CN1774268A - Bifunctional tridentate pyrazolyl containing ligands for Re and Tc tricarbonyl complexes - Google Patents

Bifunctional tridentate pyrazolyl containing ligands for Re and Tc tricarbonyl complexes Download PDF

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CN1774268A
CN1774268A CN 200480010214 CN200480010214A CN1774268A CN 1774268 A CN1774268 A CN 1774268A CN 200480010214 CN200480010214 CN 200480010214 CN 200480010214 A CN200480010214 A CN 200480010214A CN 1774268 A CN1774268 A CN 1774268A
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alkyl
aryl
coor
chelating agen
biomolecule
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伊莎贝尔·R·桑托斯
乔奥·D·加兰巴科雷亚
安东尼奥·M·罗查保罗
苏萨娜·阿尔维斯
拉特·维托尔
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Mallinckrodt Inc
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Mallinckrodt Inc
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Abstract

The present invention relates to a chelating agent of the general formula: (I), wherein m is 0 or 1; X is NR4 or S; Y is SR5, NHR5 or P(R5)2; R1 and R3 are the same or different and are selected from H, alkyl or aryl; R2 is H, COOH, NHR6 or (CH2)nCOOR6; R4 is H, alkyl, aryl, (CH2)nCOOR6 or (CH2)nOR6; R5 is H, alkyl, aryl, (CH2)nCOOR6 or (CH2)nOR6, R6 is H, alkyl or aryl; n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and when R1=R3=CH3, R2, R4 and R5 are not all three H. The invention further relates to a method and kit for the preparation of radiolabeled biomolecules while using the chelating agent.

Description

The pyrazolyl containing ligands of bifunctional tridentate that is used for the tricarbonyl complexes of rhenium and technetium
The present invention relates to radiopharmaceutic field, and provide and be used to connect the new chelating agen that biomolecule (biomolecule) links to each other with the carbonyl moiety that is marked with technetium and rhenium.Especially, the present invention relates to pyrazolyl-polyamines, pyrazolyl-amino-thioether, pyrazolyl-polythiaether, pyrazolyl-amino-phosphine and the pyrazolyl-thioether phosphine of bifunctional tridentate, it can stablize [M (CO) 3] +Partly (M=Re, Tc, Mn) and combine with the biomolecule of in ill tissue, accumulating.The present invention relates to such chelating agen, relate to the chelating agen that is coupled to biomolecule and relate in these chelating agen with the carbonyl complexation any.In addition, the present invention relates to be used for providing the test kit (kit) of radiolabeled biomolecule and relate to the diagnosis and the treatment this radiolabeled molecule use.
The diagnosis of cancer and treatment still need to consider from chemistry, radiochemistry and pharmacy aspect significantly.It is stable in vitro and in vivo that tumor is sought (seeking) chemical compound, has the high specific activity, and this specificity is still important problem in the radiopharmaceutical field.Since to [Re (CO) 3] +[Tc (CO) 3] +[1] disclosing of international monopoly shows tangible interest to this state of oxidation, and it has opened the new prospect to pharmacy and the field of nuclear medicine.Research to new chelating agen is important, because they are the determiners for the picked-up of biological vector.Many chelating agen are described in patent [1,2] and the publication [3,4,5].
The objective of the invention is to enlarge the family of bifunctional chelating agent.
This purpose is to realize by the chelating agen of following general formula of the present invention:
Wherein m is 0 or 1;
X is NR 4Or S;
Y is SR 5, NHR 5Or P (R 5) 2
R 1And R 3Identical or different, and be selected from H, alkyl or aryl;
R 2Be H, COOH, NHR 6Or (CH 2) nCOOR 6
R 4Be H, alkyl, aryl, (CH 2) nCOOR 6Or (CH 2) nOR 6
R 5Be H, alkyl, aryl, (CH 2) nCOOR 6Or (CH 2) nOR 6
R 6Be H, alkyl or aryl;
N is 1,2,3,4,5,6,7,8,9 or 10; With
Work as R 1=R 3=CH 3The time, R 2, R 4And R 5Three not all is H.
These molecules have two kinds of functions concurrently.A kind of function is used for stable metal center (comprising radioactive metal), and comprises different donor atom subclass (sets), and another function is the functional group that is used in conjunction with significant molecule (molecule of interest).
Alkyl is C 1Alkyl, C 2Alkyl, C 3Alkyl, C 4Alkyl, C 5Alkyl or C 6Alkyl, particularly be selected from methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl, isopentyl, neopentyl, n-hexyl, isohesyl (2-methyl amyl), new hexyl (2, the 2-dimethylbutyl), 3-methyl amyl, 2, the 3-dimethylbutyl.
This aryl is monocycle C 5-C 8Or multi-ring C 10-C 18, and this aryl is optional is replaced by alkyl, carboxyl, oxo, amino, alkoxyl or aldehyde radical.
N is 2,3,4,5 or 6, and is preferably 2,3 or 4.
This chelating agen is the pyrazolyl-polyamines (polyamine) of for example following general formula:
5
Figure A20048001021400081
R wherein 1, R 2, R 3, R 4And R 5As defined above.
Perhaps, this chelating agen is the pyrazolyl-amino-thioether of following general formula:
Figure A20048001021400082
R wherein 1, R 2, R 3, R 4And R 5As defined above.
In another embodiment, this chelating agen is the pyrazolyl-polythiaether of following general formula:
Figure A20048001021400083
R wherein 1, R 2, R 3, R 4And R 5As defined above.
In another embodiment, this chelating agen is the pyrazolyl-amino-phosphine of following general formula:
R wherein 1, R 2, R 3, R 4And R 5As defined above.
In another embodiment, this chelating agen is the pyrazolyl-thioether phosphine of following general formula:
Figure A20048001021400092
R wherein 1, R 2, R 3, R 4And R 5As defined above.
The present invention more particularly provides formula I chelating agen, and wherein X and Y are N, R 6Be H, C 1Alkyl, C 2Alkyl, C 3Alkyl, C 4Alkyl, C 5Alkyl or C 6Alkyl, monocyclic aryl are preferably phenyl or benzyl, or multi-ring C 10-C 18Aryl, described monocyclic aryl or multi-ring C 10-C 18Aryl is optional to be replaced by alkyl, carboxyl, oxo amino, alkoxyl or aldehyde radical, or is biomolecule, and R 1, R 3, R 3, R 4And R 5As listed in Table 1.
In another embodiment, the present invention relates to the chelating agen of formula I, wherein X and Y are S, R 6Be H, C 1Alkyl, C 2Alkyl, C 3Alkyl, C 4Alkyl, C 5Alkyl or C 6Alkyl, monocyclic aryl are preferably phenyl or benzyl, or multi-ring C 10-C 18Aryl, described monocyclic aryl or multi-ring C 10-C 18Aryl is optional to be replaced by alkyl, carboxyl, oxo amino, alkoxyl or aldehyde radical, or is biomolecule, and R 1, R 2, R 3, R 4And R 5As listed in Table 1.
In another embodiment, provide the chelating agen of formula I, wherein X is that N and Y are S, R 6Be H, C 1Alkyl, C 2Alkyl, C 3Alkyl, C 4Alkyl, C 5Alkyl or C 6Alkyl, monocyclic aryl are preferably phenyl or benzyl, or multi-ring C 10-C 18Aryl, described monocyclic aryl or multi-ring C 10-C 18Aryl is optional to be replaced by alkyl, carboxyl, oxo amino, alkoxyl or aldehyde radical, or is biomolecule, and R 1, R 2, R 3, R 4And R 5As listed in Table 1.
According to it on the other hand, the present invention relates to the chelating agen of formula I, wherein X is that S and Y are N, R 6Be H, C 1Alkyl, C 2Alkyl, C 3Alkyl, C 4Alkyl, C 5Alkyl or C 6Alkyl, monocyclic aryl are preferably phenyl or benzyl, or multi-ring C 10-C 18Aryl, described monocyclic aryl or multi-ring C 10-C 18Aryl is optional to be replaced by alkyl, carboxyl, oxo amino, alkoxyl or aldehyde radical, or is biomolecule, and R 1, R 2, R 3, R 4And R 5As listed in Table 1.
According to a further aspect in the invention, provide the chelating agen of formula I, wherein X is that N and Y are P, R 6Be H, C 1Alkyl, C 2Alkyl, C 3Alkyl, C 4Alkyl, C 5Alkyl or C 6Alkyl, monocyclic aryl are preferably phenyl or benzyl, or multi-ring C 10-C 18Aryl, described monocyclic aryl or multi-ring C 10-C 18Aryl is optional to be replaced by alkyl, carboxyl, oxo amino, alkoxyl or aldehyde radical, or is biomolecule, and R 1, R 2, R 3, R 4And R 5As listed in Table 1.
In another embodiment, the present invention relates to the chelating agen of formula I, wherein X is that S and Y are P, R 6Be H, C 1Alkyl, C 2Alkyl, C 3Alkyl, C 4Alkyl, C 5Alkyl or C 6Alkyl, monocyclic aryl are preferably phenyl or benzyl, or multi-ring C 10-C 18Aryl, described monocyclic aryl or multi-ring C 10-C 18Aryl is optional to be replaced by alkyl, carboxyl, oxo amino, alkoxyl or aldehyde radical, or is biomolecule, and R 1, R 2, R 3, R 4And R 5As listed in Table 1.
In order to obtain target is had the biomolecule of the labelling of high specific, chelating agen of the present invention is particularly suitable for connecting biomolecule and carbonyl moiety.Therefore, R in formula I 6Can be biomolecule.
The possible position of biomolecule (BM) as shown in fig. 1.
Biomolecule can be can be used for the treatment of and diagnosing tumour, and can with the mutually link coupled any material of chelating agen of the present invention.Those skilled in the art can determine which kind of biomolecule chelating agen of the present invention can be used for.Especially, this biomolecule is selected from aminoacid, peptide, protein, oligonucleotide, polynucleotide, sugar.
More particularly, this biomolecule is selected from part such as CCK, thioglucose, glycosamine, somatostatin, neurotensin, bombesin, CCK, annexin, interleukin, somatomedin, the steroid hormone of antibody, tumor receptor and is bonded to the molecule of GPIIb/IIIa receptor.Other biomolecule can be inhibitor such as benzo thiapyran ketone (benzothiopyranones), anilino-phthalimide (anilinophthalimides), quinazoline, Pyridopyrimidine and the pyrrolopyrimidine of glucose, thioglucose, neurotransmitter, tyrosine kinase activity.
The present invention is special, and reagent is as follows:
Figure A20048001021400101
Figure A20048001021400111
Have or do not have the biomolecule that is coupled on it all chelating agen can with formula [M (CO) 3] +The carbonyl moiety complexation, wherein M is rhenium (Re), technetium (Tc) or manganese (Mn).
Chelating agen of the present invention is the molecule according to formula I, and wherein X and Y one of can be among N and N, N and S, S and N, S and S, N and P or S and the P.These the combination in each can with R 1, R 2, R 3, R 4And R 5Various combination combine.R 1, R 2, R 3, R 4And R 5All possible composite column in table 1.In table 1, alkyl is C 1Alkyl, C 2Alkyl, C 3Alkyl, C 4Alkyl, C 5Alkyl or C 6Alkyl, particularly be selected from methyl, ethyl, just-propyl group, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl, isopentyl, neopentyl, n-hexyl, isohesyl (2-methyl amyl), new hexyl (2, the 2-dimethylbutyl), 3-methyl amyl, 2, the 3-dimethylbutyl; This aryl is monocycle C 5-C 8Or multi-ring C 10-C 18, and this aryl is optional is replaced by alkyl, carboxyl, oxo, amino, alkoxyl or aldehyde radical, and this aryl is phenyl or benzyl especially, and n is 1,2,3,4,5,6,7,8,9 or 10.R 6Be H, alkyl, aryl or biomolecule as defined above.All chemical compounds that will obtain in the form in the claim 1 are introduced in above-mentioned each variable, and therefore it be disclosed.
