CN101316615A - Bifunctional metal chelating conjugates - Google Patents
Bifunctional metal chelating conjugates Download PDFInfo
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- CN101316615A CN101316615A CNA2006800448365A CN200680044836A CN101316615A CN 101316615 A CN101316615 A CN 101316615A CN A2006800448365 A CNA2006800448365 A CN A2006800448365A CN 200680044836 A CN200680044836 A CN 200680044836A CN 101316615 A CN101316615 A CN 101316615A
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Abstract
The present invention is directed to metal chelating conjugates for use as metallopharmaceutical diagnostics or therapeutic agents. Specifically, conjugates of the present invention include a carrier, a metal coordinating moiety, and a urea linkage chemically linking the metal coordinating moiety to the carrier. The carrier is generally utilized for targeting the conjugate to a biological tissue or organ.
Description
Background technology
Relate generally to of the present invention is as the metal chelating conjugates (conjugate) of metal pharmacodiagnosis or therapeutic agent.
Find that metal pharmacodiagnosis and therapeutic agent just more and more are more widely used in biological and medical research and in diagnosis and Therapeutic Method.Usually, these reagent contain radiosiotope or paramagnetic metal, and it is positioned in selected specific organ, tissue or the framing structure when importing the experimenter.When the purpose of operation is in order to diagnose, can carry out imaging by various means, with distribution situation in the body of describing radiosiotope or paramagnetic metal.The radiosiotope that is detected or the distribution of paramagnetic metal and corresponding relative intensity are not only represented the space that occupied by target tissue, and expression receptor, antigen, distortion, pathological conditions and/or etc. existence.When the purpose of program was treatment, described reagent typically contained radiosiotope, and described radioactivity reagent gives radiation dose to local place.
Depend on target organ or tissue and required diagnosis or the treatment procedure be concerned about, can use a series of metal pharmaceutical agent.A kind of common form is a kind of conjugate, and it comprises radioactivity or paramagnetic metal, is used for the support agent and the base that is connected that chemically described metal and described carrier is being coupled together at the organ or tissue position that the conjugate targeting is specific.In these conjugates, described metal typical ground is relevant with conjugate, exists with the form of co-ordination complex, and more typically the form with the chelate of macrocyclic compound exists.For example referring to the U.S. Patent number 6,916,460 of Liu.
At U.S. Patent number 5,435, in 990, people such as Cheng have disclosed functionalized macro ring polyaminocarboxylic acid ester chelating agen, and itself and rare earth ion coordination are to be used for the treatment of and/or the diagnosing tumour method.People such as Cheng are connected base connection with support agent by thiourea with their macrocyclic chelants, and under their situation, described support agent is antibody or antibody fragment.Yet under the reaction condition that they form, thiourea trends towards oxygen is exchanged into sulfur, has covered the complete molecular forms of product conjugate thus.Thiourea connects the bonded risk of tissue non-specific that also may cause except that specified target is marked with, and it will cause unfriendly that release of radiation dosage is to inappropriate position.
At U.S. Patent number 6,143, in 274, people such as Tweedle have disclosed a kind of paramagnetic ion of lanthanide series and unionized complex of macrocyclic chelants of using mammalian tissues have been carried out imaging method.Yet the unionized complex is than anion complex more unsettled (that is, described anion complex trends towards showing stronger electrostatic interaction between cationic metal and anion ligand).
Summary of the invention
Some aspects of the present invention provide the conjugate that uses in diagnosis and treatment procedure.Advantageously, conjugate of the present invention can or be treated in interested certain organs, tissue or the framing structure and accumulate in diagnosis, reduced the risk with non-target tissue's non-specific binding like this, and if necessary, made the specific disease disease of described conjugate targeting thus.
On the one hand, the present invention relates to a kind of conjugate, it comprises metal coordinating moiety (metalcoordinating moiety) and one or more carrier, and described carrier is for conjugate target biology tissue or organ.In addition, described conjugate comprises the connection base, and it comprises that the urea that chemically metal coordinating moiety is connected with carrier connects.In some embodiments, metal (for example radioactivity or paramagnetic metal) can be by the metal coordinating moiety complexation of conjugate.
Another aspect of the present invention relates to a kind of diagnosis or Therapeutic Method.In this method, will be the conjugate administration experimenter (for example patient) of this open type.
Of the present inventionly relate to a kind of test kit that is used to prepare metal medicine (metallopharmaceutical) in addition on the other hand.Described test kit is included in the conjugate of this open type.
Of the present inventionly relate to a kind of test kit in addition on the other hand, it comprises protected metal coordinating moiety, deprotection acid, buffer agent and the radioactive metal solution with active urea.
Others of the present invention are significantly and to a certain extent to point out by following to a certain extent.
The detailed description of various embodiments
The invention provides the conjugate that can form co-ordination complex with metal fast, it is used for diagnosis or therapeutic metal radiopharmaceutical or magnetic resonance imaging contrast.These conjugates can be used as bifunctional chelants (bifunctional chelator), and (BFC ' s) is used to connect metal ion and bio-orientation carrier, be sometimes referred to as biomolecule, its in vivo with composition or the receptors bind expressed types of organization, organ or other biology.By nuclear magnetic resonance or scintigraphy, target specificity of the present invention the present invention is used to diagnose the illness or is used for the treatment of disease by general radiotherapy.
Usually, conjugate of the present invention comprises one or more bio-orientation carriers and passes through the covalently bound directly or indirectly metal coordinating moiety of urea part with it.Described urea part can directly be connected with the bio-orientation carrier, or is connected with the bio-orientation carrier by a series of atoms indirectly.Similarly and independently, described urea part can also directly be connected with metal coordinating moiety, or is connected with metal coordinating moiety by a series of atoms indirectly.Schematically, the conjugate that comprises bio-orientation carrier, urea part and metal coordinating moiety of the present invention is corresponding to following formula:
Formula A
Wherein
S
1And S
2Be base at interval, each be independently key or a series of atom and
Z
1And Z
2Be hydrogen, aryl, C independently
1-7Alkyl, C
1-7Hydroxyalkyl or C
1-7Alkoxyalkyl.
In combination, described sequence-S
1-N (Z
1) C (O) N (Z
2) S
2-can be called connection base, covalently bound bio-orientation carrier and metal coordinating moiety.Consider this mode, described connection base comprises urea part and the basic S in interval
1And S
2, each interval base is key or a series of atom independently, described key or a series of atom connect the urea part respectively to metal coordinating moiety or one or more bio-orientation carrier.Perhaps, yet, at interval base separately or both can be considered to the independent and independent component of conjugate, or be respectively the member of metal coordinating moiety and bio-orientation carrier.For example, under the situation that does not break away from spirit of the present invention, S
1Can be considered to a part and/or the S of metal coordinating moiety
2Can be considered to the part of bio-orientation carrier.
Though formula A has only described one bio-orientation carrier, can consider, conjugate can comprise a plurality of carriers.For example, in some embodiments, a plurality of carriers can pass through S
2Being connected base with urea connects.As another example, a plurality of carriers can be connected with metal coordinating moiety by a plurality of independent bases that are connected with different.In other words, a plurality of connection bases can be connected with metal coordinating moiety, and at least one carrier can be connected the base connection with each.
Before in diagnosis and/or treatment procedure, using, the conjugate of formula A usually and metal complex to form metal pharmacodiagnosis of the present invention or therapeutic agent.
Bio-orientation carrier (bio-directing carrier)
As previously shown, conjugate of the present invention comprises one or more bio-orientation carriers, also is called biomolecule, and it is directed to conjugate the composition of expressing target tissue, organ, receptor or other biology.Ideally, each carrier is optionally or specific for target organ or tissue site.
Typical bio-orientation carrier comprises hormone, aminoacid, peptide, plan peptide (peptidomimetics), albumen, nucleoside, nucleotide, nucleic acid, enzyme, saccharide, plan sugar (glycomimetic), lipid, albumin, list-and polyclonal antibody, receptor, clathrate such as cyclodextrin, and the receptors bind molecule.The instantiation of carrier comprises the steroid hormone of treatment breast and injury of prostate; The somatostatin of treatment neuroendocrine tumor, bombesin, CCK, and neurotensin receptor binding molecule; The cck receptor binding molecule of treatment pulmonary carcinoma; The ST receptor and carcinoembryonic antigen (CEA) binding molecule of treatment colorectal carcinoma; Preparation is used for the treatment of dihydroxy indole carboxylic acid and other melanin of melanomatous biosynthesis intermediate; The integrin receptor and the atheromatous plaque binding molecule of treatment angiopathy; Amyloid plaque binding molecule with the treatment brain injury.Exemplary bio-orientation carrier also comprises synthetic polymer such as polyamino acid, polyhydric alcohol, polyamine, polyprotic acid (polyacid), oligonucleotide, aborols, dendritic and fit (aptamers).
In some embodiments, described bio-orientation carrier is selected from imidazoles, triazole, and antibody is (for example,
With
), albumen (for example TCII, HSA, annexin and Hb), peptide (for example, octreotide, bombesin, neurotensin and angiotensin), nitrogenous single or glycoconjugates (for example glucamine and glucose), nitrogenous vitamin (for example vitamin A, B1, B2, B12, C, D2, D3, E, H and K), nitrogenous hormone (for example estradiol, Progesterone and testosterone), nitrogenous active medicine (for example celecoxib or other nitrogenous NSAIDS, AMD3100, CXCR4 and CCR5 antagonist) and nitrogenous steroidal.In a kind of example of these embodiments, described bio-orientation carrier is selected from imidazoles, triazole, peptide, the single or glycoconjugates that nitrogen replaces, the vitamin of nitrogen replacement and the micromolecule that nitrogen replaces.In another example, described bio-orientation carrier can be the peptide of imidazoles, triazole, N-end, the single or glycoconjugates that nitrogen replaces, or the vitamin of nitrogen replacement.In also having another example, described bio-orientation carrier (or its terminal groups) can be imidazoles or triazole.
As mentioned above, embodiments more of the present invention can comprise the conjugate with a plurality of bio-orientation carriers.For example, in order to increase the specificity of the composition of expressing particular target tissue, organ receptor or other biology, can use a plurality of bio-orientation carriers.In these situations, described bio-orientation carrier can be identical or different.For example, one conjugate can have a plurality of antibody or antibody fragment, antigen or hapten that it is directed required.Typically, the antibody that is used for conjugate is directed required antigen or haptenic monoclonal antibody or antibody fragment.Therefore, for example, described conjugate comprises that two or more have the specific monoclonal antibody of required epitope, increases the concentration of conjugate thus at desired area.Similarly, and independently, conjugate can comprise the bio-orientation carrier that two or more are different, its each different position of targeting on identical target tissue or organ.By using a plurality of bio-orientation carriers in such a way, described conjugate is advantageously concentrated at the several regions place of target tissue or organ, increases the effectiveness of treatment potentially.In addition, described conjugate can have and is designed to described conjugate is concentrated at target tissue or organ place, and it obtains required treatment and/or diagnostic result best and makes the minimum bio-orientation carrier ratio of non-target deposition.
Connect base
As previously shown, one or more bio-orientation carriers can be covalently bound by the connection base and the metal coordinating moiety that comprise urea groups.In some embodiments, described connection is basic corresponding to formula B:
Formula B
Wherein
S
1And S
2Be covalent bond or atomic link independently, their respectively covalently bound urea parts are to metal coordinating moiety or one or more bio-orientation carrier; With
Z
1And Z
2Be independently selected from hydrogen, aryl, C
1-7Alkyl, C
1-7Hydroxyalkyl and C
1-7Alkoxyalkyl.For example, Z
1And Z
2Can be selected from hydrogen, C
1-7Alkyl, alkoxyalkyl and phenyl.As other example, Z
1And Z
2Can be selected from more restrictive group (for example hydrogen, C
1-4Alkyl and C
1-4Alkoxyalkyl).In some embodiments, Z
1And Z
2Both can be hydrogen.
No matter be considered to connect the part of base, the independent and independent component of conjugate, or be respectively the part of metal coordinating moiety and bio-orientation carrier, described interval base (spacer), S
1And S
2, be preferably designed to and help influencing bioturbation (biodistribution) and render a service, and between metal coordinating moiety and bio-orientation carrier, provide separation.For example, saccharide, polyalkylene glycol, peptide or other polyamino acid and/or cyclodextrin can increase or reduce the blood clearance rate as basic to influence the bioturbation of conjugate at interval, and/or the approach that guides conjugate to eliminate.Usually, preferably be to cause that mitigation is to quick blood clearance and those interval bases that increase renal excretion at interval.Ideally, described interval base is still removed by kidney not by liver metabolism, weakens the influence of conjugate to hepatic tissue thus.Yet should be pointed out that embodiments more of the present invention can comprise one or more interval bases by liver metabolism.
