2-azabicyclo[3.3.1]nonane derivatives

Abstract

The subject invention relates to 2-azabicyclo[3.3.1]nonane derivatives, pharmaceutical compositions comprising such derivatives and methods of using such derivatives to treat disease states, disorders and conditions mediated by opioid receptors. The subject invention also particularly relates to using such derivatives to treat certain disorders and conditions, for example irritable bowel syndrome, drug addiction, including alcohol addiction, depression, anxiety, schizophrenia and eating disorders, among others, as are more fully described herein.

Description

where lC₅₀ is the concentration at which 50% of the ³H ligand is displaced by the test compound and K_D is the dissociation constant for the ³H ligand at the receptor site.

The Ki values of certain compounds of formula 1 of the Examples, as described, infra, in a mu opioid receptor binding assay to brain tissue such as that described above, were determined. All of the compounds tested in this manner were all found to have Ki values of about 800 nM or less for the mu opioid receptor.

The inhibition (%) of [³H]-DAMGO binding by certain compounds of formula I of the Examples, as described, infra, in a mu opioid receptor binding assay to brain tissue such as that described above, were determined. Most of the compounds tested at 100 nM were found to inhibit [³H]-DAMGO binding at the mu opioid receptor in a range of 10-100%.

Other assays which may be used for determining the binding of compounds according to the present invention to opioid receptors are well known in the art. These assays may be used to assess the ability of a compound to modulate (i.e., inhibit, partially inhibit, activate or partially activate) an opioid receptor or receptors by determining a compound's agonist or antagonist activity in the in vitro or in vivo assay. These assays include, for example, the GTP gamma S binding assay as described in Martin, et al., J. Pharm. Exp. Ther., 301, 661-671 (2003) and Zaki, et al., J. Pharm. Exp. Ther., 298, 1015-1020 (2002), as well as other binding assays, such as the isolated guinea pig ileum and receptor binding assay as disclosed, for example, by Takayama, et al., J. Med. Chem., 45, 1949-1956 (2002) and the guinea pig brain binding assay as described by Wentland, et al., J. Med. Chem., 46, 838-849 (2003). The use of mouse brain tissue to determine the functional activity of the compounds of interest is another binding assay which can be used for characterizing the modulation of the present compounds at opioid receptors, as disclosed by Martin, et al., Idem. Other binding assays include the tail-flick assay in mice or the radiant heat paw-withdrawal hyperalgesic testing in mice, as described by Hosohata, et al., J. Pharm. Exp. Ther., 304, 683-688 (2003), among others. These assays or variations of these assays are well-known to those of ordinary skill in the art.

EXAMPLES

Preparation 1

3-(2-Benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenol

¹H NMR (400 MHz, CD₃OD) δ 7.55 (m, 2H), 7.46 (m, 3H), 7.10 (t, J=7.9 Hz, 1H), 6.78 (d, J=7.9 Hz, 1H), 6.74 (dd, J=2.1, 0.8 Hz, 1H), 6.61 (dd, J=7.9, 1.6 Hz, 1H), 4.42 (s, 2H), 3.70 (m, 2H), 3.36 (m, 1H), 2.42 (m, 1H), 2.31 (brd, J=14.5 Hz, 1H), 2.23 (m, 1H), 2.20-210 (m, 3H), 1.94 (m, 1H), 1.84 (m, 2H),k 1,70 (m, 1H); ¹³C NMR (100 MHz, HCl salt, DMSO_d6) δ □157.9, 151.8, 131.8, 130.9, 129.9, 129.9, 129.5, 129.4, 115.8, 113.6, 112.3, 56.9, 53.7, 49.6, 37.4, 35.1, 34.2, 34.0, 21.9, 21.2; APCl MS m/z 308.3 (M+1)⁺.

Trifluoro-methanesulfonic acid 3-(2-benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl ester

3-(2-Benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenol (31.51 g, 102 mmol) was dissolved in CH₂Cl₂ (250 mL) with triethylamine (20 mL, 143 mmol) and N-phenyltrifluoromethanesulfonimide (43.94 g, 123 mmol). The reaction was judged complete by TLC after 18 h, then quenched with saturated aqueous NaHCO₃ solution (100 mL). The product was extracted with CH₂Cl₂ (3×100 mL), washed with water (200 mL), saturated aqueous NaCl solution (200 mL), dried through a cotton plug and concentrated to an oil. This was filtered through a silica pad (6×6 in), eluted with 15-20% EtOAc/hexanes and concentrated to a semi-solid (37.4 g, 83%). (TLC 25% EtOAc/hexanes R_f 0.30); ¹H NMR (400 MHz, CDCl₃) δ 7.46 (m, 2H), 7.34 (m, 3H), 7.28 (m, 1H), 7.13 (m, 1H), 7.08 (m, 1H), 6.95 (m, 1H), 3.90 (AB q, ΔAB=14.8, J=13.3 Hz, 2H), 3.27 (m, 1H), 3.16 (m, 1H), 3.04 (m, 1H), 2.22 (m, 2H), 2.03 (m, 4H), 1.81 (br d. J=12.9 Hz, 1H), 1.76 (m, 1H), 1.60 (m, 1H), 1.44 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ □ 154.4, 149.9, 130.2, 129.7, 129.0, 128.8, 128.0, 125.2, 125.1, 128.3, 118.2, 59.5, 52.4, 49.3, 38.1, 37.7, 36.5, 35.2, 24.2, 22.4; APCl MS m/z 440.1 (M+1)⁺.

