Process for the production of tetraaminobiphenol macrocyclic ligands; and novel tetraaminobiphenol macrocyclic ligands

Abstract

A process for preparing a tetra-substituted aminobiphenol macrocyclic ligand having the structure (I), comprising the step of treating a precursor compound having the structure (II) with a compound having the structure R6-L where L represents a leaving group (hereinafter compound (III)) in the presence of a base.

Claims

1. A process for preparing a tetra-substituted aminobiphenol macrocyclic ligand having a structure (I), comprising the step of treating a precursor compound having a structure (II) with a compound having a structure R.sub.6-L where L represents a leaving group (hereinafter compound (III)) in the presence of a base; ##STR00020## wherein R.sub.1 and R.sub.2 are independently selected from hydrogen, halide, a nitro group, a nitrile group, an imine group, —NCR.sub.13R.sub.14, an amine, an ether group —OR.sub.15 or —R.sub.16OR.sub.17, an ester group —OC(O)R.sub.10 or —C(O)OR.sub.10, an amido group —NR.sub.9C(O)R.sub.9 or —C(O)—NR.sub.9(R.sub.9), —COOH, —C(O)R.sub.15, —OP(O)(OR.sub.18)(OR.sub.19), —P(O)R.sub.20R.sub.21, a silyl group, a silyl ether group, a sulfoxide group, a sulfonyl group, a sulfinate group or an acetylide group or an optionally substituted alkyl, alkenyl, alkynyl, haloalkyl, aryl, heteroaryl, alkoxy, aryloxy, alkylthio, arylthio, alicyclic or heteroalicyclic group; R.sub.3 is independently selected from optionally substituted alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, arylene, heteroarylene or cycloalkylene, wherein alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene and heteroalkynylene, in each case optionally interrupted by aryl, heteroaryl, alicyclic or heteroalicyclic; R.sub.4 is independently selected from hydrogen, or optionally substituted aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl, heteroaryl, alkylheteroaryl or alkylaryl; R.sub.5 is independently selected from hydrogen, optionally substituted aliphatic, heteroaliphatic, alicyclic, alkanoate, arylate, carboxyl, heteroalicyclic, aryl, heteroaryl, alkylheteroaryl or alkylaryl, or two R5 species may together be selected from optionally substituted alkylene, alkenylene or alkynylene, bonded to two different N groups of the compound of structure (II), with the proviso that at least one of the species R.sub.5 is hydrogen; and E is independently selected from NR.sub.5 and NR.sub.6, with the proviso that at least one of the species E is NR.sub.6; wherein R.sub.6 is independently selected from optionally substituted alkylaryl, C(2-10) alkenyl group, C(2-10) alkynyl group, C(1-10) alkyl, allyl, propargyl or benzyl; wherein R.sub.9, R.sub.10, R.sub.13, R.sub.14, R.sub.18, R.sub.19, R.sub.20 and R.sub.21 are independently selected from hydrogen or an optionally substituted aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl or heteroaryl group and R.sub.15, R.sub.16 and R.sub.17 are independently selected from an optionally substituted aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aryl or heteroaryl group; and wherein the molar ratio of compound (III) to the number of NH sites in the compound of structure (II) is at least 0.6.

2. The process of claim 1, wherein the molar ratio of the compound having the structure (III) to the number of NH sites in the macrocycle is at least 0.8.

3. The process of claim 2, wherein the molar ratio of the compound having the structure (III) to the number of NH sites in the macrocycle (II) is at least 1.

4. The process of claim 3, wherein the molar ratio of the compound having the structure (III) to the number of NH sites in the macrocycle (II) is at least 1.1.

5. The process of claim 1, wherein R.sub.1 and R.sub.2 are independently selected from hydrogen, halide, amino, nitro, sulfoxide, sulfonyl, sulfinate, silyl, silyl ether and an optionally substituted alkyl, alkenyl, aryl, heteroaryl, heteroalicyclic, alkoxy, aryloxy or alkylthio or arylthio.

