CA1296019C - Thyronine derivatives - Google Patents
Thyronine derivativesInfo
- Publication number
- CA1296019C CA1296019C CA000545158A CA545158A CA1296019C CA 1296019 C CA1296019 C CA 1296019C CA 000545158 A CA000545158 A CA 000545158A CA 545158 A CA545158 A CA 545158A CA 1296019 C CA1296019 C CA 1296019C
- Authority
- CA
- Canada
- Prior art keywords
- formula
- compound
- alkyl
- denotes hydrogen
- ester
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
- C08G65/33396—Polymers modified by chemical after-treatment with organic compounds containing nitrogen having oxygen in addition to nitrogen
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
- G01N33/78—Thyroid gland hormones, e.g. T3, T4, TBH, TBG or their receptors
Abstract
ABSTRACT OF THE DISCLOSURE
Novel thyronine derivatives The invention relates to novel thyronine derivatives of the formula
Novel thyronine derivatives The invention relates to novel thyronine derivatives of the formula
Description
HOECHST AKTIENGESFLLSCHAFT HOE 86/F 209 DrO~I/MW
Description Novel thyronine derivatives The invention relates to novel thyronine derivatives of the general formula I
~-(O-CH2-CH2-)n~-~-NH-IH-CH2 ~ -0- ~ R20H (I) in which R denotes hydrogen, (C1-C6)-alkyl or a group wh;ch can be quantified using chemical or physical methods~
such as, for exa~ple, a radical of the formula COOR3 ~ ~~ ~ R
R1 and R2 are identical or different and denote iodine or hydrogen, R denotes hydrogen or (C1-C6)-alkyl, and n represents an integer between 10 and 400, and the physio~ogically acceptable salts thereof ~ith cations.
Preferred compounds of the formula I are those in which R1 ~` ;35 and R2 are as defined above and n is 10 - 1~D, ;n part-icular 35 - 70~ R denotes SC1-C4)-alkyl, ;n particular methyl or hydrogen, and R3 denotes hydrogen or (C1-C4~-alkyl, in particular ~ethyl or ethyl.
z Salts of the compounds of the formula I are taken to mean, in particular, alkal; metal, akaline-earth metal and ammonium salts.
A group wh;rh can be quantified using chemica~ or physical methods is taken to mean an organic radical which is used for labeling in an immunoassay. Such a radical can be labeled fluorescently, luminescently, electroactively, by spin or radioactively (cf. Neumuller, R~mpps Chemie Lexikon [R~mpPs Lexicon of Chemistry~, 8th Edition, Stuttgart 1983; Gunzer, Rieke, Kontakte Merck 1980, No.3, 3-11;
Eckert, Angew. Chem. _ C1976] 565-574).
The invention furthermore relates to a process for the preparation of compounds of the formula I, ~herein, in the compounds of the general formula II
R- (O-CH2-CH2-)n-OH (II) in which R and n are as defined above, the free alcoholic OH group is reacted, either as carbonic acid ester chloride or as esters of carbonic acid substituted by suitable activated ester groups, with a compound of the formula III
~5 I ~1 H2~-~H-CH2- ~ -O- ~ _0~
COOR I R ( II I ) in which R1 and R2 are as defined above and R3 denotes hydrogen, or, if appropriate~ an ester of the formula III
(R ~ H) is employed, the resultant esters of the formula I sR3 $ H) are converted, if appropriate, into free acids of the formula I ~R3 = H), and, if appropriate, the compound of the formula I thus obtained is converted into its salts.
Further details of the invention are described below with the help of the examples illustrated in the accompanying drawings in which:
Figure 1 is a graph showing the stan~ard cur~e of human serums with increasing FT4 content, using the compound of the invention;
Figure 2 is a graph showing the results of the determination of T4 antibodies in human serums(x) and serums of pregnant women(o); and Figure 3 is a graph showing the results of the determination of the T4/TBG quotient for human serums(x) and serums of pregnant women(o).
