LIPOPHOSPHONOXINS, THEIR PREPARATION AND USE

Abstract

Lipophosphonoxins of general formula I, diastereomers and mixtures of diastereomers of compounds of general formula I and their pharmaceutically acceptable salts and hydrates as antibacterial agents, forming an active ingredient in pharmaceutical compositions for the treatment of resistant bacterial infections, disinfectants and/or selective culture media is disclosed.

Claims

1. Lipopolyphosphonoxin of the general formula I ##STR00067## wherein: the X substituent is independently selected from the following structures: ##STR00068## wherein m=1-3; the Y substituent is independently selected from the following structures: ##STR00069## wherein n=0-12, and o=0-12, and p=0-12, and R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are independently selected from the group consisting of: H-, CH.sub.3-, CH.sub.2CH.sub.3, propyl, isopropyl, isobutyl, tert-butyl, CH.sub.3O—, CH.sub.2CH.sub.3O—, propoxy, isopropoxy, isobutyloxy or tert-butyloxy; and the Z substituent is selected from the following structures: ##STR00070## wherein q=2-14, and r=0-10, and s=0-10, or a diastereomer or a mixture of diastereomers of the compound of formula I, or a pharmaceutically acceptable salt or hydrate thereof.

2. A method of administering a medicament, comprising the step of administering lipophosphonoxin of general formula I according to claim 1 or a diastereomer or a pharmaceutically acceptable salt or hydrate thereof, and/or mixture of such compounds to a subject in need thereof.

3. A method of administering an antibacterial drug comprising the step of administering lipophosphonoxin of general formula I according to claim 1 or a diastereomer or a pharmaceutically acceptable salt or hydrate thereof, and/or mixture of such compounds to a subject in need thereof.

4. An antibacterial drug comprising at least one lipophosphonoxin of general formula I as claimed in claim 1, or a diastereomer or a pharmaceutically acceptable salt or hydrate thereof, and/or mixture of such compounds.

5. A disinfectant for non-therapeutic purposes comprising at least one lipophosphonoxin of general formula I as claimed in claim 1, or a diastereomer or a pharmaceutically acceptable salt or hydrate thereof, and/or mixtures of such compounds as the active ingredient.

6. A selective culture medium comprising at least one lipophosphonoxin of general formula I as claimed in claim 1, or a diastereomer or a pharmaceutically acceptable salt or hydrate thereof, and/or mixtures of such compounds as the active ingredient.

7. A method of preparing an antibacterial drug comprising the step of adding lipophosphonoxins of general formula I as claimed in claim 1, or their diastereomers or pharmaceutically acceptable salts or hydrates, and/or mixtures of such compounds.

8. A method of preparing active ingredients of disinfectants for non-therapeutic purposes and/or selective culture media for in vitro cultivation of bacteria, fungi or eukaryotic cells comprising the step of adding lipophosphonoxins of general formula I as claimed in claim 1, or their diastereomers or pharmaceutically acceptable salts or hydrates, and/or mixtures of such compounds.

9. A method of treatment of bacterial infections, said method comprising the step of administering at least one lipophosphonoxin of the general formula I as claimed in claim 1, or diastereomer or a pharmaceutically acceptable salt or hydrate thereof to a subject in need of such treatment.

Description

EXAMPLES

[0028] Formula (I) includes the compounds listed in Examples 34-37 and 39-58.

LIST OF ABBREVIATIONS

[0029] DCM dichlormethan [0030] TPSCl triisopropyl benzenesulfonyl chloride [0031] IR infrared spectrum [0032] HR-ESI high resolution mass spectrum using electron spray ionization [0033] HR-EI high resolution mass spectrum using electron impact ionization [0034] n-BuOH n-butyl alcohol [0035] DMTr dimethoxy trityl [0036] THF tetrahydrofuran [0037] EC.sub.50 mean effective concentration (causing 50% of maximum effect) [0038] IC.sub.50 inhibitory concentration (causing 50% of the maximum inhibitory effect) [0039] rpm rotations per minute [0040] rt room temperature

General Methods

General Method A—Removal of Phosphonate Methyl Ester Group

[0041] Methyl phosphonate (1 mmol) is dissolved in 60% aqueous pyridine (20 mL) and the reaction mixture is stirred at 60° C. for 24 h. The reaction mixture is concentrated in vacuo at temperature below 40° C., the residue is dissolved in ethanol (20 mL) and passed through a column of Dowex 50 v H.sup.+ form (5 g). The column is washed with EtOH (40 ml). The solvent is removed in vacuo. Product is obtained by column chromatography on silica gel using linear gradient of solvent system H1 (ethyl acetate, acetone, ethanol, water 4:1:1:1) in ethyl acetate.

General Method B1—Esterification of Monomethyl Vinylphosphonate Using Oxalylchloride

[0042] Mono alkyl vinylphosphonate (1 mmol) is randered dry by co-evaporation with EtOH (10 ml/mmol) and toluene (10 ml), dissolved in DCM (3 ml) and cooled to −78° C. under argon atmosphere. Oxalylchloride (2 mol/L) in DCM (0.3 ml) is slowly added and the reaction mixture is stirred at rt for 30 min. Catalytic ammount of DMF (50 μL) is added and the reaction mixture is stirred until gass evolution ceassed. Hydroxyderivative (1 mmol) is then added folowed by addition of triethylamine (1.1 mmol). The reaction mixture is stirred at rt for 12 h under argon atmosphere. The reaction mixture is extracted with sat. soln. NaHCO.sub.3 (10 mL) and sat. soln. NaCl (10 mL). Organic phase is dried over Na.sub.2SO.sub.4 and concentrated in vacuo. Product is obtained by column chromatography using linear gradient of acetone in toluene or linear gradient of ethanol in chloroform.

General Method B2—Esterification of Monomethyl Vinylphosphonate Using TPSCl

[0043] Mono alkyl vinylphosphonate (1 mmol) and hydroxyderivative (2 mmol) is randered anhydrous by co-evaporation with DCM (2×10 ml) and dissolved in the same solvent (5 mL). Methylimidazole (3 mmol) and TPSCl (2 mmol) were added and the reaction mixture is stirred at re under argon atmosphere for 24-48 h. Progress of the reaction is followed by TLC using mixture of acetone/toluene (1:1). The reaction mixture is diluted with DCM (10 mL) and washed subsequently with sat. soln NaHCO.sub.3 (10 ml) and brine (10 mL). Organic phases were combined, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. Product is obtained by column chromatography using linear gradient of acetone in toluene or linear gradient of ethanol in chloroform.

General Method C—Reaction of Monoalkyl Vinylphosphonate with α,ω-dibromoalkane

[0044] Mono alkyl vinylphosphonate (1 mmol) and tetrabutylammonium hydroxide (1 mmol) is randered anhydrous by co-evaporation with ethanol (2x 10 mL) and DMF (10 mL) and dissolved in DMF (5 mL). α,ω-Dibromalkan (0.36 mmol) is added and the reaction mixture is stirred under argon atmosphere at 90° C. for 24-48 h. Progress of the reaction is followed by TLC using mixture of acetone/toluene (1:1). The reaction mixture is concentrated in vacuo and product is obtained by column chromatography using linear gradient of acetone in toluene.

General Method D—Michael Addition

[0045] The mixture of vinylphosphonate dimer (1 mmol) and secondary amine (3 mmol) in n-butanol (50 mL/mmol) is stirred at 105° C. for 24-72 h in sealed flask. Progress of the reaction is followed by TLC using mixture of EtOH/CHCl.sub.3 (1:10). The reaction mixture is concentrated in vacuo and product is obtained by column chromatography using linear gradient of ethanol in chloroform.

General Method E—Removal of Boc Protecting Groups

[0046] Starting Boc derivative (1 mmol) is dissolved in 0.5M methanolic HCl (10 mL). The reaction mixture is stirred at rt for 24 h. The reaction mixture is concentrated in vacuo and product is obtained by precipitation from anhydrous ethyl acetate. If necessary, the final product is repurified by preparative HPLC on reversed phase using linear gradient of methanil in 0.1% aqueous TFA.

Example 1: Butyl Vinylphosphonate

[0047] ##STR00009##

[0048] Butyl vinylphosphonate is prepared from mono methyl vinylphosphonate (7.0 g, 57.3 mmol) and 1-butanol using general method B2 and general method A in 47% (4.39 g, 26.7 mmol) overall yield in the form of colorless oil.

[0049] .sup.1H NMR (400.1 MHz, CDCl.sub.3): 0.90-0.95 (m, 3H), 1.35-1.45 (m, 2H,), 1.62-1.69 (m, 2H), 3.98-4.04 (m, 2H), 5.99-6.34 (m, 3H), 9.78 (s, 1H).

[0050] .sup.13C NMR (100.6 MHz, CDCl.sub.3): 13.57, 18.70, 32.35 (d, J.sub.C,P=7.0), 65.46 (d, J.sub.C,P=6.0), 126.19 (d, J.sub.C,P=189.1), 134.61 (d, J.sub.C,P=2.0).

[0051] .sup.1P{H} NMR (162.0 MHz, CDCl.sub.3): 21.72.

[0052] IR v.sub.max (KBr) 3090 (vw), 2963 9s), 2935 (s), 2876 (m), 2847 (m), 2739 (w, vbr), 2671 (w, vbr), 2337 (m, vbr), 2177 (w, vbr), 1666 (m, vbr), 1615 (m), 1476 (w), 1466 (m), 1459 (w), 1403 (m), 1276 (w), 1199 (s), 1062 (s), 1031 (vs), 986 (vs), 899 (w).

[0053] HR-MS (ESI.sup.+) For C.sub.6H.sub.13O.sub.3NaP (M+Na).sup.+ calcd 187.04945, found 187.04951.

Example 2: Pentyl Vinylphosphonate

[0054] ##STR00010##

[0055] Pentyl vinylphosphonate is prepared from mono methyl vinylphosphonate (6.50 g, 53.3 mmol) and 1-pentanol using general method B2 and general method A in 47% (4.43 g g, 24.9 mmol) overall yield in the form of colorless oil.

[0056] .sup.1H NMR (400.1 MHz, CDCl.sub.3): 0.87-0.93 (m, 3H), 1.28-1.39 (m, 4H), 1.64-1.71 (m, 2H), 3.72 (d, 3H, J.sub.H,P=8.0), 3.98-4.05 (m, 2H), 5.97-6.36 (m, 3H).

[0057] .sup.13C NMR (100.6 MHz, CDCl.sub.3): 13.93, 22.21, 27.62, 30.14 (d, J.sub.C,P=7.0), 52.31 (d, J.sub.C,P=5.0), 66.08 (d, J.sub.C,P=6.0), 125.21 (d, J.sub.C,P=184.1), 135.91 (d, J.sub.C,P=2.0).

[0058] .sup.31P{.sup.1H} NMR (162.0 MHz, CDCl.sub.3): 21.11.

[0059] IR v.sub.max (KBr) 3090 (vw), 2959 (s), 2934 (s), 2874 (m), 2861 (m), 1613 (w), 1467 (w), 1461 (w), 1435 (vw), 1400 (m), 1381 (w), 1280 (w), 1242 (s), 1185 (w), 1057 (vs), 1042 (vs), 1022 (vs), 1004 (s), 989 (s), 856 (w), 814 (m).

[0060] HR-MS (ESI.sup.+) For C.sub.8H.sub.18O.sub.3P (M+H).sup.+ calcd 193.09881, found 193.09872.

Example 3: Hexyl Vinylphosphonate

[0061] ##STR00011##

[0062] Hexyl vinylphosphonate is prepared from mono methyl vinylphosphonate (5.70 g, 46.7 mmol) and 1-hexanol using general method B2 and general method A in 42% (3.77 g g, 19.6 mmol) overall yield in the form of colorless oil.

[0063] .sup.1H NMR (400.1 MHz, CDCl.sub.3): 0.86-0.90 (m, 3H), 1.23-1.40 (m, 6H), 1.63-1.70 (m, 2H), 3.97-4.02, 5.99-6.34 (m, 3H), 10.53 (s, 1H). .sup.13C NMR (100.6 MHz, CDCl.sub.3): 13.98, 22.52, 25.15, 31.33, 30.31 (d, J.sub.C,P=6.0), 65.79 (d, J.sub.C,P=6.0), 126.2 (d, J.sub.C,P=189.1), 134.61 (d, J.sub.C,P=2.0).

[0064] .sup.31P{.sup.1H} NMR (162.0 MHz, CDCl.sub.3): 21.48.

[0065] IR v.sub.max (KBr) 3089 (vw), 2959 (s), 2932 (s), 2873 (s), 2861 (s), 2732 (m, vbr), 2672 (m, vbr), 2337 (m,vbr), 2181 (m, vbr), 1672 (m, vbr), 1615 (w), 1468 (m), 1462 (m), 1458 (m), 1276 (m), 1199 (s), 1059 (s), 1042 (vs), 1020 (vs), 986 (vs), 895 (w).

[0066] HR-MS (ESI.sup.+) For C.sub.8H.sub.17O.sub.3NaP (M+Na).sup.+ calcd 215.08075, found 215.08069.

Example 4: Heptyl Vinylphosphonate

[0067] ##STR00012##

[0068] Heptyl vinylphosphonate is prepared from mono methyl vinylphosphonate (9.65 g, 79.1 mmol) and 1-heptanol (11.2 mL, 79.1 mmol) using general method B1 and general method A in 70% (11.5 g, 55.5 mmol) overall yield in the form of colorless oil.

[0069] .sup.1H NMR (401 MHz, Chloroform-d) δ 10.83 (s, 1H), 6.34-5.98 (m, 3H), 3.99 (q, J=6.7 Hz, 2H), 1.66 (p, J=6.6 Hz, 2H), 1.41-1.19 (m, 8H), 0.92-0.83 (m, 3H).

[0070] .sup.31P NMR (162 MHz, Chloroform-d) δ 21.89.

[0071] .sup.13C NMR (101 MHz, Chloroform-d) δ 134.92, 126.20 (d, J=189.2 Hz), 66.02 (d, J=6.1 Hz), 31.84, 30.48 (d, J=7.0 Hz), 28.96, 25.57, 22.71, 14.19.

[0072] IR v.sub.max(film) 3086 (w), 2957 (m), 2930 (s), 2872 (m), 2858 (m), 2594 (w, br), 2280 (w), 1615 (m), 1468 (m), 1457 (m), 1402 (m), 1276 (m), 1208 (s), 1064 (s), 1053 (s), 1013 (vs), 988 (vs), 850 (m), 727 (m), 607 (m).

[0073] HR-MS (ESL): For C.sub.9H.sub.18O.sub.3P (M−H).sup.− m/z calculated 205.09990, found 205.10001±0.49665 ppm.

Example 5: Octyl Vinylphosphonate

[0074] ##STR00013##

[0075] Octyl vinylphosphonate is prepared from mono methyl vinylphosphonate (4.0 g, 32.8 mmol) and 1-octanol using general method B1 and general method A in 27% (1.92 g, 8.86 mmol) overall yield in the form of colorless oil.

[0076] .sup.1H NMR (401 MHz, Chloroform-d) δ 6.43-5.94 (m, 3H), 4.00 (q, J=6.8 Hz, 2H), 1.66 (dt, J=8.1, 6.5 Hz, 2H), 1.44-1.18 (m, 10H), 0.95-0.78 (m, 3H).

[0077] .sup.31P NMR (162 MHz, Chloroform-d) δ 22.38.

[0078] .sup.13C NMR (101 MHz, Chloroform-d) δ 134.87 (d, J=2.0 Hz), 126.27 (d, J=189.4 Hz), 65.95 (d, J=6.1 Hz), 31.92, 30.49 (d, J=6.6 Hz), 29.32, 29.27, 25.63, 22.78, 14.23.

[0079] IR v.sub.max(CHCl.sub.3) 3089 (vw), 2958 (s), 2929 (vs), 2872 (s), 2858 (s), 2673 (w, vbr), 2338 (w, vbr), 1673 (m, vbr), 1615 (m), 1468 (m), 1458 (m), 1403 (m), 1379 (w), 1277 (m), 1196 (s), ˜1061 (s, sh), 1025 (vs), 986 (vs), 855 (w), 605 (w).

[0080] HR-MS (APCI.sup.+): For C.sub.10H.sub.22O.sub.3P (M+H).sup.+ m/z calculated 221.13011, found 221.12992±0.83273 ppm.

Example 6: Decyl Vinylphosphonate

[0081] ##STR00014##

[0082] Decyl vinylphosphonate is prepared from mono methyl vinylphosphonate (9.98 g, 81.8 mmol) and 1-octanol (12.9 mL, 81.8 mmol) using general method B1 and general method A in 41% (8.52 g, 34.3 mmol) overall yield in the form of colorless oil.

[0083] .sup.1H NMR (401 MHz, Chloroform-d) δ 10.98 (brs, 1H), 6.35-5.99 (m, 3H), 3.99 (q, J=6.8 Hz, 2H), 1.71-1.62 (m, 2H), 1.40-1.19 (m, 14H), 0.91-0.84 (m, 3H).

[0084] .sup.31P NMR (162 MHz, Chloroform-d) δ 22.13.

[0085] .sup.13C NMR (101 MHz, Chloroform-d) δ 134.86, 126.27 (d, J=189.3 Hz), 65.97 (d, J=6.1 Hz), 32.03, 30.50 (d, J=6.6 Hz), 29.68, 29.66, 29.45, 29.31, 25.63, 22.82, 14.26.