3-(2-Benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenylamine

Trifluoro-methanesulfonic acid 3-(2-benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl ester (13.33 g, 30.33 mmol) was azeotroped with THF (2×50 mL) then dissolved in anhydrous THF (150 mL) with benzophenone imine (6.3 mL, 17.61 mmol), cesium carbonate (14.23 g, 43.67 mmol) and BlNAP (racemic, 1.89 g, 3.03 mmol). The reaction vessel was degassed (evac./N₂ purge 3×) before charging with palladium (11) acetate (410 mg, 1.82 mmol). The reaction was warmed to 80° C. for 18 h, at which point it was judged incomplete by APCl MS. After cooling additional BlNAP (racemic, 1.89 g, 3.03 mmol) and palladium (11) acetate (410 mg, 1.82 mmol) were introduced and the reaction was warmed to 80° C. for 60 h. at which point it was judged complete by APCl MS. The reaction was cooled and filtered through Celite, rinsed with THF and concentrated. The resulting oil was dissolved in CH₂Cl₂ (200 mL), washed with water (100 mL) and saturated aqueous NaCl solution (100 mL), dried through a cotton plug and concentrated to give the crude product. To this was added fresh THF (150 mL) followed by 2N HCl (150 mL) and this stirred solution was warmed to 65° C. for 60 min then at room temperature for 18 h. The reaction mixture was treated with hexanes (150 mL). The resulting orange solid is filtered. (On occasion an orange gum separates and is separated by decantation or filtration.) The biphasic filtrate was separated and the hexane layer discarded. The aqueous layer was extracted with Et₂O (150 mL) and the Et₂O layer discarded. The aqueous layer was then neutralized with 25% aqueous NaOH solution to achieve pH 9 and the product was extracted with CH₂Cl₂ (5×40 mL), washed with saturated aqueous NaCl solution (1×30 mL), dried over Na₂SO₄ and concentrated to give the crude product. Flash chromatography provided the title compound as a thick yellow oil (3.36 g, 36%). (TLC 50% EtOAc/hexanes R_f 0.30); ¹H NMR (400 MHz, CDCl₃) δ 7.24 (m, 2H), 7.36 (m, 2H), 7.26 (m, 2H), 7.07 (t, J=7.9 Hz, 1H), 6.71 (dd, J=7.9, 1.6 Hz, 1H). 6.64 (m, 1H), 6.50 (dd, J=7.9, 2.0 Hz, 1H), 3.80 (m, 2H), 3.61 (m, 1H), 3.15 (m, 2H), 2.80 (m, 1H), 2.17 (br d, J=14.2 Hz, 2H), 2.00 (m, 3H), 1.79 (br d, J=12.5 Hz, 1H), 1.72 (m, 1H), 1.64 (m, 1H), 1.38 (m, 1H); APCl MS m/z 307.1 (M+1)⁺.

2-Methoxy-ethanesulfonic acid [3-(2-benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-amide

3-(2-Benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenylamine (2.71 g, 8.84 mmol) stirred in pyridine (25 ml) at 0° C. was charged with 2-methoxy-ethanesulfonyl chloride (2.1 g, 13.26 mmol) dropwise causing a color change from yellow to bright orange. The reaction was allowed to warm to room temperature gradually and stirred 18 h. The reaction mixture was diluted with toluene and concentrated in vacuo. The residue was dissolved in CH₂Cl₂ and washed with saturated aqueous NaHCO₃ solution (100 mL). The aqueous layer was extracted with CH₂Cl₂ (2×50 ml) and the organic layer was concentrated to an oil. This was dissolved in EtOAc which caused an oil to separate. The EtOAc layer was separated and washed with saturated aqueous NaHCO₃ solution (100 mL). The aqueous layer was extracted with EtOAc (2×50 ml) and the combined organic layer was washed with saturated aqueous NaCl solution (50 ml), dried over Na₂SO₄, filtered and concentrated to a crude orange liquid (3.77 g, ˜100%). (TLC 75% EtOAc/hexanes R_f 0.48);

