CN101123995A - Stilbene derivatives and their use for binding and imaging amyloid plaques - Google Patents
Stilbene derivatives and their use for binding and imaging amyloid plaques Download PDFInfo
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Abstract
This invention relates to a method of imaging amyloid deposits and to labeled compounds, and methods of making labeled compounds useful in imaging amyloid deposits. This invention also relates to compounds, and methods of making compounds for inhibiting the aggregation of amyloid proteins to form amyloid deposits, and a method of delivering a therapeutic agent to amyloid deposits.
Description
Background of invention
Invention field
The present invention relates to new bioactive compound, use the method for radio-labelled compound diagnosing image and prepare the method for radio-labelled compound.
Background technology
Alzheimer (AD) is a kind of progressive neurodegenerative disorders, it is characterized in that cognitive decline, the irreversible loss of memory, disorientation and aphasis.The postmortem of AD brain section shows in a large number the senile plaque (SP) that is made of amyloid-β (A β) peptide and many neurofibrillary tangleses that is formed by the filament of hyperphosphorylation tau protein (NFT), and (recent summary is quoted as proof referring to Ginsberg with other, S.D. wait the people, " Molecular Pathology of Alzheimer ' s Disease and Related Disorders; " inCerebral Cortex:Neurodegenerative and Age-related Changes in Structureand Function of Cerebral Cortex, Kluwer Academic/Plenum, NY (1999), pp.603-654; Vogelsberg-Ragaglia, people such as V., " Cell Biology of Tau and CytoskeletalPathology in Alzheimer ' s Disease, " Alzheimer ' s Disease, Lippincot, Williams﹠amp; Wilkins, Philadelphia, PA (1999), pp.359-372).
Amyloidosis is to be characterised in that the disease of various insoluble fibrins (fibrillar protein) in the patient tissue inner accumulated.The following formation of amyloid beta deposition thing (amyloid pdeposit): amyloid aggregation, aggregation and/or amyloid further make up then.Amyloid-beta (A β) peptide aggregation body in brain formation and to gather be that AD takes place and the key factor of development.
Except the effect of amyloid beta deposition thing in Alzheimer, confirmed in such as following disease, to exist the amyloid beta deposition thing: Mediterranean fruit fly, Mu-Wei syndrome, idiopathetic myeloma, the amyloid polyneuropathy, the amyloid cardiomyopathy, the senile amyloidosis of general, the amyloid polyneuropathy, hereditary cerebral hemorrhage with amyloidosis, mongolism, itch, creutzfeldt-jakob disease, kuru, Ge-Shi-Sha syndrome, thyroid medullary carcinoma, isolated atrial amyloid (isolated atrial amyloid), β in the dialysis patient
2β in-microglobulin amyloid, occlusion body myositis, the muscular atrophy diseases
2-amyloid beta deposition thing and islets of langerhans type ii diabetes insulinoma.
Amyloid peptide A β
1-40With A β
1-42Fibrous aggregation be to be derived from the main metabolic peptide (Xia, people such as W., J.Proc.Natl.Acad.Sci U.S.A.97:9299-9304 (2000)) that sees the amyloid precursor protein in AD patient's senile plaque and the cerebrovascular amyloid beta deposition thing.Treat this disease target prevent and reverse A β speckle form (Selkoe, D.J.JAMA 283:1615-1617 (2000); Wolfe, people such as M.S., J.Med.Chem.41:6-9 (1998); Skovronsky, D.M. and Lee, V.M., Trends Pharmacol.Sci.21:161-163 (2000)).
Familial AD (FAD) is by A precursor protein (APP), presenilin 1 (PS1) and presenilin 2 (PS2) gene many places sudden change causing (Ginsberg, S.D. wait the people, " Molecular Pathology ofAlzheimer ' s Disease and Related Disorders; " in Cerebral Cortex:Neurodegenerative and Age-related Changes in Structure and Function ofCerebral Cortex, Kluwer Academic/Plenum, NY (1999), pp.603-654; Vogelsberg-Ragaglia, people such as V., " Cell Biology of Tau and CytoskeletalPathology in Alzheimer ' s Disease, " Alzheimer ' s Disease, Lippincot, Williams﹠amp; Wilkins, Philadelphia, PA (1999), pp.359-372).
Although also do not understand AD cutter system really fully, the pathogenic FAD sudden change of Yan Jiu all up to now all makes the generation of the A β peptide form of producing 42-43 stronger amino acid long of amyloid increase.Therefore, as if in FAD, the insufficiency of accommodation that A β produces is enough to induce the cascade that causes neurodegenerative incident at least.In fact, this amyloid cascade hypothesis prompting, the formation of extracellular fiber shape A beta peptide aggregation body in brain may be the critical events (Selkoe in the AD pathogenesis, D.J., " Biology of β-amyloid Precursor Protein and the Mechanism of Alzheimer ' sDisease; " Alzheimer ' s Disease, Lippincot Williams﹠amp; Wilkins, Philadelphia, PA (1999), pp.293-310; Selkoe, D.J., J.Am.Med.Assoc.283:1615-1617 (2000); Naslund, people such as J., J.Am.Med.Assoc.283:1571-1577 (2000); Golde, people such as T.E., Biochimica et Biophysica Acta 1502:172-187 (2000)).
Estimating at present and managing to suppress the interior fibrous A β generation of brain and reduce the whole bag of tricks that it gathers, as potential therapy (Skovronsky, D.M. and Lee, V.M., the Trends Pharmacol.Sci.21:161-163 (2000) of AD; Vassar, people such as R., Science 286:735-741 (1999); Wolfe, people such as M.S., J.Med.Chem.41:6-9 (1998); Moore, people such as C.L., J.Med.Chem.43:3434-3442 (2000); Findeis, M.A., Biochimica et Biophysica Acta 1502:76-84 (2000); Kuner, P., people such as Bohrmann, J.Biol.Chem.275:1673-1678 (2000)).Therefore, interesting for the part of exploitation specificity binding fiber shape A beta peptide aggregation body.Because extracellular SP is obtainable target,, and in the patient that research is lived, be used as probe to manifest the progressive deposition of A β in the AD amyloid generation (amyloidogenesis) so these new parts can be used as the in-vivo diagnostic instrument.
For this reason, reported several interesting method (Ashburn, people such as T.T., the Chem.Biol.3:351-358 (1996) that is used to develop fibrous A beta peptide aggregation body ligands specific; Han, people such as G., J.Am.Chem.Soc.118:4506-4507 (1996); Klunk, people such as W.E., Biol.Psychiatry 35:627 (1994); Klunk, people such as W.E., Neurobiol. Aging 16:541-548 (1995); Klunk, people such as W.E., Society for Neuroscience Abstract 23:1638 (1997); Mathis, people such as C.A., Proc.XIIth Intl.Symp.Radiopharm.Chem., Uppsala, Sweden:94-95 (1997); Lorenzo, A. and Yankner, B.A., Proc.Natl Acad.Sci.U.S.A.91:12243-12247 (1994); Zhen, people such as W., J.Med.Chem.42:2805-2815 (1999)).The most attracting method is based on highly conjugated chrysamine-G (CG) and Congo red (CR), the latter be used to dissect a body fluorescence staining (Ashburn, people such as T.T., the Chem.Biol.3:351-358 (1996) of SP and NFT in the AD brain section; Klunk, people such as W.E., J.Histochem.Cytochem.37:1273-1281 (1989)).3 of CR, CG and CG '-bromo-and 3 '-iodine derivant and the fibrous bonded inhibition constant of A beta peptide aggregation body (Ki) be respectively 2800,370,300 and 250nM (Mathis, C.A. wait the people, Proc.XIIth Intl.Symp.Radiopharm.Chem., Uppsala, Sweden:94-95 (1997)).Verified these chemical compounds optionally combine with A β (1-40) peptide aggregation body external, and in the AD brain section, optionally combine (Mathis with fibrous A β deposit, C.A. wait the people, Proc.XIIth Intl.Symp.Radiopharm.Chem., Uppsala, Sweden:94-95 (1997)).
A beta peptide aggregation body in the imaging brain has several potential benefits.By having the potential patient of excessive A β speckle in the identification brain, imaging technique can improve diagnosis; Therefore, Alzheimer may take place in them.It also can be used for monitoring this advancing of disease.When anti-speckle Drug therapy becomes can obtain the time, the A β speckle in the imaging brain can be monitor therapy provides basic instrument.Therefore, seek the simple noninvasive method that is used to detect with the interior amyloid beta deposition thing of quantitative patient forwardly always.At present, the detection of amyloid beta deposition thing comprises the histologic analysis of biopsy or obduction material.These two kinds of methods are defectiveness all.For example, obduction only can be used for postmortem diagnosis.
Because the amyloid beta deposition thing has many identical physical propertys (for example density and water content) with normal structure, so direct imaging is difficult in this sedimental body.With nuclear magnetic resonance (MRI) and the sedimental trial of computer assisted tomography art (CAT) imaging amyloid is disappointed, and they only detect the amyloid beta deposition thing under some advantage.In addition, provide certain selectivity with the effort of antibody, serum amyloid protein P albumen or other probe molecule labelling amyloid beta deposition thing in peripheral tissues, but poor organization internal imaging is provided.
The potential part that is used to detect the A beta peptide aggregation body in the brain alive must pass complete blood brain barrier.Therefore, relative less and have the lipophilic part of increase by using molecular size (comparing) with Congo red, can improve brain capture.Highly conjugated thioflavine (S and T) is used as the dyestuff (Elhaddaoui, people such as A., Biospectroscopy 1:351-356 (1995)) of A beta peptide aggregation body in the dyeing AD brain usually.
Reported the highly lipophilic tracer that is used in conjunction with (mainly forming) entanglement and (containing a aggregation) speckle by the tau protein of excessive phosphorylation [
18F] FDDNP (people such as Shoghi-Jadid K, Am.J.Geriatr.Psychiatry.2002; 10:24-35).Use positron emission fault art (PET), reported in nine AD patients and seven contrast experimenters the deposit of this tracer-specific labelling speckle and entanglement (Nordberg A.Lancet Neurol.2004; 3:519-27).Use the new pharmacokinetic analysis program of prediction (call) institute interested brain district and the relative holdup time of pons, shown AD patient and contrasted difference between the experimenter.In AD patient, the holdup time is obviously higher relatively.This is complicated by following attractive discovery, promptly for external (in vitro) in conjunction with A β fibril and exsomatize (ex vivo) in conjunction with A β speckle, FDDNP and some NSAID compete (people such as Agdeppa ED, 2001; People such as Agdeppa ED, Neuroscience.2003; 117:723-30).
Reported in the recent period by use the benzothiazole anil [
11C] 6-OH-BTA-1 (be also referred to as [
11C] PIB) amyloid-beta (people such as Mathis CA, Curr.Pharm.Des.2004 in the imaging AD patient brain; 10:1469-92; People such as Mathis CA, Arch.Neurol.2005,62:196-200).With [
18F] observed opposite among the FDDNP, [
11C] 6-OH-BTA-1 combines with fibrous A β in vivo specifically.Diagnosis have the patient of mild AD show [
11C] the remarkable delay of 6-OH-BTA-1 in cortex, known in AD cortex contain a large amount of amyloid beta deposition things.In AD patient's group, [
11C] increase that is retained in the volume cortex of 6-OH-BTA-1 is the most remarkable.Also in calvarium portion, temporo and occipitalia cortex, reach and in striatum, observed huge increase.Relatively be not subjected in the zone (as subcortical white, pons and cerebellum) that amyloid beta deposition influences known, [
11C] 6-OH-BTA-1 is trapped among AD patient and the contrast experimenter and equates.In the recent period, after deliberation another kind
11The A β speckle targeted probes of C labelling, promptly stilbene derivative [
11C] SB-13.Use should [
3H] binding affinity that this compound exhibits is fabulous can clearly be measured combination in the cortex grey matter in conjunction with prompting for SB-13 external, but really not so in the white matter of AD case (people such as Kung M-P, Brain Res.2004; 1025:98-105).In the cortex tissue homogenate of contrast brain, has low-down specificity combination.[
3H] the Kd value of SB-13 in the homogenate of AD cortex be 2.4 ± 0.2nM.High binding ability and comparable value (14-45pmol/mg albumen) (the same) have been observed.As expected, slightly to moderate AD patients, [
11C] SB-B demonstration in volume cortex (being speculated as the zone of containing high density A β speckle) is highly gathered, but really not so in the contrast experimenter of age-matched (people such as VerhoeffNP, Am.J.Geriatr.Psychiatry.2004; 12:584-95).
The Noninvasive technology that is used for amyloid beta deposition thing in imaging and the quantitative patient can be useful.In addition, suppressing amyloid aggregation forms the chemical compound of amyloid beta deposition thing and is used for determining that the method for the ability of chemical compound inhibition amyloid aggregation can be useful.
Summary of the invention
The invention provides the noval chemical compound of formula I, II and III.
The present invention also provides the radio-labelled compound that comprises formula I, II or III and the diagnosis composition of pharmaceutically acceptable carrier or diluent.
The present invention also provides the formation method of amyloid beta deposition thing, but described method comprises formula I, the II of detection limit or labelled compound or the acceptable salt of its pharmacy, ester, amide or the prodrug of III is introduced in the patient.
The present invention also is provided for suppressing the method for amyloid aggregation, and described method comprises to the chemical compound of formula I, the II of mammal administration amyloid amount of suppression or III or the acceptable salt of its pharmacy, ester, amide or prodrug.
Others of the present invention relate to and are used for synthesizing the amyloid inhibition of formula I as herein described, II or III and the method and the intermediate of imaging compounds.
The accompanying drawing summary
Fig. 1 describes the K of several chemical compounds of the present invention
iBinding data.
Detailed Description Of The Invention
In first aspect, the present invention relates to compound or the acceptable salt of its pharmacy or the prodrug of formula I:
Wherein:
R
1Be selected from:
a.NR
aR
b, R whereinaAnd RbBe hydrogen, C independently1-4Alkyl, (CH2)
d 18F, and d is 1 to 4 integer,
B. hydroxyl,
C.C
1-4Alkoxyl,
D. hydroxyl (C
1-4) alkyl,
E. halogen,
F. cyano group,
G. hydrogen,
H. nitro,
I. (C
1-C
4) alkyl,
J. halo (C
1-C
4) alkyl and
K. formoxyl,
R
1' be selected from:
a.
123I、
125I、
131I、
18F、
76Br，
B. hydrogen,
C.
18F (C
1-4) alkyl,
D.[
18F (C
1-4) alkyl] amino,
E.[
18F (C
1-C
4) alkyl] alkyl amino,
F.
