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US 2022/0096667 A1Published application
Compound Targeting Norepinephrine Transporter
AssigneeGuangzhou Miphere Medical Technology Co., Ltd.
InventorsXinyu CHEN, Michael Decker, Takahiro Higuchi
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Abstract
A compound according to following formula can be prepared, where R1 is an F or I residue.
Claims13
1:
- A compound according to following formula
- wherein R1 is a halogen residue.
2:
- A method, comprising:
- administering the compound according to claim 1.
3:
- The method according to claim 2, wherein the compound is administered to a living human or animal body suspected of having a disorder in generation, degradation, distribution, or function of norepinephrine transporter (NET).
4:
- The method according to claim 3, wherein after administration of the compound, the living human or animal body is scanned with Positron Emission Tomography (PET).
5:
- The method according to claim 4, wherein the disorder in generation, degradation, distribution, or function of NET is associated with a cardiovascular disease, a dysregulated blood pressure, a renal disorder, a neuroendocrine tumor disease, or Parkinson's disease.
6:
- A method for synthesizing the compound according to claim 1, comprising:
- a) removing the methyl group of the following compound 14
- to receive the following compound 15
- wherein R1 is a halogen residue,
- b) performing a chloroalkylation of compound 15 with 1-chloro-3-iodopropane, to receive the following compound 25
- c) performing a Wittig reaction with compound 25 with a (methoxymethyl)triphenylphosphonium halide and potassium tert-butoxide or sodium hydride, to receive the following compound 26
- d) reducing compound 26 in a two-step one pot reaction by addition of mercury acetate to allow formation of an intermediate followed by addition of an alkali metal borohydride, to receive the following compound 28
- e) performing a Mitsunobu reaction with compound 28 in the presence of triphenylphosphine, an azodicarboxylate, and the following compound 24
- to receive the following compound 29
- f) replacing the chlorine atom at the terminal of the alkyl chain of the compound resulting from any of b) to e) by iodine in a Finkelstein reaction, followed by a tosylation using silver p-toluenesulfonate in the dark, to receive the following compound 30
- wherein a)-f) are performed in any order to obtain the compound 30, and
- g) radiolabeling compound 30 by a nucleophilic substitution using an alkali metal salt of 18F followed by deprotection under acidic condition at a temperature of at least 70° C. to receive the following compound
- wherein the halogen residue is an F or an I residue.
10 more elements
7:
- The method according to claim 6, wherein the (methoxymethyl)triphenylphosphonium halide of c) is (methoxymethyl)triphenylphosphonium chloride.
8:
- The method according to claim 6, wherein the azodicarboxylate of e) is diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD).
9:
- The method according to claim 6, wherein the alkali metal borohydride of d) is sodium borohydride or potassium borohydride.
10:
- The method according to claim 6, wherein the alkali metal salt of 18F used in g) is K18F.
11:
- The method according to claim 6, wherein the deprotection under acidic condition of g) is performed at a temperature of at most 100° C.
12:
- The method according to claim 6, wherein synthesis of compound 24 comprises:
- h) reacting benzyl carbamate, N,N′-dimethylurea, and water at a temperature of at least 80° C., to receive the following compound 23
- i) reacting compound 23 with hydrogen catalyzed by palladium on activated charcoal, to receive compound 22
- and
- j) reacting compound 22 with the following compound 13
- in the presence of N,N-diisopropylethylamine (DIPEA) to receive compound 24,
- wherein Boc is a tert-butoxycarbonyl protecting group.
4 more elements
13:
- The method according to claim 12, wherein compound 13 of j) is synthesized by reacting 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea and 5-chlorobenzotriazole in the presence of mercury (II) chloride (HgCl2).