[0086] IR v.sub.max(CHCl.sub.3) 3090 (vw), 2957 (vs), 2928 (vs), 2872 (s), 2856 (vs), 2731 (m, br), 2675 (m, vbr), 2327 (m, br), 2174 (m, br, sh), 1667 (m, vbr), 1615 (s), 1467 (s), 1458 (m), 1403 (s), 1379 (m), 1277 (m), 1197 (vs), 1024 (vs, br), 986 (vs, br), 901 (m). P HR-MS (ESI.sup.+): For C.sub.12H.sub.25O.sub.3NaP (M+Na).sup.+ m/z calculated 271.14335, found 271.14340±0.18190 ppm; for C.sub.12H.sub.26O.sub.3P (M+H).sup.+ m/z calculated 249.16141, found 249.16152±0.45265 ppm.

Example 7: Phenethyl Vinylphosphonate

[0087] ##STR00015##

[0088] Phenethyl vinylphosphonate is prepared from mono methyl vinylphosphonate (7.0 g, 57.5 mmol) and phenethyl bromide (98%, 8.56 mL, 61.4 mmol) using general method C and general method A in 36% (4.42 g, 20.7 mmol) overall yield in the form of colorless oil.

[0089] .sup.1H NMR (401 MHz, Chloroform-d) δ 8.49 (brs, 1H), 7.39-7.12 (m, 5H), 6.43-5.73 (m, 3H), 4.18 (q, J=7.4 Hz, 2H), 2.98 (t, J=7.2 Hz, 2H).

[0090] .sup.31P NMR (162 MHz, Chloroform-d) δ 22.26.

[0091] .sup.13C NMR (101 MHz, Chloroform-d) δ 137.28, 135.12, 129.17, 128.64, 126.81, 125.94 (d, J=189.4 Hz), 66.23 (d, J=6.0 Hz), 37.02 (d, J=6.6 Hz).

[0092] IR v.sub.max(film) 3086 (w), 3063 (w), 3029 (w), 2867 (w), 1614 (w), 1605 (m), 1497 (m), 1473 (w), 1454 (m), 1402 (m), 1276 (m), 1216 (s), 1179 (m), 1154 (m), 1061 (s), 1019 (vs), 1002(s), 988 (vs), 748 (m), 699 (s), 496 (m).

[0093] HR-MS (ESI.sup.+): For C.sub.10H.sub.13O.sub.3NaP (M+Na).sup.+ m/z calculated 235.04945, found 235.04909±1.55059 ppm. For C.sub.10H.sub.14O.sub.3P (M+H).sup.+ m/z calculated 213.06751, found 213.06721±1.37212 ppm.

Example 8: 2-(adamantan-1-yl)ethyl vinylphosphonate

[0094] ##STR00016##

[0095] 2-(Adamantan-1-yl)ethyl vinylphosphonate is prepared from mono methy vinylphosphonate (0.63 g, 5.18 mmol) and 2-(adamantan-1-yl)ethanol using general method B1 and general method A in overall 40% yield (0.56 g, 2.07 mmol) in the form of white foam.

[0096] .sup.1H NMR (400.1 MHz, CDCl.sub.3): .sup.1H NMR (401 MHz, CDCl.sub.3) δ 1.37-1.46 (m, 2H); 1,49 (m, 6H); 1.51-1.75 (m, 6H); 1.91-1.92 (m, 3H); 3.60-4.09 (m, 2H); 5.75-6.12 (m, 3H).

[0097] .sup.31P{.sup.1H} NMR (162.0 MHz, CDCl.sub.3): δ 16.79.

[0098] IR v.sub.max (CHCl.sub.3) 3083 (vw), 2960 (m, sh), 2926 (s), 2904 (vs), 2849 (s), 2753-2637 (vw), 1160 (w, vbr), 1614 (w), 1451 (m), 1400 (m), 1362 (vw), 1346 (m), 1276 (m), 1201 (s), 1106 (m), 1072 (s), 1046 (s), 1029 (s, sh), 1018 (s), 989 (s), 972 (s), 811 (m), 437 (w).

[0099] HR-MS (ESI.sup.−): For C.sub.14H.sub.22O.sub.3P (M−H).sup.− m/z calcd 269.13120, found 269.13132.

Example 9: (adamantan-1-yl)methyl vinylphosphonate

[0100] ##STR00017##

[0101] (Adamantan-1-yl)methyl vinylphosphonate is prepared from mono methy vinylphosphonate (1.68 g, 13.8 mmol) and (adamantan-1-yl)methanol using general method B1 and general method A in overall 40% yield (8.87 g, 34.61 mmol) bezbarvého oleje.

[0102] .sup.1H NMR (401 MHz, Chloroform-d) δ 1.53 (s, 6H), 1.59-1.79 (m, 6H), 1.98 (s, 3H), 3,55 (d, J=5.8 Hz, 2H), 5.58-6.77 (m, 3H), 10.61 (s, 1H).

[0103] .sup.13C NMR (101 MHz, Chloroform-d) δ 28.14, 33.86 (d, J=7,1 Hz), 38.96, 75.31, 75.37, 76.84, 77.16, 77.48, 126.23 (d, J=189.8 Hz), 134.73 (d, J=1.8 Hz).

[0104] .sup.31P NMR (162 MHz, Chloroform-d) δ 22.39.

[0105] IR v.sub.max (CHCl.sub.3) 3090 (vw), 2940 (vs, sh), 2906 (vs), 2851 (vs), 2799, 2777, 2720 (m, vbr), 2660, 2326 (m, vbr), 1666 (m, vbr), 1616 (m), 1462 (m), 1453 (m), 1403 (m), 1387 (w), 1365 (w), 1276 (m), 1196 (s), 1191 (s), 1106 (m), 1060 (s), 1029 (vs, br), 1002 (vs), 987 (vs), 975 (vs), 942 (m), 923 (m), 809 (m), 437 (w).

[0106] HR-MS (ESI.sup.+) For C.sub.13H.sub.21O.sub.3NaP (M+Na).sup.+ calcd 279.11205, found 279.11202.

Example 10: 3-(cyclohexyl)propyl vinylphosphonate

[0107] ##STR00018##

[0108] 3-(Cyclohexyl)propyl vinylphosphonate is prepared from mono methyl vinylphosphonate (5 g, 40.96 mmol) and 3-(cyclohexyl)propanol (8.32 g, 58.52 mmol) general method B2 and general method A in 32% (3-01 g, 12-96 mmol) overall yield in the form of colorless oil.

[0109] .sup.1H NMR (401 MHz, Chloroform-d) δ 0-71-0-99 (m, 2H), 1.02-1.44 (m, 6H), 1.47-1.93 (m, 7H), 3.84 -4.15 (m, 2H), 5.74-6.49 (m, 3H), 9.98 (s, 1H).

[0110] .sup.13C NMR (101 MHz, Chloroform-d) δ 26.15, 26.45, 27.60 (d, J=6,7 Hz), 32.92, 33.08, 37.10, 65,97 (d, J=6,1 Hz), 76.53, 76.84, 77.16, 126.01 (d, J=189.2 Hz), 134.49 (d, J=1.8 Hz).

[0111] .sup.31P NMR (162 MHz, Chloroform-d) δ 22.18.

[0112] IR v.sub.max (CHCl.sub.3) 3090 (vw), 2926 (vs), 2853 (s), 2710 (w, vbr), 2330 (m, vbr), 1669 (m, vbr), 1615 (m), 1474 (w), 1463 (w), 1449 (m), 1403 (m), 1276 (w), 1198 (s), 1068 (s), 1053 (s), 1041 (s), 1013 (vs), 986 (vs).

[0113] HR-TOF MS CI+ For C.sub.11H.sub.22O.sub.3P (M+H).sup.+ calcd 233.1307, found 233.1310.

Example 11: (Z)-non-3-en-1-yl vinylphosphonate

[0114] ##STR00019##

[0115] (Z)-non-3-en-1-yl vinylphosphonate is prepared from mono methyl vinylphosphonate (3.0 g, 24.6 mmol) and (Z)-non-3-en-1-ol using general method B1 and general method A in 35% (2.0 g, 8.61 mmol) overall yield in the form of colorless oil.

[0116] .sup.1H NMR (401 MHz, Methanol-d.sub.4) δ 0.87-0.95 (m, 3H), 1.23-1.44 (m, 6H), 2.06 (qd, J=7.3, 1.3 Hz, 2H), 2.41 (qd, J=7.0, 1.4 Hz, 2H), 3.92 (q, J=7.0 Hz, 2H), 5.38 (ddd, J=10.9, 7.1, 1.4 Hz, 1H), 5.51 (dtt, J=10.3, 7.2, 1.5 Hz, 1H), 5.97-6.27 (m, 3H).

[0117] .sup.13C NMR (101 MHz, Methanol-d.sub.4) δ 14.41, 23.61, 29.72 (d, J=6.6 Hz), 29.75, 30.40, 32.62, 48.36, 48.58, 48.79, 49.00, 49.21, 49.42, 49.64, 66.04 (d, J.sub.C,P=5.7 Hz), 125.37, 128.92 (d, J=181.4 Hz), 133.87, 134.31 (d, J=1.4 Hz).

[0118] .sup.31P NMR (162 MHz, Methanol-d.sub.4) δ 18.44.

[0119] IR v.sub.max (KBr) 3088 (vw), 2959 (s), 2930 (s), 2873 (m), 2858 (s), 2733 (w), 2669 (w, vbr), 2337 (m, br), 1660 (m, vbr), 1655 (w), 1615 (m), 1468 (m), 1460 (m), 1403 (m), 1380 (w), 1277 (m), 1198 (s), 1165 (s, sh), 1155 (s), 1023 (vs), 986 (vs).

[0120] HR-MS (ESI.sup.+) For C.sub.11H.sub.21O.sub.3NaP (M+Na).sup.+ calcd 255.11205, found 255.11186.

Example 12: (Z)-hept-3-en-1-yl vinylphosphonate

[0121] ##STR00020##

[0122] (Z)-hept-3-en-1-yl vinylphosphonate is prepared from mono methyl vinylphosphonate (5.0 g, 41.0 mmol) and 1-hexanol using general method B2 and general method A in 46% (3.42 g, 19.6 mmol) overall yield in the form of colorless oil.

[0123] .sup.1H NMR (400.1 MHz, CDCl.sub.3): 0.89 (m, 3H), 1.32-1.41 (m, 2H), 1.98-2.04 (m, 2H), 2.35-2.46 (m, 2H), 3.98 (q, 2H, J.sub.vic=7.2), 5.31-5.38 (m, 1H), 5.47-5.54 (m, 1H), 5.99-6.34 (m, 3H), 11.10 (s, 1H).

[0124] .sup.13C NMR (100.6 MHz, CDCl.sub.3): 13.73, 22.67, 28.59 (d, J.sub.C,P=7.0), 29.36, 65.06 (d, J.sub.C,P=6.0), 123.80, 126.13 (d, J.sub.C,P=189.1), 133.05, 134.72 (d, J.sub.C,P=2.0).

[0125] .sup.1P{.sup.1H} NMR (162.0 MHz, CDCl.sub.3): 21.58.

[0126] IR v.sub.max (KBr) 3091 (w), 3013 (m), 2960 (m), 2931 (m), 2873 (s), 2700-2100 (w, vbr), 1665 (w), 1657 (w), 1615 (w), 1466 (w), 1458 (w), 1403 (m), 1379 (vw), 1277 (w), 1210 (m), 1144 (m, sh), 1066 (m), 1016 (vs), 1023 (vs), 989 (vs), 849 (w).

[0127] HR-ESI(ESI.sup.30 ) For C.sub.9H.sub.16O.sub.3P (M−H).sup.− calcd 203.08425, found 203.08435.

Example 13: (Z)-oct-3-en-1-yl vinylphosphonate

[0128] ##STR00021##

[0129] (Z)-oct-3-en-1-yl vinylphosphonate is prepared from mono methyl vinylphosphonate (4.0 g, 32.8 mmol) and (Z)-oct-3-en-1-ol using general method B2 and general method A in 60% (3.42 g, 15.7 mmol)

[0130] .sup.1H NMR (400.1 MHz, CDCl.sub.3): 0.86-0.92 (m, 3H), 1.25-1.37 (m, 4H), 2.0-2.06 (m, 2H), 2.35-2.46 (m, 2H), 3.98 (q, 2H, J.sub.vic=12.0), 5.30-5.37 (m, 1H), 5.47-5.54 (m, 1H), 5.99-6.34 (m, 3H), 10.79 (s, 1H).

[0131] .sup.13C NMR (100.6 MHz, CDCl.sub.3): 13.96, 22.30, 27.04, 28.57 (d, J.sub.C,P=7.0), 31.72, 65.06 (d, J.sub.C,P=6.0, 123.59, 126.12 (d, J.sub.C,P=189.1), 133.27, 134.73 (d, J.sub.C,P=2.0).

[0132] .sup.1P{.sup.1H} NMR (162.0 MHz, CDCl.sub.3): 21.66.

[0133] IR v.sub.max (KBr) 3090 (w), 2960 (s), 2930 (s), 2873 (s), 2860 (s), 2734 (m, br), 2672 (m, vbr), 2330 (m, vbr), 2169 (m, vbr), 1665 (m, vbr), 1654 (m), 1615 (m), 1467 (m), 1458 (m), 1403 (s), 1379 (m), 1277 (m), 1198 (s), 1066 (s), 1053 (s), 1023 (vs), 986 (vs), 894 (w).

[0134] HR-MS (ESI.sup.+) For C.sub.10H.sub.19O.sub.3NaP (M+Na).sup.+ calcd 241.09640, found 241.09653.

Example 14: Isobutyl Vinylphosphonate

[0135] ##STR00022##

[0136] Isobutyl vinylphosphonate is prepared from mono methyl vinylphosphonate (4.03 g, 33.0 mmol) and isobutyl alcohol (3.71 mL, 40.0 mmol) using general method B1 and general method A in 37% (2.00 g, 12.2 mmol) overall yield in the form of colorless oil.

[0137] .sup.1H NMR (401 MHz, Chloroform-d) δ 6.45 (brs, 1H), 6.36-5.98 (m, 3H), 3.77 (t, J=6.6 Hz, 2H), 1.95 (dt, J=13.3, 6.7 Hz, 1H), 0.94 (d, J=6.7 Hz, 6H).

[0138] .sup.31P NMR (162 MHz, Chloroform-d) δ 22.26.

[0139] .sup.13C NMR (101 MHz, Chloroform-d) δ 134.69, 126.11 (d, J=189.6 Hz), 71.63 (d, J=6.6 Hz), 29.06 (d, J=7.0 Hz), 18.69 (d, J=1.8 Hz).

[0140] IR v.sub.max (CHCl.sub.3) 3088 (w), 2962 (m), 2877 (m), 2853 (w), 2585 (m, br), 2278 (m, br), 1673 (m), 1615 (m), 1472 (m), 1403 (m), 1370 (w), 1278 (m), 1206 (s), 1032 (vs), 989 (s), 854 (m), 732 (m), 610 (m).

[0141] HR-MS (ESI.sup.+): For C.sub.6H.sub.13O.sub.3NaP (M+Na).sup.+m/z calculated 187.04945, found 187.04957±0.64909 ppm.

Example 15: Di((Z)-oct-3-en-1-yl) propane-1,3-diyl bis(vinylphosphonate)

[0142] ##STR00023##

[0143] Di((Z)-oct-3-en-1-yl) propan-1,3-diyl bis(vinylphosphonate) is prepared from compound in Example 13 (0.9 g, 4.12 mmol) and 1,3-dibromopropane (0.32 g, 1.37 mmol) using general method C in 73% (0.48 g, 1.01 mmol) overall yield in the form of colorless oil.

[0144] .sup.1H NMR (400.1 MHz, CDCl.sub.3): 0.86-0.94 (m, 6H), 1.25-1.36 (m, 8H), 1.42-1.50 (m, 2H), 1.65-1.73 (m, 4H), 2.0-2.06 (m, 4H), 2.35-2.45 (m, 4H), 3.97-4.04 (m, 8H), 5.30-5.37 (m, 2H), 5.47-5.54 (m, 2H), 5.97-6.35 (m, 6H).

[0145] .sup.13C NMR (100.6 MHz, CDCl.sub.3): 13.97, 21.69, 22.31, 27.07, 28.68 (d, J.sub.C,P=7.0), 29.99 (d, J.sub.C,P=7.0), 31.71, 65.28, 65.48 (d, J.sub.C,P=6.0), 123.68, 125.75 (d, J.sub.C,P=184.1), 133.28, 135.63 (d, J.sub.C,P=3.0).

[0146] .sup.1P{.sup.1H} NMR (162.0 MHz, CDCl.sub.3): 19.87.

[0147] IR v.sub.max (KBr) 3086 (w), 3011 (m), 2957 (s), 2929 (s), 2872 (m), 2860 (m), 1613 (w), 1467 (m), 1363 (w), 1278 (m, sh), 1251 (vs), 1184 (w), 1054 (s), 1007 (vs), 970 (s, sh), 726 (m), 608 (m).

[0148] HR-MS (ESI.sup.+) For C.sub.25H.sub.47O.sub.6P.sub.2 (M+H).sup.+ calcd 505.28424, found 505.28375.

Example 16: Di((Z)-oct-3-en-1-yl) pentane-1,5-diyl bis(vinylphosphonate)

[0149] ##STR00024##

[0150] Di((Z)-oct-3-en-1-yl) pentane-1,5-diyl bis(vinylphosphonate) is prepared from compound in Example 13 (0.9 g, 4.12 mmol) and 1,5-dibromopropane (0.32 g, 1.37 mmol) using general method C in 79% (0.56 g, 1.11 mmol) overall yield in the form of colorless oil.