When being not covalent bond, S
1And S
2Comprise atomic link.This chain can be linear, side chain, cyclic or its combination.In some embodiments, described chain comprises about at the most 40 atoms, or even about at the most 20 atoms.In some embodiments, described chain comprises about 15 atoms of about 2-.The atom that is included in this chain typically is selected from carbon, oxygen, nitrogen, sulfur, selenium, silicon and phosphorus.In some embodiments, described atom can be selected from carbon, oxygen, nitrogen, p and s.And in other embodiments, described atom can be selected from carbon, nitrogen, oxygen and phosphorus.In some embodiments, at least some in the described chain atom can be optional substituted, wherein exemplary substituent group include, but not limited to one or more hydroxyls ,-OR and R substituent group.
In some embodiments, for example, S
1And S
2Be key (for example single covalent bond) independently, optional by one or more aldehyde radicals (carbaldehyde), ketone group, carboxyl (CO
2H), cyano group (CN), halogen, nitro (NO
2), acylamino-(amido) (C (O) R
1R
2), sulfate (sulfato) (OSO
3H), sulfonic group (sulfito) (SO
3H), phosphate (phosphato) (OPO
3H
2), phosphonate group (phosphito) (PO
3H
2), hydroxyl (OH), oxygen base, sulfydryl (SH), sulfenyl (thio) (SR
1), sulfoxide group (sulfoxo) (S (O) R
1) aryl or the C that replace
1-20Alkylidene, wherein R, R
1And R
2Be the optional C that is replaced by one or more sulfoxide groups, carboxyl, cyano group, nitro, acylamino-, hydroxyl, amino, sulfonic group, phosphonate group, sulfate and phosphate independently
1-20Alkyl.For these embodiments, S
1And S
2In each can be singly-bound independently, the optional aryl that is replaced by one or more oxygen bases, ketone group, halogen and acylamino-, or the optional C that is replaced by one or more oxygen bases and ketone group (keto)
1-8Alkylidene.In a kind of example of these embodiments, S
1And S
2Be singly-bound or the optional C that is replaced by the oxygen base independently
1-4Alkylidene.And in another example of these embodiments, S
1And S
2It respectively is singly-bound.
In some embodiments, S
2Can be: (i) optional by one or more oxygen atoms such as ehter bond or have the side chain of one or more hydroxyls such as the C that alcohols replaces
2-20Alkyl chain or ring; (ii) with the conjugated peptide chain of forming by one or more amino acid residues of natural or non-natural mode or encircle for example alanine, isoleucine, leucine, valine, phenylalanine, tryptophan, tyrosine, agedoite, methionine, cysteine, serine, glutamine, threonine, aspartic acid, glutamic acid, arginine, histidine, lysine, glycine or proline; Or it is (iii) one or more with the chain form or with the aromatic ring of multi-ring condensed forms, optional by one or more sulfoxide groups, carboxyl, cyano group, nitro, acylamino-, hydroxyl, amino, sulfonic group, phosphonate group, sulfate, phosphate, C
1-20Alkyl chain or cyclosubstituted, described C
1-20Alkyl chain or ring are optional to be replaced by one or more sulfoxide groups, carboxyl, cyano group, nitro, acylamino-, hydroxyl, amino, sulfonic group, phosphonate group, sulfate and phosphate.
Metal
Can be in vivo or the in-vitro diagnosis program be detected or useful any metal can be as the metal in the conjugate of the present invention in the treatment disease.Especially, can use in human body or animal body or in the in-vitro diagnosis test, can produce any radioactive metal ion or the paramagnetic metal ion that diagnostic result or treatment are replied.Based on specified purpose, the selection of suitable metal is known to those skilled in the art.In some embodiments, described metal can be selected from Lu, Lu-177, Y, Y-90, In, In-111, Tc, Tc=O, Tc-99m, Tc-99m=O, Re, Re-186, Re-188, Re=O, Re-186=O, Re-188=O, Ga, Ga-67, Ga-68, Cu, Cu-62, Cu-64, Cu-67, Gd, Gd-153, Dy, Dy-165, Dy-166, Ho, Ho-166, Eu, Eu-169, Sm, Sm-153, Pd, Pd-103, Pm, Pm-149, Tm, Tm-170, Bi, Bi-212, As and As-211.For example, described metal can be selected from Y-90, In-111, Tc-99m, Re-186, Re-188, Cu-64, Ga-67, Ga-68 and Lu-177.As another example, described metal can be selected from more restrictive group, and (for example being selected from Y-90, In-111, Tc-99m, Re-186, Cu-64, Ga-67 and Lu-177 forms; Or be selected from Y-90, In-111 and Tc-99m).
Metal coordinating moiety
Described metal coordinating moiety can be any part that is used for one or more metals of complexation (being also referred to as " coordination ") under physiological condition.Preferably, described metal coordinating moiety and metal form on the thermodynamics and stable complex on the kinetics, to remain on the complete of complex under the physiological condition; Otherwise the general that may produce the coordination metal discharges.
Usually, described metal coordinating moiety can be acyclic or cyclic.For example, metal coordinating moiety comprises polybasic carboxylic acid for example EDTA, DTPA, DCTA, DOTA, TETA or its analog or homologue.In order to obtain bigger stability under physiological condition, yet big loop section (for example three azepines and four nitrogen heterocyclic rings) is normally preferred.In some embodiments, described Macrocyclic metal coordination partly is 1,4,7,10-tetraazacyclododecanand or 1,4,7-7-triazacyclononane.
In some embodiments, described metal coordinating moiety comprises the heterocycle of replacement, and wherein said hetero atom is a nitrogen.Typically, described heterocycle comprises about 15 atoms of about 9-, and at least 3 of these annular atomses is nitrogen.In a kind of example of these embodiments, described heterocycle comprises 3-5 theheterocyclic nitrogen atom, and at least one in the wherein said theheterocyclic nitrogen atom is substituted.For these embodiments, described ring carbon atom can be optional substituted.A kind of such macro ring is corresponding to formula (1):
Wherein
N is 0,1 or 2;
M is 0-16, wherein when m greater than 0 the time, each A is independently selected from the optional C that replaces
1-20Alkyl and aryl.
When described metal coordinating moiety corresponding to formula (1) and m greater than 0 the time, its usually preferred each A influences stability and bioturbated substituent group energetically.When existing, each A can be independently by one or more aryl, C
1-20Alkyl, aldehyde radical, ketone group, carboxyl, cyano group, halogen, nitro, acylamino-, sulfate, sulfonic group, phosphate, phosphonate group, hydroxyl, oxygen base, sulfydryl and sulfenyl substituent group replace.When A was aryl or alkyl, each in these can be optional by aryl or C
1-20Alkyl (it is optional by one or more aryl, aldehyde radical, ketone group, carboxyl, cyano group, halogen, nitro, acylamino-, sulfate, sulfonic group, phosphate, phosphonate group, hydroxyl, oxygen base, sulfydryl and the replacement of sulfenyl substituent group) replaces.
For the metal coordinating moiety of formula (1), described A substituent group if exist, is connected with any described ring carbon atom.In addition, each ring carbon atom can be substituted, and the substituent number of possible like this A will change with the number of ring carbon atom.In a kind of embodiment of the metal coordinating moiety with substituent formula of at least one A (1), each A is aryl or C independently
1-8Alkyl, it is optional by one or more aryl, ketone group, carboxyl, cyano group, nitro, C
1-20Alkyl, acylamino-, sulfate, sulfonic group, phosphate, phosphonate group, oxygen base and sulfenyl replace.For example, each A can be aryl or C
1-6Alkyl, it is optional by one or more aryl, ketone group, acylamino-and the replacement of oxygen base.As a further example, each A can be a methyl.
Usually, when the n value increases, the size of macro ring also will increase.By this way, can control the size of macro ring to mate required size and the ligancy for the treatment of coordinate metal.
In some embodiments, wherein said metal coordinating moiety comprises the heterocycle of replacement, and described metal coordinating moiety is corresponding to formula (1a)
Wherein
N is 0,1 or 2;
M is 0-16, wherein when m greater than 0 the time, each A is optional by one or more aryl, C
1-20The C that alkyl, aldehyde radical, ketone group, carboxyl, cyano group, halogen, nitro, acylamino-, sulfate, sulfonic group, phosphate, phosphonate group, hydroxyl, oxygen base, sulfydryl or sulfenyl replace
1-20Alkyl or aryl.
Q is 0-3, wherein when q greater than 0 the time, each D is independently selected from fluorine, chlorine, bromine, iodine, carboxyl, cyano group, nitro, acylamino-, hydroxyl, amino, sulfate, sulfonic group, phosphate, phosphonate group, aryl and C
1-20Alkyl, it is optional by one or more C
1-20Alkyl, carboxyl, cyano group, nitro, acylamino-, hydroxyl, amino, sulfate, sulfonic group, phosphate and phosphonate group replace;
X
1, X
2, X
3, X
4Be the optional methylene that replaces independently, wherein said substituent group is selected from aryl, C
1-20Alkyl, aldehyde radical, ketone group, carboxyl, cyano group, halogen, nitro, acylamino-, sulfate, sulfonic group, phosphate, phosphonate group, hydroxyl, oxygen base, sulfydryl and sulfenyl;
Q
2-Q
4Be independently selected from:
q
2Be 0-4, wherein work as q
2Greater than 0 o'clock, each E was independently selected from fluorine, chlorine, bromine, iodine, carboxyl, cyano group, nitro, acylamino-, hydroxyl, amino, sulfonic group, phosphonate group and optional by one or more C
1-20The C that alkyl, carboxyl, cyano group, nitro, acylamino-, hydroxyl, sulfonic group, phosphonate group, sulfate and phosphate replace
1-20Alkyl; With
T
1Be hydroxyl or sulfydryl.
For the metal coordinating moiety of formula (1a), described D substituent group if exist, is connected with any described commutable carbon atoms on a benzene ring independently.In some embodiments, each D can be fluorine, chlorine, bromine, iodine, carboxyl, cyano group, nitro, acylamino-, hydroxyl, amino, sulfonic group, phosphonate group, sulfate, phosphate, aryl or C
1-8Alkyl, it is optional by one or more C
1-20Alkyl, carboxyl, cyano group, nitro, acylamino-, hydroxyl, amino, sulfonic group, phosphonate group, sulfate and phosphate replace.For example, in some embodiments, each D can be bromine, iodine, carboxyl or hydroxyl.In some embodiments, work as T
1When being hydroxyl, D can be at X
1The α position and the T of junction point
1Ingredient (constituent) beyond the hydroxyl-removal of the β position of junction point.
For the metal coordinating moiety of formula (1a), described E substituent group if exist, is connected with any described commutable carbon atoms on a benzene ring independently.In some embodiments, each E can be fluorine, chlorine, bromine, iodine, carboxyl, cyano group, nitro, acylamino-, hydroxyl, amino, sulfonic group, phosphonate group, sulfate, phosphate, aryl or C independently
1-8Alkyl, it is optional by one or more C
1-20Alkyl, carboxyl, cyano group, nitro, acylamino-, hydroxyl, amino, sulfonic group, phosphonate group, sulfate and phosphate replace.For example, in some embodiments, each E can be bromine, iodine, carboxyl or hydroxyl independently.
Typically, for the metal coordinating moiety of formula (1a), X
1-X
4Be optional independently by C
1-6The methylene that alkyl, halogen or hydroxyl replace.
In some embodiments of the metal coordinating moiety of formula (1a), q
2Be 0.Therefore, Q
2, Q
3And Q
4Can be independently selected from:
Except that metal coordinating moiety comprises heterocycle, described metal coordinating moiety or can comprise the assorted alkyl chain that replaces.Typically, described assorted substituted alkyl chain comprises about 10 atoms of about 4-in described assorted substituted alkyl chain, and at least 2 is nitrogen in the described atom.In a kind of example of the metal coordinating moiety that comprises assorted substituted alkyl chain, described chain comprises 2-4 nitrogen-atoms, and at least one in the wherein said chain nitrogen-atoms is substituted.For these embodiments, described chain carbon atom can be optional substituted.Typically, comprise that the assorted substituted alkyl chain of described nitrogen-atoms is separated by 2 carbon atoms each other, described thus metal coordinating moiety can use following formula (2) to describe
Wherein
N is 0,1 or 2; With
M is 0-8, wherein when m greater than 0 the time, each A is independently selected from the optional C that replaces
1-20Alkyl and aryl.
