U.S. patent application number 12/513112 was filed with the patent office on 2010-08-26 for [f-18]-labeled l-glutamic acid, [f-18]-labeled l-glutamine, derivatives thereof and use thereof and processes for their preparation.
This patent application is currently assigned to BAYER SCHERING PHARMA AKTIENGESELLSCHAFT. Invention is credited to Yuri Belokon, Mathias Berndt, Ludger Dinkelborg, Matthias Friebe, Keith Graham, Nikolaevna Raisa Krasikowa, Fedorovna Olga Kuznetsova, Lutz Lehmann.
Application Number | 20100217011 12/513112 |
Document ID | / |
Family ID | 38896929 |
Filed Date | 2010-08-26 |
United States Patent
Application |
20100217011 |
Kind Code |
A1 |
Dinkelborg; Ludger ; et
al. |
August 26, 2010 |
[F-18]-LABELED L-GLUTAMIC ACID, [F-18]-LABELED L-GLUTAMINE,
DERIVATIVES THEREOF AND USE THEREOF AND PROCESSES FOR THEIR
PREPARATION
Abstract
The compounds and the synthesis of [F-18]-labeled L-glutamic
acid, [F-18]-labeled L-glutamate, their derivatives as set forth in
formula (I) and their uses are described.
Inventors: |
Dinkelborg; Ludger; (Berlin,
DE) ; Friebe; Matthias; (Berlin, DE) ;
Krasikowa; Nikolaevna Raisa; (St. Petersburg, RU) ;
Belokon; Yuri; (Moscow, RU) ; Kuznetsova; Fedorovna
Olga; (St. Petersburg, RU) ; Graham; Keith;
(Berlin, DE) ; Lehmann; Lutz; (Wuppertal, DE)
; Berndt; Mathias; (Berlin, DE) |
Correspondence
Address: |
MILLEN, WHITE, ZELANO & BRANIGAN, P.C.
2200 CLARENDON BLVD., SUITE 1400
ARLINGTON
VA
22201
US
|
Assignee: |
BAYER SCHERING PHARMA
AKTIENGESELLSCHAFT
Berlin
DE
INEOS RAS
Moscow
RU
IHB RAS
ST. PETERSBURG
RU
|
Family ID: |
38896929 |
Appl. No.: |
12/513112 |
Filed: |
October 30, 2007 |
PCT Filed: |
October 30, 2007 |
PCT NO: |
PCT/EP2007/009518 |
371 Date: |
December 11, 2009 |
Current U.S.
Class: |
548/403 ;
548/530; 548/537; 562/568; 562/571 |
Current CPC
Class: |
C07B 59/001 20130101;
C07B 2200/05 20130101; C07F 15/045 20130101; C07C 309/73 20130101;
C07C 271/22 20130101; C07C 251/24 20130101; C07D 207/28 20130101;
C07C 227/16 20130101; C07D 207/26 20130101; C07C 229/24 20130101;
A61K 51/0402 20130101; A61P 43/00 20180101; C07C 309/66 20130101;
C07D 207/16 20130101 |
Class at
Publication: |
548/403 ;
548/530; 548/537; 562/568; 562/571 |
International
Class: |
C07F 15/04 20060101
C07F015/04; C07D 207/24 20060101 C07D207/24; C07D 207/16 20060101
C07D207/16; C07C 229/24 20060101 C07C229/24; C07C 227/16 20060101
C07C227/16 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 1, 2006 |
RU |
2006138584 |
Nov 18, 2006 |
EP |
06090211.1 |
Claims
1) A compound of the general formula I ##STR00034## wherein A
represents a) hydroxyl, b) branched or unbranched C.sub.1-C.sub.5
alkoxy, c) branched or unbranched hydroxy C.sub.1-C.sub.5 alkoxy,
d) branched or unbranched O--C.sub.1-C.sub.5
alkyl-(O--C.sub.1-C.sub.4 alkyl).sub.n-O--C.sub.1-C.sub.4 alkyl, e)
N(C.sub.1-C.sub.5 alkyl).sub.2, f) NH.sub.2, g) N(H)-L, h) O-L or
i) O--Z, G represents a) hydroxyl, b) O--Z b) branched or
unbranched O--C.sub.1-C.sub.5 alkyl, c) branched or unbranched
O--C.sub.2-C.sub.5 alkenyl, d) branched or unbranched
O--C.sub.1-C.sub.5 alkyl-(O--C.sub.1-C.sub.4
alkyl).sub.n-O--C.sub.1-C.sub.4 alkyl or e) branched or unbranched
O--C.sub.2-C.sub.5 alkynyl, R.sup.1 and R.sup.2 represent a)
hydrogen, b) .sup.18F, c) branched or unbranched
.sup.18F--C.sub.1-C.sub.5 alkoxy, d) branched or unbranched
.sup.18F--C.sub.1-C.sub.5 alkyl, e) branched or unbranched
.sup.18F-hydroxy-C.sub.1-C.sub.5 alkyl, f) branched or unbranched
.sup.18F-C.sub.2-C.sub.5 alkenyl, or g) branched or unbranched
.sup.18F-C.sub.2-C.sub.5 alkynyl, h) hydroxyl, i) branched or
unbranched C.sub.1-C.sub.5 alkyl or j) branched or unbranched
C.sub.1-C.sub.5 alkoxy, with the proviso that one of the
substituents R.sup.1 or R.sup.2 contains exactly one .sup.18F
isotope and the other substituent in each case contains no .sup.18F
isotope, L represents a) branched or unbranched C.sub.1-C.sub.5
alkyl, b) branched or unbranched C.sub.2-C.sub.5 alkenyl, c)
branched or unbranched C.sub.1-C.sub.5 alkyl-(O--C.sub.1-C.sub.4
alkyl).sub.n-O--C.sub.1-C.sub.4 alkyl or d) branched or unbranched
C.sub.2-C.sub.5 alkynyl, and Z represents a metal cation
equivalent, where n is =0, 1, 2 or 3 and diastereomers and
enantiomers.
2) A compound as claimed in claim 1, characterized in that A
represents OH, methoxy or NH.sub.2.
3) A compound as claimed in claim 1, characterized in that A
represents OH.
4) A compound as claimed in claim 1, characterized in that A
represents NH.sub.2.
5) A compound as claimed in claim 1, characterized in that R.sup.1
and R.sup.2 are selected from the group consisting of hydrogen,
.sup.18F, .sup.18F-methoxy, .sup.18F-ethoxy, .sup.18F-propoxy,
.sup.18F-methyl, .sup.18F-ethyl and .sup.18F-propyl, with the
proviso that one of the substituents R.sup.1 or R.sup.2 contains
exactly one .sup.18F isotope and the other substituent in each case
is hydrogen.
6) A compound as claimed in claim 1, characterized in that R.sup.1
is selected from the group consisting of hydroxyl, CH.sub.3,
C.sub.2H.sub.5 and C.sub.3H.sub.7, and R.sup.2 represents
.sup.18F.
7) A compound as claimed in claim 1, characterized in that R.sup.2
is selected from the group consisting of hydroxyl, CH.sub.3,
C.sub.2H.sub.5 and C.sub.3H.sub.7, and R.sup.1 represents
.sup.18F.
8) A compound as claimed in claim 1, characterized in that R.sup.1
represents .sup.18F and R.sup.2 represents hydrogen.
9) A compound as claimed in claim 1, characterized in that R.sup.2
represents .sup.18F and R.sup.1 represents hydrogen.
10) A compound as claimed in claim 1, characterized in that G is
selected from the group consisting of OH, methoxy or ethoxy.
11) A compound as claimed in claim 1, characterized in that Z is
selected from the group consisting of Mg.sup.2+, Ca.sup.2+,
Na.sup.+ and K.sup.+.
12) A compound as claimed in claim 1, characterized in that A is
Ni.sup.2+.
13) A compound as claimed in claim 1 selected from the group
consisting of compounds having the formula: ##STR00035##
##STR00036##
14) A compound of the general formula (II): ##STR00037## wherein A'
represents a) hydroxyl, b) branched or unbranched C.sub.1-C.sub.5
alkoxy, c) branched or unbranched hydroxy C.sub.1-C.sub.5 alkoxy,
d) branched or unbranched O--C.sub.1-C.sub.5
alkyl-(O--C.sub.1-C.sub.4 alkyl).sub.n-O--C.sub.1-C.sub.4 alkyl, e)
N(C.sub.1-C.sub.5 alkyl).sub.2, f) NH.sub.2, g) N(H)--U, h)
N(H)-L', or i) O-L, G' represents a) hydroxyl, b) O--Z', c)
branched or unbranched O--C.sub.1-C.sub.5 alkyl, d) branched or
unbranched O--C.sub.2-C.sub.5 alkenyl, e) branched or unbranched
O--C.sub.1-C.sub.5 alkyl-(O--C.sub.1-C.sub.4
alkyl).sub.n-O--C.sub.1-C.sub.4 alkyl or f) branched or unbranched
O--C.sub.2-C.sub.5 alkynyl, R.sup.1 and R.sup.2 represent a)
hydrogen, b) .sup.18F, c) branched or unbranched
.sup.18F--C.sub.1-C.sub.5 alkoxy, d) branched or unbranched
.sup.18F--C.sub.1-C.sub.5 alkyl, e) branched or unbranched
.sup.18F-hydroxy-C.sub.1-C.sub.5 hydroxyalkyl, f) branched or
unbranched .sup.18F-C.sub.2-C.sub.5 alkenyl, g) branched or
unbranched .sup.18F-C.sub.2-C.sub.5 alkynyl, h) hydroxyl, i)
branched or unbranched C.sub.1-C.sub.5 alkyl, or j) branched or
unbranched C.sub.1-C.sub.5 alkoxy, with the proviso that one of the
substituents R.sup.1 or R.sup.2 contains exactly one .sup.18F
isotope and the other substituent in each case contains no .sup.18F
isotope, Q represents a) N(H)-tert-butoxycarbonyl, b)
N(H)-allyloxycarbonyl, c) N(H)-benzyloxycarbonyl, d)
N(H)-ethoxycarbonyl, e) N(H)-methoxycarbonyl, f)
N(H)-propoxycarbonyl, e) N(H)-2,2,2-trichloroethoxycarbonyl, f)
N(H)-1,1-dimethylpropynyl, g) N(H)-1-methyl-1-phenylethoxycarbonyl,
h) N(H)-1-methyl-1-(4-biphenylyl)ethoxycarbonyl, i)
N(H)-cyclobutylcarbonyl, j) N(H)-1-methylcyclobutylcarbonyl, k)
N(H)-vinylcarbonyl, l) N(H)-allylcarbonyl, m)
N(H)-adamantylcarbonyl, n) N(H)-diphenylmethylcarbonyl, o)
N(H)-cinnamylcarbonyl, p) N(H)-formyl, q) N(H)-benzoyl, r)
N(H)-trityl, s) N(H)-p-methoxyphenyldiphenylmethyl, t)
N(H)-di(p-methoxyphenyl)phenylmethyl, ##STR00038## v)
N-(tert-butoxycarbonyl).sub.2, L' represents a) branched or
unbranched C.sub.1-C.sub.5 alkyl, b) branched or unbranched
C.sub.2-C.sub.5 alkenyl, c) branched or unbranched C.sub.1-C.sub.5
alkyl-(O--C.sub.1-C.sub.4 alkyl).sub.n-O--C.sub.1-C.sub.4 alkyl, or
d) branched or unbranched C.sub.2-C.sub.5 alkynyl, U represents a)
tert-butoxycarbonyl, b) allyloxycarbonyl, c) benzyloxycarbonyl, d)
ethoxycarbonyl, e) methoxycarbonyl, or f) propoxycarbonyl, X' and
X'' independently of one another represent a) branched or
unbranched C.sub.1-C.sub.5 alkyl, b) substituted or unsubstituted
aryl or c) aralkyl, and Z' represents a metal cation equivalent,
where n is =0, 1, 2 or 3 and diastereomers and enantiomers.
15) A compound as claimed in claim 14, characterized in that A'
represents OH, branched or unbranched C.sub.1-C.sub.5 alkoxy,
--NH-tert-butoxycarbonyl or NH.sub.2.
16) A compound as claimed in claim 14, characterized in that A'
represents ethoxy.
17) A compound as claimed in claim 14, characterized in that A'
represents NH.sub.2.
18) A compound as claimed in claim 14, characterized in that
R.sup.1 and R.sup.2 are selected from the group consisting of
hydrogen, .sup.18F, .sup.18F-methoxy, .sup.18F-ethoxy,
.sup.18F-propoxy, .sup.18F-methyl, .sup.18F-ethyl and
.sup.18F-propyl, with the proviso that one of the substituents
R.sup.1 or R.sup.2 contains exactly one .sup.18F isotope and the
other substituent in each case is hydrogen.
19) A compound as claimed in claim 14, characterized in that
R.sup.1 is selected from the group consisting of hydroxyl,
CH.sub.3, C.sub.2H.sub.5 and C.sub.3H.sub.7, and R.sup.2 represents
.sup.18F.
20) A compound as claimed in claim 14, characterized in that
R.sup.2 is selected from the group consisting of hydroxyl,
CH.sub.3, C.sub.2H.sub.5 and C.sub.3H.sub.7, and R.sup.1 represents
.sup.18F.
21) A compound as claimed in claim 14, characterized in that
R.sup.1 represents .sup.18F and R.sup.2 represents hydrogen.
22) A compound as claimed in claim 14, characterized in that
R.sup.2 represents .sup.18F and R.sup.1 represents hydrogen.
23) A compound as claimed in claim 14, characterized in that G' is
selected from the group consisting of OH, ethoxy, methoxy and
OZ'.
24) A compound as claimed in claim 14, characterized in that G'
represents ethoxy.
25) A compound as claimed in claim 14, characterized in that Z' is
selected from the group consisting of Na.sup.+, K.sup.+, Ca.sup.2+
and Mg.sup.2+.
26) A compound as claimed in claim 14, characterized in that Z' is
Ni.sup.2+.
27) A compound as claimed in claim 14, characterized in that Q is
selected from the group consisting of N(H)-tert-butoxycarbonyl,
N(H)-benzyloxycarbonyl and ##STR00039## wherein X and X'
independently of one another represent a) branched or unbranched
C.sub.1-C.sub.5 alkyl, b) substituted or unsubstituted aryl or c)
aralkyl.
28) A compound as claimed in claim 14, characterized in that Q
represents N(H)-tert-butoxycarbonyl.
29) A compound as claimed in claim 14, characterized in that Q
represents ##STR00040##
30) A compound as claimed in claim 14 selected from the group
consisting of compounds having the formula: ##STR00041##
31) A process for the preparation of compounds of the general
formula (I) as claimed in claim 1 by reacting a precursor compound
of the compound as set forth in formula (II) ##STR00042## wherein
A' represents a) hydroxyl, b) branched or unbranched
C.sub.1-C.sub.5 alkoxy, c) branched or unbranched hydroxy
C.sub.1-C.sub.5 alkoxy, d) branched or unbranched
O--C.sub.1-C.sub.5 alkyl-(O--C.sub.1-C.sub.4
alkyl).sub.n-C.sub.1-C.sub.4 alkyl, e) N(C.sub.1-C.sub.5
alkyl).sub.2. f) NH.sub.2, g) N(H)--U, h) N(H)-L', or i) O-L', G'
represents a) hydroxyl, b) O--Z', c) branched or unbranched
O--C.sub.1-C.sub.5 alkyl, d) branched or unbranched
O--C.sub.2-C.sub.5 alkenyl, e) branched or unbranched
O--C.sub.1-C.sub.5 alkyl-(O--C.sub.1-C.sub.4
alkyl).sub.n-C.sub.1-C.sub.4 alkyl, or f) branched or unbranched
O--C.sub.2-C.sub.5 alkynyl, R.sup.1 and R.sup.2 represent a)
hydrogen, k) .sup.18F, l) branched or unbranched
.sup.18F--C.sub.1-C.sub.5 alkoxy, m) branched or unbranched
.sup.18F--C.sub.1-C.sub.5 alkyl, n) branched or unbranched
.sup.18F--C.sub.1-C.sub.5-hydroxyalkyl, o) branched or unbranched
.sup.18F--C.sub.2-C.sub.5 alkenyl, p) branched or unbranched
.sup.18F--C.sub.2-C.sub.5 alkynyl, q) hydroxyl, r) branched or
unbranched C.sub.1-C.sub.5 alkyl, or s) branched or unbranched
C.sub.1-C.sub.5 alkoxy, with the proviso that exactly one of the
substituents R.sup.1 or R.sup.2 contains exactly one .sup.18F
isotope and the other substituent in each case contains no .sup.18F
isotope, Q represents a) N(H)-tert-butoxycarbonyl, b)
N(H)-allyloxycarbonyl, c) N(H)-benzyloxycarbonyl, d)
N(H)-ethoxycarbonyl, e) N(H)-methoxycarbonyl, f)
N(H)-propoxycarbonyl, e) N(H)-2,2,2-trichloroethoxycarbonyl, f)
N(H)-1,1-dimethylpropynyl, g) N(H)-1-methyl-1-phenylethoxycarbonyl,
h) N(H)-1-methyl-1-(4-biphenylyl)ethoxycarbonyl, i)
N(H)-cyclobutylcarbonyl, j) N(H)-1-methylcyclobutylcarbonyl, k)
N(H)-vinylcarbonyl, l) N(H)-allylcarbonyl, m)
N(H)-adamantylcarbonyl, n) N(H)-diphenylmethylcarbonyl, o)
N(H)-cinnamylcarbonyl, p) N(H)-formyl, q) N(H)-benzoyl, r)
N(H)-trityl, s) N(H)-p-methoxyphenyldiphenylmethyl, t)
N(H)-di(p-methoxyphenyl)phenylmethyl, ##STR00043## v)
N-(tert-butoxycarbonyl).sub.2. L' represents a) branched or
unbranched C.sub.1-C.sub.5 alkyl, b) branched or unbranched
C.sub.2-C.sub.5 alkenyl, c) branched or unbranched C.sub.1-C.sub.5
alkyl-(O--C.sub.1-C.sub.4 alkyl).sub.n-C.sub.1-C.sub.4 alkyl, or d)
branched or unbranched C.sub.2-C.sub.5 alkynyl, U represents a)
tert-butoxycarbonyl, b) allyloxycarbonyl, c) benzyloxycarbonyl, d)
ethoxycarbonyl, e) methoxycarbonyl or f) propoxycarbonyl, X' and
X'' independently of one another represent a) branched or
unbranched C.sub.1-C.sub.5 alkyl, b) substituted or unsubstituted
aryl or c) aralkyl, and Z' represents a metal cation equivalent,
where n is =0, 1, 2 or 3 and diastereomers and enantiomers and F-18
fluoride.
32) A process for the preparation of compounds of the general
formula (II) as claimed in claim 14 by reacting a precursor
compound of the compound as set forth in formula (III) ##STR00044##
wherein A'' represents a) hydroxyl, b) branched or unbranched
C.sub.1-C.sub.5 alkoxy, c) branched or unbranched hydroxy
C.sub.1-C.sub.5 alkoxy, d) branched or unbranched
O--C.sub.1-C.sub.5 alkyl-(O--C.sub.1-C.sub.4
alkyl).sub.n-C.sub.1-C.sub.4 alkyl, e) N(C.sub.1-C.sub.5
alkyl).sub.2. f) NH.sub.2, g) N(H)--U', h) N(H)-L'' or i) O-L'',
G'' represents a) hydroxyl, b) O--Z'', c) branched or unbranched
O--C.sub.1-C.sub.5 alkyl, d) branched or unbranched
O--C.sub.2-C.sub.5 alkenyl, e) branched or unbranched
O--C.sub.1-C.sub.5 alkyl-(O--C.sub.1-C.sub.4
alkyl).sub.n-C.sub.1-C.sub.4 alkyl, f) branched or unbranched
O--C.sub.2-C.sub.5 alkynyl, or g) triphenylmethoxy, R.sup.3 and
R.sup.4 represent a) hydrogen, b) branched or unbranched
E-C.sub.1-C.sub.5 alkoxy, c) branched or unbranched
E-C.sub.1-C.sub.5 alkyl, d) branched or unbranched
E-hydroxy-C.sub.1-C.sub.5-alkyl, e) branched or unbranched
E-C.sub.2-C.sub.5 alkenyl, f) branched or unbranched
E-C.sub.2-C.sub.5 alkynyl, g) hydroxyl, h) branched or unbranched
C.sub.1-C.sub.5 alkyl, or i) branched or unbranched C.sub.1-C.sub.5
alkoxy, with the proviso that exactly one of the substituents
R.sup.3 or R.sup.4 contains an E and the other substituent in each
case contains no E, E represents a) chloro, b) bromo, c) mesyloxy,
d) trifluoromesyloxy, e) nonafluorobutyloxy, or f) tosyloxy, Q'
represents a) N(H)-tert-butoxycarbonyl, b) N(H)-allyloxycarbonyl,
c) N(H)-benzyloxycarbonyl, d) N(H)-ethoxycarbonyl, e)
N(H)-methoxycarbonyl, f) N(H)-propoxycarbonyl, g)
N(H)-2,2,2-trichloroethoxycarbonyl, h) N(H)-1,1-dimethylpropynyl,
i) N(H)-1-methyl-1-phenylethoxycarbonyl, j)
N(H)-1-methyl-1-(4-biphenylyl)ethoxycarbonyl, k)
N(H)-cyclobutylcarbonyl, l) N(H)-1-methylcyclobutylcarbonyl, m)
N(H)-vinylcarbonyl, n) N(H)-allylcarbonyl, o)
N(H)-adamantylcarbonyl, p) N(H)-diphenylmethylcarbonyl, q)
N(H)-cinnamylcarbonyl, r) N(H)-formyl, s) N(H)-benzoyl, t)
N(H)-trityl, u) N(H)-p-methoxyphenyldiphenylmethyl, v)
N(H)-di(p-methoxyphenyl)phenylmethyl, ##STR00045## x)
N-(tert-butoxycarbonyl).sub.2, L'' represents a) branched or
unbranched C.sub.1-C.sub.5 alkyl, b) branched or unbranched
C.sub.2-C.sub.5 alkenyl, c) branched or unbranched C.sub.1-C.sub.5
alkyl-(O--C.sub.1-C.sub.4 alkyl).sub.n-C.sub.1-C.sub.4 alkyl or d)
branched or unbranched C.sub.2-C.sub.5 alkynyl, U' represents a)
tert-butoxycarbonyl, b) allyloxycarbonyl, c) benzyloxycarbonyl, or
d) ethoxycarbonyl, X' and X'' independently of one another
represent a) branched or unbranched C.sub.1-C.sub.5 alkyl, b)
substituted or unsubstituted aryl, c) alkylaryl or d) heteroaryl,
and Z'' represents a metal cation equivalent, where n is =0, 1 or 2
and diastereomers and enantiomers and F-18 fluoride.
