CA1318668C - Radioiodine benzodiazepine derivatives - Google Patents
Radioiodine benzodiazepine derivativesInfo
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- CA1318668C CA1318668C CA000607447A CA607447A CA1318668C CA 1318668 C CA1318668 C CA 1318668C CA 000607447 A CA000607447 A CA 000607447A CA 607447 A CA607447 A CA 607447A CA 1318668 C CA1318668 C CA 1318668C
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/041—Heterocyclic compounds
- A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
- A61K51/0468—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K51/047—Benzodiazepines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2123/00—Preparations for testing in vivo
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Abstract
Abstract Radioiodine 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a]-[1,4]benzodiazepine derivativesof the formula I
wherein I* is a radioactive iodine and R is an alkyl group with 1-4 C-atoms, and their use in diagnosing diseases and disorders of the brain through their ability to image the brain.
wherein I* is a radioactive iodine and R is an alkyl group with 1-4 C-atoms, and their use in diagnosing diseases and disorders of the brain through their ability to image the brain.
Description
13~8~8 R~N 4090/19 The present invention is concerned with radioiodinated benzodiazepine derivatives of the formula ~N~OOR
1 o f~ N~
~./
~ ~'C~
I* 3 wherein I~ is a radioactive iodine and R is an alkyl group with 1-4 C-atoms, and their use in diagnosing diseases and disordecs of the brain through their ability to image the brain.
The radioactive iodine is preferably iodine 123. The alkyl group R is prefeeably methyl, ethyl, isoeropyl, sec.butyl or tert.butyl, most preferably ethyl.
Thus the most preferred compound according to the instant invention is ethyl-7- iodo-5,6-dihydro-5-methyl-6-oxo -4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate.
The compounds of formula I are useful for imaging the brain. As will therefore be appreciated the compounds of formula I demonstrate rapid accumulation in the brain indicative of an ability to penetrate the so-termed "blood/bcain barrier". The compounds of formula I demonstrate rapid localization of the radioiodine in the brain following intravenous administration.
Klt/13.6.89 131~8 The compounds of formula I can be used to diagnose diseases or disorders of the brain by imaging changes in the distribution of the benzodiazepine receptors in the brain. In this manner the compounds of formula I can be used to diagnose such brain diseases and disorders as cerebro--vascular diseases ~e.g. strokes), neurological diseases (e.g. epilepsy) and psychotic diseases.
The compounds of formula I can be prepared by methods recognized in the art. For example a compound of formula I
can be prepared from a cold compound of formula I, i.e. a compound, wherein I is a stable iodine, by exchange with a radioactive iodine, preferably iodine 123.
For the exchange radiolabeling process, iodine 123 in a O.lN sodiumhydroxide solution is utilized. This solution is heated with a solution of the cold compound of formula I;
i.e. a compound correseonding to formula I but wherein I is stable iodine and not iodine 123 for from about 1/4 to about 2 hours. The exchange radiolabeling is carried out in the presence of a solvent such as, for example, glacial acetic acid.
A further and preferred method for preparing the compounds of formula I consists in reacting a compound of the formula // \_C OO R
\ /1 ~ ~
B~ 0 35 with a radioactive iodine.
Most preferably iodine 123 is used.
~3~8 The same reac~ion conditionE; are used as in the case of the e~change of the non-radioactive iodine by the 123 iodine.
The cold compounds of formula I and the compounds of formula II are either known from European patent publications No. 27214 or 59389 or ~.S. Patent No. 4,316,839. These cold compounds can be prepared according to the methods given in the above European and US patent publications.
As stated above, the radioiodine containing compounds of the invention rapidly localize in the brain following intravenous administration. In most instances, a sufficient amount of the administered dose will accumulate in the brain within from about two to ten minutes to permit the taking of scintiphotos. The comeounds of the invention will show meaningful presence in the brain for at least 60 minutes so that significant studies may be carried out.
The radioiodinated compounds of the subject invention may be administered in an aqueous or aqueous/alcoholic medium.
Such media may also contain conventional pharmaceutical adjunct materials such as, for example, pharmaceutically acceptable salts to adjust the osmotic pressure, buffers, preservatives and the like.
