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8'-hydroxy-dihydroergotamine compounds and compositions

a technology of dihydroergotamine and hydroxydihydroergotamine, which is applied in the direction of heterocyclic compound active ingredients, drug compositions, dispersed delivery, etc., can solve the problems of gastrointestinal cramping and distress, medication side effects that are significant, and the research no longer fully supports the vasodilator/vasoconstrictor mechanism of vascular headache,

Inactive Publication Date: 2016-09-15
MAP PHARMACEUTICAL INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention provides new compounds called 8′-OH DHE derivatives with specific substitutions that reduce the side effects of drugs, such as fibrosis, and enhance their activity in treating migraines and other neurological disorders. Additionally, these compounds have reduced activity at dopamine receptors, which could lead to improved safety and efficacy.

Problems solved by technology

However, most people with migraines do not have such warning signs.
Present research no longer fully supports the vasodilator / vasoconstrictor mechanism of vascular headache, i.e., arterial dilation causes pain and constriction equals relief.
All of these medications have significant side effects including sedation, loss of energy and drive, dry mouth, constipation, weight gain, and gastrointestinal cramping and distress.
When narcotics, such as butalbital with codeine are used frequently, additional hazards, including the considerable potential for rebound headaches and habituation are encountered.
Although effective in the treatment of migraine, DHE administration is often accompanied by side effects such as nausea, vomiting and chest pain (Winner, et al., Arch. Neurol. 53:180-184 (1996)).
Due to the possibility for fibrotic side effects, patients with known cardiovascular disease are not qualified to receive IV DHE treatment.

Method used

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  • 8'-hydroxy-dihydroergotamine compounds and compositions
  • 8'-hydroxy-dihydroergotamine compounds and compositions

Examples

Experimental program
Comparison scheme
Effect test

example 1

Hydroxylation of DHE to Give 8′-hydroxy-dihydroergotamine (8′-OH-DHE)

[0164]Bioconversion of the parent dihydroergotamine (DHE) molecule (the mesylate salt form) was carried out using Rhodococcus sp. AMRI-411 (Albany Molecular Research, Inc., Albany, N.Y.), a strain isolated from environmental samples used for biocatalysis screening. The AMRI-411 cells were grown according to the following protocol. Vials stored under liquid nitrogen vapor were thawed and approximately 1.0 mL of seed material was inoculated into 250 mL DeLong culture flasks containing 30 mL of Soybean Flour Glycerol Medium. Soybean Flour Glycerol Medium was composed of soy flour (5 g / L), yeast extract (5 g / L), NaCl (5 g / L), K2HPO4 (5 g / L) and glycerol (20 g / L) in deionized water. The pH was adjusted to 6.8 with 1 N HCl. The medium was autoclaved for 30 minutes at 16 psi and 122° C. and mixed prior to dispensing into flasks. This culture was grown at 28° C., 200 RPM with a 5 cm orbit for 24 hours. The resulting cultur...

example 2

Determination of Association / Dissociation Constants on Human D2L, 5-HT1A, 5-HT1B, 5-HT1D and 5-HT2B Receptors

[0167]Determination of association (kon) / dissociation (koff) constants for 8′-OH DHE and the parent DHE molecule (compared against sumatriptan) on human D2L, 5-HT1A, 5-HT1B, 5-HT1D and 5-HT2B receptors was carried out using the following radioligand binding assay.

[0168]Compounds: the 8′-OH DHE and DHE compounds were in powder form and stored at room temperature (RT) prior to testing. For the testing, the compounds were prepared according to Table 1 below.

TABLE 1SolventCompoundStorageMaster Solution100% DMSO10 mM−20° C.Intermediate dilution100% DMSO2 mM-2 nM Max 4 hoursfor all compounds onat RT5-HT1A, 5-HT1B and5-HT1D receptors andtest compounds on5-HT2B receptor.Assay plate for allAssay buffer20 μM-20 pMMax 4 hourscompounds onat RT5-HT1A, 5-HT1B and5-HT1D receptors andtest compounds on5-HT2B receptor.Intermediate dilution100% DMSO 10 mM-200 nMMax 4 hoursfor all compounds onat...

example 3

Determination of Agonist and Antagonist Activities on Human Adrenergic α1D, Dopamine D2L, and Serotonin 5-HT1B, 5-HT1D, 5-HT1F, 5-HT3, 5-HT4e and 5-HT5A Receptors

[0186]Functional profiling of agonist and antagonist activities of 8′-OH DHE on human Adrenergic α1D, Dopamine D2L, and Serotonin 5-HT1B, 5-HT1D, 5-HT1F, 5-HT3, 5-HT4e and 5-HT5A receptors (compared against the parent (DHE) molecule) was carried out as follows.

[0187]Compounds: the 8′-OH DHE and DHE test compounds were in powder form and stored at 4° C. (DHE) or −20° C. (8′-OH DHE) prior to testing. For the testing, the compounds were prepared according to Tables 8 and 9 below.

TABLE 8(Dose-Response Curves)SolventCompoundStorageMaster Solution100% DMSO10 mM−20° C.Intermediate dilution100% DMSO 4 mM-2.048 nMMax 4 hoursfor Aequorin andat RTcAMP HTRF assays.Assay plate forAssay buffer40 μM-20.48 pMMax 4 hoursAequorin and cAMPat RTHTRF assaysIntermediate dilution100% DMSO 2 mM-1.024 nMMax 4 hoursfor GTPγS assay.at RTAssay plate f...

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Abstract

8′-Hydroxy-Dihydroergotamine (8′-OH DHE) medicinal compounds, compositions, and dosage forms containing such compositions are provided. Also provided herein are methods of treatment, prevention, or amelioration of migraine disorders using the compounds, compositions, dosage forms and administration techniques disclosed herein.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of U.S. patent application Ser. No. 14 / 134,100 filed on Dec. 19, 2013, which claims priority under 35 U.S.C. §119(e) from U.S. Provisional Application Ser. No. 61 / 745,104, filed Dec. 21, 2012, each of which is hereby incorporated by reference in its entirety.TECHNICAL FIELD OF THE INVENTION[0002]Provided herein are 8′-Hydroxy-Dihydroergotamine (8′-OH DHE) medicinal compounds, compositions, and dosage forms containing such compositions. Also provided herein are methods of treatment, prevention, or amelioration of migraine disorders using the compounds, compositions and dosage forms disclosed herein. Still further provided herein are methods of agonizing receptors such as, for example, the 5-HT1D and / or the 5-HT1B receptor, without agonizing the 5-HT2B receptor using the compounds, compositions and dosage forms disclosed herein. In addition, provided herein are methods of antagonizing or inhibiting activit...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/48A61K9/00
CPCA61K31/48A61K9/008A61K9/007C07D498/04A61P25/06A61P29/00
Inventor KELLERMAN, DONALD J.ARMER, THOMASZHANG, JIAN
Owner MAP PHARMACEUTICAL INC
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