33) A compound as claimed in claim 1 for use as a medicament.
34) A compound as claimed in claim 1 for use in the diagnosis of
tumors.
35) A method of using the compounds as claimed in claim 1
comprising producing a medicament for the diagnosis of tumors.
36) A compound of the formula (III) ##STR00046## wherein A''
represents a) hydroxyl, b) branched or unbranched C.sub.1-C.sub.5
alkoxy, c) branched or unbranched hydroxy C.sub.1-C.sub.5 alkoxy,
d) branched or unbranched O--C.sub.1-C.sub.5
alkyl-(O--C.sub.1-C.sub.4 alkyl).sub.n-O--C.sub.1-C.sub.4 alkyl, e)
N(C.sub.1-C.sub.5 alkyl).sub.2, f) NH.sub.2, g) N(H)--U', h)
N(H)-L'' or i) O-L'', G'' represents a) hydroxyl, b) O--Z'', c)
branched or unbranched O--C.sub.1-C.sub.5 alkyl, d) branched or
unbranched O--C.sub.2-C.sub.5 alkenyl, e) branched or unbranched
O--C.sub.1-C.sub.5 alkyl-(O--C.sub.1-C.sub.4
alkyl).sub.n-O--C.sub.1-C.sub.4 alkyl, f) branched or unbranched
O--C.sub.2-C.sub.5 alkynyl, or g) triphenylmethoxy, R.sup.3 and
R.sup.4 represent a) hydrogen, b) branched or unbranched
E-C.sub.1-C.sub.5 alkoxy, c) branched or unbranched
E-C.sub.1-C.sub.5 alkyl, d) branched or unbranched
E-hydroxy-C.sub.1-C.sub.5-alkyl, e) branched or unbranched
E-C.sub.2-C.sub.5 alkenyl, f) branched or unbranched
E-C.sub.2-C.sub.5 alkynyl, g) hydroxyl, h) branched or unbranched
C.sub.1-C.sub.5 alkyl, or i) branched or unbranched C.sub.1-C.sub.5
alkoxy, with the proviso that exactly one of the substituents
R.sup.3 or R.sup.4 contains an E and the other substituent in each
case contains no E, E represents a) chloro, b) bromo, c) mesyloxy,
d) trifluoromesyloxy, e) nonafluorobutyloxy, or 0 tosyloxy, Q'
represents a) N(H)-tert-butoxycarbonyl, b) N(H)-allyloxycarbonyl,
c) N(H)-benzyloxycarbonyl, d) N(H)-ethoxycarbonyl, e)
N(H)-methoxycarbonyl, f) N(H)-propoxycarbonyl, g)
N(H)-2,2,2-trichloroethoxycarbonyl, h) N(H)-1,1-dimethylpropynyl,
i) N(H)-1-methyl-1-phenylethoxycarbonyl, j)
N(H)-1-methyl-1-(4-biphenylyl)ethoxycarbonyl, k)
N(H)-cyclobutylcarbonyl, l) N(H)-1-methylcyclobutylcarbonyl, m)
N(H)-vinylcarbonyl, n) N(H)-allylcarbonyl, o)
N(H)-adamantylcarbonyl, p) N(H)-diphenylmethylcarbonyl, q)
N(H)-cinnamylcarbonyl, r) N(H)-formyl, s) N(H)-benzoyl, t)
N(H)-trityl, u) N(H)-p-methoxyphenyldiphenylmethyl, v)
N(H)-di(p-methoxyphenyl)phenylmethyl, ##STR00047## x)
N-(tert-butoxycarbonyl).sub.2, L'' represents a) branched or
unbranched C.sub.1-C.sub.5 alkyl, b) branched or unbranched
C.sub.2-C.sub.5 alkenyl, c) branched or unbranched C.sub.1-C.sub.5
alkyl-(O--C.sub.1-C.sub.4 alkyl).sub.n-O--C.sub.1-C.sub.4 alkyl or
d) branched or unbranched C.sub.2-C.sub.5 alkynyl, U' represents a)
tert-butoxycarbonyl, b) allyloxycarbonyl, c) benzyloxycarbonyl, or
d) ethoxycarbonyl, X' and X'' independently of one another
represent a) branched or unbranched C.sub.1-C.sub.5 alkyl, b)
substituted or unsubstituted aryl, c) alkylaryl or d) heteroaryl,
and Z'' represents a metal cation equivalent, where n is =0, 1 or 2
and diastereomers and enantiomers.
37) A method of using the compounds of the formula (IV) comprising
preparing compounds of the formula (I) or (II): ##STR00048##
wherein A''' represents a) hydroxyl, b) branched or unbranched
C.sub.1-C.sub.5 alkoxy, c) branched or unbranched hydroxy
C.sub.1-C.sub.5 alkoxy, d) branched or unbranched
O--C.sub.1-C.sub.5 alkyl-(O--C.sub.1-C.sub.4
alkyl).sub.n-O--C.sub.1-C.sub.4 alkyl, e) N(C.sub.1-C.sub.5
alkyl).sub.2, f) NH.sub.2, g) N(H)--U'', h) N(H)-L''' or i) O-L''',
G'' represents a) hydroxyl, b) branched or unbranched
O--C.sub.1-C.sub.5 alkyl, c) branched or unbranched
O--C.sub.2-C.sub.5 alkenyl, d) branched or unbranched
O--C.sub.1-C.sub.5 alkyl-(O--C.sub.1-C.sub.4
alkyl).sub.n-O--C.sub.1-C.sub.4 alkyl, e) branched or unbranched
O--C.sub.2-C.sub.5 alkynyl, or f) triphenylmethoxy, R.sup.5 and
R.sup.6 represent a) hydrogen or b) E', with the proviso that
exactly one of the substituents R.sup.5 or R.sup.6 contains E' and
the other substituent in each case contains hydrogen, E' represents
a) chloro, b) bromo, c) mesyloxy, d) trifluoromesyloxy, e)
nonafluorobutyloxy or tosyloxy, Q'' represents a)
N(H)-tert-butoxycarbonyl, b) N(H)-allyloxycarbonyl, c)
N(H)-benzyloxycarbonyl, d) N(H)-ethoxycarbonyl, e)
N(H)-methoxycarbonyl, N(H)-propoxycarbonyl, g)
N(H)-2,2,2-trichloroethoxycarbonyl, h) N(H)-1,1-dimethylpropynyl,
i) N(H)-1-methyl-1-phenylethoxycarbonyl, j)
N(H)-1-methyl-1-(4-biphenylyl)ethoxycarbonyl, k)
N(H)-cyclobutylcarbonyl, l) N(H)-1-methylcyclobutylcarbonyl, m)
N(H)-vinylcarbonyl, n) N(H)-allylcarbonyl, o)
N(H)-adamantylcarbonyl, p) N(H)-diphenylmethylcarbonyl, q)
N(H)-cinnamylcarbonyl, r) N(H)-formyl, s) N(H)-benzoyl, t)
N(H)-trityl, u) N(H)-p-methoxyphenyldiphenylmethyl, v)
N(H)-di(p-methoxyphenyl)phenylmethyl, ##STR00049## x)
N-(tert-butoxycarbonyl).sub.2, L''' represents a) branched or
unbranched C.sub.1-C.sub.5 alkyl, b) branched or unbranched
C.sub.2-C.sub.5 alkenyl, c) branched or unbranched C.sub.1-C.sub.5
alkyl-(O--C.sub.1-C.sub.4 alkyl).sub.n-O--C.sub.1-C.sub.4 alkyl, or
d) branched or unbranched C.sub.2-C.sub.5 alkynyl, U'' represents
a) tert-butoxycarbonyl, b) allyloxycarbonyl, c) benzyloxycarbonyl,
or d) ethoxycarbonyl, X'' and X''' independently of one another
represent a) branched or unbranched C.sub.1-C.sub.5 alkyl, b)
substituted or unsubstituted aryl, c) alkylaryl, or d) heteroaryl,
where n is =0, 1 or 2 and diastereomers and enantiomers.
38) A method of using the compounds of the formula (V) for the
preparation of compounds of the formula (I) or (II): ##STR00050##
wherein G''' represents a) hydroxyl, b) branched or unbranched
O--C.sub.1-C.sub.5 alkyl, c) branched or unbranched
O--C.sub.2-C.sub.5 alkenyl, d) branched or unbranched
O--C.sub.1-C.sub.5 alkyl-(O--C.sub.1-C.sub.4
alkyl).sub.n-O--C.sub.1-C.sub.4 alkyl, e) branched or unbranched
O--C.sub.2-C.sub.5 alkynyl, or f) triphenylmethoxy, R.sup.5 and
R.sup.6 represent c) hydrogen or d) E', with the proviso that
exactly one of the substituents R.sup.5 or R.sup.6 contains an E
and the other substituent in each case contains no E, E' represents
a) chloro, b) bromo, c) mesyloxy, d) trifluoromesyloxy, e)
nonafluorobutyloxy or f) tosyloxy, Q''' represents a)
N-tert-butoxycarbonyl, b) N-allyloxycarbonyl, c)
N-benzyloxycarbonyl, d) N-ethoxycarbonyl, e) N-methoxycarbonyl, f)
N-propoxycarbonyl, g) N-2,2,2-trichloroethoxycarbonyl, h) hydrogen,
i) N-1-methyl-1-phenylethoxycarbonyl, j)
N-1-methyl-1-(4-biphenylyl)ethoxycarbonyl, k) N-cyclobutylcarbonyl,
l) N-1-methylcyclobutylcarbonyl, m) N-vinylcarbonyl, n)
N-allylcarbonyl, o) N-adamantylcarbonyl, p)
N-diphenylmethylcarbonyl, q) N-cinnamylcarbonyl, r) N-formyl, or s)
N-benzoyl, where n is =0, 1, 2 or 3 and all possible diastereomers
and enantiomers.
39) A compound as claimed in claim 1, characterized in that the
compounds are suitable for PET diagnostics in a dose range of
37-600 MBq.
40) A compound as claimed in claim 39, characterized in that the
compounds are particularly suitable in a dose range of 150 MBq-370
MBq.
Description
[0001] The invention relates to the subjects characterized in the
patent claims, namely [F-18]-labeled L-glutamic acid and
[F-18]-labeled L-glutamine of the general formula I, their
derivatives, and their use and processes for their preparation.
[0002] The early diagnosis of malignant tumors plays a very
important role in the survival prognosis of a tumor patient. In
this diagnosis, noninvasive, diagnostic imaging processes are an
important tool. In recent years, PET technology (Positron Emission
Tomography), especially, has proven particularly useful. The
sensitivity and specificity of PET technology depends significantly
on the signal-transmitting substance (tracer) used and its
distribution in the body. In the search for suitable tracers, it
has been attempted to utilize certain properties of tumors which
differentiate tumor tissue from healthy, surrounding tissue. The
preferred commercially utilized isotope which is used for PET is
.sup.18F. Owing to its short half life of under 2 hours, .sup.18F
makes particular demands on the preparation of suitable
tracers.
[0003] Laborious, long synthesis routes and purifications are not
possible with this isotope, since otherwise a considerable part of
the radioactivity of the isotope has already decayed before the
tracer can be employed for diagnosis. It is therefore often not
possible to use established synthesis routes for nonradioactive
fluorinations in the synthesis of .sup.18F tracers. In addition,
the high specific activity of .sup.18F (about 80 GBq/nmol) leads to
very small amounts of [.sup.18F] fluoride substance for the tracer
synthesis, which in turn requires an extreme excess of precursor
and makes the success of a radiosynthesis strategy based on
nonradioactive fluorination reactions unpredictable.
[0004] FDG ([.sup.18F]2-fluorodeoxyglucose)-PET is a widely
accepted and widespread tool in the diagnosis and further clinical
monitoring of tumors. Malignant tumors compete with the host
organism for the glucose supply to the nutrient supply (Warburg O.
Uber den Stoffwechsel der Carcinomzelle [Concerning the Metabolism
of the Carcinoma Cell]. Biochem. Zeitschrift 1924; 152: 309-339;
Kellof G. Progress and Promise of FDG-PET Imaging for Cancer
Patient Management and Oncologic Drug Development. Clin Cancer Res.
2005; 11(8): 2785-2807). Here, tumor cells usually have an
increased glucose metabolism in comparison to surrounding cells of
the normal tissue. This is utilized in the use of
fluorodeoxyglucose (FDG), a glucose derivative, which is
transported into the cells in increased amount, but is
metabolically trapped there after phosphorylation as FOG
6-phosphate ("Warburg effect"). .sup.18F-labeled FOG is therefore
an effective tracer for the detection of tumors in patients by
means of PET technology. In the search for novel PET tracers,
recently amino acids have also increasingly been employed for
.sup.18F PET imaging (e.g. (review): Eur J Nucl Med Mol Imaging.
2002 May; 29(5):681-90). Here, some of the .sup.18F-labeled amino
acids are suitable for the measurement of the rate of protein
synthesis, but most other derivatives for the measurement of direct
cell uptake in the tumor. Known .sup.18F-labeled amino acids are
derived, for example, from tyrosine, phenylalanine, proline,
asparagine and unnatural amino acids (e.g. J. Nucl Med 1991;
32:1338-1346, J Nucl Med 1996; 37:320-325, J Nucl Med 2001;
42:752-754 and J Nucl Med 1999; 40:331-338). Glutamic acid and
glutamine are not known as .sup.18F-labeled derivatives, whereas
nonradioactive fluorinated glutamine and glutamic acid derivatives
are commonly used; as, for example, those which contain fluorine in
the .gamma.-position (for example (review): Amino Acids. (2003)
April; 24(3):245-61) or in the 6-position (for example Tetrahedron
Lett.; 30; 14; 1989; 1799-1802, J. Org. Chem.; 54; 2; 1989;
498-500, Tetrahedron: Asymmetry; 12; 9; 2001; 1303-1312).
[0005] It has already been reported in the past on glutamic acid
derivatives which have protective groups on the chemical
functionalities and a leaving group in the .beta.- or
.gamma.-position. Thus information was provided about glutamate as
a mesylate or bromide in the .gamma.-position, the acid and amine
functions of which were provided with ester or Z protective groups
(J. Chem. Soc. Perkin Trans, 1; 1986; 1323-1328) or, for example,
on .gamma.-chloroglutamic acid without protective groups
(Synthesis; (1973); 44-46). An account has likewise been given on
various occasions of similar derivatives in which, however, the
leaving group is positioned in the .beta.-position: for example
Chem. Pharm. Bull.; 17; 5; (1969); 879-885, J. Gen. Chem. USSR
(Engl. Transl.); 38; (1968); 1645-1648; Tetrahedron Lett.; 27; 19;
(1986); 2143-2144, Chem. Pharm. Bull.; EN; 17; 5; 1969; 873-878, FR
patent 1461184, JP patent 13142.
[0006] The present PET tracers which are employed for tumor
diagnosis have some indisputable disadvantages: thus although FOG
preferably accumulates in those cells having increased glucose
metabolism, there is also an increased glucose metabolism in the
cells and tissues involved in other pathological and physiological
states, for example foci of infection or wound healing (summarized
in J. Nucl. Med. Technol. (2005), 33, 145-155). It is often still
difficult to decide whether a lesion detected by means of FDG-PET
is actually of neoplastic origin or is to be attributed to other
physiological or pathological states of the tissue. All in all,
diagnostic activity by means of FDG-PET in oncology has a
sensitivity of 84% and a specificity of 88% (Gambhir et al. "A
tabulated summary of the FDG PET literature" J. Nucl. Med. 2001,
42, 1-93S). Tumors in the brain can only be very poorly
demonstrated, for example, owing to the high accumulation of FDG in
healthy brain tissue.
[0007] The .sup.18F-labeled amino acid derivatives known hitherto
are in some cases highly suitable for detecting tumors in the brain
((review): Eur J Nucl Med Mol. Imaging. 2002 May; 29(5):681-90),
however in other tumors they cannot compete with the imaging
properties of the "gold standard" [.sup.18F]2-FDG. The metabolic
accumulation and retention of the so far F-18-labeled amino acids
in tumorous tissue is generally lower than for FOG. Moreover, the
accessibility of isomerically pure F-18-labeled nonaromatic amino
acids is chemically very highly demanding.
[0008] In a similar manner to glucose, an increased metabolism in
proliferating tumor cells has also been described for glutamic acid
and glutamine (Medina, J Nutr. 1131:2539 S-2542S, 2001; Souba, Ann
Surg 218: 715-728, 1993). The increased rate of protein and nucleic
acid syntheses and the energy generation per se are assumed as
reasons for an increased glutamine consumption of tumor cells. The
synthesis of corresponding C-11- and C-14-labeled compounds, that
are identical with the natural substrate, has already been
described in the literature (for example Antoni, Enzyme Catalyzed
Synthesis of L-[4-C-11]Aspartate and L-[5-C-11]Glutamate. J.
Labelled Compd. Radiopharm. 44; (4) 2001: 287-294) and Buchanan,
The biosynthesis of showdomycin: studies with stable isotopes and
the determination of principal precursors. J. Chem. Soc. Chem.
Commun.; EN; 22; 1984; 1515-1517). First indications with the
C-11-labeled compound do not point to any significant tumor
accumulation.
[0009] The object of the present invention is to find novel
compounds which are suitable in [.sup.18F]-labeled form for
PET-based diagnosis.
[0010] The object is achieved by the provision according to the
invention of [.sup.18F]-labeled L-glutamic acid and
[.sup.18F]-labeled L-glutamine, and their derivatives according to
the general formula (I), including their diastereomers and
enantiomers:
##STR00001##
wherein A represents
[0011] a) hydroxyl,
[0012] b) branched or unbranched C.sub.1-C.sub.5 alkoxy,
[0013] c) branched or unbranched hydroxy C.sub.1-C.sub.5
alkoxy,
[0014] d) branched or unbranched O--C.sub.1-C.sub.5
alkyl-(O--C.sub.1-C.sub.4alkyl).sub.n-O--C.sub.1-C.sub.4alkyl,
[0015] e) N(C.sub.1-C.sub.5 alkyl).sub.2,
[0016] f) NH.sub.2,
[0017] g) N(H)-L,
[0018] h) O-L, or
[0019] i) O--Z,
G represents
[0020] a) hydroxyl,
[0021] b) branched or unbranched O--C.sub.1-C.sub.5 alkyl,
[0022] c) branched or unbranched O--C.sub.2-C.sub.5 alkenyl,
[0023] d) branched or unbranched O--C.sub.1-C.sub.5
alkyl-(O--C.sub.1-C.sub.4alkyl).sub.n-O--C.sub.1-C.sub.4alkyl
or
[0024] e) branched or unbranched O--C.sub.2-C.sub.5 alkynyl,
R.sup.1 and R.sup.2 represent
[0025] a) hydrogen,
[0026] b) .sup.18F,
[0027] c) branched or unbranched .sup.18F--C.sub.1-C.sub.5
alkoxy,
[0028] d) branched or unbranched .sup.18F--C.sub.1-C.sub.5
alkyl,
[0029] e) branched or unbranched .sup.18F-hydroxy-C.sub.1-C.sub.5
alkyl,
[0030] f) branched or unbranched .sup.18F--C.sub.2-C.sub.5 alkenyl,
or
[0031] g) branched or unbranched .sup.18F--C.sub.2-C.sub.5
alkynyl,
[0032] h) hydroxyl,
[0033] i) branched or unbranched C.sub.1-C.sub.5 alkyl or
[0034] j) branched or unbranched C.sub.1-C.sub.5 alkoxy,
with the proviso that exactly one of the substituents R.sup.1 or
R.sup.2 contains exactly one .sup.18F isotope and the other
substituent in each case contains no .sup.18F isotope, L
represents
[0035] a) branched or unbranched C.sub.1-C.sub.5 alkyl,
[0036] b) branched or unbranched C.sub.2-C.sub.5 alkenyl,
[0037] c) branched or unbranched C.sub.1-C.sub.5
alkyl-(O--C.sub.1-C.sub.4alkyl-(O--C.sub.1-C.sub.4alkyl or
[0038] d) branched or unbranched C.sub.2-C.sub.5 alkynyl,
and Z represents a metal cation equivalent, which can be mono- or
divalent, where divalent metals can lead to ionic bonding with two
radicals of the structures according to the invention, where n is
=0, 1, 2 or 3, and where all possible diastereomers and enantiomers
are part of the present subject of the invention.