18F (C
1-C
4) alkoxyl,
R
2Be selected from:
I. hydroxyl, C
1-4Alkoxyl, (C
1-C
4)-alkyl oxo (C
1-C
4) alkoxyl, (C
1-C
4)-alkyl oxo (C
1-C
4)-alkyl oxo (C
1-C
4) alkoxyl, (C
1-C
4)-alkyl oxo (C
1-C
4)-alkyl oxo (C
1-C
4)-alkyl oxo (C
1-C
4) alkoxyl, carboxyl (C
1-C
4) alkyl, halo (C
1-C
4) alkoxyl, halo (C
1-C
4)-alkyl oxo (C
1-C
4) alkoxyl, halo (C
1-C
4) alkyl oxo (C
1-C
4) alkyl oxo (C
1-C
4)-alkoxyl, halo (C
1-C
4) alkyl oxo (C
1-C
4) alkyl oxo (C
1-C
4) alkyl oxo (C
1-C
4) alkoxyl, halo (C
1-C
4) alkyl, NR
6R
6', phenyl (C
1-C
4) alkyl,
18F (C
1-C
4) alkoxyl,
18F (C
1-C
4) alkyl oxo (C
1-C
4) alkoxyl,
18F (C
1-C
4) alkyl oxo (C
1-C
4) alkyl oxo (C
1-C
4) alkoxyl,
18F (C
1-C
4) alkyl oxo (C
1-C
4) alkyl oxo (C
1-C
4) alkyl oxo (C
1-C
4) alkoxyl,
18F (C
1-C
4) alkyl,
R wherein
6And R
6' be independently selected from hydrogen, hydroxyl (C
1-C
4) alkyl and C
1-C
4Alkyl,
Wherein q is 1 to 10 integer; Z is selected from
18F,
18The benzoxy that F replaces,
18The benzyloxy that F replaces, be preferably
18The F-phenoxy group,
18Phenyl (the C that F replaces
1-4) alkyl,
18(the C that F replaces
1-4) alkoxyl,
18The aryloxy group that F replaces and
18The C that F replaces
6-10Aryl, be preferably
18The F-phenyl; And R
30, R
31, R
32And R
33Be selected from hydrogen, hydroxyl, C independently of one another
1-4Alkoxyl, C
1-4Alkyl and hydroxyl (C
1-4) alkyl;
Wherein Z, R
30, R
31, R
32And R
33As mentioned above;
Wherein Y is selected from
18F,
18The benzoxy that F replaces,
18Phenyl (the C that F replaces
1-4) alkyl,
18The aryloxy group that F replaces, be preferably
18The F-phenoxy group and
18The C that F replaces
6-10Aryl, be preferably
18The F-phenyl;
U be selected from hydrogen, hydroxyl,
18F,
18The benzoxy that F replaces,
18Phenyl (the C that F replaces
1-4) alkyl,
18The aryloxy group that F replaces, be preferably
18The F-phenoxy group and
18The C that F replaces
6-10Aryl, be preferably
18The F-phenyl; And
R
34, R
35, R
36, R
37, R
38, R
39And R
40Be selected from hydrogen, hydroxyl, C independently of one another
1-4Alkoxyl, C
1-4Alkyl and hydroxyl (C
1-4) alkyl; And
R
7And R
8Be selected from halogen (as F, Cl, Br), hydrogen, hydroxyl, amino, methylamino, dimethylamino, C independently of one another
1-4Alkoxyl, C
1-4Alkyl and hydroxyl (C
1-4) alkyl, wherein R
7And R
8In at least one is a halogen, preferred F.
In preferred embodiments,
R
1Be independently selected from hydrogen, halogen (as F, Cl, Br), C
1-C
4Alkyl, cyano group, hydroxyl, nitro, (C
1-C
4) alkyl amino, two (C
1-C
4) alkyl amino, halo (C
1-C
4) alkyl, formoxyl and (C
1-4) the oxygen base,
R
1' be independently selected from hydrogen,
123I,
125I,
131I,
18F,
18F (C
1-4) alkyl, [
18F (C
1-4) alkyl] amino, [
18F (C
1-C
4) alkyl] alkyl amino,
18F (C
1-C
4) alkoxyl and
76Br;
R
2Be independently selected from hydroxyl, C
1-4Alkoxyl, (C
1-C
4) alkyl oxo (C
1-C
4) alkoxyl, carboxyl (C
1-C
4) alkyl, halo (C
1-C
4) alkoxyl, halo (C
1-C
4) alkyl oxo (C
1-C
4) alkoxyl, halo (C
1-C
4) alkyl oxo (C
1-C
4) alkyl oxo (C
1-C
4) alkoxyl, halo (C
1-C
4) alkyl oxo (C
1-C
4) alkyl oxo (C
1-4) alkyl oxo (C
1-C
4) alkoxyl, halo (C
1-C
4) alkyl, MR
6R
6', phenyl (C
1-C
4) alkyl,
18F (C
1-C
4) alkoxyl,
18F (C
1-C
4) alkyl oxo (C
1-C
4) alkoxyl,
18F (C
1-C
4) alkyl oxo (C
1-C
4) alkyl oxo (C
1-C
4) alkoxyl,
18F (C
1-C
4) alkyl oxo (C
1-C
4) alkyl oxo (C
1-4) alkyl oxo (C
1-C
4) alkoxyl,
18F (C
1-C
4) alkyl,
R
6And R
6' be independently selected from hydrogen, hydroxyl (C
1-C
4) alkyl and C
1-C
4Alkyl,
R
7And R
8Be selected from H, F, Cl or Br, wherein R
7Or R
8Be halogen.
In other embodiment preferred,
R
1Be selected from hydrogen, hydroxyl, (C
1-C
4) alkyl amino, two (C
1-C
4) alkyl amino, methyl and methoxyl group, especially hydrogen, methylamino and dimethylamino,
R
1' be selected from hydrogen,
123I,
125I,
131I and
18F, especially hydrogen;
R
1Be selected from hydroxyl, C
1-C
4Alkoxyl, NR
6R
6',
18F (C
1-C
4) alkoxyl,
18F (C
1-C
4) alkyl oxo (C
1-C
4) alkoxyl,
18F (C
1-C
4) alkyl oxo (C
1-C
4) alkyl oxo (C
1-C
4) alkoxyl,
18F (C
1-C
4) alkyl oxo (C
1-C
4) alkyl oxo (C
1-C
4) alkyl oxo (C
1-C
4) alkoxyl,
18F (C
1-C
4) alkyl, especially be selected from (C
1-C
4) alkyl oxo (C
1-C
4) alkoxyl,
18F (C
1-C
4) alkyl oxo (C
1-C
4) alkyl oxo (C
1-C
4) alkoxyl and
18F (C
1-C
4) alkyl oxo (C
1-C
4) alkyl oxo (C
1-4) alkyl oxo (C
1-4) alkoxyl,
R
6And R
6' be independently selected from hydrogen, hydroxyl (C
1-C
4) alkyl and C
1-4Alkyl,
R
7And R
8Be selected from hydrogen and fluorine, wherein R
7Or R
8Be fluorine.
Have surprisingly been found that the stilbene derivative that carries extra halogen, especially fluorine atom on two keys demonstrates pharmacokinetics character and/or the metabolic stability of increase and/or the geometric isomer stability and the uniformity of increase of improvement.
The chemical compound of preferred formula I has following structure:
R wherein
7And R
8In one be hydrogen, and another is a halogen.
A second aspect of the present invention relates to chemical compound or the acceptable salt of its pharmacy of formula II:
Wherein:
R
1Be selected from:
A.MR
aR
b, R wherein
aAnd R
bBe hydrogen, C independently
1-4Alkyl, (CH
2)
d 18F, and d is 1 to 4 integer, perhaps R
aAnd R
bBe oxygen, form nitro,
B. hydroxyl,
C.C
1-4Alkoxyl and
D. hydroxyl (C
1-4) alkyl;
R
2Be selected from:
Wherein q is 1 to 10 integer; Z is selected from
18F,
18The benzoxy that F replaces,
18(the C that F replaces
1-4) alkoxyl,
18The benzyloxy that F replaces, be preferably
18The F-phenoxy group,
18Phenyl (the C that F replaces
1-4) alkyl,
18The aryloxy group that F replaces and
18The C that F replaces
6-10Aryl, be preferably
18The F-phenyl; And R
30, R
31, R
32And R
33Be selected from hydrogen, hydroxyl, C independently of one another
1-4Alkoxyl, C
1-4Alkyl and hydroxyl (C
1-4) alkyl;
Wherein Z, R
30, R
31, R
32And R
33As mentioned above;
Wherein Y is selected from
18F,
18The benzoxy that F replaces,
18Phenyl (the C that F replaces
1-4) alkyl,
18The aryloxy group that F replaces, be preferably
18The F-phenoxy group and
18The C that F replaces
6-10Aryl, be preferably
18The F-phenyl;
U be selected from hydrogen, hydroxyl,
18F,
18The benzoxy that F replaces,
18Phenyl (the C that F replaces
1-4) alkyl,
18The aryloxy group that F replaces, be preferably
18The F-phenoxy group and
18The C that F replaces
6-10Aryl, be preferably
18The F-phenyl; And
R
34, R
35, R
36, R
37, R
38, R
39And R
40Be selected from hydrogen, hydroxyl, C independently of one another
1-4Alkoxyl, C
1-4Alkyl and hydroxyl (C
1-4) alkyl; And
R
7And R
8Be selected from hydrogen, hydroxyl, amino, methylamino, dimethylamino, C independently of one another
1-4Alkoxyl, C
1-4Alkyl and hydroxyl (C
1-4) alkyl.
More preferably, R
30, R
31, R
32, R
33, R
34, R
35, R
36, R
37, R
38, R
39And R
40The value of each is selected from hydrogen, hydroxyl, amino, methylamino, dimethylamino and methoxyl group independently of one another.
Preferably, R
2Position or para-position between being in respect to ethylene bridge.
Work as R
2During for following structure,
R
30, R
31, R
32And R
33The preferred value hydrogen of respectively doing for oneself, and Z is
18F.The useful value of q comprises 1 to 10 integer.Preferably, q is 2 to 5 integer.More preferably, the value of q is 3 or 4.
The preferred embodiment of formula II comprises following structure, wherein R
aAnd R
bBe hydrogen or methyl independently, preferred R
aAnd R
bIn at least-individual be methyl:
And X is
18F.
The preferred series of the chemical compound of formula II comprises having following structure
18The Polyethylene Glycol of F labelling (PEG)-stilbene derivative:
Wherein, q is 1 to 10 integer.Preferred chemical compound comprises following chemical compound, and wherein q equals:
Two,
Three,
Or four,
In this serial chemical compound,
18F is connected in Stilbene by the PEG chain, has the ethyoxyl of variable number.In the mensuration of AD brain homogenate was dissected a body in use, all fluorizated Stilbene all demonstrated high binding affinity (K
i=2.9-6.7nM).Shown in this paper route 1-3, by with [
18F] the fluoride methanesulfonates group that replaces 10a-d successfully carries out radioactive label, provide target compound [
18F] (EOS is than 900-1500Ci/mmol alive for 12a-d; Radiochemical purity＞99%).After intravenous injection, these
18The bio distribution of F part in normal mouse demonstrates the infiltration of fabulous brain and removes (washout) rapidly and (be respectively 6.6-8.1 and 1.2-2.6% dosage/g) at 2min and 60min.[
18F] autoradiography of the AD brain section of dissecting a body of 12a-d has confirmed and there is relevant specificity combination in A β speckle.In addition, in transgenic mice (Tg2576), use these
18The reagent of F labelling can clearly manifest speckle labelling in the body, and Tg2576 is the useful animal model that is used for Alzheimer.
The invention still further relates to the chemical compound of formula III:
Wherein n is 1 to 4 integer, R
7And R
8Separately as mentioned above, and R
41Be selected from hydroxyl and NR
aP
b, R wherein
8And R
bBe hydrogen, C independently
1-4Alkyl, perhaps R
aAnd R
bBe oxygen, form nitro.
Preferably, n is 1, and R
41Be hydroxyl, methylamino or dimethylamino.
C
6-10Preferred value in the aryl groups range comprises phenyl, naphthyl or tetralyl.Preferred value in the heteroaryl scope comprises thienyl, furyl, pyranose, pyrrole radicals, pyridine radicals, indyl and imidazole radicals.Preferred value in the heterocycle scope comprises piperidyl, pyrrolidinyl and morpholinyl.
The chemical compound of formula I, II and III also can be solvation, especially hydration.Hydration can occur in described chemical compound or comprise in the preparation process of described compound compositions, and perhaps hydration can take place in time owing to the hygroscopicity of described chemical compound.In addition, chemical compound of the present invention not solvation form and exist with the form of pharmacy acceptable solvent such as water, ethanol equal solventization.Usually, be purpose of the present invention, think that the form of solvation and the form of solvation not are equal to.
It is also understood that, think to the present invention includes stereoisomer, as the cis and the transisomer of this Stilbene type chemical compound.Also comprise: optical isomer, as mixture and the single enantiomer and the diastereomer of enantiomer, they are owing to structural asymmetry in the chemical compound of formula I, II through selecting or III produces.
When any variable occurred more than one time in any component or in formula I, II or III, its definition when at every turn occurring all was independent of its definition when other occur at every turn.And, have only the combination of substituent group and/or variable to cause stable chemical compound, these combinations are only permission.
The term " alkyl " that uses separately herein or use as the part of another group refers to have 8 carbon at the most, preferred 6 carbon, the more preferably straight chain of 4 carbon and branched group are as methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group and isobutyl group.
Unless chain length is restricted, term " alkoxyl " is used in reference to the straight or branched alkyl of the above definition that is bonded to oxygen atom in this article, includes but not limited to methoxyl group, ethyoxyl, positive propoxy, isopropoxy etc.Preferably, the alkoxyl chain length is a 1-6 carbon atom, and more preferably chain length is a 1-4 carbon atom.
The term " monoalkylamine " that uses separately herein or use as the part of another group refers to by the amino of the alkyl of definition more than replacement.
The term " dialkylamine " that uses separately herein or use as the part of another group refers to by the amino of the alkyl of definition more than two replacement.
Unless in concrete purposes explanation is arranged in addition in article and/or the claim, the term " halo " or " halogen " that use separately herein or use as the part of another group refer to chlorine, bromine, fluorine or iodine.
Term used herein " haloalkyl " refers to that wherein fluorine and chlorine are preferred by any abovementioned alkyl of one or more chlorine, bromine, fluorine or iodine replacement, as chloromethyl, iodomethyl, trifluoromethyl, 2,2, and 2-trifluoroethyl and 2-chloroethyl.