Table 1
R1 R2 R3 R4 R5
H H H H H
H H H H Alkyl
H H H H Aryl
H H H H (CH 2) nCOOR 6
H H H H (CH 2) nOR 6
H H H Alkyl H
H H H Alkyl Alkyl
H H H Alkyl Aryl
H H H Alkyl (CH 2) nCOOR 6
H H H Alkyl (CH 2) nOR 6
H H H Aryl H
H H H Aryl Alkyl
H H H Aryl Aryl
H H H Aryl (CH 2) nCOOR 6
H H H Aryl (CH 2) nOR 6
H H H (CH 2) nCOOR 6 H
H H H (CH 2) nCOOR 6 Alkyl
H H H (CH 2) nCOOR 6 Aryl
H H H (CH 2) nCOOR 6 (CH 2) nCOOR 6
H H H (CH 2) nCOOR 6 (CH 2) nOR 6
H H H (CH 2) nOR 6 H
H H H (CH 2) nOR 6 Alkyl
H H H (CH 2) nOR 6 Aryl
H H H (CH 2) nORR 6 (CH 2) nCOOR 6
H H H (CH 2) nOR 6 (CH 2) nOR 6
H H Alkyl H H
H H Alkyl H Alkyl
H H Alkyl H Aryl
H H Alkyl H (CH 2) nCOOR 6
H H Alkyl H (CH 2) nOR 6
H H Alkyl Alkyl H
H H Alkyl Alkyl Alkyl
H H Alkyl Alkyl Aryl
H H Alkyl Alkyl (CH 2) nCOOR 6
H H Alkyl Alkyl (CH 2) nOR 6
H H Alkyl Aryl H
H H Alkyl Aryl Alkyl
H H Alkyl Aryl Aryl
H H Alkyl Aryl (CH 2) nCOOR 6
H H Alkyl Aryl (CH 2) nOR 6
H H Alkyl (CH 2) nCOOR 6 H
H H Alkyl (CH 2) nCOOR 6 Alkyl
H H Alkyl (CH 2) nCOOR 6 Aryl
H H Alkyl (CH 2) nCOOR 6 (CH 2) nCOOR 6
H H Alkyl (CH 2) nCOOR 6 (CH 2) nOR 6
H H Alkyl (CH 2) nOR 6 H
H H Alkyl (CH 2) nOR 6 Alkyl
H H Alkyl (CH 2) nOR 6 Aryl
H H Alkyl (CH 2) nOR 6 (CH 2) nCOOR 6
H H Alkyl (CH 2) nOR 6 (CH 2) nOR 6
H H Aryl H H
H H Aryl H Alkyl
H H Aryl H Aryl
H H Aryl H (CH 2) nCOOR 6
H H Aryl H (CH 2) nOR 6
H H Aryl Alkyl H
H H Aryl Alkyl Alkyl
H H Aryl Alkyl Aryl
H H Aryl Alkyl (CH 2) nCOOR 6
H H Aryl Alkyl (CH 2) nOR 6
H H Aryl Aryl H
H H Aryl Aryl Alkyl
H H Aryl Aryl Aryl
H H Aryl Aryl (CH 2) nCOOR 6
H H Aryl Aryl (CH 2) nOR 6
H H Aryl (CH 2) nCOOR 6 H
H H Aryl (CH 2) nCOOR 6 Alkyl
H H Aryl (CH 2) nCOOR 6 Aryl
H H Aryl (CH 2) nCOOR 6 (CH 2) nCOOR 6
H H Aryl (CH 2) nCOOR 6 (CH 2) nOR 6
H H Aryl (CH 2) nOR 6 H
H H Aryl (CH 2) nOR 6 Alkyl
H H Aryl (CH 2) nOR 6 Aryl
H H Aryl (CH 2) nOR 6 (CH 2) nCOOR 6
H H Aryl (CH 2) nOR 6 (CH 2) nOR 6
H COOH H H H
H COOH H H Alkyl
H COOH H H Aryl
H COOH H H (CH 2) nCOOR 6
H COOH H H (CH 2) nOR 6
H COOH H Alkyl H
H COOH H Alkyl Alkyl
H COOH H Alkyl Aryl
H COOH H Alkyl (CH 2) nCOOR 6
H COOH H Alkyl (CH 2) nOR 6
H COOH H Aryl H
H COOH H Aryl Alkyl
H COOH H Aryl Aryl
H COOH H Aryl (CH 2) nCOOR 6
H COOH H Aryl (CH 2) nOR 6
H COOH H (CH 2) nCOOR 6 H
H COOH H (CH 2) nCOOR 6 Alkyl
H COOH H (CH 2) nCOOR 6 Aryl
H COOH H (CH 2) nCOOR 6 (CH 2) nCOOR 6
H COOH H (CH 2) nCOOR 6 (CH 2) nOR 6
H COOH H (CH 2) nOR 6 H
H COOH H (CH 2) nOR 6 Alkyl
H COOH H (CH 2) nOR 6 Aryl
H COOH H (CH 2) nOR 6 (CH 2) nCOOR 6
H COOH H (CH 2) nOR 6 (CH 2) nOR 6
H COOH Alkyl H H
H COOH Alkyl H Alkyl
H COOH Alkyl H Aryl
H COOH Alkyl H (CH 2) nCOOR 6
H COOH Alkyl H (CH 2) nOR 6
H COOH Alkyl Alkyl H
H COOH Alkyl Alkyl Alkyl
H COOH Alkyl Alkyl Aryl
H COOH Alkyl Alkyl (CH 2) nCOOR 6
H COOH Alkyl Alkyl (CH 2) nOR 6
H COOH Alkyl Aryl H
H COOH Alkyl Aryl Alkyl
H COOH Alkyl Aryl Aryl
H COOH Alkyl Aryl (CH 2) nCOOR 6
H COOH Alkyl Aryl (CH 2) nOR 6
H COOH Alkyl (CH 2) nCOOR 6 H
H COOH Alkyl (CH 2) nCOOR 6 Alkyl
H COOH Alkyl (CH 2) nCOOR 6 Aryl
H COOH Alkyl (CH 2) nCOOR 6 (CH 2) nCOOR 6
H COOH Alkyl (CH 2) nCOOR 6 (CH 2) nOR 6
H COOH Alkyl (CH 2) nOR 6 H
H COOH Alkyl (CH 2) nOR 6 Alkyl
H COOH Alkyl (CH 2) nOR 6 Aryl
H COOH Alkyl (CH 2) nOR 6 (CH 2) nCOOR 6
H COOH Alkyl (CH 2) nOR 6 (CH 2) nOR 6
H COOH Aryl H H
H COOH Aryl H Alkyl
H COOH Aryl H Aryl
H COOH Aryl H (CH 2) nCOOR 6
H COOH Aryl H (CH 2) nOR 6
H COOH Aryl Alkyl H
H COOH Aryl Alkyl Alkyl
H COOH Aryl Alkyl Aryl
H COOH Aryl Alkyl (CH 2) nCOOR 6
H COOH Aryl Alkyl (CH 2) nOR 6
H COOH Aryl Aryl H
H COOH Aryl Aryl Alkyl
H COOH Aryl Aryl Aryl
H COOH Aryl Aryl (CH 2) nCOOR 6
H COOH Aryl Aryl (CH 2) nOR 6
H COOH Aryl (CH 2) nCOOR 6 H
H COOH Aryl (CH 2) nCOOR 6 Alkyl
H COOH Aryl (CH 2) nCOOR 6 Aryl
H COOH Aryl (CH 2) nCOOR 6 (CH 2) nCOOR 6
H COOH Aryl (CH 2) nCOOR 6 (CH 2) nOR 6
H COOH Aryl (CH 2) nOR 6 H
H COOH Aryl (CH 2) nOR 6 Alkyl
H COOH Aryl (CH 2) nOR 6 Aryl
H COOH Aryl (CH 2) nOR 6 (CH 2) nCOOR 6
H COOH Aryl (CH 2) nOR 6 (CH 2) nOR 6
H NHR 6 H H H
H NHR 6 H H Alkyl
H NHR 6 H H Aryl
H NHR 6 H H (CH 2) nCOOR 6
H NHR 6 H H (CH 2) nOR 6
H NHR 6 H Alkyl H
H NHR 6 H Alkyl Alkyl
H NHR 6 H Alkyl Aryl
H NHR 6 H Alkyl (CH 2) nCOOR 6
H NHR 6 H Alkyl (CH 2) nOR 6
H NHR 6 H Aryl H
H NHR 6 H Aryl Alkyl
H NHR 6 H Aryl Aryl
H NHR 6 H Aryl (CH 2) nCOOR 6
H NHR 6 H Aryl (CH 2) nOR 6
H NHR 6 H (CH 2) nCOOR 6 H
H NHR 6 H (CH 2) nCOOR 6 Alkyl
H NHR 6 H (CH 2) nCOOR 6 Aryl
H NHR 6 H (CH 2) nCOOR 6 (CH 2) nCOOR 6
H NHR 6 H (CH 2) nCOOR 6 (CH 2) nOR 6
H NHR 6 H (CH 2) nOR 6 H
H NHR 6 H (CH 2) nOR 6 Alkyl
H NHR 6 H (CH 2) nOR 6 Aryl
H NHR 6 H (CH 2) nOR 6 (CH 2) nCOOR 6
H NHR 6 H (CH 2) nOR 6 (CH 2) nOR 6
H NHR 6 Alkyl H H
H NHR 6 Alkyl H Alkyl
H NHR 6 Alkyl H Aryl
H NHR 6 Alkyl H (CH 2) nCOOR 6
H NHR 6 Alkyl H (CH 2) nOR 6
H NHR 6 Alkyl Alkyl H
H NHR 6 Alkyl Alkyl Alkyl
H NHR 6 Alkyl Alkyl Aryl
H NHR 6 Alkyl Alkyl (CH 2) nCOOR 6
H NHR 6 Alkyl Alkyl (CH 2) nOR 6
H NHR 6 Alkyl Aryl H
H NHR 6 Alkyl Aryl Alkyl
H NHR 6 Alkyl Aryl Aryl
H NHR 6 Alkyl Aryl (CH 2) nCOOR 6
H NHR 6 Alkyl Aryl (CH 2) nOR 6
H NHR 6 Alkyl (CH 2) nCOOR 6 H
H NHR 6 Alkyl (CH 2) nCOOR 6 Alkyl
H NHR 6 Alkyl (CH 2) nCOOR 6 Aryl
H NHR 6 Alkyl (CH 2) nCOOR 6 (CH 2) nCOOR 6
H NHR 6 Alkyl (CH 2) nCOOR 6 (CH 2) nOR 6
H NHR 6 Alkyl (CH 2) nOR 6 H
H NHR 6 Alkyl (CH 2) nOR 6 Alkyl
H NHR 6 Alkyl (CH 2) nOR 6 Aryl
H NHR 6 Alkyl (CH 2) nOR 6 (CH 2) nCOOR 6
H NHR 6 Alkyl (CH 2) nOR 6 (CH 2) nOR 6
H NHR 6 Aryl H H
H NHR 6 Aryl H Alkyl
H NHR 6 Aryl H Aryl
H NHR 6 Aryl H (CH 2) nCOOR 6
H NHR 6 Aryl H (CH 2) nOR 6
H NHR 6 Aryl Alkyl H
H NHR 6 Aryl Alkyl Alkyl
H NHR 6 Aryl Alkyl Aryl
H NHR 6 Aryl Alkyl (CH 2) nCOOR 6
H NHR 6 Aryl Alkyl (CH 2) nOR 6
H NHR 6 Aryl Aryl H
H NHR 6 Aryl Aryl Alkyl
H NHR 6 Aryl Aryl Aryl
H NHR 6 Aryl Aryl (CH 2) nCOOR 6
H NHR 6 Aryl Aryl (CH 2) nOR 6
H NHR 6 Aryl (CH 2) nCOOR 6 H
H NHR 6 Aryl (CH 2) nCOOR 6 Alkyl
H NHR 6 Aryl (CH 2) nCOOR 6 Aryl
H NHR 6 Aryl (CH 2) nCOOR 6 (CH 2) nCOOR 6
H NHR 6 Aryl (CH 2) nCOOR 6 (CH 2) nOR 6
H NHR 6 Aryl (CH 2) nOR 6 H
H NHR 6 Aryl (CH 2) nOR 6 Alkyl
H NHR 6 Aryl (CH 2) nOR 6 Aryl
H NHR 6 Aryl (CH 2) nOR 6 (CH 2) nCOOR 6
H NHR 6 Aryl (CH 2) nOR 6 (CH 2) nOR 6
H (CH 2) nCOOR 6 H H H
H (CH 2) nCOOR 6 H H Alkyl
H (CH 2) nCOOR 6 H H Aryl
H (CH 2) nCOOR 6 H H (CH 2) nCOOR 6
H (CH 2) nCOOR 6 H H (CH 2) nOR 6
H (CH 2) nCOOR 6 H Alkyl H
H (CH 2) nCOOR 6 H Alkyl Alkyl
H (CH 2) nCOOR 6 H Alkyl Aryl
H (CH 2) nCOOR 6 H Alkyl (CH 2) nCOOR 6
H (CH 2) nCOOR 6 H Alkyl (CH 2) nOR 6
H (CH 2) nCOOR 6 H Aryl H
H (CH 2) nCOOR 6 H Aryl Alkyl
H (CH 2) nCOOR 6 H Aryl Aryl
H (CH 2) nCOOR 6 H Aryl (CH 2) nCOOR 6
H (CH 2) nCOOR 6 H Aryl (CH 2) nOR 6
H (CH 2) nCOOR 6 H (CH 2) nCOOR 6 H
H (CH 2) nCOOR 6 H (CH 2) nCOOR 6 Alkyl
H (CH 2) nCOOR 6 H (CH 2) nCOOR 6 Aryl
H (CH 2) nCOOR 6 H (CH 2) nCOOR 6 (CH 2) nCOOR 6
H (CH 2) nCOOR 6 H (CH 2) nCOOR 6 (CH 2) nOR 6
H (CH 2) nCOOR 6 H (CH 2) nOR 6 H
H (CH 2) nCOOR 6 H (CH 2) nOR 6 Alkyl
H (CH 2) nCOOR 6 H (CH 2) nOR 6 Aryl
H (CH 2) nCOOR 6 H (CH 2) nOR 6 (CH 2) nCOOR 6
H (CH 2) nCOOR 6 H (CH 2) nOR 6 (CH 2) nOR 6
H (CH 2) nCOOR 6 Alkyl H H
H (CH 2) nCOOR 6 Alkyl H Alkyl
H (CH 2) nCOOR 6 Alkyl H Aryl
H (CH 2) nCOOR 6 Alkyl H (CH 2) nCOOR 6
H (CH 2) nCOOR 6 Alkyl H (CH 2) nOR 6
H (CH 2) nCOOR 6 Alkyl Alkyl H
H (CH 2) nCOOR 6 Alkyl Alkyl Alkyl
H (CH 2) nCOOR 6 Alkyl Alkyl Aryl
H (CH 2) nCOOR 6 Alkyl Alkyl (CH 2) nCOOR 6
