm−1) 3281, 2935, 2793, 1458. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.26 (s, 4H, Ph), 3.76 (s, 4H, CH2-Ph), 2.66 (t, 4H, J=6.9 Hz, CH2—N), 2.42 (m, 22H, CH2, NH), 2.27 (s, 6H, CH3), 1.70 (m, 4H, 6.9 Hz, CH2). 13C-NMR (75 MHz, CDCl3): δ (ppm) 138.8, 128.0, 57.0, 55.1, 53.7, 53.2, 48.1, 46.0, 26.9. MS (IE): m/z 417.0 [M+1H]+, 416.0, 289.0, 260.0, 156.0, 141.0, 127.0, 113.0. HRMS: Calculated for C24H44N6: 417.3706 [M+1H]+. Obtained: 417.3700.
Like 1{1,1} but using 0.54 g (4.0 mmol) of terephthaldehyde (9a), 1.05 g (8.0 mmol) of 2-morpholinoethylamine {7} and 0.31 g (8.0 mmol) of NaBH4. 0.93 g (2.6 mmol, 64%) of an off-white solid 1{7,7} are obtained. IR (CHCl3 evaporated film): ν (cm−1) 3341 2968, 2930, 2817, 1446, 1117. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.27 (s, 4H, Ph), 3.79 (s, 4H, CH2-Ph), 3.69 (t, 8H, J=4.6 Hz, CH2—O), 2.70 (t, 4H, J=6.0 Hz, CH2), 2.496 (t, 4H, J=6.0 Hz, CH2), 2.403 (t, 8H, J=4.6 Hz, CH2—N), 1.82 (s, 2H, NH). 13C-NMR (75 MHz, CDCl3): δ (ppm) 139.0, 128.0, 67.0, 58.3, 53.7, 53.7, 45.3. MS (IE): m/z 363.4 [M+1H]+, 362.4, 262.3, 233.2, 232.2, 100.0. Anal. Calculated for C20H34N4O2: C, 66.26%, H, 9.45%, N, 15.46%, O, 8.83%. Obtained: C, 66.40%, H, 9.68%, N, 15.43%.
As for 1{1,1}, but using 0.47 g (3.5 mmol) of terephthaldehyde (9a), 1.00 g (7.0 mmol) of 3-morpholinopropan-1-amine {8} and 0.27 g (7.0 mmol) of NaBH4. 1.16 g (3.0 mmol, 85%) of a yellow oil 1{8,8} are obtained. IR (CHCl3 evaporated film): ν (□cm−1) 3301, 2948, 2852, 2806, 1456, 1118. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.27 (s, 4H, Ph 3.79 (s, 4H, CH2-Ph 3.70 (t, 8H, J=6 Hz, CH2O), 2.68 (t, 4H, J=7.0 Hz, CH2—NH), 2.41 (m, 12H, CH2—N), 1.81 (s, 2H, NH), 1.70 (m 4H, J=7.0 Hz, CH2). 13C-NMR (75 MHz, CDCl3): δ (ppm) 138.9, 128.0, 67.0, 57.39, 53.8, 53.8, 48.0, 26.8. MS (IE): m/z 390.3 [M]+, 247.2, 100.0. HRMS: Calculated for C22H38N4O2: 390.2995. Obtained: 390.2995.
1.51 g (14.7 mmol) of 1-aminopiperidine {9} are dissolved in 30 mL of anhydrous MeOH. Immediately afterwards, 0.992 g (7.33 mmol) of terephthaldehyde (9a) are added. The resulting solution is heated under reflux for 16 h under a nitrogen atmosphere and in the presence of 4 Å molecular sieve. The molecular sieve is then filtered in hot conditions. The filtrate is collected and the solvent is partially eliminated almost to dryness and is cooled at 4° C. The solid is filtered and washed with cold MeOH. The obtained solid is dried on P2O5. 1.42 g (4.8 mmol, 65%) of a yellow solid 3{9,9} are obtained. IR (CHCl3 evaporated film): ν (□cm−1) 1576. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.55 (s, 4H, Ph), 7.53 (s, 2H, CH═N), 3.16 (m, 8H, CH2—N), 1.79-1.71 (m, 8H, CH2), 1.58-1.50 (m, 4H, CH2). 13C-NMR (75 MHz, CDCl3): δ (ppm) 136.0, 134.3, 125.9, 52.1, 25.3, 24.2. Anal. Calculated for C18H26N4: C, 72.44%, H, 8.78%, N, 18.77%. Obtained: C, 72.40%, H, 8.81%, N, 18.83%.
As for 3{9,9} but using 1.20 g (8.4 mmol) of 1-amino-2,6-dimethylpiperidine {10} and 0.57 g (4.2 mmol) of terephthaldehyde (9a). 1.05 g (3.0 mmol, 65%) of a yellow solid 3{10,10} are obtained. IR (CHCl3 evaporated film): ν (□□cm−1) 1620. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.87 (s, 2H, CH═N), 7.64 (s, 4H, Ph), 3.31-3.27 (m, 4H, CH), 1.83-1.51 (m, 12H, CH2), 1.03 (d, J=6.0 Hz, 12H, CH3). 13C-NMR (75.5 MHz, CDCl3): δ (ppm) 146.6, 136.0, 126.8, 56.1, 32.4, 20.0, 19.9. Anal. Calculated for C22H34N4: C, 74.53%, H, 9.67%, N, 15.80%. Obtained: C, 74.30%, H, 9.35%, N, 15.84%.
As for 3{9,9}, but using 0.64 g (5.4 mmol) of 1-amino-4-methylpiperazine {11} and 0.37 g (2.7 mmol) of terephthaldehyde (9a). 0.67 g (2.0 mmol, 75%) of a yellowish solid 3{11,11} are obtained. IR (CHCl3 evaporated film): ν (cm−1) 1579. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.57 (s, 4H, Ph), 7.53 (s, 2H, CH═N), 3.23 (m, 8H, CH2—N), 2.62 (m, 8H, CH2—N), 2.36 (s, 6H, CH3). 13C-NMR (75.5 MHz, CDCl3): δ (ppm) 135.8, 135.4, 126.2, 54.5, 51.0, 46.0. Anal. Calculated for C18H28N6: C, 65.82%, H, 8.59%, N, 25.59%. Obtained: C, 65.51%, H, 8.72%, N, 25.17%.
2.01 g (9.3 mmol) of diethyl monoacetal of the terephthaldehyde (4a) and 1.09 g (9.3 mmol) of 2-(pyrrolidin-1-yl)ethylamine {1} are dissolved in 30 mL of anhydrous MeOH. 4 Å molecular sieve is added and it is stirred at reflux temperature and under a nitrogen atmosphere for 36 h. The molecular sieve is filtered and 0.36 g (9.3 mmol) of NaBH4 are added. It is allowed to react at room temperature for 5 h. Water is added and it is extracted with CH2Cl2. The organic phase is washed with brine and dried on anhydrous MgSO4. The solvent is eliminated under reduced pressure and 2.66 g (8.7 mmol, 93%) of a yellow oil corresponding to the acetal 8{1} are obtained. 20 mL of 2M HCl are added to 2.64 g (8.6 mmol) of the acetal 8{1} and it is stirred at room temperature for 2 h. It is basified with NaOH and extracted with CH2Cl2. The organic phase is washed with brine and dried on MgSO4. The solvent is eliminated under reduced pressure and 1.79 g (7.7 mmol, 89% yield) of (7{1} are obtained. IR (film): ν (□cm−1) 3309, 3051, 2961, 2930, 2875, 2799, 1700, 1606, 780. 1H-NMR (300 MHz, CDCl3): δ (ppm) 10.00 (s, 1H, CHO), 7.84 (d, 2H, 8.1 Hz, Ph), 7.51 (d, 2H, J=8.1 Hz, Ph), 3.90 (s, 2H, CH2-Ph), 2.75 (t, 2H, J=6.0 Hz, CH2—N), 2.64 (t, 2H, J=6.0 Hz, CH2—N), 2.51 (m, 4H, CH2—N), 2.01 (bs, 1H, NH), 1.77 (m, 4H, CH2). 13C-NMR (75 MHz, CDCl3): δ (ppm) 191.8, 147.6, 135.1, 129.7, 128.4, 55.8, 54.2, 53.7, 47.8, 23.5. MS (IE): m/z 233.2 [M+1H]+, 232.2, 148.1, 119.0, 84.1. HRMS: Calculated for C14H20N2O: 232.1576. Obtained: 232.1572.
As for 7{1}, but using 6.01 g (28.0 mmol) of diethyl monoacetal of the terephthaldehyde (4a), 3.70 g (28.0 mmol) of 3-(pyrrolidin-1-yl)propan-1-amine {2} and 1.07 g (28.0 mmol) of NaBH4. 8.01 g (25.0 mmol, 89%) of a yellow oil corresponding to the acetal 8{2} are obtained. 7.98 g (24.9 mmol) of 8{2} are hydrolized with 2M HCl and 4.59 g (18.6 mmol, 75%) of 7{2} are obtained. IR (film): ν (□cm−1) 3276, 2934, 2874, 2790, 1700, 1606, 1458, 822. 1H-NMR (300 MHz, CDCl3): δ (ppm) 10.00 (s, 1H, CHO), 7.84 (d, 2H, Ph), 7.50 (d, 2H, Ph), 3.88 (s, 2H, CH2-Ph), 2.70 (t, 2H, CH2—N), 2.51 (m, 6H, CH2—N), 1.87 (bs, 1H, NH), 1.75 (m, 6H, CH2). 13C-NMR (75 MHz, CDCl3): δ (ppm) 191.8, 147.7, 135.2, 129.8, 128.3, 54.7, 54.3, 53.7, 48.2, 29.2, 23.5. MS (IE): m/z 247.2 [M+1H]+, 246.2, 127.2, 119.0, 84.1. Anal. Calculated for C15H22N2O: C, 73.13%, H, 9.00%, N, 11.37%, O, 6.49%. Obtained: C, 73.28%, H, 9.30%, N, 11.45%.