[0151] .sup.1H NMR (400.1 MHz, CDCl.sub.3): 0.86-0.94 (m, 6H), 1.25-1.36 (m, 8H), 1.42-1.50 (m, 2H), 1.65-1.73 (m, 4H), 2.0-2.06 (m, 4H), 2.35-2.45 (m, 4H), 3.97-4.04 (m, 8H), 5.30-5.37 (m, 2H), 5.47-5.54 (m, 2H), 5.97-6.35 (m, 6H).

[0152] .sup.13C NMR (100.6 MHz, CDCl.sub.3): 13.97, 21.69, 22.31, 27.07, 28.68 (d, J.sub.P,C=7.0), 29.99 (d, J.sub.C,P=7.0), 31.71, 65.28, 65.48 (d, J.sub.C,P=6.0), 123.68, 125.75 (d, J.sub.C,P=184.1), 133.28, 135.63 (d, J.sub.C,P=3.0).

[0153] .sup.1P{.sup.1H} NMR (162.0 MHz, CDCl.sub.3): 19.87.

[0154] IR v.sub.max (KBr) 3086 (w), 3011 (m), 2957 (s), 2929 (s), 2872 (m), 2860 (m), 1613 (w), 1467 (m), 1363 (w), 1278 (m, sh), 1251 (vs), 1184 (w), 1054 (s), 1007 (vs), 970 (s, sh), 726 (m), 608 (m).

[0155] HR-MS (ESI.sup.+) For C.sub.25H.sub.47O.sub.6P.sub.2 (M+H).sup.+ calcd 505.28424, found 505.28375.

Example 17: Di((Z)-oct-3-en-1-yl) hexane-1,5-diyl bis(vinylphosphonate)

[0156] ##STR00025##

[0157] Hexan-1,6-diyl di((Z)-oct-3-en-1-yl) bis(vinylphosphonate) is prepared from compound in Example 13 (0.9 g, 4.12 mmol) and 1,6-dibromohexane (0.32 g, 1.37 mmol) using general method C in 83% (0.59 g, 1.14 mmol) overall yield in the form of colorless oil.

[0158] .sup.1H NMR (400.1 MHz, CDCl.sub.3): 0.86-0.92 (m, 6H), 1.25-1.35 (m, 8H), 1.36-1.41 (m, 4H), 1.62-1.70 (m, 4H), 2.0-2.06 (m, 4H), 2.39-2.45 (m, 4H), 3.97-4.03 (m, 8H), 5.30-5.37 (m, 2H), 5.47-5.54 (m, 2H), 5.97-6.34 (m, 6H).

[0159] .sup.13C NMR (100.6 MHz, CDCl.sub.3): 13.96, 22.31, 25.15, 27.07, 28.67 (d, J.sub.C,P=6.0), 30.35 (d, J.sub.C,P=7.0), 31.71, 65.26 (d, J.sub.C,P=6.0), 65.67 (d, J.sub.C,P=6.0), 123.70, 125.78 (d, J.sub.C,P=184.1), 133.26, 135.58 (d, J.sub.C,P=3.0).

[0160] .sup.1P{.sup.1H} NMR (162.0 MHz, CDCl.sub.3): 19.83.

[0161] IR v.sub.max (KBr) 3085 (w), 3011 (m), 2956 (s), 2929 (s), 2871 (m), 2859 (m), 1654 (w), 1613 (w), 1467 (m), 1398 (m), 1278 (m, sh), 1251 (s), 1053 (s), 1003 (s), 970 (s, sh), 854 (m), 729 (m), 698 (m).

[0162] HR-MS (ESI.sup.+) For C.sub.26H.sub.49O.sub.6P.sub.2 (M+H).sup.+ calcd 519.29989, found 519.29947.

Example 18: Di((Z)-hept-3-en-1-yl) hexane-1,6-diyl bis(vinylphosphonate)

[0163] ##STR00026##

[0164] Di((Z)-hept-3-en-1-yl) hexane-1,6-diyl bis(vinylphosphonate) is prepared from compound in Example 12 (1.10 g, 5.39 mmol) and 1,6-dibromohexane (0.44 g, 1.80 mmol) using general method C in 79% (0.68 g, 1.42 mmol) overall yield in the form of colorless oil.

[0165] .sup.1H NMR (400.1 MHz, CDCl.sub.3): 0.89 (m, 6H), 1.32-1.43 (m, 8H), 1.62-1.70 (m, 4H), 1.98-2.04 (m, 4H), 2.39-2.45 (m, 4H), 3.96-4.03 (m, 8H), 5.31-5.38 (m, 2H), 5.47-5.54 (m, 2H), 5.97-6.34 (m, 6H).

[0166] .sup.13C NMR (100.6 MHz, CDCl.sub.3): 13.74, 22.66, 25.15, 28.69 (d, J.sub.C,P=6.0), 29.39, 30.35 (d, J.sub.C,P=7.0), 65.24 (d, J.sub.C,P=6.0), 65.66 (d, J.sub.C,P=6.0), 123.91, 125.80 (d, J.sub.C,P=184.1), 133.04, 135.56 (d, J.sub.C,P=2.0).

[0167] .sup.1P{.sup.1H} NMR (162.0 MHz, CDCl.sub.3): 19.84.

[0168] IR v.sub.max (KBr) 3085 (vw), 3011 (m), 2958 (s), 2931 (m), 2871 (m), 1654 (w), 1613 (w), 1465 (m), 1398 (m), 1280 (m, sh), 1251 (vs), 1066 (vs), 1053 (vs), 1003 (vs), 976 (s, sh), 851 (m), 727 (m).

[0169] HR-MS (ESI.sup.+) For C.sub.24H.sub.45O.sub.6P.sub.2 (M+H).sup.+ calcd 491.26859, found 491.26863.

Example 19: Di((Z)-hept-3-en-1-yl) pentane-1,5-diyl bis(vinylphosphonate)

[0170] ##STR00027##

[0171] Di((Z)-hept-3-en-1-yl) pentane-1,5-diyl bis(vinylphosphonate) is prepared from compound in Example 12 (1.10 g, 5.39 mmol) and 1,6-dibromopentane (0.40 g, 1.80 mmol) using general method C in 84% (0.72 g, 1.50 mmol) overall yield in the form of colorless oil.

[0172] .sup.1H NMR (400.1 MHz, CDCl.sub.3): 0.88 (m, 6H), 1.29-1.39 (m, 4H), 1.41-1.49 (m, 2H), 1.65-1.72 (m, 4H), 1.97-2.03 (m, 4H), 2.38-2.44 (m, 4H), 3.96-4.03 (m, 8H), 5.30-5.38 (m, 2H), 5.46-5.53 (m, 2H), 5.96-6.33 (m, 6H).

[0173] .sup.13C NMR (100.6 MHz, CDCl.sub.3): 13.74, 21.68, 22.65, 28.68 (d, J.sub.C,P32 6.0), 29.38, 29.97 (d, J.sub.C,P32 7.0), 65.27, 65.42 (d, J.sub.C,P=6.0, 5.0), 123.88, 125.73 (d, J.sub.C,P=184.1), 133.05, 135.62 (d, J.sub.C,P=2.0).

[0174] .sup.1P{.sup.1H} NMR (162.0 MHz, CDCl.sub.3): 19.86.

[0175] IR v.sub.max (KBr) 3086 (vw), 3011 (m), 2960 (s), 2930 (m), 2872 (m), 1656 (w), 1613 (w), 1466 (m), 1457 (m, sh), 1380 (w), 1281 (m), 1252 (s), 1066 (vs), 1051 (vs), 1011 (vs), 981 (s, sh), 722 (m).

[0176] HR-MS (ESI.sup.+) For C.sub.23H.sub.42O.sub.6NaP.sub.2 (M+Na).sup.+ calcd 499.23488, found 499.23491.

Example 20: Hexane-1,6-diyl dihexyl bis(vinylphosphonate)

[0177] ##STR00028##

[0178] Hexane-1,6-diyl dihexyl bis(vinylphosphonate) is prepared from compound in Example 3 (1.20 g, 6.24 mmol) and 1,6-dibromohexane (0.51 g, 2.08 mmol) using general method C in 71% (0.69 g, 1.48 mmol) overall yield in the form of colorless oil.

[0179] .sup.1H NMR (400.1 MHz, CDCl.sub.3): 0.86-0.90 (m, 6H), 1.24-1.43 (m, 16H), 1.62-1.71 (m, 8H), 3.97-4.02 (m, 8H), 5.97-6.33 (m, 6H).

[0180] .sup.13C NMR (100.6 MHz, CDCl.sub.3): 13.98, 22.52, 25.16, 25.18, 31.33, 30.39 (d, J.sub.C,P=7.0, 6.0), 65.63, 66.98 (d, J.sub.C,P=6.0, 5.0), 135.47 (d, J.sub.C,P=183.1), 135.47 (d, J.sub.C,P=3.0).

[0181] .sup.1P{.sup.1H} NMR (162.0 MHz, CDCl.sub.3): 19.82.

[0182] IR v.sub.max (KBr) 3090 (vw), 2959 (s), 2934 (s), 2872 (m), 2861 (m), 1614 (w), 1468 (m), 1460 (m, sh), 1455 (m, sh), 1400 (m), 1380 (w), 1279 (m), 1241 (s), 1058 (s), 1039 (s), 1010 (vs, sh), 998 (vs), 862 (m).

[0183] HR-MS (ESI.sup.+) For C.sub.22H.sub.45O.sub.6P.sub.2 (M+H).sup.+ calcd 467.26859, found 467.26821.

Example 21: Dihexyl octane-1,8-diyl bis(vinylphosphonate)

[0184] ##STR00029##

[0185] Dihexyl octane-1,8-diyl bis(vinylphosphonate) is prepared from compound in Example 3 (1.0 g, 5.20 mol) and 1,8-dibromooctane (0.64 g, 1.74 mmol) using general method C in 74% (0.64 g, 1.29 mmol) overall yield in the form of colorless oil.

[0186] .sup.1H NMR (400.1 MHz, CDCl.sub.3): 0.83-0.90 (m, 6H), 1.24-1.40 (m, 20H), 1.62-1.70 (m, 8H), 3.97-4.11 (m, 8H), 5.97-6.34 (m, 6H).

[0187] .sup.13C NMR (100.6 MHz, CDCl.sub.3): 13.98, 22.52, 25.18, 25.45, 29.04, 31.33, 30.43 (d, J.sub.C,P=6.0), 65.81, 65.94 (d, J.sub.C,P=5.0), 125.91 (d, J.sub.C,P=184.1), 135.38 (d, J.sub.C,P=3.0).

[0188] .sup.1P{.sup.1H} NMR (162.0 MHz, CDCl.sub.3): 19.77.

[0189] IR v.sub.max (KBr) 3091 (vw), 2959 (s), 2934 (s), 2872 (m), 2860 (w), 1614 (w), 1468 (w), 1456 (w, sh), 1434 (w), 1400 (m), 1279 (m), 1241 (s), 1059 (s), 1040 (s, sh), 1009 (vs), 998 (vs), 606 (w).

[0190] HR-MS (ESI.sup.+) For C.sub.24H.sub.49O.sub.6P.sub.2 (M+H).sup.+ calcd 495.29989, found 495.29906.

Example 22: Decane-1,10-diyl dihexyl bis(vinylphosphonate)

[0191] ##STR00030##

[0192] Decane-1,10-diyl dihexyl bis(vinylphosphonate) is prepared from compound in Example 3 (1.0 g, 5.20 mmol) and 1,10-dibromodecane (0.62 g, 1.74 mmol) using general method C in 75% (0.68 g, 1.31 mmol) overall yield in the form of colorless oil.

[0193] .sup.1H NMR (400.1 MHz, CDCl.sub.3): 0.85-0.90 (m, 6H), 1.25-1.40 (m, 24H), 1.62-1.69 (m, 8H), 3.96-4.04 (m, 8H), 5.97-6.33 (m, 6H).

[0194] .sup.13C NMR (100.6 MHz, CDCl.sub.3): 13.98, 22.52, 25.18, 25.51, 29.14, 29.42, 31.33, 30.42, 30.48 (d, J.sub.C,P=6.0), 65.88, 65.93 (d, J.sub.C,P=6.0), 125.92 (d, J.sub.C,P=184.1), 135.35 (d, J.sub.C,P=2.0).

[0195] .sup.1P{.sup.1H} NMR (162.0 MHz, CDCl.sub.3): 19.76.

[0196] IR v.sub.max (KBr) 3091 (vw), 2959 (s), 2932 (vs), 2872 (m), 2858 (m), 1614 (w), 1468 (m), 1458 (w), 1434 (w), 1400 (m), 1380 (w), 1279 (w), 1241 (s), 1058 (s), 1038 (s, sh), 1007 (vs), 997 (vs), 606 (w).

[0197] HR-MS (ESI.sup.+) For C.sub.26H.sub.53O.sub.6P.sub.2 (M+H).sup.+ calcd 523.33119, found 523.33031.

Example 23: Dihexyl tetradecane-1,14-diyl bis(vinylphosphonate)

[0198] ##STR00031##

[0199] Dihexyl tetradecane-1,14-diyl bis(vinylphosphonate) is prepared from compound in Example 3 (1.0 g, 5.20 mmol) and 1,14-dibromotetradecane (0.62 g, 1.74 mmol) using general method C in 85% (0.86 g, 1.47 mmol) overall yield in the form of colorless oil.

[0200] .sup.1H NMR (400.1 MHz, CDCl.sub.3): 0.86-0.90 (m, 6H), 1.24-1.39 (m), 1.62-1.69 (m, 8H), 3.95-4.04 (m, 8H), 5.97-6.33 (m, 6H).

[0201] .sup.13C NMR (100.6 MHz, CDCl.sub.3): 13.98, 22.52, 25.19, 25.53, 29.17, 29.52, 29.57, 29.62, 31.34, 30.44, 30.48, 65.91 (d, J.sub.C,P=6.0), 125.95 (d, J.sub.C,P=184.1), 135.31 (d, J.sub.C,P=2.0).

[0202] .sup.1P{.sup.1H} NMR (162.0 MHz, CDCl.sub.3): 19.74.

[0203] IR v.sub.max (KBr) 3090 (vw); 2958 (s), 2930 (vs), 2871 (m), 2857 (s), 1614 (w), 1468 (m), 1458 (w), 1434 (w), 1400 (m), 1380 (w), 1279 (w), 1241 (s), 1058 (s), 1038 (s), 1010 (vs), 998 (vs), 861 (w), 606 (w).

[0204] HR-MS (ESI.sup.+) For C.sub.30H.sub.61O.sub.6P.sub.2 (M+H).sup.+ calcd 579.39379, found 579.39286.

Example 24: Octane-1,8-diyl dipentyl bis(vinylphosphonate)

[0205] ##STR00032##

[0206] Octan-1,8-diyl dipentyl bis(vinylphosphonate) is prepared from compound in Example 2 (1.20 g, 6.73 mmol) and 1,8-dibromooctane (0.61 g, 2.24 mmol) using general method C in 71% (0.75 g, 1.61 mmol) overall yield in the form of colorless oil.

[0207] .sup.1H NMR (400.1 MHz, CDCl.sub.3): 0.84-0.89 (m, 6H), 1.26-1.37 (m, 16H), 1.60-1.68 (m, 8H), 3.95-4.02 (m, 8H), 5.97-6.33 (m, 6H).

[0208] .sup.13C NMR (100.6 MHz, CDCl.sub.3): 13.94, 22.21, 25.43, 27.63, 29.02, 30.14, 30.36 (d, J.sub.C,P=7.0, 6.0), 64.40, 65.79 (d, J.sub.C,P=6.0, 5.0), 125.86 (d, J.sub.C,P=184.1), 135.40 (d, J.sub.C,P=2.0).

[0209] .sup.1P{.sup.1H} NMR (162.0 MHz, CDCl.sub.3): 20.01.

[0210] IR v.sub.max (KBr) 3090 (vw), 2960 (s), 2935 (s), 2873 (m), 2860 (m), 1614 (w), 1467 (m), 1400 (m), 1381 (w), 1279 (w), 1240 (s), 1381 (w), 1075 (m, sh), 1051 (s), 1017 (vs), 992 (vs), 855 (w).

[0211] HR-MS (ESI.sup.+) For C.sub.22H.sub.44O.sub.6NaP.sub.2 (M+Na).sup.+ calcd 489.25053, found 489.25015.

Example 25: Decane-1,8-diyl dipentyl bis(vinylphosphonate)

[0212] ##STR00033##

[0213] Decane-1,8-diyldipentyl bis(vinylphosphonate) is prepared from compound in Example 2 (1.20 g, 6.73 mmol) and 1,10-dibromodecane (0.67 g, 2.24 mmol) using general method C in 76% (0.84 g, 1.70 mmol) overall yield in the form of colorless oil.

[0214] .sup.1H NMR (400.1 MHz, CDCl.sub.3): 0.85-0.92 (m, 6H), 1.25-1.39 (m, 20H), 1.62-1.70 (m, 8H), 3.97-4.04 (m, 8H), 5.97-6.33 (m, 6H).