H (CH 2) nCOOR 6 Alkyl Alkyl (CH 2) nOR 6
H (CH 2) nCOOR 6 Alkyl Aryl H
H (CH 2) nCOOR 6 Alkyl Aryl Alkyl
H (CH 2) nCOOR 6 Alkyl Aryl Aryl
H (CH 2) nCOOR 6 Alkyl Aryl (CH 2) nCOOR 6
H (CH 2) nCOOR 6 Alkyl Aryl (CH 2) nOR 6
H (CH 2) nCOOR 6 Alkyl (CH 2) nCOOR 6 H
H (CH 2) nCOOR 6 Alkyl (CH 2) nCOOR 6 Alkyl
H (CH 2) nCOOR 6 Alkyl (CH 2) nCOOR 6 Aryl
H (CH 2) nCOOR 6 Alkyl (CH 2) nCOOR 6 (CH 2) nCOOR 6
H (CH 2) nCOOR 6 Alkyl (CH 2) nCOOR 6 (CH 2) nOR 6
H (CH 2) nCOOR 6 Alkyl (CH 2) nOR 6 H
H (CH 2) nCOOR 6 Alkyl (CH 2) nOR 6 Alkyl
H (CH 2) nCOOR 6 Alkyl (CH 2) nOR 6 Aryl
H (CH 2) nCOOR 6 Alkyl (CH 2) nOR 6 (CH 2) nCOOR 6
H (CH 2) nCOOR 6 Alkyl (CH 2) nOR 6 (CH 2) nOR 6
H (CH 2) nCOOR 6 Aryl H H
H (CH 2) nCOOR 6 Aryl H Alkyl
H (CH 2) nCOOR 6 Aryl H Aryl
H (CH 2) nCOOR 6 Aryl H (CH 2) nCOOR 6
H (CH 2) nCOOR 6 Aryl H (CH 2) nOR 6
H (CH 2) nCOOR 6 Aryl Alkyl H
H (CH 2) nCOOR 6 Aryl Alkyl Alkyl
H (CH 2) nCOOR 6 Aryl Alkyl Aryl
H (CH 2) nCOOR 6 Aryl Alkyl (CH 2) nCOOR 6
H (CH 2) nCOOR 6 Aryl Alkyl (CH 2) nOR 6
H (CH 2) nCOOR 6 Aryl Aryl H
H (CH 2) nCOOR 6 Aryl Aryl Alkyl
H (CH 2) nCOOR 6 Aryl Aryl Aryl
H (CH 2) nCOOR 6 Aryl Aryl (CH 2) nCOOR 6
H (CH 2) nCOOR 6 Aryl Aryl (CH 2) nOR 6
H (CH 2) nCOOR 6 Aryl (CH 2) nCOOR 6 H
H (CH 2) nCOOR 6 Aryl (CH 2) nCOOR 6 Alkyl
H (CH 2) nCOOR 6 Aryl (CH 2) nCOOR 6 Aryl
H (CH 2) nCOOR 6 Aryl (CH 2) nCOOR 6 (CH 2) nCOOR 6
H (CH 2) nCOOR 6 Aryl (CH 2) nCOOR 6 (CH 2) nOR 6
H (CH 2) nCOOR 6 Aryl (CH 2) nOR 6 H
H (CH 2) nCOOR 6 Aryl (CH 2) nOR 6 Alkyl
H (CH 2) nCOOR 6 Aryl (CH 2) nOR 6 Aryl
H (CH 2) nCOOR 6 Aryl (CH 2) nOR 6 (CH 2) nCOOR 6
H (CH 2) nCOOR 6 Aryl (CH 2) nOR 6 (CH 2) nOR 6
Alkyl H H H H
Alkyl H H H Alkyl
Alkyl H H H Aryl
Alkyl H H H (CH 2) nCOOR 6
Alkyl H H H (CH 2) nOR 6
Alkyl H H Alkyl H
Alkyl H H Alkyl Alkyl
Alkyl H H Alkyl Aryl
Alkyl H H Alkyl (CH 2) nCOOR 6
Alkyl H H Alkyl (CH 2) nOR 6
Alkyl H H Aryl H
Alkyl H H Aryl Alkyl
Alkyl H H Aryl Aryl
Alkyl H H Aryl (CH 2) nCOOR 6
Alkyl H H Aryl (CH 2) nOR 6
Alkyl H H (CH 2) nCOOR 6 H
Alkyl H H (CH 2) nCOOR 6 Alkyl
Alkyl H H (CH 2) nCOOR 6 Aryl
Alkyl H H (CH 2) nCOOR 6 (CH 2) nCOOR 6
Alkyl H H (CH 2) nCOOR 6 (CH 2) nOR 6
Alkyl H H (CH 2) nOR 6 H
Alkyl H H (CH 2) nOR 6 Alkyl
Alkyl H H (CH 2) nOR 6 Aryl
Alkyl H H (CH 2) nOR 6 (CH 2) nCOOR 6
Alkyl H H (CH 2) nOR 6 (CH 2) nOR 6
Alkyl H Alkyl H H
Alkyl H Alkyl H Alkyl
Alkyl H Alkyl H Aryl
Alkyl H Alkyl H (CH 2) nCOOR 6
Alkyl H Alkyl H (CH 2) nOR 6
Alkyl H Alkyl Alkyl H
Alkyl H Alkyl Alkyl Alkyl
Alkyl H Alkyl Alkyl Aryl
Alkyl H Alkyl Alkyl (CH 2) nCOOR 6
Alkyl H Alkyl Alkyl (CH 2) nOR 6
Alkyl H Alkyl Aryl H
Alkyl H Alkyl Aryl Alkyl
Alkyl H Alkyl Aryl Aryl
Alkyl H Alkyl Aryl (CH 2) nCOOR 6
Alkyl H Alkyl Aryl (CH 2) nOR 6
Alkyl H Alkyl (CH 2) nCOOR 6 H
Alkyl H Alkyl (CH 2) nCOOR 6 Alkyl
Alkyl H Alkyl (CH 2) nCOOR 6 Aryl
Alkyl H Alkyl (CH 2) nCOOR 6 (CH 2) nCOOR 6
Alkyl H Alkyl (CH 2) nCOOR 6 (CH 2) nOR 6
Alkyl H Alkyl (CH 2) nOR 6 H
Alkyl H Alkyl (CH 2) nOR 6 Alkyl
Alkyl H Alkyl (CH 2) nOR 6 Aryl
Alkyl H Alkyl (CH 2) nOR 6 (CH 2) nCOOR 6
Alkyl H Alkyl (CH 2) nOR 6 (CH 2) nOR 6
Alkyl H Aryl H H
Alkyl H Aryl H Alkyl
Alkyl H Aryl H Aryl
Alkyl H Aryl H (CH 2) nCOOR 6
Alkyl H Aryl H (CH 2) nOR 6
Alkyl H Aryl Alkyl H
Alkyl H Aryl Alkyl Alkyl
Alkyl H Aryl Alkyl Aryl
Alkyl H Aryl Alkyl (CH 2) nCOOR 6
Alkyl H Aryl Alkyl (CH 2) nOR 6
Alkyl H Aryl Aryl H
Alkyl H Aryl Aryl Alkyl
Alkyl H Aryl Aryl Aryl
Alkyl H Aryl Aryl (CH 2) 2COOR 6
Alkyl H Aryl Aryl (CH 2) nOR 6
Alkyl H Aryl (CH 2) nCOOR 6 H
Alkyl H Aryl (CH 2) nCOOR 6 Alkyl
Alkyl H Aryl (CH 2) nCOOR 6 Aryl
Alkyl H Aryl (CH 2) nCOOR 6 (CH 2) nCOOR 6
Alkyl H Aryl (CH 2) nCOOR 6 (CH 2) nOR 6
Alkyl H Aryl (CH 2) nOR 6 H
Alkyl H Aryl (CH 2) nOR 6 Alkyl
Alkyl H Aryl (CH 2) nOR 6 Aryl
Alkyl H Aryl (CH 2) nOR 6 (CH 2) nCOOR 6
Alkyl H Aryl (CH 2) nOR 6 (CH 2) nOR 6
Alkyl COOH H H H
Alkyl COOH H H Alkyl
Alkyl COOH H H Aryl
Alkyl COOH H H (CH 2) nCOOR 6
Alkyl COOH H H (CH 2) nOR 6
Alkyl COOH H Alkyl H
Alkyl COOH H Alkyl Alkyl
Alkyl COOH H Alkyl Aryl
Alkyl COOH H Alkyl (CH 2) nCOOR 6
Alkyl COOH H Alkyl (CH 2) nOR 6
Alkyl COOH H Aryl H
Alkyl COOH H Aryl Alkyl
Alkyl COOH H Aryl Aryl
Alkyl COOH H Aryl (CH 2) nCOOR 6
Alkyl COOH H Aryl (CH 2) nOR 6
Alkyl COOH H (CH 2) nCOOR 6 H
Alkyl COOH H (CH 2) nCOOR 6 Alkyl
Alkyl COOH H (CH 2) nCOOR 6 Aryl
Alkyl COOH H (CH 2) nCOOR 6 (CH 2) nCOOR 6
Alkyl COOH H (CH 2) nCOOR 6 (CH 2) nOR 6
Alkyl COOH H (CH 2) nOR 6 H
Alkyl COOH H (CH 2) nOR 6 Alkyl
Alkyl COOH H (CH 2) nOR 6 Aryl
Alkyl COOH H (CH 2) nOR 6 (CH 2) nCOOR 6
Alkyl COOH H (CH 2) nOR 6 (CH 2) nOR 6
Alkyl COOH Alkyl H H
Alkyl COOH Alkyl H Alkyl
Alkyl COOH Alkyl H Aryl
Alkyl COOH Alkyl H (CH 2) nCOOR 6
Alkyl COOH Alkyl H (CH 2) nOR 6
Alkyl COOH Alkyl Alkyl H
Alkyl COOH Alkyl Alkyl Alkyl
Alkyl COOH Alkyl Alkyl Aryl
Alkyl COOH Alkyl Alkyl (CH 2) nCOOR 6
Alkyl COOH Alkyl Alkyl (CH 2) nOR 6
Alkyl COOH Alkyl Aryl H
Alkyl COOH Alkyl Aryl Alkyl
Alkyl COOH Alkyl Aryl Aryl
Alkyl COOH Alkyl Aryl (CH 2) nCOOR 6
Alkyl COOH Alkyl Aryl (CH 2) nOR 6
Alkyl COOH Alkyl (CH 2) nCOOR 6 H
Alkyl COOH Alkyl (CH 2) nCOOR 6 Alkyl
Alkyl COOH Alkyl (CH 2) nCOOR 6 Aryl
Alkyl COOH Alkyl (CH 2) nCOOR 6 (CH 2) nCOOR 6
Alkyl COOH Alkyl (CH 2) nCOOR 6 (CH 2) nOR 6
Alkyl COOH Alkyl (CH 2) nOR 6 H
Alkyl COOH Alkyl (CH 2) nOR 6 Alkyl
Alkyl COOH Alkyl (CH 2) nOR 6 Aryl
Alkyl COOH Alkyl (CH 2) nOR 6 (CH 2) nCOOR 6
Alkyl COOH Alkyl (CH 2) nOR 6 (CH 2) nOR 6
Alkyl COOH Aryl H H
Alkyl COOH Aryl H Alkyl
Alkyl COOH Aryl H Aryl
Alkyl COOH Aryl H (CH 2) nCOOR 6
Alkyl COOH Aryl H (CH 2) nOR 6
Alkyl COOH Aryl Alkyl H
Alkyl COOH Aryl Alkyl Alkyl
Alkyl COOH Aryl Alkyl Aryl
Alkyl COOH Aryl Alkyl (CH 2) nCOOR 6
Alkyl COOH Aryl Alkyl (CH 2) nOR 6
Alkyl COOH Aryl Aryl H
Alkyl COOH Aryl Aryl Alkyl
Alkyl COOH Aryl Aryl Aryl
Alkyl COOH Aryl Aryl (CH 2) nCOOR 6
Alkyl COOH Aryl Aryl (CH 2) nOR 6
Alkyl COOH Aryl (CH 2) nCOOR 6 H
Alkyl COOH Aryl (CH 2) nCOOR 6 Alkyl
Alkyl COOH Aryl (CH 2) nCOOR 6 Aryl
Alkyl COOH Aryl (CH 2) nCOOR 6 (CH 2) nCOOR 6
Alkyl COOH Aryl (CH 2) nCOOR 6 (CH 2) nOR 6
Alkyl COOH Aryl (CH 2) nOR 6 H
Alkyl COOH Aryl (CH 2) nOR 6 Alkyl
Alkyl COOH Aryl (CH 2) nOR 6 Aryl
Alkyl COOH Aryl (CH 2) nOR 6 (CH 2) nCOOR 6
Alkyl COOH Aryl (CH 2) nOR 6 (CH 2) nOR 6
Alkyl NHR 6 H H H
Alkyl NHR 6 H H Alkyl
Alkyl NHR 6 H H Aryl
Alkyl NHR 6 H H (CH 2) nCOOR 6
Alkyl NHR 6 H H (CH 2) nOR 6
Alkyl NHR 6 H Alkyl H
Alkyl NHR 6 H Alkyl Alkyl
Alkyl NHR 6 H Alkyl Aryl
Alkyl NHR 6 H Alkyl (CH 2) nCOOR 6
Alkyl NHR 6 H Alkyl (CH 2) nOR 6
Alkyl NHR 6 H Aryl H
Alkyl NHR 6 H Aryl Alkyl
Alkyl NHR 6 H Aryl Aryl
Alkyl NHR 6 H Aryl (CH 2) nCOOR 6
Alkyl NHR 6 H Aryl (CH 2) nOR 6
Alkyl NHR 6 H (CH 2) nCOOR 6 H
Alkyl NHR 6 H (CH 2) nCOOR 6 Alkyl
Alkyl NHR 6 H (CH 2) nCOOR 6 Aryl
Alkyl NHR 6 H (CH 2) nCOOR 6 (CH 2) nCOOR 6
Alkyl NHR 6 H (CH 2) nCOOR 6 (CH 2) nOR 6
Alkyl NHR 6 H (CH 2) nOR 6 H
Alkyl NHR 6 H (CH 2) nOR 6 Alkyl
Alkyl NHR 6 H (CH 2) nOR 6 Aryl
Alkyl NHR 6 H (CH 2) nOR 6 (CH 2) nCOOR 6
Alkyl NHR 6 H (CH 2) nOR 6 (CH 2) nOR 6
Alkyl NHR 6 Alkyl H H
Alkyl NHR 6 Alkyl H Alkyl
Alkyl NHR 6 Alkyl H Aryl
Alkyl NHR 6 Alkyl H (CH 2) nCOOR 6
Alkyl NHR 6 Alkyl H (CH 2) nOR 6
Alkyl NHR 6 Alkyl Alkyl H
Alkyl NHR 6 Alkyl Alkyl Alkyl
Alkyl NHR 6 Alkyl Alkyl Aryl
Alkyl NHR 6 Alkyl Alkyl (CH 2) nCOOR 6
Alkyl NHR 6 Alkyl Alkyl (CH 2) nOR 6
Alkyl NHR 6 Alkyl Aryl H
Alkyl NHR 6 Alkyl Aryl Alkyl
