U.S. patent application number 10/721423 was filed with the patent office on 2005-04-07 for method for expedient synthesis of [18f]-labeled alpha-trifluoromethyl ketones.
Invention is credited to Alauddin, Main M., Conti, Peter S., Hu, Jinbo, Olah, George A., Prakash, G.K. Surya.
Application Number | 20050074398 10/721423 |
Document ID | / |
Family ID | 34316150 |
Filed Date | 2005-04-07 |
United States Patent
Application |
20050074398 |
Kind Code |
A1 |
Prakash, G.K. Surya ; et
al. |
April 7, 2005 |
METHOD FOR EXPEDIENT SYNTHESIS OF [18F]-LABELED
ALPHA-TRIFLUOROMETHYL KETONES
Abstract
The present invention is directed to a convenient method of
synthesizing radiolabeled .alpha.-trifluoromethyl ketones by a
fluorination reaction. The present invention also relates to
imaging agents and markers for identifying cell proliferation, or
viral infection. The markers and imaging agents including the
radiolabeled .alpha.-trifluoromethyl ketones that are prepared by
the present method.
Inventors: |
Prakash, G.K. Surya;
(Hacienda Heights, CA) ; Alauddin, Main M.;
(Alhambra, CA) ; Hu, Jinbo; (Los Angeles, CA)
; Conti, Peter S.; (Pasadena, CA) ; Olah, George
A.; (Beverly Hills, CA) |
Correspondence
Address: |
WINSTON & STRAWN
PATENT DEPARTMENT
1400 L STREET, N.W.
WASHINGTON
DC
20005-3502
US
|
Family ID: |
34316150 |
Appl. No.: |
10/721423 |
Filed: |
November 26, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60429602 |
Nov 27, 2002 |
|
|
|
Current U.S.
Class: |
424/1.11 ;
568/419 |
Current CPC
Class: |
C07C 49/813 20130101;
C07C 45/511 20130101; C07C 45/511 20130101; C07C 49/80 20130101;
C07C 45/511 20130101; C07C 49/80 20130101; C07C 49/813
20130101 |
Class at
Publication: |
424/001.11 ;
568/419 |
International
Class: |
A61K 051/00; C07C
049/173 |
Claims
What is claimed is:
1. A method for the synthesis of [.sup.18F]-labeled
trifluoromethylketones comprising the steps of reacting
[.sup.18F]-F.sub.2 with a silyl ether compound having the general
formula 1 6wherein R refers to an alkyl group having between 1 and
24 carbon atoms or an aryl group having between 6 and 24 carbon
atoms under reaction conditions sufficient to form a
[.sup.18F]-labeled trifluoromethylketone.
2. The method of claim 1, wherein the alkyl or the aryl group
comprises a ring.
3. The method of claim 1, wherein the alkyl group is substituted
with at least one halogen, nitro, or alkoxy group.
4. The method of claim 3, wherein the alkoxy group has one to eight
carbon atoms.
5. The method of claim 3, wherein the substituent does not
participate in the reaction.
6. The method of claim 3, wherein the alkoxy is substituted with at
least one substituents selected from the group consisting of an
alkyl group having between 1 and 8 carbon atoms, a halogen, and an
amino group, or any combination thereof.
7. The method of claim 1, wherein the condition sufficient to form
a [.sup.18F]-labeled trifluoromethylketone include a reaction
temperature of between about -50.degree. C. to about -15.degree.
C.
8. The method of claim 1, wherein the [.sup.18/19F]-F.sub.2 is
prepared by bombardment with [.sup.18O]O.sub.2 in a cyclotron and
mixing with non-radioactive F.sub.2.
9. The method of claim 1, wherein the [.sup.18F]-F.sub.2 mixture is
bubbled into a solution comprising silyl ether compounds for about
5 to 15 minutes.
10. The method of claim 1, wherein the silyl ether is
2,2-difluoroenol silyl ether and further wherein the
2,2-difluroenol silyl ether is prepared by: mixing magnesium,
tetrahydrofuran, and chlorotrimethylsilane to form a reactant
mixture; cooling the mixture to between about -15.degree. C. to
5.degree. C.; adding trifluoroacetophenone to the cooled mixture;
and stirring the mixture for about 0.5 to 1.5 hours to produce the
difluoroenol silyl ether.