As for 7{1}, but using 2.01 g (9.3 mmol) of diethyl monoacetal of the terephthaldehyde (4a), 1.20 g (9.3 mmol) of 3-(1H-imidazol-1-yl)propan-1-amine {3} and 0.36 g (9.3 mmol) of NaBH4. 2.68 g (8.4 mmol, 90%) of a yellow oil corresponding to the acetal 8{3} are obtained. 2.68 g (8.4 mmol) of 8{3} are hydrolized with 2M HCl and 1.76 g (7.2 mmol, 86%) of a yellowish oil 7{3} are obtained. IR (film): ν (□cm−1) 3268, 3108, 2936, 2831, 2738, 1696, 1606, 1508. 1H-NMR (300 MHz, CDCl3): δ (ppm) 10.00 (s, 1H, CHO), 7.85 (d, 2H, J=8.1 Hz, Ph), 7.48 (d, 2H, J=8.1 Hz, CArH), 7.46 (s, 1H, CH), 7.05 (s, 1H, CH), 6.90 (s, 1H, CH), 4.07 (t, 2H, J=6.9 Hz, CH2—N), 3.85 (s, 2H, CH2-Ph), 2.62 (t, 2H, J=6.9 Hz, CH2—N), 1.95 (m, 2H, J=6.9 Hz, CH2), 1.75 (bs, 1H, NH). 13C-NMR (75 MHz, CDCl3): δ (ppm) 191.7, 147.2, 137.0, 135.3, 129.8, 129.3, 128.4, 118.7, 53.6, 45.8, 44.6, 31.3. MS (IE): m/z 244.1 [M+1H]+, 243.1, 148.1, 119.0. HRMS: Calculated for C14H17N3O: 243.1372. Obtained: 243.1366.
Like 7{1} but using 2.01 g (9.4 mmol) of diethyl monoacetal of the terephthaldehyde (4a), 1.23 g (9.4 mmol) of 2-(piperidin-1-yl)ethylamine {4} and 0.36 g (9.4 mmol) of NaBH4. 2.79 g (8.7 mmol, 93%) of a yellow oil corresponding to the acetal 8{4} are obtained. 2.75 g (8.6 mmol) of 8{4} are hydrolized with 2M HCl and 2.11 g (8.6 mmol, 100%) of a yellowish oil 7{4} are obtained. IR (film): ν (□cm−1) 3308, 3050, 2934, 2851, 2809, 1701, 1606, 779. 1H-NMR (300 MHz, CDCl3): δ (ppm) 10.00 (s, 1H, CHO), 7.84 (d, 2H, J=8.1 Hz, Ph), 7.50 (d, 2H, J=8.1 Hz, Ph), 3.89 (s, 2H, CH2-Ph), 2.70 (t, 2H, J=6.2 Hz, CH2—N), 2.47 (t, 2H, J=6.2 Hz, CH2—N), 2.36 (bs, 4H, CH2—N), 2.18 (bs, 1H, NH), 1.57 (m, 4H, J=5.7 Hz, CH2), 1.43 (m, 2H, CH2). 13C-NMR (75 MHz, CDCl3): δ (ppm) 191.8, 147.7, 135.2, 129.8, 128.4, 58.4, 54.7, 53.7, 45.9, 25.9, 24.4. MS (IE): m/z 246.2 [M]+, 119.1, 98.1. HRMS: Calculated for C15H22N2O: 246.1732. Obtained: 246.1731.
As for 7{1}, but using 2.01 g (9.3 mmol) of diethyl monoacetal of the terephthaldehyde (4a), 1.52 g (9.3 mmol) of 3-(2-methylpiperidin-1-yl)propan-1-amine {5} and 0.36 g (9.3 mmol) of NaBH4. 3.18 g (9.1 mmol, 98%) of a yellow oil corresponding to the acetal 8{5} are obtained. 3.18 g (9.1 mmol) of 8{5} are hydrolized and 2.45 g (8.9 mmol, 98%) of a yellowish oil 7{5} are obtained. IR (film): ν (□cm−1) 3271, 2930, 2852, 2793, 2732, 1702, 1606, 1449, 1372, 781. 1H-NMR (300 MHz, CDCl3): δ (ppm) 10.00 (s, 1H, CHO), 7.85 (d, 2H, J=8.1 Hz, Ph), 7.50 (d, 2H, J=8.1 Hz, Ph), 3.87 (s, 2H, CH2-Phr), 2.87 (m, 1H, CH), 2.77 (m, 1H, CH2), 2.65 (t, 2H, J=6.8 Hz, CH2), 2.36 (m, 1H, CH2), 2.27 (m, 1H, CH2), 2.11 (m, 1H, CH2), 2.00 (bs, 1H, NH), 1.75-1.48 (m, 6H, CH2), 1.29 (m, 2H, CH2), 1.06 (d, 3H, J=6.0 Hz, CH3). 13C-NMR (75 MHz, CDCl3): δ (ppm) 191.8, 147.7, 135.2, 129.8, 128.4, 56.1, 53.8, 52.3, 52.0, 48.5, 34.6, 26.1, 25.9, 23.9, 19.0. MS (IE): m/z 275.2 [M+1H]+, 274.2, 119.0, 112.1. HRMS: Calculated for C17H26N2O: 274.2045. Obtained: 274.2046.
As for 7{1}, but using 2.00 g (9.3 mmol) of diethyl monoacetal of the terephthaldehyde (4a), 1.49 g (9.3 mmol) of 3-(4-methylpiperazin-1-yl)propan-1-amine {6} and 0.36 g (9.3 mmol) of NaBH4. 2.94 g (8.4 mmol, 90%) of a yellow oil corresponding to the acetal 8{6} are obtained. 2.93 g (8.4 mmol) of 8{6} are hydrolized with 2M HCl and 2.31 g (8.4 mmol, 100%) of a yellow oil 7{6} are obtained. IR (film): ν (□cm−1) 3276, 2936, 2875, 2794, 2769, 2740, 1700, 1606, 1458. 1H-NMR (300 MHz, CDCl3): δ (ppm) 10.00 (s, 1H, CHO), 7.85 (d, 2H, J=8.1 Hz, Ph), 7.50 (d, 2H, J=8.1 Hz, Ph), 3.87 (s, 2H, CH2-Ph), 2.69 (t, 2H, J=6.9 Hz, CH2—N), 2.45 (bs, 8H, CH2—N), 2.42 (t, 2H, J=6.9 Hz, CH2—N), 2.27 (s, 3H, CH3), 2.08 (bs, 1H, NH), 1.72 (m, 2H, J=6.9 Hz, CH2). 13C-NMR (75 MHz, CDCl3): δ (ppm) 191.8, 147.7, 135.2, 129.8, 128.3, 57.0, 55.1, 53.7, 53.2, 48.3, 46.0, 27.0. MS (IE): m/z 276.2 [M+1H]+, 275.2, 231.2. HRMS: Calculated for C16H25N3O: 275.1998. Obtained: 275.2001.
As for 7{1}, but using 2.00 g (9.3 mmol) of diethyl monoacetal of the terephthaldehyde (4a), 1.23 g (9.3 mmol) of 2-morpholinoethylamine {7} and 0.36 g (9.3 mmol) of NaBH4. 2.55 g (7.9 mmol, 85%) of a yellow oil corresponding to the acetal 8{7} are obtained. 2.52 g (7.8 mmol) of 8{7} are hydrolized with 2M HCl and 1.94 g (7.8 mmol, 100%) of a yellowish oil 7{7} are obtained. IR (film): ν (□cm−1) 3309, 2954, 2917, 2894, 2852, 2818, 1698, 1607, 1455, 1117, 824, 766. 1H-NMR (300 MHz, CDCl3): δ (ppm) 10.00 (s, 1H, CHO), 7.86 (d, 2H, J=8.1 Hz, Ph), 7.50 (d, 2H, J=8.1 Hz, Ph), 3.90 (s, 2H, CH2-Ph), 3.70 (t, 4H, J=4.5 Hz, CH2—O), 2.71 (t, 2H, J=6.0 Hz, CH2—N), 2.51 (t, 2H, J=6.0 Hz, CH2—N), 2.42 (t, 4H, J=4.5 Hz, CH2—N), 1.93 (bs, 1H, NH). 13C-NMR (75 MHz, CDCl3): δ (ppm) 191.7, 147.5, 135.2, 129.8, 128.4, 66.9, 58.2, 53.7, 45.4. MS (IE): m/z 249.2 [M+1H]+, 248.2, 119.0, 100.0. HRMS: Calculated for C14H20N2O2: 248.1525. Obtained: 248.1531.
As for 7{1}, but using 2.01 g (9.3 mmol) of diethyl monoacetal of the terephthaldehyde (4a), 1.35 g (9.3 mmol) of 3-morpholinopropan-1-amine {8} and 0.36 g (9.3 mmol) of NaBH4. 2.91 g (8.6 mmol, 92%) of a yellow oil corresponding to the acetal 8{8} are obtained. 2.86 g (8.5 mmol) of 8{8} are hydrolized and 1.60 g (6.1 mmol, 72%) of a yellow oil 7{8} are obtained. IR (film): ν (□cm−1) 3307, 2950, 2892, 2853, 2814, 1698, 1607, 1457, 1117, 861, 755. 1H-NMR (300 MHz, CDCl3): δ (ppm) 10.00 (s, 1H, CHO), 7.85 (d, 2H, J=8.1 Hz, Ph), 7.50 (d, 2H, J=8.1 Hz, Ph), 3.88 (s, 2H, CH2-Ph), 3.70 (t, 4H, J=4.7 Hz, CH2—O), 2.70 (t, 2H, J=6.9 Hz, CH2—N), 2.45-2.39 (m, 6H, CH2—N), 1.81 (bs, 1H, NH), 1.72 (m, 2H, J=6.9 Hz, CH2). 13C-NMR (75 MHz, CDCl3): δ (ppm) 191.2, 147.6, 135.2, 129.8, 128.3, 66.9, 57.3, 53.8, 53.7, 48.1, 26.7. MS (IE): m/z 262.2 [M]+, 84.0. HRMS: Calculated for C15H22N2O2: 262.1681. Obtained: 262.1682.
1.00 g (7.4 mmol) of terephthaldehyde (9a) is dissolved in 30 mL of anhydrous MeOH and 4 Å molecular sieve is added. A solution of 0.38 g (3.7 mmol) of 1-aminopiperidine {9} in 5 mL of anhydrous MeOH is added dropwise and under a nitrogen atmosphere. The mixture is stirred at reflux temperature for 36 h. The solvent is eliminated under reduced pressure and the obtained solid is purified by column chromatography (hexane/AcOEt 5:1). 0.48 g (2.2 mmol, 60%) of a yellow oil 10{9} are obtained. IR (CHCl3 evaporated film): ν (□cm−1) 2938, 2854, 2818, 2731, 1694, 1605, 1579, 1549, 1448. 1H-NMR (300 MHz, CDCl3): δ (ppm) 9.96 (s, 1H, CHO), 7.83 (d, 2H, J=8.4 Hz, Ph), 7.71 (d, 2H, J=8.4 Hz, CArH), 7.48 (s, 1H, CH═N), 3.25 (t, 4H, J=5.7 Hz, CH2—N), 1.76 (m, 4H, J=5.7 Hz, CH2), 1.61-1.54 (m, 2H, CH2). 13C-NMR (75 MHz, CDCl3): δ (ppm) 191.6, 142.8, 135.0, 131.0, 130.0, 125.8, 51.7, 25.1, 24.0. MS (IE): m/z 217.0 [M+1H]+, 216.0, 187.0, 132.0, 84.0. Anal. Calculated for C13H16N2O: C, 72.19%, H, 7.46%, N, 12.95%, O, 7.40%. Obtained: C, 72.31%, H, 7.56%, N, 12.88%.