Alkyl NHR 6 Alkyl Aryl Aryl
Alkyl NHR 6 Alkyl Aryl (CH 2) nCOOR 6
Alkyl NHR 6 Alkyl Aryl (CH 2) nOR 6
Alkyl NHR 6 Alkyl (CH 2) nCOOR 6 H
Alkyl NHR 6 Alkyl (CH 2) nCOOR 6 Alkyl
Alkyl NHR 6 Alkyl (CH 2) nCOOR 6 Aryl
Alkyl NHR 6 Alkyl (CH 2) nCOOR 6 (CH 2) nCOOR 6
Alkyl NHR 6 Alkyl (CH 2) nCOOR 6 (CH 2) nOR 6
Alkyl NHR 6 Alkyl (CH 2) nOR 6 H
Alkyl NHR 6 Alkyl (CH 2) nOR 6 Alkyl
Alkyl NHR 6 Alkyl (CH 2) nOR 6 Aryl
Alkyl NHR 6 Alkyl (CH 2) nOR 6 (CH 2) nCOOR 6
Alkyl NHR 6 Alkyl (CH 2) nOR 6 (CH 2) nOR 6
Alkyl NHR 6 Aryl H H
Alkyl NHR 6 Aryl H Alkyl
Alkyl NHR 6 Aryl H Aryl
Alkyl NHR 6 Aryl H (CH 2) nCOOR 6
Alkyl NHR 6 Aryl H (CH 2) nOR 6
Alkyl NHR 6 Aryl Alkyl H
Alkyl NHR 6 Aryl Alkyl Alkyl
Alkyl NHR 6 Aryl Alkyl Aryl
Alkyl NHR 6 Aryl Alkyl (CH 2) nCOOR 6
Alkyl NHR 6 Aryl Alkyl (CH 2) nOR 6
Alkyl NHR 6 Aryl Aryl H
Alkyl NHR 6 Aryl Aryl Alkyl
Alkyl NHR 6 Aryl Aryl Aryl
Alkyl NHR 6 Aryl Aryl (CH 2) nCOOR 6
Alkyl NHR 6 Aryl Aryl (CH 2) nOR 6
Alkyl NHR 6 Aryl (CH 2) nCOOR 6 H
Alkyl NHR 6 Aryl (CH 2) nCOOR 6 Alkyl
Alkyl NHR 6 Aryl (CH 2) nCOOR 6 Aryl
Alkyl NHR 6 Aryl (CH 2) nCOOR 6 (CH 2) nCOOR 6
Alkyl NHR 6 Aryl (CH 2) nCOOR 6 (CH 2) nOR 6
Alkyl NHR 6 Aryl (CH 2) nOR 6 H
Alkyl NHR 6 Aryl (CH 2) nOR 6 Alkyl
Alkyl NHR 6 Aryl (CH 2) nOR 6 Aryl
Alkyl NHR 6 Aryl (CH 2) nOR 6 (CH 2) nCOOR 6
Alkyl NHR 6 Aryl (CH 2) nOR 6 (CH 2) nOR 6
Alkyl (CH 2) nCOOR 6 H H H
Alkyl (CH 2) nCOOR 6 H H Alkyl
Alkyl (CH 2) nCOOR 6 H H Aryl
Alkyl (CH 2) nCOOR 6 H H (CH 2) nCOOR 6
Alkyl (CH 2) nCOOR 6 H H (CH 2) nOR 6
Alkyl (CH 2) nCOOR 6 H Alkyl H
Alkyl (CH 2) nCOOR 6 H Alkyl Alkyl
Alkyl (CH 2) nCOOR 6 H Alkyl Aryl
Alkyl (CH 2) nCOOR 6 H Alkyl (CH 2) nCOOR 6
Alkyl (CH 2) nCOOR 6 H Alkyl (CH 2) nOR 6
Alkyl (CH 2) nCOOR 6 H Aryl H
Alkyl (CH 2) nCOOR 6 H Aryl Alkyl
Alkyl (CH 2) nCOOR 6 H Aryl Aryl
Alkyl (CH 2) nCOOR 6 H Aryl (CH 2) nCOOR 6
Alkyl (CH 2) nCOOR 6 H Aryl (CH 2) nOR 6
Alkyl (CH 2) nCOOR 6 H (CH 2) nCOOR 6 H
Alkyl (CH 2) nCOOR 6 H (CH 2) nCOOR 6 Alkyl
Alkyl (CH 2) nCOOR 6 H (CH 2) nCOOR 6 Aryl
Alkyl (CH 2) nCOOR 6 H (CH 2) nCOOR 6 (CH 2) nCOOR 6
Alkyl (CH 2) nCOOR 6 H (CH 2) nCOOR 6 (CH 2) nOR 6
Alkyl (CH 2) nCOOR 6 H (CH 2) nOR 6 H
Alkyl (CH 2) nCOOR 6 H (CH 2) nOR 6 Alkyl
Alkyl (CH 2) nCOOR 6 H (CH 2) nOR 6 Aryl
Alkyl (CH 2) nCOOR 6 H (CH 2) nOR 6 (CH 2) nCOOR 6
Alkyl (CH 2) nCOOR 6 H (CH 2) nOR 6 (CH 2) nOR 6
Alkyl (CH 2) nCOOR 6 Alkyl H H
Alkyl (CH 2) nCOOR 6 Alkyl H Alkyl
Alkyl (CH 2) nCOOR 6 Alkyl H Aryl
Alkyl (CH 2) nCOOR 6 Alkyl H (CH 2) nCOOR 6
Alkyl (CH 2) nCOOR 6 Alkyl H (CH 2) nOR 6
Alkyl (CH 2) nCOOR 6 Alkyl Alkyl H
Alkyl (CH 2) nCOOR 6 Alkyl Alkyl Alkyl
Alkyl (CH 2) nCOOR 6 Alkyl Alkyl Aryl
Alkyl (CH 2) nCOOR 6 Alkyl Alkyl (CH 2) nCOOR 6
Alkyl (CH 2) nCOOR 6 Alkyl Alkyl (CH 2) nOR 6
Alkyl (CH 2) nCOOR 6 Alkyl Aryl H
Alkyl (CH 2) nCOOR 6 Alkyl Aryl Alkyl
Alkyl (CH 2) nCOOR 6 Alkyl Aryl Aryl
Alkyl (CH 2) nCOOR 6 Alkyl Aryl (CH 2) nCOOR 6
Alkyl (CH 2) nCOOR 6 Alkyl Aryl (CH 2) nOR 6
Alkyl (CH 2) nCOOR 6 Alkyl (CH 2) nCOOR 6 H
Alkyl (CH 2) nCOOR 6 Alkyl (CH 2) nCOOR 6 Alkyl
Alkyl (CH 2) nCOOR 6 Alkyl (CH 2) nCOOR 6 Aryl
Alkyl (CH 2) nCOOR 6 Alkyl (CH 2) nCOOR 6 (CH 2) nCOOR 6
Alkyl (CH 2) nCOOR 6 Alkyl (CH 2) nCOOR 6 (CH 2) nOR 6
Alkyl (CH 2) nCOOR 6 Alkyl (CH 2) nOR 6 H
Alkyl (CH 2) nCOOR 6 Alkyl (CH 2) nOR 6 Alkyl
Alkyl (CH 2) nCOOR 6 Alkyl (CH 2) nOR 6 Aryl
Alkyl (CH 2) nCOOR 6 Alkyl (CH 2) nOR 6 (CH 2) nCOOR 6
Alkyl (CH 2) nCOOR 6 Alkyl (CH 2) nCOR 6 (CH 2) nOR 6
Alkyl (CH 2) nCOOR 6 Aryl H H
Alkyl (CH 2) nCOOR 6 Aryl H Alkyl
Alkyl (CH 2) nCOOR 6 Aryl H Aryl
Alkyl (CH 2) nCOOR 6 Aryl H (CH 2) nCOOR 6
Alkyl (CH 2) nCOOR 6 Aryl H (CH 2) nOR 6
Alkyl (CH 2) nCOOR 6 Aryl Alkyl H
Alkyl (CH 2) nCOOR 6 Aryl Alkyl Alkyl
Alkyl (CH 2) nCOOR 6 Aryl Alkyl Aryl
Alkyl (CH 2) nCOOR 6 Aryl Alkyl (CH 2) nCOOR 6
Alkyl (CH 2) nCOOR 6 Aryl Alkyl (CH 2) nOR 6
Alkyl (CH 2) nCOOR 6 Aryl Aryl H
Alkyl (CH 2) nCOOR 6 Aryl Aryl Alkyl
Alkyl (CH 2) nCOOR 6 Aryl Aryl Aryl
Alkyl (CH 2) nCOOR 6 Aryl Aryl (CH 2) nCOOR 6
Alkyl (CH 2) nCOOR 6 Aryl Aryl (CH 2) nOR 6
Alkyl (CH 2) nCOOR 6 Aryl (CH 2) nCOOR 6 H
Alkyl (CH 2) nCOOR 6 Aryl (CH 2) nCOOR 6 Alkyl
Alkyl (CH 2) nCOOR 6 Aryl (CH 2) nCOOR 6 Aryl
Alkyl (CH 2) nCOOR 6 Aryl (CH 2) nCOOR 6 (CH 2) nCOOR 6
Alkyl (CH 2) nCOOR 6 Aryl (CH 2) nCOOR 6 (CH 2) nOR 6
Alkyl (CH 2) nCOOR 6 Aryl (CH 2) nOR 6 H
Alkyl (CH 2) nCOOR 6 Aryl (CH 2) nOR 6 Alkyl
Alkyl (CH 2) nCOOR 6 Aryl (CH 2) nOR 6 Aryl
Alkyl (CH 2) nCOOR 6 Aryl (CH 2) nOR 6 (CH 2) nCOOR 6
Alkyl (CH 2) nCOOR 6 Aryl (CH 2) nOR 6 (CH 2) nOR 6
Aryl H H H H
Aryl H H H Alkyl
Aryl H H H Aryl
Aryl H H H (CH 2) nCOOR 6
Aryl H H H (CH 2) nOR 6
Aryl H H Alkyl H
Aryl H H Alkyl Alkyl
Aryl H H Alkyl Aryl
Aryl H H Alkyl (CH 2) nCOOR 6
Aryl H H Alkyl (CH 2) nOR 6
Aryl H H Aryl H
Aryl H H Aryl Alkyl
Aryl H H Aryl Aryl
Aryl H H Aryl (CH 2) nCOOR 6
Aryl H H Aryl (CH 2) nOR 6
Aryl H H (CH 2) nCOOR 6 H
Aryl H H (CH 2) nCOOR 6 Alkyl
Aryl H H (CH 2) nCOOR 6 Aryl
Aryl H H (CH 2) nCOOR 6 (CH 2) nCOOR 6
Aryl H H (CH 2) nCOOR 6 (CH 2) nOR 6
Aryl H H (CH 2) nOR 6 H
Aryl H H (CH 2) nOR 6 Alkyl
Aryl H H (CH 2) nOR 6 Aryl
Aryl H H (CH 2) nOR 6 (CH 2) nCOOR 6
Aryl H H (CH 2) nOR 6 (CH 2) nOR 6
Aryl H Alkyl H H
Aryl H Alkyl H Alkyl
Aryl H Alkyl H Aryl
Aryl H Alkyl H (CH 2) nCOOR 6
Aryl H Alkyl H (CH 2) nOR 6
Aryl H Alkyl Alkyl H
Aryl H Alkyl Alkyl Alkyl
Aryl H Alkyl Alkyl Aryl
Aryl H Alkyl Alkyl (CH 2) nCOOR 6
Aryl H Alkyl Alkyl (CH 2) nOR 6
Aryl H Alkyl Aryl H
Aryl H Alkyl Aryl Alkyl
Aryl H Alkyl Aryl Aryl
Aryl H Alkyl Aryl (CH 2) nCOOR 6
Aryl H Alkyl Aryl (CH 2) nOR 6
Aryl H Alkyl (CH 2) nCOOR 6 H
Aryl H Alkyl (CH 2) nCOOR 6 Alkyl
Aryl H Alkyl (CH 2) nCOOR 6 Aryl
Aryl H Alkyl (CH 2) nCOOR 6 (CH 2) nCOOR 6
Aryl H Alkyl (CH 2) nCOOR 6 (CH 2) nOR 6
Aryl H Alkyl (CH 2) nOR 6 H
Aryl H Alkyl (CH 2) nOR 6 Alkyl
Aryl H Alkyl (CH 2) nOR 6 Aryl
Aryl H Alkyl (CH 2) nOR 6 (CH 2) nCOOR 6
Aryl H Alkyl (CH 2) nOR 6 (CH 2) nOR 6
Aryl H Aryl H H
Aryl H Aryl H Alkyl
Aryl H Aryl H Aryl
Aryl H Aryl H (CH 2) nCOOR 6
Aryl H Aryl H (CH 2) nOR 6
Aryl H Aryl Alkyl H
Aryl H Aryl Alkyl Alkyl
Aryl H Aryl Alkyl Aryl
Aryl H Aryl Alkyl (CH 2) nCOOR 6
Aryl H Aryl Alkyl (CH 2) nOR 6
Aryl H Aryl Aryl H
Aryl H Aryl Aryl Alkyl
Aryl H Aryl Aryl Aryl
Aryl H Aryl Aryl (CH 2) nCOOR 6
Aryl H Aryl Aryl (CH 2) nOR 6
Aryl H Aryl (CH 2) nCOOR 6 H
Aryl H Aryl (CH 2) nCOOR 6 Alkyl
Aryl H Aryl (CH 2) nCOOR 6 Aryl
Aryl H Aryl (CH 2) nCOOR 6 (CH 2) nCOOR 6
Aryl H Aryl (CH 2) nCOOR 6 (CH 2) nOR 6
Aryl H Aryl (CH 2) nOR 6 H
Aryl H Aryl (CH 2) nOR 6 Alkyl
Aryl H Aryl (CH 2) nOR 6 Aryl
Aryl H Aryl (CH 2) nOR 6 (CH 2) nCOOR 6
Aryl H Aryl (CH 2) nOR 6 (CH 2) nOR 6
Aryl COOH H H H
Aryl COOH H H Alkyl
Aryl COOH H H Aryl
Aryl COOH H H (CH 2) nCOOR 6
Aryl COOH H H (CH 2) nOR 6
Aryl COOH H Alkyl H
Aryl COOH H Alkyl Alkyl
Aryl COOH H Alkyl Aryl
Aryl COOH H Alkyl (CH 2) nCOOR 6
Aryl COOH H Alkyl (CH 2) nOR 6
Aryl COOH H Aryl H
Aryl COOH H Aryl Alkyl
Aryl COOH H Aryl Aryl
Aryl COOH H Aryl (CH 2) nCOOR 6
Aryl COOH H Aryl (CH 2) nOR 6
Aryl COOH H (CH 2) nCOOR 6 H
Aryl COOH H (CH 2) nCOOR 6 Alkyl
Aryl COOH H (CH 2) nCOOR 6 Aryl
Aryl COOH H (CH 2) nCOOR 6 (CH 2) nCOOR 6
Aryl COOH H (CH 2) nCOOR 6 (CH 2) nOR 6
Aryl COOH H (CH 2) nOR 6 H
Aryl COOH H (CH 2) nOR 6 Alkyl
Aryl COOH H (CH 2) nOR 6 Aryl
Aryl COOH H (CH 2) nOR 6 (CH 2) nCOOR 6
Aryl COOH H (CH 2) nOR 6 (CH 2) nOR 6
Aryl COOH Alkyl H H