11. The method of claim 10, wherein the difluroenol silyl ether is
2,2-difluoro-1-phenyl-1-trimethylsiloxy-ethene.
12. The method of claim 1, which further comprises: dissolving the
silyl ether compound in acetonitrile to form a solution; cooling
the solution to about -50.degree. to about -15.degree. C.;
preparing a mixture of [.sup.18/19F]-F.sub.2 and nitrogen; and
bubbling the mixture of [.sup.18/19F]-F.sub.2 and nitrogen into the
solution for about 5 to 15 minutes to form a reaction mixture.
13. The method of claim 1, wherein the [.sup.18F]-labeled
trifluoromethylketones synthesized have a radiochemical purity
greater than 99%.
14. The method of claim 1, wherein the [.sup.18F]-labeled
trifluoromethylketones that are synthesized have specific
activities between about 15 to 20 GBq/mmol at the end of
synthesis.
15. The method of claim 1, wherein the radiochemical yields of the
[.sup.18F]-labeled trifluoromethylketones are between about 45 to
55%.
16. The method of claim 1, wherein the [.sup.18F]-labeled
trifluoromethylketones synthesized has the following general
formula 2a. 7
17. The method of claim 1, wherein the [.sup.18F]-labeled
trifluoromethylketones synthesized has the following general
formula 2b. 8
18. The method of claim 1, wherein the [.sup.18F]-labeled
trifluoromethylketones synthesized has the following general
formula 2c. 9
19. The method of claim 1, wherein the [.sup.18F]-labeled
trifluoromethylketones synthesized has the following general
formula 2d. 10
20. An imaging agent comprising the [.sup.18F]-labeled
trifluoromethyl ketone of claim 1.
21. The imaging agent of claim 20, having a radiochemical purity of
about 99% for use in positron emission tomography.
22. A marker for detecting cell proliferation or viral infections
comprising the [.sup.18F]-labeled trifluoromethyl ketone of claim
1.
23. The marker of claim 22, having a radiochemical purity of about
99%.
Description
[0001] This application claims the benefit of provisional
application No. 60/429,602 filed on Nov. 27, 2002, the content of
which is incorporated herein by reference thereto.
FIELD OF THE INVENTION
[0002] This invention relates generally to a method for the
synthesis of [.sup.18F]-labeled trifluoromethyl ketones. The
invention more particularly relates to a method for the synthesis
of [.sup.18F]-labeled trifluoromethyl ketones by [.sup.18F]-labeled
fluorination of 2,2-difluoroenol silyl ethers.
BACKGROUND ART
[0003] There has been increasing interest in biologically active
compounds known as .alpha.-Trifluoromethyl ketones (TFMKs). It has
been found that many TFMK compounds have unique properties due to
its .alpha.-trifluoromethyl ketone functionality. In example,
TFMK's have been found to be potential hydrolytic enzyme
inhibitors. In particular, TFMK's have been found to be inhibitors
of protease
[0004] Kawase has reported that the trifluoromethyl group in the
.alpha.-position of the carbonyl of the TFMK facilitates the
formation of tetrahedral hemiketals or hydrates with water. The
hydrated molecule interacts with protease, and inhibits the enzyme
activity Kawase, M. J. Syn. Org. Chem. Jpn. 2001, 59, 755, which is
incorporated herein by reference thereto.
[0005] It has also been demonstrated that TFMK's are cytotoxic
agents against human oral tumor cell lines, such as human squamous
carcinoma cells HSC-2 and salivary gland tumor cells HSG. Kawase,
M.; Sakagami, H.; Kusama, K.; Motohashi, N.; Saito, S. Bioorg. Med.
Chem. Lett. 1999, 9, 3113, incorporated herein by reference.
[0006] Traditionally, TFMKs are prepared from inexpensive
trifluoroacetic acid derivatives. See, Creary, X. J. Org. Chem.
1987, 52, 5026; Keumi, T.; Shimada M.; Takahashi, M.; Kitajama, H.
Chem. Lett. 1990, 783. Both of which are incorporated herein by
reference. Additionally, the present inventors have recently
reported the direct preparation of TFMKs from carboxylic esters
with (trifluoromethyl)trimethylsilane (TMS-CF.sub.3). See,
Wiedemann, J.; Heiner, T.; Mloston, G.; Prakash, G. K. S.; Olah, G.