When described metal coordinating moiety corresponding to formula (2) and m greater than 0 the time, its usually preferred each A influences stability and bioturbated substituent group energetically.When existing, each A can be independently by one or more aryl, C
1-20Alkyl, aldehyde radical, ketone group, carboxyl, cyano group, halogen, nitro, acylamino-, sulfate, sulfonic group, phosphate, phosphonate group, hydroxyl, oxygen base, sulfydryl and sulfenyl substituent group replace.In addition, when A was aryl or alkyl, each in these can be chosen wantonly by aryl or C
1-20Moieties (described aryl or C
1-20Moieties is optional to be replaced by one or more aryl, aldehyde radical, ketone group, carboxyl, cyano group, halogen, nitro, acylamino-, sulfate, sulfonic group, phosphate, phosphonate group, hydroxyl, oxygen base, sulfydryl and sulfenyl) replacement.
For the metal coordinating moiety of formula (2), described A substituent group if exist, is connected with any described ring carbon atom.Each ring carbon atom can be substituted, and the substituent number of possible like this A will change with the number of ring carbon atom.In a kind of embodiment of the metal coordinating moiety with substituent formula of at least one A (2), each A is optional by one or more aryl, ketone group, carboxyl, cyano group, nitro, C independently
1-20Aryl or C that alkyl, acylamino-, sulfate, sulfonic group, phosphate, phosphonate group, oxygen base and sulfenyl replace
1-8Alkyl.For example, each A can be optional aryl or the C that is replaced by one or more aryl, ketone group, acylamino-and oxygen base
1-6Alkyl.As a further example, each A can be a methyl.
Usually, when the n value increases, the length of assorted substituted alkyl chain also will increase.By this way, can control the length of assorted substituted alkyl chain to mate described size and the coordination ability for the treatment of coordinate metal.
In some embodiments, wherein said metal coordinating moiety comprises assorted substituted alkyl chain, and described metal coordinating moiety meets following formula (2a)
Wherein
N is 0,1 or 2;
M be 0-8 wherein when m greater than 0 the time, each A is optional by one or more aryl, C
1-20The C that alkyl, aldehyde radical, ketone group, carboxyl, cyano group, halogen, nitro, acylamino-, sulfate, sulfonic group, phosphate, phosphonate group, hydroxyl, oxygen base, sulfydryl or sulfenyl replace
1-20Alkyl or aryl;
Q is 0-3, wherein when q greater than 0 the time, each D is independently selected from fluorine, chlorine, bromine, iodine, carboxyl, cyano group, nitro, acylamino-, hydroxyl, amino, sulfate, sulfonic group, phosphate, phosphonate group, aryl and C
1-20Alkyl, it is optional by one or more C
1-20Alkyl, carboxyl, cyano group, nitro, acylamino-, hydroxyl, amino, sulfate, sulfonic group, phosphate and phosphonate group replace;
X
1, X
2, X
3, X
4And X
5Be the optional methylene that replaces independently, wherein said substituent group is selected from aryl, C
1-20Alkyl, aldehyde radical, ketone group, carboxyl, cyano group, halogen, nitro, acylamino-, sulfate, sulfonic group, phosphate, phosphonate group, hydroxyl, oxygen base, sulfydryl and sulfenyl;
Q
2-Q
5Be independently selected from:
q
2Be 0-4, wherein work as q
2Greater than 0 o'clock, each E was independently selected from fluorine, chlorine, bromine, iodine, carboxyl, cyano group, nitro, acylamino-, hydroxyl, amino, sulfonic group, phosphonate group and optional by one or more C
1-20The C that alkyl, carboxyl, cyano group, nitro, acylamino-, hydroxyl, sulfonic group, phosphonate group, sulfate and phosphate replace
1-20Alkyl; With
T
1Be hydroxyl or sulfydryl.
For the metal coordinating moiety of formula (2a), described D substituent group if exist, is connected with any described commutable carbon atoms on a benzene ring independently.In some embodiments, each D can be fluorine, chlorine, bromine, iodine, carboxyl, cyano group, nitro, acylamino-, hydroxyl, amino, sulfonic group, phosphonate group, sulfate, phosphate, aryl or C independently
1-8Alkyl, it is optional by one or more C
1-20Alkyl, carboxyl, cyano group, nitro, acylamino-, hydroxyl, amino, sulfonic group, phosphonate group, sulfate and phosphate replace.For example, in some embodiments, each D can be bromine, iodine, carboxyl or hydroxyl independently.In some embodiments, work as T
1When being hydroxyl, D can be at X
1The α position and the T of junction point
1Ingredient beyond place, the β position hydroxyl-removal of junction point.
For the metal coordinating moiety of formula (2a), described E substituent group if exist, can be connected with any described commutable carbon atoms on a benzene ring independently.In some embodiments, each E can be fluorine, chlorine, bromine, iodine, carboxyl, cyano group, nitro, acylamino-, hydroxyl, amino, sulfonic group, phosphonate group, sulfate, phosphate, aryl or C independently
1-8Alkyl, it is optional by one or more C
1-20Alkyl, carboxyl, cyano group, nitro, acylamino-, hydroxyl, amino, sulfonic group, phosphonate group, sulfate and phosphate replace.For example, in some embodiments, each E can be bromine, iodine, carboxyl or hydroxyl independently.
Typically, for the metal coordinating moiety of formula (2a), X
1-X
4Be optional independently by C
1-6The methylene that alkyl, halogen or hydroxyl replace.
In some embodiments of the metal coordinating moiety of formula (2a), q
2Be 0.Therefore, Q
2, Q
3, Q
4And Q
5Be independently selected from:
For any above-mentioned embodiment, described metal coordinating moiety can with the metal M complexation, form metal complex thus.
In some embodiments, wherein said metal coordinating moiety be heterocycle and with the metal M complexation, described complex has following formula (3):
Wherein
N is 0,1 or 2;
M is 0-16, wherein when m greater than 0 the time, each A is optional by one or more aryl, C
1-20The C that alkyl, aldehyde radical, ketone group, carboxyl, cyano group, halogen, nitro, acylamino-, sulfate, sulfonic group, phosphate, phosphonate group, hydroxyl, oxygen base, sulfydryl or sulfenyl replace
1-20Alkyl or aryl.
Q is 0-3, wherein when q greater than 0 the time, each D is independently selected from fluorine, chlorine, bromine, iodine, carboxyl, cyano group, nitro, acylamino-, hydroxyl, amino, sulfate, sulfonic group, phosphate, phosphonate group, aryl and C
1-20Alkyl, it is optional by one or more C
1-20Alkyl, carboxyl, cyano group, nitro, acylamino-, hydroxyl, amino, sulfate, sulfonic group, phosphate and phosphonate group replace;
X
1, X
2, X
3, X
4Be the optional methylene that replaces independently, wherein said substituent group is selected from aryl, C
1-20Alkyl, aldehyde radical, ketone group, carboxyl, cyano group, halogen, nitro, acylamino-, sulfate, sulfonic group, phosphate, phosphonate group, hydroxyl, oxygen base, sulfydryl and sulfenyl;
Q
2-Q
4Be independently selected from:
q
2Be 0-4, wherein work as q
2Greater than 0 o'clock, each E was independently selected from fluorine, chlorine, bromine, iodine, carboxyl, cyano group, nitro, acylamino-, hydroxyl, amino, sulfonic group, phosphonate group and optional by one or more C
1-20The C that alkyl, carboxyl, cyano group, nitro, acylamino-, hydroxyl, sulfonic group, phosphonate group, sulfate and phosphate replace
1-20Alkyl;
T
1Be hydroxyl or sulfydryl; With
M is selected from Lu, Lu-177, Y, Y-90, In, In-111, Tc, Tc=O, Tc-99m, Tc-99m=O, Re, Re-186, Re-188, Re=O, Re-186=O, Re-188=O, Ga, Ga-67, Ga-68, Cu, Cu-62, Cu-64, Cu-67, Gd, Gd-153, Dy, Dy-165, Dy-166, Ho, Ho-166, Eu, Eu-169, Sm, Sm-153, Pd, Pd-103, Pm, Pm-149, Tm, Tm-170, Bi, Bi-212, As and As-211.
In some embodiments, wherein said metal coordinating moiety be assorted substituted alkyl chain and with the metal M complexation, described complex has following formula (4):
Wherein
N is 0,1 or 2;
M is 0-8, wherein when m greater than 0 the time, each A is optional by one or more aryl, C
1-20The C that alkyl, aldehyde radical, ketone group, carboxyl, cyano group, halogen, nitro, acylamino-, sulfate, sulfonic group, phosphate, phosphonate group, hydroxyl, oxygen base, sulfydryl or sulfenyl replace
1-20Alkyl or aryl;
Q is 0-3, wherein when q greater than 0 the time, each D is independently selected from fluorine, chlorine, bromine, iodine, carboxyl, cyano group, nitro, acylamino-, hydroxyl, amino, sulfate, sulfonic group, phosphate, phosphonate group, aryl and C
1-20Alkyl, it is optional by one or more C
1-20Alkyl, carboxyl, cyano group, nitro, acylamino-, hydroxyl, amino, sulfate, sulfonic group, phosphate and phosphonate group replace;
X
1, X
2, X
3, X
4And X
5Be the optional methylene that replaces independently, wherein said substituent group is selected from aryl, C
1-20Alkyl, aldehyde radical, ketone group, carboxyl, cyano group, halogen, nitro, acylamino-, sulfate, sulfonic group, phosphate, phosphonate group, hydroxyl, oxygen base, sulfydryl and sulfenyl;
Q
2-Q
5Be independently selected from:
q
2Be 0-4, wherein work as q
2Greater than 0 o'clock, each E was independently selected from fluorine, chlorine, bromine, iodine, carboxyl, cyano group, nitro, acylamino-, hydroxyl, amino, sulfonic group, phosphonate group and optional by one or more C
1-20The C that alkyl, carboxyl, cyano group, nitro, acylamino-, hydroxyl, sulfonic group, phosphonate group, sulfate and phosphate replace
1-20Alkyl;
T
1Be hydroxyl or sulfydryl; With
M is selected from Lu, Lu-177, Y, Y-90, In, In-111, Tc, Tc=O, Tc-99m, Tc-99m=O, Re, Re-186, Re-188, Re=O, Re-186=O, Re-188=O, Ga, Ga-67, Ga-68, Cu, Cu-62, Cu-64, Cu-67, Gd, Gd-153, Dy, Dy-165, Dy-166, Ho, Ho-166, Eu, Eu-169, Sm, Sm-153, Pd, Pd-103, Pm, Pm-149, Tm, Tm-170, Bi, Bi-212, As and As-211.
The complex of tubular type (3) still is not that the complex of formula (4) all typically depends on selected coordinate concrete metal.For example, for yttrium and lanthanide series, the complex of formula (3) is preferred.For ferrum, copper and manganese, formula (3) also is preferred, and for remaining transition metal, formula (4) is preferred complex.The preferred complex of any concrete metal is relevant with the electromotive force that carries out metal transfer with the endogenous ion.Thus, formula (3) provides bigger stability for height exchange metal, includes, but not limited to yttrium, lanthanide series and gallium.For the transition metal of rule, the metal transfer that does not exist the endogenous ion to carry out.Though the complex of formula (3) is described above uses as some metals is preferred, though the complex of formula (4) is described above uses as other metal is preferred, but can consider that the complex of formula (3) and (4) can be used for except that the listed metal those of each complex.
Macrocyclic metal coordination part with three-dimensional lumen often forms the metal complex of high stability.Based on metal size and Coordinative Chemistry, these complex often show the selectivity to some metal ion, and can take a kind of pre-organized structure (preorganized conformation) with form complexed not, and it promotes metal complexation.The suitable Macrocyclic metal coordination part and the selection of metal are known to those skilled in the art.
The value of n, the size of metal coordinating moiety or length depend on and treat coordinate concrete metal thus.For yttrium and lanthanide series, for example, n normally 1.For transition metal, n typically 0 or 1.For manganese and technetium, n is 0,1 or 2, and this depends on X
2-X
4Value.Yet, should consider that other value of n may also be suitable for one or more above-mentioned metals.
General synthetic method
For illustrative purpose, following reaction represents to use the activation of carbonyl diurethane (triazine) metal-chelator (CDT):
In order to prevent the reaction of free hydroxyl before the preparation conjugate, the hydroxyl protection of described metal coordinating moiety is got up.Any conventional method of protection hydroxyl is permitted.The various protecting groups of hydroxyl and synthetic method thereof can be at " Protective Groups in Organic Synthesis, 3rd Edition ", and by T.W.Greene and P.G.M.Wuts, John Wiley and Sons write, and find in 1999.Exemplary protecting group comprises the tert-butyl group, methoxy, 1-ethoxyl methyl, benzyloxymethyl, (β-trimethylsilylethoxy)) methyl, THP trtrahydropyranyl, 2; 2; 2-trichloro-ethoxycarbonyl, the tert-butyl group (diphenyl) silicyl, trialkylsilkl, trichlorine methoxycarbonyl group and 2; 2,2-trichlorine ethoxyl methyl.
