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Usage of treating allergic rhinitis and other disorders using descarboethoxyloratadine

A technology of decarboxyethoxy loratadine and carboethoxy loratadine, applied in hepta[1, a new method, decarboxyethoxy loratadine, relates to a treatment related to diabetes, capable of Fix issues like bad interactions

Inactive Publication Date: 2006-08-02
散诺为用药品有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because it interferes with loratadine metabolism, use with loratadine or other nonsedating antihistamines known to inhibit cytochrome P450 such as ketoconazole, itraconazole, and erythromycin (but not only limited to these) there is likely to be an undesirable interaction between

Method used

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  • Usage of treating allergic rhinitis and other disorders using descarboethoxyloratadine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] 4.1 Example 1: Preparation of loratadine and its metabolites

[0067] Loratadine can be synthesized by the method taught in US Patent 4,282,233. Metabolites thereof are similarly prepared using reaction procedures conventional in the art, as described in US Patent 4,659,716, the contents of which are incorporated herein by reference. A common method for preparing DCL is to reflux loratadine in NaOH and ethanol as shown below.

[0068]

[0069] Extraction of commercial medicine Claritin tablet (600×10mg)

[0070] Dilute loratadine tablets with water and chloroform. The mixture was stirred, then filtered through Celite, rinsing with chloroform until the filtrate was free of loratadine. The separated aqueous layer was extracted twice with chloroform. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the solvent gave pure white immobilized loratadine.

[0071] Saponification of Loratadine

[0072] Loratadine (4.0 g) w...

Embodiment 2

[0074] Antihistamine activity

[0075] The antihistamine activity of loratadine and DCL was compared using isolated guinea pig ileal strips against histamine contractility. This method is widely accepted by those skilled in the art as a method for predicting the efficiency of peripheral histamine H-1 receptors.

[0076] method:

[0077] Experiments were performed on ileal segments taken from male guinea pigs (Hartley strain, 419-560 g; Elm Hill Breeding Laboratories, Chelmsford, MA). The tissue was suspended in a tissue chamber containing 40mL Tiger solution, filled with 95% oxygen and 5% CO 2 , cultured at 35°C. Tiger solution includes (mM) 137NaCl, 2.7KCl, 2.2CaCl 2 , 0.025MgCl 2 , 0.4NaHPO 4 , 11.9NaHCO 3 and 5.5 glucose. Contractions produced in response to histamine were recorded with an isotonic transducer (Model 357, Harvard Instruments, South Natick, MA) and a Modograph (Model 7, Grass Instruments, Quincy, MA). A tension of 1 gram was maintained in all tissues...

Embodiment 3

[0088] receptor binding assay

[0089] Receptor binding assays for the binding affinity of loratadine and DCL to the histamine H-1 receptor were performed.

[0090] The method of Dini et al., which is incorporated herein by reference (Agents and Actions, 33:181-184, 1991), was used in this binding assay. Guinea pig cerebellum was incubated with 0.5 nM 3H-pyrilamine at 25°C for 10 minutes, then assayed using a Brandel cell harvester, filtered through GF / B glass fiber filter paper (Whatman) under vacuum, and ice-cold buffer Fluid several times. Bound radioactivity was determined with a liquid scintillation meter (LS 6000, Beckman) by using liquid scintillation fluid (Formula 989, DuPont NEN).

[0091] The IC of the tested compounds and neoantigen on the H-1 histamine receptor was determined. 50 value.

[0092] H-1 receptor

compound

Loratadine

DCL

Antigen

IC 50 (nM)

721

51.1

1.4

(nH)

(1.55)

(1.12)

(0.98)...

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Abstract

A composition comprising DCL, or a pharmaceutically acceptable salt thereof, for treating allergic rhinitis, allergic asthma, retinopathy or other small vessel diseases associated with diabetes mellitus, urticaria, or symptomatic dermographism in a human, while avoiding the concomitant liability of adverse side effects associated with the administration of non-sedating antihistamines, by administering to said human a therapeutically effective amount of DCL or pharmaceutically acceptable salt thereof.

Description

1. Background of the invention [0001] The methods of the present invention comprise administering a therapeutically effective amount of a metabolic derivative of loratadine. Chemically, this derivative is 8-chloro-6,11-dihydro-11-(4-piperidinylene)-5H-benzo[5,6]arhepta[1,2-b] Pyridine, known as descarboethoxyloratadine (DCL). Quercia is waiting Hosp. Formul 28: 137-53 (1993) and US Pat. No. 4,659,716. This compound is described in detail. [0002] Loratadine is an antagonist of the histamine H-1 receptor protein. The H-1 receptor and the H-2 receptor of histamine are two well characterized forms. H-1 receptors mediate antagonistic responses to conventional antihistamines. H-1 receptors are found, for example, in the ileum, skin and bronchial smooth muscle of humans and other mammals. [0003] Loratadine preferentially binds to peripheral H-1 receptors rather than central H-1 receptors. Quercia et al., Hosp. Formul .28:137-53 (1993). In guinea pigs, loratadine was a mo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/44A61P11/02C07D401/04A61K31/4427A61K31/445A61K31/451A61K31/4545A61K45/06A61P3/08A61P3/10A61P25/04A61P27/00A61P27/02A61P27/14A61P27/16A61P29/00A61P31/12A61P31/16A61P37/08
CPCA61K31/4545Y10S514/826A61K45/06A61K31/451A61P11/00A61P11/02A61P11/06A61P17/00A61P25/00A61P25/04A61P27/00A61P27/02A61P27/14A61P27/16A61P29/00A61P31/00A61P31/12A61P31/16A61P3/08A61P37/00A61P37/08A61P9/10A61P3/10A61K2300/00A61K31/137
Inventor A·K·阿伯尔格J·R·麦克库罗E·R·史密斯
Owner 散诺为用药品有限公司
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