As for 10{9}, but using 3.82 g (28.2 mmol) of terephthaldehyde (9a) and 2.01 g (14.1 mmol) of 1-amino-2,6-dimethylpiperidine {10}. It is purified by column chromatography (hexane/AcOEt 3:1) and 2.71 g (11.1 mmol, 78%) of a yellow oil 10{10} are obtained. IR (CHCl3 evaporated film): ν (□cm−1) 2967, 2935, 2869, 2820, 2728, 1693, 1604, 1572, 1468, 1372. 1H-NMR (300 MHz, CDCl3): δ (ppm) 9.95 (s, 1H, CHO), 7.81 (d, 2H, J=8.3 Hz, Ph), 7.69 (d, 2H, J=8.3 Hz, Ph), 7.35 (s, 1H, CH═N), 3.92 (m, 2H, CH), 1.87-1.56 (m, 6H, CH2), 1.15 (d, 6H, J=6.6 Hz, CH3). 13C-NMR (75 MHz, CDCl3): δ (ppm) 191.5, 143.5, 134.4, 130.0, 129.5, 125.3, 53.1, 30.8, 18.3, 15.6. MS (IE): m/z 245.2 [M+1H]+, 244.2, 89.0, 55.0. Anal. Calculated for C15H20N2O: C, 73.74%, H, 8.25%, N, 11.47%, O, 6.55%. Obtained: C, 73.38%, H, 8.27%, N, 11.41%.
As for 10{9}, but using 1.14 (8.4 mmol) of terephthaldehyde (9a) and 0.50 g (4.2 mmol) of 1-amino-4-methylpiperazine {11}. It is purified by column chromatography (gradient of CH2Cl2 to CH2Cl2/MeOH 9:1). 0.80 g (3.5 mmol, 82%) of a yellow solid 10{11} are obtained. 1H-NMR (300 MHz, CDCl3): δ (ppm) 9.98 (s, 1H, CHO), 7.84 (d, 2H, J=7.7 Hz, Ph), 7.72 (d, 2H, J=7.7 Hz, Ph), 7.50 (s, 1H, CH═N), 3.30 (t, 4H, J=5.1 Hz, CH2—N), 2.62 (t, 4H, J=5.1 Hz, CH2—N), 2.37 (s, 3H, CH3).
0.52 g (2.1 mmol) of 10{10} and 0.25 g (2.1 mmol) of 2-(pyrrolidin-1-yl)ethylamine {1} are dissolved in 30 mL of anhydrous MeOH. 4 Å molecular sieve is added and it is stirred at reflux temperature and under a nitrogen atmosphere for 36 h. The molecular sieve is filtered and 0.08 g (2.1 mmol) of NaBH4 is added. It is allowed to react at room temperature for 16 h. Water is added and it is extracted with CH2Cl2. The organic phase is washed with brine and dried on MgSO4. The solvent is eliminated under reduced pressure and 0.61 g (1.8 mmol, 85%) of a yellow oil 2{10,1} are obtained. IR (film): ν (□cm−1) 3311, 2962, 2931, 2872, 2794, 1624, 1459, 1447, 1369. 1H-NMR (300 MHz, CDCl3): δ (ppm) 8.07 (s, 1H, CH), 7.64 (d, 2H, J=8.1 Hz, Ph), 7.34 (d, 2H, J=8.1 Hz, Ph), 3.83 (s, 2H, CH2-Ph), 3.06 (m, 2H, CH), 2.77 (t, 2H, J=6.0 Hz, CH2—N), 2.63 (t, 2H, J=6.0 Hz, CH2—N), 2.50 (m, 4H, CH2—N), 2.34 (bs, 1H, NH), 1.77 (m, 8H, CH2), 1.50 (m, 2H, CH2), 1.00 (d, 6H, J=6.3 Hz, CH3). MS (IE): m/z 342.3 [M]+, 84.0. HRMS: Calculated for C21H34N4: 342.2783. Obtained: 342.2786.
As for 2{10,1}, but using 0.49 g (2.0 mmol) of 10{10}, 0.26 g (2.0 mmol) of 3-(1H-imidazol-1-yl)propan-1-amine {3} and 0.08 g (2.0 mmol) of NaBH4. 0.70 g (2.0 mmol, 100%) of a yellow oil 2{10,3} are obtained. IR (film): ν (□cm−1) 3284, 3106, 2961, 2931, 2867, 2856, 2824, 1624, 1508, 1449, 1369. 1H-NMR (300 MHz, CDCl3): δ (ppm) 8.04 (s, 1H, CH═N), 7.65 (d, 2H, J=8.1 Hz, Ph), 7.46 (s, 1H, CH), 7.31 (d, 2H, J=8.1 Hz, Ph), 7.04 (s, 1H, CH), 6.89 (s, 1H, CH), 4.05 (t, 2H, J=6.9 Hz, CH2—N), 3.77 (s, 2H, CH2-Ph), 3.10 (m, 2H, CH), 2.61 (t, 2H, J=6.9 Hz, CH2—N), 1.93 (m, 2H, J=6.9 Hz, CH2), 1.85 (bs, 1H, NH), 1.77 (m, 4H, CH2), 1.51 (m, 2H, CH2), 1.00 (d, 6H, J=6.6 Hz, CH3). 13C-NMR (75 MHz, CDCl3): δ (ppm) 151.7, 141.4, 137.0, 134.0, 129.2, 128.2, 127.3, 118.7, 57.2, 53.7, 45.7, 44.7, 32.8, 31.4, 21.2, 20.5. MS (IE): m/z 354.2 [M+1H]+, 112.1, 81.0. HRMS: [M+1H]+ Calculated for C21H32N5: 354.2658 [M+1H]+. Obtained: 354.2666.
As for 2{10,1}, but using 0.47 g (1.9 mmol) of 10{10}, 0.31 g (1.9 mmol) of 3-(4-methylpiperazin-1-yl)propan-1-amine {6} and 0.07 g (1.9 mmol) of NaBH4. 0.72 g (1.9 mmol, 97%) of a yellow oil 2{10,6} are obtained. IR (film): ν (□cm−1) 3286, 2932, 2872, 2837, 2794, 1625, 1458, 1370. 1H-NMR (300 MHz, CDCl3): δ (ppm) 8.05 (s, 1H, CH), 7.65 (d, 2H, J=8.1 Hz, Ph), 7.34 (d, 2H, J=8.1 Hz, Ph), 3.81 (s, 2H, CH2-Ph), 3.08 (m, 2H, CH), 2.69 (t, 2H, J=6.9 Hz, CH2—N), 2.44 (bs, 8H, CH2—N), 2.41 (t, 2H, J=6.9 Hz, CH2—N), 2.30 (bs, 1H, NH), 2.27 (s, 3H, CH3), 1.81-1.68 (m, 6H, CH2), 1.51 (m, 2H, CH2), 1.00 (d, 6H, J=6.3 Hz, CH3). 13C-NMR (75 MHz, CDCl3): δ (ppm) 152.1, 141.3, 133.8, 128.2, 127.3, 57.2, 57.0, 55.1, 53.6, 53.2, 48.1, 46.0, 32.9, 26.7, 21.4, 20.6. MS (IE): m/z 386.3 [M+1H]+, 385.3, 273.2, 229.1, 113.0. HRMS: Calculated for C23H39N5: 385.3205. Obtained: 385.3211.
As for 2{10,1}, but using 0.46 g (1.9 mmol) of 10{10}, 0.27 g (1.9 mmol) of 3-morpholinopropan-1-amine {8} and 0.07 g (1.9 mmol) of NaBH4. 0.63 g (1.7 mmol, 91%) of a yellow oil 2{10,8} are obtained. IR (CHCl3 evaporated film): ν (□cm−1) 3293, 2930, 2854, 2808, 1625, 1456, 1369, 1118, 863. 1H-NMR (300 MHz, CDCl3): δ (ppm) 8.06 (s, 1H, CH═N), 7.65 (d, 2H, J=8.1 Hz, Ph), 7.33 (d, 2H, J=8.1 Hz, Ph), 3.81 (s, 2H, CH2-Ph), 3.70 (t, 4H, J=4.7 Hz, CH2—O), 3.08 (m, 2H, CH), 2.69 (t, 2H, J=6.9 Hz, CH2—N), 2.45-2.38 (m, 6H, CH2—N), 2.06 (bs, 1H, NH), 1.81-1.66 (m, 6H, CH2), 1.51 (m, 2H, CH2), 1.00 (d, 6H, J=6.3 Hz, CH3). 13C-NMR (75 MHz, CDCl3): δ (ppm) 152.2, 141.6, 133.8, 128.1, 127.3, 66.9, 57.4, 57.3, 53.8, 53.7, 47.9, 32.9, 26.6, 21.4, 20.6. MS (IE): m/z 372.2 [M]+, 143.1, 100.0. HRMS: Calculated for C22H36N4O: 372.2889. Obtained: 372.2895.
As for 2{10,1}, but using 0.32 g (1.4 mmol) of 10{11}, 1.16 g of 2-(pyrrolidin-1-yl)ethylamine {1} and 0.053 g (1.4 mmol) of NaBH4. 0.42 g (1.3 mmol, 92%) of a yellow oil 2{11,1} are obtained. IR (CHCl3 evaporated film): ν (□cm−1) 3309, 2935, 2875, 2795, 1592, 1452. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.55 (d, 2H, J=8.0 Hz, Ph), 7.55 (s, 1H, CH═N), 7.29 (d, 2H, J=8.0 Hz, Ph), 3.80 (s, 2H, Ph-CH2), 3.21 (t, 4H, J=5.0 Hz, CH2—N), 2.73 (t, 2H, J=6.0 Hz, NH—CH2), 2.61 (m, 6H, CH2—N), 2.48 (m, 4H, CH2—N), 2.36 (s, 3H, CH3), 1.87 (s, 1H, NH), 1.75 (m, 4H, CH2). 13C-NMR (75 MHz, CDCl3): δ (ppm) 140.4, 135.8, 134.8, 128.2, 126.0, 55.9, 54.5, 54.2, 53.8, 51.1, 47.8, 46.0, 23.5. MS (IE): m/z 330.4 [M+1H]+, 329.3, 245.2, 244.2, 216.2, 99.1, 84.0. Anal. Calculated for C19H31N5: C, 69.26%, H, 9.48%, N, 21.26%. Obtained: C, 69.05%, H, 9.61%, N, 20, 95%.