~ preferred vehicle for the parenteral administration of the compounds of formula I is normal saline which would contain from about 0.5% by weight to about 2% by weight of a suitable preservative.
The radioactive benzodiazepine of this invention can be injected intraveneously into a patient for diagnostic imaging of the brain. In accordance with this invention, the radio-active benzodiazepine of formula I is administeced in a single unit injectable dose. ~ny of the common carriers, such as sterile saline solution, plasma, etc. can be used for preparing the injectable solution for use to diagnostically ~, , ..... ~ ~
~3~6~8 image in accordance with this invention. Generally, the unit dose to be administered contains radioactivity of about 2 mCi to about 10 mCi, preferably about 4 to 5 mCi. However, any amount of the compounds which is effective for imaging the brain can be injected in accordance with this invention. The solution to be injec~ed is preferably in a unit dosage form of about from 0.1 milliliters to about 10 milliliters preferably from about 1 to 5 milliliters and more preferable 4 to 5 milliliters. After intravenous administration, the radioactive benzodiazepine of formula I will image the organs ln vivo. Any conventional method of visualizing or imaging for diagnostic purposes can be utilized in accordance with this invention. In this respect scintiscanning means can be used to visualize or image the brain.
In accordance with this invention, the compound of formula I and particularly ethyl-7- iodo-5,6-dihydro-S--methyl-6-oxo-4H-imidazo~1,5-a][1,4]benzodiazepine-3--carboxy-late is administered to humans intraveneously in a normal saline solution containing 5% glucose. The dose injected into humans contained 4 to 5 mCi of this radioactive compound.
Within 40-60 minutes after injection, scintiphotos were made during Z5 minutes with a Gamma Spect. camera. In accordance with a preferred enbodiment this compound is injected at a dose of 0.0543 mCi per kg.
The compound of formula I can be administered as a free base or as a pharmaceutically acceptable acid addition salt.
The following examples further illustrate the invention.
Unless otherwise noted, all temperatures are in degrees centigrade.
Example 1 The labelling procedure for halogen exchange (bromide-iodide) was performed in a conical reaction vial 13~ 8~
tightly closed by a teflon laminated silicon septum. I-123 activity (up to 300 mCi) in O.ln Na~H was evaporated to dryness by means of a gentle stream of nitrogen at soo. Then 1 mg of ethyl-7-bromo-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a][1,4]benzodiazepino-3-carboxylate dissolved in 200 ~1 glacial acetic acid was added and the r~action mixture heated for 1 h at 150~ ~fter cooling this mixture was dissolved in 5 ml water and eufified by HPLC. The HPLC
conditions were as follows: RP-18 column (8 x 250) Knauer Lichrosorb 10 ~m, MeOH/H20 45/55, 2 ml/min, iodide:
k'=0.0, bromo-derivate: k'=2.75, iodo-derivate: k'=4.00. The purification was performed on a device consisting of a valco 6-port valve with 20 ml loop, a Waters 510 pump, a Kontron 740 LC detector and a NaI scintillation detector. Labelling and ~urification was done in a lead box which was equipped for remote control handling. The labelling was virtually quantitative.
Example 2 During the HPLC-separation the product peak was collected and afterwards evaporated to dryness with a Rota-Vapor. The residue was dissolved in a solution containing 5% glucose and passed through a silver powder column to adsorb iodine liberated during the Rota-Vapoc*treatment. ~fter sterile filtration and adjustment of the activity concentration to 1 mCi/ml the ethyl-7-123iodo-5,6-dihydro-5~-methyl-6-oxo--4H-imidazo[1,5-a]tl,4]benzodiazepino-3-carboxylate was ready for use.
The product quality was monitored with thin layer chromatography on silica gel, developed with ethylacetate/
NH40H 200/1.
*Trade mark A
-` 13i8668 Example 3 The starting material used in Example 1 was prepared as follow~:
To a mixture of 167.95 g (624 mmol) of 6-bromo-3,4--dihydro-4-methyl-2H-l,~-benzodiazepine -2,5~1H)-dione, 600 ml of N,N-dimethyl-p-toluidine and 800 ml of chloroform are added dropwise at the boiling temperature of the mixture 160.8 g (1,05 mol) phosphorus oxychloride whereupon the reaction mixture is boiled under reflux for 4 hours. The resulting solution is poured on a cold mixture of 500 g sodium bicarbonate and 2 1 of water and stirred during 40 minutes. The anorganic phase is separated and extracted three times with chloroform. The combined organic layers are dried over magnesium sulfate and the chloroform is removed under reduced pressure.