6. The process of claim 5, wherein R.sub.2 is hydrogen or alkyl and R.sub.1 is independently selected from hydrogen, C.sub.1-6alkyl, C.sub.1-6haloalkyl, alkoxy, aryl, halide, nitro, sulfonyl, silyl or alkylthio.

7. The process of claim 6, wherein R.sub.2 is hydrogen and R.sub.1 is independently selected from t-butyl, n-butyl, i-propyl, methyl, piperidinyl, methoxy, hexyl methyl ether, —SCH.sub.3, —S(C.sub.6H.sub.5), H, nitro, trimethylsilyl, triethylsilyl, methylsulfonyl (—SO.sub.2CH.sub.3), triethylsilyl, halogen or phenyl.

8. The process of claim 1, wherein R.sub.3 is selected from alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene or heteroalkynylene group which may optionally be interrupted by an aryl, heteroaryl, alicyclic or heteroalicyclic group, or may be a divalent arylene or cycloalkylene group which acts as a bridging group between two nitrogen centres in the macrocycle of formula (I).

9. The process of claim 8, wherein R.sub.3 is a substituted or unsubstituted alkylene, cycloalkylene, alkenylene, heteroalkylene and arylene.

10. The process of claim 9, wherein R.sub.3 is selected from 2,2-dimethylpropane-1,3-diyl, ethane-1,2-diyl, 2,2-fluoropropane-1,3-diyl, 2,2- propane-1,3-diyl, butane-1,4-diyl, phenylene, cyclohexane-1,4-diyl cyclohexane-1,2-diyl or biphenylene.

11. The process of claim 1, wherein R.sub.4 is independently selected from hydrogen, and optionally substituted aliphatic or aryl.

12. The process of claim 11, wherein R.sub.4 is independently selected from hydrogen, and optionally substituted alkyl or aryl.

13. The process of claim 11, wherein R.sub.4 groups are selected from hydrogen, methyl, ethyl, n-propyl, n-butyl, phenyl and trifluoromethyl.

14. The process of claim 1, wherein R.sub.5 is independently selected from hydrogen, optionally substituted alkyl which is optionally interrupted by at least one N atom, or by at least one O atom, or by at least one S atom, optionally substituted alkylthio, alkylaryl, alkylheteroaryl, alkenyl, alkynyl, heteroalkenyl, heteroalkynyl, aryl, alicyclic, heteroalicyclic, heteroaryl, sulfonate, alkanoate (—C(O)—OR.sub.10), arylate (arylC(O)O—), aryl-C(O)OR.sub.10, alkylaryl-C(O)OR.sub.10, alkyl-C(O)—OR.sub.10, carbonyl (—C(O)—R.sub.10), ether, polyether, alkylarylC(O)O— or carboxyl; or two R.sub.5 groups together comprise an optionally substituted alkylene group bonded to two different N groups on the same macrocycle; wherein at least one species R.sub.5 is hydrogen.

15. The process of claim 14, wherein R.sub.5 is independently selected from optionally substituted alkyl, alkylaryl, alkenyl, alkynyl, sulfonate, alkanoate, aryl-C(O)OR.sub.10, alkylaryl-C(O)OR.sub.10, alkyl-C(O)—OR.sub.10 or alkyl-C≡N.

16. The process of claim 15, wherein R.sub.5 is independently selected from methyl, ethyl, propyl, butyl, allyl, propargyl, benzyl, 4-nitrobenzyl, —CH.sub.2CH.sub.2—C(O)—OR.sub.10, CH.sub.2CH.sub.2C≡N, or —C(1-4)alkylC(O)O—, or benzoate which is unsubstituted or ring-substituted by 1, 2 or 3 C(1-4)alkyl groups.

17. The process of claim 14, wherein one species R.sub.5 is hydrogen and the remaining three species R.sub.5 are independently selected from the substituent group.

18. The process of claim 14 wherein two species R.sub.5 are hydrogen and the remaining two species R.sub.5 are independently selected from the substituent.

19. The process of claim 14, wherein three species R.sub.5 are hydrogen and the remaining one species R.sub.5 is independently selected from the substituent group.