¹H NMR (400 MHz, CDCl₃) δ 7.31 (t, J=7.9 Hz, 1H), 7.28-7.15 (m, 6H), 7.14 (br d, J=7.9 Hz, 1H), 7.03 (br d, J=7.9 Hz, 1H), 3.82 (m, 1H), 3.80 (dd, J=5.3, 4.6 Hz, 2H), 3.39 (s, 3H), 3.37 (m, 1H), 3.18 (dd, J=5.3, 4.6 Hz, 2H), 2.30-1.45 (m, 10H); ¹³C NMR (100 MHz, CDCl₃) δ 154.0, 137.0, 129.3, 129.1, 128.5, 127.1, 122.4, 119.5, 119.2, 67.0, 60.1, 59.4, 52.3, 50.0, 49.4, 38.8, 38.7, 37.4, 35.3, 25.0, 23.0.

5-[3-(2-Methoxy-ethanesulfonylamino)-phenyl]-2-aza-bicyclo[3.3.1]nonane-2-carboxylic acid tert-butyl ester

2-Methoxy-ethanesulfonic acid [3-(2-benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-amide

(3.41 g, 7.96 mmol) was dissolved in EtOAc (20 ml), charged with 2.5 N HCl/EtOAc (6 ml), stripped in vacuo then azeotroped with MeOH (2×50 ml) to yield the HCl salt. This salt was dissolved in MeOH (30 ml). In a separate vessel, MeOH (10 mL) and piperidine (3.9 mL, 39.8 mmol) were stirred at 0° C. and treated with formic acid (0.92 mL, 23.88 mmol) dropwise. This solution was added to the mixture in the first vessel. To the combined mixture was added 20% Pd(OH)₂/C (680 mg) and the resulting mixture was stirred and heated under reflux at 65° C. for 18 h. The reaction was not complete (TLC) at this time. Heating was continued for an additional 60 h at which time it was deemed complete by TLC analysis. The reaction was filtered through a Celite pad and concentrated to afford the crude product that was dissolved in CH₂Cl₂ (40 mL) and saturated aqueous Na₂CO₃ solution (40 mL) and cooled to 0° C. This was treated with t-Boc₂O (di-tert-butyldicarbonate, 2.08 g, 9.55 mmol) in CH₂Cl₂ (10 mL) dropwise and the mixture was vigorously stirred for 18 h at ambient temperature. Dilute HCl solution was added to achieve pH 9 and the mixture was extracted with CH₂Cl₂ (3×40 mL). The organic layer was washed with saturated aqueous NaCl solution (50 mL), dried through a cotton plug and concentrated to a red oil. This was chromatographed on silica gel eluting with 10 to 30% EtOAc/hexanes to provide product as a clear oil (2.44 g, 70%). (TLC 50% EtOAc/hexanes R_f 0.42); ¹H NMR (400 MHz, CDCl₃) δ 7.23 (t, J=7.9 Hz, 1H), 7.18 (br s, 1H), 7.12 (br d, J=7.9 Hz, 1H), 7.03 (br d, J=7.9 Hz, 1H), 6.35 (s, NH), 4.31 (m, 1H), 3.81 (t, J=5.6 Hz, 2H), 3.61 (m, 2H), 3.40 (s, 3H), 3.19 (t, J=5.6 Hz, 2H), 2.10 (m, 2H), 1.95 (m, 2H), 1.82 (m, 2H), 1.82 (m, 2H), 1.65 (m, 1H), 1.50-1.35 (m, 3H), 1.44 (s, 9H); APCl MS m/z 424.1 (M−14)⁺.

2-Methoxy-ethanesulfonic acid [3-(2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-amide

5-[3-(2-Methoxy-ethanesulfonylamino)-phenyl]-2-aza-bicyclo[3.3.1]nonane-2-carboxylic acid tert-butyl ester (2.42 g, 5.52 mmol) in EtOAc (30 mL) was charged with 2.5 N HCl/EtOAc (30 ml) and the resulting mixture was heated under reflux 18 h. The mixture was stripped in vacuo to yield the HCl salt as a white foam (1.56 g, 83%). ¹H NMR (400 MHz, CD₃OD, HCl salt) δ 7.28 (t, J=7.9 Hz, 1H), 7.25 (m, 1H), 7.14 (m, 1H), 7.10 (m, 1H), 3.87 (br s, 1H), 3.72 (t, J=5.8 Hz, 2H), 3.71 (m, 1H), 3.27 (t, J=5.8 Hz, 2H) , 3.25 (s, 3H), 2.34 (m, 1H), 2.18 (m, 5H), 1.98-1.78 (m, 3H), 1.64 (m, 1H); ¹³C NMR (100 MHz, CD₃OD) δ 151.1, 138.4, 129.4, 120.7, 118.6, 117.1, 66.3, 57.9, 50.4, 48.9, 40.5, 36.9, 34.1, 33.8, 33.6, 25.6, 20.7.