As for 2{10,1}, but using 0.81 g (3.5 mmol) of 9{1}, 0.46 g (3.5 mmol) of 3-(pyrrolidin-1-yl)propan-1-amine {2} and 0.13 g (3.5 mmol) of NaBH4. 1.11 g (3.2 mmol, 92%) of a yellowish oil 1{1,2} are obtained. IR (film): ν (□cm−1) 3281, 2961, 2930, 2874, 2790, 1458, 1445. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.27 (s, 4H, PhH), 3.79 (s, 2H, CH2-Ph), 3.77 (s, 2H, CH2-Ph), 2.73 (m, 4H, CH2—N), 2.61 (t, 2H, J=6.0 Hz, CH2—N), 2.49 (m, 10H, CH2—N), 2.14 (bs, 2H, NH), 1.79-1.71 (m, 10H, CH2). 13C-NMR (75 MHz, CDCl3): δ (ppm) 138.0, 138.8, 128.1, 128.0, 55.9, 54.7, 54.2, 53.8, 53.7, 48.0, 29.2, 23.5. MS (IE): m/z 345.3 [M+1H]+, 260.2, 84.1. HRMS: Calculated for C21H37N4: 345.3018 [M+1H]+. Obtained: 345.3022.
As for 2{10,1}, but using 0.89 g (3.7 mmol) of 9{3}, 0.43 g (3.7 mmol) of 2-(pyrrolidin-1-yl)ethylamine {1} and 0.14 g (3.7 mmol) of NaBH4. 1.14 g (3.3 mmol, 91%) of a yellow oil 1{3,1} are obtained. IR (CHCl3 evaporated film): ν (□cm−1) 3279, 3104, 2929, 2875, 2799, 1508, 1458, 1446. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.44 (s, 1H, CH), 7.27 (s, 4H, Ph), 7.03 (s, 1H, CH), 6.88 (s, 1H, CH), 4.04 (t, 2H, J=6.9 Hz, CH2—N), 3.79 (s, 2H, CH2-Ph), 3.73 (s, 2H, CH2-Ph), 2.74 (t, 2H, J=5.9 Hz, CH2—N), 2.61 (m, 4H, CH2—N), 2.48 (m, 4H, CH2—N), 2.18 (bs, 2H, NH), 1.92 (m, 2H, J=6.9 Hz, CH2), 1.76 (m, 2H, J=3.3 Hz, CH2). 13C-NMR (75 MHz, CDCl3): δ (ppm) 139.1, 138.6, 137.0, 129.2, 128.2, 128.0, 118.7, 55.9, 54.2, 53.8, 53.7, 47.9, 45.6, 44.7, 31.4, 23.5. MS (IE): m/z 342.2 [M+1H]+, 257.2, 84.0. HRMS: Calculated for C20H32N5: 342.2658 [M+1H]+. Obtained: 342.2666.
As for 2{10,1}, but using 0.91 g (3.3 mmol) of 9{6}, 0.39 g (3.3 mmol) of 2-(pyrrolidin-1-yl)ethylamine {1} and 0.13 g (3.3 mmol) of NaBH4. 0.96 g (2.6 mmol, 77%) of a yellow oil 1{6,1} are obtained. IR (film): ν (□cm−1) 3288, 2934, 2875, 2793, 1458, 1447, 1372, 1354, 1015. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.27 (s, 4H, Ph), 3.79 (s, 2H, CH2-Ph), 3.76 (s, 2H, CH2-Ph), 2.74 (t, 2H, J=6.5 Hz, CH2—N), 2.67 (t, 2H, J=6.9 Hz, CH2—N), 2.61 (t, 2H, J=6.5 Hz, CH2—N), 2.50-2.38 (m, 14H, CH4—N), 2.27 (s, 3H, CH3), 2.11 (bs, 2H, NH), 1.77-1.66 (m, 6H, CH2). 13C-NMR (75 MHz, CDCl3): δ (ppm) 138.9, 138.8, 128.1, 128.0, 57.0, 55.9, 55.1, 54.2, 53.8, 53.7, 53.2, 48.1, 47.9, 46.0, 27.0, 23.5. MS (IE): m/z 374.3 [M+1H]+, 303.2, 289.2, 113.1, 84.0. HRMS: Calculated for (C22H40N5): 374.3284 [M+1H]+. Obtained: 374.3276.
As for 2{10,1}, but using 0.84 g (3.2 mmol) of 9{8}, 0.37 g (3.2 mmol) of 2-(pyrrolidin-1-yl)ethylamine {1} and 0.12 g (3.2 mmol) of NaBH4. 1.05 g (2.9 mmol, 91%) of a yellow oil 1{8,1} are obtained. IR (CHCl3 evaporated film): ν (□cm−1) 3305, 2953, 2932, 2872, 2852, 2802, 1457, 1446, 1118, 862, 757. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.27 (s, 4H, Ph), 3.79 (s, 2H, CH2-Ph), 3.77 (s, 2H, CH2-Ph), 3.69 (t, 4H, 4.7 Hz, CH2—O), 2.74 (t, 2H, J=5.9 Hz, CH2—N), 2.68 (t, 2H, J=6.9 Hz, CH2—N), 2.61 (t, 2H, J=5.9 Hz, CH2—N), 2.50-2.37 (m, 10H, CH2—N), 2.04 (bs, 2H, NH), 1.80-1.68 (m, 6H, CH2). 13C-NMR (75 MHz, CDCl3): δ (ppm) 139.0, 138.7, 128.1, 128.0, 67.0, 57.4, 55.9, 54.2, 53.8, 53.7, 48.0, 47.9, 26.7, 23.5. MS (IE): m/z 361.2 [M+1H]+, 276.2, 100.0, 84.0. HRMS: Calculated for (C21H37N4O): 361.2967 [M+1H]+. Obtained: 361.2965.
As for 2{10,1}, but using 0.91 g (3.7 mmol) of 9{3}, 0.49 g (3.7 mmol) of 3-(pyrrolidin-1-yl)propan-1-amine {2} and 0.14 g (3.7 mmol) of NaBH4. 1.33 g (3.7 mmol, 100%) of a yellowish oil 1{3,2} are obtained. IR (film): ν (□cm−1) 3281, 3104, 2931, 2875, 2794, 1508, 1458, 737. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.43 (s, 1H, CH), 7.27 (s, 4H, Ph), 7.03 (s, 1H, CH), 6.88 (s, 1H, CH), 4.04 (t, 2H, J=6.9 Hz, CH2—N), 3.78 (s, 2H, CH2-Ph), 3.74 (s, 2H, CH2-Ph), 2.70 (t, 2H, J=6.9 Hz, CH2—N), 2.60 (t, 2H, J=6.6 Hz, CH2—N), 2.50 (m, 6H, CH2—N), 2.05 (bs, 2H, NH), 1.92 (m, 2H, J=6.6 Hz, CH2), 1.79-1.10 (m, 6H, CH2). 13C-NMR (75 MHz, CDCl3): δ (ppm) 139.1, 138.6, 137.0, 129.2, 128.1, 128.0, 118.7, 54.7, 54.2, 53.7, 48.0, 45.6, 44.7, 31.4, 29.2, 23.4. MS (IE): m/z 357.4 [M+2H]+, 356.4, 355.5, 84.2. HRMS: Calculated for C21H33N5: 355.2736. Obtained: 355.2740.
As for 2{10,1}, but using 0.85 g (3.5 mmol) of 9{4}, 0.46 g (3.5 mmol) of 3-(pyrrolidin-1-yl)propan-1-amine {2} and 0.13 g (3.5 mmol) of NaBH4. 1.13 g (3.2 mmol, 92%) of a yellowish oil 1{4,2} are obtained. IR (film): ν (□cm−1) 3298, 3047, 2933, 2876, 2851, 2792, 1454, 1443, 756. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.27 (s, 4H, Ph), 3.78 (s, 2H, CH2-Ph), 3.77 (s, 2H, CH2-Ph), 2.69 (t, 4H, J=6.6 Hz, CH2—N), 2.52 (m, 6H, CH2—N), 2.44 (t, 2H, J=6.0 Hz, CH2—N), 2.33 (bs, 4H, CH2—N), 2.08 (bs, 2H, NH), 1.79-1.70 (m, 6H, CH2), 1.55 (m, 4H, CH2), 1.42 (m, 2H, CH2). 13C-NMR (75 MHz, CDCl3): δ (ppm) 138.9, 138.7, 128.0, 58.5, 54.7, 54.2, 53.7, 53.6, 48.0, 45.9, 29.2, 26.0, 24.5, 23.4. MS (IE): m/z 359.3 [M+1H]+, 260.2, 231.2, 98.2, 84.1. HRMS: Calculado C22H39N4: 359.3175 [M+1H]+. Obtained: 359.3175.
As for 2{10,1}, but using 0.96 g (3.9 mmol) of 9{2}, 0.63 g (3.9 mmol) of 3-(2-methylpiperidin-1-yl)propan-1-amine {5} and 0.15 g (3.9 mmol) of NaBH4. 1.24 g (3.2 mmol, 83%) of a yellowish oil 1{2,5} are obtained. IR (film): ν (□cm−1) 3281, 3047, 2930, 2874, 2855, 2790, 1678, 1448, 1372, 755. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.27 (s, 4H, Ph), 3.77 (s, 2H, CH2-Ph), 3.76 (s, 2H, CH2-Ph), 2.86 (m, 1H, CH), 2.68 (m, 5H, CH2), 2.49 (m, 6H, CH2), 2.36 (m, 1H, CH2), 2.26 (m, 1H, CH2), 2.11 (m, 1H, CH2), 2.02 (bs, 2H, NH), 1.79-1.58 (m, 12H, CH2), 1.27 (m, 2H, CH2), 1.05 (d, 3H, J=6.3 Hz, CH3). 13C-NMR (75 MHz, CDCl3): δ (ppm) 138.9, 138.8, 128.1, 128.0, 56.0, 54.8, 54.3, 53.8, 53.7, 52.3, 52.1, 48.3, 48.0, 34.7, 29.3, 26.2, 25.8, 24.0, 23.5, 19.1. MS (IE): m/z 387.3 [M+1H]+, 386.3, 288.2, 259.2, 231.2, 112.1. HRMS: Calculated for C24H42N4: 386.3409. Obtained: 386.3412.