[0039] Preferred compounds of the invention according to the
formula (I) are distinguished in that
A represents
[0040] a) hydroxyl,
[0041] b) methoxy,
[0042] c) ethoxy,
[0043] d) propoxy,
[0044] e) NMe.sub.2,
[0045] f) NEt.sub.2,
[0046] g) NH.sub.2,
[0047] h) N(H)-L or
[0048] i) O-L
[0049] j) O--Z.
[0050] Further preferred compounds of the invention according to
the formula (I) are distinguished in that
A represents
[0051] a) hydroxyl,
[0052] b) methoxy,
[0053] c) ethoxy,
[0054] d) NMe.sub.2,
[0055] e) NH.sub.2, or
[0056] f) N(H)-L.
[0057] Particularly preferred compounds of the invention according
to the formula (I) are distinguished in that
A represents
[0058] a) hydroxyl,
[0059] b) methoxy or
[0060] c) NH.sub.2.
[0061] Preferred compounds of the invention according to the
formula (I) are distinguished in that
A represents
[0062] OH.
[0063] Preferred compounds of the invention according to the
formula (I) are distinguished in that
A represents
[0064] NH.sub.2.
[0065] Preferred compounds of the invention according to the
formula (I) are distinguished in that
G represents
[0066] a) hydroxyl,
[0067] b) methoxy,
[0068] c) ethoxy,
[0069] d) propoxy,
[0070] e) isopropoxy, or
[0071] f) O--C.sub.2H.sub.4--OMe.
[0072] Further preferred compounds of the invention according to
the formula (I) are distinguished in that
G represents
[0073] a) hydroxyl,
[0074] b) methoxy, or
[0075] c) ethoxy.
[0076] Particularly preferred compounds of the invention according
to the formula (I) are distinguished in that
G represents
[0077] a) hydroxyl or
[0078] b) methoxy.
[0079] Preferred compounds of the invention according to the
formula (I) are distinguished in that
R.sup.1 and R.sup.2 represent
[0080] a) hydrogen,
[0081] b) .sup.18F,
[0082] c) .sup.18F-methoxy,
[0083] d) .sup.18F-ethoxy,
[0084] e) .sup.18F-propoxy,
[0085] f) .sup.18F-methyl,
[0086] g) .sup.18F-ethyl, or
[0087] h) .sup.18F-propyl, [0088] with the proviso that exactly one
of the substituents R.sup.1 or R.sup.2 contains exactly one
.sup.18F isotope and the other substituent in each case is
hydrogen.
[0089] Further preferred compounds of the invention according to
the formula (I) are distinguished in that
R.sup.1 and R.sup.2 represent
[0090] a) hydrogen,
[0091] b) .sup.18F,
[0092] c) .sup.18F-methoxy,
[0093] d) .sup.18F-methyl, or
[0094] e) .sup.18F-ethyl, [0095] with the proviso that exactly one
of the substituents R.sup.1 or R.sup.2 contains exactly one
.sup.18F isotope and the other substituent in each case is
hydrogen.
[0096] Particularly preferred compounds of the invention according
to the formula (I) are distinguished in that
R.sup.1 and R.sup.2 represent
[0097] a) hydrogen,
[0098] b) .sup.18F or
[0099] c) .sup.18F-methyl,
with the proviso that exactly one of the substituents R.sup.1 or
R.sup.2 contains exactly one .sup.18F isotope and the other
substituent in each case is hydrogen.
[0100] Particularly preferred compounds of the invention according
to the formula (I) are distinguished in that R.sup.1 is selected
from the group consisting of OH, CH.sub.3, C.sub.2H.sub.5 and
C.sub.3H.sub.7, and R.sup.2 represents .sup.18F.
[0101] Particularly preferred compounds of the invention according
to the formula (I) are distinguished in that R.sup.2 is selected
from the group consisting of OH, CH.sub.3, C.sub.2H.sub.5 and
C.sub.3H.sub.7, and R.sup.1 represents .sup.18F.
[0102] Particularly preferred compounds of the invention according
to the formula (I) are distinguished in that R.sup.1 represents H
and R.sup.2 represents .sup.18F.
[0103] Particularly preferred compounds of the invention according
to the formula (I) are distinguished in that R.sup.1 represents
.sup.18F and R.sup.2 represents H.
[0104] Preferred compounds of the invention according to the
formula (I) are distinguished in that
L represents
[0105] a) methyl,
[0106] b) ethyl,
[0107] c) propyl,
[0108] d) isopropyl,
[0109] e) --C.sub.2H.sub.4--OMe, or
[0110] f) --C.sub.2H.sub.4--O--C.sub.2H.sub.4--OMe.
[0111] Particularly preferred compounds of the invention according
to the formula (I) are distinguished in that
L represents
[0112] a) methyl or
[0113] b) ethyl.
[0114] Likewise preferred compounds of the invention according to
the formula (I) are distinguished in that
Z represents alkali metal and alkaline earth metal ions and also
nickel which can be mono- or divalent, where divalent metals can
lead to ionic bonding with two radicals of the structures according
to the invention.
[0115] A preferred Z is selected from the group consisting of
Na.sup.+, K.sup.+, Ca.sup.2+ and Mg.sup.2+.
[0116] All possible diastereomers and enantiomers of the preferred
compounds as set forth in formula (I) are part of the present
subject of the invention.
[0117] Furthermore particularly preferred is any individual
compound of the compounds from the following group, where all
possible diastereomers and enantiomers are part of the present
subject of the invention:
##STR00002## ##STR00003##
[0118] The process for the preparation of the compounds of the
general formula (I) according to the invention is distinguished in
that the compound as set forth in formula (I) is released from a
precursor compound of the compound as set forth in formula (II)
after introduction of the .sup.18F isotope. In a second aspect, the
present invention thus relates to compounds of the formula
(II):
##STR00004##
wherein A' represents
[0119] a) hydroxyl,
[0120] b) branched or unbranched C.sub.1-C.sub.5 alkoxy,
[0121] c) branched or unbranched hydroxy C.sub.1-C.sub.5
alkoxy,
[0122] d) branched or unbranched
O--C.sub.1-C.sub.5alkylalkyl).sub.n-O--C.sub.1-C.sub.4 alkyl,
[0123] e) N(C.sub.1-C.sub.5 alkyl).sub.2,
[0124] f) NH.sub.2,
[0125] g) N(H)--U,
[0126] h) N(H)-L'', or
[0127] i) O-L'',
G'' represents
[0128] a) hydroxyl,
[0129] b) O--Z'',
[0130] c) branched or unbranched O--C.sub.1-C.sub.5 alkyl,
[0131] d) branched or unbranched O--C.sub.2-C.sub.5 alkenyl,
[0132] e) branched or unbranched O--C.sub.1-C.sub.5
alkyl-(O--C.sub.1-C.sub.4 alkyl).sub.n-O--C.sub.1-C.sub.4 alkyl,
or
[0133] f) branched or unbranched O--C.sub.2-C.sub.5 alkynyl,
R.sup.1 and R.sup.2 represent
[0134] a) hydrogen,
[0135] b) .sup.18F,
[0136] c) branched or unbranched .sup.18F--C.sub.1-C.sub.5
alkoxy,
[0137] d) branched or unbranched .sup.18F--C.sub.1-C.sub.5
alkyl,
[0138] e) branched or unbranched .sup.18F-hydroxy-C.sub.1-C.sub.5
alkyl,
[0139] f) branched or unbranched .sup.18F--C.sub.2-C.sub.5 alkenyl,
or
[0140] g) branched or unbranched .sup.18F--C.sub.2-C.sub.5
alkynyl,
[0141] h) hydroxyl,
[0142] i) branched or unbranched C.sub.1-C.sub.5 alkyl, or
[0143] j) branched or unbranched C.sub.1-C.sub.5 alkoxy,
with the proviso that exactly one of the substituents R.sup.1 or
R.sup.2 contains exactly one .sup.18F isotope and the other
substituent in each case contains no .sup.18F isotope, Q
represents
[0144] a) N(H)-tert-butoxycarbonyl,
[0145] b) N(H)-allyloxycarbonyl,
[0146] c) N(H)-benzyloxycarbonyl,
[0147] d) N(H)-ethoxycarbonyl,
[0148] e) N(H)-methoxycarbonyl,
[0149] f) N(H)-propoxycarbonyl,
[0150] e) N(H)-2,2,2-trichloroethoxycarbonyl,
[0151] f) N(H)-1,1-dimethylpropynyl,
[0152] g) N(H)-1-methyl-1-phenylethoxycarbonyl,
[0153] h) N(H)-1-methyl-1-(4-biphenylyl)ethoxycarbonyl,
[0154] i) N(H)-cyclobutylcarbonyl,
[0155] j) N(H)-1-methylcyclobutylcarbonyl,
[0156] k) N(H)-vinylcarbonyl,
[0157] l) N(H)-allylcarbonyl,
[0158] m) N(H)-adamantylcarbonyl,
[0159] n) N(H)-diphenylmethylcarbonyl,
[0160] o) N(H)-cinnamylcarbonyl,
[0161] p) N(H)-formyl,
[0162] q) N(H)-benzoyl,
[0163] r) N(H)-trityl,
[0164] s) N(H)-p-methoxyphenyldiphenylmethyl,
[0165] t) N(H)-di(p-methoxyphenyl)phenylmethyl,
##STR00005##
[0166] v) N-(tert-butoxycarbonyl).sub.2,
L' represents
[0167] a) branched or unbranched C.sub.1-C.sub.5 alkyl,
[0168] b) branched or unbranched C.sub.2-C.sub.5 alkenyl,
[0169] c) branched or unbranched C.sub.1-C.sub.5
alkyl-(O--C.sub.1-C.sub.4 alkyl).sub.n-O--C.sub.1-C.sub.4 alkyl,
or
[0170] d) branched or unbranched C.sub.2-C.sub.5 alkynyl,
U represents
[0171] a) tert-butoxycarbonyl,
[0172] b) allyloxycarbonyl,
[0173] c) benzyloxycarbonyl,
[0174] d) methoxycarbonyl,
[0175] e) propoxycarbonyl, or
[0176] f) ethoxycarbonyl,
X' and X'' independently of one another represent
[0177] a) branched or unbranched C.sub.1-C.sub.5 alkyl,
[0178] b) substituted or unsubstituted aryl,
[0179] c) aralkyl or
[0180] d) heteroaryl,
and Z' represents a metal cation equivalent, which can be mono- or
divalent, where divalent metals can lead to ionic bonding with two
radicals of the structures according to the invention or can form
coordinative bonds with a carboxyl and amine function of the amino
acid derivative, A preferred Z'' is selected from the group
consisting of Na.sup.+, K.sup.+, Ca.sup.2+ and Mg.sup.2+ or is
Ni.sup.2+, where n is =0, 1, 2 or 3 and all possible diastereomers
and enantiomers are part of the present subject of the
invention.
[0181] Preferred compounds of the invention according to the
formula (II) are distinguished in that
A'' represents
[0182] a) hydroxyl,
[0183] b) methoxy,
[0184] c) ethoxy,
[0185] d) tert-butoxy,
[0186] e) NMe.sub.2,
[0187] f) NEt.sub.2,
[0188] g) NH.sub.2,
[0189] h) N(H)--U,
[0190] i) N(H)-L' or
[0191] j) O-L'
[0192] Further preferred compounds of the invention according to
the formula (II) are distinguished in that
A'' represents
[0193] a) hydroxyl,
[0194] b) methoxy,
[0195] c) ethoxy,
[0196] d) NMe.sub.2,
[0197] e) N(H)--U,
[0198] f) NH.sub.2, or
[0199] g) N(H)-L'.
[0200] Particularly preferred compounds of the invention according
to the formula (II) are distinguished in that
A' represents
[0201] a) hydroxyl,
[0202] b) ethoxy,
[0203] b) methoxy,
[0204] c) N(H)--U or
[0205] d) NH.sub.2.
[0206] Particularly preferred compounds of the invention according
to the formula (II) are distinguished in that
A' represents
[0207] a) hydroxyl,
[0208] b) branched or unbranched C.sub.1-C.sub.5 alkoxy,
[0209] c) --NH-tert-butoxycarbonyl, or
[0210] d) NH.sub.2.
[0211] Particularly preferred compounds of the invention according
to the formula (II) are distinguished in that
A' represents ethoxy.
[0212] Particularly preferred compounds of the invention according
to the formula (II) are distinguished in that
A' represents NH.sub.2.
[0213] Preferred compounds of the invention according to the
formula (II) are distinguished in that
G'' represents
[0214] a) hydroxyl,
[0215] b) OZ',
[0216] c) methoxy,
[0217] d) ethoxy,
[0218] e) tert-butoxy,
[0219] f) isopropoxy, or
[0220] g) O--C.sub.2H.sub.4--OMe.
[0221] Further preferred compounds of the invention according to
the formula (II) are distinguished in that
G' represents
[0222] a) hydroxyl,
[0223] b) OZ',
[0224] c) methoxy, or
[0225] d) ethoxy.
[0226] Particularly preferred compounds of the invention according
to the formula (II) are distinguished in that
G' represents
[0227] a) hydroxyl,
[0228] b) OZ', or
[0229] c) methoxy.
[0230] Particularly preferred compounds of the invention according
to the formula (II) are distinguished in that
G' represents ethoxy.
[0231] Preferred compounds of the invention according to the
formula (II) are distinguished in that R.sup.1 and R.sup.2
represent
[0232] a) hydrogen,
[0233] b) .sup.18F,
[0234] c) .sup.18F-methoxy,
[0235] d) .sup.18F-ethoxy,
[0236] e) .sup.18F-propoxy,
[0237] f) .sup.18F-methyl,
[0238] g) .sup.18F-ethyl, or
[0239] h) .sup.18F-propyl,
with the proviso that exactly one of the substituents R.sup.1 or
R.sup.2 contains exactly one .sup.18F isotope and the other
substituent in each case is hydrogen.
[0240] Further preferred compounds of the invention according to
the formula (II) are distinguished in that
R.sup.1 and R.sup.2 represent
[0241] a) hydrogen,
[0242] b) .sup.18F,
[0243] c) .sup.18F-methoxy,
[0244] d) .sup.18F-methyl, or
[0245] e) .sup.18F-ethyl,
with the proviso that exactly one of the substituents R.sup.1 or
R.sup.2 contains exactly one .sup.18F isotope and the other
substituent in each case is hydrogen.
[0246] Particularly preferred compounds of the invention according
to the formula (II) are distinguished in that
R.sup.1 and R.sup.2 represent
[0247] a) hydrogen,
[0248] b) .sup.18F or
[0249] c) .sup.18F-methyl,
with the proviso that exactly one of the substituents R.sup.1 or
R.sup.2 contains exactly one .sup.18F isotope and the other
substituent in each case is hydrogen.
[0250] Particularly preferred compounds of the invention according
to the formula (II) are distinguished in that R.sup.1 is selected
from the group consisting of OH, CH.sub.3, C.sub.2H.sub.5 and
C.sub.3H.sub.7, and R.sup.2 represents .sup.18F.
[0251] Particularly preferred compounds of the invention according
to the formula (II) are distinguished in that R.sup.2 is selected
from the group consisting of OH, CH.sub.3, C.sub.2H.sub.5 and
C.sub.3H.sub.7, and R.sup.1 represents .sup.18F.
[0252] Particularly preferred compounds of the invention according
to the formula (II) are distinguished in that R.sup.1 represents H
and R.sup.2 represents .sup.18F.
[0253] Particularly preferred compounds of the invention according
to the formula (II) are distinguished in that R.sup.1 represents
.sup.18F and R.sup.2 represents H.
[0254] Preferred compounds of the invention according to the
formula (II) are distinguished in that
Q represents
[0255] a) N(H)-tert-butoxycarbonyl,
[0256] b) N(H)-benzyloxycarbonyl,
[0257] c) N-(tert-butoxycarbonyl).sub.2, or
##STR00006##
[0258] Further preferred compounds of the invention according to
the formula (II) are distinguished in that
Q represents
[0259] a) N(H)-tert-butoxycarbonyl,
[0260] b) N-(tert-butoxycarbonyl).sub.2, or
##STR00007##
[0261] Particularly preferred compounds of the invention according
to the formula (II) are distinguished in that
Q represents
[0262] a) N(H)-tert-butoxycarbonyl, or
##STR00008##
[0263] Particularly preferred compounds of the invention according
to the formula (II) are distinguished in that
Q represents N(H)-tert-butoxycarbonyl.
[0264] Particularly preferred compounds of the invention according
to the formula (II) are distinguished in that Q represents
##STR00009##
[0265] Preferred compounds of the invention according to the
formula (II) are distinguished in that
L' represents
[0266] a) methyl,
[0267] b) ethyl,
[0268] c) propyl,
[0269] d) isopropyl,
[0270] e) --C.sub.2H.sub.4--OMe, or
[0271] f) --C.sub.2H.sub.4--O--C.sub.2H.sub.4--OMe.
[0272] Further preferred compounds of the invention according to
the formula (II) are distinguished in that
L' represents
[0273] a) methyl, or
[0274] b) ethyl.
[0275] Preferred compounds of the invention according to the
formula (II) are distinguished in that
U represents
[0276] a) tert-butoxycarbonyl,
[0277] b) allyloxycarbonyl, or
[0278] c) ethoxycarbonyl.
[0279] Further preferred compounds of the invention according to
the formula (II) are distinguished in that
U represents
[0280] a) tert-butoxycarbonyl, or
[0281] b) ethoxycarbonyl.
[0282] Particularly preferred compounds of the invention according
to the formula (II) are distinguished in that
U represents
[0283] tert-butoxycarbonyl.
[0284] Preferred compounds of the invention according to the
formula (II) are distinguished in that
X' and X'' independently of one another represent
[0285] a) branched or unbranched C.sub.1-C.sub.5 alkyl,
[0286] b) substituted or unsubstituted aryl or
[0287] c) aralkyl.
[0288] Further preferred compounds of the invention according to
the formula (II) are distinguished in that
X' and X'' independently of one another represent
[0289] a) branched or unbranched C.sub.1-C.sub.5 alkyl, or
[0290] b) substituted or unsubstituted aryl.
[0291] Particularly preferred compounds of the invention according
to the formula (II) are distinguished in that
X' and X'' represent phenyl or represent phenyl substituted in the
2-position.
[0292] Z' represents a metal cation equivalent, which can be mono-
or divalent, where divalent metals can lead to ionic bonding with
two radicals of the structures according to the invention or can
form coordinative bonds with a carboxyl and amine function of the
amino acid derivative,
[0293] Preferred compounds of the invention according to the
formula (II) are distinguished in that
Z' represents an Ni.sup.2+ ion or Z'' is selected from the group
consisting of: Na.sup.+, K.sup.+, Ca.sup.2+ and Mg.sup.2+, where
all possible diastereomers and enantiomers of the preferred
compounds of the invention as set forth in formula (II) are part of
the present subject of the invention.
[0294] Furthermore particularly preferred is any individual
compound of the compounds from the following group where all
possible diastereomers and enantiomers are part of the present
subject of the invention:
##STR00010##
[0295] The process for the preparation of the compounds of the
general formula (II) according to the invention is distinguished in
that the majority of the compounds as set forth in formula (II) can
be formed from a precursor compound of the compound of the formula
(III) after introduction of the .sup.18F isotope.