In order to generate active urea groups by amine, preferred gentle activator.Exemplary activator comprises carbonyl diurethane (triazine) or carbonyl dimidazoles (CDI), or its mixture.Other activator comprises phosgene, two (trichloromethyl) carbonic ester and trichloromethyl chloroformate.Reactive intermediate can be separated with solid form, and it is stable under anhydrous condition.Therefore, a kind of so active urea can make itself and synthetic or natural product (biological example molecule) reaction, obtains protected intermediates.Described product can for example use dichloromethane to separate with ether by precipitating from reactant mixture.If desired, for example, the purification of described product can be undertaken by using positive or C18 reversed phase chromatography.This intermediate can be subsequently by using acid, and for example trifluoromethanesulfonic acid is carried out deprotection in trifluoroethanol, sloughs phenolic hydroxyl group and carboxylate thus.
For this embodiment, described bio-orientation carrier (bio-directing carrier) and metal can be any foregoing those.Described radiosiotope or paramagnetic metal ion typically are dissolved in the solution.This solution can be any other solution of aqueous acids or dissolving radiosiotope known in the art or paramagnetic metal ion.This solution should can stably be stored described metal in test kit, and the performance that does not hinder described metal.The dissolution aids that uses in preparation radiopharmaceutical and diagnostic kit comprises, but be not limited to ethanol, glycerol, Polyethylene Glycol, propylene glycol, polyoxyethylene sorbitan monooleate, sorbitan monooleate, polysorbate, poly-(oxygen ethylene)-poly-(oxypropylene)-poly-(oxygen ethylene) block copolymer (Pluronic) and lecithin.Preferred dissolution aids is Polyethylene Glycol and Pluronic.
The metal pharmaceutical composition
Metal pharmaceutical composition of the present invention comprises conjugate, itself and a kind of metal complex, and be dispersed in the pharmaceutically acceptable carrier.Described pharmaceutically acceptable carrier, be known in the art equally and exist with the form of excipient, solvent (vehicle), auxiliary agent, adjuvant or diluent, so typically material, it pharmaceutically is being inert, give suitable viscosity of described compositions or form, and can not weaken the treatment or the diagnosis effectiveness of this conjugate.Described carrier usually considers it is " pharmaceutically or pharmacology go up acceptable ", and when giving especially man-hour of mammal, it can not produce unacceptably disadvantageous, hypersensitive or other untoward reaction.
The selection of pharmaceutically acceptable carrier at least to a certain extent, is to change with required route of administration.Usually, metal pharmaceutical composition of the present invention can be mixed with any route of administration, and needing only by the sort of route of administration is effective to target tissue.For example, suitable route of administration includes, but are not limited to, oral, parenteral (for example in intravenous, intra-arterial, subcutaneous, rectum, subcutaneous, intramuscular, the socket of the eye in (intraorbital), the capsule, in the spinal column, in intraperitoneal or the breastbone), local (nose, percutaneous, ophthalmic), intravesical, in the sheath, enteral (enteral), pulmonary, intralymphatic, intracavity, vagina, per urethra, Intradermal, ear, in the breast, oral cavity (buccal), original position, in the trachea, damage zone, percutaneous (percutaneous), endoscope, stride mucosa, Sublingual and enteral (intestinal) administration.
The example of the pharmaceutically acceptable carrier that uses in compositions of the present invention is known to the conventional those of skill in the art in this area, and can select based on some following factors: the bioavailability of employed concrete conjugate and concentration thereof, stability and expection; Disease, obstacle or disease that preparation is treated with said composition or diagnosed; Patient and age thereof, body weight and general physical condition; And route of administration.Suitable is non-aqueous, pharmaceutically acceptable polar solvent comprises, but be not limited to, alcohols (α-glycerine acetal (glycerol formal) for example, β-glycerine acetal, 1, the 3-butanediol, has for example methanol of the aliphatic of 2-30 carbon atom or aromatic series alcohols, ethanol, propanol, isopropyl alcohol, butanols, the tert-butyl alcohol, hexanol, capryl alcohol, amylene hydrate, benzylalcohol, glycerol (glycerol), glycol, hexanediol, tetrahydrofurfuryl alcohol, lauryl alcohol, spermol or stearyl alcohol, the fatty acid ester of aliphatic alcohol be polyalkylene glycol (polypropylene glycol for example for example, Polyethylene Glycol), sorbitan, sucrose and cholesterol); Amide (for example dimethyl acetylamide (DMA), benzyl benzoate DMA, dimethyl formamide, N-(beta-hydroxyethyl)-lactamide, N, N-dimethyl lactamide, 2-Pyrrolidone, 1-Methyl-2-Pyrrolidone or polyvinylpyrrolidone); Ester (1-Methyl-2-Pyrrolidone for example, 2-Pyrrolidone, acetas is monoacetin for example, Glycerine 1,3-diacetate, and glycerol triacetate, aliphatic or aromatic ester be ethyl caprilate (ethylcaprylate) or caprylate (octanoate) for example, the alkyl oleate, benzyl benzoate, benzyl acetate, dimethyl sulfoxine (DMSO), glyceride are for example single, two or Three-glycerol base citrate or tartrate, ethyl benzoate, ethyl acetate, ethyl carbonate, ethyl lactate, ethyl oleate, the fatty acid ester of sorbitan, the PEG ester of fatty acid derived, glyceryl monostearate, glyceride is for example single, two or the Three-glycerol ester, fatty acid ester is isopropyl myristate for example, and the PEG ester of fatty acid derived is PEG-hydroxy oleate ester and PEG-hydroxy stearic acid ester for example, N-Methyl pyrrolidone, Pluronic 60, polyoxyethylene sorbitol oleic acid polyester be poly-(ethoxylation) for example
30-60Sorbitol gathers (oleate)
2-4, poly-(oxygen ethylene)
15-20Monoleate, poly-(oxygen ethylene)
15-20Single 12-hydroxy stearic acid ester and poly-(oxygen ethylene)
15-20Single ricinoleate, polyoxyethylene sorbitan ester such as polyoxyethylene-dehydrated sorbitol mono-fatty acid ester, polyoxyethylene-sorbitan monopalmitate, polyoxyethylene-sorbitan monolaurate, polyoxyethylene-sorbitan monostearate, and from ICI Americas, Wilmington, DE's
20,40,60 or 80, polyvinylpyrrolidone, the fatty acid ester of alkene oxygen base modification such as polyoxyl 40 hydrogenated castor oil (polyoxyl 40 hydrogenated casoil) and polyoxyethylene castor oil (polyoxyethylated castor) is (for example
EL solution or
RH 40 solution), sugar fatty acid ester (saccharide fatty acid ester) (promptly, monosaccharide (for example pentose such as ribose, ribulose, arabinose, xylose, lyxose and xylulose, hexose such as glucose, fructose, galactose, mannose and sorbose, triose, tetrose, heptose and octose), disaccharide (for example sucrose, maltose, lactose and trehalose) or oligosaccharide or its mixture and C
4-C
22The condensation product of fatty acid (for example satisfied fatty acid such as sad, capric acid, lauric acid, myristic acid, Palmic acid and stearic acid, and unsaturated fatty acid such as palmitoleic acid, oleic acid, elaidic acid, erucic acid and linoleic acid)), or the steroidal ester); The alkyl ether of 2-30 carbon atom, aryl ether or cyclic ethers (for example ether, oxolane, Isosorbide dimethyl ether, diethylene glycol monoethyl ether); Sugar furfuryl alcohol (glycofurol) (tetrahydrofurfuryl alcohol polyglycol ether); The ketone of 3-30 carbon atom (for example acetone, methyl ethyl ketone, methyl iso-butyl ketone (MIBK)); The aliphatic hydrocarbon of 4-30 carbon atom, cycloaliphatic hydrocarbon or aromatic hydrocarbon (for example benzene, cyclohexane extraction, dichloromethane, dioxolanes (dioxolanes), hexane, n-decane, n-dodecane, normal hexane, sulfolane, tetramethylene sulfone (tetramethylenesulfon), tetramethylene sulfoxide (tetramethylenesulfoxide), toluene, dimethyl sulfoxine (DMSO) or tetramethylene sulfoxide (tetramethylenesulfoxide); Mineral oils, plant oil, animal oils, (for example mineral oil is as the hydrocarbon based on aliphatic or paraffin for essential or synthetic source oils, aromatic hydrocarbon, based on mixing-in fat family and aromatic hydrocarbon, and purified paraffin oil, vegetable oil such as Semen Lini oil, tung oil, safflower oil, soybean oil, Oleum Ricini, Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, Oleum Brassicae campestris, Oleum Cocois, Petiolus Trachycarpi oil, olive oil, Semen Maydis oil, Fructus Maydis oil, Oleum sesami, peach kernel oil (persic) and Oleum Arachidis hypogaeae semen and glyceride as single-, two-or triglyceride, animal oil such as fish oil, Bufo siccus oil, whale oil, cod liver oil, cod-liver oil (haliver), Squalene, squalane and shark liver oil, oleic oil, and polyoxyethylenated castor oil); The alkyl or aryl halogenide of 1-30 carbon atom and optional above a halogenic substituent; Dichloromethane; Monoethanolamine; Petroleum ether (petroleum benzin); Triethanolamine; ω-3 polybasic unsaturated fatty acid (for example alpha-linolenic acid, eicosapentaenoic acid, clupanodonic acid or docosahexenoic acid); The macrogol ester of 12-hydroxy stearic acid and Polyethylene Glycol (polyglycol ester) (
HS-15, available from BASF, Ludwigshafen, Germany); The polyoxyethylene glycerol; Sodium laurate; Enuatrol; Or dehydrated sorbitol mono-fatty acid ester.
The pharmaceutically acceptable solvent of other of Shi Yonging is known to the conventional those of skill in the art in this area in the present invention, and can reference
The Chemotherapy Source Book(Williams ﹠amp; Wilkens Publishing),
The Handbook of Pharmaceutical Excipients, (association of pharmacists (American Pharmaceutical Association), Washington, D.C. and Britain pharmaceutical society (ThePharmaceutical Society of Great Britain), London, Britain, 1968),
Modern Pharmaceutics, (people such as G.Banker, eds., 3d ed.) (Marcel Dekker, Inc., New York, New York, 1995),
The Pharmacological Basis of Therapeutics, (Goodman ﹠amp; Gilman, McGraw Hill Publishing),
Pharmaceutical Dosage Forms, (people such as H.Lieberman, eds.) (Marcel Dekker, Inc., New York, New York, 1980),
Remington ' s Pharmaceutical Sciences(A.Gennaro, ed., 19th ed.) (Mack Publishing, Easton, PA, 1995),
The United States Pharmacopeia 24,
The National Formulary 19(NationalPublishing, Philadelphia, PA, 2000), people such as A.J.Spiegel, with Use of NonaqueousSolvents in Parenteral Products, JOURNAL OF PHARMACEUTICAL SCIENCES, the 52nd volume, No. 10,917-927 page or leaf (1963).
Dosage
The dosage of pharmaceutical composition of the present invention and dosage regimen can easily be determined by the those of skill in the art in diagnosis or treatment disease field.Very clear, the dosage of conjugate depends on receiver's age, sex, health and body weight, the type of co-therapy (concurrent treatment), and the frequency of treatment and the character (if any) of required effect.For any administering mode, the actual quantity of the conjugate of institute's administration, and in order to obtain the required dosage of beneficial effect described herein, also will depend on some factors so to a certain extent, disease as the bioavailability of conjugate, to be treated or diagnosis, required treatment or diagnostic dose, and the known other factors of those skilled in the art.In the context of the present invention, give animal particularly people's dosage should in rational time period, in animal, be enough to influence required treatment or diagnosis is replied.
The radioactivity that has appropriate amount by radiolabeled flicker developing agent provided by the present invention.In the process that forms the diagnostic radioactive complex, preferably form the radioactivity complex in the radioactive solution of every mL to 100mCi containing about 0.01 millicurie of concentration (mCi) usually.Usually, the unit dose that is given has the radioactivity of about 0.01mCi～about 100mCi, preferably has the radioactivity of about 1mCi～about 30mCi.Solution with the unit dose injection is about the about 10mL of 0.01mL-.The quantity that is suitable for the radiolabeled conjugate of administration will depend on the distribution curve of selected conjugate, say in a sense, and the conjugate of removing may need to give higher dosage than removing slower conjugate fast.A suitable time point after administration can be followed the tracks of distribution and location in the body by the standard scintillation technique; Typically between 30 minutes to 180 minutes, this depends on the clearance rate of the accumulation rate of target point with respect to the non-target tissue place.
