PH26382A - Radioiodine benzodiazepine derivatives - Google Patents
Radioiodine benzodiazepine derivatives Download PDFInfo
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- PH26382A PH26382A PH39046A PH39046A PH26382A PH 26382 A PH26382 A PH 26382A PH 39046 A PH39046 A PH 39046A PH 39046 A PH39046 A PH 39046A PH 26382 A PH26382 A PH 26382A
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- brain
- benzodiazepine
- iodine
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- 229940053197 benzodiazepine derivative antiepileptics Drugs 0.000 title abstract 2
- -1 Radioiodine benzodiazepine derivatives Chemical class 0.000 title description 3
- 125000003310 benzodiazepinyl group Chemical class N1N=C(C=CC2=C1C=CC=C2)* 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 30
- 210000004556 brain Anatomy 0.000 claims description 17
- 229910052740 iodine Inorganic materials 0.000 claims description 12
- 230000002285 radioactive effect Effects 0.000 claims description 12
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 11
- 239000011630 iodine Substances 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 10
- ZCYVEMRRCGMTRW-AHCXROLUSA-N Iodine-123 Chemical group [123I] ZCYVEMRRCGMTRW-AHCXROLUSA-N 0.000 claims description 6
- 238000003384 imaging method Methods 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 238000002347 injection Methods 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000012216 imaging agent Substances 0.000 abstract 1
- 238000002610 neuroimaging Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000002372 labelling Methods 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 229940049706 benzodiazepine Drugs 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 229940093499 ethyl acetate Drugs 0.000 description 3
- 235000019439 ethyl acetate Nutrition 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000014644 Brain disease Diseases 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- FPULFENIJDPZBX-UHFFFAOYSA-N ethyl 2-isocyanoacetate Chemical compound CCOC(=O)C[N+]#[C-] FPULFENIJDPZBX-UHFFFAOYSA-N 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- ILVUABTVETXVMV-UHFFFAOYSA-N hydron;bromide;iodide Chemical compound Br.I ILVUABTVETXVMV-UHFFFAOYSA-N 0.000 description 2
- XMBWDFGMSWQBCA-RNFDNDRNSA-M iodine-131(1-) Chemical compound [131I-] XMBWDFGMSWQBCA-RNFDNDRNSA-M 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- GYVGXEWAOAAJEU-UHFFFAOYSA-N n,n,4-trimethylaniline Chemical compound CN(C)C1=CC=C(C)C=C1 GYVGXEWAOAAJEU-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 210000001672 ovary Anatomy 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000000163 radioactive labelling Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- FXAXGHCUXZNILI-UHFFFAOYSA-N 6-bromo-4-methyl-1,3-dihydro-1,4-benzodiazepine-2,5-dione Chemical compound O=C1N(C)CC(=O)NC2=CC=CC(Br)=C21 FXAXGHCUXZNILI-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 102000004300 GABA-A Receptors Human genes 0.000 description 1
- 108090000839 GABA-A Receptors Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- 239000004809 Teflon Substances 0.000 description 1
- 229920006362 Teflon® Polymers 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 150000001557 benzodiazepines Chemical class 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002059 diagnostic imaging Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- BVJUXXYBIMHHDW-UHFFFAOYSA-N iodane Chemical group I.I BVJUXXYBIMHHDW-UHFFFAOYSA-N 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229940083608 sodium hydroxide Drugs 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000011146 sterile filtration Methods 0.000 description 1
- 210000001694 thigh bone Anatomy 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2123/00—Preparations for testing in vivo
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Physics & Mathematics (AREA)
- Pharmacology & Pharmacy (AREA)
- Optics & Photonics (AREA)
- Medicinal Chemistry (AREA)
- Radiology & Medical Imaging (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Lubricants (AREA)
- Vessels And Coating Films For Discharge Lamps (AREA)
- Particle Accelerators (AREA)
Abstract
Radioiodinated 5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a][1.4]benzodiazepine derivatives and the use thereof as brain-imaging agents are described.
Description
fl 2 0 0D . SFE
The present invention is concerned with radioiodinated benzodiazepine derivatives of the formula 7 OOR ’ QC
N en
I* 0 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 disorders of the brain through their ability to image the brain. 20 .
The radioactive iodine is preferably iodine 123. The alkyl group R is preferably methyl, ethyl, isopropyl, sec. butyl or tert.butyl, most preferably ethyl.
Thus the most preferred compound according to the instant invention is ethyl-7-Y23i0do-5,6-dihydro-5-methyl-6-oxo -qH-imidazo[l.5-a]({l,4]benzodiazepine-3-carboxylate.
The compounds of formula I are useful for imaging the brain. As will therefore be appreciated the compounds of formula 1 demonstrate rapid accumulation in the brain indicative of an ability to penetrate the so-termed "blood/brain barrier". The compounds of formula 1 demonstrate rapid localization of the radioiodine in the brain following intravenous administration.