[0215] .sup.13C NMR (100.6 MHz, CDCl.sub.3): 13.95, 22.23, 25.51, 27.65, 29.13, 29.41, 30.16, 30.47 (d, J.sub.C,P=7.0, 6.0), 65.88, 65.91 (d, Jc.sub.C,P=6.0, 5.0), 125.92 (d, J.sub.C,P=184.1), 135.35 (d, J.sub.C,P=2.0).

[0216] .sup.1P{.sup.1H} NMR (162.0 MHz, CDCl.sub.3): 19.76.

[0217] IR v.sub.max (KBr) 3085 (vw), 2956 (s), 2930 (vs), 2857 (s), 1613 (w), 1467 (m), 1458 (m), 1397 (m), 1377 (w,sh), 1280 (m), 1253 (vs), 1018 (vs), 1051 (s), 1074 (m), 990 (vs).

[0218] HR-MS (ESI.sup.+) For C.sub.24H.sub.48O.sub.6NaP.sub.2 (M+Na).sup.+ calcd 517.28183, found 517.28171.

Example 26: Dodecane-1,12-diyl dipentyl bis(vinylphosphonate)

[0219] ##STR00034##

[0220] Dodecane-1,8-diyl dipentyl bis(vinylphosphonate) is prepared from compound in Example 2 (1.50 g, 8.42 mmol) and 1,12-dibromododecane (0.92 g, 2.81 mmol) using general method C in 78% (1.15 g, 2.19 mmol) overall yield in the form of colorless oil.

[0221] NMR (400.1 MHz, CD.sub.3OD): 0.91-0.96 (m, 6H), 1.29-1.43 (m, 24H), 1.65-1.73 (m, 8H), 3.99-4.05 (m, 8H), 6.08-6.32 (m, 6H).

[0222] .sup.13C NMR (100.6 MHz, CD.sub.3OD): 12.93, 21.87, 25.24, 27.44, 28.82, 29.24, 29.25, 29.82, 30.09 (d, J.sub.C,P6.0), 66.05 (d, J.sub.C,P=6.0), 125.05 (d, J.sub.C,P=184.1), 135.53 (d, J.sub.C,P=2.0).

[0223] .sup.1P{.sup.1H} NMR (162.0 MHz, CD.sub.3OD): 20.44.

[0224] IR v.sub.max (KBr) 3089 (vw), 3013 (w), 2968 (s), 2930 (vs), 2873 (s), 2857 (s), 1614 (w), 1467 (m), 1458 (m), 1434 (w), 1398 (m), 1381 (w), 1279 (m), 1253 (vs), 1052 (vs), 1020 (vs, sh), 989 (vs), 854 (m).

[0225] HR-MS (ESI.sup.+) For C.sub.26H.sub.52O.sub.6NaP.sub.2 (M+Na).sup.+ calcd 545.31313, found 545.31275.

Example 27: Dipentyl tetradecane-1,14-diyl bis(vinylphosphonate)

[0226] ##STR00035##

[0227] Dipentyl tetradecane-1,14-diyl bis(vinylphosphonate) is prepared from compound in Example 2 (1.50 g, 8.42 mmol) and 1,14-dibromotetradecane (1.24 g, 2.25 mmol) using general method C in 80% (1.24 g, 2.25 mmol) overall yield in the form of colorless oil.

[0228] .sup.1H NMR (400.1 MHz, CD.sub.3OD): 0.91-0.96 (m, 6H), 1.31-1.42 (m, 28H), 1.65-1.73 (m, 8H), 3.99-4.05 (m, 8H), 6.08-6.32 (m, 6H).

[0229] .sup.13C NMR (100.6 MHz, CD.sub.3OD): 14.33, 23.27, 26.63, 28.84, 30.22, 30.64, 30.68, 30.75, 31.22, 31.49 (d, J.sub.C,P=7.0, 6.0), 67.44 (d, J.sub.C,P=6.0), 126.44 (d, J.sub.C,P=185.1), 136.92 (d, J.sub.C,P=2.0).

[0230] .sup.1P{.sup.1H} NMR (162.0 MHz, CD.sub.3OD): 20.44.

[0231] IR v.sub.max (KBr) 3090 (vw), 2960 (s), 2930 (vs), 2873 (m), 2857 (s), 1467 (m), 1455 (w, sh), 1381 (w), 1279 (m), 1240 (s), 1050 (s), 1021 (vs, sh), 993 (vs).

[0232] HR-MS (ESI.sup.+) For C.sub.28H.sub.56O.sub.6NaP.sub.2 (M+Na).sup.+ calcd 573.34443, found 545.34422.

Example 28: Dibutyl octane-1,8-diyl bis(vinylphosphonate)

[0233] ##STR00036##

[0234] Dibutyl octane-1,8-diyl bis(vinylphosphonate) is prepared from compound in Example 1 (0.63 g, 3.84 mmol) and 1,8-dibromooctane (0.35 g, 1.28 mmol) using general method C in 71% (0.40 g, 0.91 mmol) overall yield in the form of colorless oil.

[0235] .sup.1H NMR (400.1 MHz, CDCl.sub.3): 0.93 (t, 6H, J.sub.vic=8.0), 1.36-1.45 (m, 12H), 1.62-1.70 (m, 8H), 3.97-4.05 (m, 8H), 5.98-6.34 (m, 6H).

[0236] .sup.13C NMR (100.6 MHz, CDCl.sub.3): 13.46, 18.62, 25.31, 28.89, 30.30, 32.36 (d, J.sub.C,P=6.0), 65.46, 65.66 (d, J.sub.C,P=6.0), 125.80 (d, J.sub.C,P=184.1), 135.24 (d, J.sub.C,P=2.0).

[0237] .sup.1P{.sup.1H} NMR (162.0 MHz, CDCl.sub.3): 19.79.

[0238] IR v.sub.max (KBr) 3091 (vw), 2963 (s), 2936 (s), 2875 (m), 2860 (m), 1614 (w), 1466 (m), 1459 (m), 1433 (w), 1400 (m), 1380 (w, sh), 1279 (m), 1241 (s), 1063 (s), 1021 9vs, br), 988 (vs), 852 (m), 606 (m).

[0239] HR-MS (ESI.sup.+) For C.sub.20H.sub.40O.sub.6NaP.sub.2 (M+Na).sup.+ calcd 461.21923, found 461.21878.

Example 29: Decane-1,10-diyl dipentyl bis(vinylphosphonate)

[0240] ##STR00037##

[0241] Decane-1,10-diyl dipentyl bis(vinylphosphonate) is prepared from compound in Example 1 (1.50 g, 9.14 mmol) and 1,10-dibromodecane (0.91 g, 3.05 mmol) using general method C in 62% (0.88 g, 1.89 mmol) overall yield in the form of colorless oil.

[0242] .sup.1H NMR (400.1 MHz, CDCl.sub.3): 0.92 (t, 6H, J.sub.vic=8.0), 1.24-1.44 (m, 16H), 1.61-1.69 (m, 8H), 3.97-4.04 (m, 8H), 5.97-6.33 (m, 6H).

[0243] .sup.13C NMR (100.6 MHz, CDCl.sub.3: 13.59, 18.74, 25.50, 29.12, 29.40, 30.46, 32.47 (d, J.sub.C,P=6.0), 65.60, 65.88 (d, J.sub.C,P=6.0), 125.91 (d, J.sub.C,P=184.1), 135.36 (d, J.sub.C,P=2.0).

[0244] .sup.1P{.sup.1H} NMR (162.0 MHz, CDCl.sub.3): 19.77.

[0245] IR v.sub.max (KBr) 3090 (vw), 3001 (vw), 2962 (s), 2935 (vs), 2850 (s), 1612 (w), 1463 (m), 1395 (m), 1271 (m, sh), 1250 (vs), 1068 (vs), 1025 (vs), 985 (vs), 980 (m, sh), 726 (m).

[0246] HR-MS (ESI.sup.+) For C.sub.22H.sub.44O.sub.6NaP.sub.2 (M+Na).sup.+ calcd 489.25053, found 489.24997.

Example 30: Dibutyl dodecane-1,12-diyl bis(vinylphosphonate)

[0247] ##STR00038##

[0248] Dibutyl dodecane-1,12-diyl bis(vinylphosphonate) is prepared from compound in Example 1 (1.50 g, 9.14 mmol) and 1,12-dibromododecane (1.0 g, 3.05 mmol) using general method C in 65% (0.98 g, 1.98 mmol) overall yield in the form of colorless oil.

[0249] .sup.1H NMR (400.1 MHz, CDCl.sub.3): 0.92 (t, 6H, J.sub.vic=8.0), 1.24-1.44 (m, 20H), 1.61-1.69 (m, 8H), 3.96-4.04 (m, 8H), 5.97-6.33 (m, 6H).

[0250] .sup.13C NMR (100.6 MHz, CDCl.sub.3): 13.72, 18.87, 25.64, 29.28, 29.61, 29.64, 30.60, 32.61 (d, J.sub.C,P=7.0), 65.71, 66.03 (d, J.sub.C,P=6.0), 126.05 (d, J.sub.C,P=183.1), 135.45 (d, J.sub.C,P=2.0).

[0251] .sup.1P{.sup.1H} NMR (162.0 MHz, CDCl.sub.3): 19.74.

[0252] IR v.sub.max (KBr) 3086 (vw), 3007 (vw), 2959 (s), 2929 (vs), 2855 (s), 1613 (w), 1466 (m), 1397 (m), 1275 (m, sh), 1252 (vs), 1065 (vs), 1022 (vs), 985 (vs), 980 (m, sh), 721 (m).

[0253] HR-MS (ESI.sup.+) For C.sub.24H.sub.49O.sub.6P.sub.2 (M+H).sup.+ calcd 495.29989, found 495.29965.

Example 31 Dibutyl tetradecane-1,14-diyl bis(vinylphosphonate)

[0254] ##STR00039##

[0255] Dibutyl tetradecane-1,14-diyl bis(vinylphosphonate) is prepared from compound in Example 1 (1.50 g, 9.14 mmol) and 1,14-dibromododecane (1.09 g, 3.05 mmol) using general method C in 81% (1.29 g, 2.47 mmol) overall yield in the form of colorless oil.

[0256] .sup.1H NMR (400.1 MHz, CDCl.sub.3): 0.91 (t, 6H, J.sub.vic=8.0), 1.23-1.43 (m, 24H), 1.60-1.68 (m, 8H), 3.96-4.04 (m, 8H), 5.96-6.33 (m, 6H).

[0257] .sup.13C NMR (100.6 MHz, CDCl.sub.3): 13.58, 18.73, 25.50, 29.15, 29.50, 29.55, 29.60, 30.45, 32.46 (d, J.sub.C,P=6.0), 65.62, 65.95 (d, J.sub.C,P=6.0), 125.85 (d, J.sub.C,P=184.1), 135.40 (d, J.sub.C,P=2.0).

[0258] .sup.1P{.sup.1} NMR (162.0 MHz, CDCl.sub.3): 20.04.

[0259] IR v.sub.max (KBr) 3091 (w), 3015 (m), 2963 (m), 2931 (s), 2872 (m), 2856 (m), 1614 (w), 1467 (w, sh), 1466 (w), 1400 (m), 1277 (m, sh), 1240 (m), 1020 (s), 988 (s), 980 (m, sh), 857 (w), 606 (w).

[0260] HR-MS (ESI.sup.+) For C.sub.26H.sub.52O.sub.6NaP.sub.2 (M+Na).sup.+ calcd 545.31313, found 545.31335.

Example 32 hexane-1,6-diyl di((Z)-non-3-en-1-yl) bis(vinylphosphonate)

[0261] ##STR00040##

[0262] hexane-1,6-diyl dn(Z)-non-3-en-1-yl) bis(vinylphosphonate) is prepared from compound in Example 11 (2 g, 8.61 mmol) and 1,14-dibromhexane (0.74 g, 3.01 mmol) using general method C in 23% (1,1 g, 2 mmol) overall yield in the form of colorless oil.

[0263] .sup.1H NMR (401 MHz, Chloroform-d) δ 0.91 (t, J=7.0 Hz, 6H); 1.24-1.47 (m, 16H); 1.64-1.77 (m, 4H); 2.01-2.09 (qd, J=7.3, 1,6 Hz, 4H); 2.34-2.56 (m, 4H); 4.03 (qd, J=6.9, 4.5 Hz, 8H); 5.30-5.59 (m, 4H); 5.98-6.41 (m, 6H).

[0264] .sup.13C NMR (101 MHz, CDCl.sub.3) δ 14.04; 22.54; 25.14; 27.32; 28.66 (d, J=6.4 Hz); 29.20; 30.34 (d, J=6.4 Hz); 31.46; 65.23 (d, J=5.8 Hz); 65.65 (d, J=5.8 Hz); 76.68; 77.00; 77.32; 123.67; 125.77 (d, J=184.1 Hz); 133.31; 135.58 (d, J=2.0 Hz).

[0265] .sup.1P{.sup.1H} NMR (162.0 MHz, CDCl.sub.3): 20.09.

[0266] IR v.sub.max (CHCl.sub.3) 3090 (vw), 2959 (s), 2931 (s), 2872 (m), 2859 (m), 1653 (vw), 1614 (w), 1468 (w), 1455 (w, sh), 1434 (vw), 1400 (w), 1380 (w), 1279 (w), 1240 (s), 1070 (m, sh), 1054 (s), 1004 (vs), 986 (s, sh).

[0267] HR-MS (ESI.sup.+) For C.sub.28H.sub.53O.sub.6P.sub.2 (M+H).sup.+ vcalcd 547.33119, found 547.33133.

Example 33 Diisobutyl tetradecane-1,14-diyl bis(vinylphosphonate)

[0268] ##STR00041##

[0269] Diisobutyl tetradecane-1,14-diyl bis(vinylphosphonate) is prepared from the compound from Example 14 (527 mg, 3.21 mmol) and 1,14-dibromotetradecane, (381 mg, 1.07 mmol) using general method C in 89% (496 mg, 0.95 mmol) overall yield in the form of colorless oil.

[0270] .sup.1H NMR (401 MHz, Chloroform-d) δ 6.38-5.96 (m, 6H), 4.08-3.96 (m, 4H), 3.77 (tt, J=6.7, 1.0 Hz, 4H), 1.94 (dp, J=13.3, 6.7 Hz, 2H), 1.66 (dt, J=8.2, 6.5 Hz, 4H), 1.44-1.20 (m, 20H), 0.94 (d, J=6.7 Hz, 12H).

[0271] .sup.31P NMR (162 MHz, Chloroform-d) δ 19.95.

[0272] .sup.13C NMR (101 MHz, Chloroform-d) δ 135.53, 125.97 (d, J=184.6 Hz), 71.92 (d, J=6.1 Hz), 66.09 (d, J=6.0 Hz), 30.62 (d, J=6.3 Hz), 29.76, 29.70, 29.65, 29.31 (d, J=7.3 Hz), 29.30, 25.66, 18.86.

[0273] IR v.sub.max(CHCl.sub.3) 3091 (vw), 2964 (s), 2929 (vs), 2875 (m), 2856 (s), 1614 (w), 1471 (m), —1458 (w, sh), 1400 (m), 1370 (w), 1279 (m), 1239 (s), —1048 (s, sh), 1012 (vs), —988 (s, sh).

[0274] HR-MS (ESI.sup.+): For C.sub.26H.sub.53O.sub.6P.sub.2 (M+H).sup.+ m/z calculated 523.33119, found 523.33167±0.91003 ppm. For C.sub.26H.sub.52O.sub.6NaP.sub.2 (M+Na).sup.+ m/z calculated 545.31313, found 545.31342±0.51726 ppm.

Example 34 Diisobutyl dodecane-1,12-diyl bis(vinylphosphonate)

[0275] ##STR00042##

[0276] Diisobutyl dodecane-1,12-diyl bis(vinylphosphonate) is prepared from the compound from Example 14 (523 mg, 3.19 mg) and 1,12-dibromododecane, (98%, 356 4, 1.06 mmol) using general method C in 69% (360 mg, 0.73 mmol) overall yield in the form of colorless oil.

[0277] .sup.1H NMR (401 MHz, Chloroform-d) δ 6.60-5.95 (m, 6H), 4.01 (q, J=6.9 Hz, 4H), 3.77 (td, J=6.6, 1.6 Hz, 4H), 1.94 (dt, J=13.3, 6.7 Hz, 2H), 1.65 (dt, J=8.1, 6.6 Hz, 4H), 1.47-1.21 (m, 16H), 0.94 (d, J=6.7 Hz, 12H).

[0278] .sup.31P NMR (162 MHz, Chloroform-d) δ 19.95.

[0279] .sup.13C NMR (101 MHz, Chloroform-d) δ 135.54, 125.96 (d, J=184.7 Hz), 71.92 (d, J=6.2 Hz), 66.08 (d, J=6.0 Hz), 30.61 (d, J=6.4 Hz), 29.66, 29.63, 29.30 (d, J=7.6 Hz), 29.30, 25.65, 18.88.

[0280] IR v.sub.max(CHCl.sub.3) 3090 (vw), 2964 (s), 2930 (vs), 2875 (m), 2856 (s), 1614 (w), 1471 (s), 1399 (s), 1370 (m), 1279 (m), 1240 (vs), 1167 (w), 1047 (vs, sh), 1012 (vs, vbr), ˜988 (vs, sh), ˜965 (s, sh), 862 (m).

[0281] HR-MS (ESI.sup.+): For C.sub.24H.sub.48O.sub.6NaP.sub.2 (M+Na).sup.+ m/z calculated 517.28183, found 517.28131±1.00971 ppm.