Typically, the In-111 diagnostic dose is 3-6mCi, and the diagnostic dose of typical Tc-99m is 10-30mCi.Usually, radiopharmaceutic X-ray therapy dosage changes with tumor and cycle frequency injection to a great extent.For example, the cumulative dose of Y-90 is in the scope of about 100-600mCi (20-150mCi/ dosage), and the cumulative dose of Lu-177 is in the scope of about 200-800mCi (50-200mCi/ dosage).
Test kit
For simplicity, metal pharmaceutical composition of the present invention can offer user with the form of test kit, and described test kit contains the component of some or all of necessity.The use of test kit is especially easily, because some components, for example radiosiotope has the limited shelf life, particularly when combination.Thus, this test kit can comprise one or more following component (i) conjugates, and (ii) coordination is to the metal of conjugate or be used for the coordinate metal of conjugate, (iii) carrier solution and (iv) with their combinations and the description used.According to metal, may need a kind of Reducing agent with the metal of preparation with the conjugate reaction.Exemplary Reducing agent comprises Ce (III), Fe (II), Cu (I), Ti (III), Sb (III) and Sn (II).In the middle of these, Sn (II) is particularly preferred.Usually, the component of test kit is unit dosage forms (for example every kind of composition is in independent bottle).
For stability, preferably allow described conjugate provide with dry, lyophilised state.Then, user is by adding carrier or other solution with described conjugate reconstruct.
Because the half-life that suitable radionuclide is short, it is not having under the situation of radionuclide test kit to be offered user with frequent most convenient.Then, when this step of needs, described radionuclide separates successively.Perhaps, if described radionuclide is included in the test kit, this test kit will just be delivered in face of the user before needs use probably so.
Except that metal coordinating moiety, biomolecule, active urea, metal and deprotection acid, test kit of the present invention typically comprises buffer agent.Exemplary buffer agent comprises citrate, phosphate and borate.
Optional other component that contains of test kit, by the training terminal user, this other component is through being usually used in improving the synthetic easiness of radiopharmaceutical, the easiness of preparation test kit, improve the shelf life of test kit, or improve the stability and the shelf life of radiopharmaceutical.Such component of the present invention comprises lyophilization aid, for example mannitol, lactose, Sorbitol, dextran, Fei Keer (Ficoll) and polyvinylpyrrolidone (PVP); Stabilization aid, for example ascorbic acid, cysteine, thioglycerol (monothioglycerol), sodium sulfite, sodium pyrosulfite, gentisic acid and inositol; And antibacterial, for example benzylalcohol, benzalkonium chloride, chlorobutanol and methyl, propyl group or butyl p-Hydroxybenzoate.
Typically; when described conjugate is formulated into test kit; this test kit comprises a plurality of bottles (vials); described bottle is by the protected metal coordinating moiety with active urea groups, deprotection acid, buffer agent and radioactive metal solution composition; described radioactive metal for example; but be not limited to In-111, Y-90 or Lu-177.In fact, user has active amino (NH with obtaining to contain the bottle of this metal coordinating moiety, then adding
2) solution that makes the interested bio-orientation carrier of people of group.In case finish conjugation, described deprotection acid is added to carry out deprotection, then add radioactive metal.Then, mixture is cushioned to finish radioactive metal by the complexation of metal-chelator.
Definition
Chemical compound described herein can have asymmetric center.The The compounds of this invention that contains asymmetric replacement atom can be separated with optically active form or racemic form.The cis of The compounds of this invention and trans geometric isomer have been described and as mixture of isomers form or separated with independent isomeric forms.Unless specifically point out concrete spatial chemistry or isomeric forms, be meant all chiralitys, diastereomer, racemic form and all geometric isomer forms.All methods that are used to prepare The compounds of this invention and intermediate are considered to a part of the present invention.
The present invention includes the isotope of all atoms that in The compounds of this invention, occur.Isotope comprises that those have identical atomic number but the atom of different mass number.
Except as otherwise noted, alkyl described herein preferably has 1-8 carbon atom and has altogether low alkyl group up to 20 carbon atoms in main chain.They can be straight or brancheds or cyclic and comprise methyl, ethyl, propyl group, isopropyl, butyl, hexyl etc.
Comprise replacement acylamino-part at this employed term " acylamino-", wherein said substituent group includes, but are not limited to, one or more aryl and C
1-20Alkyl, its each can be optional by one or more aryl, aldehyde radical, ketone group, carboxyl, cyano group, halogen, nitro, C
1-20Alkyl, sulfate, sulfonic group, phosphate, phosphonate group, hydroxyl, oxygen base, sulfydryl and sulfenyl substituent group replace.
Comprise the amino part of replacement at this employed term " amino ", wherein said substituent group includes, but are not limited to, one or more aryl and C
1-20Alkyl, its each can be optional by one or more aryl, aldehyde radical, ketone group, carboxyl, cyano group, halogen, nitro, C
1-20Alkyl, sulfate, sulfonic group, phosphate, phosphonate group, hydroxyl, oxygen base, sulfydryl and sulfenyl substituent group replace.
Choose the carbocyclic aromatic base that replaces wantonly separately or as the employed term of the part of another group " aryl " or " ar " expression at this, the monocycle or the bicyclic radicals that preferably in loop section, contain 6-12 carbon, for example naphthyl of the xenyl of phenyl, xenyl, naphthyl, substituted-phenyl, replacement or replacement.The phenyl of phenyl and replacement is preferred aryl.
Term " complex " is meant metal coordinating moiety of the present invention, and formula (1) for example is with metal complex or coordination.Described metal typical ground is radiosiotope or paramagnetic metal ion.
Term " conjugate " is meant metal coordinating moiety of the present invention, and for example formula (1) is connected with bio-orientation carrier (biomolecule), no matter this metal coordinating moiety whether with metal complex.For the present invention, described metal coordinating moiety is connected with the bio-orientation carrier directly or indirectly by the urea part.
Be meant chlorine, bromine, fluorine and iodine separately or as the employed term of the part of another group " halogen " or " halo (halo) " at this.
Term " hetero atom " is meant the atom beyond de-carbon and the hydrogen.
This separately or as the employed term of the part of another group " heterocycle " or " heterocyclic radical " expression optional that replace, all saturated or unsaturated, monocycle or dicyclo, aromatic or non-aromatic at least one ring, have at least one heteroatomic group.This heterocyclic radical preferably has 1-5 nitrogen-atoms in described ring, and can be connected with the remainder of molecule by carbon atom.Exemplary heterocyclics comprises macro ring, 1,4,7,10-tetraazacyclododecanand, 1,4,7-7-triazacyclononane (tacn), DOTA, DOTMA, DOTP and TETA.
" assorted replace alkyl " described herein part is an alkyl, wherein carbon atom and at least one hetero atom and choose wantonly and hydrogen covalently bound, described hetero atom for example is a nitrogen-atoms.
Be meant the pharmaceutically acceptable chemical compound that comprises metal at this employed " metal medicine ", wherein said chemical compound is used for imaging or treatment.
Embodiment
Embodiment 1:1,4,7,10-tetraazacyclododecanand-1,4,7-triacetic acid synthetic, 10-[(2-butoxy
-5-(N-(CNCbl-5 '-[(13-amino)-4,7,10-trioxa tridecane carbamate])-carbonylamino)
Phenyl) methyl], three-butyl ester (8)
Synthesizing of 2-tert-butoxy-5-nitrobenzyl bromine (1)
The three chloroethene imidic acid tert-butyl esters (t-Butyl trichloroacetimidate) (TBTA)
With 69mL, the potassium tert-butoxide of 0.069mole (1M is in the tert-butyl alcohol) is dissolved in the ether (69mL) to form solution.In 30 minutes, this drips of solution is added to Tritox, and (100g is 0.69mole) in 0 ℃ of solution in ether (69mL).In 1 hour, described mixture is warmed to room temperature and heated restir 1 hour under refluxing.Mixture is cooled to room temperature and vapourisation under reduced pressure to grease.Described grease is dissolved in the hexane (140mL), then filters to remove potassium salt.Then, the filtrate vapourisation under reduced pressure with the residue vacuum distilling, is collected in 2.4mm Hg and 40 ℃ of following distillatory fractions.Yield is 105g, 69%, and based on Tritox.
1H?nmr(300MHz?CDCl
3)：1.58，(s，9H)，8.21(br，s，1H).
13C(75.45MHz，CDCl
3)27.23，83.86，92.78，160.33.
2-tert-butoxy-5-nitrobenzyl bromine (1)
With 2-hydroxyl-5-nitrobenzyl bromine (19.4g, 0.0836mole), the suspension of cyclohexane extraction (334mL) and dichloromethane (167mL) stirs in nitrogen.In 3.5 hours, in this suspension, drip the three chloroethene imidic acid tert-butyl esters (73.08g, 0.334mole) solution in cyclohexane extraction (669mL).After finishing, mixture was stirred one hour, then add boron trifluoride etherate (200 μ L).The mixture stirring is spent the night.Form a large amount of precipitation trichloroacetamides.(4.00g 0.0418mole) handles described reactant mixture, stirs 1 hour, then filters with sodium bicarbonate.Described solid washs with ether, and the filtrate of merging under reduced pressure is concentrated into grease.This grease is handled with hexane (100mL), followed described solution stirring till forming crystal.Also restir is after one hour to be cooled to-20 ℃, and the gained solid is collected in filtration, with cold, fresh hexane wash, drains and vacuum drying.Yield is 13.2g, 55%, and based on 2-hydroxyl-5-nitrobenzyl bromine.Value of calculation C 45.85, H 4.90, and N 4.86, Br 27.73. discovery value C 45.39, H 5.07, and N 4.94, Br 27.66.
1H nmr (300MHz CDCl
3) 1.58 (s, 9H), 4.48 (s, 2H), 7.10 (d, JH=9Hz, 1H), 8.11 (dd, J=9Hz, J=2.7Hz, 1H), 8.22 (d, J=2.7Hz, 1H).
13C (75.45MHz, CDCl
3) 28.92,81.59,116.86,125.07,126.34,129.98,140.69,159.97.
1,4,7,10-tetraazacyclododecanand-1,4,7-triacetic acid, 10-[(2-tert-butoxy-5-nitrobenzophenone) methyl]-, three-tert-butyl ester (3) synthetic
1,4,7,10-tetraazacyclododecanand-1,4,7-triacetic acid, three-tert-butyl ester hydrobromate (2) synthetic
1,4,7,10-tetraazacyclododecanand (Cyclen) (32.0g, 0.186mole) and sodium acetate trihydrate (75.8g 0.557mole) stirred one hour with dimethyl acetylamide (600mL).In four hours, dripping bromine tert-butyl acetate in this mixture (109g, 0.557mole) solution in dimethyl acetylamide (150mL).Regulate the speed that drips, so that make the temperature of reactant mixture be lower than 25 ℃.Mixture was stirred for two nights.Be cooled to-10 ℃ and stir 2 hours after, filter to collect the gained solid, wash with cold, fresh dimethyl acetylamide (50mL), then drain.Described solid is dissolved in the chloroform (0.5L), then with solution with water (3 * 200mL) washings.Collect organic facies, use dried over mgso, filter, under reduced pressure be concentrated into 300mL.Add hexane (300mL), then solution was at room temperature stirred one hour.After a few minutes, the beginning crystallization.Gained slurry (slurry) is cooled to-20 ℃, stirred 2 hours, then filter.Described solid is drained with cold, fresh chloroform-hexane (50mL, 1: 1) washing, and at room temperature vacuum drying spends the night.Productive rate is 69g, 62%, and based on 1,4,7, the 10-tetraazacyclododecanand.
1Hnmr(300MHz，CDCl
3)1.44(s，9H)，1.45(s，18H)，2.87-2.90(br，m，12H)，3.07-3.08(br，m，4H)，3.27(s，2H)，3.56(s，4H)，9.97(br，s，2H).
13Cnmr(75.45MHz，CDCl
3)28.15，28.18，47.44，48.68，49.11，51.15，51.25，58.11，81.54，81.70，169.32，170.21.
