NZ618113B2 - Methylphenidate-prodrugs, processes of making and using the same - Google Patents

Methylphenidate-prodrugs, processes of making and using the same Download PDF

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Publication number
NZ618113B2
NZ618113B2 NZ618113A NZ61811312A NZ618113B2 NZ 618113 B2 NZ618113 B2 NZ 618113B2 NZ 618113 A NZ618113 A NZ 618113A NZ 61811312 A NZ61811312 A NZ 61811312A NZ 618113 B2 NZ618113 B2 NZ 618113B2
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New Zealand
Prior art keywords
methylphenidate
acid
mmol
mph
present technology
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NZ618113A
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NZ618113A (en
Inventor
Bindu Bera
Guochen Chi
Sven Guenther
Travis Mickle
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Kempharm Inc
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Priority claimed from PCT/US2012/048641 external-priority patent/WO2013016668A2/en
Publication of NZ618113A publication Critical patent/NZ618113A/en
Publication of NZ618113B2 publication Critical patent/NZ618113B2/en

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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
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    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
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Abstract

Disclosed herein are methylphenidate prodrug compositions comprising the compound of the general formula shown. The compositions are intended for the treatment of various diseases and/or disorders including ADHD. Also disclosed is the synthesis of methylphenidate and the prodrug derivatives thereof. (...)

Description

METHYLPHENIDATE-PRODRUGS, PROCESSES OF MAKING AND USING THE SAME RELATED ATIONS This application claims the benefit of the priority of US. Provisional Application No. 61/512,658, entitled METHYLPHENIDATE-OXOACID CONJUGATES, PROCESSES OF MAKING AND USING THE SAME, filed July 28, 2011, which is incorporated herein by reference in its entirety.
FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT [Not Applicable] BACKGROUND OF THE INVENTION Methylphenidate is a psychostimulant which is a chain substituted amphetamine tive. Similar to amphetamine and cocaine, phenidate targets the central s system, ically the dopamine transporter (DAT) and nephrine orter (NET). Methylphenidate is thought to act by increasing the concentrations of dopamine and norepinephrine in the synaptic cleft, as methylphenidate has both dopamine transporter (DAT) and norepinephrine transporter (NET) binding capabilities. gh an amphetamine derivative, the pharmacology of methylphenidate and amphetamine differ, as amphetamine is a dopamine transport substrate whereas methylphenidate works as a dopamine transport blocker. As a norepinephrine and dopamine re-uptake inhibitor, methylphenidate thus blocks re- uptake of dopamine and norepinephrine (noradrenaline) into presynaptic neurons (and possibly stimulates the release of dopamine from dopamine nerve terminals at high doses), thereby increasing the levels of dopamine and norepinephrine in the synapse.
In some in vitro studies, methylphenidate has been shown to be more potent as an inhibitor of norepinephrine uptake/re-uptake when compared to dopamine. However, some in vivo studies have indicated that methylphenidate is more potent in potentiating extracellular ne concentrations than norepinephrine trations. Unlike amphetamine, it has been duggested in the scientific and/or al research comunity that methylphenidate does not seem to significantly facilitate the release of these two monoamine neurotransmitters at therapeutic doses.
Four isomers of methylphenidate are known to exist: d—erythromethylphenidate , /-erythro-methylphenidate, d—threo-methylphenidate, and /-threo- methylphenidate. Originally, methylphenidate was ed as a mixture of two tes, d/l-erythro—methylphenidate and d/l-threo—methylphenidate. Subsequent research showed that most of the pharmacological activity of the mixture is associated with the threo—isomer resulting in the marketing of the isolated threo—methylphenidate racemate. Later, the scientific community determined that the d—threo—isomer is mostly responsible for the stimulant activity. Consequently, new products were ped containing only d—threo—methylphenidate (also known as “d—threo—MPH”).
Stimulants, including methylphenidate (“MPH”), are believed to enhance the ty of the sympathetic nervous system and/or l nervous system (CNS).
Stimulants such as MPH and the various forms and derivatives thereof are used for the treatment of a range of conditions and disorders predominantly assing, for example, attention deficit hyperactivity er (ADHD), attention deficit disorder (ADD), obesity, narcolepsy, appetite suppression, depression, anxiety and/or wakefulness.
Methylphenidate is currently approved by the United States Food and Drug Administration (“FDA”) for the treatment of attention-deficit hyperactivity disorder and narcolepsy. phenidate has also shown efficacy for some off-label indications that include depression, y and lethargy. In some embodiments, the prodrugs of the present technology may be administered for the ent of attention-deficit hyperactivity disorder and narcolepsy, or any condition that requires the blocking of the norepinephrine and/or dopamine orters.
Attention deficit hyperactivity disorder (ADHD) in en has been treated with stimulants for many years. However, more recently, an increase in the number of iptions for ADHD therapy in the adult population has, at times, formed the growth of the pediatric market. Although there are various drugs currently in use for the treatment of ADHD, including some stimulants and some non-stimulant drugs, methylphenidate (commercially available from, for example, Novartis International AG (located in Basel, Switzerland) under the trademark Ritalin®) is commonly prescribed.
Moreover, during classroom trials, non-stimulants have shown to be less effective in improving behavior and attention of ADHD afflicted children than amphetamine derivatives.
Behavioral deterioration nd or “crashing”) is ed in a significant portion of children with ADHD as the medication wears off, typically in the afternoon or early evening. Rebound symptoms include, for example, irritability, crankiness, hyperactivity worse than in the unmedicated state, sadness, , and in rare cases psychotic episodes. The symptoms may subside quickly or last several hours. Some patients may experience rebound/crashing so severe that treatment must be discontinued. Rebound/crashing effects can also give rise to addictive behavior by enticing ts to administer additional doses of stimulant with the intent to prevent anticipated rebound/crashing negative outcomes and side effects. ants, such as methylphenidate and amphetamine, have been shown in the conventional art to exhibit noradrenergic and dopaminergic effects that can lead to vascular events comprising, for example, increased heart rate, hypertension, palpitations, tachycardia and in isolated cases cardiomyopathy, , myocardial infarction and/or sudden death. Consequently, currently available stimulants expose patients with isting ural cardiac abnormalities or other severe cardiac indications to even greater health risks and are frequently not used or used with caution in this patient population.
Methylphenidate, like other stimulants and amphetamine derivatives, can become addictive and is prone to substance abuse. Oral abuse has been reported, and euphoria can be achieved through intranasal and intravenous stration.
Methylphenidate also has limited water lity ally in an unconjugated form. The ties of limited bioavailability and limited water solubility make ating methylphenidate for oral administration more difficult because the dosage forms for administration are limited. There is a need in the art for more bioavailable and water soluble forms of methylphenidate that maintain the pharmacological benefit when administered, in particular via the oral route.
BRIEF SUMMARY OF THE INVENTION The present technology utilizes, for example, covalent conjugation of methylphenidate, various forms and derivatives thereof with certain alcohol, amine, oxoacid, thiol, or derivatives thereof to provide, for example, improved bioavailability and increased water solubility when compared to unconjugated phenidate. The increased bioavailability and/or increased water solubility in some instances provides the y of the prodrug or composition to be administered in forms that are not easily utilized with the ugated methylphenidate. For example, the increased water solubility of the ate compared to unconjugated methylphenidate provides the ability of the conjugate or prodrug to be administered in an oral thin film or strip with higher dose loading capacity as compared to unconjugated methylphenidate In one aspect, the t technology provides a prodrug composition comprising at least one conjugate, the conjugate comprising at least one methylphenidate, and at least one alcohol, amine, d, thiol, or derivatives thereof.
In some aspects, the prodrug composition r ses a linker, n the linker chemically bonds the at least one methylphenidate with the at least one alcohol, amine, oxoacid, thiol, or derivatives thereof. In some aspects, the linker comprises at least one (acyloxy)alkyloxy , derivatives thereof, or combinations thereof.
In further aspects, the present technology provides one or more conjugates of methylphenidate comprising methylphenidate, a derivative thereof, or combinations thereof and at least one alcohol, amine, oxoacid, thiol, or derivatives f, n the at least one oxoacid is a carboxylic acid.
In another aspect, the present technology provides at least one g composition comprising at least one conjugate of methylphenidate, derivatives thereof or combinations thereof and at least one inorganic d, or derivatives thereof with a free —OH group, an organic derivative thereof, an inorganic derivative thereof, or a combination thereof.
In a further aspect, the present logy provides at least one prodrug composition comprising at least one conjugate of methylphenidate, derivatives thereof or combinations thereof and an alcohol, amine, oxoacid, thiol, or derivatives thereof and a linker, wherein the linker ses an (acyloxy)alkyloxy group, a derivative thereof or combination thereof with the l formula -C(O)O-X-O- , wherein, X is selected from a representative group including optionally substituted alkyl, optionally substituted aryl, optionally tuted ryl, ally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted alkenyl, optionally substituted alkynyl, ally tuted cycloalkyl, optionally substituted cycloalkenyl, optionally tuted cycloalkynyl, or optionally substituted alkoxy. [0016a] Specifically, the present invention provides a prodrug composition comprising at least one conjugate of methylphenidate wherein the conjugate is of the following structure: wherein G2 is selected from the group ting of standard amino acids, nonstandard amino acids and synthetic amino acids; and wherein the amino acid is attached to the rest of the molecule by an amide linkage.
In another aspect, the present technology provides a prodrug composition comprising at least one conjugate of methylphenidate having a structure of formula (I) or formula (II): O O X O O N Y Gm N (I) (II) (Followed by page 5a) -5a- wherein X is selected from the group consisting of O, S, Se and NR1; wherein Y is absent or selected from the group consisting of O, S, Se, NR2 and CR3R4; wherein R1 and R2 are selected independently from the group consisting of hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, carbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, arbonylamino, alkylcarbonyloxy, alkylsulfinyl, ulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, ioalkyl, cycloalkenyl, lkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, (Followed by page 6) heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, hydroxy, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol; wherein R3 and R4 are selected independently from the group consisting of hydrogen, l, alkenylaminocarbonyl, , alkoxycarbonyl, alkyl, alkylamino, minocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, amine, amino, aminocarbonyl, ammonium, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, lfonylamino, arylthio, arylthioalkyl, cyano, cycloalkenyl, cycloalkenylalkyl, carboxyl, cycloalkyl, lkylalkyl, cycloalkylamino, cycloalkyloxy, lkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, hydroxy, nitro, oxo, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, polyethylene glycol and thiol; wherein L is absent or —[-A — Z-]-n; wherein A is ed ndently for each repeating subunit from the group ting of CRSRG, aryl, substituted aryl, arylene, carbocycle, cycloalkenyl, cycloalkyl, cycloalkynyl, heterocycle and heteroaryl; wherein R5 and R6 are selected independently from each other and independently for each repeating subunit from the group consisting of hydrogen, alkenyl, laminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, amine, amino, aminocarbonyl, um, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, rbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cyano, cycloalkenyl, cycloalkenylalkyl, carboxyl, cycloalkyl, lkylalkyl, lkylamino, lkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, arylsulfonyl, heteroarylthio, hydroxy, nitro, oxo, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, polyethylene glycol and thiol; wherein Z is either absent or ed independently for each repeating subunit from the group consisting of O, 8, Se and NH; wherein n is 0-50; wherein G is selected independently for each ing subunit from the group consisting of alcohol, amine, amino acid, ammonium, d, peptide, poly(ethylene glycols) (PEG), thiol, derivatives thereof and combinations thereof; wherein E is an oxoacid; and wherein m is 0-5.
In another aspect, the present technology provides at least one prodrug composition comprising at least one conjugate, wherein the at least one conjugate can be, for e, nicotinate-CH20CO-methylphenidate, phosphate-CH20CO- methylphenidate, phosphate-CH20CO-methylphenidate, gallate-CH20CO- methylphenidate, gallate-CH20CO-methylphenidate, lactate-CH20CO-methylphenidate, phenidate-C02CH2-nicotinoyl-Asp, phenidate-C02CH2-nicotinoyl-Val, methylphenidate-C02CH2-nicotinoyl-Gly-Ala, Valaminohexanoate-CH20CO- methylphenidate, methylphenidate-C02CH2-nicotinamide, 6-Aminohexanoate-CH20CO- methylphenidate, methylphenidate-C02CH2-nicotinoyl-O‘Bu, methylphenidate-C02CH2- nicotinate, methylphenidate-C02CH2-nicotinoyl-OEt, phenidate-C02CH2-pyridine, otinate-CH20CO-methylphenidate, or phosphate-(p—salicylate)-CH20CO- methylphenidate.
Moreover, the t technology provides at least one prodrug composition comprising at least one oxyalkyl carbamate.
In yet another aspect, the present technology provides a method for chemically synthesizing any of the methylphenidate conjugates of the present technology by perforing the appropriate steps to conjugate methylphenidate to at least one ligand.
In r aspects, prodrug compositions of the present technology are believed to unexpectedly exhibit a rate of release equivalent to free or unmodified methylphenidate. In other aspects, the one or more prodrug composition of the present logy are believed to surprisingly exhibit a slower rate of release over time as compared to fied methylphenidate.
In yet other aspects, conjugates or prodrugs of the present logy are believed to unexpectedly exhibit an increased absorption when administered orally as ed to unmodified methylphenidate. onally, ates or prodrugs of the present technology are believed to surprisingly have increased bioavailability as compared to unmodified methylphenidate.
In yet a further aspect, the conjugates or prodrugs of the present logy are believed to surprisingly exhibit less interpatient variability in the oral pharmacokinetic (PK) profile when compared to ugated methylphenidate.
In yet another aspect, the conjugates or prodrugs of the present technology are provided in an amount sufficient to provide an increased AUC when compared to unconjugated methylphenidate when administered orally at equimolar doses. In still other aspects, the conjugates or gs are provided in an amount sufficient to provide an unexpected increased Cmax as compared to unconjugated phenidate when administered orally at equimolar doses.
In yet further aspects, the conjugates or prodrugs of the present technology are provided in an amount sufficient to provide a surprisingly increased Cmax and an increased AUC as compared to unconjugated methylphenidate when administered orally at equimolar doses.
In yet an alternative aspect, the conjugates or prodrugs of the present logy e reduced side effects as compared to unconjugated methylphenidate when administered at lar doses, and are also contemplated in some alternative aspects to provide reduced abuse potential as ed to unconjugated methylphenidate.
In addition, the conjugates or prodrugs of the present technology are also believed to unexpectedly provide an amount sufficient to provide an extended Tmax when compared to unconjugated methylphenidate when administered at equimolar doses, and/or provide an equivalent Tmax when compared to unconjugated methylphenidate when administered at equimolar doses.
Moreover, the present technology provides at least one method of treating one or more patients (human or animal) having at least one disease, disorder or condition mediated by controlling, preventing, limiting, or inhibiting neurotransmitter uptake/re-uptake or hormone uptake/re-uptake comprising orally administering to one or more patients a pharmaceutically effective amount of at least one of the prodrug compositions of the present technology.
In still yet a r aspect, the present technology provides at least one method of treating a t (human or animal) having at least one disorder or condition requiring stimulation of the l nervous system of the patient, comprising orally administering a pharmaceutically effective amount of one or more prodrug compositions of the present technology.
In yet another aspect, the present technology provides one or more methods of administering at least one [methylphenidate] composition or prodrug of the present technology wherein the administration decreases the number and/or amount of lites produced when ed with unconjugated phenidate. In other s, the one or more methods of administering the one or more [methylphenidate] compositions or prodrugs of the present technology is believed to decrease the exposure of the patient to ritalinic acid when compared with unconjugated methylphenidate.