The abovementioned compounds of the formula II are preferably trea-ed w~th phosgene ]n inert anhydrous solvents (for example chlorinated hydrocarbons), analo-gously to the method described by W. Krey in Houben-~eyl, Methoden der Organischen Chemie [Methods of Organic Chemistry] (Georg Thieme Verlag, Stuttgart~ 1952, Volume 8/lII, p.103) for the reaction of lo~-molecular-~eight compounds. The carbonyl chloride derivat;ves thus pro-duced are then reacted with the di-, tri- or tetraiodo-thyronine derivatives of the general formula IIl described.
Instead of the chlorides, other activated derivatives of carbonic acid, for e~ample the N-hydroxy-succinimide esters, pentachlorophenyl esters, nitrophenyl esters and the like can also be used.
The reaction of the abovementioned carbonic acid deriv-atives with compounds of the formula III is carried out in a mixed aqueous medium at a pH of 7-10~ preferably 8.5-10. The solvents used are dimethylformamide/water, or dimethylacetamide/water. Unreacted thyronine deriva-tive of the formula III is removed by dialysis,~ ephadexchromatography or ultrafiltration, for example through a UM 2 membrane (Messrs. Amicon).
Due to the preparat;on procedure, mixtures of two or more compounds for the formula I are generally produced. The ; ;nvention therefore also relates to preparations which contain two or More compounds of the formula I.
The invention furthermore relates to the use of compounds of the formula I or mixtures thereof when carry;ng out an immunoassay, preferably a radioimmuno-assay.
The following examples serve to illustrate the present invention without it being l;m;ted to these.
Example 1:
~Polyethylene glycol)-bis-oxycarbonyl-L-3,3',5-triiodothyronine ~6~
220 mg t0.3 mmol) of L-triiodothyronine are dissolved ~ith stirring in a mixture of 4 ml of dimethylformamide and 4 ml of ~ater with addition of aqueous 2N NaOH in an auto-titrator at pH 10. DMF and subsequently, ;n portions, ~ithin 1 hour, 1 9 of (polyethylene glycol~-b;s-oxycarbonyl chloride of molecular ~eight 6000 are then added. The mixture is allowed to react for a further 12 hours at room temperature and pH 9.5, a small amount of insoluble material is filtered off, the solution is evaporated to dryness in high vacuum at room temperature, the residue is taken up in 100 ml of water, and the solution is acidified to pH 3 using aqueous 1N HCl. The solution thus obtained is dialyzed against a total of 30 liters of water, and the final product is isolated by freeze drying.
The pale yello~ish solid thus obtained exhibits an iodine content of 11%, which corresponds to a content of bound triiodothyronine of about 1.7 mol/mol of thyronine deriv-ative.
~ield: 975 mg Example 2:
' Monomethyl-(polyethylene glycolyl)oxycarbonyl-L-3.5-diiodo-~ 25 thyronine compound ' 940 mg ~2 mmol) of L-diiodothyronine are dissolved in a mixture of 6 ml of dimethylformamide and 3 ml of water at pH 8.8-9.5 in an autotitrator. 1 9 of monomethyl-~polyethylene glycol)oxycarbonyl chloride (molecularweight 750) ;s then added in portions within 1 hour.
After st;rring for a further 30 minutes at room temper-; ature, a further ~ g of the carbonyl chloride described above is added. After stirring over night, the solution is virtually clear. The solvent is evaporated in a highvacuun at room temperature, and the residue is taken up in 30 ml of ~ater, the solution is acidified to pH 3 using dilute hydrochLor;c acid, the water phase is ex-; tracted repeatedly with methylene chlori~de, the methylene chloride phase is dried over magnesium sulfate, and acolorless oil, which, according to elemental analysis (C, H, I)~ contains about 30% of the monomethyl-(polyethylene glycol)-diiodothyronine compound, is obtained after removing the methylene chloride by distillation.
Yield: 2.5 9 Further purification is effected by column chromatography on (R)Sephadex G 10 in aqueous 0.1 M acetic acid.
Yield: 0.5 9 of a preparation which is 80% strength according to elementaL analysis.