Contain the monocycle or the bicyclic aromatic group of 6-12 carbon herein in term " aryl " the finger ring part of using separately or using as the part of another group, preferably contain 6-10 carbon in the loop section, as phenyl, naphthyl or tetralyl.
Except as otherwise noted, the single heterocyclic ring system of 5-7 unit that term used herein " heterocycle " or " heterocyclic ring " expression are stable, it can be saturated or undersaturated, and is made up of carbon atom and 1-3 the hetero atom that is selected from N, O and S, and wherein nitrogen and sulfur heteroatom can randomly be oxidations.Useful especially ring contains a nitrogen with oxygen or sulfur combination, perhaps contains two nitrogen heteroatoms.The example of these heterocyclic groups comprises piperidyl, pyrrole radicals, pyrrolidinyl, imidazole radicals, imidazinyl, imidazolidinyl, pyridine radicals, pyrazinyl, pyrimidine radicals, oxazolyl, oxazolidinyl, isoxazolyl, isoxazole alkyl, thiazolyl, thiazolidinyl, isothiazolyl, homopiperidinyl, high piperazinyl, pyridazinyl, pyrazolyl and pyrazolidinyl, most preferably thio-morpholinyl (thiamorpholinyl), piperazinyl and morpholinyl.
Term " hetero atom " is used in reference to oxygen atom (" O "), sulphur atom (" S ") or nitrogen-atoms (" N ") in this article.Can be appreciated that when described hetero atom was nitrogen, it can form NR
aR
bGroup, wherein R
aAnd R
bBe hydrogen or C independently of each other
1-4Alkyl, C
2-4Aminoalkyl, C
1-4Haloalkyl, halogeno-benzyl, perhaps R
1And R
2Form 5-7 unit heterocycle together, it randomly contains O, S or NR in described ring
c, R wherein
cBe hydrogen or C
1-4Alkyl.
Term used herein " heteroaryl " refers to following group: they have 5 to 14 annular atomses; Share 6,10 or 14 ∏ electronics in the ring system (cyclic array); And contain carbon atom and 1,2,3 or 4 oxygen, (wherein the example of heteroaryl is: thienyl for nitrogen or sulfur heteroatom, benzo [b] thienyl, naphtho-[2,3-b] thienyl, thianthrene group, furyl, pyranose, isobenzofuran-base benzoxazolyl, chromenyl, xanthyl, benzo oxathiin base (phenoxathiinyl), the 2H-pyrrole radicals, pyrrole radicals, imidazole radicals, pyrazolyl, pyridine radicals, pyrazinyl, pyrimidine radicals, pyridazinyl, the indolizine base, isoindolyl, the 3H-indyl, indyl, indazolyl, purine radicals, the 4H-quinolizinyl, isoquinolyl, quinolyl, the 2 base, naphthyridinyl, quinazolyl, the cinnolines base, pteridyl, the 4aH-carbazyl, carbazyl, -carbolinyl, phenanthridinyl, acridinyl, perimidinyl, the phenanthroline base, phenazinyl, isothiazolyl, phenothiazinyl isoxazolyl, the furazan base is with phenoxazine group).
The C discussed above that the term " aralkyl " that uses separately herein or use as the part of another group or " aryl alkyl " refer to have aryl substituent
1-6Alkyl is as benzyl, phenethyl or 2-menaphthyl.
The invention still further relates to the preparation method of the chemical compound of above-mentioned formula I, II or III.Reaction described in the pass course 1-8 can prepare chemical compound of the present invention.
Route 1 has illustrated to be used to form the derivant of the formula I that contains thiophene, especially the synthetic route of some formula Ia chemical compound.
Prepared in reaction shown in the pass course 1 is fluoridized PEG Stilbene 12a-d.Have the chemical compound that 2 or 3 ethyoxyls connect as PEG in order to prepare, with commercially available chloride 2a, b and 4-methylamino-4 '-hydroxyl Stilbene 1 (people such as Ono M, Nucl.Med.Biol.2003; 30:565-71; People such as Wilson A, J.Labelled Cpd Radiopharm.2003; OH base coupling 46:S61) obtains 3a, b respectively.Protect the free OH of 3a, b then with TBDMSCl, obtain chemical compound 7a, b.For prepare have 4 or 5 ethyoxyls as PEG connect chemical compound, prepare bromide 6c, d as shown in Scheme 2 respectively, make they and Stilbene 1 coupling then, obtain chemical compound 7c, d that TBS protects.Handle the O-TBS protecting group of removing on chemical compound 7c, the d by the TBAF (1M) that is used among the THF, obtain 3c, d.Methylamino by with BOC protection 7a-d obtains chemical compound 8a-d.After removing the TBS protecting group of 8a-d with TBAF (1M)/THF, by in the presence of triethylamine, reacting, free OH is converted into methanesulfonates with MsCl, obtain 10a-d.By at anhydrous TBAF/THF (people such as Cox DP, J.Org.Chem.1984; Backflow 10a-d 49:3216-19) stirs to remove the BOC protecting group with TFA then, successfully obtains " cold " fluorizated PEG Stilbene 12a-d.
Required in order to prepare
18F labelling PEG Stilbene [
18F] 12a-d, the methanesulfonates 10a-d that uses the N-BOC protection is as precursor (route 3).With methanesulfonates 10a-d separately with in DMSO [
18F] fluoride/potassium carbonate and Kryptofix 222 mixing, and under 120 ℃, heat 4min.Then with HCl aqueous solution treatment mixture to remove the N-BOC protecting group.By HPLC purification crude product (radiochemical purity＞99%, radiochemistry yield 10-30%, decay correction).Each
18The F labelled compound [
18F] preparation of 12a-d spends about 90min, and when end of synthesis, estimates to be than living 900-1500Ci/mmol.
Route 1
Route 1
D) TBAF (1M), THF; E) (BOC)
2O, THF; F) MsCl, Et
3N, DCM; G) TBAF (anhydrous), TI-IF; H) TFA, DCM
Route 2
Route 2 is TBSCl a), Et
3N, DCM; B) CBr
4, PPh
3, DCM
a：n＝2
b：n＝3
Route 3 a) 1) [
18F] F
-K222, K
2CO
3.DMSO; 2) HCl aq c:n=4
d：n＝5
Route 9 show the synthetic of chemical compound 15e, 16e and be used for preparation [
18F] 15e and [
18F] radioactive label precursor 15d, 17d synthetic of 6e.In order to prepare chemical compound 15a, be used in the SnCl in the ethanol
2Reduction 4-nitro-4 '-nitro of hydroxyl Stilbene 13a, obtain corresponding amine 14a.Use (CHO) then
nAnd NaBH
3CN handles amino, obtains dimethylamino compound 15a.By making hydroxyl Stilbene 15a and bromide 20m (it is independently preparation as shown in Scheme 10) and the potassium carbonate reaction in dry DMF, obtain chemical compound 15b.Handle 15b by the 1N HCl that is used in the acetone, obtain chemical compound 15c.Can from the mixture of glycol 15c and the reaction of 1.5 equivalent toluene sulfochlorides pyridine, separate toluene monooxygenase sulphonic acid ester 15d.By refluxing, tosylate 15d is converted into fluoride 15e with anhydrous TBAF in THF.Before use, must be with TBAF at 58 ℃ and fine vacuum (＜0.5mmHg) dry 24hr down.Use tosyl based compound 15d as raw material, the acquisition radio-labelled compound [
18F] 15e.By the coupling reaction of 13a and 20m, tosylation and fluoridizing then, synthesizing nitryl chemical compound 13e similarly.By using SnCl
2The nitro of/EtOH reduction 13e is used (CHO) then
n, NaOCH
3And NaBH
4With amino monomethylation, finish the synthetic of chemical compound 16e.Intermediate 13b is reduced into amine 14c, and monomethylation obtains chemical compound 16c then.For obtain [
18F] 16e, the tosylate 17d of design N-protected is as carrying out radiolabeled precursor.The 14a monomethylation that at first will before prepare is 16a.Pass through 16a and 20n (route 10) coupling then, and BOC is introduced in 2 ° of amine, preparation chemical compound 17f.At room temperature, be used in the di-t-butyl silicyl that 1N TBAF among the THF removes 17f, obtain glycol 5c,, obtain chemical compound 17d its toluene monooxygenase sulfonylation.
Also synthesized related compound 15h as shown in Scheme 4.With DIBALH the malonate 21 that replaces is reduced into glycol 22, with monovalent TBSCl reaction, obtains 23 then.Use CBr then
4/ PPh
3Unprotected OH is converted into bromide 24.Make chemical compound 24 and 15a reaction, obtain 15g, handle 15g to remove the TBS group, obtain 15h with TBAF.
Also synthesized N, two kinds of benzyl derivatives 14 of N-dimethyl Stilbene and 15 (routes 4).By using LiAlH
4Reduce corresponding ethyl ester 13
3, obtain chemical compound 14.With HBr/HOAc benzylalcohol is converted into highly active benzyl bromide a-bromotoluene intermediate then, it is not purified, is changed into methyl ether 15 immediately by adding methanol and potassium carbonate.
(2877-2879), synthetic wherein fluorine atom is directly connected in those stilbene derivatives (formula I:R of two keys for Tetrahedron Lett.43 for example, (2002) by known method
7Or R
8Be fluorine).
For obtain [
18F] 15e, with precursor 15d with in DMSO [
18F] fluoride/potassium carbonate and Kryptofix 222 mixing, and under 120 ℃, heat 4min.By HPLC purification crude product, the radiochemistry yield with 10% obtains＞99% radiochemical purity (decay correction).This program spends 90min, and when end of synthesis, estimates than living to be 70Ci/mmol.Carry out similar program, from precursor 17d obtain [
18F] 16e.After being the primary response among the DMSO, with HCl aqueous solution treatment mixture to remove the BOC group.Behind the HPLC purification, radiochemical purity＞99%, and the radiochemistry yield is 15%.Total synthesizing spends 110min, and when end of synthesis, estimation is 90Ci/mmol than living.
Route 4
A) SnCl
2, HCl (c), EtOH; B) (CHO)
n, NaBH
3CN, AcOH, rt; C) (1) NaOMe, MeOH, (CHO)
n(2) NaBH
4D) 8m K
2CO
3, DMF, 100 ℃; E) HCl, CH
2COCH
3, rt; F) TsCl, Py, 0 ℃; G) TBAF, THF refluxes; H) 8n, K
2CO
3, DMF, 100 ℃; I) (BOC)
2O, THF refluxes; J) TBAR (1M), THF, rt.
Route 5
a)7m(CH
3O)
2C(CH
3)
2，T
sOH；7n：HOBT，Si(t-BU)
2Cl
2，Et3N，DCM；b)CBr
4，PPh
3，Py，DCM
Route 6
Route 7
(a)[
18F]HF/K
2CO
3/K222 DMSO，(b)aq HCl
Also can some chemical compounds be carried out microwave synthesize as following described in the embodiment 50-52.
The chemical compound of radioactive halogenation of the present invention easily makes them be suitable for from offering the material formation of user with test kit.The test kit that is used to form this developer can contain for example bottle, and described bottle contains the solution that the physiology of the intermediate of formula I is fit to, and its concentration and pH are fit to best complexation condition.User adds an amount of radiosiotope and oxidant such as hydrogen peroxide in bottle.Then can be with gained tagged ligand intravenous administration to the patient, and by measuring from the gamma-rays of brain or photoemission and the receptor in the imaging brain.
When needed, radioactive diagnostic agent can contain any additives such as pH controlling agent (for example acid, alkali, buffer agent), stability (for example ascorbic acid) or isotonic agent (for example sodium chloride).
Term used herein " the acceptable salt of pharmacy " refers to the carboxylate or the acid-addition salts of The compounds of this invention, in the scope of sound medical judgment (sound medical judgement), they are applicable to contact patient's tissue, and there are not over-drastic toxicity, stimulation, allergy etc., match with rational benefit/risk ratio, to its desired use is effectively, when possibility, also refers to the zwitterionic form of The compounds of this invention.Term " salt " refers to the nontoxic relatively mineral acid and the organic acid addition salt of The compounds of this invention.Also comprise those salt, described non-toxic organic such as aliphatic monocarboxylic acid and dicarboxylic acids, the alkanoic acid, hydroxyl alkane acid and the chain docosandioic acid that replace of acetic acid, phenyl for example, aromatic acid and aliphatic series and aromatic sulfonic acid derived from non-toxic organic acid.Can separate and these salt of process made acid-stable in situ of purifying compounds final, perhaps the purified chemical compound by making free alkali form separately prepares these salt with appropriate organic or inorganic acid reaction and the salt that separates such formation.Other exemplary salt comprises hydrobromate, hydrochlorate, sulfate, disulfate, nitrate, acetate, oxalates, valerate, oleate, palmitate, stearate, laruate, borate, benzoate, lactate, phosphate, toluene fulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, gluceptate, lactiobionate and dodecane sulfonate, propionate, Pivalate, cyclamate, isethionate etc.These salt can comprise based on cation of alkali metal and alkaline-earth metal such as sodium, lithium, potassium, calcium, magnesium etc. and nontoxic ammonium, quaternary ammonium and amine cation, include but not limited to that ammonium, tetramethyl-ammonium, tetraethyl ammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethamine etc. are (referring to people such as for example Berge S.M., Pharmaceutical Salts, J.Pharm.Sci.66:1-19 (1977), the document is incorporated herein by reference).
The invention still further relates to the formation method of amyloid beta deposition thing.The crucial essential condition of developer is the ability of passing complete blood brain barrier behind intravenous push in the body of brain.
In first step of formation method of the present invention, the labelled compound of formula I, II or III is introduced in tissue or the patient with detectable amount.Described chemical compound typically is part of pharmaceutical compositions, and by well known to a person skilled in the art that method is administered to described tissue or described patient.
For example, described chemical compound can by in oral, rectum, non-intestinal (intravenous, intramuscular or subcutaneous), the brain pond, intravaginal, intraperitoneal, intravesical, part (powder, ointment or drop) administration, perhaps as oral cavity or nasal spray administration.
In a preferred embodiment of the invention, labelled compound is introduced in the patient, and behind described chemical compound and amyloid beta deposition thing association time enough, non-invasively detected the labelled compound in the described patient with detectable amount.In another embodiment of the invention, with formula I, II or III
18The F labelled compound is introduced in the patient, makes described chemical compound and amyloid beta deposition thing association time enough, takes out tissue samples from the patient then, leaves the patient and detects described in-house labelled compound.In the 3rd embodiment of the present invention, take out tissue samples from the patient, and the labelled compound of formula I, II or III is introduced in the described tissue samples.With after the amyloid beta deposition thing combines time enough, detect described chemical compound at described chemical compound.
