Aralkyl ester soft drugs

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-Φ-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; Φ 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 Φ; 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.

1 . A method for programming a specific course and rate for a parent drug compound's metabolism that leads to an inactive or weakly active and non-toxic metabolite when the parent drug compound is administered, the method comprising 
 modifying the parent drug compound by forming one or more of a predetermined chemical arrangement within the parent drug compound, the chemical arrangement comprising A-Φ-R—X—R′
 wherein A is absent or is a tether moiety which allows for a metabolically stable chemical connection to be made to the parent drug compound;  
 Φ 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 already present within the parent drug compound or is specifically added to the parent drug compound via connection to Φ;  
 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;    said chemical arrangement not being used in connection with specific structural settings wherein:    i) the parent drug compound is an aryloxypropanolamine, a 2,6-bis (1-pyrrolidinylmethyl)-4-benzamidophenol,    ii) the parent drug already contains an ester moiety as an inherent component of the structure of the parent drug that also causes the parent drug to already exhibit a short duration of action,    iii), the modified drug compound consisting of a parent drug compound having a formula                          and having one predetermined chemical arrangement attached to the parent drug by a carbon-to-carbon bond at the 4-position, the predetermined chemical arrangement having a formula R—CO 2 —R′, wherein-R is an ethyl or ethylene group attached at one end to the 4-position of the parent drug compound, and R′ is an ethyl or isopropyl group, or    iv)a modified phenytoin, having the formula                          
   
   
       2 . The method of  claim 1 , in which only one chemical arrangement is used.  
   
   
       3 . The method of  claim 2 , in which X is carboxyl.  
   
   
       4 . The method of  claim 3 , in which R and R′ are unbranched alkyl from 1 to 2 carbons.  
   
   
       5 . The method of  claim 3 , in which R′ is a structural element already present as an inherent portion of the parent drug compound.  
   
   
       6 . The method of  claim 1 , in which the modified drug is used to optimize the overall pharmacological profiles of a new drug candidate during the process of drug design and development.  
   
   
       7 . The method of  claim 1 , in which the modified drug is used to enhance the overall therapeutic profile of a parent drug that is used clinically.  
   
   
       8 . The method of  claim 1 , in which the programmed metabolism of the added chemical arrangement circumvents unwanted accumulation of the drug.  
   
   
       9 . The method of  claim 1 , in which the programmed metabolism of the added chemical arrangement circumvents one or more toxic metabolic pathways.  
   
   
       10 . The method of  claim 1 , in which a programmed rate of metabolism for the added chemical arrangement is adjusted so as to produce a shorter duration of action for the modified drug as compared to the parent drug.  
   
   
       11 . The method of  claim 10 , in which the shorter duration allows the modified drug to be under precise moment-to-moment control by adjustment of the infusion rate of the modified drug when administered intravenously.  
   
   
       12 . The method of  claim 11 , in which the intravenous administration is used to treat critical care patients.  
   
   
       13 . The method of  claim 11 , in which the intravenous administration is used to treat neonates.  
   
   
       14 . The method of  claim 11 , in which the intravenous administration is used to wean a patient off an unmodified parent drug whose similar pharmacologic action is more safely removed in a controlled, step-wise manner by progressively decreasing the rate of the intravenous drip of the modified drug.  
   
   
       15 . The method of  claim 10 , in which the shorter duration allows the actions of the modified drug to remain localized when the initial delivery or activation of the modified drug is targeted to a specified compartment by use of localized injection or implant materials, or by localized photodynamic activation of the modified drug.  
   
   
       16 . The method of  claim 15 , in which the implant is a type of surgical-related material or suture wherein the modified drug is an antibiotic or a compound that promotes wound healing.  
   
   
       17 . The method of  claim 1 , in which a programmed rate of metabolism of the modified drug is matched with a release rate from a sustained-release injectable formulation or implant of the modified drug to provide for prolonged steady-state levels of the modified drug at pre-calibrated concentrations.  
   
   
       18 . The method of  claim 1 , in which the modified drug is used as a topical treatment in order to eliminate or lessen unwanted effects that the unmodified parent drug exhibits upon systemic absorption after placement on the skin or within the eye or nasal passageways.  
   
   
       19 . The method of  claim 1 , in which the parent drug plus added chemical arrangement comprises a short-acting anti-cholinergic agent.  
   