20. The process of claim 14 wherein all four R.sub.5 species are hydrogen.

21. The process of claim 1, wherein the compound R.sub.6-L has a leaving group L which is selected from halogen, or an ether group, or a tertiary amine, or a sulfonate group of formula —O—SO.sub.2—R.sub.x where R.sub.x is selected from optionally substituted aliphatic or aryl or alkylaryl; or a group of formula —O—SO.sub.2—O—R.sub.y or —O—CO—O—R.sub.y where R.sub.y represents optionally substituted aliphatic or aryl or alkaryl.

22. The process of claim 21, wherein the leaving group L is a chlorine, bromine of iodine atom or a group of formula R.sub.y—O—SO.sub.2—O— or R.sub.y—O—CO—O— where both species R.sub.y are C.sub.(1-4) alkyl groups or an alkyl sulfonate, aryl sulfonate, halo sulfonate or trihaloalkyl sulfonate.

23. The process of claim 1, wherein the base for use in the process is an inorganic base selected from carbonates, hydrogen carbonates, alkanoates, hydroxides, silicates, phosphates and borates of Group 1 and Group II metals, or from an organic base selected from tertiary amine bases.

24. The process of claim 23, wherein a base is selected from sodium carbonate, potassium carbonate, cesium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, ammonium carbonate, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, ammonium hydroxide, sodium (C1-10) alkanoates, potassium (C1-10) alkanoates, sodium metasilicate, potassium metasilicate, sodium borate, potassium borate, trisodium phosphate, disodium phosphate, monosodium phosphate, monopotassium phosphate, dipotassium phosphate or tripotassium phosphate.

25. The process of claim 1, wherein a compound of structure (I) is prepared.

26. The process of claim 21 wherein the optionally substituted aliphatic or aryl or alkylaryl of R.sub.x includes polymer-bound sulfonate groups.

Description

EXPERIMENTAL DESCRIPTION

(1) It should be noted here that the examples given demonstrate the breadth of applicability of the process of the present invention. The yields reported in the following examples are substantially unoptimized and reaction conditions have not been extensively tailored to suit individual target macrocycles. Some of the yields are therefore <40%, but it is understood with variation of the conditions that these yields could be substantially improved. In many cases very high yields were obtained, even without optimisation. It is noted that in each case, and as demonstrated by the enclosed NMR data, no alkylation of the phenols was observed. The products obtained were the desired tetra-N-alkylated-diphenol compounds.

Example Set 1: Preparation of Tetra-Benzylated Ligand 2

(2) ##STR00009##

(3) To a solution of ligand 1 (1.00 g, 1.0 eq) in tetrahydrofuran (10 mL) and acetonitrile (20 mL) were added benzyl bromide (0.96 mL, 4.5 eq) and sodium carbonate (1.05 g, 5.5 eq). The reaction mixture was stirred at reflux for 18 h. After this time, reaction mixture was filtered and the filter cake was washed with acetonitrile. The filter cake was solubilised in dichloromethane/water, and phases were separated. The aqueous phase was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, and the solvents were evaporated in vacuo to yield tetra-benzylated ligand 2 (>85%). MS (ESI): 913.6 [M+H]+; 1H NMR (400 MHz, CDCl3) δ (ppm) 10.60 (s, 2H, phenols), 7.45-7.41 (m, 8H), 7.39-7.34 (m, 8H), 7.31-7.26 (m, 4H), 6.89 (s, 4H), 3.75-3.64 (m, 16H), 2.54 (s, 8H), 1.26 (s, 18H), 0.85 (s, 12H).