In the meantime a solution of 76 g (677 mmol) potassium--t-butylate in 200 ml of dimethylformamide is cooled to -45, whereupon first 71 g (625 mmol) isocyanoacetic acid ethylester are added and then at -50 to -20 the above mentioned solution of the iminechloride is added dropwise.
~fter removing of the cooling means the reaction mixture is stirred during 1.5 hours, whereupon 13 ml acetic acid are added and then the reaction mixture is poured on to 1800 ml of water and extracted five times with each 500 ml methylene chloride. The combined organic extracts are washed three times with water, dried over magnesium sulfate and evaporated. The raw product is recrystalized from methylene chloride and ethyl acetate and yields 156.80 g of ethyl 7-bromo-5,6-dihydro-5~methyl-6-oxo -4H-imidazo[1,5-a][1,4]-benzodiazepine-3-carboxylate of melting point Z14-215.
~3~86~8 Example 4 Iodide-iodide exchange labelling was performed exactly as described for bromide-iodide exchange, but ethyl-7-iodo-5,6--dihydro-5-methyl-6-oxo -4H-imidazo[1,5-a]rl,4]benzodia-zepine-3-carboxylate was used as precursor. This labelling was performed to assure the identity of the labelled product in HPLC and thin layer chromatography.
Example 5 The starting material used in Example 4 was prepared as follows:
To a mixture of 185.5 g t558.8 mmol) ~f 3,4-dihydro -5-iodo-4-methyl-2H-1,4-benzodiazepine -2,5(lH)-dione, 70 ml of N,N-dimethyl-~-toluidine and 800 ml of chloroform are added dropwise at the boiling temperature of the mixture 91.6 ml (979 mmol) phosphorus oxychloride whereupon the reaction mixture is boiled under reflux for 2 hours. The resulting solution is poured on a cold mixture of 490 g sodium bicarbonate and 2 1 of water and stirred during 40 minutes. The anorganic phase is separated and extracted three times with chloroform. The combined organic layers are dried over magnesium sulfate and the chloroform is removed under reduced pressure.
In the meantime a solution of 75.5 g (626.6 mmol) potassium-t-butylate in 500 ml of dimethylformamide is cooled to -50, whereupon first 65.2 ml (585.8 mmol) isocyano acetic acid ethylester are added and then at -50 to -15 the above mentioned solution of the iminechloride is added dropwise.
~fter removing of the cooling means the reaction mixture is stirred during 1 hour, whereupon 120 ml of acetic acid are added and then the reaction mixture is poured on to 1900 ml of water and extracted five times with methylene chloride.
The combined organic extracts are washed three times with 13~6~
water, dried over magnesium sulfate and evaporated. The raw product is chromatographed on silica gel and yields afte{
recrystallization from ethyl acetate 96.02 g of eehyl 5,6-dihydro-7-iodo-5-methyl-6-oxo -4H-imidazo[1,5-a][1,4]-benzodiazepine-3-carboxylate of melting point 244-246.
Example 6 3 rats (female, Wistar, s~f) are measured at 7 diffeLent points of time (2',10',20',40',1h, 6h, 15h). The weight of the animals was between 113-144 g. The feeding was effected ad libitum. The i.v. injected doses varied between 184 and 355 ~Ci in each 0,2 ml at injection solution.