Preparation 2

N-[3-(2-Benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-methanesulfonamide

3-(2-Benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenylamine (3.37 g, 9.24 mmol) in pyridine (30 ml) at 0° C. was charged with methanesulfonylchloride 1.3 ml, 16.5 mmol) dropwise, causing a color change from yellow to bright orange. The reaction was warmed to room temperature and judged complete by TLC after 3 h. The mixture was diluted with toluene and stripped twice. Following a water quench (20 ml), the product was extracted with EtOAc (4×30 ml), washed with saturated aqueous NaHCO₃ solution (6×30 ml) and with saturated aqueous NaCl solution (3×30 ml), dried over Na₂SO₄, filtered and concentrated to a crude orange liquid. Flash chromatography on silica gel eluting with 2 to 5% MeOH/CH₂Cl₂ provided the title compound as orange oil (3.59 g, 85%). (TLC 5% MeOH/CH₂Cl₂ R_f 0.24); ¹H NMR (400 MHz, CDCl₃) δ 7.37-7.19 (m, 7H), 7.11 (br d, J=7.9 Hz, 1H), 7.05 (ddd, J=7.9, 2.1, 0.8 Hz, 1H), 3.73 (AB q, ΔAB 59.9, J=13.3 Hz, 2H), 3.71 (m, 1H), 3.09 (br, s, 1H), 3.04 (m, 1H), 2.94 (s, 3H), 2.80 (m, 1H), 2.18 (m, 2H), 2.07-1.95 (m, 4H), 1.82 (br d, J=12.0 Hz, 1H), 1.72 (m, 1H), 1.57 (m, 1H), 1.17 (m, 1H). ¹³C 154.2, 137.1, 132.3, 129.5, 129.4, 129.1, 128.6, 128.4, 127.1, 122.0, 118.3, 117.9, 60.1, 52.3, 49.4, 39.3, 38.9, 38.7, 37.4, 35.8, 24.9, 23.0; APCl MS m/z 385.1 (M+1)⁺.

5-(3-Methanesulfonylamino-phenyl)-2-aza-bicyclo[3.3.1]nonane-2-carboxylic acid tert-butyl ester

N-[3-(2-Benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-methanesulfonamide (3.32 g, 8.63 mmol) (3.41 g, 7.96 mmol) was dissolved in EtOAc (20 ml), charged with 2.5 N HCl/EtOAc (6 ml), stripped in vacuo then azeotroped with MeOH (2×50 ml) to yield the HCl salt. This salt was dissolved in MeOH (30 ml). In a separate vessel, MeOH (10 mL) and piperidine (4.3 mL, 43.15 mmol) were stirred at 0° C. and treated with formic acid (0.99 mL, 25.89 mmol) dropwise. This solution was added to the mixture in the first vessel. To the combined mixture was added 20% Pd(OH)₂/C (660 mg) and the resulting mixture was stirred and heated under reflux at 65° C. for 60 h at which time it was deemed complete by TLC analysis. The reaction was filtered through a Celite pad and concentrated to afford the crude product that was dissolved in CH₂Cl₂ (40 mL) and saturated aqueous Na₂CO₃ solution (40 mL) and cooled to 0° C. This was treated with t-Boc₂O (di-tert-butyldicarbonate, 2.26 g, 10.36 mmol) in CH₂Cl₂ (10 mL) dropwise and the mixture was vigorously stirred for 2 h at ambient temperature. The reaction was deemed incomplete at this time and was treated with t-Boc₂O (di-tert-butyldicarbonate, 950 mg, 4.32 mmol) in CH₂Cl₂ (10 mL) dropwise and the mixture was vigorously stirred for 18 h. Dilute HCl solution was added to achieve pH 9 and the mixture was extracted with CH₂Cl₂ (3×40 mL). The organic layer was washed with saturated aqueous NaCl solution (50 mL), dried through a cotton plug and concentrated to an oil. This was chromatographed on silica gel eluting with a gradient from 5 to 25% EtOAc/hexanes to provide product as a clear oil (1.18 g, 35%). (TLC 50% EtOAc/hexanes R_f 0.39); APCl MS m/z 336.2 (M−57)⁺; 380.2 (M−14)⁺.