Example Set 2: Preparation of Tetra-Alkylated Ligands 3, 4

(4) ##STR00010##

(5) Representative procedure: To a solution of ligand 1 (1.00 g, 1.0 eq) in toluene (12 mL) and acetonitrile (24 mL) were added diethylsulfate (1.06 mL, 4.5 eq) and sodium carbonate (1.05 g, 5.5 eq). Reaction mixture was stirred at 85° C. for 2 days. After this time, reaction mixture was filtered and the mother liquor was evaporated. The residue was solubilised in dichloromethane/water, and phases were separated. The aqueous phase was extracted with dichloromethane. The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate, and phases were separated. The organic layer was dried over sodium sulfate, and the solvents were evaporated in vacuo to yield tetra-alkylated ligand 3 (33%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 10.68 (s, 2H, phenols), 6.95 (s, 4H), 3.63 (s, 8H), 2.55 (q, J=6.9 Hz, 8H), 2.37 (s, 8H), 1.26 (s, 18H), 1.07 (t, J=6.9 Hz, 12H), 0.78 (s, 12H). MS (ESI): 665.6 [M+H].sup.+ Mass spectrometry data for compound 4 (28%): MS (ESI): 721.6 [M+H].sup.+

Example Set 3: Preparation of Tetra-Methylated Ligands 12-19

(6) ##STR00011##

(7) Representative procedure: To a suspension of ligand 1 (R.sup.1=tBu, R.sup.2═H) (1.00 g, 1.0 eq) in acetonitrile (30 mL) were added Me.sub.2SO.sub.4 (0.77 mL, 4.5 eq) and sodium carbonate (1.05 g, 5.5 eq). Reaction mixture was stirred at room temperature (RT) for 18 h. After this time, reaction mixture was filtered and the filter cake was washed with acetonitrile. The filter cake was solubilised in dichloromethane/water, and phases were separated. The aqueous phase was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, and the solvents were evaporated in vacuo to yield tetra-methylated ligand 12 (R.sup.1=tBu, R.sup.2═H>70%) as a white powder. .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 10.99 (s, 2H, phenols), 6.96 (s, 4H), 3.59 (s, 8H), 2.38 (s, 8H), 2.33 (s, 12H), 1.29 (s, 18H), 0.89 (s, 12H). MS (ESI) 609.4 [M+H].sup.+

(8) Mass spectrometry data for compounds 13-19:

(9) 13 (56%) (R.sup.1═SMe, R.sup.2═H): MS (ESI) 589.3 [M+H].sup.+

(10) 14 (53%) (R.sup.1═Br, R.sup.2═H): MS (ESI) 655.2 [M+H].sup.+

(11) 15 (52%) (R.sup.1═F, R.sup.2═H): MS (ESI) 533.4 [M+H].sup.+

(12) 16 (59%) (R.sup.1=SiEt.sub.3, R.sup.2═H): MS (ESI) 725.5 [M+H].sup.+

(13) 17 (33%) (R.sup.1═OMe, R.sup.2═H): MS (ESI) 557.4 [M+H].sup.+

(14) 18 (40%) (R.sup.1=nBu, R.sup.2═H): MS (ESI) 609.4 [M+H].sup.+

(15) 19 (40%) (R.sup.1=Me, R.sup.2=Me): MS (ESI) 581.4 [M+H].sup.+

Example 4: Preparation of Tetra-Allylated Ligand 20

(16) ##STR00012##

(17) To a solution of ligand 1 (1.00 g, 1.0 eq) in toluene (10 mL) and acetonitrile (20 mL) were added allyl bromide (0.70 mL, 4.5 eq) and sodium carbonate (1.05 g, 5.5 eq). Reaction mixture was stirred at 50° C. for 6 days. After this time, reaction mixture was filtered and the filter cake was washed with acetonitrile. The filter cake was solubilised in dichloromethane/water, and phases were separated. The aqueous phase was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, and the solvents were evaporated in vacuo to yield tetra-allylated ligand 20 (>90%) as a white powder. MS (ESI) 713.6 [M+H].sup.+

Example 5: Further Preparation of Tetra-Methylated Ligand 12

(18) ##STR00013##

(19) Representative example: To a solution of ligand 1 (1.00 g, 1.0 eq) in 2-methyl-tetrahydrofuran (9 mL) and acetone (18 mL) were added dimethylsulfate (0.77 mL, 4.5 eq) and sodium ethanoate (1.04 g, 7.0 eq). Reaction mixture was stirred at room temperature for 18 h. After this time, reaction mixture was filtered and the filter cake was washed with acetonitrile. The filter cake was solubilised in dichloromethane/water, and phases were separated. The aqueous phase was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, and the solvents were evaporated in vacuo to yield tetra-methylated ligand 12 (35%).