Aryl COOH Alkyl H Alkyl
Aryl COOH Alkyl H Aryl
Aryl COOH Alkyl H (CH 2) nCOOR 6
Aryl COOH Alkyl H (CH 2) nOR 6
Aryl COOH Alkyl Alkyl H
Aryl COOH Alkyl Alkyl Alkyl
Aryl COOH Alkyl Alkyl Aryl
Aryl COOH Alkyl Alkyl (CH 2) nCOOR 6
Aryl COOH Alkyl Alkyl (CH 2) nOR 6
Aryl COOH Alkyl Aryl H
Aryl COOH Alkyl Aryl Alkyl
Aryl COOH Alkyl Aryl Aryl
Aryl COOH Alkyl Aryl (CH 2) nCOOR 6
Aryl COOH Alkyl Aryl (CH 2) nOR 6
Aryl COOH Alkyl (CH 2) nCOOR 6 H
Aryl COOH Alkyl (CH 2) nCOOR 6 Alkyl
Aryl COOH Alkyl (CH 2) nCOOR 6 Aryl
Aryl COOH Alkyl (CH 2) nCOOR 6 (CH 2) nCOOR 6
Aryl COOH Alkyl (CH 2) nCOOR 6 (CH 2)nOR6
Aryl COOH Alkyl (CH 2) nOR 6 H
Aryl COOH Alkyl (CH 2) nOR 6 Alkyl
Aryl COOH Alkyl (CH 2) nOR 6 Aryl
Aryl COOH Alkyl (CH 2) nOR 6 (CH 2) nCOOR 6
Aryl COOH Alkyl (CH 2) nOR 6 (CH 2) nOR 6
Aryl COOH Aryl H H
Aryl COOH Aryl H Alkyl
Aryl COOH Aryl H Aryl
Aryl COOH Aryl H (CH 2) nCOOR 6
Aryl COOH Aryl H (CH 2) nOR 6
Aryl COOH Aryl Alkyl H
Aryl COOH Aryl Alkyl Alkyl
Aryl COOH Aryl Alkyl Aryl
Aryl COOH Aryl Alkyl (CH 2) nCOOR 6
Aryl COOH Aryl Alkyl (CH 2) nOR 6
Aryl COOH Aryl Aryl H
Aryl COOH Aryl Aryl Alkyl
Aryl COOH Aryl Aryl Aryl
Aryl COOH Aryl Aryl (CH 2) nCOOR 6
Aryl COOH Aryl Aryl (CH 2) nOR 6
Aryl COOH Aryl (CH 2) nCOOR 6 H
Aryl COOH Aryl (CH 2) nCOOR 6 Alkyl
Aryl COOH Aryl (CH 2) nCOOR 6 Aryl
Aryl COOH Aryl (CH 2) nCOOR 6 (CH 2) nCOOR 6
Aryl COOH Aryl (CH 2) nCOOR 6 (CH 2) nOR 6
Aryl COOH Aryl (CH 2) nOR 6 H
Aryl COOH Aryl (CH 2) nOR 6 Alkyl
Aryl COOH Aryl (CH 2) nOR 6 Aryl
Aryl COOH Aryl (CH 2) nOR 6 (CH 2) nCOOR 6
Aryl COOH Aryl (CH 2) nOR 6 (CH 2) nOR 6
Aryl NHR 6 H H H
Aryl NHR 6 H H Alkyl
Aryl NHR 6 H H Aryl
Aryl NHR 6 H H (CH 2) nCOOR 6
Aryl NHR 6 H H (CH 2) nOR 6
Aryl NHR 6 H Alkyl H
Aryl NHR 6 H Alkyl Alkyl
Aryl NHR 6 H Alkyl Aryl
Aryl NHR 6 H Alkyl (CH 2) nCOOR 6
Aryl NHR 6 H Alkyl (CH 2) nOR 6
Aryl NHR 6 H Aryl H
Aryl NHR 6 H Aryl Alkyl
Aryl NHR 6 H Aryl Aryl
Aryl NHR 6 H Aryl (CH 2) nCOOR 6
Aryl NHR 6 H Aryl (CH 2) nOR 6
Aryl NHR 6 H (CH 2) nCOOR 6 H
Aryl NHR 6 H (CH 2) nCOOR 6 Alkyl
Aryl NHR 6 H (CH 2) nCOOR 6 Aryl
Aryl NHR 6 H (CH 2) nCOOR 6 (CH 2) nCOOR 6
Aryl NHR 6 H (CH 2) nCOOR 6 (CH 2) nOR 6
Aryl NHR 6 H (CH 2) nOR 6 H
Aryl NHR 6 H (CH 2) nOR 6 Alkyl
Aryl NHR 6 H (CH 2) nOR 6 Aryl
Aryl NHR 6 H (CH 2) nOR 6 (CH 2) nCOOR 6
Aryl NHR 6 H (CH 2) nOR 6 (CH 2) nOR 6
Aryl NHR 6 Alkyl H H
Aryl NHR 6 Alkyl H Alkyl
Aryl NHR 6 Alkyl H Aryl
Aryl NHR 6 Alkyl H (CH 2) nCOOR 6
Aryl NHR 6 Alkyl H (CH 2) nOR 6
Aryl NHR 6 Alkyl Alkyl H
Aryl NHR 6 Alkyl Alkyl Alkyl
Aryl NHR 6 Alkyl Alkyl Aryl
Aryl NHR 6 Alkyl Alkyl (CH 2) nCOOR 6
Aryl NHR 6 Alkyl Alkyl (CH 2) nOR 6
Aryl NHR 6 Alkyl Aryl H
Aryl NHR 6 Alkyl Aryl Alkyl
Aryl NHR 6 Alkyl Aryl Aryl
Aryl NHR 6 Alkyl Aryl (CH 2) nCOOR 6
Aryl NHR 6 Alkyl Aryl (CH 2) nOR 6
Aryl NHR 6 Alkyl (CH 2) nCOOR 6 H
Aryl NHR 6 Alkyl (CH 2) nCOOR 6 Alkyl
Aryl NHR 6 Alkyl (CH 2) nCOOR 6 Aryl
Aryl NHR 6 Alkyl (CH 2) nCOOR 6 (CH 2) nCOOR 6
Aryl NHR 6 Alkyl (CH 2) nCOOR 6 (CH 2) nOR 6
Aryl NHR 6 Alkyl (CH 2) nOR 6 H
Aryl NHR 6 Alkyl (CH 2) nOR 6 Alkyl
Aryl NHR 6 Alkyl (CH 2) nOR 6 Aryl
Aryl NHR 6 Alkyl (CH 2) nOR 6 (CH 2) nCOOR 6
Aryl NHR 6 Alkyl (CH 2) nOR 6 (CH 2) nOR 6
Aryl NHR 6 Aryl H H
Aryl NHR 6 Aryl H Alkyl
Aryl NHR 6 Aryl H Aryl
Aryl NHR 6 Aryl H (CH 2) nCOOR 6
Aryl NHR 6 Aryl H (CH 2) nOR 6
Aryl NHR 6 Aryl Alkyl H
Aryl NHR 6 Aryl Alkyl Alkyl
Aryl NHR 6 Aryl Alkyl Aryl
Aryl NHR 6 Aryl Alkyl (CH 2) nCOOR 6
Aryl NHR 6 Aryl Alkyl (CH 2) nOR 6
Aryl NHR 6 Aryl Aryl H
Aryl NHR 6 Aryl Aryl Alkyl
Aryl NHR 6 Aryl Aryl Aryl
Aryl NHR 6 Aryl Aryl (CH 2) nCOOR 6
Aryl NHR 6 Aryl Aryl (CH 2) nOR 6
Aryl NHR 6 Aryl (CH 2) nCOOR 6 H
Aryl NHR 6 Aryl (CH 2) nCOOR 6 Alkyl
Aryl NHR 6 Aryl (CH 2) nCOOR 6 Aryl
Aryl NHR 6 Aryl (CH 2) nCOOR 6 (CH 2) nCOOR 6
Aryl NHR 6 Aryl (CH 2) nCOOR 6 (CH 2) nOR 6
Aryl NHR 6 Aryl (CH 2) nOR 6 H
Aryl NHR 6 Aryl (CH 2) nOR 6 Alkyl
Aryl NHR 6 Aryl (CH 2) nOR 6 Aryl
Aryl NHR 6 Aryl (CH 2) nOR 6 (CH 2) nCOOR 6
Aryl NHR 6 Aryl (CH 2) nOR 6 (CH 2) nOR 6
Aryl (CH 2) nCOOR 6 H H H
Aryl (CH 2) nCOOR 6 H H Alkyl
Aryl (CH 2) nCOOR 6 H H Aryl
Aryl (CH 2) nCOOR 6 H H (CH 2) nCOOR 6
Aryl (CH 2) nCOOR 6 H H (CH 2) nOR 6
Aryl (CH 2) nCOOR 6 H Alkyl H
Aryl (CH 2) nCOOR 6 H Alkyl Alkyl
Aryl (CH 2) nCOOR 6 H Alkyl Aryl
Aryl (CH 2) nCOOR 6 H Alkyl (CH 2) nCOOR 6
Aryl (CH 2) nCOOR 6 H Alkyl (CH 2) nOR 6
Aryl (CH 2) nCOOR 6 H Aryl H
Aryl (CH 2) nCOOR 6 H Aryl Alkyl
Aryl (CH 2) nCOOR 6 H Aryl Aryl
Aryl (CH 2) nCOOR 6 H Aryl (CH 2) nCOOR 6
Aryl (CH 2) nCOOR 6 H Aryl (CH 2) nOR 6
Aryl (CH 2) nCOOR 6 H (CH 2) nCOOR 6 H
Aryl (CH 2) nCOOR 6 H (CH 2) nCOOR 6 Alkyl
Aryl (CH 2) nCOOR 6 H (CH 2) nCOOR 6 Aryl
Aryl (CH 2) nCOOR 6 H (CH 2) nCOOR 6 (CH 2) nCOOR 6
Aryl (CH 2) nCOOR 6 H (CH 2) nCOOR 6 (CH 2) nOR 6
Aryl (CH 2) nCOOR 6 H (CH 2) nOR 6 H
Aryl (CH 2) nCOOR 6 H (CH 2) nOR 6 Alkyl
Aryl (CH 2) nCOOR 6 H (CH 2) nOR 6 Aryl
Aryl (CH 2) nCOOR 6 H (CH 2) nOR 6 (CH 2) nCOOR 6
Aryl (CH 2) nCOOR 6 H (CH 2) nOR 6 (CH 2) nOR 6
Aryl (CH 2) nCOOR 6 Alkyl H H
Aryl (CH 2) nCOOR 6 Alkyl H Alkyl
Aryl (CH 2) nCOOR 6 Alkyl H Aryl
Aryl (CH 2) nCOOR 6 Alkyl H (CH 2) nCOOR 6
Aryl (CH 2) nCOOR 6 Alkyl H (CH 2) nOR 6
Aryl (CH 2) nCOOR 6 Alkyl Alkyl H
Aryl (CH 2) nCOOR 6 Alkyl Alkyl Alkyl
Aryl (CH 2) nCOOR 6 Alkyl Alkyl Aryl
Aryl (CH 2) nCOOR 6 Alkyl Alkyl (CH 2) nCOOR 6
Aryl (CH 2) nCOOR 6 Alkyl Alkyl (CH 2) nOR 6
Aryl (CH 2) nCOOR 6 Alkyl Aryl H
Aryl (CH 2) nCOOR 6 Alkyl Aryl Alkyl
Aryl (CH 2) nCOOR 6 Alkyl Aryl Aryl
Aryl (CH 2) nCOOR 6 Alkyl Aryl (CH 2) nCOOR 6
Aryl (CH 2) nCOOR 6 Alkyl Aryl (CH 2) nOR 6
Aryl (CH 2) nCOOR 6 Alkyl (CH 2) nCOOR 6 H
Aryl (CH 2) nCOOR 6 Alkyl (CH 2) nCOOR 6 Alkyl
Aryl (CH 2) nCOOR 6 Alkyl (CH 2) nCOOR 6 Aryl
Aryl (CH 2) nCOOR 6 Alkyl (CH 2) nCOOR 6 (CH 2) nCOOR 6
Aryl (CH 2) nCOOR 6 Alkyl (CH 2) nCOOR 6 (CH 2) nOR 6
Aryl (CH 2) nCOOR 6 Alkyl (CH 2) nOR 6 H
Aryl (CH 2) nCOOR 6 Alkyl (CH 2) nOR 6 Alkyl
Aryl (CH 2) nCOOR 6 Alkyl (CH 2) nOR 6 Aryl
Aryl (CH 2) nCOOR 6 Alkyl (CH 2) nOR 6 (CH 2) nCOOR 6
Aryl (CH 2) nCOOR 6 Alkyl (CH 2) nOR 6 (CH 2) nOR 6
Aryl (CH 2) nCOOR 6 Aryl H H
Aryl (CH 2) nCOOR 6 Aryl H Alkyl
Aryl (CH 2) nCOOR 6 Aryl H Aryl
Aryl (CH 2) nCOOR 6 Aryl H (CH 2) nCOOR 6
Aryl (CH 2) nCOOR 6 Aryl H (CH 2) nOR 6
Aryl (CH 2) nCOOR 6 Aryl Alkyl H
Aryl (CH 2) nCOOR 6 Aryl Alkyl Alkyl
Aryl (CH 2) nCOOR 6 Aryl Alkyl Aryl
Aryl (CH 2) nCOOR 6 Aryl Alkyl (CH 2) nCOOR 6
Aryl (CH 2) nCOOR 6 Aryl Alkyl (CH 2) nOR 6
Aryl (CH 2) nCOOR 6 Aryl Aryl H
Aryl (CH 2) nCOOR 6 Aryl Aryl Alkyl
Aryl (CH 2) nCOOR 6 Aryl Aryl Aryl
Aryl (CH 2) nCOOR 6 Aryl Aryl (CH 2) nCOOR 6
Aryl (CH 2) nCOOR 6 Aryl Aryl (CH 2) nOR 6
Aryl (CH 2) nCOOR 6 Aryl (CH 2) nCOOR 6 H
Aryl (CH 2) nCOOR 6 Aryl (CH 2) nCOOR 6 Alkyl
Aryl (CH 2) nCOOR 6 Aryl (CH 2) nCOOR 6 Aryl
Aryl (CH 2) nCOOR 6 Aryl (CH 2) nCOOR 6 (CH 2) nCOOR 6
Aryl (CH 2) nCOOR 6 Aryl (CH 2) nCOOR 6 (CH 2) nOR 6
Aryl (CH 2) nCOOR 6 Aryl (CH 2) nOR 6 H
Aryl (CH 2) nCOOR 6 Aryl (CH 2) nOR 6 Alkyl
Aryl (CH 2) nCOOR 6 Aryl (CH 2) nOR 6 Aryl
Aryl (CH 2) nCOOR 6 Aryl (CH 2) nOR 6 (CH 2) nCOOR 6
Aryl (CH 2) nCOOR 6 Aryl (CH 2) nOR 6 (CH 2) nOR 6
The invention still further relates to the method for the radiolabeled biomolecule of preparation, described method comprises:
A) be used to form under the condition of chelating agen-carbonyl complex, making chelating agen of the present invention and formula [M (CO) 3] +Carbonyl moiety contact, wherein M is rhenium (Re) or technetium (Tc); With