Example 3:
Monomethyl-(polyethylene glycolyl)oxycarbonyl-L-3,3', 5,5'-tetraiodothyronine compound 350 mg of L-3,3', 5,5'-tetraiodothyronine are dissolved in a mixture of 4 ml of dimethylformamide and 4 ml of water through addition of aqueous 0.5 N sodium hydroxide solution at pH 9.5. A solution o~ 1 9 of (polyethylene glycol)-methyl ether carbonyl chloride (molecular weight about 1900) in 4 ml of dimethylformamide is added drop-wise to this solution ~ithin 1 hour with stirring and maintenance of the pH at 9.5. During the add;t;on of the acid chloride, the suspension produced initially redissolves. After allow;ng to stand overnight, the solution is ac;dified to pH 3 using dilute hydrochloric ac;d, and the solvent is removed by distillation in a h;gh vacuum at room temperature. The residue ;s dr;ed in a des;ccator, and is subsequently ~ashed by boiling three times with absolute ether. The residue ;s then taken up in 16 ~l of bo;l;ng methyl chlor;de, separated from undissolved material by filtration and then allowed to cool in an ;ce bath.
The precipitated solid is ~iltered off under suction:
565 mg. ~y concentrating the mother liquor, a further fraction is obtained: 200 mg. The two fractions exhibit development distances in the chloroform/methanol/20%
strength form;c acid (69:30:7.5) TLC system which are identical to one another and different from 3,3',5,5'-tetraiodothyronine and exhibit identical elemental analyses, ~hich indicate about 1 mol of bound 3,3',5,5'-tetraiodothyronine/mol of the compound.
Example 4:
(Polyethylene gLycolyl)oxycarbonyl-diiodothyronine compound 470 mg of 3,3-diiodothyronine and a 2.2 9 of (polyethylene glycol)-bis-oxycarbonyl chloride (molecular weight 6000) are reacted as described under Example 2, but ~orked up after a reaction time of only 1 hour. 2.8 g of a color-less solid whicll has a waxy consistency and which contains, according to the elemental analysis (;odine, C, H), about 80% of the polymer substituted by 1 mol of 3,3-diiodo-thyronine, are obtained~ Thin-layer chromatography, as described in Example 3, shows the difference bet~een the reaction product and the starting material.
; 25 Example 5:
Monomethyl-(polyethylene glycolyl)oxycarbonyl-L-3,5-diiodothyronine compound The compound is prepared as described in Example 2, but using the carbonyl chloride o~ a monomethyl-(polyethylene glycol) of molecular weight 3000. According to the elemental analysis, the crude product comprises 50% of the titLe compound.
Yield: 3.1 g of a colorless, semi-soLid substance.
Example 6:
(Polyethylene glycoL)oxycarbonyl-L-3,3',5-triiodothyronine methyl ester The compound was prepared as described by the Example 1, but using L-triiodothyronine methyl ester in place of L-triiodothyronine and using a (polyethylene glycol)-bis-oxycarbonyl chloride of molecular weight 15,D00. The reaction time was shortened to 2 hours. According to the eLemental analysis, the reaction product produced showed incorporation of 1 mol of L-triiodothyronine methyl ester/
mol of polyethylene glycol.
Yield at the same batch amount by weight as in Example 1:
750 mg.
Example 7:
Procedure for determining FT4 by the 2-step method (in this respect, cf. Eckert, Angew, Chem. 88 ~1976] 565-574).
In tubes coated with T4 antibodies (20 ng of antibody/
tube), 200 ~l of a standard ser;es (human serums with increasing FT4 content) and 1000 ~l of buffer are brought into contact for half an hour with shaking.
After pouring out the reaction solution, 1000 ~l of the tracer prepared from the compound of Example 3 (activity 3n about 60,000 impulses per minute) are poured into the pre-incubated tube. The tube is incubated for 1 hour~
and the unbound tracers are separated off and measured in a y-counter.
Figure 1 shows the standard curve of human serums with increasing FT4 content. The tracer was prepared from the derivative described in Example 3.