1,4,7,10-tetraazacyclododecanand-1,4,7-triacetic acid, 10-[(2-tert-butoxy-5-nitrobenzophenone) first
Base]-, three-tert-butyl ester, sodium bromide complex (3) synthetic
1,4,7,10-tetraazacyclododecanand-1,4, the 7-triacetic acid, three-tert-butyl ester hydrobromate (8.46g, 0.0142mole) with sodium hydrate aqueous solution (0.1N, 200mL) and ether (200mL) stir together.When whole solid dissolves, collect organic facies, (2 * 200mL) wash water with ether.The organic extract liquid dried over mgso that merges is filtered, and vapourisation under reduced pressure is to grease.This grease is dissolved in the acetonitrile (135mL).In this solution, add sodium bicarbonate (1.19g, 0.0142mole), then add 2-tert-butoxy-5-nitrobenzyl bromine (4.50g, 0.0156mole).Mixture is warmed to 35 ℃, and in argon, stirs and spend the night.When reaction detects the discovery end by NMR, amount to 12-14 hour, mixture to be filtered, filtrate under reduced pressure concentrates, and obtains grease.Described grease is suspended in the ether (50mL), stirs the back and form white precipitate.Filter and collect this solid, drain, follow dried overnight in a vacuum.Yield is 11.7g, 98%, and based on initial 1,4,7,10-tetraazacyclododecanand-1,4,7-triacetic acid, three-tert-butyl ester hydrobromate.Analytical calculation value C 52.73, H 7.77, and N 8.31, Br9.48. discovery value C 52.31, H 7.68, and N 8.26, Br 9.67.
1H nmr (300MHz, CDCl
3) 1.45 (s, 27H), 1.51 (s, 9H), 1.78 (br, s, 2H), 2.20 (m, 4H), 2.33 (br, 4H), 2.73 (br, 4H), 2.93 (complicated (complex), br, 6H), 3.10 (m, 2H), 3.29 (s, 1H), 3.37 (s, 1H), 3.57 (s, 2H), 7.15 (d
3J
H-H=9Hz, 1H), 8.07 (d of d,
3J
H-H=9Hz,
4J
H-H=2.7Hz, 1H), 8.88 (d,
4J
H-H=2.7Hz).
13C nmr (75.45MHz, CDCl
3) 28.15,28.20,29.48,50.00 (br), 55.97,56.28,81.83,82.68,83.29,118.27,124.18,127.44,131.13,141.95,161.31,172.67,173.62.
1,4,7,10-tetraazacyclododecanand-1,4,7-triacetic acid, 10-[(2-tert-butoxy-5-(triazolyl-or (and) imidazole radicals carbonylamino) phenyl) methyl]-, three-tert-butyl ester (5) and (6) synthetic
1,4,7,10-tetraazacyclododecanand-1,4,7-triacetic acid, 10-[(2-tert-butoxy-5-aminophenyl) first
Base]-, three-tert-butyl ester, sodium bromide complex, pentahydrate, (4) synthetic
Raney nickel-aqueous slurry (about 0.4g), methanol (20mL) and hydrazine hydrate (1.15mL) are placed in the 250mL round-bottomed flask of argon cleaning.Mixture heated is refluxed, then drip by 1,47,10-tetraazacyclododecanand-1,4,7-triacetic acid, 10-[(2-tert-butoxy-5-nitrobenzophenone) methyl]-, three-tert-butyl ester, and the sodium bromide complex (4.00g, 0.0047mole), the solution formed of methanol (20mL).Joining day is 30 minutes.With mixture reheat 10 minutes.Remove aliquot, evaporate and be dissolved in CDCl
3In.1H nmr shows that reaction is finished more than the 95mole%.Reactant mixture is cooled to room temperature, goes up at celite (celite) and filter.Filtrate is evaporated and is dissolved in the chloroform (14mL), filter to remove some trickle solids and to handle with ether (80mL).After stirring a few minutes, the beginning crystallization.Mixture is cooled to-10 ℃, stirred 1 hour, solid collected by filtration with fresh ether washing, is drained and vacuum drying.Yield is 3.57g, 85%, and based on initial 1,4,7,10-tetraazacyclododecanand-1,4,7-triacetic acid, 10-[(2-tert-butoxy-5-nitrobenzophenone) methyl]-, three-tert-butyl ester, sodium bromide complex.Analytical calculation value C 50.22, H 8.54, and N 7.91, Br 9.03. discovery value C 50.49, H 7.68, and N 7.80, Br 8.86.
1H nmr (300MHz, CDCl
3) 1.28 (s, 9H), 1.45 (s, 9H), 1.47 (s, 18H), 2.22 (m, 4H), 2.36 (br, 6H), 2.80 (br, 6H), 2.97 (s, br, 4H), 3.40 (s, 2H), 3.44 (s, 2H), 6.45 (d of d,
3J
H-H=9Hz,
4J
H-H=2.7Hz, 1H), 6.75 (d,
3J
H-H=9Hz, 1H), 6.92 (d,
4J
H-H=2.7Hz) .13Cnmr (75.45MHz, CDCl
3) 28.25,28.41,29.50,50.00 (br), 54.00,56.15,56.49,79.43,82.55,82.88,115.03,117.73,124.07,131.90,142.69,146.74,172.64,173.38.
1,4,7,10-tetraazacyclododecanand-1,4,7-triacetic acid, 10-[(2-tert-butoxy-5-(imidazole radicals carbonyl
Amino) phenyl) methyl]-, three-tert-butyl ester, sodium bromide complex (5) synthetic
With 1,4,7,10-tetraazacyclododecanand-1,4,7-triacetic acid, 10-[(2-tert-butoxy-5-aminophenyl) methyl]-, three-tert-butyl ester, the sodium bromide complex, (1.00g 0.0011mole) is dissolved in the dichloromethane (4ml) pentahydrate, then add carbonyl dimidazoles (0.26g, 0.16mole).The disappearance of 1H nmr by the aniline chemical shift shows that reaction finishes.With the mixture evaporation, gained grease stirs with ether (25mL).Filter and collect the gained solid, with fresh ether washing, then vacuum drying.Productive rate is 0.77g, 77%, and based on initial 1,4,7,10-tetraazacyclododecanand-1,4,7-triacetic acid, 10-[(2-tert-butoxy-5-aminophenyl) methyl]-, three-tert-butyl ester, sodium bromide complex, pentahydrate.
1Hnmr(300MHz，CDCl
3)1.33(s，9H)，1.44(s，27H)，2.24(br，m，6H)，2.58(br，m，10H)，3.00(br，s，2H)，3.05(br，s，4H)，3.72(s，2H)，7.02(d，
3J
H-H＝8.7Hz，1H)，7.06(s，1H)，7.88(d?of?d，
3J
H-H＝8.7Hz，
4J
H-H＝2.1Hz，1H)，8.01(d，
4J
H-H＝2.1Hz，1H)，8.52(s，1H)，8.57(s，1H)，10.59(br，s，1H).
13C?nmr(75.45MHz，CDCl
3)28.24，28.34，29.64，50.9(br)，56.13，56.70，79.92，82.84，83.00，117.92，122.30，122.42，126.10，128.32，130.02，132.57，137.26，147.82，151.59，172.41，173.11.
1,4,7,10-tetraazacyclododecanand-1,4,7-triacetic acid, 10-[(2-tert-butoxy-5-(triazolyl carbonyl
Amino) phenyl) methyl]-, three-tert-butyl ester (6) synthetic
With carbonyl diurethane-1,2, (0.14g 0.0009mole) is dissolved in the dichloromethane (10mL) the 4-triazole.In this solution, drip 1,4,7,10-tetraazacyclododecanand-1,4,7-triacetic acid, 10-[(2-tert-butoxy-5-aminophenyl) methyl]-, three-tert-butyl ester, the sodium bromide complex, pentahydrate (0.50g, 0.0006mole) solution in dichloromethane (5mL).Mixture was stirred 2 hours, then add ether (50mL) to separate out product.Productive rate is 0.3g, 60%, and based on 1,4,7,10-tetraazacyclododecanand-1,4,7-triacetic acid, 10-[(2-tert-butoxy-5-aminophenyl) methyl]-, three-tert-butyl ester, sodium bromide complex, pentahydrate.
1H?nmr(300MHz，CDCl
3)1.38(s，9H)，1.44(s，27H)，2.19(br，m，4H)，2.38(br，m，4H)，2.80(br，m，8H)，3.00(s，6H)，3.57(s，2H)，7.12(d，
3J
H-H＝8.1Hz，1H)，7.72(dofd，
3J
H-H＝8.7Hz，
4J
H-H＝2.7Hz，1H)，7.84(
4J
H-H＝2.7Hz，1H)，7.91(s，1H)，8.87(s，1H).
13C?nmr(75.45MHz，CDCl
3)28.23，28.44，29.54，49.9(br)，56.01，56.44，80.39，82.56，83.07，119.75，122.96，123.01，131.03，132.23，143.57，144.71，152.30，152.70，172.66，173.72.
1,4,7,10-tetraazacyclododecanand-1,4, the 7-triacetic acid, 10-[(2-tert-butoxy-5-(N-{CNCbl-5 '-[(13-amino)-4,7,10-trioxa-tridecane carbamate])-carbonylamino) phenyl) methyl] (9)
6CNCbl-5 '-[(13-amino)-4,7,10-trioxa
-The tridecane carbamate],
7
1,4,7,10-tetraazacyclododecanand-1,4, the 7-triacetic acid, 10-[(2-tert-butoxy-5-(N-{CNCbl-5 '-[(13-amino)-4,7,10-trioxa-tridecane carbamate])-carbonylamino) phenyl) methyl]-, three-tert-butyl ester,
8
1,4,7,10-tetraazacyclododecanand-1,4, the 7-triacetic acid, 10-[(2-tert-butoxy-5-(N-{CNCbl-5 '-[(13-amino)-4,7,10-trioxa-tridecane carbamate])-carbonylamino) phenyl) methyl],
9
1,4,7,10-tetraazacyclododecanand-1,4,7-triacetic acid, 10-[(2-tert-butoxy-5-(N-{CNCbl-5
'-[(13-amino)-4,7,10-trioxa-tridecane carbamate])-carbonylamino) phenyl) methyl]-, three-
Synthesizing of the tert-butyl ester (8)
In argon, CNCbl-5 '-[(13-amino)-4,7,10-trioxa-tridecane carbamate] is dissolved in the anhydrous dimethyl sulfoxide (1.0ml).In this solution, add 1,4,7,10-tetraazacyclododecanand-1,4,7-triacetic acid, 10-[(2-tert-butoxy-5-(triazolyl carbonylamino) phenyl) methyl]-, three-tert-butyl ester (0.10g, 0.0001mole).Mixture is reacted, till HPLC shows that reaction is finished.Mixture then filters and collects with dichloromethane (5mL) precipitation.Thick solid is then drained with fresh dichloromethane (25mL), ether (25mL) washing.Solid is dissolved in the methanol then with the purification of C-18 column chromatography.Merge pure fraction, under reduced pressure concentrate, by using the acetone precipitation separated product.Yield is 0.12g, 41%, based on initial 1,4,7,10-tetraazacyclododecanand-1,4,7-triacetic acid, 10-[(2-tert-butoxy-5-(N-{CNCbl-5 '-[(13-amino)-4,7,10-trioxa tridecane carbamate])-carbonylamino) phenyl) methyl]-, three-tert-butyl ester.Product carries out HPLC, single eluting peak occurs at 15min, and mass spectrum (M+3H)
3+=774.1 theories=774.1 characterize.
1,4,7,10-tetraazacyclododecanand-1,4, the 7-triacetic acid, 10-[(2-hydroxyl-5-(N-{CNCbl-5 '
-[(13-amino)-4,7,10-trioxa-tridecane carbamate]) }-and carbonylamino) phenyl) methyl]-(9)
Synthetic
With 1,4,7,10-tetraazacyclododecanand-1,4, the 7-triacetic acid, 10-[(2-tert-butoxy-5-(N-{CNCbl-5 '-[(13-amino)-4,7,10-trioxa tridecane carbamate])-carbonylamino) phenyl) methyl]-, three-tert-butyl ester (0.003g, 1.3 μ moles) is dissolved in the trifluoroethanol (1.0ml).In this solution, add trifluoromethanesulfonic acid (triflic acid) (2.3 μ L), then mixture was stirred 10 minutes.HPLC shows that starting material finishes disappearance, and 10.8 minutes eluting occur one unimodal.The mixture evaporation is dissolved in the water again, then evaporates several times.Productive rate is 2.4mg, 89%, based on initial 1,4,7,10-tetraazacyclododecanand-1,4,7-triacetic acid, 10-[(2-tert-butoxy-5-(N-{CNCbl-5 '-[(13-amino)-4,7,10-trioxa-tridecane carbamate])-carbonylamino) phenyl) methyl]-, three-tert-butyl ester.Mass spectrum shows (M+2H)
2+=1048.4 theoretical values=1048.6.