[0296] In a third aspect, the present invention relates to
compounds of the formula (III):
##STR00011##
wherein A'' represents
[0297] a) hydroxyl,
[0298] b) branched or unbranched C.sub.1-C.sub.5 alkoxy,
[0299] c) branched or unbranched hydroxy C.sub.1-C.sub.5
alkoxy,
[0300] d) branched or unbranched
alkyl-(O--C.sub.1-C.sub.4alkyl).sub.n-O--C.sub.1-C.sub.4 alkyl,
[0301] e) N(C.sub.1-C.sub.5 alkyl).sub.2,
[0302] f) NH.sub.2,
[0303] g) N(H)--U'',
[0304] h) N(H)-L'' or
[0305] i) O-L'',
G'' represents
[0306] a) hydroxyl,
[0307] b) O--Z'',
[0308] c) branched or unbranched alkyl,
[0309] d) branched or unbranched O--C.sub.2-C.sub.5 alkenyl,
[0310] e) branched or unbranched O--C.sub.1-C.sub.5
alkyl-(O--C.sub.1-C.sub.4 alkyl).sub.n-O--C.sub.1-C.sub.4
alkyl,
[0311] f) branched or unbranched O--C.sub.2-C.sub.5 alkynyl, or
[0312] g) triphenylmethoxy,
R.sup.3 and R.sup.4 represent
[0313] a) hydrogen,
[0314] b) branched or unbranched E-C.sub.1-C.sub.5 alkoxy,
[0315] c) branched or unbranched E-C.sub.1-C.sub.5 alkyl,
[0316] d) branched or unbranched
E-hydroxy-C.sub.1-C.sub.5-alkyl,
[0317] e) branched or unbranched E-C.sub.2-C.sub.5 alkenyl,
[0318] f) branched or unbranched E-C.sub.2-C.sub.5 alkynyl,
[0319] g) hydroxyl,
[0320] h) branched or unbranched C.sub.1-C.sub.5 alkyl, or
[0321] i) branched or unbranched C.sub.1-C.sub.5 alkoxy,
with the proviso that exactly one of the substituents R.sup.3 or
R.sup.4 contains an E and the other substituent in each case
contains no E, E represents
[0322] a) chloro,
[0323] b) bromo,
[0324] c) mesyloxy,
[0325] d) trifluoromesyloxy,
[0326] e) nonafluorobutyloxy, or
[0327] f) tosyloxy,
Q' represents
[0328] a) N(H)-tert-butoxycarbonyl,
[0329] b) N(H)-allyloxycarbonyl,
[0330] c) N(H)-benzyloxycarbonyl,
[0331] d) N(H)-ethoxycarbonyl,
[0332] e) N(H)-methoxycarbonyl
[0333] f) N(H)-propoxycarbonyl,
[0334] g) N(H)-2,2,2-trichloroethoxycarbonyl,
[0335] h) N(H)-1,1-dimethylpropynyl,
[0336] i) N(H)-1-methyl-1-phenylethoxycarbonyl,
[0337] j) N(H)-1-methyl-1-(4-biphenyl)-ethoxycarbonyl,
[0338] k) N(H)-cyclobutylcarbonyl,
[0339] l) N(H)-1-methylcyclobutylcarbonyl,
[0340] m) N(H)-vinylcarbonyl,
[0341] n) N(H)-allylcarbonyl,
[0342] o) N(H)-adamantylcarbonyl,
[0343] p) N(H)-diphenylmethylcarbonyl,
[0344] q) N(H)-cinnamylcarbonyl,
[0345] r) N(H)-formyl,
[0346] s) N(H)-benzoyl,
[0347] t) N(H)-trityl,
[0348] u) N(H)-p-methoxyphenyldiphenylmethyl,
[0349] v) N(H)-di(p-methoxyphenyl)phenylmethyl, or
##STR00012##
[0350] x) N-(tert-butoxycarbonyl).sub.2,
L'' represents
[0351] a) branched or unbranched C.sub.1-C.sub.5 alkyl,
[0352] b) branched or unbranched C.sub.2-C.sub.5 alkenyl,
[0353] c) branched or unbranched C.sub.1-C.sub.5
alkyl-(O--C.sub.1-C.sub.4 alkyl).sub.n-O--C.sub.1-C.sub.4 alkyl
or
[0354] d) branched or unbranched C.sub.2-C.sub.5 alkynyl,
U' represents
[0355] a) tert-butoxycarbonyl,
[0356] b) allyloxycarbonyl,
[0357] c) benzyloxycarbonyl, or
[0358] d) ethoxycarbonyl,
X' and X'' independently of one another represent
[0359] a) branched or unbranched C.sub.1-C.sub.5 alkyl,
[0360] b) substituted or unsubstituted aryl,
[0361] c) aralkyl or
[0362] d) heteroaryl,
and Z'' represents a metal cation equivalent, which can be mono- or
divalent, where divalent metals can lead to ionic bonding with two
radicals of the structures according to the invention or can form
coordinative bonds with a carboxyl and amine function of the amino
acid derivative, A preferred Z'' is selected from the group
consisting of Na.sup.+, K.sup.+, Ca.sup.2+ and Mg.sup.2+ or is
Ni.sup.2+, where n is =0, 1 or 2 and all possible diastereomers and
enantiomers are part of the present subject of the invention.
[0363] Preferred compounds of the invention according to the
formula (III) are distinguished in that
A'' represents
[0364] a) hydroxyl,
[0365] b) methoxy,
[0366] c) ethoxy,
[0367] d) tert-butoxy,
[0368] e) NMe.sub.2,
[0369] f) NEt.sub.2,
[0370] g) NH.sub.2,
[0371] h) N(H)--U'',
[0372] i) N(H)-L'' or
[0373] j) O-L'',
[0374] Further preferred compounds of the invention according to
the formula (III) are distinguished in that
A'' represents
[0375] a) hydroxyl,
[0376] b) methoxy,
[0377] c) ethoxy,
[0378] d) NMe.sub.2,
[0379] e) N(H)--U'',
[0380] f) NH.sub.2, or
[0381] g) N(H)-L''.
[0382] Particularly preferred compounds of the invention according
to the formula (III) are distinguished in that
A'' represents
[0383] a) hydroxyl,
[0384] b) ethoxy,
[0385] c) methoxy,
[0386] d) N(H)--U, or
[0387] e) NH.sub.2.
[0388] Preferred compounds of the invention according to the
formula (III) are distinguished in that
G'' represents
[0389] a) hydroxyl,
[0390] b) OZ'',
[0391] c) methoxy,
[0392] d) ethoxy,
[0393] e) tert-butoxy,
[0394] f) isopropoxy, or
[0395] g) O--C.sub.2H.sub.4--OMe.
[0396] Further preferred compounds of the invention according to
the formula (III) are distinguished in that
G'' represents
[0397] a) hydroxyl,
[0398] b) OZ'',
[0399] c) methoxy, or
[0400] d) ethoxy.
[0401] Particularly preferred compounds of the invention according
to the formula (III) are distinguished in that
G'' represents
[0402] a) hydroxyl,
[0403] b) OZ'', or
[0404] c) methoxy.
[0405] Preferred compounds of the invention according to the
formula (III) are distinguished in that
R.sup.3 and R.sup.4 represent
[0406] a) hydrogen,
[0407] b) E-methoxy,
[0408] c) E-ethoxy,
[0409] d) E-propoxy,
[0410] e) E-methyl,
[0411] f) E-ethyl, or
[0412] g) E-propyl,
with the proviso that exactly one of the substituents R.sup.3 or
R.sup.4 contains an E and the other substituent in each case is
hydrogen.
[0413] Further preferred compounds of the invention according to
the formula (III) are distinguished in that
R.sup.3 and R.sup.4 represent
[0414] a) hydrogen,
[0415] b) E-methoxy,
[0416] c) E-methyl, or
[0417] d) E-ethyl,
with the proviso that exactly one of the substituents R.sup.3 or
R.sup.4 contains an E and the other substituent in each case is
hydrogen.
[0418] Particularly preferred compounds of the invention according
to the formula (III) are distinguished in that
R.sup.3 and R.sup.4 represent
[0419] a) hydrogen or
[0420] b) E-methyl,
with the proviso that exactly one of the substituents R.sup.3 or
R.sup.4 contains an E and the other substituent in each case is
hydrogen.
[0421] Preferred compounds of the invention according to the
formula (III) are distinguished in that
E represents
[0422] a) chloro,
[0423] b) bromo,
[0424] c) mesyloxy,
[0425] d) trifluoromesyloxy or
[0426] e) tosyloxy.
[0427] Further preferred compounds of the invention according to
the formula (III) are distinguished in that
E represents
[0428] a) chloro,
[0429] b) bromo,
[0430] c) mesyloxy,
[0431] d) trifluoromesyloxy or
[0432] e) tosyloxy.
[0433] Particularly preferred compounds of the invention according
to the formula (III) are distinguished in that
E represents
[0434] a) bromo, or
[0435] b) mesyloxy.
[0436] Preferred compounds of the invention according to the
formula (III) are distinguished in that
Q' represents
[0437] a) N(H)-tert-butoxycarbonyl,
[0438] b) N(H)-benzyloxycarbonyl, or
##STR00013##
[0439] Further preferred compounds of the invention according to
the formula (III) are distinguished in that
Q' represents
[0440] a) N(H)-tert-butoxycarbonyl, or
##STR00014##
[0441] Preferred compounds of the invention according to the
formula (III) are distinguished in that
L'' represents
[0442] a) methyl,
[0443] b) ethyl,
[0444] c) propyl,
[0445] d) isopropyl,
[0446] e) --C.sub.2H.sub.4--OMe, or
[0447] f) --C.sub.2H.sub.4--O--C.sub.2H.sub.4--OMe.
[0448] Further preferred compounds of the invention according to
the formula (III) are distinguished in that
L'' represents
[0449] a) methyl, or
[0450] b) ethyl.
[0451] Preferred compounds of the invention according to the
formula (III) are distinguished in that
U' represents
[0452] a) tert-butoxycarbonyl,
[0453] b) allyloxycarbonyl, or
[0454] c) ethoxycarbonyl.
[0455] Further preferred compounds of the invention according to
the formula (III) are distinguished in that
U' represents
[0456] a) tert-butoxycarbonyl, or
[0457] b) benzyloxycarbonyl.
[0458] Particularly preferred compounds of the invention according
to the formula (III) are distinguished in that
U' represents
[0459] tert-butoxycarbonyl.
[0460] Preferred compounds of the invention according to the
formula (III) are distinguished in that
X' and X'' independently of one another represent
[0461] a) branched or unbranched C.sub.1-C.sub.5 alkyl,
[0462] b) substituted or unsubstituted aryl, or
[0463] c) aralkyl.
[0464] Further preferred compounds of the invention according to
the formula (III) are distinguished in that
X' and X'' independently of one another represent
[0465] a) branched or unbranched C.sub.1-C.sub.5 alkyl, and
[0466] b) substituted or unsubstituted aryl.
[0467] Particularly preferred compounds of the invention according
to the formula (III) are distinguished in that
X' and X'' represent phenyl or represent phenyl substituted in the
2-position.
[0468] Preferred compounds of the invention according to the
formula (III) are distinguished in that Z'' represents
Ni.sup.2+.
[0469] Where all possible diastereomers and enantiomers of the
preferred compounds as set forth in formula (III) are part of the
present subject of the invention.
[0470] The term "aryl", as it is applied here, standing by itself
or as part of another group, relates to monocyclic or bicyclic
aromatic groups which can contain six to twelve carbon atoms in the
ring, such as, for example, phenyl or naphthyl, and can be
arbitrarily substituted in position 2.
[0471] The aryl groups can be substituted in any suitable position
which leads to a stable compound by one or more radicals from the
group consisting of: hydroxyl, halogen, C1-C5-alkyl, C1-C5-alkoxy,
cyano, CF3, nitro.
[0472] Substituents which may be mentioned are methoxy, ethoxy,
propoxy, isopropoxy, hydroxyl, fluorine, chlorine, bromine, methyl,
ethyl, propyl, isopropyl or trifluoromethyl groups.
[0473] Halogen is in each case to be understood as meaning
fluorine, chlorine, bromine or iodine.
[0474] The term "alkyl", as it is applied here, standing by itself
or as part of another group, relates to C.sub.1-C.sub.6-alkyl
groups and can be straight-chain or branched and represents a
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl
or n-pentyl, 2,2-dimethylpropyl, 2-methylbutyl or 3-methylbutyl
group. A methyl or ethyl group is preferred.
[0475] Alkyl is in each case to be understood as meaning a
straight-chain or branched alkyl radical, such as, for example,
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tart-butyl, pentyl, isopentyl or hexyl, heptyl, octyl, nonyl,
decyl, undecyl, dodecyl.
[0476] The alkenyl substituents are in each case straight-chain or
branched, the following radicals, for example, being meant: vinyl,
propen-1-yl, propen-2-yl, but-1-en-1-yl, but-1-en-2-yl,
but-2-en-'1-yl, but-2-en-2-yl, 2-methylprop-2-en-1-yl,
2-methylprop-1-en-1-yl, but-1-en-3-yl, ethynyl, prop-1-yn-1-yl,
but-1-yn-1-yl, but-2-yn-1-yl, but-3-en-1-yl, allyl.
[0477] The alkynyl groups can be straight-chain or branched and
are, for example, C.ident.C, --CH.sub.2--C.ident.CH,
--C.ident.C--CH.sub.3, --CH(CH.sub.3)--C.ident.CH,
--C.ident.C--CH.sub.2(CH.sub.3), --C(CH.sub.3).sub.2--C.ident.CH,
--C.ident.C--CH(CH.sub.3).sub.2--,
--CH(CH.sub.3)--C.ident.C--CH.sub.3,
--CH.sub.2--C.ident.C--CH.sub.2(CH.sub.3).
[0478] The C.sub.1-C.sub.5-alkoxy groups can be straight-chain or
branched and represent a methoxy, ethoxy, n-propoxy, isopropoxy,
n-butoxy, isobutoxy, tert-butoxy or n-pentoxy, 2,2-dimethylpropoxy,
2-methylbutoxy or 3-methylbutoxy group. A methoxy or ethoxy group
is preferred.
[0479] The heteroaryl radical in each case comprises 5-16 ring
atoms and instead of a carbon atom can contain one or more,
identical or different heteroatoms, such as oxygen, nitrogen or
sulfur in the ring, and can be mono-, bi- or tricyclic, and can
additionally in each case be benzo-fused.
[0480] Examples which may be mentioned are:
thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,
pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,
thiadiazolyl, etc. and benzo derivatives thereof, such as, for
example, benzofuranyl, benzothienyl, benzothiazole, benzoxazolyl,
benzimidazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc. and benzo
derivatives thereof, such as, for example, quinolyl, isoquinolyl,
etc.; or azocinyl, indolizinyl, purinyl, etc. and benzo derivatives
thereof; or quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl,
quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl,
acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl,
oxepinyl.
[0481] The invention also comprises the Ni.sup.2+ complex
containing the Schiff's base of a compound as set forth in formula
(I) and the compound (S)-2-[N--(N-benzylprolyl)amino]benzophenone
as such and its use for the preparation of a compound as set forth
in formula (I).
[0482] The invention further also comprises the Ni.sup.2+ complex
containing the Schiff's base of a precursor compound of the
compound as set forth in formula (I) and the compound
(S)-2-[N--(N-benzylprolyl)amino]benzophenone as such and its use
for the preparation of a compound as set forth in formula (I).
[0483] Compounds according to the invention, such as, for example,
4-fluoro-l-glutamic acid and 4-fluoro-l-glutamine, can be prepared,
for example, as in Scheme 1, by metal-catalyzed asymmetric
synthesis with the aid of an Ni.sup.2+ complex of a
glycine-containing Schiff's base and
(S)-2-[N--(N-benzylprolyl)pamino]benzophenone (BPB) (1).sup.3 and
ethyl ethyl-.alpha.-bromoacrylate or .alpha.-bromoacrylamide
(2).
##STR00015##
[0484] Here, the C--C linkage can take place both in protic and
aprotic solvents. The reaction can be carried out under mild
conditions, such as, for example, room temperature, or elevated
temperatures.
[0485] The addition of a base here is helpful. For instance,
diisopropylamine, diisopropylethylamine, triethylamine or the like
can be used. The reaction mixture is favorably stirred for 1-3 h
and subsequently treated again with ethyl .alpha.-bromoacrylate or
.alpha.-bromoacrylamide. The reaction can be monitored by means of
TLC. Inter alia, silica gel/ethyl acetate/chloroform systems are
suitable for this. After the addition of ethyl
.alpha.-bromoacrylate or .alpha.-bromoacrylamide and stirring for
at least 1 hour, the reaction is to a considerable extent complete.
The reaction mixture is then neutralized by the addition of organic
or mineral acid (or a combination of both), for example acetic
acid, formic acid, trifluoroacetic acid, trichloroacetic acid,
propionic acid, hydrochloric acid, sulfuric acid, perchloric acid,
phosphoric acid etc. The ethyl 4-bromoglutamate-Ni complex can be
separated from the reaction mixture by extraction. Suitable
solvents for this are, for example, organic halogenated or
nonhalogenated solvents, such as, for example, chloroform,
methylene chloride, dialkyl ethers, ethyl acetate, alkanes, etc.
After drying the organic phase by means of a drying agent (for
example sodium sulfate, calcium sulfate or the like), the mixture
is concentrated to dryness in vacuo.
[0486] By means of preparative TLC (for example on silica gel using
an eluent mixture of AcOEt/CHCl.sub.3, 1:1), a mixture of
stereoisomeric complexes such as 3 (S,S,S) and 3 (S,R,S/R) can be
detected. Complex 3 (S,S,R) can be separated, for example, in the
aforementioned separation system with an R.sub.f of 0.49. The
complexes 3 can be eluted from the silica gel, for example, using
MeOH, EtOH etc. and subsequently purified by column chromatography,
for example on Sephadex using EtOH/C.sub.6H.sub.6 mixtures.
[0487] The complex obtained can then be employed for further
substitution reactions on the carbon atom substituted by
bromine.
[0488] The precursor compound 3 according to the invention can be
converted to the corresponding fluorinated precursor compound 4 by
nucleophilic substitution by [.sup.18F]F'. For this, the complexes
3 can be reacted in the presence of a base such as, for example,
NBu.sub.4OH, (NBu.sub.4).sub.2CO.sub.3, K.sub.2CO.sub.3 etc. with
the appropriate fluoride solution. The reaction preferably proceeds
at elevated temperatures. The addition of crown ethers, such as,
for example, Kryptofix (K2.2.2), can positively influence the
reaction, particularly in combination with K.sub.2CO.sub.3 as a
catalyzing base.
[0489] The fluorinated compounds 4-fluoroglutamic acid or
4-fluoroglutamine can be released from the corresponding complexes
3 by treatment with acids, such as, for example, hydrochloric acid,
phosphoric acid, perchloric acid, sulfuric acid etc. Here, both the
cleavage of the amino acid derivative and the cleavage of the ester
in the 5-position occurs when using 5-methyl 4-fluoroglutamate.
[0490] 4-Fluoroglutamic acid can be prepurified by means of a
cartridge (for example QMA (Waters), LiChrolut (VWR/Merck) or
WHAT6803-2005 SPE COLSAX (VWR/Merck)). The separation of impurities
(complex compound 3, 4, 4-bromoglutamic acid etc.) can be carried
out by means of HPLC. Suitable HPLC systems can, for example, be:
column: amino group-bearing silica gel (for example
Zorbax-NH.sub.2); eluent: 20 mM NaH.sub.2PO.sub.4 in water, flow: 4
ml/min. The purified compound 5 can be concentrated by suitable
removal of the HPLC solvents and employed for use for the purposes
of this invention. The removal of the HPLC solvents can be carried
out in different ways. Concentration on a rotary evaporator under
reduced pressure, heating of the sample in a heating block under a
stream of nitrogen etc. or application to a concentrator cartridge
(for example C-18 SepPack etc.), followed by elution with a little
EtOH/aqueous sodium chloride solution or the like with subsequent
further concentration by the aforementioned methods is
suitable.
[0491] Compounds according to the invention, in which the [F-18]
isotope is likewise positioned in the 4-position of the glutamic
acid structure (5), can also be prepared as shown in Scheme 2.
Thus, the acidic cleavage of the protective groups of the compound
6 takes place by way of example in order to obtain the compound
4-fluoromethylglutamic acid (5) according to the invention.
##STR00016##
[0492] Here, various organic acids (for example trifluoroacetic
acid), but especially inorganic acids such as, for example,
hydrobromic acid, hydrochloric acid, sulfuric acid, perchloric acid
or phosphoric acid can be used. The purification of the compound 5
according to the invention as set forth in formula (I) is possible
by HPLC, where various purification steps can in principle be
inserted upstream and inserted downstream, such as, for example,
purification by means of an RP-C18 cartridge or other separating
materials.
[0493] The radiochemical fluorination of tosylate 7, whose
synthesis took place from 8 (N. Sharma et al. Tetrahedron Lett.
2004, 45, 1403-1406.) analogously to the method described in the
literature (X. Zhang Tetrahedron Lett. 2001, 42, 5335-5338.), to
give the [F-18]-labeled glutamic acid derivative 6 is feasible
according to the methods known to the person skilled in the art
(see Scheme 3).
##STR00017##
[0494] Here, compound 7 can be reacted with the appropriate [F-18]
fluoride solution in the presence of a base such as, for example,
tetraalkylammonium and tetraalkylphosphonium carbonate and
potassium carbonate etc. The reaction preferably proceeds at
elevated temperatures. The addition of crown ethers, such as, for
example, Kryptofix (K2.2.2), can positively influence the reaction,
particularly in combination with K.sub.2CO.sub.3 as a catalyzing
base. Possible solvents are preferably aprotic, but protic solvents
or else aprotic solvent additives, such as, for example, water, can
also be used. Customarily, acetonitrile, dimethyl sulfoxide or
dimethylformamide are used as optimal solvents for the
radiochemical fluorination with [F-18] fluoride anions. Compounds
according to the invention such as 6 can be purified by HPLC and/or
cartridges, where various purification steps can in principle be
inserted upstream and inserted downstream, such as, for example,
purification by means of an RP-C18 cartridge or other separating
materials.
[0495] The preparation of the F-19 reference compounds 10 and 11
takes place as shown in Scheme 4.
##STR00018##
[0496] For instance, 10 can be prepared by oxidation of the
fluoroproline derivative 9. The open-chain reference substance 11
can be obtained by ring opening of 10.