A. Angew. Chem. Int. Ed. 1998, 37, 820, which is incorporated
herein by reference thereto.
[0007] Our reported method has been extended by others with CsF
catalyzed trifluoromethylation of esters. Most recently we have
developed a simple and convenient general synthesis of
.alpha.-trifluoromethyl ketones by fluorination using elemental
fluorine F.sub.2 (Prakash, G. K. S.; Hu, J.; Alauddin, M. M.;
Conti, P. S.; Olah, G. A. J. Fluorine Chem. 2003, 121, 239,
incorporated herein by reference thereto.
[0008] There is a need for an expedient process for radioactive
labeling of TFMKs. However, the current synthesis methods are not
suitable for the synthesis of [.sup.18F]-labeled TFMKs since it is
difficult to prepare [.sup.18F]-labeled trifluoroacetic acid
derivatives or TMS-CF.sub.3 due to the short half-life of .sup.18F
(t.sub.1/2=110 min).
SUMMARY OF THE INVENTION
[0009] The aforementioned need has been satisfied by the present
invention which discloses the first synthesis of [.sup.18F]-labeled
TFMKs by fluorination of 2,2-difluoro silyl enol ethers with
radioactive fluorine [.sup.18F]-F.sub.2.
[0010] The present invention is preferably directed to an expedient
method for synthesizing [.sup.18F]-labeled trifluoromethyl ketones
from the fluorination of silyl enol ethers. Thus, it has now been
discovered that TFMK compounds have the potential for radiolabeling
with fluorine-18. Advantageously, the radiolabeled compounds can be
used as markers for identification of cell proliferation, markers
for identification of viral infection, or for PET imaging.
[0011] In accordance with the present invention, a method of
synthesizing [.sup.18F]-labeled .alpha.-trifluoromethyl ketones is
provided by reacting [.sup.18F]-F.sub.2 under sufficient reaction
conditions with a compound having the general formula 1, wherein R
refers to an alkyl having 1 to 24 carbons or an aryl group having 6
to 24 carbon atoms. 1
[0012] In one aspect of the invention, the alkyl or aryl group
includes a ring. In another aspect of the invention, the alkyl
group is substituted with at least one halogen, nitro group, or
alkoxy group. In yet another aspect of the invention, the alkoxy
group has one to eight carbon atoms. In another aspect of the
invention, the alkoxy group is substituted with at least one
substituent including an alkyl group having 1 to 8 carbon atoms, a
halogen, an amino group, or any combination thereof.
Advantageously, the substituent does not participate in the
reaction.
[0013] In a preferred embodiment, the method further comprises
dissolving the silyl ether compound in acetonitrile to form a
solution; cooling the solution to about -50.degree. to about
-15.degree. C.; preparing a mixture of [.sup.18/19F]-F.sub.2 and
nitrogen; and bubbling the mixture of [.sup.18/19F]-F.sub.2 and
nitrogen into the solution for about 5 to 15 minutes to form a
reaction mixture. [.sup.18/19F]-F.sub.2 can be prepared by
bombardment with [.sup.18O]O.sub.2 in a cyclotron and mixing with
non-radioactive F.sub.2.
[0014] The silyl ether is preferably 2,2-difluoroenol silyl ether
and may be prepared by mixing magnesium, tetrahydrofuran, and
chlorotrimethylsilane to form a reactant mixture; cooling the
mixture to between about -15.degree. C. to 5.degree. C.; adding
trifluoroacetophenone to the cooled mixture; and stirring the
mixture for about 0.5 to 1.5 hours to produce the difluoroenol
silyl ether.
[0015] The [.sup.18F]-labeled trifluoromethylketones that are
synthesized generally have a radiochemical purity greater than 99%
and specific activities between about 15 to 20 GBq/mmol at the end
of synthesis. They are produced at yields of between about 45 to
55%.
[0016] Several [.sup.18F]-labeled .alpha.-trifluoromethyl ketones
have been synthesized by the present method. Compounds 2a.about.2d
shown below have been successfully synthesized in accordance with
the method of the invention. 2
[0017] Also in accordance with the present invention is an imaging
agent comprising the [.sup.18F]-labeled .alpha.-trifluoromethyl
ketones synthesized from the method of the invention. In one aspect
of the invention, the imaging agent is useful for positron emission
tomography (PET) imaging.