~ 3 ~
g Percentage of the injected activity per gram of the corresponding organ (rat) 2' 10' 20' 40' 60' 6h 15h blood 0.70 0.87 0.46 0.17 0.11 0.04 0.013 10 brain 2.12 3.22 2.99 2.70 1.80 0 05 0.001 thyorid gland 0.60 0.54 1.22 0.08 0.06 0.03 0.007 liver 2.38 5.66 2.62 0.58 0.19 0.02 0.016 spleen 0.60 0.53 0.29 0.14 0.07 0.02 0.010 15 kidneys 2.68 7.06 5.26 1.35 0.68 0.03 0.010 stomach 0.19 0.41 0.35 0.27 0.48 0.73 0.080 bowel 0.75 1.10 1.73 2.02 1.97 1.55 0.143 lungs 1.22 0.87 0.44 0.15 0.10 0.03 0.011 heart 0.86 0.66 0.30 0.10 0.06 O.OZ 0.007 20 ovary 0.88 0.73 0.53 0.22 0.16 0.03 0.011 thigh bone 0.54 0.45 0.24 0.10 0.07 0.02 0.007 bladder 0.59 1.07 0.69 0.24 0.42 0.57 0.023 muscle 0.68 0.4Z 0.20 0.09 0.04 0.01 0.003 ~318~68 Percentage of the injected activity in the corresponding organs (rat~
2' 10' 20' 40' 60~ 6h 15h brain3.115.38 4.20 4.02 2.42 0.08 0.0015 thyroid gland0.180.15 0.18 0.03 0.02 0.008 0.0015 liver16.9034.3717.6]3.90 1.29 0.15 0.107 spleen0.260.210.11 0.06 0.03 0.008 0.0035 kidneys 3.15 7.48 6.25 1.53 0.79 0.04 0.009 15 Stomach 0.81 1.20 1.28 1.37 1.96 1.35 0.346 bowel9.2812.7022.5325.54 28.48 19.50 1.012 lung 1.040~81 0.40 0.15 0.09 0.03 0.0095 heart0.580.37 0.17 0.06 0.03 0.009 0.0035 ovary0.090.06 0.05 0.02 0.02 0.003 0.0008 20 tigh bone 0.390.25 0.14 0.06 0.04 0.01 0.004 bladder 0.03 0.06 0.03 0.01 0.03 0.09 0.0022 rest body 63.9429.9225.9211.04 7.98 2.88 1.30 25 total body 99.7592.9678.8747.8043.1724.16 2.80 faeces and urine0.056.1719.39 48.72 51.71 48.81 42.69
1 o f~ N~
~./
~ ~'C~
I* 3 wherein I~ is a radioactive iodine and R is an alkyl group with 1-4 C-atoms, and their use in diagnosing diseases and disordecs of the brain through their ability to image the brain.
The radioactive iodine is preferably iodine 123. The alkyl group R is prefeeably methyl, ethyl, isoeropyl, sec.butyl or tert.butyl, most preferably ethyl.
Thus the most preferred compound according to the instant invention is ethyl-7- iodo-5,6-dihydro-5-methyl-6-oxo -4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate.
The compounds of formula I are useful for imaging the brain. As will therefore be appreciated the compounds of formula I demonstrate rapid accumulation in the brain indicative of an ability to penetrate the so-termed "blood/bcain barrier". The compounds of formula I demonstrate rapid localization of the radioiodine in the brain following intravenous administration.
Klt/13.6.89 131~8 The compounds of formula I can be used to diagnose diseases or disorders of the brain by imaging changes in the distribution of the benzodiazepine receptors in the brain. In this manner the compounds of formula I can be used to diagnose such brain diseases and disorders as cerebro--vascular diseases ~e.g. strokes), neurological diseases (e.g. epilepsy) and psychotic diseases.
The compounds of formula I can be prepared by methods recognized in the art. For example a compound of formula I
can be prepared from a cold compound of formula I, i.e. a compound, wherein I is a stable iodine, by exchange with a radioactive iodine, preferably iodine 123.
For the exchange radiolabeling process, iodine 123 in a O.lN sodiumhydroxide solution is utilized. This solution is heated with a solution of the cold compound of formula I;
i.e. a compound correseonding to formula I but wherein I is stable iodine and not iodine 123 for from about 1/4 to about 2 hours. The exchange radiolabeling is carried out in the presence of a solvent such as, for example, glacial acetic acid.
A further and preferred method for preparing the compounds of formula I consists in reacting a compound of the formula // \_C OO R
\ /1 ~ ~
B~ 0 35 with a radioactive iodine.
Most preferably iodine 123 is used.
~3~8 The same reac~ion conditionE; are used as in the case of the e~change of the non-radioactive iodine by the 123 iodine.