1,4,7,10-tetraazacyclododecanand-1,4,7-triacetic acid, 10-[(2-hydroxyl-5-(N-{N
ε
-lysine
(lys) (3)-bombesin (1-14) }-carbonylamino) phenyl) methyl] (11) synthetic
1,4,7,10-tetraazacyclododecanand-1,4,7-triacetic acid, 10-[(2-hydroxyl-5-(N-{N
ε
-lysine (3)-
Bombesin (1-14) }-carbonylamino) phenyl) methyl], three-tert-butyl ester (10) synthetic
With 1,4,7,10-tetraazacyclododecanand-1,4,7-triacetic acid, 10-[(2-tert-butoxy-5-(imidazole radicals carbonylamino) phenyl) methyl]-, three-tert-butyl ester (3.0mg, 3.8 mMs (millimoles)) is dissolved among the anhydrous DMSO.In this solution, add lysine (3)-bombesin (1-14) (5mg, 3.1 mMs).Mixture was stirred four hours.The HPLC demonstration reaction of aliquot is not finished.Add 1,4,7 of other aliquot, 10-tetraazacyclododecanand-1,4,7-triacetic acid, 10-[(2-tert-butoxy-5-(imidazole radicals carbonylamino) phenyl) methyl]-, three-tert-butyl ester (1.5mg, 1.9 mMs) then stirs mixture and spends the night.Crude product is then purified with reversed phase chromatography by separating with ether sedimentation.Productive rate is 3.0mg, 41%, and based on initial lysine (3)-bombesin (1-14).LCMS shows (M+2H)
2+=1155.6 (theoretical value=1155.1).
1,4,7,10-tetraazacyclododecanand-1,4,7-triacetic acid, 10-[(2-hydroxyl-5-(N-{N
ε
-lysine (3)-
Bombesin (1-14) }-carbonylamino) phenyl) methyl] (11) synthetic
1,4,7,10-tetraazacyclododecanand-1,4,7-triacetic acid, 10-[(2-hydroxyl-5-(N-{N
ε-lysine (3)-bombesin (1-14))-and carbonylamino) phenyl) methyl], the sample of three-tert-butyl ester (3.0mg, 0.0013 mM) is suspended in the deionized water (0.01ml).In this suspension, add trifluoroacetic acid (0.5mL), then mixture is stirred and spend the night.Steaming desolventizes, and residue then evaporates several times with fresh water treatment.Residue is purified with reversed-phase HPLC 5 μ C18.Productive rate is 0.001g, 37%, and based on initial 1,4,7,10-tetraazacyclododecanand-1,4,7-triacetic acid, 10-[(2-hydroxyl-5-(N-{N
ε-lysine (3)-bombesin (1-14) }-carbonylamino) phenyl) methyl], three-tert-butyl ester.LCMS shows (M+2H)
2+=1043.3 (theoretical value=1043.0).
Claims (38)
1. conjugate, the connection base that it comprises bio-orientation carrier, metal coordinating moiety and described metal coordinating moiety and described carrier chemically are connected, described connection base comprises the urea part.
2. the conjugate of claim 1, wherein said bio-orientation carrier is selected from imidazoles, triazole, antibody, albumen, peptide, saccharide, vitamin, hormone, medicine and organic molecule.
3. the conjugate of claim 1, wherein said conjugate comprises a more than bio-orientation carrier.
4. the conjugate of claim 1-3, wherein said metal coordinating moiety is a polybasic carboxylic acid.
5. the conjugate of claim 3, wherein said metal coordinating moiety is selected from EDTA, DTPA, DCTA, DOTA, TETA or its analog or homologue.
6. the conjugate of claim 1-3, wherein said metal coordinating moiety are three azepines-or four azepines-macro ring.
7. each conjugate among the claim 1-6, wherein said metal coordinating moiety and metal complex, described metal is made up of radiosiotope or paramagnetic metal.
8. the conjugate of claim 7, wherein said metal is selected from Lu, Lu-177, Y, Y-90, In, In-111, Tc, Tc=O, Tc-99m, Tc-99m=O, Re, Re-186, Re-188, Re=O, Re-186=O, Re-188=O, Ga, Ga-67, Ga-68, Cu, Cu-62, Cu-64, Cu-67, Gd, Gd-153, Dy, Dy-165, Dy-166, Ho, Ho-166, Eu, Eu-169, Sm, Sm-153, Pd, Pd-103, Pm, Pm-149, Tm, Tm-170, Bi, Bi-212, As and As-211.
9. the conjugate of claim 1, wherein said metal coordinating moiety comprises the heterocycle of replacement.
10. the conjugate of claim 9, wherein said heterocycle comprises 9-15 annular atoms, and at least 3 in the described annular atoms is nitrogen.
11. the conjugate of claim 9 or 10, wherein said heterocycle comprise 3-5 theheterocyclic nitrogen atom.
12. each conjugate among the claim 9-11, wherein said heterocycle be optional being substituted at one or more ring carbon atoms place.
13. the conjugate of claim 12, wherein said heterocycle is substituted at one or more theheterocyclic nitrogen atoms place.
14. the conjugate of claim 1, wherein said metal coordinating moiety comprises the heterocycle of the replacement with following array structure:
Wherein
N is 0,1 or 2; With
M is 0-16, wherein when m greater than 0 the time, each A is the optional C that is replaced by one or more following groups
1-20Alkyl or aryl: aryl, C
1-20Alkyl, aldehyde radical, ketone group, carboxyl, cyano group, halogen, nitro, acylamino-, sulfate, sulfonic group, phosphate, phosphonate group, hydroxyl, oxygen base, sulfydryl or sulfenyl.
15. the conjugate of claim 1, wherein said metal coordinating moiety comprises the substituted heterocycle with following array structure:
Wherein
N is 0,1 or 2;
M is 0-16, wherein when m greater than 0 the time, each A is the optional C that is replaced by one or more following groups
1-20Alkyl or aryl: aryl, C
1-20Alkyl, aldehyde radical, ketone group, carboxyl, cyano group, halogen, nitro, acylamino-, sulfate, sulfonic group, phosphate, phosphonate group, hydroxyl, oxygen base, sulfydryl or sulfenyl;
Q is 0-3, wherein when q greater than 0 the time, each D is independently selected from fluorine, chlorine, bromine, iodine, carboxyl, cyano group, nitro, acylamino-, hydroxyl, amino, sulfate, sulfonic group, phosphate, phosphonate group, optional aryl and the C that is replaced by one or more following groups
1-20Alkyl: C
1-20Alkyl, carboxyl, cyano group, nitro, acylamino-, hydroxyl, amino, sulfate, sulfonic group, phosphate and phosphonate group;
X
1, X
2, X
3, X
4Be the optional methylene that replaces independently, wherein said substituent group is selected from aryl, C
1-20Alkyl, aldehyde radical, ketone group, carboxyl, cyano group, halogen, nitro, acylamino-, sulfate, sulfonic group, phosphate, phosphonate group, hydroxyl, oxygen base, sulfydryl and sulfenyl;
Q
2-Q
4Be independently selected from:
q
2Be 0-4, wherein work as q
2Greater than 0 o'clock, each E was independently selected from fluorine, chlorine, bromine, iodine, carboxyl, cyano group, nitro, acylamino-, hydroxyl, amino, sulfonic group, phosphonate group and optional by one or more C
1-20The C that alkyl, carboxyl, cyano group, nitro, acylamino-, hydroxyl, sulfonic group, phosphonate group, sulfate and phosphate replace
1-20Alkyl; With
T
1Be hydroxyl or sulfydryl.
16. the conjugate of claim 1, wherein said metal coordinating moiety comprise assorted substituted alkyl chain.
17. the conjugate of claim 16, wherein said assorted substituted alkyl chain comprises 4-10 atom, and at least 2 in the described atom is nitrogen.
18. the conjugate of claim 16 or 17, wherein said assorted substituted alkyl chain comprises 2-4 nitrogen-atoms.
19. each conjugate of claim 16-18, wherein said assorted substituted alkyl chain be optional being substituted at one or more carbon atoms place.
20. the conjugate of claim 19, wherein said assorted substituted alkyl chain is substituted at one or more nitrogen-atoms place.
21. the conjugate of claim 1, wherein said metal coordinating moiety comprise the assorted substituted alkyl chain with following array structure:
Wherein
N is 0,1 or 2;
M is 0-8, wherein when m greater than 0 the time, each A is the optional C that is replaced by one or more following groups
1-20Alkyl or aryl: aryl, C
1-20Alkyl, aldehyde radical, ketone group, carboxyl, cyano group, halogen, nitro, acylamino-, sulfate, sulfonic group, phosphate, phosphonate group, hydroxyl, oxygen base, sulfydryl or sulfenyl.
22. the conjugate of claim 1, wherein said metal coordinating moiety comprise the assorted substituted alkyl chain with following array structure:
Wherein
N is 0,1 or 2;
M is 0-8, wherein when m greater than 0 the time, each A is the optional alkyl C that is replaced by one or more following groups
1-20Or aryl: aryl, C
1-20Alkyl, aldehyde radical, ketone group, carboxyl, cyano group, halogen, nitro, acylamino-, sulfate, sulfonic group, phosphate, phosphonate group, hydroxyl, oxygen base, sulfydryl or sulfenyl;
Q is 0-3, wherein when q greater than 0 the time, each D is independently selected from fluorine, chlorine, bromine, iodine, carboxyl, cyano group, nitro, acylamino-, hydroxyl, amino, sulfate, sulfonic group, phosphate, phosphonate group, optional aryl and the C that is replaced by one or more following groups
1-20Alkyl: C
1-20Alkyl, carboxyl, cyano group, nitro, acylamino-, hydroxyl, amino, sulfate, sulfonic group, phosphate and phosphonate group;
X
1, X
2, X
3, X
4And X
5Be the optional methylene that replaces independently, wherein said substituent group is selected from aryl, C
1-20Alkyl, aldehyde radical, ketone group, carboxyl, cyano group, halogen, nitro, acylamino-, sulfate, sulfonic group, phosphate, phosphonate group, hydroxyl, oxygen base, sulfydryl and sulfenyl;
Q
2-Q
5Be independently selected from:
q
2Be 0-4, wherein work as q
2Greater than 0 o'clock, each E was independently selected from fluorine, chlorine, bromine, iodine, carboxyl, cyano group, nitro, acylamino-, hydroxyl, amino, sulfonic group, phosphonate group and optional by one or more C
1-20The C that alkyl, carboxyl, cyano group, nitro, acylamino-, hydroxyl, sulfonic group, phosphonate group, sulfate and phosphate replace
1-20Alkyl; With
T
1Be hydroxyl or sulfydryl.
23. the conjugate of claim 15 or 22, wherein Q
2-Q
5Be selected from:
24. the conjugate of claim 1, wherein said connection base has following general formula:
Wherein
S
1And S
2Be base at interval, each be independently key or a series of atom and
Z
1And Z
2Be hydrogen, aryl, C independently
1-7Alkyl, C
1-7Hydroxyalkyl or C
1-7Alkoxyalkyl.
25. the conjugate of claim 24, wherein S
1And S
2Be single covalent bond, optional aryl or the C that is replaced by one or more following groups independently
1-20Alkylidene: aldehyde radical, ketone group, carboxyl, cyano group, halogen, nitro, acylamino-, sulfate, sulfonic group, phosphate, phosphonate group, hydroxyl, oxygen base, sulfydryl, sulfenyl or sulfoxide group.
26. the conjugate of claim 1, wherein said metal coordinating moiety and metal M complexation form the metal complex with following general formula
Wherein
N is 0,1 or 2;
M is 0-16, wherein when m greater than 0 the time, each A is the optional C that is replaced by one or more following groups
1-20Alkyl or aryl: aryl, C
1-20Alkyl, aldehyde radical, ketone group, carboxyl, cyano group, halogen, nitro, acylamino-, sulfate, sulfonic group, phosphate, phosphonate group, hydroxyl, oxygen base, sulfydryl or sulfenyl;
Q is 0-3, wherein when q greater than 0 the time, each D is independently selected from fluorine, chlorine, bromine, iodine, carboxyl, cyano group, nitro, acylamino-, hydroxyl, amino, sulfate, sulfonic group, phosphate, phosphonate group, optional aryl and the C that is replaced by one or more following groups
1-20Alkyl: C
1-20Alkyl, carboxyl, cyano group, nitro, acylamino-, hydroxyl, amino, sulfate, sulfonic group, phosphate and phosphonate group;
X
1, X
2, X
3, X
4Be the optional methylene that replaces independently, wherein said substituent group is selected from aryl, C
1-20Alkyl, aldehyde radical, ketone group, carboxyl, cyano group, halogen, nitro, acylamino-, sulfate, sulfonic group, phosphate, phosphonate group, hydroxyl, oxygen base, sulfydryl and sulfenyl;
Q
2-Q
4Be independently selected from:
q
2Be 0-4, wherein work as q
2Greater than 0 o'clock, each E was independently selected from fluorine, chlorine, bromine, iodine, carboxyl, cyano group, nitro, acylamino-, hydroxyl, amino, sulfonic group, phosphonate group and optional by one or more C
1-20The C that alkyl, carboxyl, cyano group, nitro, acylamino-, hydroxyl, sulfonic group, phosphonate group, sulfate and phosphate replace
1-20Alkyl;
T
1Be hydroxyl or sulfydryl; With
M is selected from Lu, Lu-177, Y, Y-90, In, In-111, Tc, Tc=O, Tc-99m, Tc-99m=O, Re, Re-186, Re-188, Re=O, Re-186=O, Re-188=O, Ga, Ga-67, Ga-68, Cu, Cu-62, Cu-64, Cu-67, Gd, Gd-153, Dy, Dy-165, Dy-166, Ho, Ho-166, Eu, Eu-169, Sm, Sm-153, Pd, Pd-103, Pm, Pm-149, Tm, Tm-170, Bi, Bi-212, As and As-211.
