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Oligomer-Phenothiazine Conjugates

a technology of phenothiazine and conjugates, which is applied in the field of chemically modified phenothiazine, can solve the problems of large unmet need for developing novel phenothiazine compounds, and the incidence of venous thrombosis at the injection si

Inactive Publication Date: 2012-02-23
NEKTAR THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0002]This invention comprises (among other things) chemically modified phenothiazines that possess certain advantages over phenothiazines lacking the chemical modification. The chemically modified phenothiazines described herein relate to and / or have application(s) in (among others) the fields of drug discovery, pharmacotherapy, physiology, organic chemistry and polymer chemistry.

Problems solved by technology

However, with the use of phenothiazines some incidents of venous thrombosis at the injection site have been encountered.
Thus, there is a large unmet need for developing novel phenothiazine compounds.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of Small PEG Promethazine Conjugates

[0142]Scheme 1: Synthesis of mPEGn-N-Promethazine conjugates.

[0143]Promethazine, 1-chloroethyl chloroformate, dichloroethane (DCE), phosphorous oxychloride (POCl3), sodium borohydride (NaBH4), sodium hydride (NaH), and N,N-dimethylformamide (DMF) were from Sigma-Aldrich (St Louis, Mo.). mPEGn-OMs and mPEGn-Br were from Sai Chemicals (India). Sodium carbonate (Na2CO3), sodium bicarbonate (NaHCO3), sodium sulfate (Na2SO4), potassium carbonate (K2CO3), sodium chloride (NaCl), and sodium hydroxide (NaOH) were from EM Science (Gibbstown, N.J.). DCM was distilled from CaH2.

[0144]Desalting of Promethazine-HCl: The Sigma-Aldrich promethazine.HCl (10 g, 31.2 mmol) was dissolved in H2O (250 mL) in a 500-mL flask. Na2CO3 (8.2 g, 78 mmol) was added in one portion. The salt was first dissolved in water and then a thick oil-like product appeared sticking to the stirring bar. DCM (50 mL) was added to dissolve the product and the solution became clear a...

example 2

In Vitro Receptor Binding

[0166]Binding to Histamine Receptors

[0167]The receptor binding affinity of promethazine (parent) and N- and O-PEG derivatives are evaluated using radioligand binding assays in membranes prepared from CHO cells that express the recombinant human H1, H2, H3 or H4 histamine receptors. Competition binding experiments are conducted by incubating membranes with a fixed concentration of radioligand in the presence of variable concentrations of test compounds. The radioligands used are specific for each receptor subtype and the assay conditions are described in Table 2. Following incubations, the membranes are washed, and the bound radioactivity is measured. Non-specific binding is measured in the presence of excess cold ligand and subtraction of this value from the total binding yields the specific binding at each test compound concentration. IC50 values are obtained from non-linear regression analysis of dose-response curves and are calculated only for those compo...

example 3

Scale up of mPEG4-N-promethazine

[0173]Materials: Promethazine hydrochloride, 1-chloroethyl chloroformate were purchased from Sigma-Aldrich (St Louis, Mo.). mPEG4-Br was received from India Sai CRO. Sodium bicarbonate (NaHCO3), sodium sulfate (Na2SO4), sodium chloride (NaCl), Potassium carbonate (K2CO3), Sodium hydroxide (NaOH), and hydrochloride acid (HCl) were purchased from EM Science (Gibbstown, N.J.). Toluene, dichloroethylene (DCE), dichloromethane (DCM), and other organic solvents were used as they purchased.

Desalting Promethazine

[0174]The reaction was carried out in NaHCO3 / DCM. The product was solidified in high vacuo drying.

Demethylation and Product Precipitation:

[0175]The desalted promethazine (13.16 g, 46.3 mmol) was added to a 1000-mL flask. Toluene (110 mL) and DCE (100 mL) were added and azeotropically distilled while under 45° C. then followed with distillation under high vacuum for an additional 15 min. DCE (100 mL) was added and after a homogenous solution was obtain...

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Abstract

The invention relates to (among other things) oligomer-phenothiazine conjugates and related compounds. A conjugate of the invention, when administered by any of a number of administration routes, exhibits advantages over un-conjugated phenothiazine compounds.

Description

CROSS REFERENCE TO RELATED APPLICATION[0001]This application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application Ser. No. 61 / 148,016, filed 28 Jan. 2009, the disclosure of which is incorporated herein by reference in its entirety.FIELD OF THE INVENTION[0002]This invention comprises (among other things) chemically modified phenothiazines that possess certain advantages over phenothiazines lacking the chemical modification. The chemically modified phenothiazines described herein relate to and / or have application(s) in (among others) the fields of drug discovery, pharmacotherapy, physiology, organic chemistry and polymer chemistry.BACKGROUND OF THE INVENTION[0003]Phenothiazines have been shown to possess antihistaminic, sedative, anti-motion-sickness, antiemetic, and anticholinergic effects. They are generally indicated for: 1) amelioration of allergic reactions to blood or plasma; 2) in anaphylaxis as an adjunct to epinephrine and other standa...

Claims

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Application Information

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IPC IPC(8): A61K31/5415A61P25/20A61P1/08C07D279/26
CPCA61K47/48215A61K47/60A61P1/08A61P1/12A61P25/04A61P25/20A61P25/22A61P35/00A61P37/08A61P43/00
Inventor GU, XUYUANRIGGS-SAUTHIER, JENNIFER
Owner NEKTAR THERAPEUTICS INC
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