[0497] Furthermore, compounds according to the invention such as 5
can also be prepared directly from the cyclic compound 8 (Scheme 3)
using the fluorination conditions described. The cleavage of the
protective groups or the ring opening can be carried out
analogously to the conditions for the removal of acidic protective
groups (Scheme 2). For this purpose, various organic acids (for
example trifluoroacetic acid), but especially inorganic acids such
as, for example, hydrobromic acid, hydrochloric acid, sulfuric
acid, perchloric acid or phosphoric acid can be used. Furthermore,
basic ring opening is also possible using lithium hydroxide, sodium
hydroxide, potassium hydroxide etc. (S. Baker et al. Tetrahedron
Lett. 1998, 39, 2815-2818.).
[0498] Compounds according to the invention, in which the [F-18]
isotope is positioned in the .beta.-position, such as, for example,
in the case of 3-fluoroglutamic acid (12), can be prepared as shown
in Scheme 5. Thus the acidic cleavage of the protective groups of
the compound 13 succeeds by way of example in order to obtain the
compound according to the invention 3-fluoroglutamic acid (12).
##STR00019##
[0499] Here, various organic, but especially inorganic, acids such
as, for example, hydrobromic acid, hydrochloric acid, sulfuric
acid, perchloric acid or phosphoric acid can be used. Cleavage of
the protective groups under strongly basic conditions using, for
example, sodium hydroxide solution or potassium hydroxide solution
is less favorable, but also utilizable and feasible in principle.
The purification of the compound 12 according to the invention as
set forth in formula (I) is possible by HPLC, where various
purification steps can in principle be inserted upstream and
inserted downstream, such as, for example, purification by means of
an RP-C18 cartridge or other separating materials.
[0500] The radiochemical fluorination of tosylate 14, whose
synthesis is described in the literature (Chem. Pharm. Bull., 17,
5, (1969), 879-885), to give the [F-18]-labeled glutamic acid
derivative 13 is feasible according to the methods known to the
person skilled in the art (see Scheme 6).
##STR00020##
[0501] Here, compound 14 can be reacted with the appropriate [F-18]
fluoride solution in the presence of a base such as, for example,
tetraalkylammonium and tetraalkylphosphonium carbonate and
potassium carbonate etc. The reaction preferably proceeds at
elevated temperatures. The addition of crown ethers, such as, for
example, Kryptofix (K2.2.2), can positively influence the reaction,
particularly in combination with K.sub.2CO.sub.3 as a catalyzing
base. Possible solvents are preferably aprotic, but protic solvents
or else aprotic solvent additives, such as, for example, water, can
also be used. Customarily, acetonitrile, dimethyl sulfoxide or
dimethylformamide are used as optimal solvents for the
radiochemical fluorination with [F-18] fluoride anions. Compound 13
customarily does not have to be subjected to purification, but can
be treated immediately using the methods described for the reaction
of 13 to 12. Purification of the compound 13 is, however, possible
in principle, preferably by means of preparative HPLC using a
nonpolar phase, such as, for example, RP C-18. Moreover,
purification by means of cartridges is also possible.
[0502] Compounds according to the invention in which the [F-18]
isotope is positioned in the 4-position of the glutamic acid
structure by means of a methylene group, such as, for example, in
the case of 4-[F-18]fluoromethylglutamic acid (15), can be prepared
as shown in Scheme 7. Thus, by way of example, the acidic cleavage
of the protective groups of the compound 16 succeeds in order to
obtain the compound according to the invention
4-[F-18]fluoromethylglutamic acid (15).
##STR00021##
[0503] Here, various organic acids (for example trifluoroacetic
acid), but especially inorganic acids such as, for example,
hydrobromic acid, hydrochloric acid, sulfuric acid, perchloric acid
or phosphoric acid can be used. The purification of the compound
according to the invention 16 as set forth in formula (I) is
possible by HPLC, where in principle various purification steps can
be inserted upstream and inserted downstream, such as, for example,
purification by means of an RP-C18 cartridge or other separating
materials.
[0504] The radiochemical fluorination of tosylate 17, the synthesis
of which was carried out analogously to the method described in the
literature (Chem. Pharm. Bull., 17, 5, (1969), 879-885) from 18
(Tetrahedron, 45, 5, (1989) 1453-1464), to give the [F-18]-labeled
glutamic acid derivative 16 is feasible according to the methods
known to the person skilled in the art (see Scheme 8).
##STR00022##
[0505] Here, compound 17 can be reacted with the appropriate [F-18]
fluoride solution in the presence of a base such as, for example,
tetraalkylammonium and tetraalkylphosphonium carbonate and
potassium carbonate etc. The reaction preferably proceeds at
elevated temperatures. The addition of crown ethers, such as, for
example, Kryptofix (K2.2.2), can positively influence the reaction,
particularly in combination with K.sub.2CO.sub.3 as a catalyzing
base. Possible solvents are preferably aprotic solvents, but protic
solvents or else aprotic solvent additives, such as, for example,
water, can also be used. Customarily, acetonitrile, dimethyl
sulfoxide or dimethylformamide are used as optimal solvents for the
radiochemical fluorination with [F-18] fluoride anions. Compound 16
customarily does not have to undergo purification, but can be
treated immediately using the methods described for the reaction of
16 to 15. Purification of the compound 16 is, however, possible in
principle, preferably by means of preparative HPLC using a nonpolar
phase, such as, for example, RP C-18.
[0506] Compounds according to the invention in which the [F-18]
isotope is positioned in the 4-position of the glutamic acid
structure by means of an alkoxy group, such as, for example, in the
case of 4-[F-18]-fluoroethoxyglutamic acid (20), can be prepared as
shown in Scheme 9. Thus the acidic cleavage of the protective
groups of the compound 21 or 22 succeeds by way of example in order
to obtain the compound according to the invention
4-[F-18]fluoroethoxyglutamic acid (20).
##STR00023##
[0507] Here, various organic acids (for example trifluoroacetic
acid), but especially inorganic acids such as, for example,
hydrobromic acid, hydrochloric acid, sulfuric acid, perchloric acid
or phosphoric acid can be used. Furthermore, basic ring opening of
21 is also possible using lithium hydroxide, sodium hydroxide,
potassium hydroxide etc. (S. Baker et al. Tetrahedron Lett. 1998,
39, 2815-2818.)
[0508] The purification of the compound according to the invention
20 as set forth in formula (I) is possible by HPLC, where various
purification steps can in principle be inserted upstream and
inserted downstream, such as, for example, purification by means of
an RP-C18 cartridge or other separating materials.
[0509] The radiochemical fluorination of tosylate 23 whose
synthesis was carried out from 24 analogously to the method
described in the literature (N. Sharma et al. Tetrahedron Lett.
2004, 45, 1403-1406.) to give the [F-18]-labeled glutamic acid
derivative 21 is feasible according to the methods known to the
person skilled in the art (see Scheme 10).
##STR00024##
[0510] Here, compound 21 can be reacted with the appropriate [F-18]
fluoride solution in the presence of a base such as, for example,
tetraalkylammonium and tetraalkylphosphonium carbonate and
potassium carbonate etc. The reaction preferably proceeds at
elevated temperatures. The addition of crown ethers, such as, for
example, Kryptofix (K2.2.2), can positively influence the reaction,
particularly in combination with K.sub.2CO.sub.3 as a catalyzing
base. Possible solvents are preferably aprotic solvents, but protic
solvents or else aprotic solvent additives, such as, for example,
water, can also be used. Customarily, acetonitrile, dimethyl
sulfoxide or dimethylformamide are used as optimal solvents for the
radiochemical fluorination with [F-18] fluoride anions. Compound 21
customarily does not have to be subjected to purification, but can
be treated immediately using the methods described for the reaction
of 21 to 20. Purification of the compound 21 is, however, possible
in principle, preferably by means of preparative HPLC using a
nonpolar phase, such as, for example, RP C-18. Moreover,
purification by means of cartridges is possible.
[0511] The radiochemical fluorination of tosylate 25, whose
synthesis was carried out from 23 analogously to the method
described in the literature (X. Zhang Tetrahedron Lett. 2001, 42,
5335-5338.), to give the [F-18]-labeled glutamic acid derivative 22
is feasible according to the methods known to the person skilled in
the art (see Scheme 11).
##STR00025##
[0512] Here, compound 25 can be reacted with the appropriate [F-18]
fluoride solution in the presence of a base such as, for example,
tetraalkylammonium and tetraalkylphosphonium carbonate and
potassium carbonate etc. The reaction preferably proceeds at
elevated temperatures. The addition of crown ethers, such as, for
example, Kryptofix (K2.2.2), can positively influence the reaction,
particularly in combination with K.sub.2CO.sub.3 as a catalyzing
base. Possible solvents are preferably aprotic, but protic solvents
or else aprotic solvent additives, such as, for example, water, can
also be used. Customarily, acetonitrile, dimethyl sulfoxide or
dimethylformamide are used as optimal solvents for the
radiochemical fluorination with [F-18] fluoride anions. Compound 22
customarily does not have to undergo purification, but can be
treated immediately using the methods described for the reaction of
22 to 20. Purification of the compound 22 is, however, possible in
principle, preferably by means of preparative HPLC using a nonpolar
phase, such as, for example, RP C-18. Moreover, purification by
means of cartridges is possible.
[0513] The synthesis of F-19 reference compounds 26, 27 and 28 can
be carried out as shown in Scheme 12.
##STR00026##
[0514] 26 can be obtained by alkylation and oxidation of the
hydroxyproline derivative 24. By ring opening of the pyroglutamine
derivative 26, the open-chain reference compound 27 is obtained.
The acidic cleavage of the protective groups leads to the glutamic
acid derivative 28.
[0515] Compounds according to the invention in which the [F-18]
isotope is positioned in the 4-position of the glutamic acid
structure by means of an alkyl group, such as, for example, in the
case of 4-[F-18]fluoropropylglutamic acid (29) or
4-[F-18]fluorobutylglutamic acid (30) can be prepared as shown in
Scheme 13. Thus, the acidic cleavage of the protective groups of
the compounds 31 and 32 succeeds by way of example, in order to
obtain the compound 4-[F-18]fluoropropylglutamic acid (29) or
4-[F-18]fluorobutylglutamic acid (30) according to the
invention.
##STR00027##
[0516] Here, various organic acids (for example trifluoroacetic
acid), but especially inorganic acids such as, for example,
hydrobromic acid, hydrochloric acid, sulfuric acid, perchloric acid
or phosphoric acid can be used. The purification of the compound 29
and 30 according to the invention as set forth in formula (I) is
possible by HPLC, where various purification steps can in principle
be inserted upstream and inserted downstream, such as, for example,
purification by means of an RP-C18 cartridge or other separating
materials.
[0517] The radiochemical fluorination of bromide 33 or tosylate 34,
whose synthesis was carried out from 35 analogously to the method
described in the literature (S. Hanessian, et al. J. Org. Chem.
2005, 70, 5070-5085), to give the [F-18]-labeled glutamic acid
derivatives 31 and 32 is feasible according to the methods known to
the person skilled in the art (see Scheme 14).
##STR00028##
[0518] Here, the compounds 33 and 34 can be reacted with the
appropriate [F-18] fluoride solution in the presence of a base such
as, for example, tetraalkylammonium and tetraalkylphosphonium
carbonate and potassium carbonate etc. The reaction preferably
proceeds at elevated temperatures. The addition of crown ethers,
such as, for example, Kryptofix (K2.2.2), can positively influence
the reaction, particularly in combination with K.sub.2CO.sub.3 as a
catalyzing base. Possible solvents are preferably aprotic solvents,
but protic solvents or else aprotic solvent additives, such as, for
example, water, can also be used. Customarily, acetonitrile,
dimethyl sulfoxide or dimethylformamide are used as optimal
solvents for the radiochemical fluorination with [F-18] fluoride
anions. The compounds 31 and 32 customarily do not have to be
subjected to purification, but can immediately be treated using the
methods described for the reaction of 31 to 29 or 32 to 30.
Purification of the compounds 31 and 32 is possible, however, in
principle, preferably by means of preparative HPLC using a nonpolar
phase, such as, for example, RP C-18.
[0519] The synthesis of the F-19 reference compounds 36 and 37 can
be carried out by alkylation of the glutamic acid derivative 35
(Scheme 15).
##STR00029##
[0520] The cleavage of the protective groups leads to the
fluoroalkylated glutamic acid derivatives 38 and 39.
[0521] In a fourth aspect of the invention, compounds of the
formula (IV) are used for the preparation of compounds of the
formula (I) or (II):
##STR00030##
wherein A''' represents
[0522] a) hydroxyl,
[0523] b) branched or unbranched C.sub.1-C.sub.5 alkoxy,
[0524] c) branched or unbranched hydroxy C.sub.1-C.sub.5
alkoxy,
[0525] d) branched or unbranched O--C.sub.1-C.sub.5
alkyl-(O--C.sub.1-C.sub.4 alkyl), --O--C.sub.1-C.sub.4 alkyl,
[0526] e) N(C.sub.1-C.sub.5 alkyl).sub.2,
[0527] f) NH.sub.2,
[0528] g) N(H)--U'',
[0529] h) N(H)-L''' or
[0530] i) O-L''',
G''' represents
[0531] a) hydroxyl,
[0532] b) branched or unbranched O--C.sub.1-C.sub.5 alkyl,
[0533] c) branched or unbranched O--C.sub.2-C.sub.5 alkenyl,
[0534] d) branched or unbranched O--C.sub.1-C.sub.5
alkyl-(O--C.sub.1-C.sub.4alkyl).sub.n-O--C.sub.1-C.sub.4 alkyl
or
[0535] e) branched or unbranched O--C.sub.2-C.sub.5 alkynyl,
[0536] f) triphenylmethoxy,
R.sup.5 and R.sup.6 represent
[0537] a) hydrogen or
[0538] b) E'',
with the proviso that exactly one of the substituents R.sup.5 or
R.sup.6 contains an E and the other substituent in each case
contains no E, E represents
[0539] a) chloro,
[0540] b) bromo,
[0541] c) mesyloxy,
[0542] d) trifluoromesyloxy,
[0543] e) nonafluorobutyloxy or
[0544] f) tosyloxy,
Q'' represents
[0545] a) N(H)-tert-butoxycarbonyl,
[0546] b) N(H)-allyloxycarbonyl,
[0547] c) N(H)-benzyloxycarbonyl,
[0548] d) N(H)-ethoxycarbonyl,
[0549] e) N(H)-methoxycarbonyl,
[0550] f) N(H)-propoxycarbonyl,
[0551] g) N(H)-2,2,2-trichloroethoxycarbonyl,
[0552] h) N(H)-1,1-dimethylpropynyl,
[0553] i) N(H)-1-methyl-1-phenylethoxycarbonyl,
[0554] j) N(H)-1-methyl-1-(4-biphenylyl)ethoxycarbonyl,
[0555] k) N(H)-cyclobutylcarbonyl,
[0556] l) N(H)-1-methylcyclobutylcarbonyl,
[0557] m) N(H)-vinylcarbonyl,
[0558] n) N(H)-allylcarbonyl,
[0559] o) N(H)-adamantylcarbonyl,
[0560] p) N(H)-diphenylmethylcarbonyl,
[0561] q) N(H)-cinnamylcarbonyl,
[0562] r) N(H)-formyl,
[0563] s) N(H)-benzoyl,
[0564] t) N(H)-trityl,
[0565] u) N(H)-p-methoxyphenyldiphenylmethyl,
[0566] v) N(H)-di(p-methoxyphenyl)phenylmethyl, or
##STR00031##
[0567] x) N-(tert-butoxycarbonyl).sub.2,
L''' represents
[0568] a) branched or unbranched C.sub.1-C.sub.5 alkyl,
[0569] b) branched or unbranched C.sub.2-C.sub.5 alkenyl,
[0570] c) branched or unbranched C.sub.1-C.sub.5
alkyl-(O--C.sub.1-C.sub.4alkyl).sub.n-O--C.sub.1-C.sub.4alkyl,
or
[0571] d) branched or unbranched C.sub.2-C.sub.5 alkynyl,
U'' represents
[0572] a) tert-butoxycarbonyl,
[0573] b) allyloxycarbonyl,
[0574] c) benzyloxycarbonyl, or
[0575] d) ethoxycarbonyl,
X' and X'' independently of one another represent
[0576] a) branched or unbranched C.sub.1-C.sub.5 alkyl,
[0577] b) substituted or unsubstituted aryl,
[0578] c) aralkyl, or
[0579] d) heteroaryl
where n is =0, 1, 2 or 3 and all possible diastereomers and
enantiomers are part of the present subject of the invention.
[0580] The process for the preparation of the compounds of the
general formula (I) or (II) according to the invention is
distinguished in that the majority of the compounds as set forth in
formula (I) or (II) can be formed from a precursor compound of the
compounds of the formula (IV) after introduction of the .sup.18F
isotope.
[0581] The present invention relates to compounds of the general
formula (IV).
[0582] In a fifth aspect of the invention, compounds of the formula
(V) are used for the preparation of compounds of the formula (I) or
(II):
##STR00032##
wherein G''' represents
[0583] a) hydroxyl,
[0584] b) branched or unbranched O--C.sub.1-C.sub.5 alkyl,
[0585] c) branched or unbranched O--C.sub.2-C.sub.5 alkenyl,
[0586] d) branched or unbranched O--C.sub.1-C.sub.5
alkyl-(O--C.sub.1-C.sub.4alkyl), --O--C.sub.1-C.sub.4alkyl,
[0587] e) branched or unbranched O--C.sub.2-C.sub.5 alkynyl, or
[0588] f) triphenylmethoxy,
R.sup.5 and R.sup.6 represent
[0589] c) hydrogen or
[0590] d) E',
with the proviso that exactly one of the substituents R.sup.5 or
R.sup.6 contains an E and the other substituent in each case
contains hydrogen, E' represents
[0591] a) chloro,
[0592] b) bromo,
[0593] c) mesyloxy,
[0594] d) trifluoromesyloxy,
[0595] e) nonafluorobutyloxy or
[0596] f) tosyloxy,
Q''' represents
[0597] a) N-tert-butoxycarbonyl,
[0598] b) N-allyloxycarbonyl,
[0599] c) N-benzyloxycarbonyl,
[0600] d) N-ethoxycarbonyl,
[0601] e) N-methoxycarbonyl,
[0602] f) N-propoxycarbonyl,
[0603] g) N-2,2,2-trichloroethoxycarbonyl,
[0604] h) hydrogen,
[0605] i) N-1-methyl-1-phenylethoxycarbonyl,
[0606] j) N-1-methyl-1-(4-biphenylyl)ethoxycarbonyl,
[0607] k) N-cyclobutylcarbonyl,
[0608] l) N-1-methylcyclobutylcarbonyl,
[0609] m) N-vinylcarbonyl,
[0610] n) N-allylcarbonyl,
[0611] o) N-adamantylcarbonyl,
[0612] p) N-diphenylmethylcarbonyl,
[0613] q) N-cinnamylcarbonyl,
[0614] r) N-formyl, or
[0615] s) N-benzoyl,
where n is =0, 1, 2 or 3 and all possible diastereomers and
enantiomers are part of the present subject of the invention.
[0616] The process for the preparation of the compounds of the
general formula (I) or (II) according to the invention is
distinguished in that the majority of the compounds as set forth in
formula (I) or (II) can be formed from a precursor compound of the
compounds of the formula (V) after introduction of the .sup.18F
isotope.
[0617] The present invention relates to compounds of the general
formula (V).
[0618] Preferred compounds for the introduction of the .sup.18F
isotope are
4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane
K.sup.18F (crown ether salt Kryptofix K.sup.18F),
K.sup.18F,
KH.sup.18F.sub.2,
Cs.sup.18F,
Na.sup.18F or
[0619] .sup.18F tetraalkylammonium salt (e.g. [F-18]
tetrabutylammonium fluoride).
[0620] The present invention relates to compounds of the general
formula (I) or (II) and processes where the fluorine isotopes
.sup.18F and .sup.19F are used.
[0621] If one or more chiral centers is or are present in a
compound of the present subject of the invention of the formula
(I), formula (II), formula (III), formula (IV) or formula (V), all
forms of this isomer, including both enantiomers and all possible
diastereomers, should be contained herein. Compounds which contain
at least one chiral center can be employed as a racemic mixture,
optionally as a diastereomer or diastereomer-enriched mixture or as
an enantiomer-enriched mixture. The racemic, enantiomer-enriched
mixture or diastereomer mixture can optionally be separated
according to the methods known to the person skilled in the art, so
that the enantiomers or diastereomers can be employed individually.
In those cases in which a carbon-carbon double bond is present,
both "cis" and "trans" isomers are part of the present invention.
In those cases in which tautomeric forms can be present, such as,
for example, keto-enol tautomerism, all tautomeric forms are
contained in the present invention, where these forms can be
present in equilibrium or preferably in one form.
[0622] The compounds of the general formula I or II according to
the invention and their preferred embodiments are used as
medicaments.
[0623] The compounds of the general formula I or II according to
the invention and their preferred embodiments are used in the
diagnosis of physiological or pathological states.
[0624] Preferably, these compounds are used in noninvasive
PET-based diagnosis on the human or animal body.
[0625] Particularly preferably, the compounds of the general
formula I or II according to the invention and their preferred
embodiments are used in the diagnosis of tumors. Examples of tumors
of this type are malignant tumors of the gastrointestinal or
colorectal tract, carcinoma of the liver, pancreas, kidney,
bladder, thyroid gland, prostate, endometrium, ovary, testes,
melanomocarcinoma, small-cell and non-small-cell bronchial
carcinoma, dysplastic carcinoma of the oral mucosa, invasive oral
cancer; breast cancer, including hormone-dependent and
hormone-independent breast cancer, squamous epithelial carcinoma,
neurological cancers including neuroblastoma, glioma, astrocytoma,
osteosarcoma, meningioma; soft-tissue sarcoma; hemangioama and
endocrine tumors, including hypophyseal adenoma, chromocytoma,
paraganglioma, hematological tumors including lymphoma and
leukemias; or metastases of one of the abovementioned tumors.