Co WAY - 2 -
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 0.1N sodiumhydroxide solution is utilized. This solution is heated with a solution of the cold compound of formula I; i.e. a compound corresponding to formula I but wherein I is stable iodine and not iodine 123 for from about 1/4 to about : 20 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
N . ) ¢ ) OOR 3 N
I
N
Sen,
BY 0 } 35 with a radioactive iodine. a Most preferably iodine 123 is used.
oo 7 gt 26382
Q9
The same reaction conditions are used as in the case of the exchange of the non-radioactive iodine by the 123 iodine.
The cold compounds of formula I and the compounds of formula 11 are either known from European patent publications
No. 27214 or 59389 or us 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 compounds 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 o0 be administered in an aqueous or aqueous/alcoholic medium. i 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.
A 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 1 is administered in a . 35 single unit injectable dose. Any of the common carriers, such as sterile saline solution, plasma, etc. can be used for preparing the injectable solution for use to diagnostically
Co Hh - 4 = 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 injected 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 in 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-7-1%330d0-5,6-dihydro-5- -methyl-6-oxo-4H-imidazo(1l,5-a)[1l.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
B during 25 minutes with a Gamma Spect. camera. In accordance with a preferred enbodiment this compound is injected at a - 25 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. : 30 The following examples further illustrate the invention.
Unless otherwise noted, all temperatures are in degrees centigrade.
Example 1 . 35
The labelling procedure for halogen exchange : (bromide-iodide) was performed in a conical reaction vial
- 5 = DG359
Td SH A tightly closed by a teflon laminated silicon septum. 1-123 activity (up to 300 mCi) in 0.1n NaOH was evaporated to dryness by means of a gentle stream of nitrogen at 90°. Then 1 mg of ethyl-7-bromo-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [l,5-a]{l.4)benzodiazepino-3-carboxylate dissolved in 200 ul glacial acetic acid was added and the reaction mixture heated for 1 h at 150°. After cooling this mixture was dissolved in 5 ml water and pufified by HPLC. The HPLC conditions were as follows: RP-18 column (8 x 250) Knauer
Lichrosorb 10 um, MeOH/H,0 45/55, 2 ml/min, iodide: k'=0.0, bromo-derivate: k'=2.75%5, 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 Nal scintillation detector. Labelling and purification 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-Vapor treatment. After sterile filtration and adjustment of the activity concentration to . 1 mCi/ml the ethyl-7-1%3i0d0-5,6-dihydro-5-methyl-6-oxo- -4H-imidazo[1,5-a][1.,4]benzodiazepino-3-carboxylate was ready : for use.
The product quality was monitored with thin layer chromatography on silica gel, developed with ethylacetate/
NH, OH 200/1.
: } v4’ ¥ - 6 -
Example 3
The starting material used in Example 1 was prepared as follows:
To a mixture of 167.95 g (624 mmol) of 6-bromo-3,4- -dihydro-4-methyl-2H-1,4-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 i5 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- : 20 -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.
After removing of the cooling means the reaction mixture is 75 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 . 30 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-6-0xo0 -4H-imidazo[l,5-a](1,4]- benzodiazepine-3-carboxylate of melting point 214-215°.
oo I 926382
Example 4
Iodide-iodide exchange labelling was performed exactly as described for bromide-iodide exchange, but ethyl-7-iodo-5,6- -dihydro-5-methyl-6-0x0 -4H-imidazo[1l,5-a)(1,4}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 (558.8 mmol) of 3,4-dihydro -5-iodo-4-methyl-2H-1,4-benzodiazepine -2,5(1H)-dione., 70 ml of N,N-dimethyl-p-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 ¢ 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.
After removing of the cooling means the reaction mixture is stirred during 1 hour, whereupon 120 ml of acetic acid are , 35 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 oo WHY - 8 - water, dried over magnesium sulfate and evaporated. The raw product is chromatographed on silica gel and yields after : recrystallization from ethyl acetate 96.02 g of ethyl 5,6-dihydro-7-iodo-5-methyl-6-0oxo -4H-imidazo[l.5-a)(1,4]- benzodiazepine-3-carboxylate of melting point 244-246°.
Example 6 3 rats (female, Wistar, spf) are measured at 7 different 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 uCi in each 0,2 ml at injection solution. : 20
- - — cy » ! 0 26552 —_ - { @ Foo } 9 - <p? SF wy !