Can labelled compound be administered to the patient by whole body or topical approach.For example, labelled compound can be administered to the patient, it be sent spread all over whole body.Perhaps, can or organize the administration labelled compound to interested certain organs.For example, in order to diagnose the Alzheimer in the patient or to follow the tracks of its progress, wish the amyloid beta deposition thing in location and the quantitative brain.
Term " tissue " refers to the part of patient's body.The example of tissue comprises brain, heart, liver, blood vessel and tremulous pulse.Detectable amount is to detect the amount of required labelled compound by selected detection method.Those skilled in the art can easily determine will introduce for detection is provided the amount of the labelled compound in the patient.For example, can give the labelled compound of the ever-increasing amount of patient, until detecting described chemical compound by selected detection method.Label is introduced in the chemical compound with detection compound.
Term " patient " refers to people and other animal.Those skilled in the art also are familiar with determining to be enough to make chemical compound and the associating time quantum of amyloid beta deposition thing.By but formula I, the II of detection limit or the labelled compound of III are introduced in the patient, the different time certification mark chemical compound after administration can easily be determined required time quantum then.
Chemical interaction between term " association " digit synbol chemical compound and the amyloid beta deposition thing.Associating example comprises covalent bond, ionic bond, hydrophilic-the aqueous favoring mutual effect, hydrophobic-hydrophobic interaction and complexation.
Those skilled in the art be familiar with the positron emission atom as
18The positron emission fault art (PET) of F detects.The invention still further relates to specific compound, wherein
18The F atom is replaced by nonradioactive labeling's fluorine atom.
Radioactive diagnostic agent should have enough radioactivity and radioactive concentration, and they can guarantee reliable diagnostic.The preparation method of the chemical compound by formula I provided herein, II or III can obtain required radioactive level.
Also the imaging of amyloid beta deposition thing can be carried out quantitatively, thereby the amount of amyloid beta deposition thing can be determined.
Another aspect of the present invention is to suppress the accumulative method of amyloid plaque.The present invention also provides by suppressing the method that amyloid aggregation forms the amyloid beta deposition thing to above-mentioned formula I, the II of patient's administration amyloid amount of suppression or the chemical compound of III.
, reduce or stop until the growth of amyloid beta deposition thing with the chemical compound of ever-increasing amount to patient's Medicine-feeding type I, II or III by simply, those skilled in the art can easily determine the amyloid amount of suppression.Use above-mentioned imaging or, can estimate the speed of growth by take out tissue samples and observation amyloid beta deposition thing wherein from the patient.Can be with the dosage level in about 0.1 to the about 1000mg/ days scope with compound administration of the present invention to the patient.Be the normal adult of about 70kg for body weight, about 0.01 dosage to about 100mg/kg body weight/day scope is just enough.Yet used concrete dosage can change.For example, described dosage can be depending on many factors, comprises patient's demand, by the seriousness of the disease of being treated and the pharmacologically active of compound used therefor.The optimal dose that is identified for particular patient is well known to a person skilled in the art.
Radioactive diagnostic agent should have enough radioactivity and radioactive concentration, and they can guarantee reliable diagnostic.The preparation method of the chemical compound by formula I provided herein, II or III can obtain required radioactive level.
Also the imaging of amyloid beta deposition thing can be carried out quantitatively, thereby the amount of amyloid beta deposition thing can be determined.
Following examples are illustrative and unrestricted method and compositions of the present invention.Usually run into and conspicuous to those skilled in the art to various conditions and parameter other suitably revised and changed all within the spirit and scope of the present invention.
Except as otherwise noted, synthetic middle all reagent that use all are the commercially available prod, and use without being further purified.On Bruker DPX spectrometer (200MHz), at CDCl
3The middle acquisition
1H NMR spectrum.Chemical shift is reported as δZhi (a few millionths) with respect to interior mark TMS.Coupling constant is reported as hertz.Multiplicity is by s (unimodal), d (bimodal), t (triplet), br (broad peak), m (multiplet) definition.Carry out elementary analysis by Atlantic Microlab INC.For each program, " standard processing " refers to following steps: add specified organic solvent, wash organic layer with water, use salt water washing organic layer then, separate organic layer and water layer, with the organic layer of anhydrous sodium sulfate drying merging, filtering sodium sulfate, and organic solvent is removed in decompression.
Embodiment 1
2-(2-{4-[2-(4-methylamino-phenyl)-vinyl]-phenoxy group }-ethyoxyl)-ethanol (3a)
Under blanket of nitrogen, with 4-methylamino-4 '-hydroxyl Stilbene 1 (people such as Ono M, Nucl.Med.Biol.2003; People such as Wilson A, J.Labelled Cpd Radiopharm.2003) (63mg, 0.28mmol) and 2a (42mg 0.34mmol) is dissolved in the dry DMF (5.0ml), add then potassium carbonate (125mg, 0.91mmol).Suspension is heated to 100 ℃, and stirs and spend the night.After being cooled to room temperature, carrying out standard with dichloromethane and handle, and, obtain chemical compound 3a (67mg, 76%) by preparation of silica gel TLC (4% methanol in dichloromethane) purification residue:
1H NMR δ 7.37 (m, 4H), 6.89 (m, 4H), 6.63 (d, 2H, J=8.48Hz), 4.16 (t, 2H), 3.88 (t, 2H), 3.78 (t, 2H), 3.68 (t, 2H), 2.87 (s, 3H), 2.20 (br, 1H), 1.55 (br, 1H).
Embodiment 2
2-[-2-(2-{4-[2-(4-methylamino-phenyl)-vinyl]-phenoxy group }-ethyoxyl)-ethyoxyl]-ethanol (3b)
Use is about the described same program of chemical compound 3a, among DMF (10ml) 1 (150mg, 0.67mmol), 2b (136mg, 0.81mmol) and potassium carbonate (277mg, 2.01mmol) preparation chemical compound 3b.3b(180mg，76％)：
1H NMR δ7.37(m，4H)，6.89(m，4H)，6.65(d，2H，J＝8.50Hz)，4.15(t，2H)，3.87(t，2H)，3.72(t，6H)，3.62(t，2H)，2.87(s，3H)，2.20(br，1H)，1.60(b，1H)。
2-{2-[2-(2-{4-[2-(4-methylamino-phenyl)-vinyl]-phenoxy group }-ethyoxyl)-ethyoxyl]-ethyoxyl }-ethanol (3c)
(1M is in THF, and (12mg is 0.023mmol) in the solution in THF (1ml) 0.06ml) to add chemical compound 7c to TBAF by syringe.Solution was at room temperature stirred 2 hours.Carry out the standard processing with dichloromethane after,, obtain 3c (8.7mg, 94%) by preparation of silica gel TLC (4.5% methanol in dichloromethane) purification residue:
1H NMR δ 7.36 (m, 4H), 6.88 (m, 4H), 6.58 (d, 2H, J=8.5Hz), 4.15 (t, 2H), 3.86 (t, 2H), 3.70 (m, 12H), 2.86 (s, 3H).
Embodiment 4
2-(2-{2-[2-(2-{4-[2-(4-methylamino-phenyl)-vinyl]-phenoxy group }-ethyoxyl)-ethyoxyl]-ethyoxyl }-ethyoxyl)-ethanol (3d)
Use is about the described same program of chemical compound 3c, from the 7d among THF (1ml) (15mg, 0.027mmol) and TBAF (1M in THF, 0.06ml) preparation chemical compound 3d.3d(7.8mg，65％)：
1H NMR δ7.36(m，4H)，6.87(m，4H)，6.60(d，2H，J＝8.5Hz)，4.14(t，2H)，3.85(t，2H)，3.66(m，16H)，2.86(s，3H)。
Embodiment 5
2-(2-{2-[2-(tert-butyl group-dimethyl-silicon alkoxyl)-ethyoxyl]-ethyoxyl }-ethyoxyl)-ethanol (5c)
With tetraethylene glycol (TEG) 4c (1.12g, 5.77mmol) and TBDMSCl (0.87g 5.77mmol) is dissolved in the dichloromethane (25ml), be dissolved in then triethylamine (1.46g, 14.4mmol) in.Solution was at room temperature stirred 2 hours.Carry out the standard processing with dichloromethane after,, obtain 5c (744mg, 42%) by silica gel column chromatography (50% ethyl acetate in hexane) purification residue:
1H NMR δ 3.66 (m, 16H), 2.51 (t, 1H, J=5.86Hz), 0.89 (s, 9H), 0.07 (s, 6H).
Embodiment 6
2-[2-(2-{2-[2-(tert-butyl group-dimethyl-silicon alkoxyl)-ethyoxyl]-ethyoxyl }-ethyoxyl)-ethyoxyl]-ethanol (5d)
Use is about the described same program of chemical compound 5c, from five glycol 4d dichloromethane (25ml) (1.13g, 4.72mmol), TBDMSCl (0.78g, 5.19mmol) and triethylamine (1.2g, 11.8mmol) preparation chemical compound 5d.5d(668mg，40％)：
1H NMR δ3.67(m，20H)，2.64(t，1H，J＝5.63Hz)，0.89(s，9H)，0.06(s，6H)。
Embodiment 7
(2-{2-[2-(2-bromo-ethyoxyl)-ethyoxyl]-ethyoxyl }-ethyoxyl)-tert-butyl group-dimethyl-silane (6c)
With chemical compound 5c (680mg, 2.20mmol) and carbon tetrabromide (947mg 2.86mg) is dissolved in the dichloromethane (20ml).With ice bath solution is cooled to 0 ℃, and adds pyridine (2.0ml), add then triphenyl phasphine (749mg, 0.286mmol).Solution is stirred half an hour at 0 ℃, and at room temperature stirred 2 hours.Carry out the standard processing with dichloromethane after,, obtain chemical compound 6c (680mg, 79.6%) by silica gel column chromatography (20% ethyl acetate in hexane) purification residue:
1H NMR δ 3.79 (m, 4H), 3.66 (m, 8H), 3.56 (t, 2H), 3.47 (t, 2H), 0.89 (s, 9H), 0.07 (s, 6H).
[2-(2-{2-[2-(2-bromine oxethyl)-ethyoxyl]-ethyoxyl }-ethyoxyl)-ethyoxyl]-tert-butyl group-dimethylsilane (6d)
Use is about the described same program of chemical compound 6c, from the 5d dichloromethane (20ml) (624mg, 1.77mmol), carbon tetrabromide (761mg, 2.30mmol), triphenyl phasphine (602mg, 2.30mmol), pyridine (2.0ml) preparation chemical compound 6d.6d(400mg，52.3％)：
1H NMR δ3.79(m，4H)，3.66(m，12H)，3.55(t，2H)，3.47(t，2H)，0.89(s，9H)，0.06(s，6H)。
Embodiment 9
4-[2-(4-{2-[2-(tert-butyl group-dimethyl-silicon alkoxyl)-ethyoxyl]-ethyoxyl }-phenyl)-vinyl]-phenyl }-methylamine (7a)
With chemical compound 3a (45mg, 0.14mmol) and TBDMSCl (33mg 0.22mmol) is dissolved in the dichloromethane (10ml), be dissolved in then imidazoles (20mg, 0.29mmol) in.Solution was at room temperature stirred 2 hours.Carry out the standard processing with dichloromethane after,, obtain 7a (56mg, 91%) by silica gel column chromatography (1.5% methanol in dichloromethane) purification residue:
1H NMR δ 7.40 (m, 4H), 6.90 (m, 4H), 6.75 (d, 2H, J=7.9Hz), 4.15 (t, 2H), 3.88 (t, 2H), 3.82 (t, 2H), 3.66 (t, 2H), 2.85 (s, 3H), 0.92 (s, 9H), 0.09 (s, 6H).
Embodiment 10
(4-{2-[4-(2-{2-[2-(tert-butyl group-dimethyl-silicon alkoxyl)-ethyoxyl]-ethyoxyl }-ethyoxyl)-phenyl]-vinyl }-phenyl)-methylamine (7b)
Use is about the described same program of chemical compound 7a, from the 3b dichloromethane (10ml) (136mg, 0.38mmol), TBDMSCl (86mg, 0.57mmol), imidazoles (52mg, 0.76mmol) preparation chemical compound 7b.7b(170mg，95％)：
1H NMR δ7.37(m，4H)，6.88(m，4H)，6.66(d，2H，J＝8.6Hz)，4.14(t，2H)，3.86(t，2H)，3.75(m，6H)，3.57(t，2H)，2.88(s，3H)，0.90(s，9H)，0.07(s，6H)。
Embodiment 11
[4-(2-{4-[2-(2-{2-[2-(tert-butyl group-dimethyl-silicon alkoxyl)-ethyoxyl]-ethyoxyl }-ethyoxyl)-ethyoxyl]-phenyl }-vinyl)-phenyl]-methylamine (7c)
Use is about the described same program of chemical compound 3a, among DMF (10ml) 1 (98mg, 0.44mmol), 6c (210mg, 0.57mmol), K
2CO
3(300mg, 2.18mmol) preparation chemical compound 7c.7c(213mg，95％)：
1H NMR δ7.36(m，4H)，6.87(m，4H)，6.59(d，2H，J＝8.5Hz)，4.14(t，2H)，3.86(t，2H)，3.75(m，10H)，3.55(t，2H)，2.86(s，3H)，0.89(s，9H)，0.06(s，6H)。
Embodiment 12
4-[2-(4-{2-[2-(2-{2-[2-(tert-butyl group-dimethyl-silicon alkoxyl)-ethyoxyl]-ethyoxyl }-ethyoxyl)-ethyoxyl]-ethyoxyl }-phenyl)-vinyl]-phenyl }-methylamine (7d)
Use is about the described same program of chemical compound 3a, among DMF (10ml) 1 (97mg, 0.43mmol), 6d (197mg, 0.47mmol), K
2CO
3(297mg, 2.15mmol) preparation chemical compound 7d.7d(220mg，91％)：
1H NMR δ7.36(m，4H)，6.87(m，4H)，6.59(d，2H，J＝8.5Hz)，4.14(t，2H)，3.85(t，2H)，3.75(m，14H)，3.55(t，2H)，2.86(s，3H)，0.89(s，9H)，0.06(s，6H)。
Embodiment 13
4-[2-(4-{2-[2-(tert-butyl group-dimethyl-silicon alkoxyl)-ethyoxyl]-ethyoxyl }-phenyl)-vinyl]-phenyl }-methyl-t-butyl carbamate (8a)
Under blanket of nitrogen, with 7a (54mg 0.13mmol) is dissolved among the anhydrous THF (5.0ml), be dissolved in then the Boc anhydride (84mg, 0.25mmol) in.The solution backflow is spent the night.Carry out the standard processing with dichloromethane after,, obtain 8a (60mg, 90%) by preparation of silica gel TLC (2% methanol in dichloromethane) purification residue:
1H NMR δ 7.43 (d, 4H, J=8.4Hz), 7.20 (d, 2H, J=8.4Hz), 6.97 (q, 2H), 6.90 (d, 2H, J=8.7Hz), 4.14 (t, 2H), 3.87 (t, 2H), 3.80 (t, 2H), 3.64 (t, 2H), 3.27 (s, 3H), 1.46 (s, 9H), 0.90 (s, 9H), 0.08 (s, 6H).