[0018] The invention also relates to a marker that can be used for
detecting cell proliferation or for detecting viral infection. The
marker of the invention comprises the [.sup.18F]-labeled
.alpha.-trifluoromethyl ketones synthesized according to the method
of the invention and preferably includes those having a
radiochemical purity of about 99%.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] The invention is better understood by reference to the
drawings figures, wherein:
[0020] FIG. 1 illustrates a chromatogram of purified labeled
trifluoromethyl ketones;
[0021] FIG. 2 illustrates a HPLC chromatogram of a labeled
trifluoromethyl ketone; and
[0022] FIG. 3 illustrates a radio TLC of a labeled trifluoromethyl
ketone of the invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0023] The present invention relates to a general and expedient
method for the preparation of [.sup.18F]-labeled trifluoromethyl
ketones. In accordance with the method of the invention, a
fluorination reaction between [.sup.18F]-labeled F.sub.2 and
2,2-difluoroenol silyl ether 1 produces [.sup.18F]-labeled
trifluoromethyl ketones 2 as shown below. The R group of
2,2-difluoroenol silyl ethers 1 preferably include an alkyl or aryl
group. 3
[0024] As noted above, radiolabeled trifluoromethyl ketone
compounds 2a.about.2d, shown below, have been successfully
synthesized in accordance with the method of the invention. 4
[0025] In accordance with one aspect of the invention, difluoroenol
silyl ether compounds 2a-d, shown above, can be prepared from a
mixture of compound 1, which is shown below, TMSCl, and Mg.sup.11
in anhydrous THF or DMF. The mixture is stirred for about 15 to 30
minutes, preferably 20 minutes, at a temperature between about
-10.degree. C. to about 5.degree. C., and preferably at 0.degree.
C. 5
[0026] Difluoroenol silyl ether is obtained after filtration. The R
of compound 1 includes but is not limited to Ph,
4-MeOC.sub.6H.sub.4, 4-CF.sub.3C.sub.6H.sub.4, 4-ClC.sub.6H.sub.4,
2-furyl, 2-thienyl, C.sub.6H.sub.13, or Cy. The method is disclosed
in Amii, H.; Kobayashi, T.; Hatamoto, Y.; Uneyama, K. Chem. Comm.
1999, 1323, the entire content of which is expressly incorporated
herein by reference. Preferably, tetrabutylammonium fluoride with
D.sub.2O is added to the THF or DMF for the preparation of the
difluoro enol silyl ethers, as disclosed in Prakash, G. K. S.; Hu,
J.; Olah, G. A. J. Fluorine Chem. 2001, 112, 357), the entire
content of which is expressly incorporated herein by reference. It
has been found that silyl enol ethers produced by this preferred
method have greater stability for hydrolysis compared to other
silyl enol ethers. Although the stability of the silyl ethers
enable simple handling without decomposition, freshly prepared
compounds were used for radiolabeling experiments.
[0027] The goal compounds, [.sup.18F]-labeled trifluoromethyl
ketones, were prepared by fluorination of 2,2-difluoroenol silyl
ethers 1 with [.sup.18/19F]-F.sub.2. The [.sup.18/19F]-F.sub.2 was
produced in the cyclotron by bombardment of [.sup.18O]O.sub.2
followed by mixing the target gas with non-radioactive F.sub.2. The
mixture of [.sup.18/19F]-F.sub.2 was bubbled into the solution of
the substrates 2,2-difluoroenol silyl ethers at low temperature for
efficient trapping of activity. Trapping of activity was quite
efficient for 2-3 mg (.about.10 .mu.mol) of the precursors. Since
the syntheses were carrier added, a sufficient amount of F.sub.2
was present, resulting in absence of any unreacted starting
material in the reaction mixture.