(20) Examples of other bases used in the preparation of ligand 12:

(21) Base=sodium hydroxide (NaOH—5.5 eq), solvent=tetrahydrofuran/acetonitrile (1:3), room temperature, 16 hours. Yield=18%.

(22) Base=disodium phosphate (Na.sub.2HPO.sub.4— 5.5 eq), solvent=tetrahydrofuran/acetonitrile (1:3), room temperature, 16 hours. Yield=20%.

Example 6: Preparation of Tetra-Methylated Ligand 22

(23) ##STR00014##

(24) To a solution of ligand 21 (1.00 g, 1.0 eq) in methanol (30 mL) were added dimethylsulfate (0.81 mL, 4.5 eq) and sodium carbonate (1.10 g, 5.5 eq). Reaction mixture was stirred at room temperature for 18 h. After this time, reaction mixture was filtered and the mother liquor was evaporated. The residue was solubilised in dichloromethane/water, and phases were separated. The aqueous phase was extracted with dichloromethane. The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate, and phases were separated. The organic layer was dried over sodium sulfate, and the solvents were evaporated. 22 (60%); MS (ESI) 581.4 [M+H].sup.+

Example 7: Preparation of Tetra-Methylated Ligand 24

(25) ##STR00015##

(26) To a solution of ligand 23 (1.00 g, 1.0 eq) in dimethyl carbonate (30 mL) was added sodium carbonate (1.06 g, 5.0 eq). Reaction mixture was stirred at reflux for 18 h. After this time, reaction mixture was filtered and the mother liquor was evaporated. The residue was solubilised in dichloromethane/water, and phases were separated. The aqueous phase was extracted with dichloromethane. The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate, and phases were separated. The organic layer was dried over sodium sulfate, and the solvents were evaporated. 24 (45%): MS (ESI) 553.4 [M+H].sup.+

Example 8: Preparation of Tri-Methylated Ligands 29-32

(27) ##STR00016##

(28) Representative procedure: To a solution of 25 (0.835 g, 1.4 mmol) in THF (5 mL) and MeCN (10 mL) was added Me.sub.2SO.sub.4 (0.48 mL, 5.0 mmol), followed by Na.sub.2CO.sub.3 (0.690 g, 6.5 mmol). The reaction mixture was stirred at room temperature of 18 h. After this time, reaction mixture was filtered and the filter cake was washed with acetonitrile. The solid collected was suspended in DCM, washed with H.sub.2O and saturated NaHCO.sub.3, before being dried over MgSO.sub.4 and reduced in volume to give 29 (70% yield) as a white solid.

(29) .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 10.92 (br s, 2H, phenol), 7.00 (d, 1H, J=2.5 Hz), 6.99 (d, 1H, J=2.5 Hz.), 6.85 (d, 1H, J=2.5 Hz,), 6.84 (d, 1H, J=2.5 Hz,), 3.65 (s, 2H), 3.62 (s, 2H), 3.42 (s, 2H), 3.41 (s, 2H), 2.56 (q, 4H, J=7.0 Hz), 2.40 (s, 2H), 2.37 (s, 2H), 2.33 (s, 3H), 2.33 (s, 2H), 2.31 (s, 2H), 2.25 (s, 3H), 2.23 (s, 3H), 1.25 (2×s, 18H), 1.05 (t, 3H, J=7.0 Hz), 0.86 (s, 6H), 0.83 (s, 6H). MS (ESI) m/z=623.5 [M+H].sup.+.