The cold compounds of formula I and the compounds of formula II are either known from European patent publications No. 27214 or 59389 or ~.S. Patent No. 4,316,839. These cold compounds can be prepared according to the methods given in the above European and US patent publications.
As stated above, the radioiodine containing compounds of the invention rapidly localize in the brain following intravenous administration. In most instances, a sufficient amount of the administered dose will accumulate in the brain within from about two to ten minutes to permit the taking of scintiphotos. The comeounds of the invention will show meaningful presence in the brain for at least 60 minutes so that significant studies may be carried out.
The radioiodinated compounds of the subject invention may be administered in an aqueous or aqueous/alcoholic medium.
Such media may also contain conventional pharmaceutical adjunct materials such as, for example, pharmaceutically acceptable salts to adjust the osmotic pressure, buffers, preservatives and the like.
~ preferred vehicle for the parenteral administration of the compounds of formula I is normal saline which would contain from about 0.5% by weight to about 2% by weight of a suitable preservative.
The radioactive benzodiazepine of this invention can be injected intraveneously into a patient for diagnostic imaging of the brain. In accordance with this invention, the radio-active benzodiazepine of formula I is administeced in a single unit injectable dose. ~ny of the common carriers, such as sterile saline solution, plasma, etc. can be used for preparing the injectable solution for use to diagnostically ~, , ..... ~ ~
~3~6~8 image in accordance with this invention. Generally, the unit dose to be administered contains radioactivity of about 2 mCi to about 10 mCi, preferably about 4 to 5 mCi. However, any amount of the compounds which is effective for imaging the brain can be injected in accordance with this invention. The solution to be injec~ed is preferably in a unit dosage form of about from 0.1 milliliters to about 10 milliliters preferably from about 1 to 5 milliliters and more preferable 4 to 5 milliliters. After intravenous administration, the radioactive benzodiazepine of formula I will image the organs ln vivo. Any conventional method of visualizing or imaging for diagnostic purposes can be utilized in accordance with this invention. In this respect scintiscanning means can be used to visualize or image the brain.
In accordance with this invention, the compound of formula I and particularly ethyl-7- iodo-5,6-dihydro-S--methyl-6-oxo-4H-imidazo~1,5-a][1,4]benzodiazepine-3--carboxy-late is administered to humans intraveneously in a normal saline solution containing 5% glucose. The dose injected into humans contained 4 to 5 mCi of this radioactive compound.
Within 40-60 minutes after injection, scintiphotos were made during Z5 minutes with a Gamma Spect. camera. In accordance with a preferred enbodiment this compound is injected at a dose of 0.0543 mCi per kg.
The compound of formula I can be administered as a free base or as a pharmaceutically acceptable acid addition salt.
The following examples further illustrate the invention.
Unless otherwise noted, all temperatures are in degrees centigrade.
Example 1 The labelling procedure for halogen exchange (bromide-iodide) was performed in a conical reaction vial 13~ 8~
tightly closed by a teflon laminated silicon septum. I-123 activity (up to 300 mCi) in O.ln Na~H was evaporated to dryness by means of a gentle stream of nitrogen at soo. Then 1 mg of ethyl-7-bromo-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a][1,4]benzodiazepino-3-carboxylate dissolved in 200 ~1 glacial acetic acid was added and the r~action mixture heated for 1 h at 150~ ~fter cooling this mixture was dissolved in 5 ml water and eufified by HPLC. The HPLC
conditions were as follows: RP-18 column (8 x 250) Knauer Lichrosorb 10 ~m, MeOH/H20 45/55, 2 ml/min, iodide:
k'=0.0, bromo-derivate: k'=2.75, iodo-derivate: k'=4.00. The purification was performed on a device consisting of a valco 6-port valve with 20 ml loop, a Waters 510 pump, a Kontron 740 LC detector and a NaI scintillation detector. Labelling and ~urification was done in a lead box which was equipped for remote control handling. The labelling was virtually quantitative.
Example 2 During the HPLC-separation the product peak was collected and afterwards evaporated to dryness with a Rota-Vapor. The residue was dissolved in a solution containing 5% glucose and passed through a silver powder column to adsorb iodine liberated during the Rota-Vapoc*treatment. ~fter sterile filtration and adjustment of the activity concentration to 1 mCi/ml the ethyl-7-123iodo-5,6-dihydro-5~-methyl-6-oxo--4H-imidazo[1,5-a]tl,4]benzodiazepino-3-carboxylate was ready for use.