   
       20 . The method of  claim 19 , in which the short-acting anti-cholinergic agent is an atropine derivative that is designed for topical administration to the eye.  
   
   
       21 . The method of  claim 19 , in which the short-acting anti-cholinergic agent is a non-depolarizing neuromuscular junction blocking agent that is designed for use by the intravenous route during surgical-related procedures.  
   
   
       22 . The method of  claim 1 , in which the parent drug plus added chemical arrangement comprises an ultra-short acting alpha 1 -adrenergic receptor blocker or an alpha 2 -adrenergic receptor agonist.  
   
   
       23 . The method of  claim 1 , in which the parent drug plus added chemical arrangement comprises a short-acting inhibitor of the sodium channel.  
   
   
       24 . The method of  claim 23 , in which the short-acting inhibitors are administered as sustained-release or implantable dosage forms.  
   
   
       25 . The method of  claim 1 , in which the parent drug plus the added chemical arrangement comprises an ultra-short acting ACE inhibitor.  
   
   
       26 . The method of  claim 1 , in which the parent drug plus the added chemical arrangement comprises an ultra-short acting histamine receptor blocker.  
   
   
       27 . The method of  claim 1 , in which the parent drug plus the added chemical arrangement comprises an ultra-short acting adenosine antagonist.  
   
   
       28 . The method of  claim 1 , in which the parent drug plus the added chemical arrangement comprises an ultra-short acting anti-inflammatory agent.  
   
   
       29 . The method of  claim 1 , in which the parent drug plus the added chemical arrangement comprises an ultra-short acting antiarrhythmic agent.  
   
   
       30 . The method of  claim 1 , in which the parent drug plus the added chemical arrangement comprises an ultra-short acting calcium channel blocker.  
   
   
       31 . The method of  claim 1 , in which the parent drug plus the added chemical arrangement comprises an ultra-short acting antibiotic compound including sulfonamide, penicillin, cephalosporin or tetracycline.  
   
   
       32 . The method of  claim 31 , in which the ultra-short acting antibiotic compounds are administered via impregnation in surgical suture material or wound-healing implantable polymeric materials.  
   
   
       33 . A method of treating a critically ill patient in need of α 2 -adrenergic agonist therapy comprising the step of using the modified drug of  claim 1  by intravenous infusion such that the drug's desirable effects are quickly equilibrated during infusion and are quickly dissipated when the infusion is stopped  
   
   
       34 . A method of weaning a patient from α 2 -adrenergic agonist therapy comprising the step of using the modified drug of  claim 1  by intravenous infusion such that the drug's effects undergo controlled withdrawal and do not prompt rebound hypertension.  
   
   
       35 . The method of  claim 1 , in which the parent drug plus the added chemical arrangement comprises a short-acting version of methotrexate.  
   
   
       36 . The method of  claim 35 , in which the short-acting version of methotrexate is administered topically.  
   
   
       37 . The method of  claim 36 , in which the topical administration is used to treat epidermoid cancers or psoriasis.  
   
   
       38 . A modified drug compound comprising methotrexate as a parent drug and having at least one chemical arrangement attached to the parent drug be a carbon-to-carbon bond, the chemical arrangement having the formula R—X—R′, wherein 
 R is an alkyl or alkene containing chain either branched or unbranched from 0 to 10 carbons that is either already present within the methotrexate parent drug or is specifically added to the methotrexate parent drug;    X is a carboxyl, sulfoxyl or phosphatyl function that is specifically added to the methotrexate parent drug 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 methotrexate parent drug.    
   
   
       39 . A method of treating a patient in need thereof, comprising administering a therapeutically effective amount of modified drug of  claim 38  by intravenous infusion such that the modified drug's desirable effects are quickly equilibrated during infusion and are quickly dissipated when the infusion is stopped.  
   
   
       40 . A method of treating a patient in need thereof, comprising administering a therapeutically effective amount of the modified drug of  claim 38  by topical administration so as to eliminate systemic toxicity upon percutaneous absorption after topical treatments:  
   
   
       41 . The method of  claim 39 , wherein the patient is suffering from epidermoid cancer or and psoriasis.  
   
   
       42 . The method of  claim 40 , wherein the patient is suffering from epidermoid cancer or and psoriasis.