B) this complex is contacted with biomolecule, obtain radiolabeled biomolecule.The method is specially adapted to the biomolecule of labelling to temperature and final (extreme) pH sensitivity.
The method can for example be finished with test kit, described test kit comprises first bottle (vial) with chelating agen of the present invention, the first reaction bottle that randomly is used to make chelating agen to contact with carbonyl moiety, have second bottle of biomolecule, and the second reaction bottle that randomly is used for making chelating agen-carbonyl complex reaction that biomolecule and reaction first step obtain.
In other embodiments of the present invention, a kind of method that is used to prepare radiolabeled biomolecule is provided, described method comprises:
A) chelating agen of the present invention is contacted with biomolecule and be used to obtain chelating agen-biomolecule; With
B) be used to form under the condition of radiolabeled biomolecule, making chelating agen-biomolecule and formula [M (CO) 3] +Carbonyl moiety contact, wherein M is rhenium (Re) or technetium (Tc).
The test kit that is used to finish the method comprises, first bottle that for example has chelating agen of the present invention, randomly be used to make the first reaction bottle of chelating agen and biomolecular reaction, have second bottle of carbonyl moiety, and the chelating agen-biomolecule that randomly is used for making the reaction first step to obtain is reacted bottle with second of carbonyl reaction.
The present invention will further be illustrated according to the following examples.
Embodiment
Introduce
Described difunctional pyrazolyl-polyamines, pyrazolyl-polythiaether, pyrazolyl amino-thioether part, pyrazolyl-amino-phosphine and pyrazolyl-thioether phosphine contain different donor atom subclass with stable metal, and can for example have different functional groups on the link coupled diverse location of monoclonal antibody, peptide, oligonucleotide and glycoprotein with the molecule of seeking (seeking molecules).They also can have the physical-chemical characteristic that different substituent groups and alkyl chain are used to regulate molecule at the diverse location of main chain.
Fig. 1 has provided general general introduction, and it has shown [M (CO) 3] +May making up of the metal segments of (M=Re, Tc, Mn) type.For the part of these five kinds of the theme of the present invention dissimilar pyrazolyls that contain bifunctional tridentate schematically is described among Fig. 2.
In Fig. 3-6 the present invention will be described in further detail, it is only used for making the present invention clear.This type of part can obtain thermodynamically stable complex, and the multiformity of main chain is to regulate the physical-chemical characteristic of chemical compound and the key factor of regulating its pharmacokinetics significantly.In Fig. 6, some Re and Tc complex as an example described schematically.
Material and method
1. 2-[2-(pyrazol-1-yl) ethyl imido grpup] ethamine (pz (CH 2) 2NH (CH 2) 2NH 2) synthetic (referring to the Fig. 3) of (1)
1-(2-bromoethyl) pyrazoles [6d] tetrahydrofuran solution (12mmol) is added drop-wise in the aqueous solution of ethylenediamine (0.24mol).Mixture was refluxed 4 hours.Vacuum is removed THF, and water is washed with dichloromethane.Obtain xanchromatic grease behind the vacuum drying, it is with pz (CH 2) 2NH (CH 2) 2NH 2(1) expression.
Productive rate: 50%
1H-NMR(D 2O)：7.53(d，H(3)pz，1H)；7.45(d，H(5)pz，1H)；6.23(t，H(4)pz，1H)；4.14(t，CH2，2H)；2.91(t，CH 2，2H)；2.77(t，CH 2，2H)；2.62(t，CH 2，2H)。
2.pz (CH 2) 2N[(CH 2) 3COOH] (CH 2) 2NH 2(4) synthetic (referring to Fig. 3)
2.1. The BOC-ON protection
With 1 (1.1g; DMF 7mmol) (20ml) solution is cooled to 0 ℃, and dropping BOC-ON (1,7g; DMF 7mmol) (20ml) solution.Reactant mixture was stirred 3 hours in 0 ℃.Solvent removed in vacuo, and solid residue is soluble in water, and wash 3 times with chloroform, 2 of grease generated.Productive rate: 68%. 1H-NMR(D 2O)：7.55(d，H(3)pz，1H)；7.47(d，H(5)pz，1H)；6.24(t，H(4)pz，1H)；4.38(t，CH 2，2H)；3.40(t，CH 2，2H)；3.20(t，CH 2，2H)；2.99(t，CH 2，2H)；1.25(s，CH 3，9H)。
2.2. With the alkylation of 4-bromo-butyric acid ethyl ester, hydrolysis and deprotection
With chemical compound 2 (757mg; 3mmol) be dissolved in the 10ml acetonitrile.With potassium carbonate (829mg; 6mmol) potassium iodide with catalytic amount joins in this solution, and dropping 4-bromo-butyric acid ethyl ester (858ml, 16mmol).Reflux after 3 days, the isolated by filtration supernatant and vacuum drying obtain 3.(733mg, (800mg in aqueous solution 20mmol), and reacted one day under room temperature 2mmol) to be dissolved in NaOH with this chemical compound.Then with HCl neutralization and the vacuum drying of this solution with 1N.This solid residue is dissolved in the methanol, removes by filter sedimentary salt and solvent removed in vacuo, obtain yellow/brown grease, be expressed as 4.Productive rate: (50%).
1H-NMR(D 2O)：7.78(d，H(3)pz，1H)；7.64(d，H(5)pz，1H)；6.42(t，H(4)pz，1H)；4.36(t，CH 2，2H)；3.10(t，CH 2，2H)；3.02(t，CH 2，2H)；2.86(t，CH 2，2H)；2.64(t，CH 2，2H)；2.15(t，CH 2，2H)；1.68(q，CH 2，2H)。
3. (4-carboxylic acid) pz (CH 2) 2NH (CH 2) 2NH 2(7) synthetic (referring to Fig. 3)
3.1. N-2-hydroxyethyl-4-pyrazole carboxylic acid ethyl ester (5)
Use the typical method of preparation pyrazoles [7] to prepare chemical compound 5.With 2-formoxyl-3-oxo ethyl propionate (2.80g; 20mmol) be dissolved in the 20ml ethanol, and be cooled to 0 ℃.With 2-hydroxyethyl hydrazine (1.44g; 20mmol) be dissolved in the 100ml ethanol, and it is added drop-wise in the solution of 2-formoxyl-3-oxo ethyl propionate.Reactant mixture is placed in room temperature to spend the night.Solvent removed in vacuo generates xanchromatic grease.Productive rate: 95%
1H-NMR(CDCl 3)：7.93(s，H(3)pz，1H)；7.91(s，H(5)pz，1H)；4.30-4.22(m，CH 2+OCH 2，5H)；3.99(t，CH 2，2H)；1.30(t，CH 3，3H)。
3.2. N-(2-p-toluenesulfonyl ethyl)-4-pyrazole carboxylic acid ethyl ester (6)
With N-2-hydroxyethyl-4-pyrazole carboxylic acid ethyl ester (5) (2.76g, 15mmol) and paratoluensulfonyl chloride (2.85g 15mmol) is suspended in the solution of acetone (15ml) and water (15ml), and is cooled to 0 ℃.Times dropping NaOH (0.6g, water 15mmol) (10ml) solution with 15 minutes.Make mixture reach room temperature then, and vigorous stirring is spent the night.Evaporation acetone, and, generate xanchromatic grease with aqueous solution chloroform extraction 3 times.Productive rate: 60%
1H-NMR(CDCl 3)：7.82(s，H(3)pz，1H)；7.76(s，H(5)pz，1H)；7.61(d，H(ph)，2H)；7.26(d，H(ph)，2H)；4.35(q，OCH 2，2H)；4.24(t，CH 2，2H)；2.15(s，CH 3，3H)1.33(t，CH 2，2H)。
According to being prepared as follows chemical compound 7.With ethylenediamine (16ml; 0.24mol) be dissolved in NaOH (9.6g; 0.24mol) water (20ml) solution in.With N-(2-p-toluenesulfonyl ethyl)-4-pyrazole carboxylic acid ethyl ester (6) (4.06g; THF 12mmol) (10ml) drips of solution is added in this ethylenediamine solution.With reaction mixture refluxed 24 hours.Thereafter, solvent removed in vacuo, and with product by silica gel column chromatography purification (eluent: methanol-NH 3/ methanol (50: 50)), generate the dark yellow solid.Productive rate: 50%.