[0626] The compounds of the general formula I or II according to
the invention and their preferred embodiments are used for the
production of a medicament for the diagnosis of tumors. Examples of
tumors of this type are malignant tumors of the gastrointestinal or
colorectal tract, carcinoma of the liver, pancreas, kidney,
bladder, thyroid gland, prostate, endometrium, ovary, testes,
melanomocarcinoma, small-cell and non-small-cell bronchial
carcinoma, dysplastic carcinoma of the oral mucosa, invasive oral
cancer; breast cancer, including hormone-dependent and
hormone-independent breast cancer, squamous epithelial carcinoma,
neurological cancers including neuroblastoma, glioma, astrocytoma,
osteosarcoma, meningioma, soft-tissue sarcoma; hemangioama and
endocrine tumors, including hypophyseal adenoma, chromocytoma,
paraganglioma, hematological tumors including lymphoma and
leukemias; or metastases of one of the abovementioned tumors.
[0627] The invention relates to pharmaceutical preparations which
contain at least one compound of the formula I or II and a
pharmaceutically tolerable vehicle.
[0628] For the use of the compounds of the formula I or II as
medicaments, these are brought into the form of a pharmaceutical
preparation which, in addition to the active substance, contains
pharmaceutical, organic or inorganic inert carrier materials
suitable for enteral or parenteral administration, such as, for
example, water, gelatin, gum arabic, lactose, starch, magnesium
stearate, talc, vegetable oils, polyalkylene glycols etc.
[0629] The invention relates to an arrangement (kit) comprising at
least one compound of the formula I, II, III, IV or V.
EXAMPLES
Example 1
Synthesis of 4-[F-18]fluoroglutamic acid
##STR00033##
[0630] Synthesis of 3:
[0631] Diisopropylamine (0.031 ml, 0.22 mmol) was added to a
suspension of complex 1 (0.1 g, 0.2 mmol) (J. Am. Chem. Soc., 1985,
107, 4252 or Tetrahedron Asymmetry, 1998, 9, 4249) in EtOH (0.4 ml)
at room temperature (RT). The reaction mixture was stirred for 30
min and subsequently treated with freshly distilled ester 2 (0.04
ml, 0.33 mmol) (Gazz. Chim. ital., 1981, 111, 249). The reaction
was monitored by means of TLC (SiO.sub.2, AcOEt/CHCl.sub.3, 1:1).
After completion of the reaction (.about.2.5 h), the reaction
mixture was neutralized by the addition of AcOH (1.5 ml; 2%). After
this, CHCl.sub.3 (15 ml) was added, the mixture was washed with
water (3.times.15 ml), and the organic phase was separated, dried
over Na.sub.2SO.sub.4 and concentrated to dryness in vacuo.
Preparative TLC (SiO.sub.2, AcOEt/CHCl.sub.3, 1:1) yielded a
mixture of the complexes 3 (S,S,S) and 3 (S,R,S/R) in a ratio of
11:1 and a yield of 28% (R.sub.f 0.52). Complex 3 (S,S,R) showed an
R.sub.f of 0.49. Complex 3 (S,S,R) was eluted from the silica gel
using MeOH (3.times.40 ml) and subsequently purified by column
chromatography on Sephadex using a 1:3 EtOH/C.sub.6H.sub.6 mixture.
Purification yielded 0.052 g (52%) of product. Elemental analysis:
found (%): C, 56.79; H, 4.85; Br, 12.14; N, 6.10; Ni, 8.17.
C.sub.32H.sub.32BrN.sub.3NiO.sub.5. Calculated (%) C, 56.75; H,
4.76; Br, 11.80; N, 6.20; Ni, 8.67.
4-[F-19]Fluoro-L-glutamic acid (nonradioactive standard for HPLC
identification of 4-[F-18]fluoro-L-glutamic acid)
[0632] Condensation of Ni--BPB-Gly with ethyl 2-fluoroacrylate. 1
ml (7.2 mmol) of i-Pr.sub.2NH was added at RT to a suspension of 3
g (6 mmol) of Ni--BPB-Gly in 15 ml of MeOH. The reaction mixture
was stirred for 30 min and subsequently treated with 3.7 ml (30
mmol) of ethyl 2-fluoroacrylate. The progress of the reaction was
monitored by means of TLC on SiO.sub.2 (AcOEt:/CHCl.sub.3 (2:3)).
After about 250 hours, the reaction was complete. After this, the
mixture was neutralized by addition of 42 ml of a 2% strength
aqueous solution of AcOH mixed with 25 ml of MeOH. The resulting
mixture of the diastereoisomeric complexes of Ni--BPB-4-F-GluOMe
was precipitated. The precipitate was filtered off and washed with
water (3.times.30 ml). The resulting solid complex was suspended in
CCl.sub.4 and concentrated to dryness in vacuo. This procedure was
repeated three times to free the mixture from water. The complexes
were purified by column chromatography (SiO.sub.2, 3.times.20 cm,
AcOEt:CHCl.sub.3, 3:2). The main fraction, 2.66 g, (4.4 mmol, 74%)
contained a mixture of Ni--BPB-(2S,4R)-4-F-GluOMe and
Ni--BPB-(2S,4S)-4-F-GluOMe in a ratio of 1.5/1. Melting point:
191-193.degree. C. [.alpha.]D25+2477 (c 0.5, CHCl3). Elemental
analysis: found (%): C, 61.76; H, 5.02; N, 6.94; Ni 9.20.
Calculated for O.sub.31H.sub.30FN.sub.3NiO.sub.5(%) C, 61.82; H,
5.02; N, 6.98; Ni, 9.74.
[0633] Separation of the complexes was achieved by
column-chromatographic separation on Toyopearl HW-55F (column
2.times.50 cm, THF/C.sub.6H.sub.6 (2:7)).
[0634] Complex Ni--BPB-(2S,4R)-4-F-GluOMe: melting point:
207-208.degree. C., [.alpha.].sub.D.sup.25+2617 (c 0.035, MeOH).
Elemental analysis: found (%): C, 61.79; H, 4.95; N, 6.88.
Calculated for C.sub.31H.sub.30FN.sub.3NiO.sub.6(%) C, 61.82; H,
5.02; N, 6.98.
[0635] Complex Ni--BPB-(2S,4S)-4-F-GluOMe. Melting point:
233-235.degree. C., [.alpha.].sub.D.sup.25+2641 (c 0.039, MeOH).
Elemental analysis: found (%): C, 61.63; H, 4.86; N, 6.84.
Calculated for C.sub.31H.sub.30FN.sub.3NiO.sub.6(%) C, 61.82; H,
5.02; N, 6.98.
[0636] Decomposition of the complex and isolation of the amino
acid. 2.75 g (4.57 mmol) of Ni--BPB-4-F-GluOMe complex were
dissolved in 30 ml of MeOH in a round-bottomed flask and treated
with stirring with 5.5 ml of HCl (6N). The reaction mixture was
heated to reflux for 15-20 min, concentrated to dryness, diluted
with 50 ml of water, and the hydro-chloride of the BPB was filtered
off and carefully washed with 3.times.30 ml of water. The combined
filtrates contain the amino acid, BPB residues and Ni.sup.2+ salts
and were adjusted to pH 5 with aqueous NH.sub.3 solution. BPB
residues were removed by extraction with CHCl.sub.3 (3.times.30
ml). The combined aqueous phases were concentrated to dryness,
treated with 3 ml of HCl (6N) and heated to reflux for 1 h. The
solution was subsequently concentrated to dryness, dissolved in 5
ml of H.sub.2O and adjusted to pH 4 using 5% strength (aqueous)
NH.sub.3 solution. The amino acid was isolated by means of ion
exchange chromatography on a Dowex column 50 w.times.8 in H.sup.+
form (eluent: 5% NH.sub.3 aq).
[0637] (2S,4R)-4-Fluoroglutamic acid: melting point:
>300.degree. C. (decomposition without melting point).
[0638] (2S,4S)-4-Fluoroglutamic acid: melting point:
>300.degree. C. (decomposition without melting point).
F-18 Radiolabeling:
[0639] Target: small-volume low-pressure silver target (1 ml)
filled with [O-18] water for .sup.18O (p,n).sub.18F reaction;
cyclotron: Scanditronix MC 17; proton bombardment at 17 MeV.
[0640] F-18 fluoride was concentrated in a QMA resin cartridge
(Waters, Sep Pak Light QMA Part No.: WAT023525) by application of
the [F-18]/[O-18] target solution. The cartridge was preconditioned
with K.sub.2CO.sub.3 solution (10 ml; 0.5 M) followed by deionized
water (15 ml).
[0641] [F-18] radioactive complex: [F-18]Fluoride (15-300 mCi) was
eluted from the QMA cartridge by means of wash solution (2 ml, MeCN
(2 ml)/tetrabutylammonium carbonate (TBAC, 0.015 ml, 20% aqueous,
pH 8)). The eluate was collected in a 5 ml vial and the solvents
were removed by azeotropic distillation at 130.degree. C. in a
stream of nitrogen.
[0642] Nucleophilic substitution: The reaction vessel containing
the dry [F-18] TBA fluoride was cooled to 80.degree. C. (preceding
step) and a solution of precursor 3 (S,S,R) (5 mg in MeCN (0.5 ml))
was added. The reaction mixture was kept at 80.degree. C. for 5-10
min. A sample of the reaction mixture was investigated by means of
radio-TLC (silica gel plate (Merck), eluent: ethyl
acetate/chloroform/acetic acid (4/1/1). Based on these radio-TLC
data, an incorporation of F-18 of 40-60% in 4 was determined.
[0643] Decomposition of the .sup.18F-fluorinated Ni complex and
release of 4-[.sup.18F]-fluoroglutamic acid (A). HCl (6 N, 0.3-0.5
ml) was added to the MeCN solution of the F-18 glutamate-nickel
precursor and the mixture was treated at 140.degree. C. for 5 min.
A sample of the resulting reaction mixture was analyzed by means of
radio-TLC (silica gel, eluent: n-butanollacetic acid/water
(12/3/5).
[0644] The TLC analysis was carried out on a MiniGita TLC scanner
(Raytest, Germany).
[0645] Decomposition of the .sup.18F-fluorinated Ni complex and
release of 4-[.sup.18]fluoroglutamic acid (B), HCl (2 N, 0.3-0.5
ml) was added to the MeCN solution of the F-18 glutamate-nickel
precursor and the mixture was treated at 140.degree. C. for 5 min.
Subsequently, it was neutralized with sodium hydroxide solution (2
N, 0.8-1.0 ml). A sample of the resulting reaction mixture was
analyzed by means of radio-TLC (silica gel, eluent:
n-butanol/acetic acid/water (12/3/5).
[0646] The TLC analysis was carried out on a MiniGita TLC scanner
(Raytest, Germany).
[0647] Prepurification: The crude product after the HCl treatment
(previous step) was taken up in 1 ml of water and added to an anion
exchange cartridge (Waters, SAX-OH form). 80% of the radioactive
products were retained on the cartridge. The radioactive products
were eluted from the cartridge by means of aqueous sodium chloride
solution NaCl (0.4 M, 2 ml). A sample was analyzed by means of
HPLC.
[0648] Identification by radio-HPLC. Pump: Gilson 305, injector:
Rheodyne (20 .mu.l injection loop), column: Zorbax-NH.sub.2;
4.6.times.150 mm, mobile phase: NaH.sub.2PO.sub.4 (10
mM)/phosphoric acid, pH 3, flow: 1 ml/min, UV absorption detector:
Gilson 116 in series with a Beckman 170 radiodetector, UV
detection: 210 nm. R.sub.t: F-19 reference ((rac)-4-F-Glu
hydrochloride (diastereomer mixture: 1/5; described vide supra)):
12.22 min (UV); radioactivity detection (Beckman): 12.64 min. A
single radioactive peak was obtained which coeluted with the
reference compound.
[0649] Identification by radio-TLC: silica gel plate (mesh 60),
eluent n-BuOH, AcOH, H20 (12:3:5). Detection: Phosphorimager: SI
Molecular Dynamics. FIG. 1.
[0650] HPLC purification: pump: Gilson 305, injector: Rheodyne (20
.mu.l injection loop), column: Zorbax-NH.sub.2; 4.6.times.150 mm,
mobile phase: NaH.sub.2PO.sub.4 (10 mM)/phosphoric acid, pH 3,
flow: 1 ml/min, UV absorption detector: Gilson 116 in series with a
Beckman 170 radiodetector, UV detection: 210 nm. An individual
radioactive peak was obtained, which coeluted with the reference
compound. If the resulting product is purified by means of HPLC,
the prepurification by means of anion exchange cartridge described
previously can be dispensed with.
[0651] It was possible to obtain the product with a radiochemical
purity of >90% and a radioactivity of 15-200 mCi (corrected for
disintegration).
Example 2
Synthesis of 2-amino-4-[F-19]fluoroglutamine (HPLC standard)
[0652] Liquid ammonia (18 g) was added to a solution of 0.27 g
(0.448 mmol) of Ni--BPB-4-F-GluOMe (M=602.28, prepared in analogy
to Example 1) in 7 ml of MeOH. The reaction solution was left at RT
for 2 h. The solution was concentrated in vacuo and the residue was
purified by preparative TLC (SiO.sub.2, CHCl.sub.3/Me.sub.2CO
(3:1)). After this, the product was further purified on Sephadex
LH-20 (C.sub.6H.sub.6/EtOH (3:1). 0.15 g (0.255 mmol, 57%) of
Ni--BPB-4-F-Gln (M.W. 587.28) was obtained.
Synthesis of 2-amino-4-[F-18]fluoroglutamine
[0653] [F-18]-radioactive Ni--BPB-4-F-GluOMe complex:
[F-18]Fluoride (15-300 mCi) was eluted from the QMA cartridge by
means of wash solution (2 ml, MeCN (2 ml)/tetrabutylammonium
carbonate (TBAC, 0.015 ml, 20% aqueous, pH 8)). The eluate was
collected in a 5 ml vial and the solvents were removed by
azeotropic distillation at 130.degree. C. in a stream of
nitrogen.
[0654] Nucleophilic substitution: The reaction vessel containing
the dry [F-18] TBA fluoride was cooled to 80.degree. C. (preceding
step) and a solution of precursor Ni--BPB-4-Br-GluOMe (5 mg in MeCN
(0.5 ml)) was added. The reaction mixture was kept at 80.degree. C.
for 5-10 min. A sample of the reaction mixture was investigated by
means of radio-TLC (silica gel plate (Merck), eluent: ethyl
acetate/chloroform/acetic acid (4/1/1). Based on these radio-TLC
data, an F-18 incorporation of 40-60% in Ni--BPB-4-F-GluOMe was
determined.
[F-18]-radioactive Ni--BPB-4-F-Gln Complex:
[0655] A mixture of 1 ml of t-BuOH and 1 g of dry NH.sub.3 (dried
over NaOH) was added to a solution of Ni--BPB-4-F-GluOMe (5-50 mCi)
in 0.5 ml of t-BuOH. The reaction mixture was heated at 42.degree.
C. for 7 min until ester complex was no longer detectable (TLC,
silica gel plate (Merck), eluent: ethyl acetate/chloroform/acetic
acid (4/1/1)). The reaction proceeded quantitatively and yielded
4-40 mCi of Ni--BPB-4-F-Gln.
[0656] Decomposition of the .sup.18F-fluorinated Ni--BPB-4-F-Gln
complex and release of 4-[.sup.18F]-fluoroglutamic acid HCl (2 N,
0.3-0.5 ml) was added to the MeCN solution of the [F-18]
Ni--BPB-4-F-Gln nickel precursor and treated for 5 min at
140.degree. C. Subsequently, the mixture was neutralized using
sodium hydroxide solution (2 N, 0.8-1.0 ml). A sample of the
resulting reaction mixture was analyzed by means of radio-TLC
(silica gel, eluent: n-butanol/acetic acid/water (12/315).
[0657] The TLC analysis was carried out on a MiniGita TLC scanner
(Raytest, Germany).
[0658] Prepurification: The crude product after the HCL treatment
(previous step) was taken up in 1 ml of water and added to an anion
exchange cartridge (Waters, SAX-OH form). 70% of the radioactive
products were retained in the cartridge. The radioactive products
were eluted from the cartridge by means of aqueous sodium chloride
solution NaCl (0.4 M, 2 ml). A sample was analyzed by means of
HPLC.
[0659] Identification by radio-HPLC. Pump: Gilson 305, injector:
Rheodyne (20 .mu.l injection loop), column: Zorbax-NH.sub.2;
4.6.times.150 mm, mobile phase: NaH.sub.2PO.sub.4 (10
mM)/phosphoric acid, pH 3, flow: 1 ml/min, UV absorption detector:
Gilson 116 in series with a Beckman 170 radiodetector, UV
detection: 210 nm. R.sub.t: F-19 reference ((rac)-4-F-Gln
hydrochloride: 8.04 min (UV); radioactivity detection (Beckman):
8.45 min. A single radioactive peak was obtained which coeluted
with the reference compound.
[0660] HPLC purification: pump: Gilson 305, injector: Rheodyne (20
.mu.l injection loop), column: Zorbax-NH.sub.2; 4.6.times.150 mm,
mobile phase: NaH.sub.2PO.sub.4 (10 mM)/phosphoric acid, pH 3,
flow: 1 ml/min, UV absorption detector: Gilson 116 in series with a
Beckman 170 radiodetector, UV detection: 210 nm. A single
radioactive peak was obtained which coeluted with the reference
compound. If the resulting product is purified by means of HPLC,
the previously described prepurification by means of anion exchange
cartridge can be dispensed with.
[0661] It was possible to obtain the product with a radiochemical
purity of >92% and a radioactivity of 3-31 mCi (corrected for
decay).
Example 3
Synthesis of 2-amino-3-[F-18]fluoropentanedicarboxylic acid
[0662] [F-18] Fluoride-containing solution (33 .mu.l, 789 MBq) was
added to a mixture of 60 .mu.l of aqueous 20% strength
tetrabutylammonium carbonate solution in 1.5 ml of acetonitrile
(1.0 ml). The solvent was removed by evaporating in a stream of
nitrogen at an oven temperature of 120.degree. C. 1 ml of anhydrous
acetonitrile was added and removed again by evaporation. This last
step was repeated again. A solution of 3 mg of diethyl
2-benzyloxycarbonylamino-3-(toluenesulfonyloxy)pentanedioate (Chem.
Pharm. Bull., 17, 5, (1969), 879-885) in 0.3 ml of anhydrous
acetonitrile was added to the residue and well stirred. After
heating at 90.degree. C. for 15 min, 2 ml of 40% strength aqueous
hydrogen bromide solution were added. The reaction mixture was
stirred at an oven temperature of 130.degree. C. for 30 min and
overpressure.
[0663] The crude product was analyzed radioanalytically by HPLC:
pump: Gilson 305, injector: Rheodyne (20 .mu.l injection loop),
column: Zorbax-NH.sub.2; 4.6.times.150 mm, mobile phase:
NaH.sub.2PO.sub.4 (10 mM)/phosphoric acid, pH 3, flow: 1 ml/min, UV
absorption detector: Gilson 116 in series with a Beckman 170
radiodetector, UV detection: 210 nm. .sup.19F reference (J. Org.
Chem.; 50; 17; (1985); 3163-3167). (UV); radioactivity detection
(Beckman). A single radioactive peak was obtained, which coeluted
with the reference compound.
[0664] The purification of the [F-18]-labeled compound was carried
out by means of HPLC purification: pump: Gilson 305, injector:
Rheodyne (20 .mu.l injection loop), column: Zorbax-NH.sub.2;
4.6.times.150 mm, mobile phase: NaH.sub.2PO.sub.4 (10
mM)/phosphoric acid, pH 3, flow: 1 ml/min, UV absorption detector:
Gilson 116 in series with a Beckman 170 radiodetector, UV
detection: 210 nm. A single radioactive peak was obtained, which
eluted simultaneously with the .sup.19F reference compound (J. Org.
Chem.; 50; 17; (1985); 3163-3167). If the resulting product is
purified by means of HPLC, the previously described prepurification
by means of anion exchange cartridge can be dispensed with. It was
possible to obtain the product with a radiochemical purity of about
92% and a radioactivity of 103 MBq.
Example 4
Di-t-butyl N-tritylglutamate
[0665] Triethylamine (40 ml) and trityl chloride (19.0 g, 68.5
mmol) were added to di-t-butylglutamic acid hydrochloride (20.0 g,
68 mmol, SIGMA, cat#: G-7501), dissolved in MeCl.sub.2 (100 ml).