(30) Data for compounds 30-32:

(31) 30 (84%) (R=Bn): MS (ESI) 685.4 [M+H].sup.+

(32) 31 (67%) (R=allyl): MS (ESI) 635.5 [M+H].sup.+

(33) 32 (73%) (R=p-NO.sub.2—C.sub.6H.sub.5—CH.sub.2): MS (ESI) 730.5 [M+H].sup.+

Example 9: Preparation of Tri-Ethylated and Tribenzylated Ligands 34, 35

(34) ##STR00017##

(35) Representative example: To a solution of 33 (1.501 g, 2.6 mmol) in toluene (5 mL) and MeCN (8 mL) was added Et.sub.2SO.sub.4 (1.2 mL, 9.3 mmol), followed by Na.sub.2CO.sub.3 (1.267 g, 11.9 mmol). The reaction was stirred at 60° C. overnight. The filter cake was collected by filtration and washed with MeCN. The solid collected was suspended in DCM, washed with H.sub.2O and saturated NaHCO.sub.3, before being dried over MgSO.sub.4 and reduced in volume to give 34 (65% yield) as a white solid.

(36) .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm) 10.80 (br s, 2H, phenol), 6.97 (dd, 4H, J=2.5, 11.6 Hz), 6.86 (dd, 4H, J=2.4, 7.4 Hz,), 3.66 (d, 4H, J=7.8 Hz,), 3.50 (s, 2H), 3.46 (s, 2H), 2.53 (m, 6H), 2.39 (d, 4H, J=7.5 Hz.), 2.35 (s, 2H), 2.31 (s, 2H), 2.23 (3H, s), 1.25 (18H, d), 1.05 (6H, td. J=1.5, 7.0 Hz), 1.01 (t, 3H, J=7.0 Hz,), 0.82 (s, 6H), 0.79 (s, 6H). MS (ESI) 651.6 [M+H].sup.+

(37) Data for compound 35 (74%): As per the representative example, except BnBr was used as the alkylating agent and toluene was substituted for THF. MS (ESI) 837.6 [M+H].sup.+

Example 10: Preparation of Di-Ethylated and Di-Benzylated Ligands 38, 39

(38) ##STR00018##

(39) Representative example: 37 (2.000 g, 3 mmol), BnBr (0.93 mL, 8 mmol), and Na.sub.2CO.sub.3 (1.182 g, 11 mmol) were suspended in MeCN (30 mL) and stirred at 40° C. for 2 days. The reaction mixture was filtered, extracted into DCM, washed with NaHCO.sub.3 (×3), dried over MgSO.sub.4, and reduced in volume to yield 39 in 75% yield. MS (ESI) 821.6 [M+H].sup.+

(40) Data for compound 38 (80%): As per representative example except Et.sub.2SO.sub.4 was used as the alkylating agent and the reaction was carried out in THF/MeCN (1:2). MS (ESI) 697.5 [M+H]+.

Example 11: Preparation of Cis-Dimethyl-Dialkylated Ligands 42 and 43

(41) ##STR00019##

(42) Representative procedure: To a solution of 40 (1 g, 1.6 mmol) in THF (3 mL) and MeCN (8 mL) was added Me.sub.2SO.sub.4 (0.34 mL, 3.6 mmol), followed by Na.sub.2CO.sub.3 (0.56 g, 5.3 mmol). The reaction mixture was stirred at room temperature overnight. After this time, the reaction mixture was filtered and the filter cake was washed with acetonitrile. The solid collected was suspended in DCM, washed with H.sub.2O and saturated NaHCO.sub.3, before being dried over MgSO.sub.4 and reduced in volume to give 42 (72% yield) as a white solid. MS (ESI) 637.2 [M+H].sup.+.

(43) Data for compound 43 (84%), MS (ESI) 761.2 [M+H].sup.+.

(44) Attention is directed to all papers and document which are filed concurrently with or previous to this specification in connection with this application and which are open to the public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.

(45) All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, expect combinations where at least some of such features and/or steps are mutually exclusive.

(46) Each feature disclosed in this specification (including any accompanying claims, abstract and drawings) may be replaced by alternative features serving the same, equivalent or similar purpose, unless expressly stated otherwise. Thus, unless expressly stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features.

(47) The invention is not restricted to the details of the foregoing embodiment(s). The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract or drawings), or to any novel one, or any novel combinations, of the steps of any method or process so disclosed.