Embodiment 14
(4-{2-[4-(2-{2-[2-(tert-butyl group-dimethyl-silicon alkoxyl)-ethyoxyl]-ethyoxyl }-ethyoxyl)-phenyl]-vinyl }-phenyl)-methyl-t-butyl carbamate (8b)
Use is about the described same program of chemical compound 8a, and (124mg is 0.26mmol) with Boc anhydride (218mg, 0.66mmol) preparation chemical compound 8b from the 7b among THF (10ml).8b(130mg，86％)：
1H NMR δ7.43(d，4H，J＝8.4Hz)，7.20(d，2H，J＝8.4Hz)，6.97(q，2H)，6.90(d，2H，J＝8.7Hz)，4.15(t，2H)，3.87(t，2H)，3.75(t，6H)，3.57(t，2H)，3.27(s，3H)，1.46(s，9H)，0.90(s，9H)，0.07(s，6H)。
Embodiment 15
[4-(2-{4-[2-(2-{2-[2-(tert-butyl group-dimethyl-silicon alkoxyl)-ethyoxyl]-ethyoxyl }-ethyoxyl)-ethyoxyl]-phenyl }-vinyl)-phenyl]-methyl-t-butyl carbamate (8c)
Use is about the described same program of chemical compound 8a, and (84mg is 0.16mmol) with Boc anhydride (163mg, 0.49mmol) preparation chemical compound 8c from the 7c among THF (5ml).8c(86mg，86％)：
1H NMR δ7.42(d，4H，J＝7.6Hz)，7.20(d，2H，J＝8.4Hz)，6.97(q，2H)，6.90(d，2H，J＝8.7Hz)，4.15(t，2H)，3.87(t，2H)，3.73(t，10H)，3.57(t，2H)，3.26(s，3H)，1.46(s，9H)，0.89(s，9H)，0.07(s，6H)。
Embodiment 16
4-[2-(4-{2-[2-(2-{2-[2-(tert-butyl group-dimethyl-silicon alkoxyl)-ethyoxyl]-ethyoxyl }-ethyoxyl)-ethyoxyl]-ethyoxyl }-phenyl)-vinyl]-phenyl }-methyl-t-butyl carbamate (8d)
Use is about the described same program of chemical compound 8a, and (210mg is 0.51mmol) with Boc anhydride (840mg, 2.54mmol) preparation chemical compound 8d from the 7d among THF (10ml).8d(174mg，66.7％)：
1H NMR δ7.42(d，4H，J＝8.4Hz)，7.20(d，2H，J＝8.4Hz)，6.97(q，2H)，6.90(d，2H，J＝8.7Hz)，4.15(t，2H)，3.86(t，2H)，3.72(t，14H)，3.55(t，2H)，3.27(s，3H)，1.46(s，9H)，0.89(s，9H)，0.06(s，6H)。
Embodiment 17
[4-(2-{4-[2-(2-hydroxyl-ethyoxyl)-ethyoxyl]-phenyl }-vinyl)-phenyl]-methyl-t-butyl carbamate (9a)
Use is about the described same program of chemical compound 3c, from the 8a among THF (5ml) (56mg, 0.11mmol) and TBAF (1M in THF, 0.21ml) preparation chemical compound 9a.9a(36mg，82％)：
1H NMR δ7.43(d，4H，J＝8.4Hz)，7.20(d，2H，J＝8.4Hz)，6.97(q，2H)，6.90(d，2H，J＝8.7Hz)，4.18(t，2H)，3.88(t，2H)，3.78(t，2H)，3.68(t，2H)，3.27(s，3H)，1.46(s，9H)。
Embodiment 18
4-[2-(4-{2-[2-(2-hydroxyl-ethyoxyl)-ethyoxyl]-ethyoxyl }-phenyl)-vinyl]-phenyl }-methyl-t-butyl carbamate (9b)
Use is about the described same program of chemical compound 3c, from the 8b among THF (10ml) (118mg, 0.21mmol) and TBAF (1M in THF, 0.42ml) preparation chemical compound 9b.9b(94mg，99.7％)：
1H NMR δ7.43(d，4H，J＝8.4Hz)，7.20(d，2H，J＝8.4Hz)，6.97(q，2H)，6.90(d，2H，J＝8.7Hz)，4.17(t，2H)，3.87(t，2H)，3.74(t，6H)，3.62(t，2H)，3.27(s，3H)，1.46(s，9H)。
Embodiment 19
(4-{2-[4-(2-{2-[2-(2-hydroxyl-ethyoxyl)-ethyoxyl]-ethyoxyl }-ethyoxyl)-phenyl]-vinyl }-phenyl)-methyl-t-butyl carbamate (9c)
Use is about the described same program of chemical compound 3c, from 8b (66mg, 0.11mmol), TBAF is (1M in THF, 0.22ml) and THF (5ml) preparation chemical compound 9c.9c(50mg，93.0％)：
1H NMR δ7.43(d，4H，J＝8.4Hz)，7.20(d，2H，J＝8.4Hz)，6.97(q，2H)，6.90(d，2H，J＝8.7Hz)，4.16(t，2H)，3.87(t，2H)，3.78(t，10H)，3.61(t，2H)，3.27(s，3H)，1.46(s，9H)。
Embodiment 20
[4-(2-{4-[2-(2-{2-[2-(2-hydroxyl-ethyoxyl)-ethyoxyl]-ethyoxyl }-ethyoxyl)-ethyoxyl]-phenyl }-vinyl)-phenyl]-methyl-t-butyl carbamate (9d)
Use is about the described same program of chemical compound 3c, from the 8d among THF (5ml) (76mg, 0.12mmol) and TBAF (1M in THF, 0.24ml) preparation chemical compound 9d.9d(52mg，82.7％)：
1H NMR δ7.43(d，4H，J＝8.4Hz)，7.20(d，2H，J＝8.4Hz)，6.97(q，2H)，6.90(d，2H，J＝8.7Hz)，4.16(t，2H)，3.87(t，2H)，3.75(t，14H)，3.60(t，2H)，3.27(s，3H)，1.46(s，9H)。
Embodiment 21
Methanesulfonic acid 2-[2-(4-{2-[4-(tertbutyloxycarbonyl-methyl-amino)-phenyl]-vinyl }-phenoxy group)-ethyoxyl]-ethyl ester (10a)
With chemical compound 9a (36mg 0.087mmol) is dissolved in the dichloromethane (5ml), be dissolved in then triethylamine (44mg, 0.44mmol) in.Then by syringe add mesyl chloride (30mg, 0.26mmol).Solution was at room temperature stirred 4 hours.Carry out the standard processing with dichloromethane after,, obtain 10a (39mg, 91%) by preparation of silica gel TLC (2.0% methanol in dichloromethane) purification residue:
1H NMR δ 7.43 (d, 4H, J=8.6Hz), 7.20 (d, 2H, J=8.4Hz), 6.98 (q, 2H), 6.89 (d, 2H, J=8.6Hz), 4.41 (m, 2H), 4.16 (m, 2H), 3.87 (m, 4H), 3.27 (s, 3H), 3.05 (s, 3H), 1.46 (s, 9H).Analyze (C
25H
33NO
7S) C.H.N.
Embodiment 22
Methanesulfonic acid 2-{2-[2-(4-{2-[4-(tertbutyloxycarbonyl-methyl-amino)-phenyl]-vinyl }-phenoxy group)-ethyoxyl]-ethyoxyl }-ethyl ester (10b)
Use is about the described same program of chemical compound 10a, from the 9b dichloromethane (8ml) (81mg, 0.18mmol), mesyl chloride (62mg, 0.54mmol) and triethylamine (88mg, 0.88mmol) preparation chemical compound 10b.10b(82mg，86.5％)：
1H NMR δ7.43(d，4H，J＝8.6Hz)，7.20(d，2H，J＝8.4Hz)，6.97(q，2H)，6.90(d，2H，J＝8.6Hz)，4.38(m，2H)，4.15(m，2H)，3.85(m，2H)，3.76(m，6H)，3.27(s，3H)，3.05(s，3H)，1.46(s，9H)。Analyze (C
27H
37NO
8S) C.H.N.
Embodiment 23
Methanesulfonic acid 2-(2-{2-[2-(4-{2-[4-(tertbutyloxycarbonyl-methyl-amino)-phenyl]-vinyl }-phenoxy group)-ethyoxyl]-ethyoxyl }-ethyoxyl)-ethyl ester (10c)
Use is about the described same program of chemical compound 10a, from the 9c dichloromethane (5ml) (50mg, 0.10mmol), mesyl chloride (46mg, 0.40mmol) and triethylamine (50mg, 0.50mmol) preparation chemical compound 10c.10c(56mg，96.9％)：
1H NMR δ7.43(d，4H，J＝8.6Hz)，7.20(d，2H，J＝8.4Hz)，6.97(q，2H)，6.90(d，2H，J＝8.6Hz)，4.37(m，2H)，4.16(m，2H)，3.86(m，2H)，3.76(m，10H)，3.27(s，3H)，3.06(s，3H)，1.46(s，9H)。Analyze (C
29H
41NO
9S) C.H.N.
Embodiment 24
Methanesulfonic acid 2-[2-(2-{2-[2-(4-{2-[4-(tertbutyloxycarbonyl-methyl-amino)-phenyl]-vinyl }-phenoxy group)-ethyoxyl]-ethyoxyl }-ethyoxyl]-ethyoxyl)-ethyl ester (10d)
Use is about the described same program of chemical compound 10a, from the 9d dichloromethane (5ml) (58mg, 0.11mmol), mesyl chloride (49mg, 0.43mmol) and triethylamine (54mg, 0.54mmol) preparation chemical compound 10d.10d(63mg，95％)：
1H NMRδ7.43(d，4H，J＝8.6Hz)，7.20(d，2H，J＝8.4Hz)，6.97(q，2H)，6.90(d，2H，J＝8.6Hz)，4.37(m，2H)，4.18(m，2H)，3.86(m，2H)，3.75(m，14H)，3.27(s，3H)，3.07(s，3H)，1.46(s，9H)。Analyze (C
31H
45NO
10S) C.H.N.
Embodiment 25
[4-(2-{4-[2-(2-fluoro-ethyoxyl)-ethyoxyl]-phenyl }-vinyl)-phenyl]-methyl-t-butyl carbamate (11a)
With anhydrous TBAF (people such as Cox DP, J.Org.Chem.1984; 49:3216-19) (38.5mg, (14.5mg is 0.03mmol) in the solution in anhydrous THF (3ml) 0.15mmol) to add chemical compound 10a to.Mixture was refluxed 4 hours.After being cooled to room temperature, carrying out standard with dichloromethane and handle, and, obtain chemical compound 11a (7mg, 57%) by preparation of silica gel TLC (2% methanol in dichloromethane) purification residue:
1H NMR δ 7.43 (d, 4H, J=8.6Hz), 7.20 (d, 2H, J=8.4Hz), 6.97 (q, 2H), 6.91 (d, 2H, J=8.6Hz), 4.60 (d, t, 2H, J1=47Hz, J2=4.0Hz), 4.17 (t, 2H), 3.90 (t, 3H), 3.75 (t, 1H), 3.27 (s, 3H), 1.46 (s, 9H).
Embodiment 26
4-[2-(4-{2-[2-(2-fluoro-ethyoxyl)-ethyoxyl]-ethyoxyl }-phenyl)-vinyl]-phenyl }-methyl-t-butyl carbamate (11b)
Use is about the described same program of chemical compound 11a, from the 10b among THF (10ml) (21mg, 0.04mmol) and TBAF (52mg, 0.2mmol) preparation chemical compound 11b.11b(17mg，94％)：
1H NMRδ7.43(d，4H，J＝8.6Hz)，7.20(d，2H，J＝8.4Hz)，6.97(q，2H)，6.91(d，2H，J＝8.6Hz)，4.58(d，t，2H，J1＝48Hz，J2＝4.0Hz)，4.16(t，2H)，3.85(t，3H)，3.74(t，5H)，3.26(s，3H)，1.46(s，9H)。
Embodiment 27
(4-{2-[4-(2-{2-[2-(2-fluoro-ethyoxyl)-ethyoxyl]-ethyoxyl }-ethyoxyl)-phenyl]-vinyl }-phenyl)-methyl-t-butyl carbamate (11c)
Use is about the described same program of chemical compound 11a, from the 10c among THF (5m1) (18mg, 0.03mmol) and TBAF (42mg, 0.16mmol) preparation chemical compound 11c.11c(12mg，77％)：
1H NMRδ7.43(d，4H，J＝8.6Hz)，7.20(d，2H，J＝8.4Hz)，6.97(q，2H)，6.91(d，2H，J＝8.6Hz)，4.67(t，1H)，4.55(d，t，2H，J1＝48Hz，J2＝4.0Hz)，3.85(t，3H)，3.74(t，9H)，3.27(s，3H)，1.46(s，9H)。
Embodiment 28
[4-(2-{4-[2-(2-{2-[2-(2-fluoro-ethyoxyl)-ethyoxyl]-ethyoxyl }-ethyoxyl)-ethyoxyl]-phenyl }-vinyl)-phenyl]-methyl-t-butyl carbamate (11d)
Use is about the described same program of chemical compound 11a, from the 10d among THF (5.0ml) (15mg, 0.024mmol) and TBAF (32mg, 0.12mmol) preparation chemical compound 11d.11d(11mg，84％)：
1H NMR δ7.43(d，4H，J＝8.4Hz)，7.20(d，2H，J＝8.4Hz)，6.97(q，2H)，6.90(d，2H，J＝8.6Hz)，4.55(d，t，2H，J1＝48Hz，J2＝4.0Hz)，4.15(t，2H)，3.86(t，3H)，3.72(t，13H)，3.26(s，3H)，1.46(s，9H)。
Embodiment 29
[4-(2-{4-[2-(2-fluoro-ethyoxyl)-ethyoxyl]-phenyl }-vinyl)-phenyl]-methylamine (12a)
(7.0mg is 0.017mmol) in the solution in dichloromethane (1ml) slowly to add trifluoroacetic acid (0.5ml) to chemical compound 11a.Then mixture was at room temperature stirred 1 hour.Carry out the standard processing with dichloromethane after,, obtain 12a (3mg, 56%) by preparation of silica gel TLC (1.0% methanol in dichloromethane) purification residue:
1H NMR δ 7.37 (m, 4H), 6.90 (m, 4H), 6.65 (d, 2H, J=8.4Hz), 4.60 (d, t, 2H, J1=46Hz, J2=4.0Hz), 4.17 (t, 2H), 3.90 (t, 3H), 3.76 (t, 1H), 2.88 (s, 3H).Analyze (C
19H
22FNO
2) C.H.N.