The solution was stirred at room temperature for 24 h and
subsequently washed with saturated sodium carbonate solution
(3.times.) and water (3.times.). The organic phase was dried over
MgSO.sub.4, the solvent was removed in vacuo and the resulting
orange-colored oil was purified by flash chromatography on silica
gel in hexane/MeCl.sub.2 (30/70). The white solid obtained
contained the product accompanied by a residue of trityl-OH. The
trityl alcohol was crystallized by dissolving the product mixture
in a minimal amount of MeCl.sub.2 and addition of hexane. After
filtration and removal of the solvent mixture, a colorless oil was
obtained. Yield: 6.0 g, (18%). TLC: Rf=0.5 (MeCl.sub.2). Elemental
analysis C.sub.32H.sub.39NO.sub.4: found C, 76.4; H, 7.6; N, 2.9.
calculated: C, 76.6; H, 7.8; N: 2.8.
t-Butyl 2-trityl-4-carbo-t-butyloxy-5-hydroxypentanoate
[0666] n-Butyllithium (5.0 ml, 11 mmol) was added at 0.degree. C.
to a cyclohexylisopropylamine solution (3.0 ml, 15 mmol) in hexane
(50 ml) in a three-necked flask. The solution was stirred at
0.degree. C. for 30 min, subsequently cooled to -78.degree. C. and
treated with di-t-butyl N-tritylglutamate (5.0 g, 10 mmol) in
hexane (50 ml). The flask was provided with a gas inlet tube and
connected to a storage vessel, which contained paraformaldehyde and
a gas inlet for argon. After the formation of the carbanion, the
paraformaldehyde was heated to 180.degree. C. and the resulting
formaldehyde gas was led into the reaction vessel in a stream of
argon for 30 min. In the course of this the bath temperature was
kept at -78.degree. C. Subsequently, the cooling bath was removed
and the reaction mixture was slowly warmed to room temperature and
filtered in order to remove paraformaldehyde residues. The filtrate
was added to saturated aqueous ammonium chloride solution and
extracted with diethyl ether (3.times.250 ml). The combined organic
phases were dried using magnesium sulfate and the solvent was
subsequently removed in vacuo. The resulting yellowish oil was
purified by means of flash chromatography (ethyl acetate/MeCl.sub.2
(10/90)). After removal of the solvent mixture, a colorless oil was
obtained. Yield: 1.2 g, (25%). TLC: Rf=0.3 (MeCl.sub.2). Elemental
analysis C.sub.33H.sub.41NO.sub.5: found C, 74.5; H, 7.6; N, 2.8.
calculated: C, 74.6; H, 7.8; N: 2.6.
t-Butyl 2-trityl-4-carbo-t-butyloxy-5-toluoylsulfonic acid
pentanoate
[0667] t-Butyl 2-trityl-4-carbo-t-butyloxy-5-hydroxyheptanoate (532
mg, 1.00 mmol) was dissolved in MeCl.sub.2 (6 ml) and pyridine (1.2
ml). Subsequently, p-toluenesulfonyl chloride (118 mg, 0.62 mmol)
and dimethylaminopyridine (13.4 mg, 0.11 mmol) were added and the
reaction mixture was stirred at room temperature overnight under a
nitrogen atmosphere. The reaction mixture was extracted with ethyl
acetate (3.times.), the combined organic phases were dried over
sodium sulfate and filtered, and the solvents were removed on a
rotary evaporator. The crude product was dissolved in a little
MeCl.sub.2, absorbed on NH.sub.2 material and purified by means of
column chromatography in ethyl acetate/hexane (8:2). Yield: 339 mg,
(70%). Elemental analysis C.sub.40H.sub.47NO.sub.7: found C, 70.3;
H, 7.1; N, 2.2; S: 5.0 calculated: C, 70.1; H, 6.9; N, 2.0; S:
4.7.
t-Butyl 2-trityl-4-carbo-t-butyloxy-5-fluoropentanoate (HPLC
reference)
[0668] Anhydrous tetrabutylammonium fluoride (102 mg, 0.4 mmol) was
added to a solution of t-butyl
2-trityl-4-carbo-t-butyloxy-5-tolylsulfonic acid (2S)-heptanoate
(54 mg, 0.08 mmol) in anhydrous THF (3 ml). The mixture was heated
at reflux for 4 h. After the reaction mixture had been cooled to
room temperature, the mixture was treated with MeCl.sub.2 and
subjected to aqueous extraction (3.times.). Preparative thin layer
chromatography (MeCl.sub.2/MeOH (90/10)) yielded the product as a
yellowish oil. Yield: 22 mg, (51%). Elemental analysis
C.sub.33H.sub.40NO.sub.4: found C, 74.4; H, 7.7; N, 2.8.
calculated: C, 74.3; H, 7.6; N: 2.6.
[F-18]-t-Butyl 2-trityl-4-carbo-t-butyloxy-5-fluoropentanoate
[0669] [F-18]Fluoride was prepared in a cyclotron by means of the
[O-18](p,n)[F-18] reaction. The isotope solution was added to a
Sep-Pack Light QMA cartridge and dried in a stream of air. The
[F-18]fluoride was eluted from the cartridge using a Kryptofix
2.2.2/K.sub.2CO.sub.3 solution (22 mg of K2.2.2, 4.6 mg of
K.sub.2CO.sub.3, 2 ml, MeCN (1.77 ml), water (0.23 ml)). The
solvents were removed at 120.degree. C. in a stream of argon. The
residue was azeotropically distilled twice at 120.degree. C. in a
stream of argon with 1 ml of anhydrous MeCN. A solution of the
tosylate precursor of t-butyl
2-trityl-4-carbo-t-butyloxy-5-tolylsulfonic acid (2S)-heptanoate (4
mg) in MeCN (0.2 ml) was added to a vessel containing the dried
[F-18]fluoride. The reaction mixture was heated at 120.degree. C.
for 10 min. Subsequently, the solvent was removed in a stream of
argon. The solvent (MeCN) was removed in a stream of nitrogen and
the residue was treated with HCl (6 N, 0.3-0.5 ml) at 140.degree.
C. for 5 min. A sample of the resulting reaction mixture was
analyzed by means of radio-TLC (silica gel, eluent:
n-butanol/acetic acid/water (12/3/5).
[0670] The TLC analysis was carried out on a MiniGita TLC scanner
(Raytest, Germany).
[0671] Prepurification: The crude product after the HCl treatment
(previous step) was taken up in 1 ml of water and added to an anion
exchange cartridge (Waters, SAX-OH form). 80% of the radioactive
products was retained on the cartridge. The radioactive products
were eluted from the cartridge by means of aqueous sodium chloride
solution NaCl (0.4 M, 2 ml). A sample was analyzed by means of
HPLC.
[0672] Identification by radio-HPLC. Pump: Gilson 305, injector:
Rheodyne (20 .mu.l injection loop), column: Zorbax-NH.sub.2;
4.6.times.150 mm, mobile phase: NaH.sub.2PO.sub.4 (10
mM)/phosphoric acid, pH 3, flow: 1 ml/min, UV absorption detector:
Gilson 116 in series with a Beckman 170 radiodetector, UV
detection: 210 nm. R.sub.t: F-19 reference ((rac)-4-F-Glu
hydrochloride): 14.53 min (UV); radioactivity detection (Beckman):
14.68 min. A single radioactive peak was obtained which coeluted
with the reference compound.
[0673] HPLC purification: pump: Gilson 305, injector: Rheodyne (20
.mu.l injection loop), column: Zorbax-NH.sub.2; 4.6.times.150 mm,
mobile phase: NaH.sub.2PO.sub.4 (10 mM)/phosphoric acid, pH 3,
flow: 1 ml/min, UV absorption detector: Gilson 116 in series with a
Beckman 170 radiodetector, UV detection: 210 nm. A single
radioactive peak was obtained which coeluted with the reference
compound. If the resulting product is purified by means of HPLC,
the previously described prepurification by means of anion exchange
cartridge can be dispensed with.
[0674] It was possible to obtain the product with a radiochemical
purity of >90% and a radioactivity of 20-200 mCi (corrected for
decay).
Example 5
[0675] Synthesis of 1-tert-butyl 2-methyl
4-methanesulfonyloxy-5-oxopyrrolidine-1,2-dicarboxylate (8a)
(according to N. Sharma et al. Tetrahedron Lett. 2004, 45,
1403-1406.) A solution of 15.29 g (71.5 mmol) of sodium periodate
and 0.18 g (0.87 mmol) of ruthenium(III) chloride hydrate in 230 ml
of water was added to 5.78 g (17.9 mmol) of Boc-gamma-MsO-proline
methyl ester in 230 ml of ethyl acetate. The mixture was left at
room temperature for three days with vigorous stirring.
Subsequently, the phases were separated, the aqueous phase was
extracted twice with ethyl acetate (80 ml) and the combined organic
phases were stirred with 50 ml of isopropanol for 30 min. The
mixture was dried over magnesium sulfate, filtered and the solvent
was removed in vacuo. The crude product was purified by column
chromatography (silica gel, hexane/ethyl acetate=6.5:3.5 to 5:5).
1.29 g (20%) of 1-tert-butyl 2-methyl
4-methanesulfonyloxy-5-oxopyrrolidine-1,2-dicarboxylate (8a) were
obtained as a colorless solid.
[0676] Elemental analysis C.sub.12H.sub.19NO.sub.8S: found C,
42.90; H, 5.68; N, 4.14. calculated: C, 42.73; H, 5.68; N,
4.15.
[0677] Synthesis of dimethyl
2-tert-butoxycarbonylamino-4-methanesulfonyloxypentane-dicarboxylate
(7a) (according to: X. Zhang Tetrahedron Lett. 2001, 42,
5335-5338.) 600 mg (1.78 mmol) of 1-tert-butyl 2-methyl
4-methanesulfonyloxy-5-oxopyrrolidine-1,2-dicarboxylate were
dissolved in 7.5 ml of dichloromethane. 1.5 ml of methanol and 12.3
mg (0.089 mmol) of potassium carbonate were added. The resulting
mixture was stirred at room temperature for three hours.
Subsequently, the solvent was removed in vacuo and the crude
product was purified by column chromatography (silica gel,
dichloromethane/methanol=99.7:0.3 to 99.6:0.4). 608 mg (83%) of
dimethyl
2-tert-butoxycarbonylamino-4-methanesulfonyloxypentanedicarboxyl-
ate (7a) were obtained as a colorless oil.
[0678] Elemental analysis C.sub.13H.sub.23NO.sub.9S: found C,
42.10; H, 6.29; N, 3.69. calculated: C, 42.27; H, 6.28; N,
3.79.
F-18 labeling of dimethyl
2-tert-butoxycarbonylamino-4-methanesulfonyloxypentane-dicarboxylate
(7a)
[0679] [F-18]Fluoride was prepared in a cyclotron by means of the
[O-18](p,n) [F-18] reaction. The isotope solution (2.47 GBq) was
added to a Sep-Pack Light QMA cartridge. The [F-18]fluoride was
eluted from the cartridge using a Kryptofix 2.2.2/K.sub.2CO.sub.3
solution (5 g of K2.2.2, 1 mg of K.sub.2CO.sub.3, MeCN (1.5 ml),
water (0.5 ml)). The solvent was removed at 120.degree. C. in a
stream of nitrogen with addition of acetonitrile (three times 1
ml).
[0680] 5 mg (13.6 .mu.mol) of dimethyl
2-tert-butoxycarbonylamino-4-methanesulfonyloxypentane-dicarboxylate
(7a) in 1 ml of acetonitrile were added and the resulting mixture
was stirred for 10 min at 100.degree. C. After cooling to about
60.degree. C., the mixture was added by means of a Silica-Plus
cartridge.
[0681] The intermediate 6a was purified by HPLC (C18,
acetonitrile/water). The HPLC fraction was diluted with water
(about 50 ml) and added by means of a C18 cartridge. The
intermediate was eluted with 1 ml of acetonitrile. 533 MBq (34%
d.c.) of dimethyl 2-tert-butoxycarbonylamino-4-[F-18]fluoropentane
dicarboxylate (6a) were obtained in a synthesis time of 64 min.
Synthesis of 4-[F-18]fluoroglutamic acid (5) by deprotection of
dimethyl
2-tert-butoxycarbonylamino-4-[F-18]fluoropentanedicarboxylate
(6a)
[0682] 533 MBq of dimethyl
2-tert-butoxycarbonylamino-4-[F-18]-fluoropentanedicarboxylate (6a)
in 1 ml of acetonitrile were treated with 0.5 ml of 4N HCl. The
mixture was heated for 5 min in an open vial with stirring at
140.degree. C. (oil bath temperature). A further 0.5 ml of 4N HCl
was added and the mixture was heated for 5 min in a closed vial
with stirring at 140.degree. C. (oil bath temperature).
[0683] After cooling to room temperature, the solution was
neutralized by addition of about 1.5 ml of 2N NaOH.
[0684] It was possible to react dimethyl
(2-tert-butoxycarbonylamino-4-[F-18]fluoropentane-dicarboxylate
(6a) quantitatively (d.c.) to give 4-[F-18]fluoroglutamic acid
(5).
Example 6
F-18 labeling of 1-tert-butyl 2-methyl
4-methanesulfonyloxy-5-oxopyrrolidine-1,2-dicarboxylate (8a)
[0685] [F-18]Fluoride was prepared in a cyclotron by means of the
[O-18](p,n)[F-18] reaction. The isotope solution (3.27 GBq) was
added to a Sep-Pack Light QMA cartridge. The [F-18]fluoride was
eluted from the cartridge using a Kryptofix 2.2.2/K.sub.2CO.sub.3
solution (5 g of K2.2.2, 1 mg of K.sub.2CO.sub.3, MeCN (1.5 ml),
water (0.5 ml)). The solvent was removed at 120.degree. C. in a
stream of nitrogen with addition of acetonitrile (three times 1
ml).
[0686] 5 mg (14.9 .mu.mol) of 1-tent-butyl 2-methyl
4-methanesulfonyloxy-5-oxopyrrolidine-1,2-dicarboxylate (8a) in 1
ml of acetonitrile were added and the resulting mixture was stirred
for 10 min at 100.degree. C. After cooling to about 60.degree. C.,
the mixture was added by means of a Silica-Plus cartridge.
[0687] The intermediate was purified by HPLC (C18,
acetonitrile/water). The HPLC fraction was diluted with water
(about 50 ml) and added by means of a C18 cartridge. The
intermediate was eluted using 1 ml of acetonitrile. 421 MBq (23%
d.c.) of 1-tert-butyl 2-methyl
4-[F-18]fluoro-5-oxopyrrolidine-1,2-dicarboxylate were obtained in
a synthesis time of 95 min.
Synthesis of 4-[F-18]fluoroglutamic acid (5) by deprotection of
1-tert-butyl 2-methyl
4-[F-18]-fluoro-5-oxopyrrolidine-1,2-dicarboxylate
[0688] 221 MBq of 1-tert-butyl 2-methyl
4-[F-18]-fluoro-5-oxopyrrolidine-1,2-dicarboxylate contained in 0.5
ml of acetonitrile were treated with 0.5 ml of 6N HCl. The mixture
was heated at 130.degree. C. (oil bath temperature) for 10 min with
stirring. After cooling to room temperature, the solution was
neutralized by addition of about 600 .mu.l of 4N NaOH.
[0689] 172 MBq (91% d.c.) of 4-[F-18]fluoroglutamic acid (5) were
obtained.
Example 7
Synthesis of 1-tert-butyl 2-methyl
4-[2-(toluene-4-sulfonyloxy)ethoxy]pyrrolidine-1,2-dicarboxylate
[0690] A solution of 2.45 g (10.0 mmol) of 1-tert-butyl 2-methyl
4-[hydroxy]pyrrolidine-1,2-dicarboxylate (24) in DMF (10 ml) was
added to a suspension of 0.65 g (15 mmol) of sodium hydride in DMF
(20 ml). After 15 min, a solution of 5.56 g (15.0 mmol) of
1,2-ethanediol bistosylate in DMF (10 ml) was added. The batch was
subsequently reacted in 3 portions at 100.degree. C. in a microwave
for 45 minutes. The batch was concentrated and treated with water
and ethyl acetate. After phase separation, the aqueous phase was
extracted with ethyl acetate. The combined organic phases were
dried over sodium sulfate, filtered and the solvent was removed in
vacuo. The crude product was purified by column chromatography
(silica gel, hexane/ethyl acetate). 1.2 g (27%) of 1-tert-butyl
2-methyl
4-[2-(toluene-4-sulfonyloxy)ethoxy]pyrrolidine-1,2-dicarboxylate
were obtained.
[0691] Elemental analysis C.sub.20H.sub.29NO.sub.5S: found C,
54.20; H, 6.66; N, 3.23. calculated: C, 54.16; H, 6.59; N,
3.16.
Synthesis of 1-tert-butyl 2-methyl
5-oxo-4-[2-(toluene-4-sulfonyloxy)ethoxy]-pyrrolidine-1,2-dicarboxylate
(23)
[0692] A solution of 1.07 g (5.0 mmol) of sodium periodate and
0.338 g (0.15 mmol) of ruthenium(III) chloride hydrate in 12.5 ml
of water was added to 0.44 g (1 mmol) of 1-tert-butyl 2-methyl
4-[2-(toluene-4-sulfonyloxy)ethoxy]pyrrolidine-1,2-dicarboxylate in
20 ml of dichloromethane. The mixture was left at room temperature
for three days with vigorous stirring. Subsequently, the phases
were separated, the aqueous phase was extracted twice with ethyl
acetate (20 ml) and the combined organic phases were stirred with 5
ml of isopropanol for 30 min. The mixture was dried over magnesium
sulfate, filtered and the solvent was removed in vacuo. The crude
product was purified by column chromatography (silica gel,
hexane/ethyl acetate). 0.11 g (24%) of 1-tert-butyl 2-methyl
5-oxo-4-[2-(toluene-4-sulfonyloxy)ethoxy]pyrrolidine-1,2-dicarboxylate
(23) was obtained as a colorless oil.
[0693] Elemental analysis C.sub.20H.sub.27NO.sub.9S: found C,
52.37; H, 6.02; N, 3.11. calculated: C, 52.51; H, 5.95; N,
3.06.
Synthesis of dimethyl
2-tert-butoxycarbonylamino-4-[2-(toluene-4-sulfonyloxy)-ethoxy]pentanedic-
arboxylate (25)
[0694] 100 mg (0.22 mmol) of 1-tert-butyl 2-methyl
5-oxo-4-[2-(toluene-4-sulfonyloxy)ethoxy]-pyrrolidine-1,2-dicarboxylate
were dissolved in 3 ml of dichloromethane. 1 ml of methanol and 6
mg (0.04 mmol) of potassium carbonate was added. The resulting
mixture was stirred at room temperature for three hours.
Subsequently, the solvent was removed in vacuo and the crude
product was by column chromatography (silica gel,
dichloromethane/methanol). 97 mg (91%) of dimethyl
2-tert-butoxycarbonylamino-4-[2-(toluene-4-sulfonyloxy)ethoxy]pentanedica-
rboxylate (25) were obtained as a colorless oil.
[0695] Elemental analysis C.sub.21H.sub.31NO.sub.10S: found C,
51.48; H, 6.36; N, 2.88. calculated: C, 51.52; H, 6.38; N,
2.86.
[0696] F-18 labeling of dimethyl
2-tert-butoxycarbonylamino-4-[2-(toluene-4-sulfonyloxy)-ethoxy]pentanedic-
arboxylate (25) [F-18]Fluoride was prepared in a cyclotron by means
of the [O-18](p,n)[F-18] reaction. The isotope solution (1.57 GBq)
was added to a Sep-Pack Light QMA-cartridge. The [F-18]fluoride was
eluted from the cartridge using a Kryptofix 2.2.2/K.sub.2CO.sub.3
solution (5 g of K2.2.2, 1 mg of K.sub.2CO.sub.3, MeCN (1.5 ml),
water (0.5 ml)). The solvent was removed at 120.degree. C. in a
stream of nitrogen with addition of acetonitrile (three times 1
ml).
[0697] 5 mg (10.2 .mu.mol) of dimethyl
2-tert-butoxycarbonylamino-4-[2-(toluene-4-sulfonyloxy)-ethoxy]pentanedic-
arboxylate (25) in 1 ml of acetonitrile were added and the
resulting mixture was stirred at 100.degree. C. for 10 min. After
cooling to about 60.degree. C., the mixture was added by means of a
Silica-Plus cartridge.
[0698] The intermediate was purified by HPLC (C18,
acetonitrile/water). The HPLC fraction was diluted with water
(about 50 ml) and added by means of a C18 cartridge. The
intermediate was eluted with 1 ml of acetonitrile. In a synthesis
time of 78 min, 337 MBq (35% d.c.) of dimethyl
2-tert-butoxycarbonylamino-4-(2-[F-18]fluoroethoxy)pentanedicarb-
oxylate were obtained (22).
Synthesis of 2-amino-4-(2-[F-18]-fluoroethoxy)pentanedicarboxylic
acid (20) by deprotection of dimethyl
2-tert-butoxycarbonylamino-4-(2-[(F-18]-fluoroethoxy)-pentanedicarboxylat-
e (22)
[0699] 337 MBq of dimethyl
2-tert-butoxycarbonylamino-4-(2-[F-18]difluoroethoxy)pentanedicarboxylate
(22) in 1 ml of acetonitrile were treated with 0.5 ml of 4N HCl.
The mixture was heated for 10 min with stirring at 130.degree. C.
(oil bath temperature). After cooling to room temperature, the
solution was neutralized by addition of about 700 .mu.l of 2N
NaOH.
[0700] 288 MBq (98% d.c.) of
2-amino-4-(2-[F-18]fluoroethoxy)pentanedicarboxylic acid (20) were
obtained.