In yet a further embodiment, the one or more compositions or prodrugs of the present technology are ed to provide an increased water solubility of the methylphenidate-based conjugate or prodrug ed to unconjugated methylphenidate. In r embodiment, the sed water solubility is believed to allow for the prodrug to be formed into certain dosage forms at higher concentrations, dosage strengths, or higher dose loading capacities than unconjugated methylphenidate. In some embodiments, such dosage forms include, for example, oral thin films or strips with.
In still yet a further embodiment, the administration of one or more methylphenidate-based itions or prodrugs are believed to provide a reduced interpatient variability of methylphenidate plasma concentrations, and are believed to have an ed safety profile when compared to unconjugated methylphenidate.
In yet another alternative embodiment, the present technology provides at least one method of treating attention-deficit hyperactivity er comprising administering a pharmaceutically effective amount of one or more conjugates or g itions of the present technology.
In another further embodiment, the present technology provides at least one prodrug composition for treating at least one patient having a disorder or condition requiring stimulation of the central nervous system of the patient, wherein the at least one prodrug or ition has a reduced abuse potential when administered compared to unconjugated methylphenidate.
In a further embodiment, the one or more methylphenidate-based prodrug or ate compositions of the present technology are contemplated to exhibit reduced or prevented pharmacological ty when administered by parenteral routes, or reduced plasma or blood concentration of released methylphenidate when administered intranasally, intravenously, intramuscularly, subcutaneously or rectally as compared to free unconjugated methylphenidate when administered at equimolar amounts.
In yet another embodiment, the present technology provides at least one phenidate-based ate prodrug composition having an extended or controlled release profile as measured by plasma trations of released methylphenidate when compared to unconjugated methylphenidate when administered orally at equimolar doses. In some embodiments, the plasma concentration of methylphenidate released from the g would increase more slowly and over a longer period of time after oral administration, resulting in a delay in peak plasma concentration of released methylphenidate and in a longer duration of action when compared to unconjugated methylphenidate.
In another aspect, the present technology provides a pharmaceutical kit comprising a specified amount of individual doses in a package containing a pharmaceutically effective amount of at least one ate of methylphenidate.
BRIEF DESCRIPTION OF THE GS Figure 1. Chemical structures of some hydroxybenzoates for use in the making of the conjugates of the present technology.
Figure 2. al structures of some aryl carboxylic acids for use in the making of the conjugates of the present technology.
Figure 3. Chemical structures of some phenylacetates for use in the making of the conjugates of the present technology.
Figure 4. Chemical structures of some benzylacetates for use in the making of the conjugates of the present technology.
Figure 5. Chemical structures of some cinnamates for use in the making of the conjugates of the present technology.
Figure 6. Chemical structures of some oxylic acids for use in the making of the conjugates of the present technology.
Figure 7. Chemical structures of some tricarboxylic acids for use in the making of the conjugates of the present technology.
Figure 8. Chemical structures of some inorganic oxoacids for use in the making of the ates of the present technology.
Figure 9. Chemical structures of some inorganic oxoacid derivatives for use in the making of the conjugates of the t technology.
Figure 10. Chemical structures of some standard amino acids for use in the making of the conjugates of the present technology.
Figure 11. Chemical ures of some non-standard amino acids for use in the making of the conjugates of the present technology.
WO 16668 Figure 12. Chemical structures of some synthetic amino acids for use in the making of the conjugates of the present technology.
Figure 13. Oral PK curves comparing the nicotinate-CHgOCO-MPH conjugate with unconjugated methylphenidate in rats.
Figure 14. Oral PK curves comparing the phosphate-CHgOCO-MPH conjugate (data combined from three studies) with unconjugated phenidate in rats (data combined from six studies).
Figure 15. Oral PK curves comparing the phosphate-CHgOCO-MPH ate with unconjugated methylphenidate in rats.
Figure 16. Oral PK curves comparing the gallate-CHgOCO-MPH conjugate with unconjugated methylphenidate (data ed from six studies) in rats.
Figure 17. Oral PK curves comparing the gallate-CHgOCO-MPH conjugate with unconjugated methylphenidate in rats.
Figure 18. Oral PK curves ing the lactate-CHgOCO-MPH conjugate with unconjugated methylphenidate in rats.
Figure 19. Oral PK curves comparing the MPH-COchg-nicotinoyl-Asp and chg-nicotinoyl-Val conjugates with unconjugated methylphenidate in rats.
Figure 20. Oral PK curves comparing the MPH-COgCHg-nicotinoyl-Gly-Ala and Valaminohexanoate-CHgOCO-MPH conjugates with unconjugated methylphenidate in rats.
Figure 21. Oral PK curves comparing the 6-aminohexanoate-CHgOCO-MPH conjugate with unconjugated methylphenidate in rats.
Figure 22. Oral PK curves ing the MPH-COchg-nicotinoyl-O‘Bu and MPH-COchg-nicotinate conjugates with unconjugated methylphenidate in rats.
Figure 23. lntranasal PK curves comparing the MPH-COgCHg-nicotinoyl-O‘Bu conjugate with unconjugated methylphenidate in rats.
Figure 24. lntranasal PK curves comparing the MPH-COchg-nicotinate conjugate with unconjugated methylphenidate in rats.
Figure 25. Oral PK curves comparing the gCHg-nicotinoyI-OEt, MPH- COgCHg-nicotinamide and gCHg-pyridine conjugates with unconjugated methylphenidate in rats.
Figure 26. asal PK curves comparing the MPH-C02CH2-nicotinamide conjugate with unconjugated methylphenidate in rats.
Figure 27. Intranasal PK curves comparing the MPH-COZCHg-pyridine conjugate with unconjugated methylphenidate in rats.
Figure 28. Intravenous PK curves comparing the MPH-C02CH2-nicotinamide conjugate with unconjugated methylphenidate in rats.
Figure 29. Intravenous PK curves comparing the MPH-COgCHg-pyridine conjugate with unconjugated methylphenidate in rats.
Figure 30. Oral PK curves ing the isonicotinate-CHgOCO-MPH and phosphate-(p-salicylate)-CHgOCO-MPH conjugates with unconjugated methylphenidate in rats.
DETAILED DESCRIPTION OF THE INVENTION The present technology provides at least one methylphenidate or one or more derivatives or combinations thereof (MPH, methyl phenyl(piperidinyl)acetate) conjugated to at least one organic or nic oxoacid to form oxylalkyl carbamates, which are novel prodrugs compositions and/or conjugates of methylphenidate. In some embodiments, the at least one conjugate or g of the present logy was singly discovered by conjugating methylphenidate to a series of organic or inorganic oxoacids through various linker molecules. In some embodiments, the linkers are (acyloxy)alkyloxy moieties or tives thereof. The linker chain is connected on one end to methylphenidate via a secondary carbamate bond and on the other to the oxoacid via an ester bond.
The use of the term “methylphenidate” herein is meant to include any of the stereoisomer forms of methylphenidate, including the four stereoisomers: d—erythro— methylphenidate, /-erythro— methylphenidate, d—threo— methylphenidate and o— methylphenidate and the salts and derivatives thereof. Methylphenidate is interchangeable with methyl phenyl(piperidin-2—yl)acetate. The term “methylphenidate” includes all salt forms. Methylphenidate is also known by its trade name Ritalin®, Ritalin® SR, Methylin®, Methylin® ER (all commercially available from Novartis ational AG, of Basil, Switzerland). The methylphenidate used in the present technology can be any stereoisomer of methylphenidate, including, but not limited to, d- erythro— methylphenidate, /-erythro—methylphenidate, d—threo—methylphenidate and /- threo— methylphenidate. In some embodiments, the methylphenidate can be a mixture of two or more racemates, for example, but not limited to, d/l-erythro—methylphenidate and d/l-threo—methylphenidate. In some preferred embodiments, the conjugates contain racemic threo—methylphenidate. In other preferred embodiments, the alcohol, amine, d, or thiol is linked to a single o—methylphenidate . Depending on the chemical structure of the linkers and alcohols, amines, oxoacids, and thiols as well as the chiral composition of the methylphenidate to which they are ed, the resulting prodrug conjugates can be optically active mixtures of isomers, racemic mixtures, single s or combinations thereof.
As used herein, the phrases such as “decreased, reduced,” ished” or “lowered” are meant to include at least about a 10% change in pharmacological activity, area under the curve (AUC) and/or peak plasma concentration (Cmax) with greater percentage changes being red for reduction in abuse potential and overdose potential of the conjugates of the present technology as compared to ugated methylphenidate. For instance, the change may also be greater than about 10%, about %, about 20%, about 25%, about 35%, about 45%, about 55%, about 65%, about 75%, about 85%, about 95%, about 96%, about 97%, about 98%, about 99%, or increments therein.
As used herein, the term “prodrug” refers to a substance converted from an inactive form of a drug to an active drug in the body by a al or biological reaction.
In the present technology, the prodrug is a conjugate of at least one drug, methylphenidate, and at least one oxoacid, for example. Thus, the conjugates of the present technology are prodrugs and the gs of the present technology are conjugates.
Prodrugs are often useful e, in some ments, they may be easier to administer or process than the parent drug. They may, for instance, be more bioavailable by oral administration s the parent drug is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. An embodiment of a prodrug would be a methylphenidate conjugate that is lized to reveal the active moiety. In certain embodiments, upon in vivo administration, a g is chemically converted to the biologically, pharmaceutically or therapeutically more active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the nd. To produce a prodrug, a pharmaceutically active compound is modified such that the active compound will be regenerated upon in vivo administration. The prodrug is designed to alter the metabolism or the transport characteristics of a drug in certain embodiments, to mask side-effects or ty, to improve bioavailability and/or water solubility, to e the flavor of a drug or to alter other characteristics or properties of a drug in other discrete embodiments.
In some ments, the present technology provides at least one prodrug composition comprising at least one conjugate. The at least one conjugate may comprise at least one methylphenidate and at least one alcohol, amine, oxoacid, thiol, or derivatives therof. In some embodiments, the conjugate r comprises at least one linker. The linker chemically bonds the methylphenidate to the alcohol, amine, oxoacid, or thiol via one or more covalent bonds.
Depending on the linker and the alcohol, amine, oxoacid, and thiol conjugated to methylphenidate or derivative thereof, the at least one prodrug formed can be either a l rged), a free acid, a free base or a pharmaceutically acceptable anionic or cationic salt form or salt mixtures with any ratio between positive and negative components. These anionic salt forms can include, but are not limited to, for example, acetate, /-aspartate, besylate, bicarbonate, carbonate, d—camsylate, l-camsylate, citrate, edisylate, formate, fumarate, gluconate, hydrobromide/bromide, hydrochloride/chloride, d—lactate, /-|actate, d,/-lactate, d,/-malate, /-ma|ate, mesylate, pamoate, phosphate, succinate, sulfate, bisulfate, d—tartrate, /-tartrate, d,/-tartrate, meso-tartrate, benzoate, gluceptate, d—glucuronate, hybenzate, isethionate, malonate, sufate, 2—napsylate, WO 16668 nicotinate, nitrate, orotate, stearate, te, anate, acefyllinate, aceturate, alicylate, ascorbate, borate, butyrate, camphorate, camphocarbonate, decanoate, hexanoate, cholate, cypionate, dichloroacetate, edentate, ethyl sulfate, furate, fusidate, galactarate (mucate), galacturonate, gallate, gentisate, glutamate, glutamate, glutarate, glycerophosphate, heptanoate (enanthate), hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, ionate, laurate, maleate, mandelate, methanesufonate, myristate, napadisilate, , oxalate, palmitate, picrate, pivalate, propionate, pyrophosphate, late, salicylsulfate, sulfosalicylate, tannate, terephthalate, licylate, tribrophenate, valerate, valproate, adipate, 4- acetamidobenzoate, camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, or undecylenate. The cationic salt forms can include, but are not limited to, for example, sodium, potassium, calcium, magnesium, zinc, aluminium, lithium, cholinate, lysinium, um, or tromethamine.
Without wishing to be limited to the ing theory, it is believed that the prodrugs/conjugates of the t technology undergo enzyme hydrolysis of the ester bond in vivo, which subsequently leads to a cascade reaction resulting in rapid regeneration of methylphenidate and the respective oxoacid, metabolites thereof and/or derivatives thereof. The alcohols, amines, oxoacids, thiols, or derivatives therof, of the present technology are non-toxic or have very low ty at the given dose levels and are preferably known drugs, natural products, metabolites, or GRAS (Generally ized As Safe) compounds (e.g., preservatives, dyes, flavors, etc.) or non-toxic cs or derivatives thereof.
General Structures and Definitions iations for the components of conjugates of the present technology include: MPH stands for methylphenidate; MPH-HCI stands for methylphenidate hydrochloride; Asp stands for aspartate; Val stands for valine; tBu stands for tert—butyl; Et stands for ethyl.
In some embodiments, the general structure of the prodrugs of methylphenidate of the present technology can be represented either by formula (I) or by formula (II): ©2511“O 0 (l) (H) To simplify the drawings, formulas (I) and (II) can also be depicted as: MPH Y Gm MPH—Gm (l) (H) wherein X is ed from O, 8, Se or NR1; Y is absent or selected from O, 8, Se, NR2 or CR3R4; Fi1 and R2 are selected independently from hydrogen, l, alkenylaminocarbonyl, , alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, ioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, kyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, arylcarbonylamino, aryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, hydroxy, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, or polyethylene glycol; R3 and R4 are selected independently from hydrogen, l, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, arbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, amine, amino, aminocarbonyl, ammonium, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, rbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, lfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, ioalkyl, cyano, cycloalkenyl, cycloalkenylalkyl, carboxyl, cycloalkyl, lkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, halo, haloalkoxy, kyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, arylthio, hydroxy, nitro, oxo, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, polyethylene glycol or thiol; L is absent or +A‘Z‘lg.
A is selected independently for each repeating subunit from CR5R6 or optionally substituted aryl, arylene, carbocycle, cycloalkenyl, cycloalkyl, cycloalkynyl, heterocycle, heteroaryl; R5 and R6 are selected ndently from each other and independently for each repeating subunit from hydrogen, l, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, arbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, amine, amino, aminocarbonyl, ammonium, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, y, yalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, ioalkyl, cyano, cycloalkenyl, cycloalkenylalkyl, carboxyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, WO 16668 heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, hydroxy, nitro, oxo, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, polyethylene glycol or thiol; Z is either absent or selected independently for each repeating subunit from O, 8, Se or NH; n is 0-50; G is selected independently for each repeating subunit from alcohol, amine, amino acid, ammonium, oxoacid, peptide, poly(ethylene s) (PEG) or thiol, or derivatives thereof or combinations thereof; E is an oxoacid; and m is 0-5.
In some embodiments of formula (I), one or more G entities are covalently bound to L, Y (if L absent), or to r G (e.g., one or more than one additional G). le ences of G can be all identical, all uniquely different or a mixture of both.
In some embodiments of formula (II), one or more E entities (up to m entities) are covalently bound to the nitrogen in the piperidine ring of methylphenidate or to another E. Multiple occurrences of E can be all identical, all uniquely different or a mixture of both.
In some red embodiments of formula (I), X is O.
In some preferred embodiments of formula (I), Y is absent or selected from O or N. In some additional prefered ments of formula (I), Y is N.