Example 35 Hexan-1,8-diyl dihexyl bis((2-(bis(3-aminopropyl)amino)ethyl)phosphonate) hexahydrochloride

[0282] ##STR00043##

[0283] Hexan-1,8-diyl dihexyl bis((2-(bis(3-aminopropyl)amino)ethyl)phosphonate) hexahydrochloride is prepared from the compound from Example 3 using general methods C, D, and E, in ther form of white amorphous solide in 28% (0.41 g, 0.41mmol) overall yield.

[0284] .sup.1H NMR (500.2 MHz, CD.sub.3OD): 0.90-0.95 (m, 6H, CH.sub.3(CH.sub.2).sub.4CH.sub.2O); 1.32-1.52 (m, 16H, CH.sub.3(CH.sub.2).sub.3CH.sub.2CH.sub.2O, OCH.sub.2CH.sub.2(CH.sub.2).sub.2CH.sub.2CH.sub.2O); 1.68-1.80 (m, 8H, CH.sub.3(CH.sub.2).sub.3CH.sub.2CH.sub.2O, OCH.sub.2CH.sub.2(CH.sub.2).sub.2CH.sub.2CH.sub.2O); 2.16-2.26 (m, 8H, NCH.sub.2CH.sub.2CH.sub.2NH.sub.2); 2.50-2.61 (m, 4H, PCH.sub.2CH.sub.2N); 3.11 (t, 8H, J.sub.vic=7.5, NCH.sub.2CH.sub.2CH.sub.2NH.sub.2); 3.36-3.43 (m, 8H, NCH.sub.2CH.sub.2CH.sub.2NH.sub.2); 3.43-3.50 (m, 4H, PCH.sub.2CH.sub.2N); 4.09-4.21 (m, 8H, CH.sub.3(CH.sub.2).sub.3CH.sub.2CH.sub.2O, OCH.sub.2CH.sub.2(CH.sub.2).sub.2CH.sub.2CH.sub.2O).

[0285] .sup.13C NMR (125.8 MHz, CD.sub.3OD): 14.37 (CH.sub.3(CH.sub.2)6CH.sub.2O); 21.33, 21.35 (d, J.sub.C,P=140.8, PCH.sub.2CH.sub.2N); 23.26 (NCH.sub.2CH.sub.2CH.sub.2NH.sub.2); 23.81, 26.14, 26.15, 26.29 (CH.sub.3(CH.sub.2).sub.3CH.sub.2CH.sub.2O, OCH.sub.2CH.sub.2(CH.sub.2).sub.2CH.sub.2CH.sub.2O); 31.37, 31.40, 31.55 (d, J.sub.C,P=5.9, CH.sub.3(CH.sub.2).sub.3CH.sub.2CH.sub.2O, OCH.sub.2CH.sub.2(CH.sub.2).sub.2CH.sub.2CH.sub.2O); 32.49 (CH.sub.3(CH.sub.2).sub.3CH.sub.2CH.sub.2O); 37.90 (NCH.sub.2CH.sub.2CH.sub.2NH.sub.2); 48.87 (PCH.sub.2CH.sub.2N); 51.07 (NCH.sub.2CH.sub.2CH.sub.2NH.sub.2); 68.05, 68.08, 68.25 (d, J.sub.C,P=6.7, CH.sub.3(CH.sub.2).sub.3CH.sub.2CH.sub.2O, OCH.sub.2CH.sub.2(CH.sub.2).sub.2CH.sub.2CH.sub.2O).

[0286] .sup.31P{.sup.1H} NMR (202.5 MHz, CD.sub.3OD): 26.62.

[0287] IR v.sub.max (CHCl.sub.3) 2957 (vs), 2933 (vs), 2860 (s), 2745 (s, br), 2640 (m, br), 2558 (m, br), 2051 (w, br), 1615 (m, br), 1513 (w, br), 1468 (m), 1397 (w, br), 1379 (w, sh), 1265 (m, sh), 1229 (m, br), 1060 (m), 1040 (m, sh), 998 (s).

[0288] HR-MS (ESI.sup.+): For C.sub.34H.sub.80O.sub.6P.sub.2 (M+2H).sup.2+ z=2 m/z calcd 365.28018, found 365.28030.

Example 36 Hexan-1,8-diyl dioctyl bis((2-(bis(3-aminopropyl)amino)ethyl)phosphonate) hexahydrochloride

[0289] ##STR00044##

[0290] Hexan-1,8-diyl dioctyl bis((2-(bis(3-aminopropyl)amino)ethyl)phosphonate) hexahydrochloride is prepared fro the compound from Example 5 using general methods C, D, and E, in ther form of white amorphous solide in 28% (0.41 g, 0.41 mmol).

[0291] .sup.1H NMR (500.0 MHz, CD.sub.3OD): 0.88-0.93 (m, 6H, CH.sub.3(CH.sub.2).sub.6CH.sub.2O); 1.26-1.52 (m, 24H, CH.sub.3(CH.sub.2).sub.5CH.sub.2CH.sub.2O, OCH.sub.2CH.sub.2(CH.sub.2).sub.2CH.sub.2CH.sub.2O); 1.67-1.79 (m, 8H, CH.sub.3(CH.sub.2).sub.5CH.sub.2CH.sub.2O, OCH.sub.2CH.sub.2(CH.sub.2).sub.2CH.sub.2CH.sub.2O); 2.17-2.27 (m, 8H, NCH.sub.2CH.sub.2CH.sub.2NH.sub.2); 2.52-2.62 (m, 4H, PCH.sub.2CH.sub.2N); 3.11 (t, 8H, J.sub.C,P=7.5, NCH.sub.2CH.sub.2CH.sub.2NH.sub.2); 3.36-3.45 (m, 8H, NCH.sub.2CH.sub.2CH.sub.2NH.sub.2); 3.42-3.51 (m, 4H, PCH.sub.2CH.sub.2N); 4.074.23 (m, 8H, CH.sub.3(CH.sub.2).sub.5CH.sub.2CH.sub.2O, OCH.sub.2CH.sub.2(CH.sub.2).sub.2CH.sub.2CH.sub.2O).

[0292] .sup.13C NMR (125.7 MHz, CD.sub.3OD): 14.47 (CH.sub.3(CH.sub.2).sub.6CH.sub.2O); 21.28, 21.31 (d, J.sub.C,P=140.5, PCH.sub.2CH.sub.2N); 23.21 (NCH.sub.2CH.sub.2CH.sub.2NH.sub.2); 23.73, 26.14, 26.16, 26.63, 30.28, 30.37 (CH.sub.3(CH.sub.2).sub.5CH.sub.2CH.sub.2O, OCH.sub.2CH.sub.2(CH.sub.2).sub.2CH.sub.2CH.sub.2O); 31.36, 31.40, 31.60 (d, J.sub.C,P=6.0, CH.sub.3(CH.sub.2).sub.5CH.sub.2CH.sub.2O, OCH.sub.2CH.sub.2(CH.sub.2).sub.2CH.sub.2CH.sub.2O); 32.99 (CH.sub.3(CH.sub.2).sub.5CH.sub.2CH.sub.2O); 37.86 (NCH.sub.2CH.sub.2CH.sub.2NH.sub.2); 48.83 (PCH.sub.2CH.sub.2N); 50.98 (NCH.sub.2CH.sub.2CH.sub.2NH.sub.2); 68.01, 68.03, 68.22 (d, .sub.C,P=6.6, CH.sub.3(CH.sub.2).sub.5CH.sub.2CH.sub.2O, OCH.sub.2CH.sub.2(CH.sub.2).sub.2CH.sub.2CH.sub.2O).

[0293] .sup.31P{.sup.1H} NMR (202.4 MHz, CD.sub.3OD): 27.32.

[0294] HR-MS (ESI.sup.+): For C.sub.38H.sub.88N.sub.6O.sub.6P.sub.2 (M+2H).sup.2+ z=2 m/z calcd 393.31148, found 393.31156.

Example 37 Octane-1,8-diyl dipentyl bis((2-(bis(3-aminopropyl)amino)-ethyl)phosphonate) hexahydrochloride

[0295] ##STR00045##

[0296] Octane-1,8-diyl dipentyl bis((2-(bis(3-aminopropyl)amino)ethyl)phosphonate) hexahydrochloride is prepared from compound in Example 24 (0.50 g, 1.0 mmol) using general methods D and E, in the form of a white amorphous solid in overall yield 53% (0.54 g, 0.57 mmol).

[0297] .sup.1H NMR (400.1 MHz, CD3OD): 0.92-0.96 (m, 6H), 1.36-1.44 (m, 16H), 1.69-1.76 (m, 8H), 2.17-2.25 (m, 8H), 2.49-2.59 (m, 4H), 3.11 (t, 8H, J.sub.vic=8.0), 3.37-3.42 (m, 8H), 3.44-3.48 (m, 4H), 4.11-4.16 (m, 8H).

[0298] .sup.13C NMR (100.6 MHz, CD.sub.3OD): 14.34, 21.28 (d, =139.8), 23.29, 26.54, 28.79, 30.15, 30.16, 31.29, 31.56 (d, J.sub.C,P=6.0), 37.89, 48.84, 51.07, 68.22 (d, J.sub.C,P=7.0).

[0299] .sup.1P{.sup.1H} NMR (162.0 MHz, CD.sub.3OD): 28.40.

[0300] IR v.sub.max (KBr) 2933 (s), 2634 (s), 2558 (m), 1600 (m), 1467 (m), 1224 (m), 1173 (m, sh), 1070 (m, sh), 1047 (s), 997 (s).

[0301] HR-MS (ESI.sup.+): For C.sub.34H.sub.79N.sub.6O.sub.6P.sub.2 (M+H).sup.+ calcd 729.55290, found 729.55308.

Example 38 Dihexyl octane-1,8-diyl bis((2-(bis(3-aminopropyl)amino)ethyl)-phosphonate) hexahydrochloride

[0302] ##STR00046##

[0303] Dihexyl octane-1,8-diyl bis((2-(bis(3-aminopropyl)amino)ethyl)phosphonate) hexahydrochloride is prepared from compound in Example 21 (0.78 g, 1.58 mmol)

using general methods D and E, in the form of a white amorphous solid in overall yield 57% (0.88 g, 0.90 mmol).

[0304] .sup.1H NMR (400.1 MHz, CD3OD): 0.90-0.94 (m, 6H), 1.33-1.46 (m, 20H), 1.69-1.77 (m, 8H), 2.17-2.25 (m, 8H), 2.48-2.58 (m, 4H), 3.11 (t, 8H, J.sub.vic=8,0), 3.34-3.41 (m, 8H), 3.43-3.49 (m, 4H), 4,11-4,16 (m, 8H).

[0305] .sup.13C NMR (100.6 MHz, CD.sub.3OD): 12.98, 19.90 (d, J.sub.C,P=140.8), 21.89, 22.23, 24.90, 25.16, 28.78, 31.10, 30.17 (d, J.sub.C,P=6.0), 36.49, 47.42, 49.68, 66.80, 66.86 (d, J.sub.C,P=7.0, 6.0).

[0306] .sup.31P{.sup.1H} NMR (162.0 MHz, CD.sub.3OD): 28.42.

[0307] IR v.sub.max (KBr) 2966 (m), 2931 (m), 2872 (m), 2623 (w), 2553 (w), 1470 (m), 1384 (w), 1236 (w), 1050 (m), 1000 (m).

[0308] HR-MS (ESI.sup.+): For C.sub.36H.sub.84N.sub.6O.sub.6P.sub.2 (M+2H).sup.2+ calcd 379.29583, found 379.29553.

Example 39 Decane-1,10-diyl diisobutyl bis(vinylphosphonate)

[0309] ##STR00047##

[0310] Decane-1,10-diyl diisobutyl bis(vinylphosphonate) is prepared from the compound from Example 14 (500 mg, 3.05 mmol) and 1,10-dibromodecane (97%, 314 μL 1.01 mmol) using general method C in 88% (416 mg, 0.89 mmol) overall yield in the form of colorless oil.

[0311] .sup.1H NMR (401 MHz, Chloroform-d) δ 6.37-5.94 (m, 6H), 4.01 (q, J=6.8 Hz, 4H), 3.77 (td, J=6.6, 1.6 Hz, 4H), 1.94 (dp, J=13.4, 6.7 Hz, 2H), 1.72-1.61 (m, 4H), 1.42-1.21 (m, 12H), 0.93 (d, J=6.7 Hz, 12H).

[0312] .sup.31P NMR (162 MHz, Chloroform-d) δ 19.92.

[0313] .sup.13C NMR (101 MHz, Chloroform-d) δ 135.56 (d, J=2.0 Hz), 125.94 (d, J=184.4 Hz), 71.92 (d, J=6.0 Hz), 66.04 (d, J=5.9 Hz), 30.60 (d, J=6.3 Hz), 29.54, 29.33, 29.25, 25.63, 18.86 (d, J=1.9 Hz).

[0314] IR v.sub.max(CHCl.sub.3) 3091 (vw), 2964 (s), 2932 (vs), 2875 (m), 2857 (s), 1614 (w), 1471 (s), 1399 (s), 1370 (m), 1278 (s), 1240 (vs), 1167 (w), -1047 (s, sh), 1013 (vs, br), -990 (vs, sh), -965 (s, sh), 862 (m).

[0315] HR-MS (ESI.sup.+): For C.sub.22H.sub.44O.sub.6NaP.sub.2 (M+Na).sup.+ m/z calculated 489.25053, found 489.25012±0.83547 ppm.

Example 40 Diisobutyl decane-1,10-diyl bis((2-(bis(3-aminopropyl)amino)ethyl)-phosphonate) hexahydrochloride

[0316] ##STR00048##

[0317] Diisobutyl decane-1,10-diyl bis((2-(bis(3-aminopropyl)amino)ethyl)phosphonate) hexahydrochloride is prepared from the compound from Example 38 (416 mg, 0.89 mmol) using general methods D and E in 31% (258 mg, 0.28 mmol) overall yield in the form of white amorphous powder.

[0318] .sup.1H NMR (401 MHz, Methanol-d.sub.4) δ 4.14 (q, J=6.7 Hz, 4H), 3.90 (tt, J=6.1, 3.2 Hz, 4H), 3.51-3.43 (m, 4H), 3.43-3.35 (m, 8H), 3.11 (t, J=7.5 Hz, 8H), 2.74-2.47 (m, 4H), 2.21 (h, J=6.4 Hz, 8H), 1.98 (dt, J=13.3, 6.6 Hz, 2H), 1.83-1.65 (m, 4H), 1.53-1.27 (m, 12H), 0.99 (d, J=6.7 Hz, 12H).

[0319] .sup.31P NMR (162 MHz, Methanol-d.sub.4) δ 28.59.

[0320] .sup.13C NMR (101 MHz, Methanol-d.sub.4) δ 73.92 (d, J=7.1 Hz), 68.29 (d, J=6.7 Hz), 51.09, 37.86, 31.63 (d, J=5.9 Hz), 30.65, 30.47 (d, J=6.4 Hz), 30.30, 26.63, 23.33, 21.86, 20.47, 19.02.

[0321] IR v.sub.max (KBr tab. 1 mm) 2961 (s), 2929 (s), 2855 (m), 3200-2700 (vs, vbr), 2700-2500 (m, vbr), 1610 (m), 1513 (m), 1468 (s), 1401 (m), 1369 (m), 1227 (vs), 1005 (vs), —869 (m, sh), 851 (m), 767 (m), 725 (w).

[0322] HR-MS (ESI.sup.+): For C.sub.34H.sub.79O.sub.6N.sub.6P.sub.2 (M+H).sup.+ m/z calculated 729.55308, found 729.55268±0.54965 ppm.

Example 41 Dibutyl decane-1,10-diyl bis((2-(bis(3-aminopropyl)amino)ethyl)phosphonate) hexahydrochloride

[0323] ##STR00049##

[0324] Dibutyl decane-1,10-diyl bis((2-(bis(3-aminopropyl)amino)ethyl)phosphonate) hexahydrochloride is prepared from compound in Example 28 (0.65, 0.54 mmol) using general methods D and E, in the form of a white amorphous solid in 55% overall yield (0.88 g, 0.90 mmol).

[0325] .sup.1H NMR (400.1 MHz, CD.sub.3OD): 0.96-0.99 (m, 6H), 1.35-1.50 (m, 16H), 1.67-1.76 (m, 8H), 2.17-2.25 (m, 8H), 2.48-2.58 (m, 4H), 3.10 (t, 8H, J.sub.vic=8.0), 3.35-3.41 (m, 8H), 3.42-3.48 (m, 4H), 4.11-4.17 (m, 8H).

[0326] .sup.13C NMR (100.6 MHz, CD.sub.3OD): 13.96, 19.79, 21.27 (d, J.sub.C,P=149.8), 23.25, 26.60, 30.26, 30.59, 31.59, 33.60 (d, J.sub.C,P=6.0), 37.87, 48.85, 51.06, 67.91, 68.24 (d, J.sub.C,P=6.0).

[0327] .sup.31P{.sup.1H} NMR (162.0 MHz, CD.sub.3OD): 28.42.

[0328] IR v.sub.max (KBr) 2932 (vs), 2632 (m), 2558 (m), 1598 (m), 1467 (m), 1224 (m), 1172 (m sh), 1070 (m, sh), 1063 (m), 1018 (vs), 997 (m, sh).

[0329] HR-MS (ESI.sup.+): For C.sub.34H.sub.79N.sub.6O.sub.6P.sub.2 (M+H).sup.+ calcd 729.55255, found 729.55308.