[0028] Reactions of 2,2-difluoro-1-aryl-1-trimethylsiloxyethenes
with [.sup.18F]-F.sub.2 at low temperature produced
[.sup.18F]-labeled .alpha.-trifluoromethyl ketones. The
radiolabeled products were isolated by purification with column
chromatography in 22-28% yields, and were decay corrected (d. c.)
in 3 runs per compound. The radiochemical purity was greater than
99%, with specific activities of 15-20 GBq/mmol at the end of
synthesis (EOS). The synthesis time was 35-40 min from the end of
bombardment (EOB). This one step simple method is highly useful for
the radiochemical synthesis of potential biologically active
[.sup.18F]-labeled .alpha.-trifluoromethyl ketones for PET.
[0029] Trifluoromethyl ketones can form hydrated products in the
presence of water which can cause difficulties during HPLC
purification using MeCN/H2O solvent system. However, compound 2c
was found to be relatively stable in aqueous system during HPLC
purification and pure product was isolated in good yield (54%).
Referring to FIG. 1, purification of 2c is represented by a
chromatogram. The desired product was eluted in 13 to 15 minutes,
which could then be isolated in pure form.
[0030] Referring to FIG. 2, analysis of pure product 2c by HPLC
showed two radioactive and three UV active peaks. The UV peaks
compared to the hydrated product (a), partial hydrated product (b),
and trifluoromethyl ketone (c). Only two radioactive peaks were
observed corresponding to the hydrated product (a) and the ketone
(c) and the ratio between the ketone and hydrated product was
approximately 10:90.
[0031] In order to verify the reactivity of the trifluoromethyl
ketones with water a pure 18F-labeled product collected by HPLC in
CH3CN/water was heated for a short time of 1 to 2 minutes. Analysis
of the product by either HPLC and TLC demonstrated 100% hydrated
compound.
[0032] Although the other radiolabeled ketones could not be
purified by HPLC since the products readily converted to the
hydrated compound and eluted much earlier than the desired ketones,
the radiolabeled ketones were in fact purified by chromatography on
a small silica gel column and eluted with the organic solvent
mixture, ethyl acetate and hexane (10:90). Fractions (0.5 mL) of
the product were collected and radioactivity was measured on a dose
calibrator. The products were eluted in the earlier fractions with
an r.f. value of approximately 0.8. Pure fractions after combining
were analyzed by TLC and found to be co-eluted with authentic
sample checked by both UV and radioactivity.
[0033] Referring to FIG. 3 illustrated is a representative radio
TLC for the compound 2b where a is the point of application and b
is the solvent front.
[0034] In non-radioactive preparations excess F.sub.2 was used and
the chemical yields were greater than 80%. However, in the
radiochemical syntheses only 50% of the activity is incorporated
into the substrate resulting lower yields in the range of 22-28%
(d. c.) from the EOB. The radiochemical purity was greater than 99%
with specific activities of 15-20 GBq/mmol. The synthesis time was
35-40 min from the EOB. In a representative preparation of 2b, 30
mCi of labeled product was obtained starting from 120 mCi of
trapped activity [.sup.18F]-F.sub.2.
[0035] The present invention will be further understood by the
examples set forth below, which are provided for purpose of
illustration and not limitation.
EXAMPLES
[0036] In the following examples, all reagents and solvents were
purchased from Aldrich Chemical Co. (Milwaukee, Wis.), and used
without further purification, unless otherwise specified.
Dichloromethane (CH.sub.2Cl.sub.2) and fluorotrichloromethane
(CFCl.sub.3) were distilled over calcium hydride (CaH.sub.2), and
acetonitrile (MeCN) was distilled over phosphorus pentoxide
(P.sub.2O.sub.5) prior to use.
[0037] .sup.1H, .sup.13C and .sup.19F NMR spectra were recorded on
a Bruker 500 or 360 MHz NMR spectrometer in chloroform-D using
tetramethysilane and trichlorofluoromethane as internal standards,
respectively. Mass spectra were obtained on a Hewlett Packard 5890
Gas Chromatograph equipped with a Hewlett Packard 5971 Mass
Selective Detector.
[0038] Column chromatography was performed using silica gel (60-200
mesh) and ethyl acetate/hexane (10:90) as eluent. Thin layer
chromatography (TLC) was performed on a silica gel plate
(1.times.10 cm) and developed in the appropriate solvent system
ethyl acetate/hexane (10:90). Radioactivity on the developed TLC
plate was scanned on a TLC scanner (Bioscan Inc., Washington D.C.)
to obtain a radiochromatogram.