Description Novel thyronine derivatives The invention relates to novel thyronine derivatives of the general formula I
~-(O-CH2-CH2-)n~-~-NH-IH-CH2 ~ -0- ~ R20H (I) in which R denotes hydrogen, (C1-C6)-alkyl or a group wh;ch can be quantified using chemical or physical methods~
such as, for exa~ple, a radical of the formula COOR3 ~ ~~ ~ R
R1 and R2 are identical or different and denote iodine or hydrogen, R denotes hydrogen or (C1-C6)-alkyl, and n represents an integer between 10 and 400, and the physio~ogically acceptable salts thereof ~ith cations.
Preferred compounds of the formula I are those in which R1 ~` ;35 and R2 are as defined above and n is 10 - 1~D, ;n part-icular 35 - 70~ R denotes SC1-C4)-alkyl, ;n particular methyl or hydrogen, and R3 denotes hydrogen or (C1-C4~-alkyl, in particular ~ethyl or ethyl.
z Salts of the compounds of the formula I are taken to mean, in particular, alkal; metal, akaline-earth metal and ammonium salts.
A group wh;rh can be quantified using chemica~ or physical methods is taken to mean an organic radical which is used for labeling in an immunoassay. Such a radical can be labeled fluorescently, luminescently, electroactively, by spin or radioactively (cf. Neumuller, R~mpps Chemie Lexikon [R~mpPs Lexicon of Chemistry~, 8th Edition, Stuttgart 1983; Gunzer, Rieke, Kontakte Merck 1980, No.3, 3-11;
Eckert, Angew. Chem. _ C1976] 565-574).
The invention furthermore relates to a process for the preparation of compounds of the formula I, ~herein, in the compounds of the general formula II
R- (O-CH2-CH2-)n-OH (II) in which R and n are as defined above, the free alcoholic OH group is reacted, either as carbonic acid ester chloride or as esters of carbonic acid substituted by suitable activated ester groups, with a compound of the formula III
~5 I ~1 H2~-~H-CH2- ~ -O- ~ _0~
COOR I R ( II I ) in which R1 and R2 are as defined above and R3 denotes hydrogen, or, if appropriate~ an ester of the formula III
(R ~ H) is employed, the resultant esters of the formula I sR3 $ H) are converted, if appropriate, into free acids of the formula I ~R3 = H), and, if appropriate, the compound of the formula I thus obtained is converted into its salts.
Further details of the invention are described below with the help of the examples illustrated in the accompanying drawings in which:
Figure 1 is a graph showing the stan~ard cur~e of human serums with increasing FT4 content, using the compound of the invention;
Figure 2 is a graph showing the results of the determination of T4 antibodies in human serums(x) and serums of pregnant women(o); and Figure 3 is a graph showing the results of the determination of the T4/TBG quotient for human serums(x) and serums of pregnant women(o).
The abovementioned compounds of the formula II are preferably trea-ed w~th phosgene ]n inert anhydrous solvents (for example chlorinated hydrocarbons), analo-gously to the method described by W. Krey in Houben-~eyl, Methoden der Organischen Chemie [Methods of Organic Chemistry] (Georg Thieme Verlag, Stuttgart~ 1952, Volume 8/lII, p.103) for the reaction of lo~-molecular-~eight compounds. The carbonyl chloride derivat;ves thus pro-duced are then reacted with the di-, tri- or tetraiodo-thyronine derivatives of the general formula IIl described.
Instead of the chlorides, other activated derivatives of carbonic acid, for e~ample the N-hydroxy-succinimide esters, pentachlorophenyl esters, nitrophenyl esters and the like can also be used.
The reaction of the abovementioned carbonic acid deriv-atives with compounds of the formula III is carried out in a mixed aqueous medium at a pH of 7-10~ preferably 8.5-10. The solvents used are dimethylformamide/water, or dimethylacetamide/water. Unreacted thyronine deriva-tive of the formula III is removed by dialysis,~ ephadexchromatography or ultrafiltration, for example through a UM 2 membrane (Messrs. Amicon).
Due to the preparat;on procedure, mixtures of two or more compounds for the formula I are generally produced. The ; ;nvention therefore also relates to preparations which contain two or More compounds of the formula I.
The invention furthermore relates to the use of compounds of the formula I or mixtures thereof when carry;ng out an immunoassay, preferably a radioimmuno-assay.