In other preferred embodiments of formula(l),LIS selected from: flit flit:- lili- filofoil} infiQ (i3 0— or ill](,3 0‘0— R8 R10 R8 O p q wherein R7, R8, R9, R10 are independently selected for each repeating subunit from hydrogen, alkenyl, alkoxy, alkyl, alkynyl, aryl, tuted aryl, alkylaryl, cycloalkenyl, cycloalkyl, cycloalkynyl, heteroalkyl, heteroaryl, or heterocycle. Preferably, R7 and R9 are independently selected for each repeating subunit from hydrogen, alkyl, alkoxy, aryl or tuted aryl, and R8 and R10 are preferably hydrogen; q is 1-10, preferably 1-5; 0 and p are 0-10, preferably 0-2; and Q is NH or O.
In some additional preferred embodiments of formula (I), L is ed from: -§-(CH2)q-NH-§-,whereinq: 1-6 ; 3‘1“o—§—(CH2)5—NH-§- , - , NH-E- A \ , oz; _§©_r \ , , 3910771: $10.2 or if In other preferred embodiments of formula (I), G is selected from oxoacids, ry amines or poly(ethylene glycol) derivatives.
In some embodiments of formula (I), G is a tertiary amine that is generally defined by formulas (Ill) and (IV): wherein R17 is independently selected for each repeating subunit from O, 8, Se, NR” or CR22R23; R14, R15, R16, R20, R21 are selected independently from alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, ulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aminocarbonyl, aryl, substituted aryl, arylalkenyl, koxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, monium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, ioalkyl, cycloalkenyl, lkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, lkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, arylsulfinyl, heteroarylsulfonyl, heteroarylthio, hydroxy, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, or polyethylene glycol; R20 may also be absent; R18, R19, R22, R23 are selected independently from each other and independently for each ing subunit (of R”) from hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, hio, alkynyl, alkynylaminocarbonyl, amine, amino, aminocarbonyl, ammonium, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, rbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, lfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cyano, cycloalkenyl, cycloalkenylalkyl, carboxyl, cycloalkyl, lkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, arylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, hydroxy, nitro, oxo, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, hylene glycol or thiol; and i is 0-10.
In some ments, formula (IV) is a heterocycle with a ring size of 3-10 atoms, of which at least one is a nitrogen atom and at least one is a carbon atom, and the ring may be aliphatic containing any chemically feasible number and combination of single, double or triple bonds or the ring may be ic.
In other embodiments, G is covalently bound to L via its tertiary nitrogen (see formulas (Ill) and (IV)) or via an amino, hydroxyl or carboxyl functional group of one of its substituents.
In some preferred embodiments of formula (I), the tertiary amines are defined by formula (V), a a sub-class of formula (IV) wherein: fl\/\)—R22 G = RzéN (V); and R18, R22 and R23 are as defined for a (IV).
Some additional preferred ments of formula (V) are defined by as (VI), (VII) and (VIII): G >~OH q = /O U/ , G2 , N N (3)6 (VI) (VII) (VIII) In these embodiments of formula (V), G is a carboxypyridine derivative, preferably nicotinic acid, optionally bound via an ester or amide bond to a second moiety, G2. In some ments, (32 is preferably an alcohol or an oxoacid, more preferably an amino acid.
In these embodiments of formula (VIII), R26 is selected from hydrogen, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, minocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, arbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, o, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, lfinyl, arylsulfinylalkyl, lfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, aryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, hydroxy, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, or polyethylene glycol.
In some ments of formula (VIII), R26 is preferably en or alkyl.
In other embodiments of formula (I), the poly(ethylene glycol) derivatives are generally defined by formula (IX): / (C H2) 1+0“’}Q \(CH2)|/ R25 G: k (IX) wherein R24 is H or NH2; R25 is H, NH2 or COzH; Q is absent or 0; j and I are 0-5; and kis1-100.
In some preferred embodiments of formula (I), the poly(ethylene glycol) derivatives are: H OH H 0 OH Ho NH G = fofl/ 3 fog , , VOi/V 2, HfO/NOH’ k k k H N2 4 /\]“o OH H c H C 3 3 [oyodkow O fofiO\/\ or NH2 k Vi]? wherein k is 1-100, preferably 1-50 or 1-10.
In some preferred embodiments of formula (II), E is an oxoacid, preferably an amino acid.
Oxoacids Oxoacids (i.e., oxyacids, oxo acids, oxy-acids, oxiacids, oxacids) of the present technology are a class of compounds which contain oxygen, at least one other element, and at least one hydrogen bound to oxygen, and which produce a ate base by loss of positive hydrogen ion(s) ns). Oxoacids can be categorized into organic acids or inorganic acids and their derivatives. Organic acids include carboxylic acids. Carboxylic acids are widespread in nature (naturally occurring), but ylic acids can also be non-natural (synthetic). Carboxylic acids can be categorized into numerous s based on their molecular structure or a, and many of the different classes may overlap.
Without wishing to limit the scope to one classification, the carboxylic acids of the present logy can be grouped into the following ries: aliphatic carboxylic acids, aryl carboxylic acids, dicarboxylic, polycarboxylic acids, and amino acids.
Suitable aliphatic carboxylic acids for use in the t technology include, but are not limited to, for example, saturated, monounsaturated, polyunsaturated, acetylenic, tuted (e.g., alkyl, hydroxyl, methoxy, halogenated, etc.), atom containing or ring containing carboxylic acids. Suitable examples of saturated carboxylic acids include, but are not limited to, for example, methanoic, ethanoic, WO 16668 propanoic, butanoic, pentanoic, hexanoic, heptanoic, octanoic, 2—propylpentanoic acid, nonanoic, decanoic, dodecanoic, tetradecanoic, canoic, heptadecanoic, octadecanoic, or eicosanoic acid. Suitable monounsaturated carboxylic acids for practice of the present technology include, but are not limited to, for example, 4- decenoic, 9—decenoic, 5-lauroleic, 4-dodecenoic, adecenoic, 5-tetradecenoic, 4- ecenoic, 9—hexadecenoic, 6-hexadecenoic, 6-octadecenoic, or 9—octadecenoic acid.
Suitable polyunsaturated carboxylic acids for use in the present technology include, but are not limited to, for example, sorbic, octadecadienoic, octadecatrienoic, octadecatetraenoic, eicosatrienoic, eicosatetraenoic, pentaenoic, docosapentaenoic, or docosahexaenoic acids. le acetylenic carboxylic acids for use in the present technology include, but are not limited to octadecynoic, octadecenynoic, tadecenynoic, heptadecenynoic, tridecatetraenediynoic, tridecadienetriynoic, octadecadienediynoic, heptadecadienediynoic, octadecadienediynoic, octadecenediynoic, or octadecenetriynoic acids.
Suitable substituted carboxylic acids for practice of the present technology include, but are not limited to, for example, methylpropanoic, isovaleric, hexadecanoic, 8—methylnonenoic, methyloctadecanoic, trimethyloctacosanoic, trimethyltetracosenoic, heptamethyltriacontanoic, tetramethylhexadecanoic, tetramethylpentadecanoic, , ic, glycolic, threonic, oxypropionic, hydroxyoctadecatrienoic, hydroxyoctadecenoic, hydroxytetracosanoic, 2—hydroxybutyric, 3-hydroxybutyric, 4-hydroxybutyric, 4-hydroxypentanoic, hydroxyoctadecadienediynoic, hydroxyoctadecadienoic, 10-hydroxydecanoic, hydroxydecenoic, hydroxyeicosenoic, hydroxyeicosadienoic, hydroxyhexadecanoic, dihydroxytetracosenoic, dihydroxydocosanoic, ydocosanoic, trihydroxyoctadecanoic, trihydroxyhexadecanoic, trihydroxyicosahexaenoic, trihydroxyicosapentaenoic, 2- methoxyhexadecenoic, 2—methoxy hexadecanoic, 7-methoxytetradecenoic, 9- methoxypentadecanoic, 1 1-methoxyheptadecanoic, 3-methoxydocosanoic, diacetoxydocosanoic, 2—acetoxydocosanoic, 2—acetoxytetracosanoic, 2- acetoxyhexacosanoic, onanoic, oxodecanoic, oxododecenoic, hydroxyoxodecenoic, 10-oxodecenoic, fluorooctadecenoic, fluorodecanoic, fluorotetradecanoic, hexadecanoic, fluorooctadecadienoic, hydroxyhexadecanoic, chlorohydroxyoctadecanoic, dichlorooctadecanoic, 3- bromononaenoic, 9,10-dibromooctadecanoic, 9,10,12,13-tetrabromooctadecanoic, -nitro-9,12-octadecadienoic, 12-nitro-9,12-octadecadienoic, 9-nitrooctadecenoic, 9- oxodecenoic, 9-oxooctadecenoic, oxooctadecatrienoic, 15-oxo-18—tetracosenoic, 17-oxohexacosenoic, or 19-oxooctacosenoic acids.
Suitable examples of heteroatom containing ylic acids include, but are not d to, for example, 9-(1,3-nonadienoxy)nonenoic, 9-(1,3,6-nonatrienoxy) nonenoic, 12-(1-hexenoxy)-9,11-dodecadienoic, 12-(1,3-hexadienoxy)-9,11- dodecadienoic, 2-dodecylsulfanylacetic, 2-tetradecylsulfanylacetic, 3- tetradecylsulfanylpropenoic, or adecylsulfanylpropanoic acid. Suitable examples of ring containing carboxylic acids include, but are not d to, for example, Hexylcyclopropyl)decanoic, 3-(2-[6-bromo-3,5-nondienylcyclopropyl)propanoic, 9- (2-hexadecylcyclopropylidene)nonenoic, 8-(2-octylcyclopropenyl)octanoic, 7-(2- octylcyclopropenyl)heptanoic, 9,10-epoxyoctadecanoic, 9,10-epoxy12-octadecenoic, 12,13-epoxyoctadecenoic, epoxyeicosenoic, 11-(2-cyclopenten yl)undecanoic, 13-(2-cyclopentenyl)tridecanoic, 13-(2-cyclopentenyl)tridecenoic, 11-cyclohexylundecanoic, 13-cyclohexyltridecanoic, -dimethylpentylfuran yl)heptanoic, 9-(4-methylpentylfuranyl)nonanoic, 4-[5]-ladderane-butanoic, 6-[5]- ladderane-hexanoic, or 6-[3]-ladderane-hexanoic acid.
Suitable aryl carboxylic acids for use in the present technology to ate methylphenidate, derivatives thereof or combinations thereof include, for example, compounds that contain at least one carboxyl group attached to an aromatic ring.
Suitable aryl carboxylic acids of the present technology can include, but are not limited to, for example: (a) aryl carboxylic acids wherein the carboxylic acid group is directly attached to the aryl moiety, which include, but are not limited to, benzoates or aryl carboxylic acids; (b) aryl carboxylic acids wherein the carboxylic acid group is separated by one carbon from the aryl moiety, which include, but are not limited to, branched phenylpropionic acids, or other derivatives of phenylacetate; or (c) aryl carboxylic acids wherein the carboxylic acid group is separated by two carbons from the aryl moiety, which include, but are not limited to, benzylacetates, substituted derivatives thereof or analogs of cinnamic acid.
Some embodiments of the present technology provide aryl carboxylic acids of ry (a), (b), or (c) conjugated to methylphenidate, derivatives thereof, or combinations thereof. Some embodiments of the present technology provide aryl carboxylic acids of category (a) conjugated to methylphenidate, derivatives thereof or combinations thereof, wherein the aryl ylic acid of ry (a) is benzoates, heteroaryl carboxylic acids or derivatives thereof.
Some embodiments of the present technology provide at least one conjugate of methylphenidate, derivatives thereof or combinations thereof, and at least one benzoate. Suitable common benzoates include, but are not d to, for example, benzoic acid, or hydroxybenzoates (e.g., salicylic acid analogs). The general structure of benzoates for use in the present technology is shown in formula (X): C02H ( R3 —Z)q fix Y// (‘Riio (F22)p wherein X, Y and Z can be independently selected from a representative group ing H, O, S or —(CH2)X—; R1, R2 and R3 can be, for example, independently selected from any of the following: H, alkyl, alkoxy, aryl, substituted aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, lkenyl or cycloalkynyl; o, p, q can be independently either 0 or 1; and x is an integer between 1 and 10.
Benzoates are common in nature and can be found either in their free form, as a salt, or as esters and . us benzoic acid analogs are also used in the food and drug industry. Some of the more abundant benzoates are derivatives with hydroxyl groups. The hydroxyl function may be present in its free form or capped with another chemical moiety, ably, but not limited to, methyl or acetyl groups. The phenyl ring may have additional substituents.
Suitable benzoates include, but are not limited to, for example, benzoic acid, or hydroxybenzoates (e.g., salicylic acid analogs). Suitable examples of hydroxybenzoates for use in the present technology e, but are not limited to, for example, benzoic acid, lic acid, acetylsalicylic acid (aspirin), 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, 6-methylsalicylic acid, cresotinic acid, anacardic acids, 4,5-dimethylsalicylic acid, o,m,p-thymotic acid, diflusinal, o,m,p-anisic acid, 2,3- oxybenzoic acid HB), oc,B,y—resorcylic acid, protocatechuic acid, gentisic acid, nylic acid, 3-methoxysalicylic acid, 4-methoxysalicylic acid, 5- methoxysalicylic acid, 6-methoxysalicylic acid, 3-hydroxymethoxybenzoic acid, 4- hydroxymethoxybenzoic acid, 5-hydroxymethoxybenzoic acid, vanillic acid, isovanillic acid, 5-hydroxymethoxybenzoic acid, 2,3-dimethoxybenzoic acid, 2,4- dimethoxybenzoic acid, 2,5-dimethoxybenzoic acid, 2,6-dimethoxybenzoic acid, veratric acid (3,4-dimethoxybenzoic acid), 3,5-dimethoxybenzoic acid, gallic acid, 2,3,4- trihydroxybenzoic acid, 2,3,6-trihydroxybenzoic acid, 2,4,5-trihydroxybenzoic acid, 3-O— methylgallic acid (3-OMGA), 4-O—methylgallic acid (4-OMGA), dimethylgallic acid, syringic acid, or 3,4,5-trimethoxybenzoic acid. Some structures of suitable hydroxybenzoates for use in the practice of the present technology can be found in Figure 1.
Heteroaryl Carboxylic Acids In other ments, the present technology provides prodrug compositions comprising at least one ate of phenidate, derivatives thereof or combinations thereof, and one or more aryl or heteroaryl carboxylic acids. Suitably, the heteroatom of common natural products and metabolites is nitrogen. The general structures of heteroaryl carboxylic acids and derivatives thereof are illustrated in formulas (XI), (Xll) and (Xlll): COZH ZCOZH COZH RBMPJX—z R3 2 //()OR1qYl/\:(R1)ONX [ 7X N (R1)O (Hi2) Y\ (F22)p (R2), (XI) (XII) (XIII) n X, Y and Z can be independently selected from the representative group including H, O, S or —(CH2)X—; R1, R2 and R3 can be independently selected from any of the following: H, alkyl, alkoxy, aryl, substituted aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, lkyl, cycloalkenyl or cycloalkynyl; o, p, q can be independently selected from 0 or 1 ; and x is an integer between 1 and 10.
