NOVEL [F-18]- LABELLED L-GLUTAMIC ACID AND L-GLUTAMINE DERIVATIVES (I), USE THEREOF AND METHOD FOR THEIR PRODUCTION
What is described are the compounds and the synthesis of [F-18]-labelled L-glutamic acid, [F-18]-labelled L-glutamate, their derivatives of the formula (I) and their use.
1 ) Compounds of the general formula I
in which
A represents
a) hydroxyl,
b) branched or straight-chain C 1 -C 5 alkoxy,
c) branched or straight-chain hydroxy C 1 -C 5 alkoxy,
d) branched or straight-chain O—C 1 -C 5 alkyl-(O—C 1 -C 4 alkyl) n -O—C 1 -C 4 alkyl,
e) N(C 1 -C 5 alkyl) 2 ,
f) NH 2 ,
g) N(H)-L,
h) O-L or
i) O—Z,
G represents
a) hydroxyl,
b) O—Z,
b) branched or straight-chain O—C 1 -C 5 alkyl,
c) branched or straight-chain O—C 2 -C 5 alkenyl,
d) branched or straight-chain O—C 1 -C 5 alkyl-(O—C 1 -C 4 alkyl) n -O—C 1 -C 4 alkyl,
e) branched or straight-chain O—C 2 -C 5 alkynyl or
f) triphenylmethoxy,
R 1 and R 2 represent
a) hydrogen,
b) branched or straight-chain 18 F—C 1 -C 5 alkoxy,
c) branched or straight-chain 18 F—C 1 -C 5 alkyl,
d) branched or straight-chain 18 F—C 2 -C 5 alkenyl,
e) branched or straight-chain 18 F—C 2 -C 5 alkynyl,
f) hydroxyl,
g) branched or straight-chain C 1 -C 5 alkyl or
h) branched or straight-chain C 1 -C 5 alkoxy,
alkyl being optionally interrupted by one or more O, S or N,
with the proviso that one of the substituents R 1 or R 2 contains exactly one 18 F isotope and the respective other substituent contains no 18 F isotope, with the proviso that R 1 is not hydrogen,
L represents
a) branched or straight-chain C 1 -C 5 alkyl,
b) branched or straight-chain C 2 -C 5 alkenyl,
c) branched or straight-chain C 1 -C 5 alkyl-(O—C 1 -C 4 alkyl) n -O—C 1 -C 4 alkyl or
d) branched or straight-chain C 2 -C 5 alkynyl,
Z represents a metal cation equivalent, and
where n=0, 1, 2 or 3.
2 . Compounds according to any of claim 1 , characterized in that R 1 is selected from the group consisting of 18 F-methoxy, 18 F-ethoxy, 18 F-propoxy, 18 F-ethyl and 18 F-propyl, and R 2 is hydrogen.
3 . Compound according to claim 1 , selected from the group of compounds of the formulae:
4 ) Compounds of the general formula (II):
in which
A′ represents
a) hydroxyl,
b) branched or straight-chain C 1 -C 5 alkoxy,
c) branched or straight-chain hydroxy C 1 -C 5 alkoxy,
d) branched or straight-chain O—C 1 -C 5 alkyl-(O—C 1 -C 4 alkyl) n -O—C 1 -C 4
alkyl,
e) N(C 1 -C 5 alkyl) 2 ,
f) NH 2 ,
g) N(H)-L′,
h) O-L′,
G′ represents
a) hydroxyl,
b) O—Z′,
c) branched or straight-chain O—C 1 -C 5 alkyl,
d) branched or straight-chain O—C 2 -C 5 alkenyl,
e) branched or straight-chain O—C 1 -C 5 alkyl-(O—C 1 -C 4 alkyl) n -O—C 1 -C 4 alkyl,
f) branched or straight-chain O—C 2 -C 5 alkynyl or
g) triphenylmethoxy,
R 1 and R 2 represent
a) hydrogen,
b) branched or straight-chain 18 F—C 1 -C 5 alkoxy,
c) branched or straight-chain 18 F—C 1 -C 5 alkyl,
d) branched or straight-chain 18 F—C 2 -C 5 alkenyl,
e) branched or straight-chain 18 F—C 2 -C 5 alkynyl,
f) hydroxyl,
g) branched or straight-chain C 1 -C 5 alkyl or
h) branched or straight-chain C 1 -C 5 alkoxy,
alkyl being optionally interrupted by one or more O, S or N,
with the proviso that exactly one of the substituents R 1 or R 2 contains exactly one 18 F isotope and the respective other substituent contains no 18 F isotope, with the proviso that R 1 is not hydrogen,
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-methoxydiphenylmethyl,
t) N(H)-di(p-methoxyphenyl)phenylmethyl,
or
v) N-(tert-butoxycarbonyl) 2 ,
L′represents
a) branched or straight-chain C 1 -C 5 alkyl,
b) branched or straight-chain C 2 -C 5 alkenyl,
c) branched or straight-chain C 1 -C 5 alkyl-(O—C 1 -C 4 alkyl) n O—C 1 -C 4 alkyl or
d) branched or straight-chain C 2 -C 5 alkynyl,
X′ and X″ independently of one another represent
a) branched or straight-chain C 1 -C 5 alkyl,
b) substituted or unsubstituted aryl,
c) substituted or unsubstituted aralkyl or
d) substituted or unsubstituted heteroaryl,
Z′ represents a metal cation equivalent, and
where n=0, 1, 2 or 3.
5 ) Compounds according to claim 4 , characterized in that R 1 is selected from the group consisting of 18 F-ethoxy, 18 F-propoxy, 18 F-ethyl, and 18 F-propyl, and R 2 is hydrogen.