The following examples serve to illustrate the present invention without it being l;m;ted to these.
Example 1:
~Polyethylene glycol)-bis-oxycarbonyl-L-3,3',5-triiodothyronine ~6~
220 mg t0.3 mmol) of L-triiodothyronine are dissolved ~ith stirring in a mixture of 4 ml of dimethylformamide and 4 ml of ~ater with addition of aqueous 2N NaOH in an auto-titrator at pH 10. DMF and subsequently, ;n portions, ~ithin 1 hour, 1 9 of (polyethylene glycol~-b;s-oxycarbonyl chloride of molecular ~eight 6000 are then added. The mixture is allowed to react for a further 12 hours at room temperature and pH 9.5, a small amount of insoluble material is filtered off, the solution is evaporated to dryness in high vacuum at room temperature, the residue is taken up in 100 ml of water, and the solution is acidified to pH 3 using aqueous 1N HCl. The solution thus obtained is dialyzed against a total of 30 liters of water, and the final product is isolated by freeze drying.
The pale yello~ish solid thus obtained exhibits an iodine content of 11%, which corresponds to a content of bound triiodothyronine of about 1.7 mol/mol of thyronine deriv-ative.
~ield: 975 mg Example 2:
' Monomethyl-(polyethylene glycolyl)oxycarbonyl-L-3.5-diiodo-~ 25 thyronine compound ' 940 mg ~2 mmol) of L-diiodothyronine are dissolved in a mixture of 6 ml of dimethylformamide and 3 ml of water at pH 8.8-9.5 in an autotitrator. 1 9 of monomethyl-~polyethylene glycol)oxycarbonyl chloride (molecularweight 750) ;s then added in portions within 1 hour.
After st;rring for a further 30 minutes at room temper-; ature, a further ~ g of the carbonyl chloride described above is added. After stirring over night, the solution is virtually clear. The solvent is evaporated in a highvacuun at room temperature, and the residue is taken up in 30 ml of ~ater, the solution is acidified to pH 3 using dilute hydrochLor;c acid, the water phase is ex-; tracted repeatedly with methylene chlori~de, the methylene chloride phase is dried over magnesium sulfate, and acolorless oil, which, according to elemental analysis (C, H, I)~ contains about 30% of the monomethyl-(polyethylene glycol)-diiodothyronine compound, is obtained after removing the methylene chloride by distillation.
Yield: 2.5 9 Further purification is effected by column chromatography on (R)Sephadex G 10 in aqueous 0.1 M acetic acid.
Yield: 0.5 9 of a preparation which is 80% strength according to elementaL analysis.
Example 3:
Monomethyl-(polyethylene glycolyl)oxycarbonyl-L-3,3', 5,5'-tetraiodothyronine compound 350 mg of L-3,3', 5,5'-tetraiodothyronine are dissolved in a mixture of 4 ml of dimethylformamide and 4 ml of water through addition of aqueous 0.5 N sodium hydroxide solution at pH 9.5. A solution o~ 1 9 of (polyethylene glycol)-methyl ether carbonyl chloride (molecular weight about 1900) in 4 ml of dimethylformamide is added drop-wise to this solution ~ithin 1 hour with stirring and maintenance of the pH at 9.5. During the add;t;on of the acid chloride, the suspension produced initially redissolves. After allow;ng to stand overnight, the solution is ac;dified to pH 3 using dilute hydrochloric ac;d, and the solvent is removed by distillation in a h;gh vacuum at room temperature. The residue ;s dr;ed in a des;ccator, and is subsequently ~ashed by boiling three times with absolute ether. The residue ;s then taken up in 16 ~l of bo;l;ng methyl chlor;de, separated from undissolved material by filtration and then allowed to cool in an ;ce bath.
The precipitated solid is ~iltered off under suction:
565 mg. ~y concentrating the mother liquor, a further fraction is obtained: 200 mg. The two fractions exhibit development distances in the chloroform/methanol/20%
strength form;c acid (69:30:7.5) TLC system which are identical to one another and different from 3,3',5,5'-tetraiodothyronine and exhibit identical elemental analyses, ~hich indicate about 1 mol of bound 3,3',5,5'-tetraiodothyronine/mol of the compound.