Nitrogen heterocyclic compounds are commonly found in nature and are involved in several biological functions in plants and animals. Suitable examples of heteroaryl carboxylic acids for use in the practice of the present technology e, but are not limited to, for example, pyridine derivatives, some of which play an important role in the nate and phan metabolism. In these compounds, one carbon of the phenyl ring is replaced by a nitrogen atom. Besides the carboxyl group, this set of nds can have additional substituents, preferably but not limited to, hydroxyl groups.
Suitable examples of heteroaryl carboxylic acids for use in the present technology include, but are not limited to, nicotinic acid (niacin), isonicotinic acid, picolinic acid, 3-hydroxypicolinic acid, 6-hydroxynicotinic acid, inic acid, 2,6- dihydroxynicotinic acid, kynurenic acid, xanthurenic acid, 6-hydroxykynurenic acid, 8- methoxykynurenic acid, hydroxykynurenic acid, or 7,8—dihydro-7,8- dihydroxykynurenic acid. Some structures of suitable heteroaryl carboxylic acids for use in the practice of the t technology can be found in Figure 2.
Aryl Carboxylic Acids Some embodiments of the present technology e aryl carboxylic acids of category (b) conjugated to methylphenidate, derivatives thereof or combinations thereof, where suitable carboxylic acids with a carboxyl group ted by one carbon from the aryl moiety include, but are not limited to, for example, branched phenylpropionic acids (i.e., 2-methylphenylacetates) or other tives of phenylacetate, for example, compounds having the general formula as described in formula (XIV) below.
In some embodiments, the carboxylic acid is a phenylacetate, a branched phenylpropionate, an unbranched phenylpropionate (benxylacetate), a phenyl propenoate (cinnamate), salts thereof, derivatives thereof, or combinations thereof.
Suitable examples of these compounds, include, but are not limited to, certain types of NSAIDs (Non-Steroidal nflammatory Drugs), such as profens, or tyrosine metabolites (such as p—hydroxyphenyl pyruvate), among others. The general structure of phenylpropionic acids or other tives of phenylacetate of the present technology is shown in a (XIV): wherein X, Y and Z can be independently selected from the representative group including H, O, S or —(CH2)X—; R1, R2 and R3 can be independently selected from any of the following: H, alkyl, alkoxy, aryl, substituted aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; o, p, q can be independently either 0 or 1; Alk is an alkyl chain —(CH2)n— with n being either 0 or 1; x is an r between 1 and 10; and R6 is selected from H, OH or carbonyl.
Phenylacetates Phenylacetic acids encompass s subsets of natural products, metabolites and pharmaceuticals. One such pharmaceutical subset are “profens”, a type of NSAID and derivatives of certain phenylpropionic acids (i.e., 2-methyl-2— phenylacetic acid s). Some other phenylacetates have central ons in the phenylalanine and tyrosine lism. Suitable phenylacetates of the present technology include, but are not limited to, acetic acid (hydratropic acid), 2- hydroxyphenylacetic acid, 3-hydroxyphenylacetic acid, 4-hydroxyphenylacetic acid, 2012/048641 homoprotocatechuic acid, homogentisic acid, 2,6-dihydroxyphenylacetic acid, homovanillic acid, homoisovanillic acid, homoveratric acid, atropic acid, d,l-tropic acid, diclofenac, d,l-mandelic acid, 3,4-dihydroxy-d,l-mandelic acid, vanillyl-d,/-mandelic acid, isovanillyl-d,/-mandelic acid, ibuprofen, ofen, fen, flurbiprofen, ketoprofen, or naproxen. Some structures of le acetates for use in the practice of the present technology can be found in Figure 3.
Benzylacetates and Cinnamates In some embodiments of the present technology, aryl carboxylic acids of category (c) are conjugated to methylphenidate, derivatives thereof or combinations thereof, wherein the aryl carboxylic acids of category (c) e, but are not limited to, for example, benzylacetates, substituted derivatives thereof or analogs of cinnamic acid, for example nds with the general formulas (XV) and (XVI) below: OVOH o OH R4 R5 (R3) —Zq (R3) _Z |\\—x q |\\_X Y// (RUG Y// (Rtio (R2)p (R2lp (XV) (XVI) wherein X, Y and Z can be independently selected from a representative group including H, O, S or —(CH2)X—; R1, R2 and R3 can be independently selected from any of the following: H, alkyl, alkoxy, aryl, substituted aryl, alkenyl, alkynyl, halo, haloalkyl, alkylaryl, arylalkyl, heterocycle, arylalkoxy, lkyl, cycloalkenyl or cycloalkynyl; o, p, q can be independently either 0 or 1; x is an integer from 1 to 10; R4 is H or OH; and R5 is H, OH or carbonyl. Both classes of nds are abundant in nature in the form of natural products or metabolites (e.g., phenylalanine metabolism). The carboxyl group can be attached directly to the aromatic ring or be ted by an alkyl or alkenyl chain. The chain length of the alkyl or alkenyl group for use in this technology should not preferably exceed two unbranched carbons, but is not limited in numbers of atoms on potential side-chains or additional functional groups.
The present technology also includes both carbon only aryl and aryl groups with heteroatoms (heteroaryl). The aryl or heteroaryl group which is connected directly or through an alkyl or alkenyl chain to the carboxyl function, should preferably be a 6- membered ring and should preferably n no or one heteroatom. It should be appreciated by those skilled in the art additional substituted or unsubstituted aromatic or tic rings may be fused to such a 6-membered aryl or heteroaryl moiety.
Benzylacetates are defined by an ethylene group between the yl function and the phenyl ring. Both the alkyl chain and the aryl moiety can have, for example, substituents, ably hydroxyl groups. Some compounds of this class can be found in the phenylalanine metabolism. Suitable examples of benzylacetates for use in the practice of the present technology e but are not limited to, for example, benzylacetic acid, melilotic acid, 3-hydroxyphenylpropanoic acid, 4- hydroxyphenylpropanoic acid, 2,3-dihydroxyphenylpropanoic acid, d,/-phenyllactic acid, o,m,p-hydroxy-d,/-phenyllactic acid, or phenylpyruvic acid. Some structures of suitable acetates for use in the practice of the present technology can be found in Figure Cinnamic acids (3-phenylacrylic acids) are unsaturated analogs of benzylacetic acids, which are found ubiquitously in plants and fruits. Cinnamates occur in two isomeric forms: cis (Z) and trans (E). Use of cinnamates in the present technology can be either isomer form, but are preferably in the trans configuration.
Similar to benzylacetates, derivatives of cinnamic acid can be substituted on the alkenyl or aryl moiety of the molecule. Preferred tuents are hydroxyl and y groups. Certain ates play a key role in the phenylalanine metabolism. Some suitable cinnamates for use in the present technology include, but are not limited to, for example, cinnamic acid, o,m,p-coumaric acid, hydroxycinnamic acid, 2,6- dihydroxycinnamic acid, caffeic acid, ferulic acid, isoferulic acid, 5-hydroxyferulic acid, sinapic acid, or oxyphenylpropenoic acid. ures of suitable cinnamates for use in the practice of the present technology can be found in Figure 5.
Dicarboxylic and Tricarboxylic Acids In some ments, the methylphenidate, derivatives thereof or combinations thereof, can be conjugated to one or more dicarboxylic or tricarboxylic acids. Dicarboxylic acids are compounds with two carboxyl groups with a general formula of -COOH, where R can be an alkyl, l, alkynyl or aryl group, or derivatives thereof. Dicarboxylic acids can have ht carbon chains or ed carbon chains. The carbon chain length may be short or long. Polycarboxylic acids are ylic acids with three or more carboxyl groups. le examples of dicarboxylic and tricarboxylic acids for the practice of the present technology include, but are not limited to, for example, oxalic, malonic, succinic, glutaric, adipic, pimelic, suberic, azelaic, sebacic, lic, thapsic, malic, ic, dihydroxymesoxalic, oc-hyroxyglutaric, methylmalonic, meglutol, diaminopimelic, carbamoyl ic, fumaric, maleic, mesaconic, 3-methylglutaconic, traumatic, phthalic acid, isophthalic, terephthalic, dipicolinic, citric acid, isocitric, carballylic, or trimesic acid. Some ures of suitable dicarboxylic acids for use in the practice of the present technology can be found in Figure 6 and some ures of suitable tricarboxylic acids for use in the practice of the present technology can be found in Figure 7.
Inorganic Oxoacids In some embodiments of the present technology, at least one methylphenidate, derivatives thereof or combinations thereof, is conjugated to at least one inorganic oxoacid or an organic or inorganic derivative thereof. Inorganic oxoacids of the present technology contain a —OH group (e.g., phosphoric acid) or they can be organic or inorganic derivatives of the same (e.g., phosphonates, diphosphates). Some suitable examples of inorganic oxoacids and their derivates include, but are not limited to, phosphates, phosphonates, phosphinates, phosphoramidates, phosphoramidites, diphosphates, triphosphates, biphosphonates, phosphorothioates, phosphorodithioates, phosphites, sulfates, sulfonates, ates, sulfites, thiosulfates, thiosulfites, sulfinates, nitrate, nitrite, borates, boronates, hypochlorite, carbonates, or carbamates. General structures of some inorganic oxoacids for use in the practice of the present technology can be found in Figure 8 and structures of some organic or inorganic derivatives of inorganic oxoacids for use in the practice of the present technology can be found in Figure 9.
Preferred embodiments of the present logy e one or more inorganic oxoacids that are phosphate esters. More preferred ments include nic oxoacids that are phosphate monoesters, even more preferably phosphoric acid.
Additional preferred oxoacids of the present technology include fatty acids, hydroxy carboxylic acids, amino acids, optionally esterified phosphoric acids and optionally esterified dicarboxylic acids. More preferred ds of the present technology are C224 carboxylic acids, aryl carboxylic acids, aminocaproic acid, phosphoric acid, standard amino acids and non-standard amino acids.
Amino Acids Amino acids are one of the most important ng blocks of life. They tute the structural subunit of proteins, peptides, and many secondary metabolites.
In addition to the 22 standard (proteinogenic) amino acids that make up the backbone of proteins, there are hundreds of other natural (non-standard) amino acids that have been discovered either in free form or as components in l products. The amino acids used in some embodiments of the prodrugs of this ion include natural amino acids, synthetic (non-natural, unnatural) amino acids, and their derivatives.
Standard Amino Acids There are currently 22 known standard or proteinogenic amino acids that make up the monomeric units of proteins and are d in the genetic code. The standard amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, e, lysine, methionine, phenylalanine, proline, pyrrolysine, selenocysteine, serine, threonine, tryptophan, tyrosine and valine. These standard amino acids have the general ure shown in Figure 10, where R represents the side chain on the d-carbon.
Non-Standard Amino Acids Non-standard amino acids can be found in proteins created by chemical modifications of rd amino acids already incorporated in the proteins. This group also includes amino acids that are not found in ns but are still present in living organisms either in their free form or bound to other molecular entities. Non-standard amino acids occur mostly as intermediates in metabolic pathways of standard amino acids and are not encoded by the c code. Examples of non-standard amino acids include but are not limited to ornithine, homoarginine, citrulline, homocitrulline, homoserine, theanine, y—aminobutyric acid, 6-aminohexanoic acid, sarcosine, ine, 2—aminoadipic acid, pantothenic acid, taurine, hypotaurine, onine, steine, cystathionine, homocysteine, B-amino acids such as B-alanine, B-aminoisobutyric acid, B-leucine, B-lysine, B-arginine, B-tyrosine, B-phenylalanine, isoserine, B-glutamic acid, B- tyrosine, B-dopa (3,4-dihydroxy-L-phenylalanine), oc,oc-disubstituted amino acids such as 2—aminoisobutyric acid, isovaline, di-n-ethylglycine, N-methyl acids such as yl- alanine, L-abrine, hydroxy-amino acids such as 4-hydroxyproline, 5-hydroxylysine, 3- hydroxyleucine, 4-hydroxyisoleucine, 5-hydroxy-L-tryptophan, cyclic amino acids such as ocyclopropylcarboxylic acid, azetidinecarboxylic acid and pipecolic acid.
Some structures of suitable non-standard amino acids that can be used in some embodiments of the prodrugs of this invention are shown in Figure 11.
Synthetic Amino Acids Synthetic amino acids do not occur in nature and are prepared synthetically.
Examples include but are not limited to allylglycine, cyclohexylglycine, N-(4- hydroxyphenyl)glycine, N-(chloroacetyl)glycline ester, 2-(trifluoromethyl)-phenylalanine, 4-(hydroxymethyl)-phenylalanine, 4-amino-phenylalanine, 2—chlorophenylglycine, 3- guanidino propionic acid, 3,4-dehydro-proline, 2,3-diaminobenzoic acid, o chlorobenzoic acid, 2—aminofluorobenzoic acid, allo-isoleucine, tert—leucine, 3- serine, isoserine, 3-aminopentanoic acid, 2—amino-octanedioic acid, 4-chloro-B- phenylalanine, B-homoproline, B-homoalanine, 3-amino(3-methoxyphenyl)propionic acid, N-isobutyryl-cysteine, 3-amino-tyrosine, 5-methyl-tryptophan, 2,3-diaminopropionic acid, ovaleric acid, and 4-(dimethylamino)cinnamic acid. Some structures of 2012/048641 suitable synthetic amino acids that can be used in some embodiments of the prodrugs of this invention are shown in Figure 12.
Linkers In some embodiments of the present technology, the methylphenidate, derivatives f or combinations thereof, is conjugated to one or more organic or inorganic ds via one or more linkers. Linker moieties of the present technology, which connect the one or more organic or inorganic oxoacids to the methylphenidate, derivatives thereof or combinations thereof, are preferably at least one xy)alkyloxy group or a derivative thereof with the general formula: —C(O)O—X—O— wherein X is selected from a entative group including optionally substituted alkyl, ally substituted aryl, optionally substituted alkylaryl, optionally substituted heteroalkyl, optionally tuted heteroaryl, optionally substituted heterocycle, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted lkynyl, or optionally substituted alkoxy substituents.
Preferred embodiments of the present logy include linkers where X is at least one aliphatic group. More preferred embodiments include linkers where X is at least one alkyl group. Even more preferred embodiments are (acyloxy)methyloxy, (acyloxy)ethyloxy, or (acyloxy)methyl(methyl)oxy linkers.
Administration, Formulation and Advantages The prodrugs or conjugate compositions of the present logy can be stered orally and, upon administration, release the active methylphenidate, derivatives f or combinations thereof, after being hydrolyzed in the body. Not wishing to be bound by any particular theory, the oxoacids that are conjugated to the methylphenidate, derivatives thereof or combinations thereof, of the present technology are naturally occurring lites, pharmaceutically active compounds or mimetics thereof or derivatives thereof. It is believed that the prodrugs or conjugates of the present technology can be easily recognized by physiological systems resulting in hydrolysis and release of phenidate.
The prodrugs of the present technology are believed to have no or limited pharmacological activity themselves and uently may follow a metabolic pathway that differs from the parent drug (i.e., methylphenidate). Without being bound by any theory, it is believed that by choosing suitable linkers and oxoacids (“ligands”), the release of methylphenidate into the systemic circulation can be controlled even when the prodrug is administered via routes other than oral administration.
In one embodiment, the at least one conjugated methylphenidate, derivatives thereof or combinations thereof, of the present technology are believed to surprisingly e methylphenidate, derivatives thereof or combinations f, similar to free or unmodified methylphenidate. In another alternative embodiment, the at least one conjugated methylphenidate, derivatives thereof or combinations f, of the present technology are believed to surprisingly be released in a controlled or sustained form.