N-[3-(2-Aza-bicyclo[3.3.1]non-5-yl)-phenyl]-methanesulfonamide

5-(3-Methanesulfonylamino-phenyl)-2-aza-bicyclo[3.3.1]nonane-2-carboxylic acid tert-butyl ester (1.07 g, 2.71 mmol) in EtOAc (10 ml) was charged with 2.5 N HCl/EtOAc (10 ml) and the resulting mixture was heated under reflux 18 h. The mixture was stripped in vacuo and recrystallized from MeOH/Et₂O to yield the HCl salt (0.64 g, 71%). ¹H NMR (400 MHz, CD₃OD, HCl salt) δ 7.30 (t, J=7.9 Hz, 1H), 7.25 (t, J=2.0 Hz, 1H), 7.15 (ddd, J=7.9, 2.0, 0.8 Hz, 1H), 7.09 (ddd, J=7.9, 2.0, 0.8 Hz, 1H), 3.86 (br s, 1H), 3.72 (m, 1H), 3.27 (m, 2H), 2.91 (s, 3H), 2.35 (m, 1H), 2.18 (m, 5H), 1.91 (m, 3H), 1.67 (m, 1H); APCl MS m/z 295.2 (M+1)⁺.

Preparation 3

3-(2-Benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzonitrile

Trifluoro-methanesulfonic acid 3-(2-benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl ester (5.00 g, 11.4 mmol) and zinc cyanide (1.47 g, 12.5 mmol) were combined in DMF (110 ml), degassed (evac./N₂ purge 3×) then charged with tetrakis(triphenylphosphine) palladium (0) (1.8 g, 1.60 mmol). The resulting reaction mixture was heated to 85° C. in an oil bath for 6 h. Upon cooling to room temperature, the reaction mixture was filtered through a Celite pad and rinsed with EtOAc (200 ml). The filtrate was washed with water and saturated aqueous NaCl solution (1×200 ml each), dried over Na₂SO₄, filtered, and concentrated and chromatographed on silica gel eluting with 50% EtOAc/hexanes to provide an oil (1.95 g, 54%). (TLC 50% EtOAc/hexanes R_f 0.28); ¹H NMR (400 MHz, CDCl₃) δ 7.49-7.52 (m, 2H), 7.45-7.48 (m, 3H), 7.35-7.39 (m, 2H), 7.10-7.14 (m, 1H), 7.00-7.02 (m, 1H), 3.98 (ABq, □AB=48.9 Hz, J=13.0 Hz, 2H), 3.31—3.33 (m, 1H), 3.16-3.21 (m, 2H), 2.21-2.25 (m, 2H), 1.95 2.07 (m, 4H), 1.76 1.80 (m, 2H), 1.41 1.59 (m, 2H); APCl MS m/z 317.2 (M+1)⁺.

3-(2-Benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzamide

3-(2-Benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzonitrile (1.95 g, 6.16 mmol) in DMSO (55 ml) was charged with potassium carbonate (120 mg, 0.86 mmol) then 30% aqueous hydrogen peroxide (3.2 ml, 30.8 mmol). The reaction mixture was allowed to stir at room temperature for 23 h at which time it was determined not to have proceeded. Additional potassium carbonate (850 mg, 6.16 mmol) and 30% aqueous hydrogen peroxide (6.4 ml, 61.6 mmol) were introduced and stirred for 5.5 h. After a water quench (50 ml), the product was extracted with EtOAc (3×50 ml), washed with 50% saturated aqueous NaCl solution (5×50 ml), dried over Na₂SO₄, filtered and concentrated to a white solid which was triturated with hexanes and collected (1.0 g, 49%). (TLC 50% EtOAc/hexanes R_f 0.08); ¹H NMR (400 MHz, CDCl₃) δ 7.83-7.85 (m, 1H), 7.49-7.57 (m, 1H), 7.40-7.47 (m, 1H), 7.38 7.28 (m, 5H), 7.21 7.25 (m, 1H), 6.10 (brs, 1H), 5.63 (brs, 1H); 3.74-3.82 (m, 2H), 3.06-3.15 (m, 2H), 2.86-2.96 (m, 1H), 2.16 2.26 (m, 2H), 1.96 2.08 (m, 4H), 1.84-1.89 (m, 1H), 1.68 1.74 (m, 1H), 1.59 1.65 (m, 1H), 1.34-1.42 (m, 1H): APCl MS m/z 335.1 (M+1)⁺.