The product quality was monitored with thin layer chromatography on silica gel, developed with ethylacetate/
NH40H 200/1.
*Trade mark A
-` 13i8668 Example 3 The starting material used in Example 1 was prepared as follow~:
To a mixture of 167.95 g (624 mmol) of 6-bromo-3,4--dihydro-4-methyl-2H-l,~-benzodiazepine -2,5~1H)-dione, 600 ml of N,N-dimethyl-p-toluidine and 800 ml of chloroform are added dropwise at the boiling temperature of the mixture 160.8 g (1,05 mol) phosphorus oxychloride whereupon the reaction mixture is boiled under reflux for 4 hours. The resulting solution is poured on a cold mixture of 500 g sodium bicarbonate and 2 1 of water and stirred during 40 minutes. The anorganic phase is separated and extracted three times with chloroform. The combined organic layers are dried over magnesium sulfate and the chloroform is removed under reduced pressure.
In the meantime a solution of 76 g (677 mmol) potassium--t-butylate in 200 ml of dimethylformamide is cooled to -45, whereupon first 71 g (625 mmol) isocyanoacetic acid ethylester are added and then at -50 to -20 the above mentioned solution of the iminechloride is added dropwise.
~fter removing of the cooling means the reaction mixture is stirred during 1.5 hours, whereupon 13 ml acetic acid are added and then the reaction mixture is poured on to 1800 ml of water and extracted five times with each 500 ml methylene chloride. The combined organic extracts are washed three times with water, dried over magnesium sulfate and evaporated. The raw product is recrystalized from methylene chloride and ethyl acetate and yields 156.80 g of ethyl 7-bromo-5,6-dihydro-5~methyl-6-oxo -4H-imidazo[1,5-a][1,4]-benzodiazepine-3-carboxylate of melting point Z14-215.
~3~86~8 Example 4 Iodide-iodide exchange labelling was performed exactly as described for bromide-iodide exchange, but ethyl-7-iodo-5,6--dihydro-5-methyl-6-oxo -4H-imidazo[1,5-a]rl,4]benzodia-zepine-3-carboxylate was used as precursor. This labelling was performed to assure the identity of the labelled product in HPLC and thin layer chromatography.
Example 5 The starting material used in Example 4 was prepared as follows:
To a mixture of 185.5 g t558.8 mmol) ~f 3,4-dihydro -5-iodo-4-methyl-2H-1,4-benzodiazepine -2,5(lH)-dione, 70 ml of N,N-dimethyl-~-toluidine and 800 ml of chloroform are added dropwise at the boiling temperature of the mixture 91.6 ml (979 mmol) phosphorus oxychloride whereupon the reaction mixture is boiled under reflux for 2 hours. The resulting solution is poured on a cold mixture of 490 g sodium bicarbonate and 2 1 of water and stirred during 40 minutes. The anorganic phase is separated and extracted three times with chloroform. The combined organic layers are dried over magnesium sulfate and the chloroform is removed under reduced pressure.
In the meantime a solution of 75.5 g (626.6 mmol) potassium-t-butylate in 500 ml of dimethylformamide is cooled to -50, whereupon first 65.2 ml (585.8 mmol) isocyano acetic acid ethylester are added and then at -50 to -15 the above mentioned solution of the iminechloride is added dropwise.
~fter removing of the cooling means the reaction mixture is stirred during 1 hour, whereupon 120 ml of acetic acid are added and then the reaction mixture is poured on to 1900 ml of water and extracted five times with methylene chloride.
The combined organic extracts are washed three times with 13~6~
water, dried over magnesium sulfate and evaporated. The raw product is chromatographed on silica gel and yields afte{
recrystallization from ethyl acetate 96.02 g of eehyl 5,6-dihydro-7-iodo-5-methyl-6-oxo -4H-imidazo[1,5-a][1,4]-benzodiazepine-3-carboxylate of melting point 244-246.