It has been surprisingly found that in some ments of the present technology, the prodrugs or conjugates of the present application provide an sed bioavailability as compared with unconjugated methylphenidate. In some embodiments, the prodrugs or conjugates of the present technology surprisingly provide increased water lity as ed with unconjugated phenidate. In some embodiments, the prodrugs or compositions of the present technology have at least about 1.2x or at least about 1.5x the water solubility of unconjugated methylphenidate.
In some embodiments, the prodrugs or compositions of the present technology have at least about 1.7x, at least about 2.0x, at least about 2.2x, at least about 2.5x, at least about 3.0x, at least about 4.0x or at least about 5x the water lity of unconjugated methylphenidate, and include any multiples in between or above that have water solubility r than unconjugated methylphenidate. Not to be bound by any particular theory, the increase in water solubility may allow for the ate to be formed into certain dosage forms at higher concentrations, dosage strengths or higher dose g capacities than unconjugated methylphenidate. In some embodiments, these dosage forms e, but are not limited to, forms that require water solubility, including, but not limited to, liquids and oral thin films or strips.
In a further embodiment, the at least one prodrug or conjugate of the present technology is believed to unexpectedly have increased absorption over unmodified phenidate. In yet another embodiment, the at least one prodrug or conjugate of the present technology is believed to unexpectedly have increased bioavailability over unconjugated methylphenidate. In some embodiments, the conjugate is capable of being enzymatically or hydrolytically activated or converted into the active form. In one embodiment, the composition or prodrug described herein would e phenidate, its active metabolites and/or derivates and their combination ing in increased peak plasma concentrations and/or exposure to methylphenidate, its active metabolites and/or derivatives and their combination when compared to free or ugated methylphenidate at lar doses. Not to be bound by any particular theory, it is believed that this may allow for administration of a lower dose with equal or improved therapeutic effect, but with fewer and/or less severe side effects when compared to unmodified methylphenidate, thereby improving the safety profile of the drug. Common side effects of methylphenidate are nervousness, agitation, anxiety, and insomnia or drowsiness. Other common side effects are abdominal pain, weight loss, ensitivity, nausea, dizziness, palpitation, headache, dyskinesia, blood pressure, pulse changes, tachycardia, angina, and cardiac arrhythmia.
In a further embodiment, the increased absorption over fied methylphenidate, or improved water solubility over free methylphenidate may provide for a better bioavailability of phenidate referring to a higher area under the curve (AUC) or having higher circulating plasma concentrations.
In one embodiment, the at least one prodrug or conjugate of the present technology would alter the metabolic profile of methylphenidate, derivatives thereof or combinations thereof, by, for example, changing the amounts and/or ratio of methylphenidate and its metabolites, such as the inactive ritalinic acid within the body.
The at least one prodrug or conjugate, for example, would decrease the number and/or amount of metabolites, including , ve, toxic or non-toxic metabolites, produced by unmodified methylphenidate. Not wishing to be bound by any particular theory, it is believed that this change in metabolism may potentially ate certain side effects and improve upon the safety profile of methylphenidate.
In another ment, the prodrugs or conjugates of the present technology would unexpectedly produce d interpatient variability of methylphenidate plasma concentrations. Not to be bound by any particular theory, it can be assumed that the reduction of interpatient ility of methylphenidate plasma concentrations may be due to either increased bioavailability or a modified lic pathway or a combination of both. In another embodiment, the prodrug of the present technology would alter the metabolic pathway of the released methylphenidate when compared to unmodified methylphenidate. It is believed that this new metabolism may decrease interpatient variability and/or reduce side effects associated with unconjugated methylphenidate or any of its metabolites.
] In a further embodiment, the at least one prodrug or ate of the present technology can comprise racemic d— and /-methy|phenidate which is ably hydrolyzed to d—methylphenidate in the body and thus delivers more of the therapeutically active d—isomer. Wishing not to be bound by any particular theory, this may reduce potential side effects caused by /-methy|phenidate and/or its metabolites.
In another embodiment, the at least one g or conjugate of the present technology is believed to unexpectedly generate a Cmax value of released methylphenidate, tives thereof or combinations thereof, that is higher than the Cmax value produced by unconjugated methylphenidate, derivatives thereof or combinations thereof, when administered orally at equimolar doses. In a r embodiment, the at least one prodrug or conjugate are ed to surprisingly generate an AUC value of released methylphenidate, derivatives thereof or combinations thereof, that is higher than the AUC value produced by unconjugated methylphenidate when administered orally at equimolar doses. In yet another ment, the at least one prodrug or conjugate is believed to surprisingly generate both a Cmax and an AUC value of released methylphenidate that is higher than the Cmax and AUC values produced by ugated methylphenidate when administered orally at equimolar doses.
In some embodiments, the AUC is about 110% or greater of the AUC of unconjugated methylphenidate, when administered orally at equimolar doses, for example about 110% to about 260%, alternatively from about 120% to about 260%, alternatively from about 110% to about 250%, ing, but not limited to, about 110%, about 130%, about 150%, about 170%, about 190%, about 210%, about 230%, about 250% or any amounts in between, in ents of about 0.5%, about 1%, about 2%, about 2.5%, about 5%, about 10%, or about 20%.
In some embodiments, the Cmax is about 110% or greater of the Cmax of unconjugated methylphenidate, when administered orally at equimolar doses, for example about 110% to about 260%, atively from about 120% to about 260%, alternatively from about 110% to about 250%, including, but not limited to, about 110%, about 130%, about 150%, about 170%, about 190%, about 210%, about 230%, about 250% or any amounts in between, in increments of about about 0.5%, about 1%, about 2%, about 2.5%, about 5%, about 10%, or about 20%.
In r embodiment, the at least one prodrug or conjugate is believed to unexpectedly generate a Tmax value of released methylphenidate that is longer than the Tmax value produced by unconjugated methylphenidate when administered at equimolar doses. In another embodiment, the at least one prodrug or ate is believed to surprisingly generate a Tmax value of released phenidate that is similar to the Tmax value produced by unconjugated methylphenidate, when administered at equimolar doses.
In some embodiments, the AUC is about 50% or smaller of the AUC of unconjugated methylphenidate, when administered intranasally or intravenously at equimolar doses, for example about 50% to about 0.1 %, alternatively from about 25% to about 0.1%, alternatively from about 50% to about 1%, including, but not limited to, about 50%, about 40%, about 30%, about 20%, about 10%, about 1% or any amounts in between, in increments of about about 0.5%, about 1%, about 2%, about 2.5%, about % or about 10%.
Methylphenidate is addictive and prone to substance abuse e of its pharmacological similarity to e and amphetamine. Oral abuse has been reported to lead to hallucinations, paranoia, euphoria, and delusional disorder. Oral abuse may subsequently escalate to intravenous and intranasal abuse. Euphoria has been reported after intravenous administration of methylphenidate. When administered intranasally the effect is found to be r to intranasal use of amphetamines.
In some alternative embodiments of the present technology, the compounds, prodrugs, compositions and/or methods of the present technology are believed to provide reduced potential for overdose, reduced potential for abuse and/or improve the characteristics of methylphenidate, derivatives thereof or combinations thereof with regard to toxicities or suboptimal release profiles. In some alternative embodiments of the present technology, some compositions of the present technology may ably have no or a substantially decreased pharmacological activity when administered through ion or intranasal routes of administration. However, they remain orally bioavailable. t wishing to be limited to the below theory, it is believed that overdose protection may occur due to the conjugates being exposed to ent enzymes and/or metabolic pathways after oral administration whereby the conjugate of the present technology is exposed to the gut and first-pass metabolism as opposed to exposure to enzymes in the circulation or mucosal membranes in the nose which limits the ability of the methylphenidate, derivatives thereof or combinations thereof, from being ed from the conjugate. Therefore, in some alternative embodiments, abuse resistance is provided by limiting the effectiveness of alternative routes of stration. Again, not wishing to be bound by any particular theory, the bioavailability can be a result of the hydrolysis of the chemical linkage (Le, a covalent linkage) following oral administration. In at least one alternative embodiment, the prodrugs of the present technology are envisioned to not yze or to hydrolyze at a reduced rate or to a limited extent via non-oral routes. As a result, they are believed to not te high plasma or blood concentrations of released phenidate when injected or snorted compared to free phenidate administered through these ] In some alternative ments, it is contemplated that at least some compositions of the present technology comprising the gs of one or more methylphenidate, derivatives thereof or ations thereof, are resistant to abuse by parenteral routes of administration, such as intravenous “shooting,” or intranasal “snorting,” that are often employed during illicit use. In at least one contemplated alternative embodiment, release of methylphenidate, derivatives thereof or combinations f, is reduced when the composition of the present technology is delivered by parenteral routes. In some other contemplated alternative embodiments, the conjugates of the present technology, since they are ed to include covalently bound phenidate, derivatives thereof or combinations thereof, are not able to be ally manipulated to release the methylphenidate, derivatives thereof or ations f, from the conjugated methylphenidate, derivatives thereof or combinations thereof, by methods, for example, of grinding up or crushing of solid forms. Further, some alternative conjugates of the present technology are contemplated to exhibit resistance to chemical hydrolysis under conditions a potential drug abuser may apply to “extract” the active portion of the molecule, for example, by boiling, or acidic or basic solution treatment of the conjugate. In some ative embodiments, some itions containing prodrugs or ates of the present technology preferably have no or a substantially decreased pharmacological activity when administered through injection or intranasal routes of administration. However, they remain orally bioavailable.
For example, in one alternate embodiment, the at least one prodrug or conjugate of the present technology is plated to surprisingly maintain its effectiveness and abuse resistance following the crushing of the tablet, capsule or other oral dosage form utilized to deliver the therapeutic component (i.e., active ingredient/drug) which is believed to be due to the inherent release profile being a property of the composition not formulation. In st, tional extended release ations used to control the release of methylphenidate are subject to release of up to the entire methylphenidate content immediately following crushing. When the content of the d tablet is injected or snorted, the large dose of methylphenidate produces the “rush” effect sought by addicts.
The present technology provides a stimulant based treatment modality and dosage form for certain disorders ing the stimulation of the CNS such as, attention-deficit hyperactivity er (ADHD), attention deficit disorder (ADD), autistic spectrum disorder, autism, Asperger’s disorder, pervasive developmental disorder, sleep disorder, obesity, depression, r disorder, eating disorder, chronic fatigue me, schizophrenia, major depressive disorder narcolepsy, or autistic spectrum disorder. Although not g to be bound by any particular theory, it is believed that the treatment of such CNS conditions as noted above with compositions of the present technology results in increased bioavailability as compared to existing stimulant treatment modalities and dosage forms. In a preferred embodiment, the at least one prodrug or ition of the present technology is used to treat attention-deficit hyperactivity disorder (ADHD).
In some embodiments, the at least one composition or prodrug of the present technology can be used in one or more methods of treating a patient having at least one disease, disorder or condition requiring stimulation of the central nervous system of one or more ts, comprising orally administering a pharmaceutically ive amount of the at least one composition or prodrug.
In some ments, the at least one composition or prodrug of the present technology can be used in one or more methods of treating one or more patients having at least one disease, er or condition mediated by controlling, ting, limiting, or inhibiting neurotransmitter uptake/re-uptake or hormone uptake/re-uptake comprising administering to at least one patient a pharmaceutically effective amount of the at least one prodrug or composition. In some embodiments, the neurotransmitter is serotonin, dopamine or norepinephrine. In some embodiments, the hormone is catecholamine.
At least some compositions of the t technology comprising the prodrugs of methylphenidate, derivatives thereof or combinations thereof, can also be used for treating stimulant (cocaine, methamphetamine) abuse and addiction, for ing battle field alertness, and/or for combating e.
] The at least one prodrug or conjugate of the present technology can be formulated in to dosage forms to be administered orally. These dosage forms include but are not limited to tablet, capsule, caplet, troche, lozenge, powder, suspension, syrup, solution, oral thin film (OTF), oral strips, inhalation compounds or suppositories.
Preferred oral administration forms are capsule, tablet, ons and OTF. Suitable dosing vehicles of the present technology include, but are not limited to, water, phosphate buffered saline (PBS), 10% Tween in water, and 50% PEG-400 in water.
Solid dosage forms can optionally include the following types of excipients: antiadherents, binders, coatings, disintegrants, fillers, flavors and colors, glidants, lubricants, preservatives, sorbents and sweeteners.
Oral ations of the present technology can also be included in a solution or a suspension in an s liquid or a non-aqueous liquid. The formulation can be an emulsion, such as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
The oils can be stered by adding the purified and sterilized liquids to a prepared enteral formula, which is then placed in the feeding tube of a t who is unable to swallow.
Soft gel or soft gelatin capsules may be prepared, for example by dispersing the formulation in an appropriate vehicle (vegetable oils are commonly used) to form a high viscosity mixture. This mixture is then encapsulated with a gelatin based film using technology and ery known to those in the soft gel industry. The individual units so formed are then dried to constant weight.
Chewable tablets, for example, may be prepared by mixing the formulations with excipients designed to form a relatively soft, flavored, tablet dosage form that is intended to be chewed rather than swallowed. tional tablet machinery and procedures, for example, direct compression and ation, i.e., or slugging, before compression, can be utilized. Those duals ed in pharmaceutical solid dosage form tion are versed in the processes and the machinery used, as the chewable dosage form is a very common dosage form in the pharmaceutical industry.
Film coated tablets, for example may be prepared by coating tablets using techniques such as rotating pan coating methods or air suspension methods to t a contiguous film layer on a tablet.
Compressed tablets, for example may be prepared by mixing the formulation with ents intended to add binding qualities to disintegration ies. The mixture is either directly compressed or granulated and then compressed using methods and machinery known to those in the ry. The resultant compressed tablet dosage units are then packaged according to market need, for example, in unit dose, rolls, bulk bottles, blister packs, etc.
The present technology also plates the use of biologically-acceptable carriers which may be prepared from a wide range of materials. Without being limited to, such als include diluents, binders and adhesives, lubricants, plasticizers, disintegrants, colorants, bulking substances, flavorings, sweeteners and miscellaneous materials such as buffers and adsorbents in order to prepare a particular medicated composition.
] Binders may be selected from a wide range of als such as hydroxypropylmethylcellulose, ethylcellulose, or other suitable cellulose derivatives, ne, acrylic and methacrylic acid co-polymers, pharmaceutical glaze, gums, milk derivatives, such as whey, starches, and derivatives, as well as other conventional binders known to persons working in the art. Exemplary miting solvents are water, ethanol, isopropyl alcohol, ene chloride or es and combinations thereof.
Exemplary non-limiting bulking substances include sugar, lactose, gelatin, starch, and silicon dioxide.
] It should be understood that in addition to the ingredients particularly mentioned above, the formulations of the present technology can include other suitable agents such as flavoring agents, preservatives and antioxidants. Such antioxidants would be food acceptable and could include vitamin E, carotene, BHT or other antioxidants.
Other nds which may be included by admixture are, for example, medically inert ingredients, e.g., solid and liquid diluents, such as lactose, dextrose, saccharose, cellulose, starch or calcium phosphate for tablets or capsules, olive oil or ethyl oleate for soft capsules and water or vegetable oil for suspensions or emulsions; lubricating agents such as silica, talc, stearic acid, magnesium or calcium stearate and/or polyethylene glycols; gelling agents such as dal clays; thickening agents such as gum anth or sodium alginate, binding agents such as starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; disintegrating agents such as , alginic acid, a|ginates or sodium starch glycolate; effervescing mixtures; dyestuff; sweeteners; wetting agents such as lecithin, polysorbates or |aury|su|fates; and other therapeutically acceptable accessory ingredients, such as humectants, preservatives, buffers and antioxidants, which are known additives for such formulations.