Example 1
Preparation of 2,2-difluoroenol silyl ethers (1a-d):
[0039] 2,2-difluoroenol silyl ethers (1a-d) were prepared from
their respective ketones by magnesium metal mediated reductive
defluorination.
[0040] To a dry 250 ml Schlenk flask the following compounds were
added: magnesium turnings (1.45 g, 60 mmol), dry tetrahydrofuran
(THF, 120 ml) and chlorotrimethylsilane (TMSCl, 13.0 g, 120 mmol).
The flask was cooled to 0.degree. C. 2,2,2-Trifluoroacetophenone
(non-radioactive) 2a (5.2 g, 30 mmol) was added drop wise into the
flask with a syringe. After addition of the
2,2,2-Trifluoroacetophenone, the reaction mixture was stirred for
an additional 1 h. The completion of the reaction was monitored by
.sup.19F NMR spectroscopy. The solvent and excess TMSCl were
removed under vacuum, and hexane (50 ml) was added to the residue.
Solid impurities were removed by suction filtration, and the
solvent was evaporated to yield
2,2-difluoro-1-phenyl-1-trimethylsiloxyethene 1a (6.8 g, 99%
yield).
[0041] The product was characterized by .sup.1H and .sup.19F NMR
spectroscopy and mass spectrometry. Spectroscopic data were
consistent with the literature for
2,2-difluoro-1-phenyl-1-trimethylsiloxyethene. .sup.1H NMR:
.delta.=0.60 (s, 9H), 7.38 (t, J=7.5 Hz, 1H), 7.47 (t, J=7.5 Hz,
2H), 7.61 (d, J=8.8 Hz, 2H); .sup.13C NMR: .delta.=0.02, 114.09 (q,
.sup.2J.sub.C-F=18.0 Hz), 125.84, 127.72, 128.25, 132.71, 154.87
(t, .sup.1J.sub.C-F=286.8 Hz); .sup.19F NMR: .delta.=-100.39 (d,
.sup.2J.sub.F-F=68.0 Hz), -112.16 (d, .sup.2J.sub.F-F=68.0 Hz).
MS(70 eV, m/z): 228 (M.sup.+), 213, 197, 186 (, 177, 131, 115, 105,
89, 81, 77, 73.
[0042] Compounds having the formulae 1b-d were also characterized
by .sup.1H and .sup.19F NMR spectroscopy and mass spectrometry.
Example 2
Preparation of [.sup.18F]-.alpha.-trifluoromethyl ketones
(2a-d)
[0043] Experiments were performed under similar conditions as
described in Example 1.
[0044] 2,2-Difluoro-1-phenyl-1-trimethylsiloxy-ethene 1a (2 .mu.L,
11 .mu.mol) was dissolved in dry acetonitrile (0.5 ml) and cooled
to -45.degree. C. A mixture of fluorine [.sup.18/19F]-F.sub.2 and
nitrogen (F.sub.2/N.sub.2 (v/v=1/8)) was bubbled into the solution
for 10 min. Radioactivity was measured on a dose calibrator
(Capintec Inc., Ramsey, N.J.), and the reaction mixture was warmed
to room temperature.
[0045] The crude product was purified by chromatography on a silica
gel column using 10% ethyl acetate in hexane as eluent. Fractions
(0.5 mL) were collected and radioactivity was measured. Fractions
containing radioactivity were combined and solvent was evaporated
to obtain the pure product. The product was analyzed by TLC with an
authentic compound as a reference. The TLC plate after development
was scanned for radioactivity on a TLC scanner, checked under UV
lamp and compared with the reference compound. Analysis of the TLC
plate showed the material to be 99% pure. Radiochemical yield was
22% (d. c).
[0046] Compounds 2b-d were produced in similar radiochemical yields
in the range of 22-28% (d. c).
[0047] It is understood that the foregoing detailed description and
accompanying examples are merely illustrative and are not to be
taken as limitations upon the scope of the invention, which is
defined solely by the appended claims and their equivalents.
Various changes and modifications to the disclosed embodiments will
be apparent to those skilled in the art. Such changes and
modifications, including without limitation those relating to the
chemical structures, substituents, derivatives, intermediates,
syntheses, and or methods of use of the invention, can be made
without departing from the spirit and scope thereof.
* * * * *