3-(2-Aza-bicyclo[3.3.1]non-5-yl)-benzamide

3-(2-Benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzamide (920 mg, 2.61 mmol) was dissolved in EtOAc (20 ml), charged with 2.5 N HCl/EtOAc (6 ml), then azeotroped with MeOH (2×50 ml) to yield the HCl salt. This salt was dissolved in MeOH (20 ml) in a 500 ml Parr bottle. To this was added 20% Pd(OH)₂/C (Pearlman's catalyst, 180 mg) and the mixture was shaken under 45 psi of H₂ for 4 h or until judged complete by TLC. The reaction was filtered through a Celite pad and concentrated to a yellow solid (1.0 g, >100%). ¹H NMR (400 MHz, CD₃OD, HCl salt) δ 7.86-7.88 (m, 1H), 7.72-7.74 (m, 1H), 7.55-7.57 (m, 1H), 7.42 (t, J=7.88 Hz, 1H), 3.87 (brs, 1H), 3.71-3.73 (m, 1H), 3.28-3.31 (m, 1H), 2.35-2.37 (m, 1H), 2.13-2.25 (m, 5H), 1.81-1.96 (m, 4H); APCl MS 245.1 (M+1)⁺. ##STR00020##

General Procedure for the Reductive Alkylation of Compounds of Formula 1 R^a=H

A compound of the general formula 1 where R^a=H in dichloromethane or dichloroethane (0.2 M) at room temperature was treated with an appropriate aldehyde of formula (1.2 equiv), glacial acetic acid (catalytic ˜2 drops) and sodium triacetoxyborohydride (1.5 equiv). The reaction mixture was stirred at room temperature for up to 24 h. The mixture was concentrated in vacuo and the resulting crude material was purified by flash chromatography to yield the desired tertiary amines in 40 95%.

The following compounds were made using the above procedure, starting with the appropriate starting amine and the appropriate corresponding aldehyde reagent.

Furthermore, pharmaceutically acceptable salts of the compounds listed below can be prepared as follows. To a stirring solution of compounds of the general formula 1 (prepared as described above, 1.0 equiv) in a suitable solvent such as methyl ethyl ketone, dichloromethane/methanol (1:1) or methanol (0.1 M) at room temperature was added the appropriate acid, such as citric acid, p-toluenesulfonic acid, methanesulfonic acid or benzene sulfonic acid (1.0 equiv) in one portion. The resulting mixture was stirred at room temperature for up to 18 h, during which time a precipitate formed. Filtration of the solid and drying under reduced pressure afforded the desired salts.

Example 1

N-[3-(2-Cyclopropylmethyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenyl]-methanesulfonamide

¹H NMR (400 MHz, CD₃OD, HCl salt) δ 7.30 (t, J=7.9 Hz, 1H), 7.26 (m, 1H), 7.15 (dd, J=7.9, 2.1 Hz, 1H), 7.07 (m, 1H), 3.97 (br s, 1H), 3.58 (m, 2H), 3.27 (m, 1H), 3.01 (dd, J=13.3, 8.2 Hz, 1H), 2.91 (s, 3H), 2.40 1.62 (m, 1OH), 1.84 (m, 1H), 0.74 (m, 2H), 0.45 (m, 2H); APCl MS m/z 349.2 (M+1)⁺.

Example 2

N-(3-{2-[3-(1-Hydroxy-cyclohexyl)-propyl]-2-aza-bicyclo[3.3.1]non-5-yl}-phenyl)-methanesulfonamide

¹H NMR (400 MHz, CD₃OD, Citrate salt) δ 7.28 (t, J=7.9 Hz, 1H), 7.23 (m, 1H), 7.14 (dd, J=7.9, 0.8 Hz, 1H), 7.09 (dd, J 7.9, 1.3 Hz, 1H), 3.84 (br s, 1H), 3.54 (m, 2H), 3.17 (m, 2H), 2.91 (m, 3H), 2.76 (AB q, AB Δ 27.9, J 15.8 Hz, 4H), 2.31-2.00 (m, 5H), 1.82 (m, 3H), 1.70-1.23 (m, 8H). ##STR00021##

General Procedure for the Alkylation of Compounds of Formula 1 where R^a=H

A compound of formula 1 where R^a=H in ethanol (0.1 M) at room temperature was treated with triethylamine (3.0 equiv) and the appropriate alkylation reagent (1.2 equiv). The resulting mixture was heated to 80° C. for 1-5 h and then cooled to room temperature. The mixture was concentrated in vacuo and the resulting crude material was purified by flash chromatography to yield the desired tertiary amines in 50-90% yield

The following compounds were made using the above procedure, starting with the appropriate starting amine and the appropriate alkylation reagent.