Example 4:
(Polyethylene gLycolyl)oxycarbonyl-diiodothyronine compound 470 mg of 3,3-diiodothyronine and a 2.2 9 of (polyethylene glycol)-bis-oxycarbonyl chloride (molecular weight 6000) are reacted as described under Example 2, but ~orked up after a reaction time of only 1 hour. 2.8 g of a color-less solid whicll has a waxy consistency and which contains, according to the elemental analysis (;odine, C, H), about 80% of the polymer substituted by 1 mol of 3,3-diiodo-thyronine, are obtained~ Thin-layer chromatography, as described in Example 3, shows the difference bet~een the reaction product and the starting material.
; 25 Example 5:
Monomethyl-(polyethylene glycolyl)oxycarbonyl-L-3,5-diiodothyronine compound The compound is prepared as described in Example 2, but using the carbonyl chloride o~ a monomethyl-(polyethylene glycol) of molecular weight 3000. According to the elemental analysis, the crude product comprises 50% of the titLe compound.
Yield: 3.1 g of a colorless, semi-soLid substance.
Example 6:
(Polyethylene glycoL)oxycarbonyl-L-3,3',5-triiodothyronine methyl ester The compound was prepared as described by the Example 1, but using L-triiodothyronine methyl ester in place of L-triiodothyronine and using a (polyethylene glycol)-bis-oxycarbonyl chloride of molecular weight 15,D00. The reaction time was shortened to 2 hours. According to the eLemental analysis, the reaction product produced showed incorporation of 1 mol of L-triiodothyronine methyl ester/
mol of polyethylene glycol.
Yield at the same batch amount by weight as in Example 1:
750 mg.
Example 7:
Procedure for determining FT4 by the 2-step method (in this respect, cf. Eckert, Angew, Chem. 88 ~1976] 565-574).
In tubes coated with T4 antibodies (20 ng of antibody/
tube), 200 ~l of a standard ser;es (human serums with increasing FT4 content) and 1000 ~l of buffer are brought into contact for half an hour with shaking.
After pouring out the reaction solution, 1000 ~l of the tracer prepared from the compound of Example 3 (activity 3n about 60,000 impulses per minute) are poured into the pre-incubated tube. The tube is incubated for 1 hour~
and the unbound tracers are separated off and measured in a y-counter.
Figure 1 shows the standard curve of human serums with increasing FT4 content. The tracer was prepared from the derivative described in Example 3.
2~I ig Figures 2 and 3 show results from the investigation of human serums (shown as "x"). The serums of pregnant ~omen (shown as "o") were included in the ;nvestigation since they have a high total T4 content. the two correlations show that there is no direct relat;onship between the content of free T4 and the total T4 content.
The correlations furthermore show that the T4/TBG
quotient conforms, at a ~irst approximation, to the curve of free T4.
~, . , "
The correlations furthermore show that the T4/TBG
quotient conforms, at a ~irst approximation, to the curve of free T4.
~, . , "
Claims (9)
1. A compound of the formula I
(I) in which R denotes hydrogen, (C1-C6)-alkyl or a radical of the formula R1 and R2 are indentical or different and denote iodine or hydrogen, R3 denotes hydrogen or (C1-C6)-alkyl, and n represents an integer between 10 and 400, and the physiologically acceptable salts thereof with cations.
(I) in which R denotes hydrogen, (C1-C6)-alkyl or a radical of the formula R1 and R2 are indentical or different and denote iodine or hydrogen, R3 denotes hydrogen or (C1-C6)-alkyl, and n represents an integer between 10 and 400, and the physiologically acceptable salts thereof with cations.
2. A compound of the formula I as claimed in claim 1, in which n is 35 - 70, R deontes H or (C1-C4)-alkyl, and R3 denotes hydrogen or (C1-C4)-alkyl.
3. A compound of the formula I as claimed in claim 1, in which R3 denotes hydrogen, methyl or ethyl.
4. A compound of the formula I as claimed in claim 1, 2 or 3, in which at least one of the iodine atoms is radioactively labeled.