Example 6 3 rats (female, Wistar, s~f) are measured at 7 diffeLent points of time (2',10',20',40',1h, 6h, 15h). The weight of the animals was between 113-144 g. The feeding was effected ad libitum. The i.v. injected doses varied between 184 and 355 ~Ci in each 0,2 ml at injection solution.
~ 3 ~
g Percentage of the injected activity per gram of the corresponding organ (rat) 2' 10' 20' 40' 60' 6h 15h blood 0.70 0.87 0.46 0.17 0.11 0.04 0.013 10 brain 2.12 3.22 2.99 2.70 1.80 0 05 0.001 thyorid gland 0.60 0.54 1.22 0.08 0.06 0.03 0.007 liver 2.38 5.66 2.62 0.58 0.19 0.02 0.016 spleen 0.60 0.53 0.29 0.14 0.07 0.02 0.010 15 kidneys 2.68 7.06 5.26 1.35 0.68 0.03 0.010 stomach 0.19 0.41 0.35 0.27 0.48 0.73 0.080 bowel 0.75 1.10 1.73 2.02 1.97 1.55 0.143 lungs 1.22 0.87 0.44 0.15 0.10 0.03 0.011 heart 0.86 0.66 0.30 0.10 0.06 O.OZ 0.007 20 ovary 0.88 0.73 0.53 0.22 0.16 0.03 0.011 thigh bone 0.54 0.45 0.24 0.10 0.07 0.02 0.007 bladder 0.59 1.07 0.69 0.24 0.42 0.57 0.023 muscle 0.68 0.4Z 0.20 0.09 0.04 0.01 0.003 ~318~68 Percentage of the injected activity in the corresponding organs (rat~
2' 10' 20' 40' 60~ 6h 15h brain3.115.38 4.20 4.02 2.42 0.08 0.0015 thyroid gland0.180.15 0.18 0.03 0.02 0.008 0.0015 liver16.9034.3717.6]3.90 1.29 0.15 0.107 spleen0.260.210.11 0.06 0.03 0.008 0.0035 kidneys 3.15 7.48 6.25 1.53 0.79 0.04 0.009 15 Stomach 0.81 1.20 1.28 1.37 1.96 1.35 0.346 bowel9.2812.7022.5325.54 28.48 19.50 1.012 lung 1.040~81 0.40 0.15 0.09 0.03 0.0095 heart0.580.37 0.17 0.06 0.03 0.009 0.0035 ovary0.090.06 0.05 0.02 0.02 0.003 0.0008 20 tigh bone 0.390.25 0.14 0.06 0.04 0.01 0.004 bladder 0.03 0.06 0.03 0.01 0.03 0.09 0.0022 rest body 63.9429.9225.9211.04 7.98 2.88 1.30 25 total body 99.7592.9678.8747.8043.1724.16 2.80 faeces and urine0.056.1719.39 48.72 51.71 48.81 42.69
Claims (8)
1. A radioiodinated benzodiazepine derivative of the formula wherein R is a lower alkyl group with 1-4 C-atoms and I*
is a radioactive iodine.
is a radioactive iodine.
2. A compound of claim 1, wherein the radioactive iodine is iodine 123.
3. Ethyl-7-123iodo-5.6-dihydro-5-methyl-6-oxo-4 imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate.
4. A process for the preparation of a compound of formula I given in claim 1 which process comprises a) labelling a compound corresponding to formula I but having a stable non-radioactive isotope of iodine with a radioactive iodine, or b) reacting a compound of the formula II
with a radioactive iodine.
with a radioactive iodine.
5. A process according to claim 4 wherein iodine 123 is used as radioactive isotope of iodine.
6. A composition for imaging the brain comprising a compound of the formula I
wherein I* is a radioactive iodine and R is an alkyl group with 1-4 carbon atoms;
and a carriere suitable for injection.
wherein I* is a radioactive iodine and R is an alkyl group with 1-4 carbon atoms;
and a carriere suitable for injection.
7. A composition according to claim 6, wherein said compound is ethyl-7-123-iodo-5.6-dihydro-5-methyl-6-oxo-imidazo[1,5-a][1.4]benzodiazepine-3-carboxylate.