Example 42 Decane-1,10-diyl dipentyl bis((2-(bis(3-aminopropyl)amino)-ethyl)phosphonate) hexahydrochloride

[0330] ##STR00050##

[0331] Decane-1,10-diyl dipentyl bis((2-(bis(3-aminopropyl)amino)ethyl)phosphonate) hexahydrochloride is prepared from compound in Example 25 (0.83, 1.67 mmol) using general methods D and E, in the form of a white amorphous solid in 45% overall yield (0.73 g, 0.75 mmol).

[0332] .sup.1H NMR (400.1 MHz, CD.sub.3OD): 0.93-0.96 (m, 6H), 1.34-1.44 (m, 20H), 1,69-1,76 (m, 8H), 2.17-2.25 (m, 8H), 2.48-2.58 (m, 4H), 3.10 (t, 8H, J.sub.vic=8.0), 3.37-3.41 (m, 8H), 3.44-3.49 (m, 4H), 4.11-4.16 (m, 8H).

[0333] .sup.13C NMR (100.6 MHz, CD.sub.3OD): 14.35, 21.25 (d, J.sub.C,P=140.8), 23.27, 23.30, 26.62, 28.80, 30.29, 30.63, 31.29, 31.61 (d, J.sub.C,P=6,0), 37,87, 48.83, 51.07, 68.20, 68.27 (d, J.sub.C,P=2.0, 3.0).

[0334] .sup.31P{.sup.1H} NMR (162.0 MHz, CD.sub.3OD): 28.41.

[0335] IR v.sub.max (KBr) 2929 (s), 2831 (m, sh), 2677-2543 (m), 1611 (m), 1514 (m), 1467 (m), 1390 (m), 1263 (m), 1228 (s), 1077-991 (s).

[0336] HR-MS (ESI.sup.+: For C.sub.36H.sub.83N.sub.6O.sub.6P.sub.2 (M+H).sup.+ calcd 757.58403, found 729.58438.

Example 43 Decane-1,10-diyl dihexyl bis((2-(bis(3-aminopropyl)amino)-ethyl)phosphonate) tetrahydrochloride

[0337] ##STR00051##

[0338] Decane-1,10-diyl dihexyl bis((2-(bis(3-aminopropyl)amino)ethyl)phosphonate) tetrahydrochloride is prepared from compound in Example 22 (0.65, 1.24 mmol)

using general methods D and E, in the form of a white amorphous solid in 61% overall yield (0.70 g, 0.76 mmol).

[0339] .sup.1 H NMR (400.1 MHz, CD.sub.3OD): 0.91-0.94 (m, 6H), 1.33-1.46 (m, 24H), 1.67-1.76 (m, 8H), 2.16-2.24 (m, 8H), 2.47-2.57 (m, 4H), 3.10 (t, 8H, J.sub.vic=8.0), 3.35-3.40 (m, 8H), 3.42-3.48 (m, 4H), 4.10-4.16 (m, 8H).

[0340] .sup.13C NMR (100.6 MHz, CD.sub.3OD): 12.98, 19.80 (d, J.sub.C,P=140.8), 21.91, 22.23, 24.91, 25.24, 28.91, 29.26, 30.02 (d, J.sub.C,P=6.0, 5.0), 31.11, 36.48, 47.64, 49.68, 66.85 (d, J.sub.C,P=7.0)

[0341] .sup.31P{.sup.1H} NMR (162.0 MHz, CD.sub.3OD): 28.45.

[0342] IR v.sub.max (KBr) 2974 (m), 2927 (w), 2895 (w), 2635 (w), 2510 (w), 1601 (w, sh), 1383 (w), 1273 (w), 1089 (m), 1050 (m).

[0343] HR-MS (ESI.sup.+): For C.sub.38H.sub.87N.sub.6O.sub.6P2 (M+H).sup.+ calcd 785.61568, found 785.61479.

Example 44 Decan-1,10-diyl dioketyl bis((2-(bis(3-aminopropyl)amino)ethyl)-phosphonate) tetrahydrochloride

[0344] ##STR00052##

[0345] Decan-1,10-diyl dioktyl bis((2-(bis(3-aminopropyl)amino)ethyl)-phosphonate) tetrahydrochloride se is prepared from the compound from Example 5 using general methods C, D, and E, in the form of a white amorphous solid in overall yield 32% (1.18 g, 1.12 mmol).

[0346] .sup.1H NMR (500.2 MHz, CD.sub.3OD): 0.88-0.93 (m, 6H, CH.sub.3(CH.sub.2).sub.6CH.sub.2O); 1.26-0 1.46 (m, 32H, CH.sub.3(CH.sub.2).sub.5CH.sub.2CH.sub.2O, OCH.sub.2CH.sub.2(CH.sub.2).sub.6CH.sub.2CH.sub.2O); 1.68-1.76 (m, 8H, CH.sub.3(CH.sub.2).sub.5CH.sub.2CH.sub.2O, OCH.sub.2CH.sub.2(CH.sub.2).sub.6CH.sub.2CH.sub.2O); 2.17-2.26 (m, 8H, NCH.sub.2CH.sub.2CH.sub.2NH.sub.2); 2.49-2.59 (m, 4H, PCH.sub.2CH.sub.2N); 3.11 (t, 8H, J.sub.vic=7.5, NCH.sub.2CH.sub.2CH.sub.2NH.sub.2); 3.36 — 3.43 (m, 8H, NCH.sub.2CH.sub.2CH.sub.2NH.sub.2); 3.43-3.49 (m, 4H, PCH.sub.2CH.sub.2N); 4.10-4.16 (m, 8H, CH.sub.3(CH.sub.2).sub.5CH.sub.2CH.sub.2O, OCH.sub.2CH.sub.2(CH.sub.2).sub.6CH.sub.2CH.sub.2O).

[0347] .sup.13C NMR (125.8 MHz, CD.sub.3OD): 14.45 (CH.sub.3(CH.sub.2).sub.6CH.sub.2O); 21.28 (d, J.sub.C,P=140.2, PCH.sub.2CH.sub.2N); 23.22 (NCH.sub.2CH.sub.2CH.sub.2NH.sub.2); 23.69, 26.62, 26.64, 30.24, 30.29, 30.34, 30.62 (CH.sub.3(CH.sub.2).sub.5CH.sub.2CH.sub.2O, OCH.sub.2CH.sub.2(CH.sub.2).sub.6CH.sub.2CH.sub.2O); 31.58, 31.59 (d, J.sub.C,P=5.8, CH.sub.3(CH.sub.2).sub.5CH.sub.2CH.sub.2O, OCH.sub.2CH.sub.2(CH.sub.2).sub.6CH.sub.2CH.sub.2O); 32.96 (CH.sub.3(CH.sub.2).sub.5CH.sub.2CH.sub.2O); 37.88 (NCH.sub.2CH.sub.2CH.sub.2NH.sub.2); 48.85 (PCH.sub.2CH.sub.2N); 51.04 (NCH.sub.2CH.sub.2CH.sub.2NH.sub.2); 68.23 (d, J.sub.C,P=6.7, CH.sub.3(CH.sub.2).sub.5CH.sub.2CH.sub.2O, OCH.sub.2CH.sub.2(CH.sub.2).sub.6CH.sub.2CH.sub.2O).

[0348] .sup.31P{.sup.1H} NMR (202.5 MHz, CD.sub.3OD): 26.64.

[0349] HR-MS (ESI.sup.+) For C.sub.42H.sub.96N.sub.6OI.sub.6P.sub.2 (M+2H).sup.2+ calcd 421.34278, found 421.34273.

Example 45 Decan-1,10-diyl didecyl bis((2-(bis(3-aminopropyl)amino)ethyl)-phosphonate) tetrahydrochloride

[0350] ##STR00053##

[0351] Decan-1,10-diyl didecyl bis((2-(bis(3-aminopropyl)amino)ethyl)-phosphonate) tetrahydrochloride is prepared from the compound from Example 6 using general methods C, D, and E, in the form of a white amorphous solid in overall yield 46% (0.41 g, 0.41mmol).

[0352] .sup.1H NMR (500.2 MHz, CD.sub.3OD): 0.88-0.93 (m, 6H, CH.sub.3(CH.sub.2).sub.8CH.sub.2O); 1.25-1.46 (m, 40H, CH.sub.3(CH.sub.2).sub.7CH.sub.2CH.sub.2O, OCH.sub.2CH.sub.2(CH.sub.2).sub.6CH.sub.2CH.sub.2O); 1.68-1.76 (m, 8H, CH.sub.3(CH.sub.2).sub.7CH.sub.2CH.sub.2O, OCH.sub.2CH.sub.2(CH.sub.2).sub.6CH.sub.2CH.sub.2O); 2.16-2.25 (m, 8H, NCH.sub.2CH.sub.2CH.sub.2NH.sub.2); 2.49-2.58 (m, 4H, PCH.sub.2CH.sub.2N); 3.11 (t, 8H, J.sub.vic=7.5, NCH.sub.2CH.sub.2CH.sub.2NH.sub.2); 3.36-3.42 (m, 8H, NCH.sub.2CH.sub.2CH.sub.2NH.sub.2); 3.42-3.49 (m, 4H, PCH.sub.2CH.sub.2N); 4.10-4.16 (m, 8H, CH.sub.3(CH.sub.2).sub.7CH.sub.2CH.sub.2O, OCH.sub.2CH.sub.2(CH.sub.2).sub.6CH.sub.2CH.sub.2O).

[0353] .sup.13C NMR (125.8 MHz, CD.sub.3OD): 14.46 (CH.sub.3(CH.sub.2).sub.8CH.sub.2O); 21.26 (d, J.sub.C,P=140.3, PCH.sub.2CH.sub.2N); 23.26 (NCH.sub.2CH.sub.2CH.sub.2NH.sub.2); 23.72, 26.62, 26.64, 30.29, 30.31, 30.45, 30.66, 30.69 (CH.sub.3(CH.sub.2).sub.7CH.sub.2CH.sub.2O, OCH.sub.2CH.sub.2(CH.sub.2).sub.6CH.sub.2CH.sub.2O); 31.59, 31.62 (d, J.sub.C,P=5.8, CH.sub.3(CH.sub.2).sub.7CH.sub.2CH.sub.2O, OCH.sub.2CH.sub.2(CH.sub.2).sub.6CH.sub.2CH.sub.2O); 33.05 (CH.sub.3(CH.sub.2).sub.7CH.sub.2CH.sub.2O); 37.87 (NCH.sub.2CH.sub.2CH.sub.2NH.sub.2); 48.83 (PCH.sub.2CH.sub.2N); 51.06 (NCH.sub.2CH.sub.2CH.sub.2NH.sub.2); 68.24 (d, J.sub.C,P=6.6, CH.sub.3(CH.sub.2).sub.7CH.sub.2CH.sub.2O, OCH.sub.2CH.sub.2(CH.sub.2).sub.6CH.sub.2CH.sub.2O).

[0354] .sup.31P{.sup.1H} NMR (202.5 MHz, CD.sub.3OD): 26.65.

[0355] IR v.sub.max (KBr) 2956 (vs), 2925 (vs), 2854 (vs), 2675 (m, br), 2620 (m, br), 2546 (s, br), 2059 (w, br), 1628 (m, sh), 1607 (m), 1542 (m), 1510 (m), 1484 (m), 1468 (m), 1456 (m, sh), 1401 (w), 1390 (w), 1377 (w, sh), 1338 (vw), 1305 (w), 1227 (s), 1075 (m), 1022 (s, sh), 992 (s), 722 (w).

[0356] HR-MS (ESI.sup.+) For C.sub.46H.sub.104N.sub.6O.sub.6P.sub.2 (M+2H).sup.2+ calcd 449.37408, found 449.37398.

Example 46 Dodecane-1,12-diyl diisobutyl bis((2-(bis(3-aminopropyl)amino)ethyl)-phosphonate) hexahydrochloride

[0357] ##STR00054##

[0358] Dodecane-1,12-diyl diisobutyl bis((2-(bis(3-aminopropyl)amino)ethyl)phosphonate) hexahydrochloride is prepared from the compound from Example 33 (360 mg, 0.728 mmol) using general methods D and E in 6% (43 mg, 43,6 μmol) overall yield in the form of white amorphous powder.

[0359] .sup.1H NMR (401 MHz, Methanol-d.sub.4) δ 4.15 (dt, J=7.8, 6.6 Hz, 4H), 3.92 (td, J=6.6, 2.4 Hz, 4H), 3.55-3.42 (m, 4H), 3.43-3.34 (m, 8H), 3.11 (t, J=7.5 Hz, 8H), 2.67-2.46 (m, 4H), 2.33-2.15 (m, 8H), 1.99 (dp, J=13.3, 6.7 Hz, 2H), 1.86-1.65 (m, 4H), 1.53-1.28 (m, 16H), 1.00 (d, J=6.7 Hz, 12H).

[0360] .sup.31P NMR (162 MHz, Methanol-d.sub.4) δ 27.12.

[0361] .sup.13C NMR (101 MHz, Methanol-d.sub.4) δ 73.92 (d, J=6.6 Hz), 68.29 (d, J=6.7 Hz), 51.09, 37.87, 31.63 (d, J=5.5 Hz), 30.74, 30.71, 30.47 (d, J=6.4 Hz), 30.32, 26.62, 23.32, 21.88, 20.49, 19.03.

[0362] IR v.sub.max(KBr tab. 1 mm) 3200-2700 (vs, vbr), 2961 (s), 2927 (s), 2854 (m), 2700-2500 (m), 1607 (m), 1510 (w), 1470 (m), 1400 (w), 1369 (w), 1226 (m), 1002 (s), ˜869 (w, sh), 851 (m), 768 (w), 724 (vw).

[0363] HR-MS (ESI.sup.+): For C.sub.36H.sub.83O.sub.6N.sub.6P.sub.2 (M+H).sup.+ m/z calculated 757.58438, found 757.58375±0.83066 ppm.

Example 47 Dibutyl dodecane-1,12-diyl bis((2-(bis(3-aminopropyl)amino)ethyl)-phosphonate) hexahydrochloride

[0364] ##STR00055##

[0365] Dibutyl dodecane-1,12-diyl bis((2-(bis(3-aminopropyl)amino)ethyl)phosphonate) hexahydrochloride is prepared from compound in Example 29 (0.97, 1.96 mmol)

using general methods D and E, in the form of a white amorphous solid in overall yield 48% (0.73 g, 0.75 mmol).

[0366] .sup.1H NMR (400.1 MHz, CD.sub.3OD): 0.95-0.99 (m, 6H), 1.32-1.50 (m, 20H), 1.64-1.76 (m, 8H), 2.16-2.24 (m, 8H), 2.47-2.57 (m, 4H), 3.10 (t, 8H, J.sub.vic=8.0), 3.35-3.40 (m, 8H), 3.44-3.46 (m, 4H), 4.10-4.17 (m, 8H).

[0367] .sup.13C NMR (100.6 MHz, CD.sub.3OD): 13.96, 19.79, 21.27 (d, J.sub.C,P=140.8), 23.24, 26.60, 30.26, 30.59, 31.59, 33.60 (d, J.sub.C,P=6.0), 37.87, 48.84, 51.05, 67.90, 68.24 (d, J.sub.C,P=6.0, 7.0)

[0368] .sup.31P{.sup.1H} NMR (162.0 MHz, CD.sub.3OD): 28.43.

[0369] IR v.sub.max (KBr) 2930 (s), 2780 (m), 2630 (m), 2557 (m), 1597 (m), 1467 (m), 1226 (m), 1168 (m, sh), 1070 (m, sh), 1064 (m), 1020 (s), 1004 (s),

[0370] HR-MS (ESI.sup.+) For C.sub.34H.sub.79N.sub.6O.sub.6P.sub.2 (M+H).sup.+ calcd 729.55308, found 729.55300.

Example 48 Dodecane-1,12-diyl dipentyl bis((2-(bis(3-aminopropyl)amino)ethyl)-phosphonate) hexahydrochloride

[0371] ##STR00056##

[0372] Dodecane-1,12-diyl dipentyl bis((2-(bis(3-aminopropyl)amino)ethyl)phosphonate) hexahydrochloride is prepared from compound in Example 26 (1.10 g, 2.10 mmol)

using general methods D and E, in the form of a white amorphous solid in overall yield 58% (0.78 g, 0.84 mmol).

[0373] .sup.1H NMR (400.1 MHz, CD.sub.3OD): 0.93-0.96 (m, 6H), 1.34-1.44 (m, 24H), 1.69-1.76 (m, 8H), 2.17-2.25 (m, 8H), 2.49-2.59 (m, 4H), 3.11 (t, 8H, J.sub.vic=8.0), 3.34-3.43 (m, 8H), 3.45-3.49 (m, 4H), 4.10-4.16 (m, 8H).

[0374] .sup.13C NMR (100.6 MHz, CD.sub.3OD): 14.35, 21.27 (d, J.sub.C,P=139.8), 23.24, 23.29, 26.62, 28.79, 30.30, 30.68, 30.71, 31.29, 31.60 (d, J.sub.C,P=5.0, 6.0) 37.87, 48.86, 51.05, 68.20, 68.26 (d, J.sub.C,P=3.0, 4.0).

[0375] .sup.31P{.sup.1H} NMR (162.0 MHz, CD.sub.3OD): 28.38.