1H-NMR(D 2O)：δ7.80(s，H(3)pz，1H)；7.64(s，H(5)pz，1H)；4.27(t，CH 2，2H)；3.24(t，CH 2，2H)；3.11-3.00(m，2CH 2，4H).IV(KBr)(ν/cm -1)：1690(C＝O)。
4.3,5-Mepz (CH 2) 2N[(CH 2) 3GlyGlyOEt)] (CH 2) 2NH 2(13) synthetic (Fig. 4)
4.1. BOC-ON protects (9)
(3.41g, 18.71mmol) [4c] is dissolved among the THF (25mL), and is cooled to-10 ℃ to 0 ℃ temperature with chemical compound 8.(4.60g, THF 18.71mmol) (20ml) solution, and reactant mixture was stirred 2 hours in 0 ℃ cause 8 conversion fully, and it detects (R by TLC to drip BOC-ON f=0.5,100%MeOH).Then reactant mixture is warmed to room temperature, and at saturated Na 2CO 3Distribute between aqueous solution and the dichloromethane.Separate organic layer, through anhydrous MgSO 4Drying is filtered, and concentrating under reduced pressure, obtain the high heavy-gravity colorless oil of quantitative yield product 9 (by 1H-NMR as can be known).This product need not be further purified and be used for next step.
1H-NMR (CDCl 3): δ 5.76 (s, pyrazoles, 1H), 5.08 (s br., NH, 1H), 4.04 (t, CH 2, 2H), 3.18 (m, CH 2, 2H), 2.99 (t, CH 2, 2H), 2.72 (t, CH 2, 2H), 2.18 (s, CH 3, 3H), 2.20 (s, CH 3, 3H), 1.40 (s, C (CH 3) 3, 9H).
4.2.3,5-Me 2Pz (CH 2) 2N[(CH 2) 3COOH] (CH 2) 2NHBOC Synthesizing (11)
CH to this crude product 9 (1.02g) 3Add in the agitating solution of CN (15mL) 4-bromo-butyric acid ethyl ester (1.4g, 7.20mmol), K 2CO 3(1.00g, 7.20mmol) and the KI of catalytic amount., make the suspension reaction of generation in vigorous stirring 11 all over the world, monitor this reaction (R by TLC fProduct=0.4,10%MeOH/CH 2Cl 2).Behind the white solid in removing by filter suspension, solvent removed in vacuo obtains flaxen thick grease.This crude product is handled with the suitable silica gel column chromatography of 75-100% ethyl acetate/hexane (gradient), obtained 10 of faint yellow heavy-gravity grease, it at room temperature leaves standstill curing in many days.Productive rate: 0.73g (51% productive rate).
(4.6g, (the 14N NaOH solution of 8.3mL, 116.0mmol) aqueous solution refluxed 8 hours for (190mL) solution of THF 11.60mmol) and NaOH with 10.This reaction is by TLC monitoring (R fProduct=0.2,10%MeOH/CH 2Cl 2).With among the HCl of 4N and back (pH6-7), with THF/H 2The O solution decompression is evaporated to dried.The product 10-50%MeOH/CHCl that this is thick 3The suitable silica gel column chromatography of (gradient) is handled, and obtains 11 of high heavy-gravity colorless oil, and it is leaving standstill many days post crystallizations.Productive rate: 2.82g (66%).
Chemical compound 10: 1H-NMR (CDCl 3): δ 5.75 (s, pyrazoles, 1H), 4.09 (q, CH 2, 2H), 3.98 (s br., CH 2, 2H), 3.08 (s br., CH 2, 2H), 2.78 (s br., CH 2, 2H), 2.45-2.51 (m, CH 2, 4H), 2.23 (s, CH 3, 3H), 2.18 (m, CH 3, CH 2, 5H), 1.63 (s b r., CH 2, 2H), 1.41 (s, C (CH 3) 3, 9H), 1.23 (t, CH 3, 3H).
Chemical compound 11: 1H-NMR (CDCl 3): δ 5.81 (s, pyrazoles, 1H), 4.93 (s br., NH, 1H) 4.12 (t br., CH 2, 2H), 3.04 (q br., CH 2, 2H), 2.86 (t b r., CH 2, 2H), 2.58-2.64 (m, CH 2, 4H), 2.42 (t, CH 2, 2H), 2.24 (s, CH 3, 3H), 2.19 (s, CH 3, 3H), 1.79 (m, CH 2, 2H), 1.40 (s, C (CH 3) 3, 9H).
Chemical compound 3,5-Me 2Pz (CH 2) 2N[(CH 2) 3CONHGlyGlyOEt] (CH 2) 2NH 2(13) obtain (referring to Fig. 4) according to being prepared as follows.
To 11 (1.51g, CH 4.09mmol) 3Add in CN (48mL) solution GlyGly carbethoxy hydrochloride (0.57g, 4.09mmol), triethylamine (1.24g, 12.27mmol) and HBTU (1.55g, 4.09mmol).With reactant mixture under nitrogen in stirring at room 20 hours.To react by TLC monitoring (R fProduct=0.8,20%MeOH/CH 2Cl 2).Evaporating solvent, and with the crude product of gained 3-5% MeOH/CHCl 3(gradient) by chromatography purification, obtains 12 of heavy-gravity colorless oil on suitable silicagel column.Productive rate: 1.23g (59%).
Make 3,5-Me 2Pz (CH 2) 2N[(CH 2) 3CONHGlyGlyOEt] (CH 2) 2(1.23g is 2.41mmol) at CH for NHBOC (12) 2Cl 2Solution reaction among the/TFA (25mL/4.1mL) 2 hours.To react by TLC monitoring (R f=0.4,20%MeOH/CH 2Cl 2).Solvent evaporated under reduced pressure and TFA, and obtain highly viscous flaxen grease.This grease is soluble in water, and with NaOH (pH 7-8) neutralization of 1N, and evaporating solvent is to doing.TLC：R f＝0.2，20％MeOH/CH 2Cl 2。This chemical compound is further used 20-40%MeOH/CHCl 3(gradient) by chromatography purification, obtains 13 of heavy-gravity colorless oil on suitable silicagel column.Productive rate: 0.97g (98%).
Chemical compound 12: 1H-NMR (CDCl 3): δ 8.66 (s br., NH, 1H), 7.00 (s br., NH, 1H), 5.80 (s, pyrazoles, 1H), 4.91 (s br., NH, 1H) 4.15 (q., CH 2, 2H), 4.04 (s br., CH 2, 2H), 3.97 (d, CH 2, 2H), 3.90 (d, CH 2, 2H), 2.89 (s br., CH 2, 2H), 2.69 (s br., CH 2, 2H), 2.51 (s br., CH 2, 2H), 2.39 (s br., CH 2, 2H), 2.30 (s br., CH 2, 2H), 2.20 (s, CH 3, 3H), 2.18 (s, CH 3, 3H), 1.74 (s br., CH 2, 2H), 1.38 (s, C (CH 3) 3, 9H), 1.23 (t, CH 3, 3H).
Chemical compound 13: 1H-NMR (CD3OD): δ 5.84 (s, pyrazoles, 1H), 4.17 (q, CH 2, 2H343665), 4.06 (t, CH 2, 2H), 3.91 (d, CH 2, 4H), 2.97 (t, CH 2, 2H), 2.71-2.80 (m, CH 2, 4H), 2.51 (t, CH 2, 2H), 2.25 (s, CH 3, 3H), 2.15 (s, CH 3, 3H), 2.12 (t, CH 2, 2H), 1.66 (m, CH 2, 2H), 1.25 (t, CH 3, 3H).
5.3,5-Mepz (CH 2) XS (CH 2) 2S (CH 2) synthetic (Fig. 5) of COOEt (16)
5.1 3,5-Mepz (CH 2) 2S (CH 2) 2OH Synthesizing (14)
HSCH with 0.70ml (10mmol) 2CH 2The NaOH of OH and 0.40g (10mmol) is mixed in water, and solution was refluxed 5 minutes.Under room temperature, in this solution, drip N-(2-p-toluenesulfonyl the ethyl)-3 that is dissolved in the 2.78g (10mmol) in the oxolane (THF), gentle reflux is 3 hours subsequently.With the mixture chloroform extraction, behind the vacuum drying from wherein reclaiming 14 (8.10mmol, 81%) of 1.62g yellow oily.
Chemical compound 14: 1H-NMR (CDCl 3): 5.67 (s, pz-H, 1H); 4.39 (s, OH, 1H); 4.03 (t, CH 2, 2H); 3.60 (t, CH 2, 2H); 2.83 (t, CH 2, 2H); 2.50 (t, CH 2, 2H); 2.14 (s, CH 3, 3H); 2.09 (s, CH 3, 3H).
5.2 3,5-Mepz (CH 2) 2S (CH 2) 2Br Synthesizing (15)
PBr with 0.19ml (2mmol) 3Join be dissolved in chloroform 14 (0.40g, 2mmol) in, and at N 2Down the solution that generates was refluxed 24 hours.With the 10%NaHCO of mixture with 20ml 3Solution-treated.Separate organic facies, and decompression removes chloroform, obtain 15 (1.25mmol, 63%) of 0.329g yellow oily.
1H-NMR(CD Cl3)：5.82(s，pz-H，1H)；4.15(t，CH 2，2H)；3.36(t，CH 2，2H)；3.00(t，CH 2，2H)；2.70(t，CH 2，2H)；2.26(s，CH 3，3H)；2.23(s，CH 3，3H)。
At N 2Exsiccant ethanol is joined in the sodium metal (0.15g, 4.56mmol), and mixture is stirred under room temperature until being converted into Sodium ethylate fully down.In this mixture, drip the alcoholic solution of 2-ethyl thioglycolate (0.50ml, 4.56mmol), add 3 of 1.20g (4.56mmol) subsequently, 5-Mepz (CH 2) 2S (CH 2) 2The alcoholic solution of Br (15).Reactant mixture stirred under room temperature spend the night.After this moment, solvent removed in vacuo, and the grease that generates is dissolved in the chloroform.After washing with water,, obtain 16 (3.3mmol, 72.4%) of 1.00g yellow oily with the organic layer vacuum drying.
Chemical compound 16: 1H-NMR (CDCl 3): 5.82 (s, pz-H, 1H); 4.14 (m, CH 2, CH 2-COO, 4H); 3.25 (s, CH 2, 2H); 2.92 (t, CH 2, 2H); 2.75 (t, CH 2, 2H); 2.57 (t, CH 2, 2H); 2.2 (s, CH 3, 3H); 2.16 (s, CH 3, 3H); 1.25 (t, CH 3, 3H).
6.Re and Tc chemical compound (referring to Fig. 6)
6.1.[Re (CO) 3(κ 3-pz (CH 2) 2NH (CH 2) 2NH 2)] Br Synthesizing (17a)
(NEt with 100mg (0.130mmol) 4) 2[ReBr 3(CO) 3] with the chemical compound 1 (pz (CH of 20mg (0.130mmol) 2) 2NH (CH 2) 2NH 2) mixed in water, and with solution backflow 2 hours.Under reduced pressure reduce this volume then, and place this mixture until being settled out white solid in 4C.By 1H-NMR surveys productive rate:＞90%,
1H-NMR (D 2O): 7.82 (d, H (3) pz, 1H); 7.76 (d, H (5) pz, 1H); 6.54 (s br, NH, 1H); 6.39 (t, H (4) pz, 1H); 4.86 (s, broad (largo), NH 2, 1H); 4.43 (m, CH 2, 1H); 4.16 (m, CH 2, 1H); 3.94 (s, broadness, NH 2, 1H); 3.50 (m, CH 2, 1H); 2.87 (m, CH 2, 1H); 2.71 (m, CH 2, 2H); 2.48 (m, CH 2, 1H); 2.08 (m, CH 2, 1H).
6.2.[ 99mTc (CO) 3(κ 3-pz (CH 2) 2NH (CH 2) 2NH 2)] + (17b) synthetic
With 100 μ l chemical compounds, 1 (pz (CH 2) 2NH (CH 2) 2NH 2) 10 -4The solution of M join 1ml's [ 99mTc (OH) 3(CO) 3In the phosphate-buffered liquor of]+(1-2mCi).Solution is hatched 30 minutes in 100C, and analyze by HPLC then.The purity of this radiochemicals is＞90%.
