Aralkyl ester soft drugs

a technology of alkyl ester and soft drugs, applied in the direction of drug compositions, phosphorous compound active ingredients, cardiovascular disorders, etc., can solve the problems of inability to know exactly what dme and toxicity-related properties may need to be addressed, and the overall profile is less than ideal, and achieves convenient and safe deployment, prolonged steady-state levels, and the effect of convenient and safe us

Inactive Publication Date: 2003-05-22
UNIVERSITY OF TOLEDO
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  • Abstract
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AI Technical Summary

Benefits of technology

0012] In another aspect, the present invention is used to program the rate for a specified metabolism in order to adjust the parent drug's duration of action to a desired shorter time interval. Alternatively, when the aralkyl ester moieties of the present invention are used in conjunction with an implant or drug depot delivery system, the rate of programmed metabolism can be matched to that for the soft drug's delivery so as to precisely provide prolonged steady-state levels of the soft drug at pre-calibrated concentrations.
0013] In another aspect, the present invention is used to program an ultra-short duration into a parent drug to allow the resulting soft drug's actions to be under precise moment-to-moment control via its intravenous administration infusion rate, an overall drug property which has already been demonstrated to be particularly useful in critical care and surgical settings. Given the paucity of drugs and drug-related technologies that have been previously targeted for very young humans, the present invention is especially useful in the development of aralkyl ester soft drugs which are conveniently and safely deployed for the specific treatment of premature, full-term newborn...

Problems solved by technology

Oftentimes, however, the pharmacophores or the presence of other chemical components within such compounds, provide a less than ideal overall profile relative to the final deployment of a given drug for a particular clinical indication.
However, unless there is compelling preclinical data which suggests that the clinical application of a lead compound is going to become problematic, DME-re...

Method used

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  • Aralkyl ester soft drugs
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Examples

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example 1

[0044] Structure 12 represents an analog of atropine that has an appended external ester metabophore. It has been designed for delivery as drops to the eye where it will then display its characteristic antimuscarinic properties that are useful during eye examinations for only about 30 minutes. Atropine's several hour duration is in large excess of the time typically needed to conduct a routine eye exam and chemical antidotes often need to be administered so that a patient's vision can be more quickly normalized. In addition, due to the same metabolic programming, the soft drug analog has a better systemic side-effect profile than atropine because the soft drug that is absorbed from this localized topical compartment is readily deactivated.

example 2

[0045] Structures 13 and 14 represent metabophore-containing, bulky analogs of decamethonium and pancuronium, respectively. Two external esters have been deployed in each case in order to further enhance the overall molecules' metabolic biotransformations given that these esters' close placements to the bulky aromatic rings slow their individual metabolic hydrolyses rates. The parent compounds' inherent anti-nicotinic activities, produced in a non-depolarizing fashion at neuromuscular junctions by virtue of the presence of the bulky functionalities, has a short half-life due to the appended metabophores. These compounds are ideally suited for use during surgery where there is a long-standing need for titrable, short-acting, non-depolarizing neuromuscular junction blocking agents: Approaches to Short-Acting Neuromuscular Blocking Agents: Nonsymmetrical Bistetrahydroisoquinolinium Mono- and Diesters, N. C. Dhar, R. B. Maehr, L. A. Masterson, J. M. Midgley, J. B. Stenlake and W. B. Was...

example 3

[0046] Structures 15 and 16 represent metabophore-containing analogs of prazosin and indoramin, respectively. Structure 15 contains a single sulfonate ester appendage while Structure 16 contains both an internal carboxylate metabophore and an external phosphonate ester appendage. In both cases, the inherent .alpha..sub.1-receptor antagonist properties are displayed as an ultra-short duration such that both compounds are better used in critical care settings via the intravenous route to treat hypertensive crises, shock or Raynaud's disease.

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Abstract

The present invention describes a method for programming a specific course and rate of metabolism for a parent drug compound that leads to an inactive or very weakly active and nontoxic metabolite when the modified drug compound is administered. The parent drug compound is modified by forming one or more of a predetermined chemical arrangement within the parent drug structure where the chemical arrangement is A--Ø--(R)-X-R'; where A is absent or is a tether moiety which allows for a metabolically stable chemical connection to be made to the parent drug compound; Ø is a substituted aryl or heteroaryl system that is already present within the parent drug compound or is specifically added to the parent drug compound via A; R is an alkyl or alkene containing chain either branched or unbranched from 0 to 10 carbons that is either also already present within the parent drug compound or is specifically added to the parent drug compound via connection to Ø; X is a carboxyl, sulfoxyl or phosphatyl function that is specifically added to the parent drug compound via connection to R; and, R' is an added alkyl, alkenyl, or aralkyl group either branched or unbranched containing from 1 to 10 carbons, other common leaving group, or a structural element already present as an inherent portion of the parent drug compound.

Description

BACKGROUND AND SIGNIFICANCE OF THE INVENTION[0001] Pharmaceutical agents or drugs exhibit desirable therapeutic properties because they contain distinct molecular arrangements called pharmacophores. Oftentimes, however, the pharmacophores or the presence of other chemical components within such compounds, provide a less than ideal overall profile relative to the final deployment of a given drug for a particular clinical indication. In some cases this situation can be improved by altering chemical features associated with a drug's distribution, metabolism or elimination (DME). This process, when successful, results in what is now referred to in the pharmaceutical community as a "soft drug" version of the original or parent drug compound: Soft Drugs. XX. Design, Synthesis and Evaluation of Ultra-Short Acting beta-Blockers, H.-S. Yang, W.-M. Wu and N. Bodor, Pharm. Res., 12, 329 (1995); and Synthesis and Enzymatic Hydrolysis of Esters, Constituting Simple Models of Soft Drugs, M. Graff...

Claims

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Application Information

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IPC IPC(8): A61K31/185A61K31/195A61K31/216C07D499/68A61K31/235A61K31/245A61K31/277A61K31/401A61K31/4025A61K31/405A61K31/4166A61K31/4168A61K31/421A61K31/426A61K31/43A61K31/4422A61K31/454A61K31/46A61K31/517A61K31/519A61K31/522A61K31/55A61K31/58A61K31/65A61K31/66A61K45/00A61K47/48A61P9/06A61P17/02A61P17/06A61P25/02A61P29/00A61P31/10A61P35/00A61P43/00C07C217/40C07C219/10C07C219/14C07C229/60C07C237/04C07D207/16C07D209/26C07D209/28C07D211/90C07D223/22C07D233/26C07D233/50C07D233/76C07D261/16C07D277/20C07D277/56C07D295/14C07D401/06C07D405/12C07D451/06C07D451/10C07D473/06C07D475/08C07D501/22C07J43/00
CPCA61K9/0048A61K31/4164C07D475/08C07D473/06C07D451/06A61K31/4166A61K45/06C07D209/28C07D211/90C07D223/22C07D233/50C07D233/76C07D261/16C07D277/56C07D401/06C07D405/12A61K2300/00A61P17/02A61P17/06A61P25/02A61P29/00A61P31/10A61P35/00A61P43/00A61P9/06
Inventor ERHARDT, PAUL W.
Owner UNIVERSITY OF TOLEDO
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