[0376] IR v.sub.max (KBr) 2930 (vs), 2631 (m, sh), 2557 (m, sh), 1599 (m), 1467 (m), 1226 (s), 1170 (m, sh), 1065 (m, sh), 1052 (s, sh), 995 (s).

[0377] HR-MS (ESI.sup.+) For C.sub.38H.sub.88N.sub.6O.sub.6P.sub.2 (M+2H).sup.2+ calcd 393.31141, found 393.31148.

Example 49 Dodecan-1,10-diyl dioctyl bis((2-(bis(3-aminopropyl)amino)ethyl)-phosphonate) tetrahydrochloride

[0378] ##STR00057##

[0379] Dodecan-1,10-diyl dioctyl bis((2-(bis(3-aminopropyl)amino)ethyl)phosphonate) tetrahydrochloride is prepared from compound in Example 6 using general methods C, D, and E, in the form of a white amorphous solid in overall yield 36% (0.67 g, 0.61 mmol).

[0380] .sup.1H NMR (500.2 MHz, CD.sub.3OD): 0.88-0.93 (m, 6H, CH.sub.3(CH.sub.2).sub.6CH.sub.2O); 1.261.46 (m, 36H, CH.sub.3(CH.sub.2).sub.5CH.sub.2CH.sub.2O, OCH.sub.2CH.sub.2(CH.sub.2).sub.8CH.sub.2CH.sub.2O); 1.68-1.76 (m, 8H, CH.sub.3(CH.sub.2).sub.5CH.sub.2CH.sub.2O, OCH.sub.2CH.sub.2(CH.sub.2).sub.sCH.sub.2CH.sub.2O); 2.15-2.25 (m, 8H, NCH.sub.2CH.sub.2CH.sub.2NH.sub.2); 2.46-2.57 (m, 4H, PCH.sub.2CH.sub.2N); 3.10 (t, 8H, J.sub.vic=7.5, NCH.sub.2CH.sub.2CH.sub.2NH.sub.2); 3.34-3.41 (m, 8H, NCH.sub.2CH.sub.2CH.sub.2NH.sub.2); 3.41-3.48 (m, 4H, PCH.sub.2CH.sub.2N); 4.09-4.16 (m, 8H, CH.sub.3(CH.sub.2).sub.5CH.sub.2CH.sub.2O, OCH.sub.2CH.sub.2(CH.sub.2).sub.8CH.sub.2CH.sub.2O).

[0381] .sup.13C NMR (125,8 MHz, CD.sub.3OD): 14.45 (CH.sub.3(CH.sub.2).sub.6CH.sub.2O); 21.24 (d, J.sub.C,P=140.4, PCH.sub.2CH.sub.2N); 23.29 (NCH.sub.2CH.sub.2CH.sub.2NH.sub.2); 23.71, 26.64, 26.64, 30.26, 30.35, 30.36, 30.74, 30.77 (CH.sub.3(CH.sub.2).sub.5CH.sub.2CH.sub.2O, OCH.sub.2CH.sub.2(CH.sub.2).sub.8CH.sub.2CH.sub.2O); 31.61, 31.63 (d, J.sub.C,P=5.8, CH.sub.3(CH.sub.2).sub.5CH.sub.2CH.sub.2O, OCH.sub.2CH.sub.2(CH.sub.2).sub.8CH.sub.2CH.sub.2O); 32.98 (CH.sub.3(CH.sub.2).sub.5CH.sub.2CH.sub.2O); 37.88 (NCH.sub.2CH.sub.2CH.sub.2NH.sub.2); 48.80 (PCH.sub.2CH.sub.2N); 51.08 (NCH.sub.2CH.sub.2CH.sub.2NH.sub.2); 68.26 (d, J.sub.C,P=6.7, CH.sub.3(CH.sub.2).sub.5CH.sub.2CH.sub.2O, OCH.sub.2CH.sub.2(CH.sub.2).sub.8CH.sub.2CH.sub.2O).

[0382] .sup.31P{.sup.1H} NMR (202.5 MHz, CD.sub.3OD): 26.67.

[0383] HR-MS (ESI.sup.+) For C.sub.44H.sub.100N.sub.6O.sub.6P.sub.2 (M+2H).sup.2+ z=2 calcd 435.35843, found 435.35823.

Example 50 Bis(2-benzylethyl)-dodecane-1,12-diyl bis((2-(bis(3-aminopropyl)amino)ethyl)-phosphonate) hexahydrochloride

[0384] ##STR00058##

[0385] Bis(2-benzylethyl)-dodecane-1,12-diyl bis((2-(bis(3-aminopropyl)amino)ethyl) phosphonate) hexahydrochloride is prepared from the compound from Example 7 (1 g, 5 mmol) and bis(3-tert-butyloxycarbonylaminopropyl)amine (1.37 g, 4.14 mmol) using general methods C, D and E in 15% (0.78 g, 0.73 mmol) overall yield in the form of white amorphous powder.

[0386] .sup.1H NMR (500.2 MHz, CD.sub.3OD): 1.28-1.37 (m, 16H, OCH.sub.2CH.sub.2(CH.sub.2).sub.sCH.sub.2CH.sub.2O); 1.59-1.67 (m, 4H, OCH.sub.2CH.sub.2(CH.sub.2).sub.8CH.sub.2CH.sub.2O); 2.13-2.22 (m, 8H, NCH.sub.2CH.sub.2CH.sub.2NH.sub.2); 2.41-2.51 (m, 4H, PCH.sub.2CH.sub.2N); 3.03 (t, 4H, J.sub.vic=6.6, OCH.sub.2CH.sub.2Ph); 3.09 (t, 8H, J.sub.vic=7.5, NCH.sub.2CH.sub.2CH.sub.2NH.sub.2); 3.30-3.36 (m, 12H, NCH.sub.2CH.sub.2CH.sub.2NH.sub.2, PCH.sub.2CH.sub.2N); 3.91-4.03 (m, 4H, OCH.sub.2CH.sub.2(CH.sub.2).sub.sCH.sub.2CH.sub.2O); 4.30-4.40 (m, 4H, OCH.sub.2CH.sub.2Ph).

[0387] .sup.13C NMR (125.8 MHz, CD.sub.3OD): 21.18 (d, J.sub.C,P=140.5, PCH.sub.2CH.sub.2N); 23.23 (NCH.sub.2CH.sub.2CH.sub.2NH.sub.2); 26.53, 30.25, 30.64, 30.68 (OCH.sub.2CH.sub.2(CH.sub.2).sub.8CH.sub.2CH.sub.2O); 31.50 (d, J.sub.C,P=6.0, OCH.sub.2CH.sub.2(CH.sub.2).sub.sCH.sub.2CH.sub.2O); 37.71 (d, J.sub.C,P=6.3, OCH.sub.2CH.sub.2Ph); 37.86 (NCH.sub.2CH.sub.2CH.sub.2NH.sub.2); 48.68 (PCH.sub.2CH.sub.2N); 51.04 (NCH.sub.2CH.sub.2CH.sub.2NH.sub.2); 68.11 (d, J.sub.C,P=6.8, OCH.sub.2CH.sub.2(CH.sub.2).sub.sCH.sub.2CH.sub.2O); 68.58 (d, J.sub.C,P=6.8, OCH.sub.2CH.sub.2Ph).

[0388] .sup.31P{.sup.1H} NMR (202.5 MHz, CD.sub.3OD): 26.48.

[0389] IR v.sub.max (KBr) 3064 (s, sh), 3015 (s), 2927 (vs), 2854 (s), 2848 (m, sh), 2635 (m, vbr), 2556 (m, vbr), 2037 (w, vbr), 1618 (m), 1607 (m, sh), 1520 (w, sh), 1497 (m), 1467, 1455 (m), 1395 (w, br), 1256 (m, sh), 1230 (m), 1155 (w), 1061 (m), 1009 (s), 999 (s), 847 (vw), 751 (w), 700 (m).

[0390] HR-MS (ESI.sup.+): For C.sub.44H.sub.84O.sub.6N.sub.6P.sub.2 (M +H).sup.+ m/2z calculated 427.29583, found 427.29547±0.84009 ppm.

Example 51 Tetradecane-1,14-diyl diisobutyl bis((2-(bis(3-aminopropyl)amino)ethyl)-phosphonate) hexahydrochloride

[0391] ##STR00059##

[0392] Tetradecane-1,14-diyl diisobutyl bis((2-(bis(3-aminopropyl)amino)ethyl)phosphonate) hexahydrochloride is prepared from the compound from Example 32 (496 mg, 0.949 mmol) using general methods D and E in 43% (409 mg, 0.407 mmol) overall yield in the form of white amorphous powder.

[0393] .sup.1H NMR (401 MHz, Methanol-d.sub.4) δ 4.15 (dt, J=7.7, 6.6 Hz, 4H), 3.92 (td, J=6.6, 2.5 Hz, 4H), 3.52-3.43 (m, 4H), 3.43-3.36 (m, 8H), 3.11 (t, J=7.5 Hz, 8H), 2.64-2.45 (m, 4H), 2.22 (h, J=7.7, 7.1 Hz, 8H), 1.99 (dp, J=13.3, 6.6 Hz, 2H), 1.84-1.64 (m, 4H), 1.53-1.22 (m, 20H), 1.00 (d, J=6.7 Hz, 12H).

[0394] .sup.31P NMR (162 MHz, Methanol-d.sub.4) δ 28.60.

[0395] .sup.13C NMR (101 MHz, Methanol-d.sub.4) δ 73.92 (d, J=7.0 Hz), 68.29 (d, J=6.8 Hz), 51.07, 37.86, 31.62 (d, J=5.8 Hz), 30.81, 30.76, 30.71, 30.46 (d, J=6.3 Hz), 30.31, 26.62, 23.30, 21.87, 20.48, 19.03. IR v.sub.max (KBr tab. 1 mm) 3200-2700 (vs, vbr), 2960 (s), 2926 (vs), 2854 (s), 2700-2500 (m), 1608 (m), 1511 (m), 1468 (m), 1400 (m), 1369 (w), 1227 (s), 1004 (vs), 852 (m), 768 (w), —725 (w, sh).

[0396] HR-MS (ESI.sup.+): For C.sub.38H.sub.87O.sub.6N.sub.6P.sub.2 (M+H).sup.+ m/z calculated 785.61568, found 785.61523±0.57208 ppm.

Example 52 Dibutyl tetradecane-1,14-diyl bis((2-(bis(3-aminopropyl)amino)ethyl)phosphonate) hexahydrochloride

[0397] ##STR00060##

[0398] Dibutyl tetradecane-1,14-diyl bis((2-(bis(3-aminopropyl)amino)ethyl)phosphonate) hexahydrochloride is prepared from compound in Example 30 (0.46, 0.88 mmol)

using general methods D and E, in the form of a white amorphous solid in overall yield 57% (0.50 g, 0.50 mmol).

[0399] .sup.1H NMR (400.1 MHz, CD.sub.3OD): 0.95-0.99 (m, 6H), 1.31-1.50 (m, 24H), 1.67-1.76 (m, 8H), 2.16-2.24 (m, 8H), 2.47-2.57 (m, 4H), 3.10 (t, 8H, J.sub.vic=8.0), 3.35-3.42 (m, 8H), 3.44-3.48 (m, 4H), 4.10-4.17 (m, 8H).

[0400] .sup.13C NMR (100.6 MHz, CD.sub.3OD): 13.96, 21.24 (d, J.sub.C,P=140.8), 23.28, 19.80, 26.61, 30.30, 30.70, 30.75, 30.79, 31.59, 33.61 (d, J.sub.C,P=6.0), 37.86, 48.90, 51.08, 67.92, 68.27 (d, J.sub.C,P=6.0).

[0401] .sup.31P{.sup.1H} NMR (162.0 MHz, CD.sub.3OD): 28.40.

[0402] IR v.sub.max (KBr) 2966 (m), 2928 (m), 2625 (m), 1604 (m), 1468 (m), 1384 (m), 1230 (m), 1050 (m), 1021 (m).

[0403] HR-MS (ESI.sup.+): For C.sub.38H.sub.87N.sub.6O.sub.6P.sub.2 (M+H).sup.+ calcd 785.61506, found 785.61568.

Example 53 Tetradecane-1,14-diyl dipentyl bis((2-(bis(3-aminopropyl)amino)ethyl)-phosphonate) hexahydrochloride

[0404] ##STR00061##

[0405] Tetradecane-1,14-diyl dipentyl bis((2-(bis(3-aminopropyl)amino)ethyl)phosphonate) hexahydrochloride is prepared from compound in Example 27 (0.61, 1.12 mmol) using general methods D and E, in the form of a white amorphous solid in overall yield 57% (0.68 g, 0.65 mmol).

[0406] .sup.1H NMR (400.1 MHz, CD.sub.3OD): 0.92-0.97 (m, 6H), 1.34-1.44 (m, 28H), 1.69-1.76 (m, 8H), 2.17-2.25 (m, 8H), 2.48-2.58 (m, 4H), 3.10 (t, 8H, J.sub.vic=8.0), 3.37-3.43 (m, 8H), 3.44-3.49 (m, 4H), 4.10-4.16 (m, 8H).

[0407] .sup.13C NMR (100.6 MHz, CD.sub.3OD): 14.34, 21.25 (d, J.sub.C,P=139.8), 23.26, 23.30, 26.62, 28.80, 30.31, 30.70, 30.74, 30.79, 31.29, 31.61 (d, J.sub.C,P=4.0, 6.0), 37.87, 48.83, 51.06 (NCH.sub.2CH.sub.2CH.sub.2NH.sub.2); 68.21, 68.27 (d, J.sub.C,P=4.0, 5.0, CH.sub.3(CH.sub.2).sub.2CH.sub.2CH.sub.2O, OCH.sub.2CH.sub.2(CH.sub.2).sub.10CH.sub.2CH.sub.2O).

[0408] .sup.31P{.sup.1H} NMR (162.0 MHz, CD.sub.3OD): 28.41

[0409] IR v.sub.max (KBr) 2928 (s), 2623 (m), 2553 (m), 1598 (m), 1468 (m), 1230 (m), 1171 (m), 1080 (m, sh), 1047 (m), 995 (vs).

[0410] HR-MS (ESI.sup.+): For C.sub.40H.sub.91N.sub.6O.sub.6P.sub.2 (M+H).sup.+ calcd 813.64643, found 813.64698.

Example 54 Dihexyl tetradecan-1,14-diyl bis((2-(bis(3-aminopropyl)amino)ethyl)-phosphonate) tetrahydrochloride

[0411] ##STR00062##

[0412] Dihexyl tetradecan-1,14-diyl bis((2-(bis(3-aminopropyl)amino)ethyl)phosphonate) tetrahydrochloride is prepared from compound in Example 27 (0.85 g, 1.47 mmol) and bis (3-tert-butyloxykarbonylaminopropyl)amine (1.95 g, 5.88 mmol) using general methods D and E, in the form of a white amorphous solid in overall yield 65% (0.93 g, 0.95 mmol).

[0413] .sup.1H NMR (400.1 MHz, CD.sub.3OD): 0.91-0.94 (m, 6H, CH.sub.3(CH.sub.2).sub.4CH.sub.2O); 1.33-1.44 (m, 32H, CH.sub.3(CH.sub.2).sub.3CH.sub.2CH.sub.2O, OCH.sub.2CH.sub.2(CH.sub.2).sub.1CH.sub.2CH.sub.2O); 1.69-1.76 (m, 8H, CH.sub.3(CH.sub.2).sub.3CH.sub.2CH.sub.2O, OCH.sub.2CH.sub.2(CH.sub.2).sub.10CH.sub.2CH.sub.2O); 2.17-2.25 (m, 8H, NCH.sub.2CH.sub.2CH.sub.2NH.sub.2); 2.48-2.57 (m, 4H, PCH.sub.2CH.sub.2N); 3.10 (t, 8H, J.sub.vic=8.0, NCH.sub.2CH.sub.2CH.sub.2NH.sub.2); 3.37-3.41 (m, 8H, NCH.sub.2CH.sub.2CH.sub.2NH.sub.2); 3.42-3.48 (m, 4H, PCH.sub.2CH.sub.2N); 4.10-4.16 (m, 8H, CH.sub.3(CH.sub.2).sub.4CH.sub.2O, OCH.sub.2CH.sub.2(CH.sub.2).sub.10CH.sub.2CH.sub.2O).

[0414] .sup.13C NMR (100.6 MHz, CD.sub.3OD): 12.99 (CH.sub.3(CH.sub.2).sub.4CH.sub.2O); 19.90 (d, J.sub.C,P=139.8, PCH.sub.2CH.sub.2N); 21.87 (NCH.sub.2CH.sub.2CH.sub.2NH.sub.2); 22.24, 24.92, 25.24, 28.92, 29.32, 29.36, 29.41 (CH.sub.3CH.sub.2 CH.sub.2CH.sub.2CH.sub.2CH.sub.2O, OCH.sub.2CH.sub.2(CH.sub.2).sub.10CH.sub.2CH.sub.2O); 29.34 (d, J.sub.C,P=4.0, CH.sub.3(CH.sub.2).sub.3CH.sub.2CH.sub.2O, OCH.sub.2CH.sub.2(CH.sub.2).sub.10CH.sub.2CH.sub.2O); 31.11 (CH.sub.3CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2O); 36.48 (NCH.sub.2CH.sub.2CH.sub.2NH.sub.2); 47.44 (PCH.sub.2CH.sub.2N); 49.68 (NCH.sub.2CH.sub.2CH.sub.2NH.sub.2); 66.82, 66.89 (d, J.sub.C,P=2.0, CH.sub.3(CH.sub.2).sub.4CH.sub.2O, OCH.sub.2CH.sub.2(CH.sub.2).sub.10CH.sub.2CH.sub.2O).