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 brain 2.12 1.22 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 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 0.02 0.007 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 0.42 0.20 0.09 0.04 0.01 0.003 2 ______
Percentage of the injected activity in the . corresponding organs (rat)
2" 10! 20! 40° 60' 6h 15h brain 3.11 5.38 4.20 4.02 2.42 0.08 0.0015 thyroid gland 0.18 0.15 0.18 0.03 0.02 0.008 0.0015 liver 16.90 34.37 17.61 3.90 1.29 0.15 0.107 ’ spleen 0.26 0.21 0.11 0.06 0.03 0.008 0.0035 kidneys 3.15 7.48 6.25 1.53 0.79 0.04 0.009 stomach 0.81 1.20 1.28 1.37 1.96 1.35 0.346 bowel 9.28 12.70 22.53 25.54 28.48 19.50 1.012 lung 1.04 0.81 0.40 0.15 0.09 0.03 0.0095 heart 0.58 0.37 0.17 0.06 0.03 0.009 0.0035 ovary 0.09 0.06 0.05 0.02 0.02 0.003 0.0008 tigh bone 0.39 0.25 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 63.94 29.92 25.92 11.04 7.98 2.88 1.30 total body 99.75 92.96 78.87 47.80 43.17 24.16 2.80 faeces ’ and . urine 0.05 6.17 19.39 48.72 51.71 48.81 42.69 ’ 30
Claims (6)
1. A radiolodinated benzodiazepine derivative of the formula 4 OOR N N i : 10 ~N CH 1* Oo 3 wherein R is a lower alkyl group with 1-4 C-atoms and 1~* is a radioactive iodine.
2. A compound of claim 1, wherein the radioactive iodine is iodine 123. 123
3. Ethyl-7- iodo-5,6-dihydro-5-methyl-6-oxo-4H- imidazo([l,5-a][l,4)}benzodiazepine-3-carboxylate.
4. A composition for imaging the brain comprising a ’ compound of the formula AN OOR / : N oo N° : : er T* 0 3 wherein I* is a radioactive iodine and R is an alkyl group with 1-4 carbon atoms; and a pharmaceutically acceptable carrier suitable for injection. ,
Co 5. A composition according to claim 4, wherein said ’ compound is ethyl1-7-123_i0do-5,6-dihydro-5-methyl-6-oxo- imidazofl.5-a)[l,4]benzodiazepihe-3-carboxylate.
6. NA composition according to claim 4, comprising about 2 . to about 10 mCi of the compound of formula I. HEINZ CARMANN WALTER HUNKELER (Inventors)
. 20 , = i
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US22906488A | 1988-08-05 | 1988-08-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| PH26382A true PH26382A (en) | 1992-06-01 |
Family
ID=22859710
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PH39046A PH26382A (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 |
| JP4637096B2 (en) * | 2004-03-25 | 2011-02-23 | 日本メジフィジックス株式会社 | Radioactive composition and method for producing the 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 |
| US4352817A (en) * | 1981-02-27 | 1982-10-05 | Hoffmann-La Roche Inc. | Imidazo-diazepines and their use |
| CA1174673A (en) * | 1981-02-27 | 1984-09-18 | Walter Hunkeler | Imidazodiazepines |
| CA1184175A (en) * | 1981-02-27 | 1985-03-19 | Walter Hunkeler | Imidazodiazepines |
| 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 CA CA000607447A patent/CA1318668C/en not_active Expired - Fee Related
- 1989-08-03 ES ES89114359T patent/ES2052837T3/en not_active Expired - Lifetime
- 1989-08-03 DK DK381989A patent/DK381989A/en not_active Application Discontinuation
- 1989-08-03 EP EP89114359A patent/EP0353754B1/en not_active Expired - Lifetime
- 1989-08-03 DE DE8989114359T patent/DE58902867D1/en not_active Expired - Fee Related
- 1989-08-03 NZ NZ230193A patent/NZ230193A/en unknown
- 1989-08-03 PH PH39046A patent/PH26382A/en unknown
- 1989-08-03 AT AT89114359T patent/ATE82851T1/en not_active IP Right Cessation
- 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
- 1989-08-04 AU AU39342/89A patent/AU622206B2/en not_active Ceased
-
1994
- 1994-11-17 HK HK127694A patent/HK127694A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| AU3934289A (en) | 1990-02-08 |
| EP0353754A2 (en) | 1990-02-07 |
| DE58902867D1 (en) | 1993-01-14 |
| NZ230193A (en) | 1992-01-29 |
| CA1318668C (en) | 1993-06-01 |
| JPH0269479A (en) | 1990-03-08 |
| ES2052837T3 (en) | 1994-07-16 |
| DK381989A (en) | 1990-02-06 |
| AU622206B2 (en) | 1992-04-02 |
| DK381989D0 (en) | 1989-08-03 |
| JPH0733387B2 (en) | 1995-04-12 |
| KR900003171A (en) | 1990-03-23 |
| ATE82851T1 (en) | 1992-12-15 |
| EP0353754A3 (en) | 1990-04-11 |
| HK127694A (en) | 1994-11-25 |
| KR930001406B1 (en) | 1993-02-27 |
| EP0353754B1 (en) | 1992-12-02 |
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