Embodiment 30
4-[2-(4-{2-[2-(2-fluoro-ethyoxyl)-ethyoxyl]-ethyoxyl }-phenyl)-vinyl]-phenyl }-methylamine (12b)
Use is about the described same program of chemical compound 12a, from the 11b trifluoroacetic acid (1ml) and dichloromethane (2ml) (17mg, 0.037mmol) preparation chemical compound 12b.12b(9mg，68％)：
1H NMR δ7.37(m，4H)，6.88(m，4H)，6.64(d，2H，J＝8.4Hz)，4.56(d，t，2H，J1＝46Hz，J2＝4.0Hz)，4.15(t，2H)，3.87(m，3H)，3.70(m，5H)，2.87(s，3H)。Analyze (C
21H
26FNO
3) C.H.N.
Embodiment 31
(4-{2-[4-(2-{2-[2-(2-fluoro-ethyoxyl)-ethyoxyl]-ethyoxyl }-ethyoxyl)-phenyl]-vinyl }-phenyl)-methylamine (12c)
Use is about the described same program of chemical compound 12a, from the 11c trifluoroacetic acid (0.5ml) and dichloromethane (1ml) (12mg, 0.024mmol) preparation chemical compound 12c.12c(7mg，73％)：
1H NMRδ7.37(m，4H)，6.89(m，4H)，6.62(d，2H，J＝8.4Hz)，4.55(d，t，2H，J1＝46Hz，J2＝4.0Hz)，4.15(t，2H)，3.86(m，3H)，3.71(m，9H)，2.87(s，3H)。Analyze (C
23H
30FNO
4) C.H.N.
Embodiment 32
[4-(2-{4-[2-(2-{2-[2-(2-fluoro-ethyoxyl)-ethyoxyl]-ethyoxyl }-ethyoxyl)-ethyoxyl]-phenyl }-vinyl)-phenyl]-methylamine (12d)
Use is about the described same program of chemical compound 12a, from the 11d trifluoroacetic acid (0.3ml) and dichloromethane (1ml) (10mg, 0.018mmol) preparation chemical compound 12d.12d(6mg，73％)：
1H NMRδ7.37(m，4H)，6.88(m，4H)，6.64(d，2H，J＝8.4Hz)，4.55(d，t，2H，J1＝46Hz，J2＝4.0Hz)，4.14(t，2H)，3.87(m，3H)，3.70(m，13H)，2.87(s，3H)。Analyze (C
25H
34FNO
5) C.H.N.
Embodiment 33
[
18F] [4-(2-{4-[2-(2-fluoro-ethyoxyl)-ethyoxyl]-phenyl }-vinyl)-phenyl]-methylamine ([
18F] 12a)
By cyclotron, use
18O (p, n)
18The F prepared in reaction [
18F] fluoride, make its as be rich in [
18O] water in aqueous solution by Sep-Pak Light QMA tube.With air-flow with the tube drying, and with 2mL Kryptofix 222 (K222)/K
2CO
3Solution (22mg K222 and 4.6mg K
2CO
3At CH
3CN/H
21.77/0.23 among the O) eluting
18The F activity.Flow down at argon, remove at 120 ℃ and desolvate.Flow down at argon, at 120 ℃ with the anhydrous CH of 1mL
3CN is with twice of residue azeotropic drying.The solution of methanesulfonates precursor 10a (4mg) in DMSO (0.2mL) added to contain drying
18In the active reaction vessel of F.Solution is heated 4min down at 120 ℃.Add water (2mL), and solution is cooled off 1min.(10% aqueous solution 0.5mL), and heats 5min once more with mixture under 120 ℃ to add HCl then.Add the NaOH aqueous solution with pH regulator to alkalescence (pH 8-9).With ethyl acetate (1mL * 2) extraction mixture, and with the organic layer drying (Na that merges
2SO
4), flow down except that desolvating in mild heat (55-60 ℃) and argon.Residue is dissolved in CH
3Among the CN, and carry out HPLC purification [Hamilton PRP-1 semi-preparative column (7.0 * 305mm, 10 μ m), CH
3CN/ Glutaric Acid Dimethyl ester buffer (5mM, pH 7) 9/1; Flow velocity 2mL/min].The retention time of 12a in this HPLC system is 8.9min, with precursor 10a (rt=12min) and hydrolysising by-product (rt=6.2min) good separation.Preparation spends 90min, and the radiochemistry yield is 20% (decay correction).Live operational analysis HPLC[Hamilton PRP-1 analytical column (4.1 * 250mm, 10 μ m), CH (Spec.Act.) in order to determine radiochemical purity and ratio
3CN/ Glutaric Acid Dimethyl ester buffer (5mM, pH 7) 9/1; Flow velocity 0.5mL/min].The retention time of 12a in this system is 10.8min, and RCP surpasses 99%.By more purified [
18F] 10 estimate than work with the UV peak intensity of the reference on-radiation chemical compound of concentration known.After preparation, be 1000-1500Ci/mmol than work (Spec.Act.).
Embodiment 34
[
18F] 4-[2-(4-{2-[2-(2-fluoro-ethyoxyl)-ethyoxyl]-ethyoxyl }-phenyl)-vinyl]-phenyl }-methylamine ([
18F] 12b)
Use similarly reaction, from 10b obtain [
18F] 12b.The radiochemistry yield is 30% (decay correction), and radiochemical purity＞99%.For above-mentioned analytical system, the HPLC retention time of 12b is 11.7min (Spec.Act.=1300-1500Ci/mmol).
Embodiment 35
[
18F] [(4-{2-[4-(2-{2-[2-(2-fluoro-ethyoxyl)-ethyoxyl]-ethyoxyl }-ethyoxyl)-phenyl]-vinyl }-phenyl)-methylamine ([
18F] 12c)
Use similarly reaction, from 10c obtain [
18F] 12c.The radiochemistry yield is 10% (decay correction), and radiochemical purity＞99%.For above-mentioned analytical system, the HPLC retention time of 12c is 11.7min (Spec.Act.=900Ci/mmol).
Embodiment 36
[
18F] [[4-(2-{4-[2-(2-{2-[2-(2-fluoro-ethyoxyl)-ethyoxyl]-ethyoxyl }-ethyoxyl)-ethyoxyl]-phenyl }-vinyl)-phenyl]-methylamine ([
18F] 12d)
Use similarly reaction, from 10b obtain [
18F] 12d.The radiochemistry yield is 20% (decay correction), and radiochemical purity＞99%.For above-mentioned analytical system, the HPLC retention time of 12d is 10.7min (Spec.Act.=1000-1500Ci/mmol).
Embodiment 37
4-amino-4 '-hydroxyl Stilbene (14a)
(11.8g, (3.0g 0.012mol) in the solution in ethanol (100mL), adds concentrated hydrochloric acid (5.0mL) then 0.062mol) to add chemical compound 13a (Frinton Lab) to stannous chloride.With the solution 3hr that refluxes, and be cooled to stirred overnight at room temperature.Add sodium hydrate aqueous solution (1N) with pH regulator to 8.5-9.After using dichloromethane to carry out the standard processing, obtain crude product 14a (2.6g ,～100%).This product is used for next step without being further purified.
1H NMR(DMSO-d
6)δ9.39(s，1H)，7.30(d，2H，J＝8.5Hz)，7.20(d，2H，J＝8.5Hz)，6.80(m，2H)，6.72(d，2H，J＝8.5Hz)，6.53(d，2H，J＝8.5Hz)，5.19(s，2H)。
Embodiment 38
4-N, N '-dimethylamino-4 '-hydroxyl Stilbene (15a)
To 14a (211mg, 1.0mmol), paraformaldehyde (300mg, 10mmol) and sodium cyanoborohydride (189mg adds acetic acid 10mL in mixture 3.0mmol)).Whole mixture at room temperature stirred spend the night, pour into then in the 100mL water.Add sodium carbonate with pH regulator to 8-9.After 5% methanol in being used in dichloromethane carries out the standard processing,, obtain 15a, be white solid (214mg, 89.5%) by silica gel column chromatography (2.5% methanol in dichloromethane) purification residue:
1H NMR δ 7.37 (m, 4H), 6.87 (s, 2H), 6.75 (m, 4H), 4.68 (s, 1H), 2.98 (s, 6H).
Embodiment 39
4-N, N '-dimethylamino-4 '-(2,2-dimethyl-[1,3] dioxane-5-ylmethoxy) Stilbene (15b)
Under blanket of nitrogen, (100mg 0.38mmol) is dissolved in the dry DMF (5.0mL) with 15a.(140mg 1.0mmol), adds 5-bromomethyl-2 then, 2-dimethyl-[1,3] dioxane 20m to add potassium carbonate in this solution
1(105mg, 0.5mmol).With mixture heated to 100 ℃ and stir and spend the night.After being cooled to room temperature, carrying out standard with dichloromethane and handle, and, obtain chemical compound 15b (100mg, 72%) by preparation of silica gel TLC (1% methanol in dichloromethane) purification residue:
1H NMR δ 7.38 (m, 4H), 6.88 (m, 4H), 6.70 (d, 2H, J=8.7Hz), 4.08 (m, 4H), 3.87 (m, 2H), 2.96 (s, 6H), 2.13 (m, 1H), 1.46 (s, 3H), 1.42 (s, 3H).Analyze (C
23H
29NO
3) C, H, N.
Embodiment 40
4-N, N '-dimethylamino-4 '-(1,3-dihydroxy-propane-2-ylmethoxy) Stilbene (15c)
(180mg 0.49mmol) is suspended in the acetone (5.0mL), and is cooled to 0 ℃ with ice bath with chemical compound 15b.In 20min, slowly add 1N HCl (5.0mL, 5.0mmol).In the interpolation process, suspension becomes limpid solution.With solution 0 ℃ of following restir half an hour, then in half an hour warm heat to room temperature.Add saturated sodium bicarbonate with pH regulator to 8.5-9.Carry out the standard processing with dichloromethane after, by preparation of silica gel TLC (5% methanol in dichloromethane) purification residue, obtain chemical compound 15c, be white solid (140mg, 87%):
1H NMR δ 7.40 (m, 4H), 6.88 (m, 4H), 6.74 (m, 2H), 4.10 (d, 2H, J=5.47Hz), 3.89 (d, 4H, J=5.28Hz), 2.98 (s, 6H), 2.22 (m, 1H).Analyze (C
20H
25NO
3) C.H.N.
Embodiment 41
4-N, N '-dimethylamino-4 '-(1-tosyl-3-hydroxyl-propane-2-ylmethoxy) Stilbene (15d)
(158mg 0.49mmol) is dissolved in the anhydrous pyridine (15mL), and is cooled to 0 ℃ with ice bath with chemical compound 15c.The interpolation toluene sulfochloride (137mg, 0.72mmol), and with solution stirring 2hr under 0 ℃.Carry out the standard processing with dichloromethane after, by preparation of silica gel TLC (5% methanol in dichloromethane) purification residue, obtain toluene monooxygenase sulfonate compound 15d, be white solid (95mg, 41%):
1H NMR δ 7.75 (d, 2H, J=8.26Hz), 7.37 (m, 4H), 7.26 (m, 2H), 6.88 (m, 2H), 6.72 (m, 4H), 4.26 (d, 2H, J=5.66Hz), 3.97 (d, 2H, J=5.96Hz), 3.79 (d, 2H, J=5.24Hz), 2.95 (s, 6H), 2.38 (m, 4H).Analyze (C
27H
31NO
5S) C, H, N.
Embodiment 42
4-N, N '-dimethylamino-4 '-(1-fluoro-3-hydroxyl-propane-2-ylmethoxy) Stilbene (15e)
(40mg 0.083mmol) is dissolved among the anhydrous THF (5.0mL) with chemical compound 15d.Under blanket of nitrogen, slowly be added on anhydrous TBAF among the anhydrous THF (1.0mL) (150mg, 0.5mmol).Then with vlil 3hr.After being cooled to room temperature, carrying out standard with dichloromethane and handle, and, obtain product 15e (17mg, 62%) by preparation of silica gel TLC (5% methanol in dichloromethane) purification residue:
1H NMR δ 7.40 (m, 4H), 6.89 (m, 4H), 6.70 (d, 2H, J=8.82Hz), 4.67 (dd, 2H, J
1=47.1Hz, J
2=5.46Hz), 4.10 (d, 2H, J=5.86Hz), 3.88 (d, 2H, J=5.24Hz), 2.97 (s, 6H), 2.40 (m, 1H), 1.76 (s, 1H).Analyze (C
20H
24FNO
2) C, H, N.
Embodiment 43
4-nitro-4 '-(2,2-dimethyl-[1,3] dioxane-5-ylmethoxy) Stilbene (13b)
Use is about the described same program of chemical compound 15b, from 13a (241mg, 1.0mmol) preparation chemical compound 13b.13b(260mg，70％)：
1H NMRδ8.19(d，2H，J＝8.80Hz)，7.49(m，4H)，7.07(m，2H)，6.90(d，2H，J＝8.80Hz)，4.12(m，4H)，3.89(d，2H)，2.10(m，1H)，1.48(s，3H)，1.43(s，3H)。Analytical calculation (C
21H
23NO
5) C, H, N.
Embodiment 44
4-nitro-4 '-(1,3-dihydroxy-propane-2-ylmethoxy) Stilbene (13c)
Use is about the described same program of chemical compound 15c, from 13b (260mg, 0.7mmol) preparation chemical compound 13c.13c(190mg，82％)：
1H NMR(CD
3OD)δ8.19(d，2H，J＝8.80Hz)，7.72(d，2H，J＝8.80Hz)，7.55(d，2H，J＝8.70Hz)，7.24(q，2H)，6.96(d，2H，J＝8.70Hz)，4.09(d，2H，J＝5.78Hz)，3.74(d，4H，J＝5.94Hz)，2.14(m，1H)。Analyze (C
18H
19NO
5) C, H, N.