As for 2{10,1}, but using 0.93 g (3.4 mmol) of 9{6}, 0.45 g (3.4 mmol) of 3-(pyrrolidin-1-yl)propan-1-amine {2} and 0.13 g (3.4 mmol) of NaBH4. 1.25 g (3.2 mmol, 95%) of a yellowish oil 1{6,2} are obtained. IR (film): ν (□cm−1) 3284, 2935, 2875, 2792, 1458, 1372, 1353, 1014. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.27 (s, 4H, Ph), 3.77 (s, 2H, CH2-Ph), 3.76 (s, 2H, CH2-Ph), 2.68 (m, 4H, CH2—N), 2.53-2.38 (m, 16H, CH2—N), 2.27 (s, 3H, CH3), 1.91 (bs, 2H, NH), 1.79-1.68 (m, 8H, CH2). 13C-NMR (75 MHz, CDCl3): δ (ppm) 138.9, 128.0, 56.9, 55.1, 54.7, 54.2, 53.7, 53.2, 48.1, 48.0, 29.3, 27.0, 23.5. MS (IE): m/z 387.4 [M]+, 289.3, 272.3, 260.2, 259.2, 231.3, 113.1, 84.1. HRMS: Calculated for C23H41N5: 387.3362. Obtained: 387.3347.
As for 2{10,1}, but using 0.96 g (3.9 mmol) of 9{2}, 0.51 g (3.9 mmol) of 2-morpholinoethylamine {7} and 0.15 g (3.9 mmol) of NaBH4. 1.27 g (3.5 mmol, 90%) of a yellowish oil 1{2,7} are obtained. IR (film): ν (□cm1) 3304, 3046, 2935, 2872, 2852, 2800, 1675, 1454, 1118, 868, 766. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.28 (s, 4H, Ph), 3.79 (s, 4H, CH2-Ph), 3.69 (t, 4H, 4.5 Hz, CH2—O), 2.71 (m, 4H, CH2—N), 2.51 (m, 8H, CH2—N), 2.40 (t, 4H, J=4.5 Hz, CH2—N), 2.18 (bs, 2H, NH), 1.78 (m, 6H, CH2). 13C-NMR (75 MHz, CDCl3): δ (ppm) 139.0, 138.6, 128.1, 67.0, 58.2, 54.8, 54.2, 53.7, 53.6, 48.0, 45.3, 28.9, 23.5. MS (IE): m/z 361.3 [M+1H]+, 360.3, 260.3, 231.2, 230.2, 100.0. HRMS: Calculated for C21H36N4O: 360.2889. Obtained: 360.2879.
As for 2{10,1}, but using 0.94 g (3.8 mmol) of 9{2}, 0.55 g (3.8 mmol) of 3-morpholinopropan-1-amine {8} and 0.15 g (3.8 mmol) of NaBH4. 1.33 g (3.5 mmol, 93%) of a yellow oil 1{2,8} are obtained. IR (film): ν (□□□cm−1) 3288, 3046, 2935, 2872, 2853, 2802, 1674, 1457, 1447, 1118, 862, 754. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.27 (s, 4H, Ph), 3.78 (s, 2H, CH2-Ph), 3.77 (s, 2H, CH2-Ph), 3.69 (t, 4H, J=4.8 Hz, CH2—O), 2.70 (m, 4H, CH2—N), 2.51 (m, 6H, CH2—N), 2.41 (m, 6H, CH2—N), 2.04 (bs, 2H, NH), 1.73 (m, 8H, CH2). 13C-NMR (75 MHz, CDCl3): δ (ppm) 138.9, 128.0, 67.0, 57.4, 54.8, 54.3, 53.8, 53.7, 48.1, 48.0, 29.3, 26.8, 23.5. MS (IE): m/z 374.3 [M+1H]+, 373.2, 231.2, 100.1. HRMS: Calculated for C22H38N4O: 388.3202. Obtained: 388.3202.
As for 2{10,1}, but using 0.90 g (3.7 mmol) of 9{3}, 0.48 g (3.7 mmol) of 2-(piperidin-1-yl)ethylamine {4} and 0.14 g (3.7 mmol) of NaBH4. 1.23 g (3.5 mmol, 94%) of a yellow oil 1{3,4} are obtained. IR (molten film): ν □□(cm−1) 3279, 2935, 2850, 2793, 1586, 1508, 1446. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.43 (s, 1H, CH), 7.28 (m, 4H, Ph), 7.03 (s, 1H, CH), 6.89 (s, 1H, CH), 4.04 (t, 2H, J=6.8 Hz, CH2—N), 3.81 (s, 2H, CH2-Ph), 3.74 (s, 2H, CH2-Ph), 2.73 (t, 2H, J=5.9 Hz, CH2—N), 2.60 (t, 2H, J=6.8 Hz, CH2), 2.48 (t, 2H, J=5.9 Hz, CH2—N), 2.46 (bs, 2H, NH), 2.37 (m, 6H, CH2—N), 1.92 (m, 2H, J=6.8 Hz, CH2), 1.56 (m, 4H, CH2), 1.43 (m, 2H, CH2). 13C-NMR (75 MHz, DMSO-d6): δ (ppm) 137.0, 128.6, 128.3, 128.1, 119.1, 55.8, 53.7, 51.8, 51.3, 44.8, 43.9, 43.7, 29.9, 25.0, 23.6. MS (IE): m/z 356.1 [M+1H]+, 256.9, 98.0, 81.0. HRMS: Calculated for C21H34N5: 356.2814. Obtained: 356.2809.
As for 2{10,1}, but using 0.88 g (3.6 mmol) of 9{3}, 0.59 g (3.6 mmol) of 3-(2-methylpiperidin-1-yl)propan-1-amine {5} and 0.14 g (3.6 mmol) of NaBH4. 1.20 g (3.1 mmol, 86%) of a yellow oil 1{3,5} are obtained. IR (CHCl3 evaporated film): ν (cm−1) 3277, 3104, 2929, 2853, 2802, 1508, 1450, 1373. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.44 (s, 1H, CH), 7.27 (s, 4H, Ph), 7.03 (s, 1H, CH), 6.89 (s, 1H, CH), 4.04 (t, 2H, J=6.9 Hz, CH2—N), 3.77 (s, 2H, CH2-Ph), 3.74 (s, 2H, CH2-Ph), 2.87 (m, 1H, CH), 2.74 (m, 1H, CH2), 2.65 (t, 2H, J=6.9 Hz, CH2), 2.60 (t, 2H, J=6.6 Hz, CH2—N), 2.37 (m, 1H, CH2), 2.27 (m, 1H, CH2), 2.12 (m, 1H, CH2), 2.09 (bs, 2H, NH), 1.92 (m, 2H, J=6.6 Hz, CH2), 1.72-1.53 (m, 6H, CH2), 1.29 (m, 2H, CH2), 1.05 (d, 3H, J=6.3 Hz, CH3). 13C-NMR (75 MHz, CDCl3): δ (ppm) 138.9, 138.7, 137.1, 129.2, 128.2, 128.0, 118.7, 56.0, 53.7, 52.3, 52.0, 48.3, 45.7, 44.7, 34.6, 31.4, 26.1, 25.7, 23.9, 19.1. MS (IE): m/z 384.3 [M+1H]+, 383.3, 243.2, 155.2, 112.0.
As for 2{10,1}, but using 0.76 g (2.8 mmol) of 9{6}, 0.35 g (2.8 mmol) of 3-(1H-imidazol-1-yl)propan-1-amine {3} and 0.11 g (2.8 mmol) of NaBH4. 0.36 g (0.9 mmol, 34%) of a yellow oil 1{6,3} are obtained. IR (CHCl3 evaporated film): ν (cm−1) 3278, 2934, 2875, 2795, 1508, 1458, 1372, 1356, 1014. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.43 (s, 1H, CH), 7.27 (s, 4H, Ph), 7.03 (s, 1H, CH), 6.88 (s, 1H, CH), 4.04 (t, 2H, J=6.9 Hz, CH2—N), 3.77 (s, 2H, CH2-Ph), 3.74 (s, 2H, CH2-Ph), 2.68 (t, 2H, J=7.2 Hz, CH2—N), 2.61 (t, 2H, J=6.6 Hz, CH2—N), 2.43 (bs, 8H, CH2—N), 2.41 (t, 2H, J=7.2 Hz, CH2—N), 2.27 (s, 3H, CH3), 1.93 (bs, 2H, NH), 1.92 (m, 2H, J=6.6 Hz, CH2), 1.71 (m, 2H, J=7.2 Hz, CH2). 13C-NMR (75 MHz, CDCl3): δ (ppm) 139.0, 138.7, 137.1, 129.2, 128.1, 128.0, 118.7, 56.9, 55.1, 53.7, 53.2, 48.1, 46.0, 45.7, 44.7, 31.4, 26.9. MS (IE): m/z 385.3 [M+1H]+, 271.2, 257.1, 113.1, 70.0. HRMS: Calculated for C22H36N6: 384.3001. Obtained: 384.3004.
As for 2{10,1}, but using 0.79 g (3.2 mmol) of 9{3}, 0.43 g (3.2 mmol) of 2-morpholinoethylamine {7} and 0.12 g (3.2 mmol) of NaBH4. 1.11 g (3.1 mmol, 96%) of a yellowish oil 1{3,7} are obtained. IR (film): ν (□□cm−1) 3299, 3105, 2934, 2890, 2851, 2811, 1508, 1454, 1117, 854. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.43 (s, 1H, CH), 7.28 (s, 4H, Ph), 7.03 (s, 1H, CH), 6.88 (s, 1H, CH), 4.05 (t, 2H, J=6.9 Hz, CH2—N), 3.79 (s, 2H, CH2-Ph), 3.74 (s, 2H, CH2-Ph), 3.69 (t, 4H, J=4.7 Hz, CH2—O), 2.71 (t, 2H, J=6.0 Hz, CH2—N), 2.60 (t, 2H, J=6.9 Hz, CH2—N), 2.50 (t, 2H, J=6.0 Hz, CH2—N), 2.41 (t, 4H, J=4.7 Hz, CH2—N), 1.95 (bs, 2H, NH), 1.93 (m, 2H, J=6.9 Hz, CH2). 13C-NMR (75 MHz, CDCl3): δ (ppm) 139.0, 138.7, 137.0, 129.2, 128.1, 128.0, 118.7, 67.0, 58.2, 53.7, 45.6, 45.3, 44.6, 31.2. MS (IE): m/z 358.2 [M+1H]+, 257.0, 100.0. HRMS: Calculated for C20H31N5O: 357.2529. Obtained: 357.2517.