For oral administration, fine powders or es containing diluting, dispersing and/or surface-active agents may be presented in a draught, in water or a syrup, in capsules or sachets in the dry state, in a non-aqueous suspension wherein suspending agents may be included, or in a suspension in water or a syrup. Where ble, flavoring, preserving, ding, thickening or emulsifying agents can be included.
Liquid dispersions for oral administration may be syrups, emulsions or suspensions. The syrups may contain as r, for example, saccharose or saccharose with glycerol and/or mannitol and/or sorbitol. In particular a syrup for diabetic patients can contain as carriers only products, for example ol, which do not metabolize to glucose or which metabolize only a very small amount to glucose.
The suspensions and the ons may contain a carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol.
Methylphenidate is being ed in numerous dosage forms and at various dosage strengths either as racemic mixture of d— and l-threo-methylphenidate or as single d—threo-isomer (Table 1). Recommended daily doses depend on the dosage form, active ingredient (single isomer or racemic mixture) and individual patient titration.
Table 1. Examples of marketed methylphenidate dosage forms and dosage ths.
Active Dosage Dosage Proprietary Ingredient Form Strength(s) Name s) methylphenidate instant e 5, 10, 20 mg Ritalin hydrochloride tablet dexmethylphenidate instant release 2.5, 5, 10 mg Focalin® h drochloride tablet methylphenidate extended release 10, 20 mg Methylin ER, h drochloride tablet te ER® methylphenidate extended release 10, 18, 20, 27, Concerta h drochloride tablet 36, 54 mo methylphenidate chewable tablet 2.5, 5, 10 mg Methylin h drochloride methylphenidate extended release 10, 20, 30, 40 mg Ritalin LA h drochloride caosules methylphenidate ed e 10, 20, 30, 40, Metadate CD hloride es 50, 60 mg dexmethylphenidate extended release 5, 10, 15, 20, 30, Focalin XFi® hydrochloride capsules 40 mg methylphenidate transdermal patch 10, 15, 20, 30 na® mg/9 h methylphenidate oral solution 5, 10 mg/5 mL Methylin® hydrochloride Doses of the prodrug of the present technology can be higher or lower than doses of unconjugated methylphenidate depending on their molecular weight, the respective weight-percentage of phenidate as part of the whole conjugate or conjugate salt and their bioavailability (with respect to released methylphenidate).
Therefore dosages may be higher or lower than the dosages of free methylphenidate.
Dosages can be calculated based on the strengths of dosages of methylphenidate hydrochloride which range between, for example, but not limited to, about 2.5 mg and about 54 mg per dose. Dose conversion from methylphenidate hydrochloride to methylphenidate prodrug can be med using the following formula: . MW(MPH prodrug) dose(MPH prodrug): fBAXdose(MPH hydrochloride)><— 269.77 L MPH = methylphenidate MW = molecularweight fBA = correction factor accounting for differences in bioavailability between unmodified methylphenidate and gs of the present technology.
This correction factor is specific for each g.
Suitable dosages of the conjugated methylphenidate or prodrugs of the present technology include, but are not limited to, formulations including an amount of conjugated methylphenidate equimolar to an amount of unconjugated methylphenidate from about 0.5 mg or higher, alternatively from about 2.5 mg or higher, alternatively from about 5.0 mg or higher, alternatively from about 7.5 mg or higher, alternatively from about 10 mg or higher, atively from about 20 mg or , alternatively from about 30 mg or higher, alternatively from about 40 mg or higher, alternatively from about 50 mg or higher, atively from about 60 mg or higher, alternatively from about 70 mg or higher, alternatively from about 80 mg or higher, alternatively from about 90 mg or higher, alternatively from about 100 mg or higher, and include any additional increments thereof, for example, about 0.1, about 0.2, about 0.25, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.75, about 0.8, about 0.9 or about 1.0 mg and multiplied factors thereof, (e.g., about x1, about x2, about x2.5, about x5, about x10, about x100, etc). The present technology also includes dosage formulations including currently approved formulations of methylphenidate (See Table 1), where the dosage can be calculated using the above-noted formula determined by the amount of methylphenidate hydrochloride. The present technology provides for dosage forms formulated as a single therapy or as a ation therapy.
In some ments, the ates of methylphenidate and oxoacids to form prodrugs have one or more advantage, including, but not limited to, reduced or improved side effect profile, formation of less potentially toxic metabolites, formation of less inactive metabolites, improved water solubility, reduced drug abuse potential and/or reduced atient variability in plasma concentrations as compared to ugated methylphenidate. tic Schemes In some embodiments, one or more protecting groups may be attached to any additional reactive functional groups that may interfere with the coupling to methylphenidate. Any suitable ting group may be used depending on the type of functional group and reaction conditions. Some protecting group suitable for use in the present technology include, but are not limited to, acetyl (Ac), tert—butyoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), oxybenzylcarbonyl (M02), 9- fluorenylmethyloxycarbonyl (Fmoc), benzyl (Bn), oxybenzyl (PMB), 3,4 dimethoxybenzyl , p—methozyphenyl (PMP), tosyl (Ts), or amides (like acetamides, pthalamides, and the like).
In other embodiments, a base may be required at any step in the synthetic scheme of prodrugs of methylphenidate of this invention. Suitable bases include, but 2012/048641 are not limited to, 4-methylmorpholine (NMM), ethylamino)pyridine , N,N- diisopropylethylamine, lithium bis(trimethylsilyl)amide, lithium diisopropylamide (LDA), any alkali metal tert.-butoxide (e.g., potassium utoxide), any alkali metal hydride (e.g., sodium hydride), any alkali metal alkoxide (e.g., sodium methoxide), triethylamine or any other tertiary amine. le solvents that can be used for any reaction at any step in the synthetic scheme of a prodrug of methylphenidate of this invention include, but are not limited to, e, acetonitrile, l, chloroform, dichloromethane, dimethylformamide (DMF), dimethylsulfoxide (DMSO), dioxane, ethanol, ethyl acetate, diethyl ether, heptane, hexane, methanol, methyl tert-butyl ether (MTBE), isopropanol, isopropyl acetate, diisopropyl ether, tetrahydrofuran, toluene, xylene or water.
In some embodiments, an acid may be used to remove certain protecting groups. Suitable acids include, but are not limited to, hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydriodic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, acetic acid, citric acid, methanesulfonic acid, p—toluenesulfonic acid and nitric acid. For n other protecting groups, a catalytic hydrogenation may be used, e.g., palladium on charcoal in the ce of hydrogen gas.
In one embodiment, the general synthesis of linking oxoacids to methylphenidate include the following ons. To a solution of iodomethyl carbamate of methylphenidate (1-1.5 mmol) in toluene (25-50 mL) was added the silver salt of the respective oxoacid (3 eq.). The reaction was heated from 80 °C to reflux for 3 hours depending on the oxoacid. uently, the solid was filtered off and the filtrate was concentrated. The residue was purified by column chromatography to give the linked oxoacid-methylphenidate ate.
Depending on the oxoacid the conjugate was either the final product or required deprotection. For example, the benzyl groups protecting the phosphate conjugate were removed by hydrogenation with 10% Pd/C in methanol using a hydrogen balloon for 2 hours. The catalyst was filtered off and the filtrate was concentrated and dried to give the final deprotected conjugate.
In some ments, the prodrug is hydrophilic and thus more water soluble than the unconjugated methylphenidate.
In some embodiments, the general procedure for the synthesis of carbamate derivatives of methylphenidate (MPH) with alkyl or aryl groups (3) is as follows: O 2 02Me COZMe R-o 0' HN N CHZCl2,TEA 1 OR 3a-b 3a:R= -CH2-Ph 3b: R: F-Ph ] To a solution of methylphenidate hydrochloride (MPH-HCI) (1 mmol) and ylamine (TEA) (4 mmol) in dichloromethane (DCM) (8 mL) was added a solution of chloroformate 2 (2 mmol) in DCM (2 mL) drop-wise at room temperature. After 4-6 h, the reaction was quenched with water (1 mL) and stirred for 15 min. The solvent was evaporated under reduced pressure. The residue was dissolved in cetate (EtOAc) (50 mL) and washed with 5% aqueous sodium bicarbonate (NaHCOs) (2 x 40 mL) and brine (1 x 40 mL). The organic phase was dried under sodium sulfate (Na2804) and concentrated in vacuum. The oily e was ed either by silica gel chromatography or preparative HPLC.
In other embodiments, the sis of 4-fluorophenol-CO-MPH (3b) is as follows: To a solution of To a solution of MPH-HCI (0.25 g, 0.93 mmol) and TEA (0.52 mL, 3.7 mmol) in DCM (8 mL) was added a solution of rophenyl chloroformate (0.33 g, 1.86 mmol) in DCM (3 mL) drop-wise at room temperature. The reaction mixture was stirred for 6 h at room temperature and then quenched with water (1 mL).
The solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with 5% aqueous NaHCOs (2 x 40 mL) and brine (1 x 40 mL). The organic phase was dried under Na2804 and concentrated in vacuum. The oily residue was purified by preparative HPLC to give 3b (0.35 g).
In some embodiments, the general procedure for the synthesis of carbamate derivatives of MPH with hydroxy carboxylic acids (8) is as s: R O o TEA, CH 2 Cl 2 OBn + fix 00*/A OBn HO O2N O 0' 02N T 4 5 ?\Ai MPH. HCI DMF TEA 75°C Pd-C/Hg/EtOH N N O\A O\A Meogc Y 0%OH M6020 TI/ 0 O O)'\OBn aq. NaOH 8a: A = -CH2- 8b: A = -CH(CH3)- 8c: A = -CH(Ph)- To a solution of protected hydroxyl acid 4 (1 mmol) in DCM (8 mL) was added TEA (2.5 mmol) and the solution was cooled down to 0 °C. A solution of 4-nitrophenyl chloroformate (5, 1 mmol) in DCM (2 mL) was added drop-wise at 0 °C. After the addition the reaction e was slowly brought to room temperature and left overnight.
The solvent was evaporated and dried in vacuum to give the carbonate derivative 6.
Compound 6 was dissolved in dimethylformamide (DMF) and to the solution were added TEA (3 mmol) and MPH-HCI (1.05 mmol). The mixture was heated for 8 h at 75 °C. Solvent was removed under reduced pressure. The residue was dissolved in EtOAc (60 mL) and washed with 5% aq. NaHCOs (2 x 40 mL) and brine (1 x 40 mL).
The organic phase was dried over Na2804 and evaporated to s to give 8, which was purified by preparative HPLC.
In other ments, the synthesis of MPH-CO-l—lactate (8b, A = -CH(CH3)-) is as follows: To a solution of benzyl lactate 4 (A = -CH(CH3)-; 0.39 g, 2 mmol) in DCM (8 mL) was added TEA (0.69 mL, 5 mmol) and the solution was cooled down to 0 °C. A solution of ophenyl chloroformate 5 (0.436 g, 2.1 mmol) in DCM (3 mL) was added ise at 0 °C. Subsequently, the on mixture was slowly brought to room temperature and left overnight. The solvent was evaporated in vacuum and dried to give the carbonate derivative 6 (A = -CH(CH3)-). nd 6 was dissolved in DMF (12 mL) and to the solution were added TEA (0.84 mL, 6 mmol) and MPH-HCI (0.604 g, 2.23 mmol). The mixture was heated for 20 h at 65 °C. Solvent was removed under reduced pressure. The residue was dissolved in EtOAc (40 mL) and was washed with % aq. NaHCOs (2 x 30 mL) and brine (1 x 30 mL). The organic phase was dried over NagSO4, evaporated to dryness and purified by preparative HPLC to give 8b (0.62 g).
In other embodiments, the general procedure for the synthesis of aminoacid derivatives of MPH with hydroxy carboxylic acid linkers (11) is as follows: HCI o N NHS, DCC N 0\A o\ Y A + H N2 #0 _, MeOZC )‘on MeOZC Y THF n )‘NH 9 R O R = side chain of amino acid K s‘AAO-E—= L 4N HCI/dioxane 8a: A = -CH2- 8b: A = -CH(CH3)- 8c: A = -CH(Ph)- To a solution of 8 (1 mmol), H-AA-O‘Bu (AA = amino acid) (9, 1.1 mmol), N- hydroxysuccinidimide (NHS) (1.1 mmol) in THF (8 mL) was added TEA (2 mmol) and the mixture was stirred for 10 min. Subsequently, a solution of MN- dicyclohexylcarbodiimide (DCC) (1 .1. mmol) in THF (2 mL) was added and the mixture was stirred overnight at room ature. The reaction mixture was filtered and the filtrate was evaporated to s to give the protected derivative 10, which was purified by preparative HPLC.
Compound 10 was dissolved in 4N HCl/dioxane solution (8 mL) and the solution was stirred for 6 h at room temperature. The solution was evaporated under vacuum, co-evaporated with isopropyl acetate and dried to give 11.
] In some embodiments, the synthesis of MPH-CO-lactoyl-Lys (11a; A = - CH(CH3)-, R = -(CH2)4NH2) is as follows: To a solution of 8b (0.12 g, 0.34 mmol), H-Lys(Boc)-O‘Bu-HC| 9 (0.145 g, 0.37 mmol), NHS (0.044 g, 0.37 mmol) in THF (8 mL) was added TEA (0.15 mL, 1.02 mmol) and the mixture was stirred for 10 min. Subsequently, a solution of DCC (0.076g, 0.37 mmol) in THF (2 mL) was added and the mixture was stirred overnight at room temperature. The reaction mixture was filtered and the filtrate was ated to dryness. The crude t was purified by preparative HPLC to give 10a (0.14 g).
] Compound 10a (A = -CH(CH3)-, = -(CH2)4NH2) (0.135g) was dissolved in 4N oxane (8 mL) and the solution was stirred for 6 h at room ature. The solution was ated in vacuum, co-evaporated with isopropyl acetate (lPAc) and dried to give 11a (0.12 g).
In other embodiments, the synthesis of MPH-CO-lactoyl-Ala (11b; A = - CH(CH3)-, R = -CH3) is as follows: To a solution of 8b (0.12g, 0.34 mmol), H-Ala-O‘Bu-HCI 9 (0.0.065g, 0.36 mmol), NHS (0.044 g, 0.37 mmol) in THF (8 mL) was added TEA (0.15 mL, 1.02 mmol) and the mixture was stirred for 10 min. Subsequently, a solution of DCC (0.075g, 0.36 mmol) in THF (2 mL) was added and the reaction was stirred overnight at room temperature. The suspension was filtered and the filtrate was ated to dryness.
The crude product was ed by ative HPLC to give 10b (A = -CH(CH3)-, = - CH3) (0.095 g).
Compound 10b (A = -CH(CH3)-, R = -CH3) (0.09 g) was dissolved in 4N HCl/dioxane (8 mL) and the solution was stirred for 4 h at room temperature. The solution was evaporated in vacuum, co-evaporated with isopropyl acetate (lPAc) and dried to give 11b (0.085 g).