4-nitro-4 '-(1-tosyl-3-hydroxyl-propane-2-ylmethoxy) Stilbene (13d)
Use is about the described same program of chemical compound 15d, from 13c (80mg, 0.24mmol) preparation chemical compound 13d.13d(66mg，56％)：
1H NMR δ8.18(d，2H，J＝8.82Hz)，7.77(d，2H，J＝8.32Hz)，7.58(d，2H，J＝8.82Hz)，7.45(d，2H，J＝8.73Hz)，7.28(d，2H，J＝8.18Hz)，7.09(q，2H)，6.81(d，2H，J＝8.73Hz)，4.27(d，2H，J＝5.70Hz)，4.01(m，2H)，3.80(d，2H，J＝5.61Hz)，2.40(m，4H)，2.02(s，1H)。Analyze (C
25H
25NO
7S) C, H, N.
Embodiment 46
4-nitro-4 '-(1-fluoro-3-hydroxyl-propane-2-ylmethoxy) Stilbene (13e)
Use is about the described same program of chemical compound 15e, from 13d (33mg, 0.069mmol) preparation chemical compound 13e.13e(20mg，88％)：
1H NMRδ8.19(d，2H，J＝8.83Hz)，7.58(d，2H，J＝8.84Hz)，7.48(d，2H，J＝8.74Hz)，7.10(q，2H)，6.94(d，2H，J＝8.68Hz)，4.69(dd，2H，J
1＝47.1Hz，J
2＝5.36Hz)，4.15(d，2H，J＝5.89Hz)，3.90(d，2H，J＝5.43Hz)，2.43(m，1H)，1.74(s，1H)。Analyze (C
18H
18FNO
4) C, H, N.
Embodiment 47
4-amino-4 '-(1-fluoro-3-hydroxyl-propane-2-ylmethoxy) Stilbene (14e)
Use is about the described same program of chemical compound 14a, from 13e (37mg, 0.11mmol) preparation chemical compound 14e.14e(24mg，71％)：
1H NMRδ7.35(m，4H)，6.90(m，4H)，6.66(d，2H，J＝8.54Hz)，4.69(dd，2H，J
1＝47.1Hz，J
2＝5.46Hz)，4.12(d，2H，J＝5.84Hz)，3.90(d，2H，J＝5.56Hz)，3.70(s，2H)，2.39(m，1H)，1.71(s，1H)。Analyze (C
18H
20FNO
2) C, H, N.
Embodiment 48
4-N-methyl-amino-4 '-(1-fluoro-3-hydroxyl-propane-2-ylmethoxy) Stilbene (16e)
Under blanket of nitrogen, with Feldalat NM (22mg, 0.4mmol) add to chemical compound 14e (24mg, 0.08mmol) in the suspension in methanol (6mL), add then paraformaldehyde (12mg, 0.4mmol).With vlil 2hr, and be cooled to 0 ℃ with ice bath.The portion-wise addition sodium borohydride (15mg, 0.4mmol).With the reactant mixture 1hr that refluxes once more, and be poured on the trash ice.Carry out the standard processing with dichloromethane after,, obtain product 16e (23mg, 92%) by preparation of silica gel TLC (4.5% methanol in dichloromethane) purification residue:
1H NMR δ 7.37 (m, 4H), 6.87 (m, 4H), 6.59 (d, 2H, J=8.56Hz), 4.69 (d, d, 2H, J
1=47.1Hz, J
2=5.44Hz), 4.12 (d, 2H, J=5.86Hz), 4.00 (s, 1H), 3.89, (d, 2H, J=5.52Hz), 2.86 (s, 3H), 2.41 (m, 1H), 1.75 (s, 1H).Analyze (C
19H
22FNO
2) C, H, N.
Embodiment 49
4-N-methyl-amino-4 '-hydroxyl Stilbene (16a)
Use is about the described same program of chemical compound 16e, from 14a (105mg, 0.5mmol) preparation chemical compound 16a.16a(100mg，89％)：
1H NMRδ7.34(m，4H)，6.86(s，2H)，6.79(d，2H，J＝8.58Hz)，6.60(d，2H，J＝8.58Hz)，2.85(s，3H)。
Embodiment 50
Be used to prepare the conventional microwave procedure of 12 (n=6,8) Stilbene
Microwave is synthetic: with 16a, alkylating agent (1eq.), K
2CO
3(3eq.) mixture in DMF (1mL/0.05mmol SB-13) is put into the sealing test tube, and heats in microwave oven under the following conditions: 180 ℃, and 10min, high absorption level.Remove then and desolvate PTLC[CH
2Cl
2-MeOH (97: 3) is as developing solvent] provide required product (yield: 42-60% depends on used alkylating agent).
Embodiment 51
(4-(2-(4-(2-(2-(2-(2-(2-(2-fluoro-ethyoxyl)-ethyoxyl)-ethyoxyl)-ethyoxyl)-ethyoxyl)-ethyoxyl)-phenyl)-vinyl)-phenyl)-methylamine (12, n=6):
Yield=60%.
1H NMR (200MHz, CDCl
3): δ 7.2-7.5 (4H, m), 6.8-7.0 (4H, m), 6.59 (2H, d, J=8.4Hz), 4.55 (2H, d, t, J
1=46Hz, J
2=4.0Hz), 4.14 (2H, t), 3.8-3.9 (3H, m), 3,6-3.8 (17H, m), 2.86 (3H, s) .HRMS (EI) m/z:[C
27H
38FNO
8]
+Value of calculation 491.2683, measured value 491.2667.
Embodiment 52
(4-(2-(4-(2-(2-(2-(2-(2-(2-(2-(2-fluoro-ethyoxyl)-ethyoxyl)-ethyoxyl)-ethyoxyl)-ethyoxyl)-ethyoxyl)-ethyoxyl)-ethyoxyl)-phenyl)-vinyl)-phenyl)-methylamine (12, n=8):
Yield: 42%.
1H NMR (200MHz, CDCl
3): δ 7.3-7.5 (4H, m), 6.8-7.0 (4H, m), 6.73 (2H, d, J=8.2Hz), 4.55 (2H, d, t, J
1=46Hz, J
2=4.0Hz), 4.14 (2H, t), 3.8-3.9 (3H, m), 3.5-3.8 (25H, m), 2.89 (3H, s) .HRMS (EI) m/z:[C
31H
46FNO
8]
+Value of calculation 579.3207, measured value 579.3192.
Embodiment 53
The preparation of brain tissue homogenate
In obduction, obtain to dissect a body cerebral tissue, and determine that by working standard the neuro pathology diagnoses (NIA-Reagan Institute Consensus Group, 1997) from AD patient.Then in phosphate buffered saline (PBS) (PBS, pH 7.4),, prepare homogenate (electric driven glass homogenizer is set to 6 grades of 30sec) by grey matter from AD patient's incision with the concentration of about 100mg wet tissue/ml.Homogenate is divided into the 1ml part, and does not lose binding signal-70 ℃ of following storages 6-12 month.
Embodiment 54
In conjunction with research
As former report, than live for 2200Ci/mmol, radiochemical purity greater than 95% [
125I] IMPY uses standard iodine detin (iododestannylation) prepared in reaction, and the small-sized column purification of C-4 by simplifying (people such as Kung M-P, Euro.J.Nucl.Med.Mol.Imag.2004; 31:1136-45).Carrying out combination in 12 * 75mm borosilicate glass test tube measures.Reactant mixture contains 50 μ l brain homogenates (20-50 μ g), 50 μ l[
125I] IMPY (0.04-0.06nM is diluted among the PBS) and 50 μ l inhibitor (in the PBS that contains 0.1% bovine serum albumin BSA by the 10-5-10-10M serial dilution), final volume is 1ml.In identical mensuration test tube, in the presence of IMPY (600nM), the definition non-specific binding.Mixture at 37 ℃ of following incubation 2hr, and at room temperature by Whatman GF/B filter vacuum filtration, is used Brandel M-24R cell harvestor, and separating and combining and free radioactivity are used PBS 2 * 3ml washing then.In gamma counter (Packard5000), the counting efficiency with 70% is measured and is contained combination
125The radioactive composition of the filter of I part.Under condition determination, the specificity bound fraction accounts for gross activity less than 15%.Use EBDA to carry out nonlinear regression analysis, by its calculating K to suppressing experimental result
iValue.The result provides in table 1.
Table 1
| K i±SEM (nM) | K i±SEM (nM) X＝OH | K i±SEM (nM) X＝F | |||
| IMPY | 1.4±0.4 * | 3a，n＝2 | 5.2±0.4 | 12a，n＝2 | 2.9±0.2 |
| SB-13 | 1.2±0.7 * | 3b，n＝3 | 2.8±0.2 | 12b，n＝3 | 6.7±0.3 |
| PIB | 2.8±0.5 * | 3c，n＝4 | 4.6±0.2 | 12c，n＝4 | 4.4±0.8 |
| FMAPO | 5.0±1.2 * | 3d，n＝5 | 5.2±0.2 | 12d，n＝5 | 6.0±0.8 |
Each numerical value independently obtains the repeated measure from three times
Fluoridize PEG Stilbene (12a-d) and show fabulous binding affinity (K
i=2.9-6.7nM); And corresponding hydroxyl replacement analog (3a-d) also shows very high binding affinity (K
i=2.8-5.2nM) (table 1).This serial labelled reagent [
18F] lipotropy of 12a-d is in the suitable scope (for n=2-5, the logP value is respectively 2.52,2.41,2.05 and 2.28).The PEG group can be adjusted the distance between molecular size and fluorine atom and the Stilbene core texture, and does not influence A β speckle specificity binding affinity.
Embodiment 55
The thin film autoradiography
By brain being chilled in the powdered dry ice and being cut into 20 microns slabs and obtaining brain section from AD experimenter.At room temperature, will cut into slices with [
18F] tracer (200000-250000cpm/200 μ l) incubation 1hr together.Then section is immersed in the saturated Li among the 40%EtOH
2CO
3In (twice two minutes washing), and, use water rinse 30sec then with 40%EtOH washing (once washing in two minutes).After drying, make
18The section contact Kodak MR thin film of F labelling spends the night.
Embodiment 56
With [
18F] 12b and [
18F] 12d body internal labeling speckle
Use is carried out interior evaluating by double transgenic APP/PS1 or the single commentaries on classics group APP2576 mice that AstraZeneca provides.After with 1% isoflurane anesthesia, by tail vein injection 250-300 μ Ci in 200 μ l 0.1%BSA solution [
18F] 12b or [
18F] 12d.Make animal recover 60min, sacrificed by decapitation then.Take out brain immediately, and be chilled in the powdered dry ice.Downcut 20 microns section, and make it to contact Kodak MR thin film and spend the night.Obtain the thin film autoradiography image that exsomatizes like this.
Embodiment 57
Organ in normal mouse distributes
Under isoflurane anesthesia, will contain [
18F] 0.15mL 0.1% bovine serum albumin solution of tracer (5-10 μ Ci) is injected directly in the tail vein of ICR mice (22-25g, male).120min after injection puts to death mice (each time point n=3) by the cervical region dislocation.Take out interested organ and weigh, measure the radioactivity of radioactive composition with automatic gamma counter.Calculate the percent dose of each organ by the injected material aliquot of relatively tissue counts and suitably dilution.Suppose that blood accounts for 7% of TBW, calculate the gross activity of blood.Calculate the % dosage/g of sample by the comparative sample counting and the counting of dilution predose.
Table 2. intravenous injection in 0.1%BSA [
18F] behind the 12a-d, the bio distribution in the ICR mice (% dosage/g, the meansigma methods of 3 mices ± SD)
2A：12b
| Organ | 2min | 30min | 1hr | 2hr |
| Blood cardiac muscle lung kidney spleen liver skin brain bone | 3.14±0.69 6.25±1.79 1.06±0.39 6.87±1.36 10.95±2.63 4.57±1.07 21.5±4.44 1.18±0.23 7.77±1.70 1.43±0.09 | 2.80±0.44 2.18±0.32 1.78±0.34 3.20±0.54 6.31±0.58 1.81±0.24 13.0±0.72 2.36±0.29 1.59±0.22 1.22±0.17 | 2.51±0.57 2.13±0.50 1.45±0.26 3.04±0.96 5.68±1.24 1.48±0.91 13.2±2.53 2.07±0.40 1.61±0.39 1.77±0.64 | 2.03±0.025 1.53±0.08 0.90±0.06 2.42±0.36 2.05±1.58 1.54±0.17 7.20±0.59 1.23±0.16 1.39±0.08 2.74±0.08 |
2B：12a、12c、12d
| 12a | 2min | 30min | 1hr | 2hr |
| Blood brain bone | 2.64±0.55 8.14±2.03 1.89±0.25 | 2.42±0.27 3.00±0.16 1.40±0.11 | 2.04±0.16 2.60±0.22 1.71±0.23 | 2.77±0.63 2.14±0.06 2.gg±0.07 |
| 12c | 2min | 30min | 1hr | 2hr |
| Blood brain bone | 3.22±0.20 6.59±0.19 2.31±0.12 | 1.88±0.08 1.27±0.03 1.00±0.02 | 1.81±0.4816 1.20±0.10 0.98±0.27 | 1.60±0.12 1.21±0.06 1.50±0.05 |
| 12d | 2min | 30min | 1hr | 2hr |
| Blood brain bone | 4.99±0.38 7.30±1.05 2.24±0.21 | 4.66±0.06 2.43±0.03 2.29±0.21 | 2.89±0.11 1.77±0.11 1.66±0.01 | 2.59±0.18 1.62±0.03 2.35±0.27 |
Comprise [
18F] 12a-d is at the interior complete blood brain barrier of radioactive compound infiltration, and 2min after intravenous injection shows fabulous brain capture (6.6-8.1% dosage/g brain) (table 2A﹠amp in normal mouse; B).Owing to use normal mouse to carry out the bio distribution experiment, do not have A β speckle in the brain in these young mice so be expected at; Therefore, 60min after intravenous injection, labelled reagent [
18F] 12a-d removing (1.2-2.6% dosage/g brain) from brain rapidly.For A β speckle targeted contrast agents, initial picked-up of the height in normal mouse brain (not having A β speckle in the brain) and rapid the removing are highly desirable character.In the table 2 report value with about [
11C] PIB and [
11C] value (people such as Mathis CA, the Curr.Pharm.Des.2004 of SB-13 report; 10:1469-92; People such as Ono M, Nucl.Med.Biol.2003; People such as MathisCA are J.Med.Chem.2003) suitable.
Shown among the table 2A [
18F] the detailed bio distribution of 12b.As if 2min after injection, chemical compound is ingested in liver, kidney, lung and muscle, reflects that systemic blood inculcates pattern.The picked-up of bone when 120min is that high (2.74% dosage/g), prompting may be deposited defluorinate in vivo.But free fluorine is not absorbed by cerebral tissue; Therefore, the bone picked-up is relatively low.Other PEG stilbene derivative 12a, c, d show similar bio distribution pattern (table 2B).