[0415] .sup.31P{.sup.1H} NMR (162.0 MHz, CD.sub.3OD): 28.40.

[0416] IR v.sub.max (KBr) 2925 (s), 2957 (s), 2857 (s), 2678 (m), 2488 (m, sh), 1608 (m ,sh). 1489 (m), 1467 (m), 1391 (m), 1227 (s), 1037 (m), 992 (s).

[0417] HR-MS (ESI.sup.+): For C.sub.49H.sub.96N.sub.6O.sub.6P.sub.2 (M+2H).sup.2+ calcd 421.34278, found 421.34226.

Example 55 Dihexyl octane-1,8-diyl bis((2-(bis(2-aminoethyl)amino)ethyl)phosphonate) hexahydrochloride

[0418] ##STR00063##

[0419] Dihexyl octane-1,8-diyl bis((2-(bis(2-aminoethyl)amino)ethyl)phosphonate) hexahydrochloride is prepared from compound in Example 21 (0.40, 0.81 mmol)

using general methods D and E, in the form of a white amorphous solid in 31% overall yield (0.21 g, 0.25 mmol).

[0420] .sup.1H NMR (400.1 MHz, CD.sub.3OD): 0.90-0.94 (m, 6H), 1.32-1.45 (m, 20H), 1.68-1.76 (m, 8H), 2.31-2.40 (m, 4H), 3.10-3.26 (m, 12H), 3.29-3.31 (m, 8H), 4.06-4.14 (m, 8H).

[0421] .sup.13C NMR (100.6 MHz, CD.sub.3OD): 14.38, 21.78 (d, J.sub.C,P=138.8), 23.63, 26.33, 26.54, 26.58, 30.18, 31.57, 32.51 (d, J.sub.C,P=5.0), 36.96, 48.42, 51.50, 67.89, 67.96 (d, J.sub.C,P=3.0, 4.0).

[0422] .sup.31P{.sup.1H} NMR (162.0 MHz, CD.sub.3OD): 31.25.

[0423] IR v.sub.max (KBr) 2926 (m), 2793 (s), 2677 (m), 2617 (m), 2542 (s), 2438 (m, sh), 1611 (m), 1514 (m), 1467 (m), 1390 (m), 1228 (s), 1050 (m, sh), 990 (s).

[0424] HR-MS (ESI.sup.+): For C.sub.30H.sub.69N.sub.4O.sub.6P.sub.2 (M+H).sup.+ calcd 701.52178, nalezeno 701.52194.

Example 56 Dibutyl decane-1,10-diyl bis((2-(bis(2-aminoethyl)amino)ethyl)phosphonate) hexahydrochloride

[0425] ##STR00064##

[0426] Dibutyl decane-1,10-diyl bis((2-(bis(2-aminoethyl)amino)ethyl)phosphonate) hexahydrochloride is prepared from compound in Example 28 (0.83, 1.77 mmol)

using general methods D and E, in the form of a white amorphous solid in 29% overall yield (0.40 g, 0.49 mmol).

[0427] .sup.1H NMR (400.1 MHz, CD.sub.3OD): 0.95-0.99 (m, 6H), 1.34-1.50 (m, 16H), 1.66-1.75 (m, 8H), 2.25-2.33 (m, 4H), 3.10-3.16 (m, 12H), 3.23-3.27 (m, 8H), 4.05-4.13 (m, 8H).

[0428] .sup.13C NMR (100.6 MHz, CD.sub.3OD): 12.57, 20.81 (d, J=138.8), 18.42, 25.23, 28.87, 29.20, 30.20, 32.20 (d, J.sub.C,P=6.0), 35, 47.10 50.10, 66.2, 66.6 (d, J=7.0).

[0429] .sup.31P{.sup.1H} NMR (162.0 MHz, CD.sub.3OD): 28.43.

[0430] IR v.sub.max (KBr) 2961 (m), 2926 (m), 2674 (m, sh), 2551 (m, br), 1613, (m), 1467 (m), 1391 (m), 1260 (m), 1236 (m), 1066 (m, sh), 991 (m, sh).

[0431] HR-MS (ESI.sup.+): For C.sub.30H.sub.71N.sub.6O.sub.6P.sub.2 (M+H).sup.+ calcd 673.49047, found 673.49048.

Example 57 Hexane-1,6-diyl di((Z)-oct-3-en-1-yl) bis((2-(bis(3-aminopropyl)amino)-ethyl)phosphonate) hexahydrochloride

[0432] ##STR00065##

[0433] Hexane-1,6-diyl di((Z)-oct-3-en-1-yl) bis((2-(bis(3-aminopropyl)amino)ethyl)phosphonate) hexahydrochloride is prepared from compound in Example 17 (0.59, 1.14 mmol) using general methods D and E, in the form of a white amorphous solid in 50% overall yield (0.66 g, 0.66 mmol).

[0434] .sup.1H NMR (400.1 MHz, CD.sub.3OD): 0.89-0.93 (m, 6H), 1.32-1.37 (m, 8H), 1.44-1.51 (m, 4H), 1.70-1.78 (m, 4H), 2.06-2.11 (m, 4H), 2.20-2.27 (m, 8H), 2.43-2.50 (m, 4H), 2.54-2.63 (m, 4H), 3.13 (t, 8H, J.sub.C,P=8.0), 3.38-3.49 (m, 12H), 4.09-4.20 (m, 8H), 5.38-5.45 (m, 2H), 5.53-5.60 (m, 2H).

[0435] .sup.13C NMR (100.6 MHz, CD.sub.3OD): 13.01, 20.06 (d, J.sub.C,P=36.8), 21.83, 21.99, 24.77, 26.71, 28.27 (d, J.sub.C,P=6.0), 29.98 (d, J.sub.C,P=6.0), 31.53, 36.59, 47.54, 49.65, 66.23 (d, J.sub.C,P=7.0), 66.67 (dd, J.sub.C,P=7.0, 2.0), 123.68, 132.89.

[0436] .sup.31 P{.sup.1H} NMR (162,0 MHz, CD.sub.3OD): 28.46.

[0437] IR v.sub.max (KBr) 3432 (m, br), 3015 (s), 2957 (vs), 2931 (vs), 2872 (s), 2500-2300 (vs, vbr), 1611 (m), 1467 (m), 1380 (w, sh), 1228 (m), 1055 (s), 1003 (s).

[0438] HR-MS (ESI.sup.+): For C.sub.38H.sub.84O.sub.6N.sub.6P.sub.2 (M+2H).sup.2+ calcd 391.29583, found 391.29589.

Example 58 Di((Z)-oct-3-en-1-yl) pentane-1,5-diyl bis((2-(bis(3-aminopropyl)amino)ethyl)-phosphonate) hexahydrochloride

[0439] ##STR00066##

[0440] Di((Z)-oct-3-en-1-yl) pentane-1,5-diyl bis((2-(bis(3-aminopropyl)amino)ethyl)phosphonate) hexahydrochloride is prepared from compound in Example 16 (0.54, 1.07 mmol) using general methods D and E, in the form of a white amorphous solid in 51% overall yield (0.53 g, 0.54 mmol).

[0441] .sup.1H NMR (400.1 MHz, CD.sub.3OD): 0.90-0.93 (m, 6H), 1.28-1.39 (m, 8), 1.51-1.59 (m, 2H), 1.74-1.81 (m, 4H), 2.06-2.11 (4H), 2.21-2.28 (m, 8H), 2.45-2.51 (m, 4H), 2.57-2.66 (m, 4H), 3.14 (t, 8H, J.sub.vic=7.5), 3.42-3.50 (m, 12H), 4.09-4.22 (m, 8H), 5.39-5.45 (m, 2H), 5.52-5.58 (m, 2H).

[0442] .sup.13C NMR (100.6 MHz, CD.sub.3OD): 13.0, 20.13 (d, J.sub.C,P=139.8), 21.43, 21.82, 21.99, 26.72, 28.27 (d, J.sub.C,P=6.0), 29.58 (d, J.sub.C,P=6.0), 31.53, 36.62, 47.57, 49.65, 66.25 (d, J.sub.C,P=6.0), 66.59 (dd, J.sub.C,P=6.0), 123.71, 132.87.

[0443] .sup.31P{.sup.1H} NMR (162.0 MHz, CD.sub.3OD): 28.45.

[0444] IR v.sub.max (KBr) 3435 (s, br), 3015 (m, sh), 2957 (m), 2927 (m), 2872 (m), 2857 (m), 2500-2300 (m, br), 1626 (w), 1467 (w), 1379 (w), 1275 (w, sh), 1226 (w), 1004 (m).

[0445] HR-MS (ESI.sup.+):For C.sub.37H.sub.82O.sub.6N.sub.6P.sub.2 (M+2H).sup.2+ calcd 384.28801, found 384.28824.

Antibacterial Activity

[0446] Antibacterial activity is measured using a standard microdilution method determining the minimum inhibitory concentration (MIC) of a test sample that results in the inhibition of bacterial growth. Disposable microtiter plates are used for testing. Samples are dissolved in infusion medium from brain and heart (BHI, HiMedia Laboraties Pvt. Ltd., Czech Republic) and Mueller-Hinton broth (HiMedia Laboraties, see above) to a final concentration ranging from 200 μg/ml to 1.5625 μg/ml. Plates are inoculated with a standard amount of test bacteria—the density of the inoculum in the well corresponds to 10.sup.5-6 CFU/ml (colony forming units/ml, i.e. the number of viable bacterial cells/ml). MIC values are read after 24/48 hours of incubation at 37° C. as the minimum inhibitory concentration of the test substance at which bacterial growth is inhibited. The minimum bactericidal concentration (MBC) is characterized as the minimum concentration of the sample required to achieve irreversible inhibition, i.e. to kill the bacteria after a defined incubation period. MBC is determined by the inoculation method. Using an applicator, 10 μl from the well of a microtiter plate with a defined concentration of the test substance is taken to inoculate the surface of blood agar (Trios, Czech Republic). MBC is determined as the lowest concentration that inhibits the visible growth of the bacterium used on agar.

TABLE-US-00002 TABLE 2 The antibacterial activity of the prepared substances measured as MIC (which in most cases corresponds to MBC at one dilution) as mentioned above. The underlined bacterial strains are representatives of resistant bacteria. Escherichia Pseudomonas Enterococcus Staphylococcus Compound coli aeruginosa faecalis aureus Staphylococcus from ATCC ATCC ATCC ATCC epidermidis example 25922 = CCM 3954 27853 = CCM 3955 29212 = CCM 4224 29213 = CCM 4223 CCM 7221 34 32 >128 128 8 4 35 0.5 2 1 0.5 0.5 36 128 >128 >128 16 4 37 2 16 16 1 0.5 39 128 128 64 32 8 40 >128 >128 128 16 4 41 64 16 32 2 1 42 2 4 4 0.5 0.5 43 0.5 1 0.5 0.5 0.5 44 2 4 2 2 1 45 >128 32 32 4 1 46 128 32 32 4 1 47 16 4 2 1 0.5 48 1 2 1 1 0.5 49 4 8 4 1 0.5 50 16 4 4 2 0.5 51 16 4 4 2 0.5 52 2 4 1 1 0.5 53 1 2 1 0.5 0.5 54 4 8 8 1 0.5 55 >128 64 128 2 2 56 4 4 2 2 4 57 2 16 16 1 0.5 58 8 32 2 0.5 2 Candida Compound Staphylococcus Enterococcus Escherichia Enterobacter Pseudomonas albicans from aureus faecium coli kobei aeruginosa ATCC example 4591 419/ANA CE5556 3683 R 90028 = CCM 8161 34 16 >128 128 >128 >128 128 35 1 8 1 2 2 16 36 8 >128 >128 >128 128 128 37 2 >128 8 >128 64 32 39 16 128 128 >128 64 >128 40 8 >128 >128 >128 >128 128 41 2 128 128 >128 8 64 42 1 32 8 64 8 16 43 0.5 1 1 1 1 1 44 1 2 2 2 4 4 45 4 128 >128 >128 16 64 46 4 >128 >128 >128 16 64 47 1 16 32 128 4 16 48 1 1 1 1 2 2 49 4 32 16 128 8 8 50 1 2 2 8 2 4 51 2 16 32 64 4 32 52 1 2 2 8 2 4 53 1 2 1 2 4 2 54 1 64 16 >128 8 16 55 4 >128 >128 >128 64 32 56 4 4 4 16 8 4 57 1 64 2 nd 16 64 58 128 4 4 nd 32 64

Testing of Haemolytic Activity of soluble Samples

[0447] Blood from three donors is mixed and centrifuged (10 min, 1000 g, 4° C.). The erythrocytes obtained are washed three times with NaCl solution (150 mmol.l.sup.−1) and then used for experiments. Sample stock solutions are prepared in DMSO so that the final concentration of DMSO in NaCl is 0.5% (v/v). NaCl solution with the appropriate volume of DMSO serves as the negative control. 1% Triton-X100 is the positive control. The erythrocytes obtained are diluted to 2% with NaCl solution and pipetted into Eppendorf tubes (250 μl) with constant stirring. Samples and positive and negative controls are added to the erythrocytes prepared in this way and incubated (3 hours, 37° C.). The tubes are stirred during the incubation. After centrifugation (5 min, 1000 g), haemolytic activity is monitored by haemoglobin determination. The HC.sub.50 value is calculated from the measured absorbance values. The test is performed in triplets in three independent replicates. Iron Fe.sup.2+ in haemoglobin is oxidized with potassium ferricyanide to iron Fe.sup.3+ in methaemoglobin, which produces stable cyanomethaemoglobin with potassium cyanide, the concentration of which is determined spectrophotometrically. After the incubation of the erythrocytes with the substances, the cells are centrifuged (5 min, 1000 g), then Drabkin's solution (200 μl) is added to the supernatant (40 μl) and after incubation (10 min), the absorbance at 540 nm is measured.

Toxicity Testing of soluble Samples

[0448] The toxicity testing of soluble samples was performed on a Balb/c 3T3 mouse fibroblast cell line. The cryopreserved cells are taken out from the deep-freezer, left for 1 min at room temperature and then sterile transferred to a 25 cm.sup.2 flask with 10 ml of culture medium (DMEM, penicillin 100 U.ml.sup.−1, L-glutamine 2 mmol.l.sup.−1, streptomycin 100 mg.l.sup.−1, fetal calf serum 5%, neonatal calf serum 5%). The cells are stored in an incubator saturated with water vapour at 37° C. and in an atmosphere of 5% CO2, the medium is changed every 48-72 h. After reaching the monolayer, the cells are washed with sterile PBS (5 ml), released by incubation with 0.25% trypsin solution with EDTA (0.5 ml; 2-3 min, 37° C.), 5 ml of culture medium is added, and the samples are centrifuged (10 min, 1300 rpm, room temperature). The pellet is resuspended in 20 ml of culture medium and the cells are transferred to a 75 cm.sup.2 culture flask and further cultured. After reaching the monolayer, the cells are washed with sterile PBS (10 ml), released by incubation with 0.25% trypsin solution with EDTA (1 ml; 2-3 min; 37° C.), and resuspended in 10 ml of culture medium. The suspension is centrifuged (10 min; 1300 rpm; room temperature). The pellet is resuspended in 10 ml of culture medium and the cells are used in experiments.

[0449] Stock solutions are prepared in DMSO so that the final concentration of DMSO in the medium is 0.5% (v/v). Control cells are prepared by incubation with an appropriate volume of DMSO.

[0450] Cell concentrations are determined by trypan blue staining. The cells are diluted in culture medium and plated in 96-well plates at a concentration of 2x10.sup.5 cells/ml at 0.2 ml per well. After incubating the culture for 24 hours (Jouan incubator-controlled atmosphere 95% air, 5% CO.sub.2, steam saturation, 37° C.), the culture medium is changed to serum-free medium containing the test substances and incubated for 24 hours in the incubator under the above conditions. After 24 h of incubation (37 ° C., 5% CO.sub.2), cell damage is monitored by determining mitochondrial dehydrogenase activity (MTT assay). The IC.sub.50 value is calculated from the measured absorbance values. The test is performed in three independent replicates.

[0451] The yellow tetrazolium salt of MTT is reduced by mitochondrial dehydrogenases of metabolically active cells to a purple, water-insoluble formazan dye, the concentration of which, after dissolution in an organic solvent, is determined spectrophotometrically at 570 nm (Sieuwerts, 1995).

TABLE-US-00003 TABLE 3 Toxicity of test substances determined by MTT test in Balb/c 3T3 mouse fibroblast line Compound from Example HC.sub.50 ± SD IC.sub.50 ± SD 34 >100 >100 35 >100 12 36 >100 >100 37 >100 76.4 39 >100 53.5 40 >100 >100 41 >100 41.3 42 74.5 19.3 43 6 2.1 44 5 4 45 >100 55.5 46 >100 31.7 47 >100 6.3 48 4 2.1 49 >100 8.4 50 >100 4.9 51 >100 4.5 52 56.4 2.4 53 10.6 2.1 54 >100 32 55 >100 70.2 56 16.8 2.7 57 34.8 62 58 70 100

INDUSTRIAL APPLICABILITY

[0452] The lipophosphonoxins according to the invention can be used, as antibacterial agents, as an active ingredient in pharmaceutical compositions for the treatment of hitherto resistant bacterial infections, in disinfectants and/or in selective culture media.