6 ) Compound according to claim 4 , characterized in that Q is selected from the group consisting of N(H)-tert-butoxycarbonyl, N(H)-benzyloxycarbonyl and
in which
X′ and X″ independently of one another represent
a) branched or straight-chain C 1 -C 5 alkyl,
b) substituted or unsubstituted aryl,
c) substituted or unsubstituted aralkyl or
d) substituted or unsubstituted heteroaryl.
7 ) Process for preparing compounds of the general formula (I) which comprises
removing one or more protective groups present in a compound of the formula (II) according to claim 4 .
8 ) Process for preparing compounds of the general formula (II) which comprises
reacting a compound of the formula (III) according to claim 12 with F-18 fluoride.
9 ) Compounds according to any of claim 1 for use as medicaments.
10 ) Compounds according to claim 1 for use for imaging in tumour disorders.
11 ) Use of compounds according to any of claim 1 for preparing a medicament for imaging in tumour disorders.
12 ) Compounds of the formula (III)
in which
A″ represents
a) branched or straight-chain C 1 -C 5 alkoxy,
b) branched or straight-chain hydroxy C 1 -C 5 alkoxy,
c) branched or straight-chain O—C 1 -C 5 alkyl-(O—C 1 -C 4 alkyl) n -O—C 1 -C 4 alkyl,
d) N(C 1 -C 5 alkyl) 2 ,
e) NH 2 ,
f) N(H)—U′
g) N(H)-L″, or
h) O-L″,
G″ represents
a) O—Z″,
b) branched or straight-chain O—C 1 -C 5 alkyl,
c) branched or straight-chain O—C 2 -C 5 alkenyl,
d) branched or straight-chain O—C 1 -C 5 alkyl-(O—C 1 -C 4 alkyl) n -O—C 1 -C 4 alkyl,
e) branched or straight-chain O—C 2 -C 5 alkynyl or
f) triphenylmethoxy,
R 3 and R 4 represent
a) hydrogen,
b) branched or straight-chain E-C 1 -C 5 alkoxy,
c) branched or straight-chain E-C 1 -C 5 alkyl,
d) branched or straight-chain E-C 2 -C 5 alkenyl,
e) branched or straight-chain E-C 2 -C 5 alkynyl,
f) hydroxyl,
g) branched or straight-chain C 1 -C 5 alkyl or
h) branched or straight-chain C 1 -C 5 alkoxy,
alkyl being optionally interrupted by one or more O, S or N,
with the proviso that exactly one of the substituents R 3 or R 4 contains an E and the respective other substituent contains no E, with the proviso that R 3 is not hydrogen,
E represents a leaving group,
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-methoxydiphenylmethyl,
v) N(H)-di(p-methoxyphenyl)phenylmethyl,
or
x) N-(tert-butoxycarbonyl) 2 ,
L″ represents
a) branched or straight-chain C 1 -C 5 alkyl,
b) branched or straight-chain C 2 -C 5 alkenyl,
c) branched or straight-chain C 1 -C 5 alkyl-(O—C 1 -C 4 alkyl) n -O—C 1 -C 4 alkyl or
d) branched or straight-chain C 2 -C 5 alkynyl,
X′ and X″ independently of one another represent
a) branched or straight-chain C 1 -C 5 alkyl,
b) substituted or unsubstituted aryl,
c) substituted or unsubstituted alkylaryl or
d) substituted or unsubstituted heteroaryl,
Z″ represents a metal cation equivalent, and
where n=0, 1, 2 or 3.
13 ) Use of compounds of the formula (IV) for preparing compounds of the formula (I) or (II):
in which
G′″ represents
a) branched or straight-chain O—C 1 -C 5 alkyl,
b) branched or straight-chain O—C 2 -C 5 alkenyl,
c) branched or straight-chain O—C 1 -C 5 alkyl-(O—C 1 -C 4 alkyl)-O—C 1 -C 4 alkyl,
d) branched or straight-chain O—C 2 -C 5 alkynyl or
e) triphenylmethoxy,
R 5 and R 6 represent
a) hydrogen,
b) hydroxyl,
c) branched or straight-chain C 1 -C 5 alkyl,
d) branched or straight-chain C 1 -C 5 alkoxy or
e) R 7 -E′,
with the proviso that exactly one of the substituents R 5 or R 6 contains an E′ and the respective other substituent contains no E′, with the proviso that R 5 is not hydrogen,
E′ represents a leaving group,
R 7 represents
a) branched or straight-chain C 1 -C 5 alkoxy,
b) branched or straight-chain C 1 -C 5 alkyl,
c) branched or straight-chain C 2 -C 5 alkenyl or
d) branched or straight-chain C 2 -C 5 alkynyl,
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-biphenyl)-pethoxycarbonyl,
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,
s) N-benzoyl,
t) N(H)-trityl,
u) N(H)-p-methoxyphenyldiphenylmethyl,
v) N(H)-di(n-methoxyphenyl)phenylmethyl,
or
x) N-(tert-butoxycarbonyl) 2 ,
X′ and X″ independently of one another represent
a) branched or straight-chain C 1 -C 5 alkyl,
b) substituted or unsubstituted aryl,
c) substituted or unsubstituted alkylaryl or
d) substituted or unsubstituted heteroaryl, and
where n=0, 1, 2 or 3.
14 ) Imaging kit, comprising compounds of the general formula III or IV.
15 ) Pharmaceutical composition, comprising compounds of the general formula I, II, III or IV and suitable pharmaceutical carrier substances.
16 ) Compounds according to claim 1 , and compounds of the general formula IV, characterized in that the compounds are suitable for imaging in a dosage range of 37-600 MBq.
17 ) Compounds according to claim 16 , characterized in that the compounds are particularly suitable in a dosage range of 150 MBq-370 MBq.