Embodiment 58
Partition coefficient
By will [
18F] tracer mixes in test tube with each 3g 1-capryl alcohol and buffer (0.1M phosphate, pH 7.4) and measures partition coefficient.With test tube vortex 3min at room temperature, centrifugal then 5min.Counting is from two parts of samples of weighing (each 0.5g) of 1-capryl alcohol and buffering liquid layer in scintillation well counter.Recently determine partition coefficient by the cpm/g that calculates 1-capryl alcohol and buffer.Will be from the sample reallocation of 1-capryl alcohol layer, until obtaining stable partition coefficient value (being generally the 3rd time or the 4th distribution).Measure and carry out in triplicate, and triplicate.
Those of ordinary skills will appreciate that, under the situation of the scope that does not influence the present invention or its any embodiment, can implement the present invention in the extensive and equivalency range of condition, preparation and other parameter.All patents, patent application and the publication that this paper quotes all is incorporated herein by reference in full.
Claims (37)
1. the chemical compound of formula I or acceptable salt of its pharmacy or prodrug:
Wherein:
R
1Be selected from:
A.NR
aR
b, R wherein
aAnd R
bBe hydrogen, C independently
1-4Alkyl or (CH
2)
d 18F, and d is 1 to 4 integer,
B. hydroxyl,
C.C
1-4Alkoxyl,
D. hydroxyl (C
1-4) alkyl,
E. halogen,
F. cyano group,
G. hydrogen,
H. nitro,
I. (C
1-C
4) alkyl,
J. halo (C
1-C
4) alkyl and
K. formoxyl;
R
1' be selected from:
a.
123I、
125I、
131I、
18F、
76Br，
B. hydrogen,
C.
18F (C
1-4) alkyl,
D.[
18F (C
1-4) alkyl] amino,
E.[
18F (C
1-C
4) alkyl] alkyl amino,
F.
18F (C
1-C
4) alkoxyl;
R
2Be selected from:
I. hydroxyl, C
1-4Alkoxyl, (C
1-C
4)-alkyl oxo (C
1-C
4) alkoxyl, (C
1-C
4)-alkyl oxo (C
1-C
4)-alkyl oxo (C
1-C
4) alkoxyl, (C
1-C
4)-alkyl oxo (C
1-C
4)-alkyl oxo (C
1-C
4)-alkyl oxo (C
1-C
4) alkoxyl, carboxyl (C
1-C
4) alkyl, halo (C
1-C
4) alkoxyl, halo (C
1-C
4)-alkyl oxo (C
1-C
4) alkoxyl, halo (C
1-C
4) alkyl oxo (C
1-C
4) alkyl oxo (C
1-C
4)-alkoxyl, halo (C
1-C
4) alkyl oxo (C
1-C
4) alkyl oxo (C
1-C
4) alkyl oxo (C
1-C
4) alkoxyl, halo (C
1-C
4) alkyl, NR
6R
6', phenyl (C
1-C
4) alkyl,
18F (C
1-C
4) alkoxyl,
18F (C
1-C
4) alkyl oxo (C
1-C
4) alkoxyl,
18F (C
1-C
4) alkyl oxo (C
1-C
4) alkyl oxo (C
1-C
4) alkoxyl,
18F (C
1-C
4) alkyl oxo (C
1-C
4) alkyl oxo (C
1-C
4) alkyl oxo (C
1-C
4) alkoxyl,
18F (C
1-C
4) alkyl,
R wherein
6And R
6' be independently selected from hydrogen, hydroxyl (C
1-C
4) alkyl and C
1-C
4Alkyl;
Wherein q is 1 to 10 integer; Z is selected from
18F,
18The benzoxy that F replaces,
18(the C that F replaces
1-4) alkoxyl,
18The benzyloxy that F replaces, optionally be
18The F-phenoxy group,
18Phenyl (the C that F replaces
1-4) alkyl,
18The aryloxy group that F replaces and
18The C that F replaces
6-10Aryl, optional be
18The F-phenyl; And R
30, R
31, R
32And R
33Be selected from hydrogen, hydroxyl, C independently of one another
1-4Alkoxyl, C
1-4Alkyl and hydroxyl (C
1-4) alkyl;
Wherein Z, R
30, R
31, R
32And R
33As mentioned above;
Wherein Y is selected from
18F,
18The benzoxy that F replaces,
18Phenyl (the C that F replaces
1-4) alkyl,
18The aryloxy group that F replaces, optionally be
18The F-phenoxy group and
18The C that F replaces
6-10Aryl, optional be
18The F-phenyl;
U be selected from hydrogen, hydroxyl,
18F,
18The benzoxy that F replaces,
18Phenyl (the C that F replaces
1-4) alkyl,
18The aryloxy group that F replaces, optionally be
18The F-phenoxy group and
18The C that F replaces
6-10Aryl, optional be
18The F-phenyl; And
R
34, R
35, R
36, R
37, R
38, R
39And R
40Be selected from hydrogen, hydroxyl, C independently of one another
1-4Alkoxyl, C
1-4Alkyl and hydroxyl (C
1-4) alkyl; And
R
7And R
8Be selected from halogen, hydrogen, hydroxyl, amino, methylamino, dimethylamino, C independently of one another
1-4Alkoxyl, C
1-4Alkyl and hydroxyl (C
1-4) alkyl, wherein R
7And R
8In at least one is a halogen.
2. the chemical compound of claim 1, wherein R
1' be hydrogen, and R
1Be NR
aR
b, R wherein
aAnd R
bBe hydrogen or C independently
1-4Alkyl.
3. the chemical compound of claim 2, wherein R
7And R
8Be hydrogen or fluorine, wherein R
7And R
8In at least one is a fluorine.
4. the chemical compound of claim 2, wherein R
2For
Wherein Z, R
30, R
31, R
32And R
33As mentioned above.
5. the chemical compound of claim 4, wherein q is 2 to 5 integer.
6. the chemical compound of claim 5, wherein R
30, R
31, R
32And R
33The hydrogen of respectively doing for oneself.
7. the chemical compound of claim 6, wherein q is 3 to 4 integer.
8. the chemical compound of claim 7, wherein Z is
18F.
9. the chemical compound of claim 8, it has following formula:
R wherein
7And R
8In one be hydrogen, and another is a halogen.
10. the chemical compound of claim 8, it has following formula:
R wherein
7And R
8In one be hydrogen, and another is a halogen.
11. the chemical compound of claim 2, wherein R
2For
Wherein Z, R
30, R
31, R
32And R
33As mentioned above.
12. the chemical compound of claim 11, wherein Z is
18F.
13. the chemical compound of claim 12, wherein R
30, R
31, R
32And R
33The hydrogen of respectively doing for oneself.
14. the chemical compound of claim 2, wherein R
2For
Wherein U is a hydroxyl.
15. the chemical compound of claim 14, wherein R
34, R
35, R
36, R
37, R
38, R
39And R
40The hydrogen of respectively doing for oneself.
16. the chemical compound of claim 15, it has following structure:
R wherein
7And R
8In one be hydrogen, and another is a halogen.
17. the chemical compound of formula II,
Wherein:
R
1Be selected from:
A.NR
aR
b, R wherein
aAnd R
bBe hydrogen, C independently
1-4Alkyl, (CH
2)
dX, wherein X is
18F, and d is 1 to 4 integer, perhaps R
aAnd R
bBe oxygen, form nitro,
B. hydroxyl,
C.C
1-4Alkoxyl and
D. hydroxyl (C
1-C
4) alkyl;
R
2Be selected from:
Wherein q is 2 to 10 integer; Z is selected from
18F,
18The benzoxy that F replaces,
18(the C that F replaces
1-4) alkoxyl,
18The benzyloxy that F replaces,
18Phenyl (the C that F replaces
1-4) alkyl,
18The aryloxy group that F replaces and
18The C that F replaces
6-10Aryl; And R
30, R
31, R
32And R
33Be selected from hydrogen, hydroxyl, C independently of one another
1-4Alkoxyl, C
1-4Alkyl and hydroxyl (C
1-4) alkyl;
Wherein Z, R
30, R
31, R
32And R
33As mentioned above; With
Wherein Y is selected from
18F,
18The benzoxy that F replaces,
18Phenyl (the C that F replaces
1-4) alkyl,
18The aryloxy group that F replaces and
18The C that F replaces
6-10Aryl;
U be selected from hydrogen, hydroxyl,
18F,
18The benzoxy that F replaces,
18Phenyl (the C that F replaces
1-4) alkyl,
18The aryloxy group that F replaces and
18The C that F replaces
6-10Aryl; And
R
34, R
35, R
36, R
37, R
38, R
39And R
40Be selected from independently of one another hydrogen,
18F, hydroxyl, C
1-4Alkoxyl, C
1-4Alkyl and hydroxyl (C
1-4) alkyl; And
R
7And R
8Be selected from hydrogen, hydroxyl, amino, methylamino, dimethylamino, C independently of one another
1-4Alkoxyl, C
1-4Alkyl and hydroxyl (C
1-4) alkyl.
18. the chemical compound of claim 17, wherein R
1Be NR
aR
b, R wherein
aAnd R
bBe hydrogen or C independently
1-4Alkyl.
19. the chemical compound of claim 18, wherein R
2For
Wherein Z, R
30, R
31, R
32And R
33As mentioned above.
20. the chemical compound of claim 19, wherein q is 2 to 5 integer.
21. the chemical compound of claim 20, wherein R
7And R
8The hydrogen of respectively doing for oneself.
22. the chemical compound of claim 21, wherein R
30, R
31, R
32And R
33The hydrogen of respectively doing for oneself.
23. the chemical compound of claim 22, it has following formula:
24. the chemical compound of claim 22, it has following formula:
25. the chemical compound of claim 18, wherein R
2For
Wherein Z, R
30, R
31, R
32And R
33As mentioned above.
26. the chemical compound of claim 25, wherein Z is
18F.
27. the chemical compound of claim 26, wherein R
7And R
8The hydrogen of respectively doing for oneself.
28. the chemical compound of claim 27, wherein R
30, R
31, R
32And R
33The hydrogen of respectively doing for oneself.
29. the chemical compound of claim 18, wherein R
2For
Wherein U is a hydroxyl.
30. the chemical compound of claim 29, wherein R
34, R
35, R
36, R
37, R
38, R
39And R
40The hydrogen of respectively doing for oneself.
31. the chemical compound of claim 30, it has following structure:
32. the chemical compound of formula III:
Wherein
N is 1 to 4 integer;
R
7And R
8Be selected from hydrogen, hydroxyl, amino, methylamino, dimethylamino, C independently of one another
1-4Alkoxyl, C
1-4Alkyl and hydroxyl (C
1-4) alkyl; And
R
41Be selected from hydroxyl and NR
aR
b, R wherein
aAnd R
bBe hydrogen, C independently
1-4Alkyl, perhaps R
aAnd R
bBe oxygen, form nitro.
33. the chemical compound of claim 32, wherein n is 1, and R
41Be selected from hydroxyl, methylamino and dimethylamino.
34. pharmaceutical composition, it comprises claim 1,17 or 32 chemical compound.
35. be used for the sedimental diagnosis composition of imaging amyloid, it comprises claim 1,17 or 32 radio-labelled compound.
36. the formation method of amyloid beta deposition thing, it comprises:
A. but the diagnosis composition of the claim 35 of detection limit is introduced in the mammal;
B. giving time enough associates described labelled compound and amyloid beta deposition thing; With
C. detect and the associating described labelled compound of one or more amyloid beta deposition things.
37. suppress the accumulative method of amyloid plaque in the mammal, it comprises that administration effectively suppresses the compositions of the claim 34 of the accumulative amount of amyloid plaque.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US63669604P | 2004-12-17 | 2004-12-17 | |
| US60/636,696 | 2004-12-17 | ||
| US68639505P | 2005-06-02 | 2005-06-02 | |
| US60/686,395 | 2005-06-02 | ||
| PCT/US2005/045682 WO2006066104A2 (en) | 2004-12-17 | 2005-12-19 | Stilbene derivatives and their use for binding and imaging amyloid plaques |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101123995A true CN101123995A (en) | 2008-02-13 |
| CN101123995B CN101123995B (en) | 2011-11-16 |
Family
ID=39085994
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
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| Country | Link |
|---|---|
| CN (1) | CN101123995B (en) |
| CR (1) | CR9206A (en) |
| UA (1) | UA91996C2 (en) |
| ZA (1) | ZA200705104B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102471177A (en) * | 2009-07-10 | 2012-05-23 | 拜耳医药股份有限公司 | Usage of low to medium-pressure liquid chromatography for the purification of radiotracers |
| CN102762229A (en) * | 2009-12-23 | 2012-10-31 | 皮拉马影像股份公司 | Formulations suitable for pet imaging with hydrophobic pet agents |
| CN115536580A (en) * | 2017-05-31 | 2022-12-30 | 五一一制药股份有限公司 | Deuterium substituted Positron Emission Tomography (PET) imaging agents and their pharmacological use |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DD231432A1 (en) * | 1984-11-01 | 1985-12-24 | Univ Leipzig | MATERIAL FOR SILVER-FREE IMAGE RECORDING |
-
2005
- 2005-12-19 UA UAA200708065A patent/UA91996C2/en unknown
- 2005-12-19 CN CN2005800484422A patent/CN101123995B/en active Active
-
2007
- 2007-06-15 ZA ZA200705104A patent/ZA200705104B/en unknown
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102471177A (en) * | 2009-07-10 | 2012-05-23 | 拜耳医药股份有限公司 | Usage of low to medium-pressure liquid chromatography for the purification of radiotracers |
| US8968701B2 (en) | 2009-07-10 | 2015-03-03 | Piramal Imaging Sa | Usage of low to medium-pressure liquid chromatography for the purification of radiotracers |
| CN102762229A (en) * | 2009-12-23 | 2012-10-31 | 皮拉马影像股份公司 | Formulations suitable for pet imaging with hydrophobic pet agents |
| CN102762229B (en) * | 2009-12-23 | 2014-11-12 | 皮拉马影像股份公司 | Formulations suitable for pet imaging with hydrophobic pet agents |
| CN102762229B9 (en) * | 2009-12-23 | 2020-12-01 | 皮拉马影像股份公司 | Formulations suitable for PET imaging with hydrophobic PET agents |
| CN115536580A (en) * | 2017-05-31 | 2022-12-30 | 五一一制药股份有限公司 | Deuterium substituted Positron Emission Tomography (PET) imaging agents and their pharmacological use |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200705104B (en) | 2008-09-25 |
| UA91996C2 (en) | 2010-09-27 |
| CN101123995B (en) | 2011-11-16 |
| CR9206A (en) | 2009-12-30 |
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