] In other embodiments, the general procedure for the synthesis of carbamate derivatives of MPH with amino alcohols (15) is as follows: BocNH>_/OH i TEA, CH20I2 )k A] + _< >_ o NHB CI 02N 0 CC R O2N@O 12 5 —§- A—NH—E— = L DMF, TEA 75 °c N o\ ,NH 4N HCl/dioxane N 2 Meogc Y A HCI ‘— Meozc YO\A/NHBOC 153: A = -(CH2)2' 153-C 15bIA= -CH20H(CH3)- 15c = 19: A = -C4H4-(CH2)2' To a solution of amino alcohol 12 (1 mmol) in DCM (8 mL) was added TEA (2.5 mmol) and the solution was cooled down to 0 °C. A solution of 4-nitrophenyl formate (5, 1 mmol) in DCM was added ise at 0 °C. uently, the reaction mixture was slowly brought to room temperature and left overnight at rt. The solvent was evaporated in vacuum and dried to give the carbonate derivative 13.
Compound 13 was dissolved in DMF and to the solution were added TEA (3 mmol) and MPH-HCI (1.05 mmol). The mixture was heated for 15 h at 65 °C. Solvent was removed under reduced pressure. The residue was dissolved in EtOAc (40 mL) and washed with 5% aq. NaHCOs (2 x 30 mL) and brine (1 x 30 mL). The organic phase was dried over NagSO4 and evaporated to s to give 14, which was purified by preparative HPLC. Compound 14 was dissolved in 4N HCl/dioxane and the solution was stirred under argon for 3-6 h depending on the amino acid derivative. The solvent was evaporated, co-evaporated with lPAc and dried to give 15.
In other ments, the synthesis of tyramine-CO-MPH (19) is as follows: To a solution of Boc-tyramine 16 (1 mmol) in DCM (8 mL) was added TEA (2.5 mmol) and the solution was cooled down to 0 °C. A solution of 4-nitrophenyl chloroformate (5, 1 mmol) in DCM was added drop-wise at 0 °C. Subsequently, the ice bath was removed and the reaction mixture was d for 4 h at room temperature.
The solvent was evaporated under vacuum and dried to give the carbonate tive 17. nd 17 was dissolved in DMF and to the solution were added TEA (3 mmol) and MPH-HCI (1.05 mmol). The mixture was heated for 15 h at 65 °C. Solvent was removed under reduced pressure. The residue was dissolved in EtOAc (40 mL) and was washed with 5% aq. NaHCOs (2 x 30 mL) and brine (1 x 30 mL). The organic phase was dried over Na2804 and evaporated to dryness to give 18, which was purified by preparative HPLC. Compound 18 was deprotected with 4N HCl/dioxane to produce 19 (0.38 g).
In some embodiments, the synthesis of succinate-tyramine-CO-MPH (20) is as follows: BocHN F< >’OH TEA, CH2C|2 )J\ C c )J\ 17 woo a MPH-HCI DMF, TEA 75 0c N o®fNHBoc N OWN—I2 4N HCI/d'onane Me02c ‘— 19 L 18 Succinic anhydride, TEA, THF N o—< >—’ Me02c Y o o WO 16668 To a solution of 19 (0.1 g, 0.23 mmol) and TEA (0.095 mL, 0.69 mmol) in THF (8 mL) was added succinic anhydride (0.025g, 0.25 mmol) and the reaction mixture was stirred for 3 h at room temperature. Solvent was evaporated under reduced pressure and the residue was dissolved in EtOAc (50 mL). The EtOAc phase was washed with 1% aq. sodium bisulfate 4) (50 mL), brine (50 mL). The organic phase was dried over Na2804 and evaporated to dryness to give 20 (0.11 g) as white solid.
In other embodiments, the general procedure for the synthesis of ylic acid derivatives of MPH with amino l linkers (23 and 25) is as follows: R2 = side chain of amino acid —§—A-NH-§- = L BOCHNVkOSU 21 H N o NH2 N \ / HCI o / M9020 \n/ A TEA, THF M9020 \n/ \A Nm)\NHBOC o —> o o rt \ CI | 4N HCI/dioxane.
TEA, CHZCIZ, rt 24 Hogc/VCO H2 H N o\ /N M9020 Y A NHZ HCI O O N O\/\ fifiqz 23 MeOzC Y H 25a-b 25a: R2 = 3-pyridinyl 25b. R2 = '(CH2)2002H To a solution of 15 (1 mmol) in THF were added TEA (2.5 mmol) and Boc-AA- OSu (AA = amino acid) (21, 1.05 mmol) and the solution was stirred for 3 h at room temperature. Solvent was ated in vacuum. The residue was dissolved in EtOAc (50 mL) and washed with 5% aq. NaHCOs (2 x 30 mL) and brine (1 x 40 mL). The organic phase was dried over NagSO4 and evaporated to dryness to give 22. After purification, compound 21 was dissolved in 4N HCl/dioxane and d for 3-6 h at room temperature. Solvent was evaporated, the residue was co-evaporated with lPAc and dried to give 23.
In some embodiments, the synthesis of Lys-alaninol-CO-MPH (23; A = - CH20H(CH3)-, R1 = -(CH2)4NH2) is as follows: To a solution of 15b (0.09 g, 0.24 mmol) in THF were added TEA (2.5 mmol) and Boc-Lys(Boc)-OSu 21 (0.113 g, 0.25 mmol) and the on was d for 3 h at room temperature. t was ated in vacuum. The residue was dissolved in EtOAc (50 mL) and was washed with 5% aq. NaHCOs (2 x 30 mL) and brine (1 x 40mL). The organic phase was dried over NagSO4 and evaporated to dryness to give 22 (A = -CH2CH(CH3)-, R1 = -(CH2)4NH2). After purification, compound 22 (0.135 g) was dissolved in 4N oxane and stirred for 2 h at room temperature. t was evaporated, the residue was co-evaporated with lPAc and dried to give 23 (0.13 g).
In other embodiments, the synthesis of nicotinate-ethanolamine-CO-MPH (25a; R2 = 3-pyridinyl) is as follows: To a solution of 15a (0.1 g, 0.28 mmol) and TEA (0.15 mL, 1.12 mmol) in DCM (8 mL) was added nicotinoyl chloride (0.055 g, 0.31 mmol). After stirring for 2 h at room temperature, the reaction was quenched with water (1 mL) and solvent was evaporated to dryness. The residue was ved in EtOAc (60 mL) and washed with % aq. NaHCOs (2 x 50 mL) and brine (1 x 50 mL). The organic phase was dried over NagSO4 and evaporated to dryness to give nicotinic acid derivative 25a (0.13 g).
In some embodiments, the synthesis of succinate-ethanolamine-CO-MPH (25b; R2 = -(CH2)2002H) is as follows: To a solution of 15a (0.11 g, 0.31 mmol) and TEA (0.13 mL, 0.9 mmol) in THF (8 mL) was added succinic anhydride (0.034 g, 0.34 mmol) and the reaction mixture was stirred for 3 h at room temperature. The on was quenched with water and the solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with 1% aq. NaHSO4 (2 x 40 mL), brine (50 mL). The organic phase was dried over NagSO4 and evaporated to s to give 25b (0.12 g) as solid.
In other embodiments, the synthesis of glycerol-CO-MPH (29) is as s: 4T\/>—/OHo 26 o TEA, CHZCIZ )b + —> OgN®O O/\<’07L )J\ 27 Moo 0. MPH- HCI DMF, TEA 75 °c N O N O O O OH O A solution of 1,2-isopropylideneglycerol 26 (0.265 g, 2 mmol) and TEA (0.55 mL, 4 mmol) in DCM (8 mL) was cooled down to 0 °C. Subsequently, a solution of 4- nitrophenyl chloroformate 5 (0.425 g, 2 mmol) in DCM was added drop-wise. The ice bath was removed and the reaction mixture was stirred for 5 h at room temperature.
Solvents were evaporated in vacuum and dried to give the carbonate derivative 27.
Compound 27 was dissolved in DMF and to the solution were added TEA (0.69 mL, 5 mmol) and MPH-HCI (0.502 g, 1.85 mmol). The mixture was heated for 15 h at 70 °C.
Solvent was d under reduced pressure. The residue was dissolved in EtOAc (70 mL) and washed with 5% aq. NaHCOs (2 x 50 mL) and brine (1 x 50mL). The organic part was dried over NagSO4 and evaporated to s to give carbamate derivative 28 (0.61 g) after purification by preparative HPLC. lsopropylidene derivative 28 (0.6 g) was dissolved in methanol (MeOH) (20 mL) and to the solution was added esulfonic acid drate (TsOH-Hgo) (0.035 g). After stirring for 3 h at room temperature, the reaction was quenched with 5% aq. NaHCOs (1 mL) and solvent was evaporated to dryness. The residue was dissolved in EtOAc (70 mL) and washed with 5% aq. NaHCOs (2 x 50 mL) and brine (1 x 50mL).
The organic phase was dried over Na2804 and evaporated to dryness to give glycerol derivative 29 (0.46 g).
In other embodiments, the synthesis of ate conjugates of MPH with poly(ethylene glycol) derivatives (32) is as follows.
H31Ar TEA CHZCIZ , —> .3.) “NowO i n O MPH-HCI, TEA DMF H3c+ /\4/oj cogue In some embodiments, the synthesis of Me-PEG-CO-MPH (32a) is as follows: To a solution of Me-PEG (poly(ethylene glycol) methyl ether) 30 (1 mmol) and TEA (2 mmol) in DCM (8 mL) was added drop-wise a solution of 4-nitrophenyl formate 5 (1.05 mmol) in DCM (3 mL) at room temperature. The solution was stirred overnight at room temperature. The solvent was evaporated in vacuum and dried to give the carbonate derivative 31. nd 31 was dissolved in DMF and to the solution were added TEA (3 mmol) and MPH-HCI (1.05 mmol). The mixture was heated for 15 h at 70 °C. Solvent was removed under d pressure. The oily e was purified by preparative HPLC to give 32a as oil.
In other ments, the synthesis of Me-(OCH2CH2)3-OCO-MPH (32b; n = 3) is as follows: To a solution of Me-PEG 30 (n :3; 0.165 g, 1 mmol) and TEA (0.3 mL, 2 mmol) in DCM (8 mL) was added drop-wise a on of 4-nitrophenyl chloroformate (0.212 g, 1.05 mmol) in DCM (3 mL) at room temperature. The solution was stirred overnight at room temperature. The solvent was evaporated in vacuum and dried to give the carbonate derivative 31 (n :3). Compound 31 was dissolved in DMF and to the solution were added TEA (0.42 mL, 3 mmol) and I (0.273 g, 1.05 mmol). The mixture was heated for 6 h at 75 °C. Solvent was removed under reduced pressure.
The oily residue was purified by preparative HPLC to give 32b (n = 3) (0.24g) as oil.
In some embodiments, the synthesis of HgN-PEG-CO-MPH (34) is as follows: EO\/\ /\/O\/\ Vko o OH + 002m O/\/ \/\NH0 HN GAO/é 1. D00, HOBt, TEA, DMF rt, 2 d 2. 4N HCI/dioxane %O/\/EN (30Me O/\/O\/\NH2 To a solution of O—[2-(Boc-amino)ethyl]-O’-(2-carboxyethyl)polyethylene glycol (Boc-NH-PEG-CogH) 33 (0.12 g, 0.26 mmol), MPH-HCI (0.93 g, 0.35 mmol), 1- hydroxybenzotriazole (HOBt) (0.035 g, 0.26 mmol) and TEA (0.11 mL, 0.78 mmol) in DMF (6 mL) was added a solution of DCC (0.056 g, 0.27 mmol) ise. The reaction mixture was stirred for 2 days at room temperature. The suspension was ed and the filtrate was evaporated to dryness in vacuum. The residue was purified and ected with 4N HCI/dioxane to give the amide derivative 34 (0.13 g) as oil.
In other embodiments, the synthesis of Me-PEG-NH-succinoyl-alaninol-CO- MPH (36) is as follows: ifo /NH H30 o-N + M9020 \A 2'“ “N 0 \lo n o —§—A-NH-§- = L H30 ArNNNI \ : N To a solution of 15b (0.075 g, 0.2 mmol) and TEA (0.085 mL, 0.6 mmol) in THF (8 mL) was added O—[(N-suooinimidyl)suooinyl-aminoethyl]-O’-methylpolyethylene glycol (Me-PEG-Suo-OSu) 35 (average. Mp = 750, 0.15 g, 0.2 mmol) and the reaction mixture was stirred for 2 days at room temperature. Solvent was evaporated under reduced pressure and the e was purified by preparative HPLC to give 36 as oil.
] In some embodiments, the synthesis of 6-aminohexanoate-CH20CO-MPH (40) is as follows: OMeCICOZCHZCI OMe OMe Na I NH DCM DMAP rt \n/OVCI Acetone rt N\n/O\/| o o 1 37 38 . . . . OMe Bocamtnohexanotc actd stlver salt e, 80 90 °C_ N O O \ll/ \/ \n/WNH-Boc O 0 4N HCI in Dioxane 2 h, rt /O\n/\/\/\NH2 HCI O O A. Synthesis of Bocaminohexanoic acid silver salt: Bocaminohexanoic acid (0.85 g, 3.68 mmol) was added to water (4 mL) and cooled in ice bath. To this suspension 1N NaOH was added with constant stirring until the pH of solution was about 7 and the mixture became a clear solution. To this solution, silver e (0.63 g, 3.68 mmol) in water (2 mL) was added slowly. The resulting precipitate was filtered and washed with water. The solid was dried in vacuum over phosphorus pentoxide to yield a white solid (1.09 g) , 88%).
B. Synthesis of chloromethyl 2-(2-methoxyoxopheny|ethy|)piperidine carboxylate (37): Methylphenidate hydrochloride (1) (2.70 g, 10 mmol) was suspended in DCM (75mL) and cooled in an ice bath. 4-Dimethylaminopyridine (DMAP) (4.887 g, 40 mmol) was added and the resulting mixture was stirred for 10 min. Chloromethyl chloroformate (3.224 g, 25 mmol) in DCM (10mL) was added slowly. The ice bath was removed and the reaction was stirred for 5 h at room temperature. Ethyl acetate (250 mL) was added, followed by water (20 mL) to quench the reaction. The ethyl acetate layer was separated and washed with 1N HCI (40mL) and brine (2 x 40 mL) and dried over ous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (hexanes:EtOAc, 3:1) to give 37 as a colorless oil (2.60 g) (yield, 80%).
C. Synthesis of iodomethyl ethoxyoxophenylethyl)piperidine carboxylate (38): ] A mixture of 37 (0.28 g, 0.86 mmol) and sodium iodide (0.387 g, 2.58 mmol) in acetone (6 mL) was stirred overnight. The acetone was evaporated. The residue was dissolved in ethyl acetate (80 mL) and washed with saturated sodium ate (30 mL) and brine (30 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dried in vacuum to give 38 as a syrup (0.263 g) (yield, 73%).
D. Synthesis of Bocaminohexanoate-CHgoco-MPH (39a): A mixture of 38 (0.43 g, 1.03 mol) and Bocaminohexanoic acid silver salt (1.05 g, 3.09 mmol) in toluene (30mL) was refluxed for 3 h. The solid was filtered off and the filtrate was concentrated to dryness. The crude residue was ed by preparative HPLC to give 39a as a hygroscopic solid (0.375 g) (yield, 70%).