27. the conjugate of claim 1, wherein said metal coordinating moiety and metal M complexation form the metal complex with following general formula
Wherein
N is 0,1 or 2;
M is 0-8, wherein when m greater than 0 the time, each A is the optional C that is replaced by one or more following groups
1-20Alkyl or aryl: aryl, C
1-20Alkyl, aldehyde radical, ketone group, carboxyl, cyano group, halogen, nitro, acylamino-, sulfate, sulfonic group, phosphate, phosphonate group, hydroxyl, oxygen base, sulfydryl or sulfenyl;
Q is 0-3, wherein when q greater than 0 the time, each D is independently selected from fluorine, chlorine, bromine, iodine, carboxyl, cyano group, nitro, acylamino-, hydroxyl, amino, sulfate, sulfonic group, phosphate, phosphonate group, optional aryl and the C that is replaced by one or more following groups
1-20Alkyl: C
1-20Alkyl, carboxyl, cyano group, nitro, acylamino-, hydroxyl, amino, sulfate, sulfonic group, phosphate and phosphonate group;
X
1, X
2, X
3, X
4And X
5Be the optional methylene that replaces independently, wherein said substituent group is selected from aryl, C
1-20Alkyl, aldehyde radical, ketone group, carboxyl, cyano group, halogen, nitro, acylamino-, sulfate, sulfonic group, phosphate, phosphonate group, hydroxyl, oxygen base, sulfydryl and sulfenyl;
Q
2-Q
5Be independently selected from:
q
2Be 0-4, wherein work as q
2Greater than 0 o'clock, each E was independently selected from fluorine, chlorine, bromine, iodine, carboxyl, cyano group, nitro, acylamino-, hydroxyl, amino, sulfonic group, phosphonate group and optional by one or more C
1-20The C that alkyl, carboxyl, cyano group, nitro, acylamino-, hydroxyl, sulfonic group, phosphonate group, sulfate and phosphate replace
1-20Alkyl;
T
1Be hydroxyl or sulfydryl; With
M is selected from Lu, Lu-177, Y, Y-90, In, In-111, Tc, Tc=O, Tc-99m, Tc-99m=O, Re, Re-186, Re-188, Re=O, Re-186=O, Re-188=O, Ga, Ga-67, Ga-68, Cu, Cu-62, Cu-64, Cu-67, Gd, Gd-153, Dy, Dy-165, Dy-166, Ho, Ho-166, Eu, Eu-169, Sm, Sm-153, Pd, Pd-103, Pm, Pm-149, Tm, Tm-170, Bi, Bi-212, As and As-211.
28. pharmaceutical composition, it comprises among the claim 1-27 each conjugate and pharmaceutically acceptable carrier.
29. the method for a cancer diagnosis in mammal, described method comprise each conjugate and the pharmaceutically acceptable carrier of the claim 1-27 that is used for cancer diagnosis that gives described mammal effective dose.
30. treat method for cancer for one kind in mammal, described method comprises among the claim 1-27 that gives described mammal effective dose each conjugate and pharmaceutically acceptable carrier.
31. test kit, it comprises protected metal coordinating moiety, active urea, deprotection acid, buffer agent and radioactive metal solution.
32. the test kit of claim 31, wherein said metal coordinating moiety comprises the substituted heterocycle with following array structure:
Wherein
N is 0,1 or 2;
M is 0-16, wherein when m greater than 0 the time, each A is the optional C that is replaced by one or more following groups
1-20Alkyl or aryl: aryl, C
1-20Alkyl, aldehyde radical, ketone group, carboxyl, cyano group, halogen, nitro, acylamino-, sulfate, sulfonic group, phosphate, phosphonate group, hydroxyl, oxygen base, sulfydryl or sulfenyl.
33. the test kit of claim 31, wherein said metal coordinating moiety comprises the substituted heterocycle with following array structure:
Wherein
N is 0,1 or 2;
M is 0-16, wherein when m greater than 0 the time, each A is the optional C that is replaced by one or more following groups
1-20Alkyl or aryl: aryl, C
1-20Alkyl, aldehyde radical, ketone group, carboxyl, cyano group, halogen, nitro, acylamino-, sulfate, sulfonic group, phosphate, phosphonate group, hydroxyl, oxygen base, sulfydryl or sulfenyl;
Q is 0-3, wherein when q greater than 0 the time, each D is independently selected from fluorine, chlorine, bromine, iodine, carboxyl, cyano group, nitro, acylamino-, hydroxyl, amino, sulfate, sulfonic group, phosphate, phosphonate group, optional aryl and the C that is replaced by one or more following groups
1-20Alkyl: C
1-20Alkyl, carboxyl, cyano group, nitro, acylamino-, hydroxyl, amino, sulfate, sulfonic group, phosphate and phosphonate group;
X
1, X
2, X
3, X
4Be the optional methylene that replaces independently, wherein said substituent group is selected from aryl, C
1-20Alkyl, aldehyde radical, ketone group, carboxyl, cyano group, halogen, nitro, acylamino-, sulfate, sulfonic group, phosphate, phosphonate group, hydroxyl, oxygen base, sulfydryl and sulfenyl;
Q
2-Q
4Be independently selected from:
q
2Be 0-4, wherein work as q
2Greater than 0 o'clock, each E was independently selected from fluorine, chlorine, bromine, iodine, carboxyl, cyano group, nitro, acylamino-, hydroxyl, amino, sulfonic group, phosphonate group and optional by one or more C
1-20The C that alkyl, carboxyl, cyano group, nitro, acylamino-, hydroxyl, sulfonic group, phosphonate group, sulfate and phosphate replace
1-20Alkyl; With
T
1Be hydroxyl or sulfydryl.
34. the test kit of claim 31, wherein said metal coordinating moiety comprises the alkyl chain of the assorted replacement with following array structure:
Wherein
N is 0,1 or 2;
M be 0-8 wherein when m greater than 0 the time, each A is the optional C that is replaced by one or more following groups
1-20Alkyl or aryl: aryl, C
1-20Alkyl, aldehyde radical, ketone group, carboxyl, cyano group, halogen, nitro, acylamino-, sulfate, sulfonic group, phosphate, phosphonate group, hydroxyl, oxygen base, sulfydryl or sulfenyl.
35. the test kit of claim 31, wherein said metal coordinating moiety comprise the assorted substituted alkyl chain with following array structure:
Wherein
N is 0,1 or 2;
M is 0-8, wherein when m greater than 0 the time, each A is the optional C that is replaced by one or more following groups
1-20Alkyl or aryl: aryl, C
1-20Alkyl, aldehyde radical, ketone group, carboxyl, cyano group, halogen, nitro, acylamino-, sulfate, sulfonic group, phosphate, phosphonate group, hydroxyl, oxygen base, sulfydryl or sulfenyl;
Q is 0-3, wherein when q greater than 0 the time, each D is independently selected from fluorine, chlorine, bromine, iodine, carboxyl, cyano group, nitro, acylamino-, hydroxyl, amino, sulfate, sulfonic group, phosphate, phosphonate group, optional aryl and the C that is replaced by one or more following groups
1-20Alkyl: C
1-20Alkyl, carboxyl, cyano group, nitro, acylamino-, hydroxyl, amino, sulfate, sulfonic group, phosphate and phosphonate group;
X
1, X
2, X
3, X
4And X
5Be the optional methylene that replaces independently, wherein said substituent group is selected from aryl, C
1-20Alkyl, aldehyde radical, ketone group, carboxyl, cyano group, halogen, nitro, acylamino-, sulfate, sulfonic group, phosphate, phosphonate group, hydroxyl, oxygen base, sulfydryl and sulfenyl;
Q
2-Q
5Be independently selected from:
q
2Be 0-4, wherein work as q
2Greater than 0 o'clock, each E was independently selected from fluorine, chlorine, bromine, iodine, carboxyl, cyano group, nitro, acylamino-, hydroxyl, amino, sulfonic group, phosphonate group and optional by one or more C
1-20The C that alkyl, carboxyl, cyano group, nitro, acylamino-, hydroxyl, sulfonic group, phosphonate group, sulfate and phosphate replace
1-20Alkyl; With
T
1Be hydroxyl or sulfydryl.
36. each test kit among the claim 31-35, wherein said radioactive metal is selected from Lu, Lu-177, Y, Y-90, In, In-111, Tc, Tc=O, Tc-99m, Tc-99m=O, Re, Re-186, Re-188, Re=O, Re-186=O, Re-188=O, Ga, Ga-67, Ga-68, Cu, Cu-62, Cu-64, Cu-67, Gd, Gd-153, Dy, Dy-165, Dy-166, Ho, Ho-166, Eu, Eu-169, Sm, Sm-153, Pd, Pd-103, Pm, Pm-149, Tm, Tm-170, Bi, Bi-212, As and As-211.
37. each test kit among the claim 31-36, wherein said buffer agent is selected from citrate, phosphate and borate.
38. each test kit among the claim 31-37, the solution of wherein said metal coordinating moiety, described active urea, described deprotection acid, described buffer agent and described radioactive metal are the forms with unit dosage forms.
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| US74039505P | 2005-11-29 | 2005-11-29 | |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101927006A (en) * | 2010-09-17 | 2010-12-29 | 上海交通大学 | Preparation method of pH-responded metal organic coordination polymer based on medicament |
| CN102977174A (en) * | 2012-12-19 | 2013-03-20 | 北京师范大学 | 99mTc(CO)3 nuclear-labeled macrocyclic polyamine triazole ring glucose-based complex as well as preparation and application of complex |
| CN108485633A (en) * | 2018-03-31 | 2018-09-04 | 青岛大学 | A kind of preparation method of the poly- quaternary amine oil/gas well shale expansion-resisting agent of novel netted |
| CN110835326A (en) * | 2018-08-15 | 2020-02-25 | 正大天晴药业集团股份有限公司 | Process for the preparation of macrocyclic chelants and intermediates therefor |
| CN111874900A (en) * | 2020-07-20 | 2020-11-03 | 河南大学 | Metal coordination block copolymer, preparation method and application thereof |
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2006
- 2006-11-29 CN CNA2006800448365A patent/CN101316615A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101927006A (en) * | 2010-09-17 | 2010-12-29 | 上海交通大学 | Preparation method of pH-responded metal organic coordination polymer based on medicament |
| CN102977174A (en) * | 2012-12-19 | 2013-03-20 | 北京师范大学 | 99mTc(CO)3 nuclear-labeled macrocyclic polyamine triazole ring glucose-based complex as well as preparation and application of complex |
| CN102977174B (en) * | 2012-12-19 | 2015-04-22 | 北京师范大学 | 99mTc(CO)3 nuclear-labeled macrocyclic polyamine triazole ring glucose-based complex as well as preparation and application of complex |
| CN108485633A (en) * | 2018-03-31 | 2018-09-04 | 青岛大学 | A kind of preparation method of the poly- quaternary amine oil/gas well shale expansion-resisting agent of novel netted |
| CN108485633B (en) * | 2018-03-31 | 2021-10-08 | 青岛大学 | Preparation method of shale anti-swelling agent for net-shaped polyquaternary amine oil and gas well |
| CN110835326A (en) * | 2018-08-15 | 2020-02-25 | 正大天晴药业集团股份有限公司 | Process for the preparation of macrocyclic chelants and intermediates therefor |
| CN111874900A (en) * | 2020-07-20 | 2020-11-03 | 河南大学 | Metal coordination block copolymer, preparation method and application thereof |
| CN111874900B (en) * | 2020-07-20 | 2022-12-23 | 河南大学 | Metal coordination block copolymer, preparation method and application thereof |
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