5. A compound of the formula I, in which R1, R2, R3 and n are as defined in claim 1, and R represents a group which can be quantified by chemical or physical methods.
6. A process for the preparation of a compound of the formula I as claimed in cLaim 1, wherein, in a compound of the formula II
R - (O-CH2-CH2-)n-OH (II) in which R and n are as defined in claim 1, the free alcoholic OH group is reacted, either as the carbonic acid ester chloride or as a carbonic acid ester which is substituted by suitable activated ester groups, with a compound of the formula III
(III) in which R1 and R2 are as defined in claim 1, and R3 denotes hydrogen, or, if desired, an ester of formula III (R3 ? H) is employed, the resultant ester of the formula I (R3 ? H) is converted, if desired, into the free acids of the formula I
(R3 = H), and the compound of the formula I thus obtained is converted, if desired, into its salts.
R - (O-CH2-CH2-)n-OH (II) in which R and n are as defined in claim 1, the free alcoholic OH group is reacted, either as the carbonic acid ester chloride or as a carbonic acid ester which is substituted by suitable activated ester groups, with a compound of the formula III
(III) in which R1 and R2 are as defined in claim 1, and R3 denotes hydrogen, or, if desired, an ester of formula III (R3 ? H) is employed, the resultant ester of the formula I (R3 ? H) is converted, if desired, into the free acids of the formula I
(R3 = H), and the compound of the formula I thus obtained is converted, if desired, into its salts.
7. A preparation containing two or more compounds as claimed in claim 1, 2 or 3.
8. The use of a compound of the formula I as claimed in any one of claims 1 to 3 or 5 when carrying out an immunoassay.
9. A compound of the formula I as claimed in any one of claims 1 to 3 or 5 for use in carrying out an immunoassay.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3628795.4 | 1986-08-25 | ||
| DE19863628795 DE3628795A1 (en) | 1986-08-25 | 1986-08-25 | NEW THYRONE DERIVATIVES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1296019C true CA1296019C (en) | 1992-02-18 |
Family
ID=6308115
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000545158A Expired - Lifetime CA1296019C (en) | 1986-08-25 | 1987-08-24 | Thyronine derivatives |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US4820860A (en) |
| EP (1) | EP0257572B1 (en) |
| JP (1) | JPS6392647A (en) |
| AT (2) | ATE115980T1 (en) |
| CA (1) | CA1296019C (en) |
| DE (2) | DE3628795A1 (en) |
| DK (1) | DK173666B1 (en) |
| ES (1) | ES2066756T3 (en) |
| NO (1) | NO169176C (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TR24238A (en) * | 1989-04-27 | 1991-07-01 | Ciba Geigy Ag | NEW N-EMERGENCY 2- (4- (HALOFENOXY) -PHENOXY) - ETHILCARBAMIC ACID ESTERS |
| DE4004296A1 (en) * | 1990-02-13 | 1991-08-14 | Hoechst Ag | IMPROVED MARKED HAPTENE, METHOD FOR THE PRODUCTION THEREOF AND USE OF THIS MARKED HAPTENE IN IMMUNOASSAYS |
| FR2662082B1 (en) * | 1990-05-15 | 1994-12-23 | Immunotech Sa | NOVEL DERIVATIVES OF ENDOGENOUS MEDIATORS, THEIR SALTS, PREPARATION METHOD AND APPLICATIONS. |
| CA2042295A1 (en) * | 1990-05-15 | 1991-11-16 | Jacques Chauveau | Endogen mediator derivatives, salts thereof, process for their preparation, applications and compositions containing such |
| US7163918B2 (en) * | 2000-08-22 | 2007-01-16 | New River Pharmaceuticals Inc. | Iodothyronine compositions |