6.3. [Re (CO) 3(κ 3-(4-carboxylic acid) pz (CH 2) 2NH CH 2) 2NH 2)] Br (18a) synthetic
(NEt with 100mg (0.130mmol) 4) 2[ReBr 3(CO) 3] mixed in water with the chemical compound 7 of 26mg (0.130mmol), and with solution backflow 2 hours.Vacuum reduces volume then, and mixture is placed until the generation of adularescent precipitation in 4C.
By 1H-NMR measures productive rate:＞90%
1H-NMR (D 2O): δ 8.22 (s, H (3) pz, 1H); 8.20 (s, H (5) pz, 1H); 6.62 (s, broadness, NH, 1H); 4.94 (s, broadness, NH 2, 1H); 4.43 (m, CH 2, 1H); 4.25 (m, CH 2, 1H); 4.05 (s, broadness, NH 2, 1H); 3.52 (m, CH 2, 1H); 2.92 (m, CH 2, 1H); 2.76 (m, CH 2, 2H); 2.53 (m, CH 2, 1H); 2.14 (m, CH 2, 1H).
IV (KBr) (ν/cm -1): 2010 (C=O); 1885 (C=O); 1690 (C=O parts (ligando)
6.4.[Re (CO) 3(κ 3-3,5-Me 2Pz (CH 2) 2N (CH 2) 2(glygly) NH 2)] Br (19a) synthetic
(NEt with 100mg (0.130mmol) 4) 2[ReBr 3(CO) 3] mixed in water with the ligand 13 of 53mg (0.130mmol), and solution refluxed spend the night.
By 1H-NMR measures productive rate: 100%
1H-NMR(D 2O)：δ6.04(s，H(4)pz，1H)；5.05(s，br，NH 2，1H)；4.36-4.31(m，CH 2，1H)；4.16-4.04(m，CH 2，1H)；3.88(s，NHCH 2CO，2H)；3.84(s，NHCH 2CO，2H)；3.65(s，br，NH 2，1H)；3.53(m，CH 2，1H)；3.30(m，CH 2，2H)；2.86(m，CH 2，1H)；2.74(m，CH 2，2H)；2.57(m，CH 2，1H)；2.40(m，CH 2，1H)；2.31(m，CH 2，1H)；2.73(s，CH 3，3H)；2.16(s，CH 3，3H)；2.10(m，CH 2，1H)；1.95(m，CH 2，1H)。
6.5.[ 99mTc (CO) 3(κ 3-3,5-Me 2Pz (CH 2) 2N (CH 2) 2(glygly) NH 2)] + Synthesizing (19b)
With 13 (10 of 100ml -3M) solution join 1ml [ 99mTc (OH) 3(CO) 3] +In the phosphate-buffered liquor (1-2mCi).This solution is hatched 1 hour in 100C, and analyze by HPLC then.The purity of radiochemicals is＞90%.
7. synthetic (Fig. 7) of pyrazolyl-amino-phosphine
The preparation of pyrazolyl-amino-phosphine of the present invention comprises the alkylating of 1-(2-amino-ethyl) pyrazoles and (2-bromoethyl) diethyl phosphate, obtains pyrazoles-amino-phosphate derivative (compound a).This chemical compound and lithium aluminium hydride (LAH) reduction obtains uncle's phosphine (compound b), then by be translated into final chelating agen (compound c) (people such as Katti, J.Am.Chem.Soc.122,1554 (2000) with the processing of the acid medium of formaldehyde.
8. synthetic (Fig. 8) of pyrazolyl-thioether phosphine
The preparation of pyrazolyl of the present invention-thioether phosphine comprises the reaction of 1-(2-mercaptoethyl) pyrazoles and (2-bromoethyl) diethyl phosphate, obtain pyrazoles-thioether-phosphate derivative (compound d) (people such as Katti, Angew.Cherm.Int.Ed.38,2020 (1999).Make the compound d reduction with lithium aluminium hydride, uncle's phosphine (Verbindung) that will generate is subsequently handled with the acid medium of formaldehyde, obtains final chelating agen (chemical compound f).
Document
[l] be people WO 98/48848 such as Alberto a),
B) people such as Alberto, WO 00/50086,
C) people such as Alberto, WO 01/00637
D) people such as Alberto, US 6,344,178B1
[2] a) people such as Hilger, US 6,488,909B1.
[3] a) people such as Alberto, Polyhedron 17 (1998) 1303
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I) people such as Alberto, AngeW.Chem.Int.Ed.40 (2001) 3062
J) people such as Alberto, Bioconjugate Chem.13 (2002) 750.
[4] a) people such as Santos, J.Am.Chem.Soc.122 (2000) 11240
B) people such as Santos, Inorg.Chem.40 (2001) 5147
C) people such as Santos, J.Chem.Soc.Dalton Trans. (2002) 4714.
[5] a) people such as Valliant, Inogr Chem.Commun.41 (2002) 628
B) people such as Valliant, Inorg Chem.41 (2002) 6417
[6] a) people such as Sorrell, Inorg.Chem.22 (1983) 1883
B) people J.Chem.Soc.Dalton Trans. (1992) 481 such as Driessen
C) people such as Parkin, Inorg.Chem.35 (1996) 2415
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[7] people such as Holzer, J.Heterocycccclic Chem.130 (1993) 865

Claims (35)

1. the chelating agen of following general formula:
Wherein m is 0 or 1;
X is NR 4Or S;
Y is SR 5, NHR 5Or P (R 5) 2
R 1And R 3Identical or different, and be selected from H, alkyl or aryl;
R 2Be H, COOH, NHR 6Or (CH 2) nCOOR 6
R 4Be H, alkyl, aryl, (CH 2) nCOOR 6Or (CH 2) nOR 6
R 5Be H, alkyl, aryl, (CH 2) nCOOR 6Or (CH 2) nOR 6
R 6Be H, alkyl or aryl;
N is 1,2,3,4,5,6,7,8,9 or 10; With
Work as R 1=R 3=CH 3The time, R 2, R 4And R 5Three not all is H.
2. according to the chelating agen of claim 1, wherein this alkyl is C 1Alkyl, C 2Alkyl, C 3Alkyl, C 4Alkyl, C 5Alkyl or C 6Alkyl.
3. according to the chelating agen of claim 2, wherein this alkyl is methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl, isopentyl, neopentyl, n-hexyl, isohesyl (2-methyl amyl), new hexyl (2, the 2-dimethylbutyl), 3-methyl amyl, 2, the 3-dimethylbutyl.
4. according to the chelating agen of claim 1, wherein this aryl is monocyclic, is preferably phenyl or benzyl, or polycyclic, C 10-C 18, and this aryl is optional is replaced by alkyl, carboxyl, oxo, amino, alkoxyl or aldehyde radical.
5. according to the chelating agen of claim 4, wherein this aryl is phenyl or benzyl.
6. according to the chelating agen of claim 1, wherein n is 2,3,4,5 or 6, and is preferably 2,3 or 4.
7. according to the chelating agen of claim 1, this reagent is the pyrazolyl-polyamines of following general formula:
R wherein 1, R 2, R 3, R 4And R 5As defined in claim 1.
8. according to the chelating agen of claim 1, this reagent is the pyrazolyl-amino-thioether of following general formula:
Figure A2004800102140003C2
R wherein 1, R 2, R 3, R 4And R 5As defined in claim 1.
9. according to the chelating agen of claim 1, this reagent is the pyrazolyl-polythiaether of following general formula:
Figure A2004800102140003C3
R wherein 1, R 2, R 3, R 4And R 5As defined in claim 1.
10. according to the chelating agen of claim 1, this reagent is the pyrazolyl-amino-phosphine of following general formula:
Figure A2004800102140003C4
R wherein 1, R 2, R 3, R 4And R 5As defined in claim 1.
11. according to the chelating agen of claim 1, this reagent is the pyrazolyl-thioether phosphine of following general formula:
Figure A2004800102140003C5
R wherein 1, R 2, R 3, R 4And R 5As defined in claim 1.
12. according to the chelating agen of claim 1, wherein X and Y are N, R 6Be H, C 1Alkyl, C 2Alkyl, C 3Alkyl, C 4Alkyl, C 5Alkyl or C 6Alkyl, phenyl, benzyl or biomolecule, and R 1, R 2, R 3, R 4And R 5As listed in the table 1.
13. according to the chelating agen of claim 1, wherein X and Y are S, R 6Be H, C 1Alkyl, C 2Alkyl, C 3Alkyl, C 4Alkyl, C 5Alkyl or C 6Alkyl, phenyl, benzyl or biomolecule, and R 1, R 2, R 3, R 4And R 5As listed in the table 1.
14. according to the chelating agen of claim 1, wherein X is that N and Y are S, R 6Be H, C 1Alkyl, C 2Alkyl, C 3Alkyl, C 4Alkyl, C 5Alkyl or C 6Alkyl, phenyl, benzyl or biomolecule, and R 1, R 2, R 3, R 4And R 5As listed in the table 1.
15. according to the chelating agen of claim 1, wherein X is that S and Y are N, R 6Be H, C 1Alkyl, C 2Alkyl, C 3Alkyl, C 4Alkyl, C 5Alkyl or C 6Alkyl, phenyl, benzyl or biomolecule, and R 1, R 2, R 3, R 4And R 5As listed in the table 1.
16. according to the chelating agen of claim 1, wherein X is that S and Y are P (R 5) 2, R 6Be H, C 1Alkyl, C 2Alkyl, C 3Alkyl, C 4Alkyl, C 5Alkyl or C 6Alkyl, phenyl, benzyl or biomolecule, and R 1, R 2, R 3, R 4And R 5As listed in the table 1.
17. according to the chelating agen of claim 1, wherein X is that N and Y are P (R 5) 2, R 6Be H, C 1Alkyl, C 2Alkyl, C 3Alkyl, C 4Alkyl, C 5Alkyl or C 6Alkyl, phenyl, benzyl or biomolecule, and R 1, R 2, R 3, R 4And R 5As listed in the table 1.
18. according to the chelating agen of claim 1, wherein R 6Be biomolecule.
19. according to the chelating agen of claim 18, wherein this biomolecule is selected from aminoacid, peptide, protein, oligonucleotide, polynucleotide, sugar.
20. according to the chelating agen of claim 19, wherein this biomolecule is selected from the part of antibody, tumor receptor.
21. according to the chelating agen of claim 19, wherein this biomolecule is selected from CCK, thioglucose, glycosamine, somatostatin, neurotensin, bombesin, CCK, annexin, interleukin, somatomedin, steroid hormone and is bonded to the molecule of GPIIb/IIIa receptor.
22. according to the chelating agen of claim 19, wherein this biomolecule is selected from glucose, thioglucose, neurotransmitter.
23. according to the chelating agen of claim 19, wherein this biomolecule is the inhibitor of tyrosine kinase activity, as benzo thiapyran ketone, anilino-phthalimide, quinazoline, Pyridopyrimidine and pyrrolopyrimidine.
24. according to the chelating agen of claim 1, this reagent is the chemical compound of following formula:
Figure A2004800102140005C1
25. according to the chelating agen of claim, this reagent is the chemical compound of following formula:
Figure A2004800102140005C2
26. according to the chelating agen of claim 1, this reagent is the chemical compound of following formula:
Figure A2004800102140005C3
27. according to the chelating agen of claim 1, this reagent and formula [M (CO) wherein 3] +The carbonyl moiety complexation, wherein M is rhenium (Re), technetium (Tc) or manganese (Mn).
28. according to the chelating agen of claim 18, this reagent and formula [M (CO) wherein 3] +The carbonyl moiety complexation, wherein M is rhenium (Re) or technetium (Tc).
29. prepare the method for radiolabeled biomolecule, described method comprises:
A) be used to form under the condition of chelating agen-carbonyl complex, making the chelating agen and the formula [M (CO) of claim 1 3] +Carbonyl moiety contact, wherein M is rhenium (Re) or technetium (Tc); With
B) complex that obtains is contacted with biomolecule, obtain radiolabeled biomolecule.
30. be used to carry out the test kit of claim 29 method, described test kit comprises first bottle with chelating agen of the present invention, the first reaction bottle that randomly is used to make this chelating agen to contact with carbonyl moiety, have second bottle of biomolecule, and the second reaction bottle that randomly is used for making this chelating agen-carbonyl complex reaction that this biomolecule and reaction first step obtain.
31. prepare the method for radiolabeled biomolecule, described method comprises:
A) chelating agen of claim 1 is contacted with biomolecule and be used to obtain chelating agen-biomolecule; With
B) be used to form under the condition of radiolabeled biomolecule, making this chelating agen-biomolecule and formula [M (CO) 3] +Carbonyl moiety contact, wherein M is rhenium (Re) or technetium (Tc).
32. be used to carry out the test kit of claim 31 method, described test kit comprises first bottle with chelating agen of the present invention, randomly be used to make the first reaction bottle of this chelating agen and biomolecular reaction, have second bottle of carbonyl moiety, and this chelating agen-biomolecule that randomly is used for making the reaction first step to obtain is reacted bottle with second of carbonyl reaction.
33., be used to prepare the diagnosis or the curative drug of diagnosis or treatment tumor according to the chelating agen of claim 1.
34. according to the chelating agen of claim 27, as the diagnosis or the curative drug of diagnosis or treatment tumor.
35. be used for diagnosing or treat the diagnosis of tumor or the purposes of curative drug in preparation according to the chelating agen of claim 1.
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