Furthermore, pharmaceutically acceptable salts of the compounds listed below can be prepared as follows. To a stirring solution of compounds of the general formula 1 (prepared as described above, 1.0 equiv) in a suitable solvent such as methyl ethyl ketone, dichloromethane/methanol (1:1) or methanol (0.1 M) at room temperature was added the appropriate acid, such as citric acid, p-toluenesulfonic acid, methanesulfonic acid or benzene sulfonic acid (1.0 equiv) in one portion. The resulting mixture was stirred at room temperature for up to 18 h, during which time a precipitate formed. Filtration of the solid and drying under reduced pressure afforded the desired salts.

Example 3

N-{3-[2-(2-Hydroxy-indan-2-ylmethyl)-2-aza-bicyclo[3.3.1]non-5-yl]-phenyl}-methanesulfonamide

¹H NMR (400 MHz, CD₃OD 27.9 salt) δ 7.29 (t, 7.9 Hz, 1H), 7.25 (m, 1H), 7.26-7.07 (m, 6H), 3.88 (br s, 1H), 3.57 (m, 1H), 3.49-3.39 (m, 3H), 3.18 (AB d, J=16.2 Hz, 2H), 3.08 (AB dd, J=16.2, 4.1 Hz, 2H), 2.91 (s, 3H), 2.70 (AB q, ΔAB=27.9, J=15.4 Hz, 2H), 2.44 (m, 1H), 2.36 (m, 1H), 2.25 (m, 1H), 2.14 (m, 3H), 1.83 (m, 2H), 1.71 (m, 1H); APCl MS m/z 441.2 (M+1)⁺.

General Procedure (a) for the Reductive Alkylation of Salts of Compounds of Formula 1
(R^a—H)

An appropriate aldehyde (2.0 equiv) in dichloroethane (0.1 M) at room temperature was treated with triethylamine (4.0 equiv) and an amine of formula 1 R^a=H (1 equiv) as the HCl salt. The reaction vessel was sealed and briefly shaken to mix these materials. The vessel was then opened and sodium triacetoxyborohydride (approximately 2.0 or more equiv) was introduced. The reaction vessel was again sealed then briefly vortexed. The reaction vessel was then shaken at room temperature for up to 24 h. The mixture was then quenched with the addition of 1 N NaOH (2.0 mL) and extracted with dichloromethane (3×2.45 mL). Each sequential extract was loaded onto SPE cartridges that contained 1 g of preconditioned SCX adsorbent. (The SCX adsorbent, “strong cation exchange modified silica”, was preconditioned by pre-eluting with methanol (1×5 mL) then dichloromethane (2×5 mL). After the extract solutions were passed through the adsorbent, the adsorbent was washed with methanol (5 mL). These filtrates were eventually discarded. Crude product was then eluted into separate tared collection vessels with 1 N triethylamine in methanol (5 mL). The material was concentrated under a stream of nitrogen and weighed. The resulting crude material was purified by reverse phase HPLC to yield the desired tertiary amines.

The following compounds were made using the above procedure, starting with the appropriate starting amine of formula 1 (R^a=H) and the appropriate aldehyde reagent.

General Procedure (b) for the Reduction Alkylation of Salts of Compounds of Formula 1
(R^a=H)

An appropriate aldehyde (2.0 equiv) at room temperature was treated with a slurry of an amine of formula 1 R^a=H (1 equiv) as the HCl salt in 9:1 dichloroethane:methanol. The reaction vessel was sealed and briefly shaken to mix these materials. The vessel was then opened and sodium triacetoxyborohydride (approximately 5.0 or more equiv) was introduced. The reaction vessel was shaken at room temperature for up to 24 h. The mixture was then quenched by the addition of water (0.75 mL) and extracted with dichloromethane (3×2.45 mL). Each sequential extract was loaded onto SPE cartridges that contained 1 g of preconditioned SCX adsorbent. (The SCX adsorbent, “strong cation exchange modified silica”, was preconditioned by pre-eluting with MeOH (1×5 mL) then dichloromethane (2×5 mL). After the extract solutions were passed through the adsorbent, the adsorbent was washed with dichloromethane (5 mL) then methanol (5 mL). These filtrates were eventually discarded. Crude product was then eluted into separate tared collection vessels with 1N triethylamine in methanol (5 mL). The material was concentrated under a stream of nitrogen and weighed. The resulting crude material was purified by reverse phase HPLC to yield the desired tertiary amines.

A number of compounds according to the present invention were made using the above procedure, starting with the appropriate starting amine of formula 1 R^a=H and the appropriate aldehyde reagent.