Synthesis of 1-tent-butyl 2-methyl
4-(2-fluoroethoxy)pyrrolidine-1,2-dicarboxylate
[0701] A solution of 2.45 g (10.0 mmol) of 1-tert-butyl 2-methyl
4-[hydroxy]pyrrolidine-1,2-dicarboxylate (24) in DMF (10 ml) was
added to a suspension of 0.65 g (15 mmol) of sodium hydride in DMF
(20 ml). After 15 min, a solution of 1.90 g (15.0 mmol) of
1-bromo-2-fluoroethane in DMF (10 ml) was added. The batch was
subsequently reacted in 3 portions at 100.degree. C. in a microwave
for 45 minutes. The batch was concentrated and treated with water
and ethyl acetate. After phase separation, the aqueous phase was
extracted with ethyl acetate. The combined organic phases were
dried over sodium sulfate, filtered and the solvent was removed in
vacuo. The crude product was purified by column chromatography
(silica gel, hexane/ethyl acetate). 2.10 g (48%) of 1-tert-butyl
2-methyl 4-(2-fluoroethoxy)-pyrrolidine-1,2-dicarboxylate were
obtained.
[0702] Elemental analysis C.sub.93H.sub.22FNO.sub.5: found C,
53.48; H, 7.70; N, 4.85. calculated: C, 53.60; H, 7.61; N,
4.81.
1-tert-Butyl 2-methyl
4-(2-fluoroethoxy)-5-oxopyrrolidine-1,2-dicarboxylate (26)
[0703] A solution of 4.3 g (20.0 mmol) of sodium periodate and 1.7
g (0.6 mmol) of ruthenium(III) chloride hydrate in 50 ml of water
was added to 1.45 g (5 mmol) of 1-tert-butyl 2-methyl
4-(2-fluoroethoxy)pyrrolidine-1,2-dicarboxylate in 80 ml of
dichloromethane. The mixture was left at room temperature for three
days with vigorous stirring. Subsequently, the phases were
separated, the aqueous phase was extracted twice with ethyl acetate
(25 ml) and the combined organic phases were stirred with 10 ml of
isopropanol for 30 min. The mixture was dried over sodium sulfate,
filtered and the solvent was removed in vacuo. The crude product
was purified by column chromatography (silica gel, hexane/ethyl
acetate). 0.26 g (17%) of 1-tert-butyl 2-methyl
4-(2-fluoroethoxy)-5-oxopyrrolidine-1,2-dicarboxylate (26) was
obtained as.
[0704] Elemental analysis C.sub.13H.sub.20FNO.sub.6: found C,
51.18; H, 6.55; N, 3.54. calculated: C, 51.14; H, 6.60; N,
4.59.
Dimethyl
2-tert-butoxycarbonylamino-4-(2-fluoroethoxy)pentanedicarboxylate
(27)
[0705] 150 mg (0.49 mmol) of 1-tert-butyl 2-methyl
4-(2-fluoroethoxy)-5-oxopyrrolidine-1,2-dicarboxylate (26) were
dissolved in 5 ml of dichloromethane. 2 ml of methanol and 6 mg
(0.04 mmol) of potassium carbonate were added. The resulting
mixture was stirred at room temperature for three hours.
Subsequently, the solvent was removed in vacuo and the crude
product was by column chromatography (silica gel,
dichloromethane/methanol). 145 mg (88%) of dimethyl
2-tert-butoxycarbonylamino-4-(2-fluoroethoxy)pentanedicarboxylate
(27) were obtained.
[0706] Elemental analysis C.sub.14H.sub.24FNO.sub.7: found C,
40.06; H, 7.11; N, 4.12. calculated: C, 49.85; H, 7.17; N, 4.15
2-Amino-4-(2-fluoroethoxy)pentanedicarboxylic acid (28)
[0707] 100 mg of dimethyl
3-tert-butoxycarbonylamino-4-(2-fluoroethoxy)pentanedicarboxylate
(27) were dissolved in 50 ml of MeOH and treated with stirring with
1 ml of HCl (6N). The reaction mixture was heated to reflux for
15-20 min, concentrated to dryness, diluted with 50 ml of water,
and the hydrochloride was filtered off and carefully washed with
3.times.5 ml of water. The amino acid 28 was isolated by means of
ion exchange chromatography on a 50 w.times.8 Dowex column in
H.sup.+ form (eluent: 5% NH.sub.3 aq).
Example 8
[0708] Synthesis of dimethyl
2-(3-bromopropyl)-4-tert-butoxycarbonylaminopentane-dicarboxylate
(33) (according to: S. Hanessian, et al. J. Org. Chem. 2005, 70,
5070-5085.) LiHMDS (7.8 ml, 1M solution in THF) was added at
-78.degree. C. to a solution of 1.00 g (3.63 mmol) of dimethyl
N-Boc-glutamate (26) in dry THF (20 ml). The resulting mixture was
stirred for 45 min at -78.degree. C. Subsequently, a solution of
1.10 g (5.45 mmol) of 1,3-dibromopropane in THF (10 ml) was slowly
added dropwise at -78.degree. C. The mixture was stirred for 60
min. It was quenched by addition of ammonium chloride solution,
warmed to RT and extracted with dichloromethane. The combined
organic phases were washed with saturated sodium chloride solution
and dried over sodium sulfate. The solvent was removed in vacuo and
the crude product was purified by column chromatography (silica
gel, ethyl acetate/hexane 10:90 to 40:60). 0.490 g (34%) of
dimethyl
2-(3-bromopropyl)-4-tert-butoxycarbonylaminopentanedicarboxylate
(33) were obtained as a colorless oil.
[0709] Elemental analysis C15H26BrNO6: found C, 45.21; H, 6.53; N,
3.60. calculated: C, 45.46; H, 6.61; N, 3.53.
F-18 labeling of dimethyl
2-(3-bromopropyl)-4-tert-butoxycarbonylaminopentane-dicarboxylate
(33)
[0710] [F-18]Fluoride was prepared in a cyclotron by means of the
[O-18](p,n)[F-18] reaction. The isotope solution (1.33 GBq) was
added to a Sep-Pack Light QMA cartridge. The [F-18]fluoride was
eluted from the cartridge using a Kryptofix 2.2.2/K.sub.2CO.sub.3
solution (5 g of K2.2.2, 1 mg of K.sub.2CO.sub.3, MeCN (1.5 ml),
water (0.5 ml)). The solvent was removed at 120.degree. C. in a
stream of nitrogen with addition of acetonitrile (three times 1
ml).
[0711] 5 mg (12.6 .mu.mol) of dimethyl
2-(3-bromopropyl)-4-tert-butoxycarbonylaminopentane-dicarboxylate
(33) in 1 ml of acetonitrile were added and the resulting mixture
was stirred for 10 min at 100.degree. C. After cooling to about
60.degree. C., the mixture was added by means of a Silica-Plus
cartridge.
[0712] The intermediate was purified by HPLC (C18,
acetonitrile/water). The HPLC fraction was diluted with water
(about 50 ml) and added by means of a C18 cartridge. The
intermediate was eluted using 1 ml of acetonitrile. In a synthesis
time of 90 min, 346 MBq (46% d.c.) of dimethyl
2-tert-butoxycarbonylamino-4-(3-[F-18]fluoropropyl)pentanedicarb-
oxylate (31) were obtained.
Synthesis of 2-amino-4-(3[F-18]fluoropropyl)pentanedicarboxylic
acid (29) by deprotection of dimethyl
2-tert-butoxycarbonylamino-4-(3-[F-18]fluoropropyl)-pentanedicarboxylate
(31)
[0713] 346 MBq of dimethyl
2-tert-butoxycarbonylamino-4-(3-[F-18]-fluoropropyl)pentane-dicarboxylate
(3) in 1 ml of acetonitrile were treated with 0.5 ml of 4N HCl. The
mixture was heated with stirring at 130.degree. C. (oil bath
temperature) for 10 min. After cooling to room temperature, the
solution was neutralized by addition of about 650 .mu.l of 2N
NaOH.
[0714] 288 MBq (96% d.c.) of
2-amino-4-(3-[F-18]fluoropropyl)pentanedicarboxylic acid (29) were
obtained.
[0715] Synthesis of dimethyl
2-tert-butoxycarbonylamino-4-(3-fluoropropyl)pentane-dicarboxylate
(36) (according to: S. Hanessian, et al. J. Org. Chem. 2005, 70,
5070-5085.) LiHMDS (7.8 ml, 1M solution in THF) was added at
-78.degree. C. to a solution of 1.00 g (3.63 mmol) of dimethyl
N-Boc-glutamate (26) in dry THF (20 ml). The resulting mixture was
stirred for 45 min at -78.degree. C. Subsequently, a solution of
0.77 g (5.45 mmol) of 1-bromo-3-fluoropropane in THF (10 ml) was
slowly added dropwise at -78.degree. C. The mixture was stirred for
60 min. It was quenched by addition of ammonium chloride solution,
warmed to RT and extracted with dichloromethane. The combined
organic phases were washed with saturated sodium chloride solution
and dried over sodium sulfate. The solvent was removed in vacuo and
the crude product was purified by column chromatography (silica
gel, ethyl acetate/hexane 10:90 to 40:60). 0.318 g (29%) of
dimethyl
2-tert-butoxycarbonylamino-4-(3-fluoropropyl)pentanedicarboxylate
(36) was obtained.
[0716] Elemental analysis C.sub.15H.sub.26FNO.sub.6: found C,
53.88; H, 7.87; N, 4.13. calculated: C, 53.72; H, 7.81; N,
4.18.
2-Amino-4-(2-fluoropropyl)pentanedicarboxylic acid (38)
[0717] 200 mg of dimethyl
2-tert-butoxycarbonylamino-4-(3-fluoropropyl)pentanedicarboxylate
(36) were dissolved in 75 ml of MeOH and treated with 1.5 ml of HCl
(6N) with stirring. The reaction mixture was heated to reflux for
15-20 min, concentrated to dryness, diluted with 50 ml of water,
and the hydrochloride was filtered off and carefully washed with
3.times.10 ml of water. The amino acid 38 was isolated in H.sup.+
form by means of ion exchange chromatography on a 50 w.times.8
Dowex column (eluent: 5% NH.sub.3 aq).
Example 9
Synthesis of dimethyl
2-tert-butoxycarbonylamino-4-[4-(toluene-4-sulfonyloxy)butyl]-pentanedica-
rboxylate (34) (according to: S. Hanessian, et al. J. Org. Chem.
2005, 70, 5070-5085.)
[0718] LiHMDS (7.8 ml, 1M solution in THF) was added at -78.degree.
C. to a solution of 1.00 g (3.63 mmol) of dimethyl N-Boc-glutamate
(35) in dry THF (20 ml). The resulting mixture was stirred at
-78.degree. C. for 45 min. Subsequently, a solution of 2.17 g (5.45
mmol) of 1,4-butanediol ditosylate in THF (10 ml) was slowly added
dropwise at -78.degree. C. The mixture was stirred for 60 min. It
was quenched by addition of ammonium chloride solution, warmed to
RT and extracted with dichloromethane. The combined organic phases
were washed with saturated sodium chloride solution and dried over
sodium sulfate. The solvent was removed in vacuo and the crude
product was purified by column chromatography (silica gel, ethyl
acetate/hexane 10:90 to 20:80). 0.418 g (23%) of dimethyl
2-tert-butoxycarbonylamino-4-[4-(toluene-4-sulfonyloxy)butyl]pentanedicar-
boxylate (34) was obtained.
[0719] Elemental analysis C.sub.23H.sub.35NO.sub.9S: found C, 54.9;
H, 7.1; N, 2.7. calculated: C, 55.07; H, 7.03; N, 2.79.
F-18 labeling of dimethyl
2-tert-butoxycarbonylamino-4-[4-(toluene-4-sulfonyloxy)-butyl]pentanedica-
rboxylate (34)
[0720] [F-18]Fluoride was prepared in a cyclotron by means of the
[O-18](p,n)[F-18] reaction. The isotope solution (3.08 GBq) was
added to a Sep-Pack Light QMA cartridge. The [F-18]fluoride was
eluted from the cartridge using a Kryptofix 2.2.2/K.sub.2CO.sub.3
solution (5 g of K2.2.2, 1 mg of K.sub.2CO.sub.3, MeCN (1.5 ml),
water (0.5 ml)). The solvent was removed at 120.degree. C. in a
stream of nitrogen with addition of acetonitrile (three times 1
ml).
[0721] 5 mg (10.0 .mu.mol) of dimethyl
2-tert-butoxycarbonylamino-4-[4-(toluene-4-sulfonyloxy)butyl]-pentanedica-
rboxylate (34) in 1 ml of acetonitrile were added and the resulting
mixture was stirred at 100.degree. C. for 10 min. After cooling to
about 60.degree. C., the mixture was added by means of a
Silica-Plus cartridge.
[0722] The intermediate was purified by HPLC (C18,
acetonitrile/water). The HPLC fraction was diluted with water
(about 50 ml) and added by means of a C18 cartridge. The
intermediate was eluted using 1 ml of acetonitrile. In a synthesis
time of 92 min, 812 MBq (48% d.c.) of dimethyl
2-tert-butoxycarbonylamino-4-(4-[F-18]fluorobutyl)pentanedicarbo-
xylate (32) were obtained.
Synthesis of dimethyl 2-amino-4-(4-fluorobutyl)pentanedicarboxylic
acid (30) by deprotection of
2-tert-butoxycarbonylamino-4-(4-[F-18]fluorobutyl)pentane-dicarboxylate
(32)
[0723] 812 MBq of dimethyl
2-tert-butoxycarbonylamino-4-(4-[F-18]fluorobutyl)pentan-
dicarboxylate (32) in 1 ml of acetonitrile were treated with 0.5 ml
of 4N HCl. The mixture was heated with stirring to 130.degree. C.
(oil bath temperature) for 10 min. After cooling to room
temperature, the solution was neutralized by addition of about 700
.mu.l of 2N NaOH.
[0724] 691 MBq (97% d.c.) of
2-amino-4-(4-fluorobutyl)pentanedicarboxylic acid (30) were.
[0725] Synthesis of dimethyl
2-tert-butoxycarbonylamino-4-(3-fluorobutyl)pentane-dicarboxylate
(37) (according to: S. Hanessian, et al. J. Org. Chem. 2005, 70,
5070-5085.) LiHMDS (7.8 ml, 1M solution in THF) was added at
-78.degree. C. to a solution of 1.00 g (3.63 mmol) of dimethyl
N-Boc-glutamate (26) in dry THF (20 ml). The resulting mixture was
stirred for 45 min at -78.degree. C. Subsequently, a solution of
0.84 g (5.45 mmol) of 1-bromo-3-fluoropropane in THF (10 ml) was
slowly added dropwise at -78.degree. C. The mixture was stirred for
60 min. It was quenched by addition of ammonium chloride solution,
warmed to RT and extracted with dichloromethane. The combined
organic phases were washed with saturated sodium chloride solution
and dried over sodium sulfate. The solvent was removed in vacuo and
the crude product was purified by column chromatography (silica
gel, ethyl acetate/hexane 10:90 to 40:60). 0.596 g (47%) of
dimethyl
2-tert-butoxycarbonylamino-4-(3-fluorobutyl)-pentanedicarboxylate
(37) was obtained.
[0726] Elemental analysis C.sub.16H.sub.28FNO.sub.6: found C,
54.94; H, 8.01; N, 4.04. calculated: C, 55.00; H, 8.08; N,
4.01.
2-Amino-4-(2-fluoropropyl)pentanedicarboxylic acid (39)
[0727] 300 mg of dimethyl
2-tert-butoxycarbonylamino-4-(3-fluorobutyl)pentanedicarboxylate
(37) were dissolved in 100 ml of MeOH and treated with 5 ml of HCl
(6N) with stirring. The reaction mixture was heated to reflux for
15-20 min, concentrated to dryness, diluted with 100 ml of water,
and the hydrochloride was filtered off and carefully washed with
3.times.25 ml of water. The amino acid 38 was isolated by means of
ion exchange chromatography on a 50 w.times.8 Dowex column in
H.sup.+ form (eluent: 5% NH.sub.3 aq).
Example 10
Biological Characterization
[0728] For the evaluation of the tumor cell uptake of
[.sup.18F]glutamic acid, cell uptake experiments were carried out
in human A549 (non-small-cell bronchial carcinoma) and HT29
(colonic carcinoma) cells. The tumor cell uptake of the glutamic
acid derivatives was compared to [.sup.18F]FDG (gold standard for
oncological PET investigations).
[0729] The results are shown in FIG. 1.
[0730] FIG. 2: Comparison of the time-dependent tumor cell uptake
of [.sup.18F]-4-glutamic acid [20-35 .mu.M] (on the left) and
[F-18]FDG [2 .mu.M] (on the right) in A549 cells. The cells were
incubated with 250 kBq/well. For displacement experiments,
L-glutamic acid (1 mM) or glucose (5 mM) was used (mean
value.+-.standard deviation, n=3).
[0731] The surprisingly high uptake of [.sup.18F]-4-glutamic acid
in A549 and HT29 tumor cells shows that these fluorinated glutamic
acid derivatives should have potential for tumor demonstration for
the purposes of the invention.
[0732] Analogous uptake results were achieved for
[.sup.18F]-4-glutamine,
2-amino-4-(2-[F-18]fluoro-ethoxy)pentanedicarboxylic acid and
2-amino-4-(3-[F-18]fluoropropyl)pentanedicarboxylic acid.
[0733] For the evaluation of the tumor enrichment and the tissue
distribution in experimental animals, [.sup.18F]-4-glutamic acid
was tested in a murine F9 teratocarcinoma model in NMRI nude mice
and a murine B16F1 melanoma model in C57B16 mice.
[0734] For this, 1.times.10.sup.6 cells (F9) or 5.times.10.sup.5
cells (B16F1) respectively were suspended in 100 .mu.l of
phosphate-buffered physiological saline solution and inoculated
subcutaneously into the right, rear flank of the corresponding
experimental animal species (NMRI for F9 and C57-B16 for B16F1)
(Berndorff et al. Clin. Cancer Res. 2005, 11, 2005). After 14 days
(F9) and 10 days (B16), the tumors achieved a size of about 80-100
mm.sup.2. [.sup.18F]-4-Glutamic acid (370 kBq, in 100 .mu.l of
physiological saline solution) was administered intravenously to
the tail vein. After 15; 60 and 120 min in each case, the animals
were killed, organ and tumor removed, weighed and measured for
radioactive content. The corresponding data are summarized in
tables 1-4.
[0735] The tissue distributions of [.sup.18F]-4-glutamic acid were
compared in the same tumor models with those of C-14 labeled
glutamic acid, where 111 kBq of [.sup.14C]5-glutamic acid was
administered intravenously and the animals were killed and analyzed
after 30, 60 and 240 min (F9) and after 15, 60 and 120 min (B16F1)
(tables 5-8).
[0736] In comparison to these results, C-14-labeled glutamic acid
was investigated in both tumor models. The corresponding organ
distribution results are reproduced in tab. 5-9.
[0737] Surprisingly, [.sup.18F]-4-glutamic acid after intravenous
injection (15 min) shows a maximal tumor enrichment of 2.90% ID/g
(F9 teratocarcinoma) or 3.55% ID/g (B16 melanoma) whereas the
maximal tumor enrichment at the similarly early time (30 min) for
the natural substrate glutamic acid is only 0.81% ID/g in the F9
teratocarcinoma and at the same time 1.23 in the B16F1
melanoma.
[0738] Even 1 h after intravenous administration, the values are
distinctly higher with 1.75% ID/g in the F9 teratocarcinoma and
2.14% ID/g in the B16F1 melanoma than for [.sup.14C]5-glutamic acid
with only 0.98% ID/g (F9 teratocarcinoma) and 1.03% ID/g (B16F1
melanoma).
[0739] The higher tumor enrichment of the fluorinated compound
linked with a rapid excretion from physiological, vital
tissue/organs leads to a distinctly improved tumor/background ratio
of [.sup.18F]-4-glutamic acid relative to [.sup.14C]5-glutamic
acid. The tumor/blood quotient in the B16F1 melanoma model for the
fluorinated compound is 5.3 (1 h p.i.) and 7.9 (2 h p.i.), and is
thus higher by the factor 2 and 3.5 respectively than for
[.sup.14C]5-glutamic acid.
[0740] The tumor/liver quotient, an important parameter for the
suitability assessment of a PET tracer, for the fluorinated
compound in the B16F1 melanoma model is 3.6 (1 h p.i.) and 4.4 (2 h
p.i.), and is thus higher by the factor 4.6 and 5.5 respectively
than for [.sup.14C]5-glutamic acid.
[0741] [.sup.18F]-4-Glutamic acid has distinctly improved
pharmacokinetic properties compared with the C-14-substituted
natural substrate [.sup.14C]5-glutamic acid.
[0742] In FIG. 1, the tumor enrichment and the uptake is shown in
selected relevant organs after 1 h (a) and 2 h (b)
respectively.
[0743] FIG. 3 shows the distribution after 1 h.
[0744] In FIG. 4, the distribution after 2 h is shown.
[0745] FIG. 5 shows the resulting tissue quotients including
tumor/muscle tissue after 1 h.
[0746] FIG. 6 shows the resulting tissue quotients including
tumor/muscle tissue after 2 h.
* * * * *