8. A composition according to claim 6, comprising about 2 to about 10 mCi of the compound of formula I.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US22906488A | 1988-08-05 | 1988-08-05 | |
| US229,064 | 1988-08-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1318668C true CA1318668C (en) | 1993-06-01 |
Family
ID=22859710
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000607447A Expired - Fee Related CA1318668C (en) | 1988-08-05 | 1989-08-03 | Radioiodine benzodiazepine derivatives |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP0353754B1 (en) |
| JP (1) | JPH0733387B2 (en) |
| KR (1) | KR930001406B1 (en) |
| AT (1) | ATE82851T1 (en) |
| AU (1) | AU622206B2 (en) |
| CA (1) | CA1318668C (en) |
| DE (1) | DE58902867D1 (en) |
| DK (1) | DK381989A (en) |
| ES (1) | ES2052837T3 (en) |
| HK (1) | HK127694A (en) |
| NZ (1) | NZ230193A (en) |
| PH (1) | PH26382A (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FI101305B (en) * | 1996-03-18 | 1998-05-29 | Map Medical Technologies Oy | Radioiodinated benzodiazepine derivatives useful as radiopharmaceuticals and their use in diagnostics |
| WO2005092395A1 (en) * | 2004-03-25 | 2005-10-06 | Nihon Medi-Physics Co., Ltd. | Radioactive composition and process for producing radioactive composition |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1143728A (en) * | 1979-10-04 | 1983-03-29 | Max Gerecke | Imidazodiazepine derivatives |
| CA1174673A (en) * | 1981-02-27 | 1984-09-18 | Walter Hunkeler | Imidazodiazepines |
| CA1184175A (en) * | 1981-02-27 | 1985-03-19 | Walter Hunkeler | Imidazodiazepines |
| US4352817A (en) * | 1981-02-27 | 1982-10-05 | Hoffmann-La Roche Inc. | Imidazo-diazepines and their use |
| US4777169A (en) * | 1987-07-24 | 1988-10-11 | Hoffmann-La Roche Inc. | Benzodiazepine derivatives |
| JPH0780858B2 (en) * | 1987-10-19 | 1995-08-30 | 住友化学工業株式会社 | Radioactive benzodiazepine derivative and method for producing the same |
-
1989
- 1989-08-03 NZ NZ230193A patent/NZ230193A/en unknown
- 1989-08-03 CA CA000607447A patent/CA1318668C/en not_active Expired - Fee Related
- 1989-08-03 DK DK381989A patent/DK381989A/en not_active Application Discontinuation
- 1989-08-03 AT AT89114359T patent/ATE82851T1/en not_active IP Right Cessation
- 1989-08-03 DE DE8989114359T patent/DE58902867D1/en not_active Expired - Fee Related
- 1989-08-03 ES ES89114359T patent/ES2052837T3/en not_active Expired - Lifetime
- 1989-08-03 EP EP89114359A patent/EP0353754B1/en not_active Expired - Lifetime
- 1989-08-03 PH PH39046A patent/PH26382A/en unknown
- 1989-08-04 AU AU39342/89A patent/AU622206B2/en not_active Ceased
- 1989-08-04 JP JP1202704A patent/JPH0733387B2/en not_active Expired - Lifetime
- 1989-08-04 KR KR1019890011140A patent/KR930001406B1/en not_active IP Right Cessation
-
1994
- 1994-11-17 HK HK127694A patent/HK127694A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| ATE82851T1 (en) | 1992-12-15 |
| EP0353754B1 (en) | 1992-12-02 |
| KR930001406B1 (en) | 1993-02-27 |
| AU3934289A (en) | 1990-02-08 |
| JPH0733387B2 (en) | 1995-04-12 |
| JPH0269479A (en) | 1990-03-08 |
| NZ230193A (en) | 1992-01-29 |
| EP0353754A2 (en) | 1990-02-07 |
| DK381989D0 (en) | 1989-08-03 |
| ES2052837T3 (en) | 1994-07-16 |
| EP0353754A3 (en) | 1990-04-11 |
| DK381989A (en) | 1990-02-06 |
| KR900003171A (en) | 1990-03-23 |
| PH26382A (en) | 1992-06-01 |
| DE58902867D1 (en) | 1993-01-14 |
| AU622206B2 (en) | 1992-04-02 |
| HK127694A (en) | 1994-11-25 |
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