Furthermore, pharmaceutically acceptable salts of the compounds described above can be prepared as follows. To a stirring solution of compounds of the general formula 1 (prepared as described above, 1.0 equiv) in a suitable solvent such as methyl ethyl ketone, dichloromethane/methanol (1:1) or methanol (0.1 m) at room temperature was added the appropriate acid, such as citric acid, p-toluenesulfonic acid, methanesulfonic acid or benzene sulfonic acid (1.0 equiv) in one portion. The resulting mixture was stirred at room temperature for up to 18 h, during which time a precipitate formed. Filtration of the solid and drying under reduced pressure afforded the desired salts. ##STR00022##

Alternative General Procedure for the Preparation of Compounds of Formula 1.

To a stirring solution of 1.0 equiv of a compound of formula 1 where R^a=H in anhydrous THF (0.1 M) at room temperature, was added Et₃N (5.0 equiv) or pyridine (5.0 equiv) and an appropriately substituted acid chloride (2.0 equiv). After stirring up to 24 h, the reaction was quenched by the addition of water and diluted with methylene chloride. The layers were separated, the aqueous layer was extracted with methylene chloride and the combined organic layers were dried over anhydrous Na₂SO₄ and concentrated. The resulting crude material was purified through flash chromatography, then carried onto the next step.

To a stirring solution of 1.0 equiv of the amide prepared above in THF (0.2M) at room temperature was added lithium aluminum hydride (4.0 equiv). The resulting mixture was stirred at room temperature until judged complete by TLC. The reaction was cooled to 0° C. then carefully quenched by the slow addition of water (1.0 equiv by mass relative to LAH), 10% NaOH (1.0 equiv by mass relative to LAH) then water (3.0 equiv by mass relative to LAH). The resulting slurry was stirred at room temperature for up to 16 hours. The slurry was filtered and washed with THF. The resulting solution was concentrated to yield crude material that was purified by flash chromatography to afford the desired tertiary amines of formula 1.

The following compound was made using the above procedure, starting with the appropriate starting amine of formula 1 and the appropriate acid chloride reagent.

Furthermore, pharmaceutically acceptable salts of the compounds listed below can be prepared as follows. To a stirring solution of compounds of the general formula 1 (prepared as described above, 1.0 equiv.) in a suitable solvent such as methyl ethyl ketone, methylene chloride/methanol (1:1) or methanol (0.1 M) at room temperature was added the appropriate acid, such as citric acid, p-toluenesulfonic acid, methansulfonic acid or benzene sulfonic acid (1.0 equiv) in one portion. The resulting mixture was stirred at room temperature for up to 18 h, during which time a precipitate formed. Filtration of the solid and drying under reduced pressure afforded the desired salts.

Claims

1. A compound of formula 1: ##STR00023##

2. A compound according to claim 1 wherein R^a is a ##STR00027##

3. A compound according to claim 1 wherein Q is C(═O)NH₂ or NHSO₂R⁸.

4. A compound according to claim 1 wherein Q is NHSO₂R⁸.

5. A compound according to claim 3, wherein R^a is a ##STR00028##

6. A compound according to claim 1 or 2 wherein X is H or F.

7. A compound according to claim 6 wherein Q is —C(═O)NH₂ or —NHSO₂R⁸.

8. A compound according to claim 1 wherein R¹ and R² taken together with the carbon to which they are attached form a cyclobutane, cyclopentane, cyclohexane, indane-2-yl or 1,2,3,4-tetrahydronaphth-2-yl, which may be unsubstituted or substituted with R¹⁰ groups.

9. A compound according to claim 8 wherein Q is —C(═O)NH₂ or —NHSO₂R⁸.

10. A compound according to claim 1, wherein Q is C(═O)NH₂ or NHSO₂R⁸; R^a is a ##STR00029##

11. A compound according to claim 10 wherein R³ is H, OH, —NH(═O)—CH₃, —C(═O)NH₂, —CH₂OH or —OCH₃.

12. A compound according to claim 10 wherein R³ is OH.

13. A compound according to claim 2 wherein n is 1, 2 or 3.

14. A compound according to claim 1 wherein R⁴ and R⁹ are independently H or a —C₁-C₄ alkyl.

15. A compound according to claim 1 wherein R⁴ and R⁹ are independently H or CH₃.

16. A compound according to claim 1 wherein R⁴ and R⁹ are both CH₃.

17. A compound according to claim 1 wherein Q is —C(═O)NH₂ or —NHSO₂R⁸ and R⁸ is CH₃, —(CH_j)₂—O—CH₃ or -4-(1-methylimidazole).

18. A compound according to claim 1 wherein Q is —C(═O)NH₂, —NHSO₂CH₃ or —NHSO₂CH₂CH₂OCH₃ and X is H.

19. A compound according to claim 1 selected from:

20. A compound according to claim 1 selected from:

21. A compound according to claim 1 selected from:

22. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 in combination with a pharmaceutically acceptable carrier, excipient or additive.