Antibodies to Paliperidone Haptens and Use Thereof

a technology of anti-haptens and paliperidone, which is applied in the field of immunoassays, can solve the problems of increased mortality, poor adherence to medication, and relapse of daily administered oral medications, and achieves the effects of improving survival rate, hospital admission and suicide, and improving drug safety

Inactive Publication Date: 2014-02-27
JANSSEN PHARMA NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0006]A need exists for other methods for determining the levels of anti-psychotic drugs, particularly methods that can be performed in a prescribing clinician's office (where the treatment for an individual patient can be adjusted accordingly in a much more timely manner) and in other medical settings lacking LC or GC / MS equipment or requiring rapid test results.

Problems solved by technology

While many patients with schizophrenia are able to achieve symptom stability with the available antipsychotic medications, poor adherence to medication is a common reason for relapse with daily administered oral medications.
“Pharmacotherapy Challenges in Patients with First-Episode Psychosis”Journal of Affective Disorders 2012, 138, S3-S14) investigating the outcomes of non-compliance have shown that patients with schizophrenia who do not take their medication as prescribed have higher rates of relapse, hospital admission and suicide as well as increased mortality.
Some of these methods, namely HPLC and GC / MS, can be expensive and labor-intensive, and are generally only performed in large or specialty labs having the appropriate equipment.

Method used

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  • Antibodies to Paliperidone Haptens and Use Thereof
  • Antibodies to Paliperidone Haptens and Use Thereof
  • Antibodies to Paliperidone Haptens and Use Thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

4-((3-(2-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)ethyl)-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)oxy)-4-oxobutanoic acid

[0150]

[0151]Paliperidone (10 g, 23.45 mmol) was dissolved in pyridine (100 mL) together with N,N-dimethyl-4-pyridinamine (0.5 g; 4.09 mmol) and succinic anhydride (18.3 g; 182.86 mmol). The mixture was stirred under an argon atmosphere for 4 h at 60° C. and for 48 h at room temperature. The reaction mixture was evaporated and dissolved in dichloromethane / methanol (100 mL / 10 mL) and water (100 mL). The aqueous phase was extracted five times with dichloromethane / methanol (100 mL / 10 mL). The organic layers were combined, dried over Na2SO4 and evaporated under vacuum. The residue was purified by silica gel chromatography (gradient elution with chloroform / ethanol 80 / 20 to 70 / 30). The product was dissolved in isopropanol (50 mL) and the resulting precipitate was filtered and washed with isopropanol (10 mL). The precipitate was dried in va...

example 2

Step A 3-(2-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)ethyl)-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl 3-pivalamidopropanoate

[0152]

[0153]A solution of Paliperidone (1.0 g, 2.34 mmol) in dichloromethane (20 mL) was treated with Boc-b-Ala-OH (443.65 mg, 2.34 mmol), dicyclohexylcarbodiimide (483.79 mg, 2.34 mmol) and N,N-dimethyl-4-pyridinamine (14.32 mg, 0.117 mmol). The reaction was stirred at room temperature under argon atmosphere. After 18 h, the reaction mixture was poured into an aqueous saturated sodium bicarbonate solution (20 mL) and the aqueous layer extracted with dichloromethane (three times 20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography (elution with dichloromethane / methanol (95 / 5) to give the title compound. ESI-MS (M+1) 598.

Step B 3-(2-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)ethyl)-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin...

example 3

Step A N-(3-((3-(2-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)ethyl)-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)oxy)propyl)pivalamide

[0156]

[0157]A solution of paliperidone (746.26 mg, 1.75 mmol) in THF (15 mL) was treated with 3-(Boc-amino)propyl bromide (500 mg, 2.10 mmol), 18-Crown-6 (231.25 mg, 0.874 mmol) and sodium hydride (60 w / w %, 139.97 mg, 3.5 mmol). The mixture was stirred at room temperature for 6 h. The solvent was removed under vacuum, dissolved in dichloromethane / water (50 mL / 50 mL) and the aqueous layer extracted with dichloromethane (three times 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to give the title compound, which was used without further purification in the next step.

Step B 9-(3-aminopropoxy)-3-(2-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one

[0158]

[0159]A solution of N-(3-((3-(2-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperid...

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Abstract

Disclosed is an antibody which binds to paliperidone, which can be used to detect paliperidone in a sample such as in a competitive immunoassay method. The antibody can be used in a lateral flow assay device for point-of-care detection of paliperidone, including multiplex detection of aripiprazole, olanzapine, quetiapine, risperidone and paliperidone in a single lateral flow assay device.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Application No. 61 / 691,634, filed Aug. 21, 2012.FIELD OF THE INVENTION[0002]The present invention relates to the field of immunoassays, and in particular to antibodies that bind to paliperidone which can be used in immunoassays for detection of paliperidone.BACKGROUND[0003]Schizophrenia is a chronic and debilitating psychiatric disorder affecting approximately 0.45-1% of the world's population (van Os, J.; Kapur, S. “Schizophrenia”Lancet 2009, 374, 635-645). The principal goals of treatment are to achieve sustained remission from psychotic symptoms, reduce the risk and consequences of relapse, and improve patient functioning and overall quality of life. While many patients with schizophrenia are able to achieve symptom stability with the available antipsychotic medications, poor adherence to medication is a common reason for relapse with daily administered oral medications. Several s...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K16/44G01N33/94
CPCG01N33/94C07K16/44A61P25/18A61P25/24C07K2317/14G01N33/9406
Inventor HRYHORENKO, ERICSANKARAN, BANUMATHIDECORY, THOMAS R.TUBBS, THERESACOLT, LINDAVLIEGEN, MAARTENHASPESLAGH, PIETER RIK
Owner JANSSEN PHARMA NV
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