As for 2{10,1}, but using 1.15 g (4.4 mmol) of 9{8}, 0.56 g (4.4 mmol) of 3-(1H-imidazol-1-yl)propan-1-amine {3} and 0.17 g (4.4 mmol) of NaBH4. 1.36 g (3.7 mmol, 85%) of a yellow oil 1{8,3} are obtained. IR (CHCl3 evaporated film): ν (□cm1) 3282, 2935, 2852, 2808, 1509, 1456, 1117. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.42 (s, 1H, CH), 7.27 (m, 4H, Ph), 7.03 (s, 1H, CH), 6.88 (s, 1H, CH), 4.04 (t, 2H, J=6.9 Hz, CH2—N), 3.79 (s, 2H, CH2-Ph), 3.74 (s, 2H, CH2-Ph), 3.69 (t, 4H, J=4.7 Hz, CH2—O), 2.71 (t, 2H, J=6.9 Hz, CH2), 2.60 (t, 2H, J=6.9 Hz, CH2), 2.42 (m, 6H, CH2—N), 1.92 (m, 2H, J=6.9 Hz, CH2), 1.88 (s, 2H, NH), 1.72 (m, 2H, J=6.9 Hz, CH2). 13C-NMR (75 MHz, CDCl3): δ (ppm) 138.9, 138.18, 137.0, 129.1, 128.2, 128.2, 118.7, 66.9, 57.4, 53.7, 53.6, 53.4, 48.0, 45.5, 44.6, 31.3, 26.1. MS (IE): m/z 373.0 [M+2H]+, 372.0, 114.0, 100.0, 95.0, 81.0. HRMS: Calculated for C21H34N5O: 372.2763 [M+1H]+. Obtained: 372.2758.
As for 2{10,1}, but using 0.73 g (2.6 mmol) of 9{6}, 0.34 g (2.6 mmol) of 2-(piperidin-1-yl)ethylamine {4} and 0.10 g (2.6 mmol) of NaBH4. 0.48 g (1.2 mmol, 47%) of a yellowish oil 1{6,4} are obtained. IR (CHCl3 evaporated film): ν (□□□cm−1) 3285, 2934, 2878, 2849, 2794, 1457, 1446, 1372, 1349, 1015. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.27 (s, 4H, Ph), 3.78 (s, 2H, CH2-Ph), 3.77 (s, 2H, CH2-Ph), 2.69 (m, 4H, CH2—N), 2.47-2.34 (m, 16H, CH2—N), 2.27 (s, 3H, CH3), 2.22 (bs, 2H, NH), 1.72 (m, 2H, J=6.9 Hz, CH2), 1.55 (m, 4H, CH2), 1.42 (m, 2H, CH2). 13C-NMR (75 MHz, CDCl3): δ (ppm) 139.0, 138.5, 128.1, 128.8, 58.5, 57.0, 55.1, 54.7, 53.7, 53.6, 53.2, 48.1, 46.0, 45.9, 26.8, 26.0, 24.5.
As for 2{10,1}, but using 0.89 g (3.4 mmol) of 9{8}, 0.44 g (3.4 mmol) of 2-(piperidin-1-yl)ethylamine {4} and 0.13 g (3.4 mmol) of NaBH4. 1.24 g (3.3 mmol, 98%) of a yellow oil 1{8,4} are obtained. IR (CHCl3 evaporated film): ν (□□□cm−1) 3304, 2933, 2852, 2806, 1454, 1444, 1119, 862, 756. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.27 (s, 4H, Ph), 3.78 (s, 2H, CH2-Ph), 3.77 (s, 2H, CH2-Ph), 3.69 (t, 4H, J=4.7 Hz, CH2—O), 2.69 (m, 4H, CH2—N), 2.47-2-34 (m, 12H, CH2—N), 2.11 (bs, 2H, NH), 1.71 (m, 2H, J=7.2 Hz, CH2), 1.55 (m, 4H, CH2), 1.42 (m, 2H, CH2). 13C-NMR (75 MHz, CDCl3): δ (ppm) 139.0, 138.6, 128.1, 128.0, 66.9, 58.5, 57.4, 54.7, 53.8, 53.7, 48.0, 45.9, 26.6, 26.0, 24.5. MS (IE): m/z 373.3 [M−1H]+, 98.0. Anal. Calculated for C22H38N4O: C, 70.54%, H, 10.23%, N, 14.96%, O, 4.27%. Obtained: C, 70.68%, H, 10.05%, N, 14.67%.
As for 2{10,1}, but using 0.75 g (2.7 mmol) of 9{6}, 0.45 g (2.7 mmol) of 3-(2-methylpiperidin-1-yl)propan-1-amine {5} and 0.10 g (2.7 mmol) of NaBH4. 0.45 g (1.1 mmol, 39%) of a yellow oil 1{6,5} are obtained. IR (CHCl3 evaporated film): ν (□cm−1) 3280, 2931, 2875, 2852, 2793, 1458, 1448, 1372, 1015. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.28 (s, 4H, Ph), 3.77 (s, 4H, CH2-Ph), 2.88 (m, 1H, CH), 2.75 (m, 1H, CH2), 2.67 (t, 2H, J=6.6 Hz, CH2—N), 2.65 (t, 2H, J=6.6 Hz, CH2—N), 2.43 (bs, 12H, CH2—N), 2.27 (s, 3H, CH3), 2.23 (bs, 2H, NH), 2.12 (m, 1H, CH2), 1.76-1.53 (m, 8H, CH2), 1.32-1.21 (m, 2H, CH2), 1.05 (d, 3H, J=6.3 Hz, CH3). 13C-NMR (75 MHz, CDCl3): δ (ppm) 138.8, 138.6, 128.1, 128.0, 57.0, 56-0, 55.1, 53.7, 53.2, 52.3, 52.0, 48.3, 48.1, 46.0, 34.5, 26.9, 26.0, 25.6, 23.9, 19.0. MS (IE): m/z 415.4 [M]+, 218.2, 112.2, 98.0. HRMS: Calculated for C25H45N5: 415.3675. Obtained: 415.3660.
As for 2{10,1}, but using 1.35 g (8.5 mmol) of 9{5}, 1.12 g (8.5 mmol) of 2-morpholinoethylamine {7} and 0.33 g (8.5 mmol) of NaBH4. 2.46 g (6.3 mmol, 74%) of a yellowish oil 1{5,7} are obtained. IR (CHCl3 evaporated film): ν (□cm−1) 3305, 2930, 2853, 2807, 1453, 1119. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.27 (s, 4H, Ph), 3.79 (s, 2H, CH2-Ph), 3.77 (s, 2H, CH2-Ph), 3.69 (t, 4H, J=4.5 Hz, CH2—O), 2.86 (m, 1H, CH), 2.74 (m, 1H, CH2), 2.70 (t, 2H, J=6.0 Hz, CH2—N), 2.633 (t, 2H, J=6.9 Hz, CH2—N), 2.49 (t, 2H, J=6.0 Hz, CH2—N), 2.40 (m, 4H, CH2—N), 2.34 (m, 1H, CH2), 2.25 (m, 1H, CH2), 2.11 (m, 1H, CH2), 1.91 (bs, 2H, NH), 1.63 (m, 6H, CH2), 1.27 (m, 2H, CH2), 1.05 (d, 3H, J=6.0 Hz, CH3). 13C-NMR (75 MHz, CDCl3): δ (ppm) 139.0, 138.9, 128.0, 128.0, 67.0, 58.3, 55.9, 53.8, 53.7, 53.7, 52.3, 52.1, 48.4, 45.3, 34.7, 26.2, 25.8, 24.0, 19.2. MS (IE): m/z 389.3 [M+1H]+, 155.2, 126.2, 112.1, 100.0, 98.0. HRMS: Calculated for C23H40N4O: 374.3046. Obtained: 374.3049.
As for 2{10,1}, but using 1.00 g (3.8 mmol) of 9{18}, 0.62 g (3.8 mmol) of 3-(2-methylpiperidin-1-yl)propan-1-amine {5} and 0.15 g (3.8 mmol) of NaBH4. 1.54 g (3.8 mmol, 100%) of a yellow oil 1{8,5} are obtained. IR (CHCl3 evaporated film): ν (□□□cm−1) 3286, 2929, 2853, 2806, 1448, 1372, 1119, 862, 752. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.27 (s, 4H, Ph), 3.77 (s, 4H, CH2-Ph), 3.70 (t, 4H, J=4.7 Hz, CH2—O), 2.87 (m, 1H, CH), 2.79-2.62 (m, 5H, CH2), 2.43-2.32 (m, 7H, CH2), 2.27 (m, 1H, CH2), 2.12 (bs, 2H, NH), 2.11 (m, 1H, CH2), 1.75-1.52 (m, 8H, CH2), 1.30 (m, 2H, CH2), 1.05 (d, 3H, J=6.0 Hz, CH3). 13C-NMR (75 MHz, CDCl3): δ (ppm) 138.9, 138.7, 128.1, 128.0, 67.0, 57.4, 56.0, 53.8, 53.7, 52.3, 52.0, 48.3, 48.0, 34.6, 27.0, 26.1, 25.7, 23.9, 19.1. MS (IE): m/z 403.4 [M+1H]+, 112.0, 100.0. HRMS: Calculated for C24H42N4O: 402.3359. Obtained: 402.3354.
As for 2{10,1}, but using 0.68 g (2.7 mmol) of 9{7}, 0.44 g (2.7 mmol) of 3-(4-methylpiperazin-1-yl)propan-1-amine {6} and 0.10 g (2.7 mmol) of NaBH4. 0.92 g (2.4 mmol, 86%) of a yellow oil 1{7,6} are obtained. IR (film): ν (□cm−1) 3300, 2935, 2872, 2796, 1456, 1372, 1355, 1118, 1014, 868, 765. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.27 (s, 4H, Ph), 3.79 (s, 2H, CH2-Ph), 3.77 (s, 2H, CH2-Ph), 3.68 (t, 4H, J=4.7 Hz, CH2—O), 2.69 (m, 4H, CH2—N), 2.52-2.39 (m, 16H, CH2—N), 2.27 (s, 3H, CH3), 2.11 (bs, 2H, NH), 1.72 (m, 2H, J=6.9 Hz, CH2). 13C-NMR (75 MHz, CDCl3): δ (ppm) 138.9, 138.7, 128.0, 67.0, 58.2, 57.0, 55.1, 53.7, 53.2, 48.1, 46.0, 45.3, 26.9. MS (IE): m/z 389.4 [M]+, 100.1. HRMS: Calculated for C22H39N5O: 389.3155. Obtained: 389.3153.