| US6423549B1 (en) * | 2001-03-14 | 2002-07-23 | Bio-Rad Laboratories, Inc. | Phycoerythrin labeled thyronine analogues and assays using labeled analogues |
| AU2003216382A1 (en) * | 2002-02-22 | 2003-09-09 | New River Pharmaceuticals | Idothyronine compositions |
| CN109212194B (en) * | 2018-10-11 | 2020-06-16 | 郑州安图生物工程股份有限公司 | Kit for quantitatively detecting transtriiodothyronine |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1047082A (en) * | 1963-02-01 | 1966-11-02 | Pfizer & Co C | Thyronine derivatives |
| US3930017A (en) * | 1965-10-07 | 1975-12-30 | Horst Kummer | Lowering blood cholesterol and lipid levels |
| EP0052094A1 (en) * | 1979-04-25 | 1982-05-19 | BIOCHEMIE Gesellschaft m.b.H. | N-isopropoxycarbonylphenylglycines and their production |
| US4894479A (en) * | 1981-06-01 | 1990-01-16 | Rohm And Haas Company | Herbicidal diphenyl ethers |
| US4399121A (en) * | 1981-11-04 | 1983-08-16 | Miles Laboratories, Inc. | Iodothyronine immunogens and antibodies |
| US4358604A (en) * | 1981-11-04 | 1982-11-09 | Miles Laboratories, Inc. | N-Aminoalkyl iodothyronine derivatives |
| CA1195995A (en) * | 1982-11-08 | 1985-10-29 | Curtis L. Kirkemo | Substituted carboxyfluoresceins |
| US4476228A (en) * | 1982-11-08 | 1984-10-09 | Abbott Laboratories | Determination of unsaturated thyroxine binding protein sites using fluorescence polarization techniques |
| JPS6056947A (en) * | 1983-09-07 | 1985-04-02 | Sumitomo Chem Co Ltd | Carbamate derivative and controlling agent against injurious organism containing the same as active constituent |
| DE3504406A1 (en) * | 1985-02-08 | 1986-08-14 | Boehringer Mannheim Gmbh, 6800 Mannheim | METHOD FOR DETERMINING THE BINDING CAPACITY OF THYROXIN BINDING GLOBULIN |
| US4741897A (en) * | 1986-07-08 | 1988-05-03 | Baxter Travenol | Thyroxine analogs and reagents for thyroid hormone assays |
-
1986
- 1986-08-25 DE DE19863628795 patent/DE3628795A1/en not_active Withdrawn
-
1987
- 1987-08-21 US US07/087,805 patent/US4820860A/en not_active Expired - Lifetime
- 1987-08-21 DE DE3750891T patent/DE3750891D1/en not_active Expired - Lifetime
- 1987-08-21 ES ES87112127T patent/ES2066756T3/en not_active Expired - Lifetime
- 1987-08-21 EP EP87112127A patent/EP0257572B1/en not_active Expired - Lifetime
- 1987-08-21 AT AT87112127T patent/ATE115980T1/en not_active IP Right Cessation
- 1987-08-24 NO NO873564A patent/NO169176C/en unknown
- 1987-08-24 JP JP62208385A patent/JPS6392647A/en active Pending
- 1987-08-24 DK DK198704409A patent/DK173666B1/en not_active IP Right Cessation
- 1987-08-24 CA CA000545158A patent/CA1296019C/en not_active Expired - Lifetime
- 1987-10-08 AT AT0259887A patent/AT388373B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| AT388373B (en) | 1989-06-12 |
| EP0257572B1 (en) | 1994-12-21 |
| NO169176C (en) | 1992-05-20 |
| DK440987A (en) | 1988-02-26 |
| NO873564L (en) | 1988-02-26 |
| EP0257572A2 (en) | 1988-03-02 |
| ATA259887A (en) | 1988-11-15 |
| DE3750891D1 (en) | 1995-02-02 |
| NO873564D0 (en) | 1987-08-24 |
| DK440987D0 (en) | 1987-08-24 |
| JPS6392647A (en) | 1988-04-23 |
| NO169176B (en) | 1992-02-10 |
| ATE115980T1 (en) | 1995-01-15 |
| DK173666B1 (en) | 2001-05-28 |
| ES2066756T3 (en) | 1995-03-16 |
| EP0257572A3 (en) | 1988-12-14 |
| DE3628795A1 (en) | 1988-03-03 |
| US4820860A (en) | 1989-04-11 |
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