As for 2{10,1}, but using 0.71 g (2.7 mmol) of 9{8}, 0.43 g (2.7 mmol) of 3-(4-methylpiperazin-1-yl)propan-1-amine {6} and 0.10 g (2.7 mmol) of NaBH4. 0.91 g (2.3 mmol, 84%) of a yellow oil 1{8,6} are obtained. IR (film): ν (□cm−1) 3288, 2935, 2872, 2851, 2795, 1476, 1372, 1356, 1118, 1014, 862, 751. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.27 (s, 4H, Ph), 3.77 (s, 4H, CH2-Ph), 3.69 (t, 4H, J=4.8 Hz, CH2—O), 2.68 (t, 2H, J=6.9 Hz, CH2—N), 2.67 (t, 2H, J=6.9 Hz, CH2—N), 2.45-2.37 (m, 16H, CH2—N), 2.27 (s, 3H, CH3), 2.03 (bs, 2H, NH), 1.71 (m, 4H, J=6.9 Hz, CH2). 13C-NMR (75 MHz, CDCl3): δ (ppm) 138.8, 128.0, 127.9, 66.9, 57.3, 56.9, 55.1, 53.7, 53.2, 48.1, 47.9, 46.0, 26.9, 26.7. MS (IE): m/z 403.4 [M]+, 113.2, 100.1. HRMS: Calculated for C23H41N5O: 403.3311. Obtained: 403.3311.
As for 2{10,1}, but using 0.88 g (3.3 mmol) of 9{8}, 0.44 g (3.3 mmol) of 2-morpholinoethylamine {7} and 0.13 g (3.3 mmol) of NaBH4. 1.16 g (3.1 mmol, 92%) of an orange oil 1{8,7} are obtained. IR (CHCl3 evaporated film): ν (□cm−1) 3307, 2950, 2891, 2852, 2808, 1455, 1118, 863, 765. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.27 (s, 4H, Ph), 3.79 (s, 2H, CH2-Ph), 3.77 (s, 2H, CH2-Ph), 3.69 (m, 8H, CH2—O), 2.69 (m, 4H, CH2—N), 2.50 (t, 2H, J=6.0 Hz, CH2—N), 2.45-2.38 (m, 10H, CH2—N), 1.96 (bs, 2H, NH), 1.71 (m, 2H, J=6.9 Hz, CH2). 13C-NMR (75 MHz, CDCl3): δ (ppm) 138.9, 138.8, 128.1, 128.0, 67.0, 58.2, 57.4, 53.8, 53.7, 48.0, 45.3, 26.7. MS (IE): m/z 377.2 [M+1H]+, 376.2, 276.2, 100.0. HRMS: Calculated for C21H36N4O2: 376.2838. Obtained: 376.2849.
0.53 g (2.3 mmol) of 10{11} and 0.24 g (2.3 mmol) of 1-aminopiperidine {9} are dissolved in 30 mL of anhydrous MeOH. 4 Å molecular sieve is added and it is stirred at reflux temperature and under a nitrogen atmosphere for 36 h. The molecular sieve is filtered and the solvent is eliminated under reduced pressure and 0.69 g (2.2 mmol, 95%) of a yellow solid 3{11,9} are obtained. IR (film): ν (□cm−1) 2934, 2837, 2798, 1577, 1452, 1365, 1001. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.56 (s, 4H, Ph), 7.53 (s, 1H, CH═N), 7.52 (s, 1H, CH═N), 3.22 (t, 4H, J=5.1 Hz, CH2—N), 3.17 (t, 4H, J=5.6 Hz, CH2—N), 2.62 (t, 4H, J=5.1 Hz, CH2—N), 2.36 (s, 3H, CH3), 1.75 (m, 4H, CH2), 1.54 (m, 2H, CH2). 13C-NMR (75 MHz, CDCl3): δ (ppm) 136.4, 135.6, 135.5, 134.0, 126.2, 126.0, 54.6, 52.1, 51.0, 46.0, 25.3, 24.2. MS (IE): m/z 314.2 [M+1H]+, 313.2, 99.2. HRMS: Calculated for C18H27N5: 313.2266. Obtained: 313.2266.
As for 3{11,9}, but using 1.04 g (4.2 mmol) of 9{2} and 0.44 g (4.2 mmol) 1-aminopiperidine {9}. 1.17 g (3.6 mmol, 84%) of a yellow oil 2{2,9} are obtained. IR (film): ν (□cm−1) 3287, 2935, 2874, 2854, 2793, 1591, 1450. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.55 (d, 2H, J=8.1 Hz, Ph), 7.54 (s, 1H, CH═N), 7.27 (d, 2H, J=8.1 Hz, Ph), 3.78 (s, 2H, CH2-Ph), 3.15 (t, 4H, J=5.7 Hz, CH2—N), 2.28 (t, 2H, J=6.9 Hz, CH2—N), 2.50 (m, 6H, CH2—N), 2.03 (bs, 1H, NH), 1.79-1.69 (m, 10H, CH2), 1.55 (m, 2H, CH2). 13C-NMR (75 MHz, CDCl3): δ (ppm) 139.7, 135.3, 134.5, 128.1, 125.9, 54.8, 54.2, 53.7, 52.1, 48.0, 29.1, 25.2, 24.2, 23.5. MS (IE): m/z 328.3 [M]+, 244.2, 201.2, 84.1. HRMS: Calculated for C20H32N4: 328.2627. Obtained: 328.2624.
As for 3{11,9}, but using 0.98 g (4.0 mmol) of 9{3} and 0.42 g (4.0 mmol) of 1-aminopiperidine {9}. 1.31 g (4.0 mmol, 100%) of a reddish oil 2{3,9} are obtained. IR (CHCl3 evaporated film): ν (□cm−1) 3282, 3105, 2935, 2853, 2809, 1590, 1508, 1450. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.56 (s, 1H, CH═N), 7.55 (d, 2H, J=8.1 Hz, Ph), 7.45 (s, 1H, CH), 7.26 (d, 2H, J=8.1 Hz, Ph), 7.03 (s, 1H, CH), 6.88 (s, 1H, CH), 4.03 (t, 2H, J=6.9 Hz, CH2—N), 3.74 (s, 2H, CH2-Ph), 3.15 (t, 4H, J=5.6 Hz, CH2—N), 2.60 (t, 2H, J=6.9 Hz, CH2—N), 2.07 (bs, 1H, NH), 1.92 (m, 2H, J=6.9 Hz, CH2), 1.75 (m, 4H, J=5.7 Hz, CH2), 1.54 (m, 2H, J=5.7 Hz, CH2). 13C-NMR (75 MHz, CDCl3): δ (ppm) 139.5, 137.0, 135.5, 134.2, 129.2, 128.1, 125.9, 118.7, 53.7, 52.1, 45.6, 44.7, 31.3, 25.2, 24.2. MS (IE): m/z 326.2 [M+1H]+, 243.2, 215.1, 91.0. HRMS: Calculated for C19H27N5: 325.2266. Obtained: 325.2277.
As for 3{11,9}, but using 0.51 g (1.9 mmol) of 9{5} and 0.19 g (1.9 mmol) of 1-aminopiperidine {9}. 0.67 g (1.9 mmol, 100%) of a reddish oil 2{5,9} are obtained. IR (film): ν (□cm−1) 3282, 2932, 2854, 2804, 1591, 1450, 1364, 992. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.55 (d, 2H, J=8.1 Hz, Ph), 7.54 (s, 1H, CH═N), 7.28 (d, 2H, J=8.1 Hz, Ph), 3.78 (s, 2H, CH2-Ph), 3.15 (t, 4H, J=5.4 Hz, CH2—N), 2.87 (m, 1H, CH), 2.74 (m, 1H, CH2), 2.65 (t, 2H, J=6.9 Hz, CH2), 2.42 (bs, 1H, NH), 2.37 (m, 1H, CH2), 2.28 (m, 1H, CH2), 2.13 (m, 1H, CH2), 1.79-1.52 (m, 12H, CH2), 1.29 (m, 2H, CH2), 1.05 (d, 3H, J=6.3 Hz, CH3). 13C-NMR (75 MHz, CDCl3): δ (ppm) 139.5, 135.4, 134.4, 128.2, 125.9, 56.0, 53.7, 52.3, 52.1, 52.0, 48.3, 34.6, 26.1, 25.5, 25.3, 24.2, 23.9, 19.0. MS (IE): m/z 356.2 [M]+, 216.0, 201.0, 155.1, 112.0, 84.0. HRMS: Calculated for C22H36N4: 356.2940. Obtained: 356.2942.
As for 3{11,9}, but using 0.96 g (3.5 mmol) of 9{6} and 0.36 g (3.5 mmol) of 1-aminopiperidine {9}. 1.21 g (3.4 mmol, 97%) of a yellow oil 2{6,9} are obtained. IR (film): ν (□cm−1) 3286, 2935, 2875, 2853, 2794, 1591, 1451, 1357, 1015. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.55 (d, 2H, J=8.1 Hz, Ph), 7.54 (s, 1H, CH═N), 7.27 (d, 2H, J=8.1 Hz, Ph), 3.77 (s, 2H, CH2-Ph), 3.15 (t, 4H, J=5.7 Hz, CH2—N), 2.67 (t, 2H, J=6.9 Hz, CH2—N), 2.42 (bs, 8H, CH2—N), 2.40 (t, 2H, J=6.9 Hz, CH2—N), 2.27 (s, 3H, CH3), 2.16 (bs, 1H, NH), 1.79-1.66 (m, 6H, CH2), 1.54 (m, 2H, CH2). 13C-NMR (75 MHz, CDCl3): δ (ppm) 139.7, 135.4, 134.5, 128.1, 125.9, 57.0, 55.1, 53.7, 53.2, 52.1, 48.1, 46.0, 26.9, 25.3, 24.2. MS (IE): m/z 358.3 [M+1H]+, 273.2, 201.1, 113.0, 84.0. HRMS: Calculated for C21H35N5: 357.2892. Obtained: 357.2903.
As for 3{11,9}, but using 0.93 g (3.6 mmol) of 9{8} and 0.37 g (3.6 mmol) of 1-aminopiperidine {9}. 1.21 g (3.5 mmol, 99%) of a yellow oil 2{8,9} are obtained. IR (CHCl3 evaporated film): ν (□cm−1) 3298, 2936, 2853, 2807, 1591, 1451, 1118, 861, 762. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.55 (d, 2H, J=8.1 Hz, Ph), 7.54 (s, 1H, CH═N), 7.27 (d, 2H, J=8.1 Hz, Ph), 3.77 (s, 2H, CH2-Ph), 3.69 (t, 4H, J=4.7 Hz, CH2—O), 3.15 (t, 4H, J=5.6 Hz, CH2—N), 2.67 (t, 2H, J=6.9 Hz, CH2—N), 2.44-2.37 (m, 6H, CH2—N), 1.99 (bs, 1H, NH), 1.79-1.65 (m, 6H, CH2), 1.54 (m, 2H, J=5.7 Hz, CH2). 13C-NMR (75 MHz, CDCl3): δ (ppm) 139.8, 135.4, 134.4, 128.1, 125.9, 67.0, 57.4, 53.8, 52.1, 47.9, 26.6, 25.3, 24.2. MS (IE): m/z 345.2 [M+1H]+, 344.2, 260.1, 100.0. HRMS: Calculated for C20H32N4O: 344.2576. Obtained: 344.2580.
As for 3{11,9}, but using 1.00 g (4.1 mmol) of 9{2} and 0.58 g (4.1 mmol) of 1-amino-2,6-dimethylpiperidine {10}. 1.18 g (3.3 mmol, 81%) of a yellow oil 2{2,10} are obtained. IR (film): ν (□cm1) 3283, 2961, 2931, 2872, 2794, 1625, 1449, 1369, 1048. 1H-NMR (300 MHz, CDCl3): δ (ppm) 8.06 (s, 1H, CH═N), 7.64 (d, 2H, J=8.1 Hz, Ph), 7.33 (d, 2H, J=8.1 Hz, Ph), 3.81 (s, 2H, CH2-Ph), 3.07 (bs, 2H, CH), 2.69 (t, 2H, J=6.9 Hz, CH2—N), 2.51 (m, 6H, CH2—N), 2.08 (bs, 1H, NH), 1.79-1.69 (m, 10H, CH2), 1.53 (m, 2H, CH2), 1.00 (d, 6H, J=6.3 Hz, CH3). 13C-NMR (75 MHz, CDCl3): δ (ppm) 152.4, 141.7, 133.7, 128.1, 127.3, 57.3, 54.8, 54.2, 53.7, 48.0, 32.9, 29.1, 23.5, 21.5, 20.6. MS (IE): m/z 356.3 [M]+, 244.2, 98.2, 84.1. HRMS: Calculated for C22H36N4: 356.2940. Obtained: 356.2934.
As for 3{11,9}, but using 1.03 g (4.2 mmol) of 9{2} and 0.50 g (4.2 mmol) of 3-(4-methylpiperazin-1-yl)propan-1-amine {6}. 1.43 g (4.2 mmol, 100%) of a yellow oil 2{2,6} are obtained. IR (film): ν (□cm−1) 3288, 2937, 2876, 2794, 1592, 1452, 1365, 1355. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.55 (d, 2H, J=8.1 Hz, Ph), 7.54 (s, 1H, CH═N), 7.28 (d, 2H, J=8.1 Hz, Ph), 3.78 (s, 2H, CH2-Ph), 3.21 (t, 4H, J=5.1 Hz, CH2—N), 2.70 (t, 2H, J=6.6 Hz, CH2—N), 2.62 (t, 4H, J=5.1 Hz, CH2—N), 2.49 (m, 6H, CH2—N), 2.35 (s, 3H, CH3), 2.02 (bs, 1H, NH), 1.76 (m, 6H, CH2). 13C-NMR (75 MHz, CDCl3): δ (ppm) 140.3, 135.8, 134.8, 128.1, 126.0, 54.8, 54.5, 54.3, 53.7, 51.0, 48.0, 46.0, 29.2, 23.5. MS (IE): m/z 343.2 [M]+, 244.2, 216.2, 99.2, 84.2. HRMS: Calculated for C20H33N5: 343.2736. Obtained: 343.2736.
As for 3{11,9}, but using 0.92 g (3.8 mmol) of 9{3} and 0.45 g (3.8 mmol) of 3-(4-methylpiperazin-1-yl)propan-1-amine {6}. 1.23 g (3.6 mmol, 96%) of a yellow oil 2{3,6} are obtained. IR (film): ν (□cm1) 3282, 3104, 2937, 2880, 2828, 2797, 1592, 1452, 1365, 1356, 999. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.56 (d, 2H, J=8.1 Hz, CH2-Ph), 7.55 (s, 1H, CH═N), 7.45 (s, 1H, CH), 7.27 (d, 2H, J=8.1 Hz, CH2-Ph), 7.04 (s, 1H, CH), 6.89 (s, 1H, CH), 4.04 (t, 2H, J=6.9 Hz, CH2—N), 3.75 (s, 2H, CH2-Ph), 3.22 (t, 4H, J=5.1 Hz, CH2—N), 2.64-2.58 (m, 6H, CH2—N), 2.36 (s, 3H, CH3), 1.92 (m, 2H, J=6.9 Hz, CH2), 1.70 (bs, 1H, NH). 13C-NMR (75 MHz, CDCl3): δ (ppm) 140.0, 137.0, 135.6, 135.1, 129.2, 128.1, 126.1, 118.7, 54.5, 53.7, 51.0, 45.9, 45.6, 44.7, 31.4. MS (IE): m/z 341.3 [M+1H]+, 98.2, 56.0. HRMS: Calculated for C19H28N6: 340.2375. Obtained: 340.2374.
As for 3{11,9} but using 0.93 g (3.4 mmol) of 9{5} and 0.40 g (3.4 mmol) of 3-(4-methylpiperazin-1-yl)propan-1-amine {6}. 1.05 g (2.8 mmol, 84%) of a red oil 2{5,6} are obtained. IR (film): ν (□cm1) 3279, 2932, 2881, 2841, 2795, 1593, 1452, 1366, 1000. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.56 (d, 2H, J=8.1 Hz, CH2-Ph), 7.55 (s, 1H, CH═N), 7.29 (d, 2H, J=8.1 Hz, CH2-Ph), 3.77 (s, 2H, CH2-Ph), 3.21 (t, 4H, J=5.1 Hz, CH2—N), 2.87 (m, 1H, CH), 2.73 (m, 1H, CH2), 2.65-2.60 (m, 7H, CH2—N), 2.36 (s, 3H, CH3), 2.29 (m, 1H, CH2), 2.11 (m, 1H, CH2), 1.95 (bs, 1H, NH), 1.73-1.48 (m, 6H, CH2), 1.27 (m, 2H, CH2), 1.04 (d, 3H, J=6.0 Hz, CH3). 13C-NMR (75 MHz, CDCl3): δ (ppm) 140.3, 135.8, 134.8, 128.2, 126.1, 56.0, 54.5, 54.0, 52.2, 52.1, 51.1, 48.3, 46.0, 34.7, 26.2, 25.8, 24.0, 19.1. MS (IE): m/z 372.4 [M+1H]+, 371.4, 272.3, 216.2, 112.2, 99.2. HRMS: Calculated for C22H37N5: 371.3049. Obtained: 371.3053.
As for 3{11,9}, but using 0.93 g (3.4 mmol) of 9{6} and 0.40 g (3.4 mmol) of 3-(4-methylpiperazin-1-yl)propan-1-amine {6}. 1.25 g (3.4 mmol, 99%) of a yellowish oil 2{6,6} are obtained. IR (film): ν (□cm−1) 3283, 2936, 2877, 2836, 2794, 2768, 1593, 1453, 1365, 1356, 999. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.55 (d, 2H, J=8.1 Hz, CH2-Ph), 7.55 (s, 1H, CH═N), 7.28 (d, 2H, J=8.1 Hz, CH2-Ph), 3.77 (s, 2H, CH2-Ph), 3.21 (t, 4H, J=5.1 Hz, CH2—N), 2.66 (t, 2H, J=6.9 Hz, CH2—N), 2.62 (t, 4H, J=5.1 Hz, CH2—N), 2.42 (bs, 10H, CH2—N), 2.40 (t, 2H, J=6.9 Hz, CH2—N), 2.36 (s, 3H, CH3), 2.71 (s, 3H, CH3), 1.82 (bs, 1H, NH), 1.70 (m, 2H, J=6.9 Hz, CH2). 13C-NMR (75 MHz, CDCl3): δ (ppm) 140.2, 135.8, 134.8, 128.1, 126.0, 57.0, 55.1, 54.5, 53.7, 53.2, 51.0, 48.0, 46.0, 45.9, 26.9. MS (IE): m/z 373.4 [M+1H]+, 372.3, 273.3, 216.2, 113.2, 99.2, 56.0. HRMS: Calculated for C21H36N6: 372.3001. Obtained: 372.2990.
As for 3{11,9}, but using 0.89 g (3.4 mmol) of 9{8} and 0.40 g (3.4 mmol) of 3-(4-methylpiperazin-1-yl)propan-1-amine {6}. 1.22 g (3.4 mmol, 100%) of a yellow oil 2{6,6} are obtained. IR (CHCl3 evaporated film): ν (□cm−1) 3293, 2939, 2888, 2844, 2799, 2592, 1453, 1364, 1356, 1118, 806. 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.56 (s, 1H, CH═N), 7.56 (d, 2H, J=8.1 Hz, Ph), 7.28 (d, 2H, J=8.1 Hz, Ph), 3.77 (s, 2H, CH2-Ph), 3.69 (t, 4H, J=4.7 Hz, CH2—O), 3.21 (t, 4H, J=5.1 Hz, CH2—N), 2.67 (t, 2H, J=6.9 Hz, CH2—N), 2.62 (t, 4H, J=5.1 Hz, CH2—N), 2.44-2.37 (m, 6H, CH2—N), 2.35 (s, 3H, CH3), 2.05 (bs, 1H, NH), 1.70 (m, 2H, J=6.9 Hz, CH2). 13C-NMR (75 MHz, CDCl3): δ (ppm) 140.2, 135.7, 134.9, 128.1, 126.1, 66.9, 57.4, 54.5, 53.8, 51.0, 47.9, 45.9, 26.6. MS (IE): m/z 359.2 [M]+, 260.2, 231.2, 100.0. HRMS: Calculated for C20H33N5O: 359.2685. Obtained: 359.2685.
| Number | Date | Country | Kind |
|---|---|---|---|
| P200602764 | Oct 2006 | ES | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/ES07/00613 | 10/26/2007 | WO | 00 | 4/27/2009 |