E. Synthesis of 6-aminohexanoate-CHgoco-MPH (40): nd 39a (0.21 g, 0.40 mmol) was stirred with 4N HCI/dioxane (5-6 mL) for 2 h at room temperature. The solvent was concentrated to dryness to yield 40 as a copic solid (0.166 g) (yield, 91%).
In other embodiments, the synthesis of lactate-CHgoco-MPH (39b) is as follows: 0 O OMe Silver lactate OMe Toulene, 80 90 Co_ N\n/O\/' NYOVO O O 38 39b A mixture of compound 38 (0.428 g, 1.03 mmol) and silver lactate (0.61 g, 3.09 mmol) in 30 mL toluene was heated at 80-90 °C for 3 h. The solid was filtered off and the filtrate was concentrated to dryness. The crude residue was purified by preparative HPLC to give 39b as syrup (0.28 g) (yield, 64%).
In some embodiments, the l procedure for the synthesis of amino acid and peptide derivatives of (6-aminohexanoyloxy)methyl methylphenidatecarboxylate conjugates (42) is as follows: -OSu OMe o NMM, THF, rt, 2-12hr N o o an/OVOWNH \n/ V \n/WNJkAA-NH-Boc 2- HCI o o H o o 4N HCl/dioxane 0 —>23h N ovo JK - n , \n’ WIN AA-NH2 HCI o o H AA = Amino acid or a dipeptide The hydrochloride salt of 40 (1 eq.) was treated with a otected amino acid or a peptide succinimidyl ester (1.05 eq.) in the presence of N—methylmorpholine (NMM) (3 eq.) in THF for 2-12 h at room temperature. The reaction mixture was concentrated to dryness and the crude residue was taken in EtOAc and washed with saturated bicarbonate, ammonium chloride solution and brine. The c layer was dried over anhydrous sodium sulfate and concentrated to dryness to yield the Boc- protected amino acid or the peptide tive 41. The Boc-protected tive 41 was ected using 4N HCl/dioxane for 2-3 h at room temperature. The solvent was evaporated to dryness to yield the hydrochloride salt of the amino acid or peptide derivative 42.
In other embodiments, the synthesis of Valaminohexanoate-CH20CO-MPH (42a) is as follows: Boc-VaI-OSu OMe 0 NMM, THF, rt, 3 h N O O NH-BOC \n/ \n/\/\/\NH2 H O O 0 O HCI 4N HCI/dioxane —> N \n/OVO\n/W\ NH2 HC' 2 h, rt O 0 Hj/Vk A. Synthesis of Boc-Valaminohexanoate-CH20CO-MPH (41a): Compound 40 (0.08 g, 0.175 mmol) was taken in anhydrous THF .
NMM (0.06 mL, 0.525 mmol) and Boc-protected succinimidyl ester (0.06 g, 0.184 mmol) were added and the reaction e was d for 2 h at room temperature. Solvent was concentrated to dryness and crude product was taken in ethyl acetate (100 mL), washed once each with saturated bicarbonate (40 mL), ammonium chloride solution (40 mL) and brine (40 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness to yield 41a (0.084 g) (yield, 77%).
B. Synthesis of Valaminohexanoate-CH20CO-MPH (42a): Compound 41a (0.084 g, 0.14 mmol) was dissolved in 4N HCl/dioxane (4- 5mL) and stirred at room temperature for 2 h. Dioxane was concentrated to dryness to yield 42a (0.078 g) (yield, 100%).
In other embodiments, the l procedure for the synthesis of amino acid and peptide conjugates of phenidate (44) is as follows: 800-AA-OH DCC HOBt TEA in DMF N AA—Boc rt, overnight \ii/ 4N HCl/dioxane OMe 44 2-3 h H N\n,AA-NH2 HCI AA = amino acid, dipeptide or tripeptide Methylphenidate hydrochloride (1 eq.) was taken in anhydrous DMF. Boc- protected amino acid or peptide (1.05 eq.), DCC (1.05 eq.), HOBt (1.1 eq.) and TEA (2.5 eq.) were added. The mixture was stirred overnight at room temperature. DMF was evaporated in vacuum and the e dissolved in ethyl acetate. The c layer was washed with 1% sodium bisulfate and brine. The organic layer was trated to dryness to yield the Boc-protected conjugate. The Boc group was deprotected by treating with 4N HCl/dioxane for 2-3 h at room temperature. Dioxane was evaporated to s to yield the amino acid or peptide derivative of methylphenidate (44).
In some embodiments, the synthesis of Ala-MPH (44a) is as follows: 800-Ala-OH DCC, HOBt, TEA in DMF rt, overnight 'BOC 4N HCl/dioxane OMe 2 h, rt NH2 HCI A. Synthesis of Boc-Ala-MPH (43a): Methylphenidate hydrochloride (0.274 g, 1.02 mmol) was taken in anhydrous DMF (10 mL). Boc-Ala-OH (0.20 g, 1.07 mmol), TEA (0.35 mL, 2.54 mmol), HOBt (0.15 g, 1.11 mmol) and DCC (0.22 g, 1.07 mmol) were added. The reaction mixture was stirred overnight at room temperature. DMF evaporated to dryness and the e was taken in EtOAc (200 mL), and washed once each with 1% sodium bisulfate (60 mL) and brine (60 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness to yield 43a (0.37 9) (yield, 90%).
B. Synthesis of Ala-MPH-HCI (44a): Compound 43a (0.37 g) was taken in 4N HCl/dioxane (8 mL) and stirred for 2 h at room temperature. Dixoane was evaporated to dryness to yield 44a (0.31 9) , 100%).
In other embodiments, the general ure for the synthesis of 1,3- eride derivatives of methylphenidate with or without linker (chain length of carboxylic acid preferably C14 or longer) is as follows: 0 it OJL R1 p-nitrophenyl chloroformate 0 R1 HO< O - O TEAin DCM,0 oCtort,3 h \[f o R2 0 R2 \ii/ 0 \ii/ 45 o 02N o R1, R2 = fatty acid chain MPH-HCI Mi TEA in DMF, rt, overnight NYC—CORR2 0 1? The yl group of 1,3-diglycerides (45) can be activated with p- nitrophenyl chloroformate. The activated glyceride 46 can then be treated with methylphenidate hydrochloride in the presence of TEA in DMF to yield the respective carbamate derivative 47. es of 1,3-diglycerides include but are not limited to glyceryl 1,3-dipalmitate, glyceryl 1,3-distearate or 1-palmitoylstearoyl-glycerol.
In some embodiments, the synthesis of 1,3-diglyceride derivatives of MPH with hydroxycarboxylic acid linkers (48) is as follows: OMe i fix OMe o A 0_ _ 0 ML \ii/o\ A A OH To )1o—CO 0 R3 0 if 8 1,3-diglyceride DCC, DMAP in DCM, rt, ght R2 R3 = fatty acid chain For example: OMe O OMe o )L N o O R2 N o ‘n’ 0 \H/ OH 1 o R3 O R 0 Fl1 \n/ 8a: R1: H 48a: Fl1 = H 8b:R1= CH. 48b:R1='CH3’ 8c: Fl1 = P—h 48c: Fl1 = -Ph A carbamate of methylphenidate and a linker with a free terminal carboxylic acid group can also be attached to a glyceride derivative. Methylphenidate carbamate conjugates of hydroxy carboxylic acids, for example, can be coupled to a 2012/048641 1,3-diglyceride using DCC and DMAP in DCM to give the respective fatty acid glycerol derivatives 48. Examples of 1,3-diglycerides include but are not d to glyceryl 1,3- dipalmitate, glyceryl 1,3-distearate or 1-palmitoylstearoyl-glycerol.
In other embodiments, the general procedure for the synthesis of conjugates of phenidate with —(OC)OCHZO- linker'Is as follows.
GIL“)MeO O MeO CICOZCHZCI Nal —> OI:ID>—OCHZCI —> MeO O O>_ MeO O OCHZI O>_OCHZOR N 1_ROAg N 2. Hg/Pd/C or HCI R = phosphoryl, acyl To a solution of iodomethyl ate of methylphenidate 38 (1-1.5 mmol) in toluene (25-50 mL) was added silver salt of acid (3 eq.). The mixture was heated from 80 °C to reflux for 3 h depending on the silver salt of the acid. After the reaction was te, the solid was filter off and the filtrate was concentrated. The residue was purified by column to give the conjugate. The conjugate was either the final product or needed to be deprotected. All protecting groups in these procedures were benzyl groups but others may be used. The conjugate in methanol was hydrogenated with % Pd/C using a hydrogen balloon for 2 h. The catalyst was filtered off. The filtrate was concentrated and dried to give the final conjugate 49.
In some embodiments, the synthesis of phosphate-CH20CO-MPH (49a), the ure of which is shown below, is as follows in steps A, B and C: M90 0 (316) we ROHo>_ 9,014 A. Synthesis of silver dibenzyl phosphate: Dibenzyl phosphate (2.78 g, 10 mmol) in water (40 mL) was cooled in an ice bath. Subsequently, 1N NaOH was added while shaking the flask until the pH of solution was about 7. The solid dissolved almost completely. Then silver nitrate (1.89 g, 11 mmol) in water (20 mL) was added slowly. After , the resulting solid was collected by filtration and washed with water. The solid was dried in vacuum over phosphorus pentoxide to yield silver dibenzyl phosphate (3.18 g) (yield, 82.5%) as a white solid.
B. Synthesis of (BnO)2-phosphate-CH20CO-MPH: MeO O O g/OBn yOCHZO—Px N OBn lodomethyl 2-(2-methoxyoxophenylethyl)piperidinecarboxylate 38 (0.260 g, 0.62 mmol) and silver dibenzyl phosphate (0.719 g, 1.87 mmol) in toluene (20 mL) were ed for 1.5 h. The solid was filtered off. The filtrate was concentrated and the residue was purified by silica gel column chomatography (hexanes:EtOAc, 3:1 to 1 :1) to give a the protected ate (0.27 g) (yield, 76.3%) as colorless oil.
C. sis of phosphate-CH20CO-MPH (49a): (Bis(benzyloxy)phosphoryloxy)methyl 2-(2-methoxyoxo phenylethyl)piperidinecarboxylate (0.267 g, 0.47 mmol) in methanol (8 mL) was enated under 10% Pd/C (dry, 90 mg) with a hydrogen n for 2 h. The catalyst was filtered off through . The filtrate was evaporated to dryness to give 49a (0.136 g) (yield, was 74.6%) as a white amorphous solid.
In some embodiments, the synthesis of nicotinate-CH20CO-MPH-HC| (49b), the structure of which is shown below, is as follows in steps A and B: MeO O O >—OCH2—o + _ \NHCI N | A. Synthesis of nicotinate-CH20CO-MPH, the structure of which is shown below: Iodomethyl 2- (2- methoxy---oxo 1-p-henylethyl)piperidine- 1--carboxylate 38 (0.457 g, 1.10 mmol) and silver nicotinate (0.755 g, 3.28 mmol) in toluene (20 mL) were refluxed for 2 h. The solid was filtered off. The filtrate was concentrated and the e was purified by silica gel column chomatography (hexanes:EtOAc, 2:1 to 1:1) to give 49b in freebase form (0.256 g) , 56.7%) a colorless oil.
B. Synthesis of nicotinate-CH20CO-MPH-HC| (49b): (2-(2-methoxyoxophenylethyl)piperidinecarbonyloxy)methyl nicotinate (0.256 g, 0.62 mmol) in acetone (8 mL) was treated with 1.25N HCl/MeOH (0.75 mL, 0.93 mmol). The solvent was ated at room temperature. The resulting e was coevaporated with acetone (2 x 3 mL) and then dissolved in acetone (0.8 mL) and ether (20 mL) was added. Upon scratching with a spatula, solid formed gradually and was collected by filtration to yield 49b (0.180 g) (yield, .
In other embodiments, the sis of isonicotinate-CH20CO-MPH-HC| (49c), the structure of which is shown below, is as follows in steps A and B: MeO O O >—OCH2—o \ N | /l>lH CI A. Synthesis of isonicotinate-CH20CO-MPH, the structure of which is shown below: OCS\~ocug—o \ ] Iodomethyl 2- (2- methoxy---oxo 1-p-henylethyl)piperidinecarboxylate 38 (0.555 g, 1.33 mmol) and silver isonicotinate (0.918 g, 3.99 mmol) in toluene (50 mL) were heated for 1.5 h at 90 °C. The solid was filtered off through celite. The filtrate was concentrated and the residue was ed by silica gel column ography (hexanes:EtOAc, 1.2:1 to 1:1) to give 49c in freebase form (0.286 g) (yield, 52.1%) as a syrup.
B. Synthesis of isonicotinate-CH20CO-MPH-HC| (49c): (2-(2-methoxyoxophenylethyl)piperidinecarbonyloxy)methyl isonicotinate (0.286 g, 0.62 mmol) in methanol (4 mL) was d with 1.25N HCl/MeOH (1 mL, 1.25 mmol). The t was evaporated at room temperature. The residue was coevaporated with methanol (2 x 5 mL) and acetone (4 mL) was added.
Solid formed gradually and acetone was evaporated. The solid was collected and washed with ether (4 x 2 mL) to yield 49c (0.228 g) (yield, 73.2%) as an off-white solid.
In other embodiments, the synthesis of palmitate-CH20CO-MPH (49d), the structure of which is shown below, is as follows: MeO OOyOCHZO”(PC(CH))40H3 Iodomethyl 2-(2-methoxyoxophenylethyl)piperidinecarboxylate 38 (0.472 g, 1.13 mmol) and silver palmitate (1.233 g, 3.39 mmol) in toluene (50 mL) were heated for 1 h at 95 °C. The solid was filtered off. The filtrate was concentrated and the residue was purified by silica gel column chomatography (hexanes:EtOAc, 5:1) to give 49d (0.48 g) (yield, 77.8%) as a white solid.
In some embodiments, the synthesis of gallate-CH20CO-MPH (49e) the structure of which is shown below, is as follows: MeO O O >—OCH2—O OH Iodomethyl ethoxyoxophenylethyl)piperidinecarboxylate 38 (0.477 g, 1.14 mmol) and silver 3,4,5-tris(benzyloxy)benzoate (1.877 g, 3.43 mmol) in toluene (50 mL) were heated for 1 h at 85 °C. The solid was filtered off through celite.
The filtrate was concentrated and the residue was purified by silica gel column chomatography es:EtOAc, 3:1) to give 0.55 g of an amorphous solid, which was hydrogenated under 10% Pd/C (dry, 150 mg) in methanol (25 mL) with a hydrogen balloon for 2 h. The catalyst was filtered off through celite. The filtrate was evaporated to dryness to give 49e (0.315 g) (yield, 60.1%) as an amorphous solid.
In other embodiments, the synthesis of phosphate-(p—salicylate)-CH20CO- MPH (49f), the structure of which is shown below, is as follows: MeO o O>—OCH2—OJ\©\ OP(O)(OH)2 Iodomethyl 2-(2-methoxyoxophenylethyl)piperidinecarboxylate 38 (0.47 g, 1.13 mmol) and silver 4-(bis(benzyloxy)phosphoryloxy)benzoate (1.01 g, 2 mmol) in toluene (50 mL) were heated for 1 h at 90 °C. The solid was filtered off h celite. The filtrate was concentrated and the residue was purified by silica gel column ography (hexanes:EtOAc, 3:1-2:1) to give 0.45 g of a colorless oil, which was hydrogenated under 10% Pd/C (dry, 100 mg) in methanol (15 mL) with a hydrogen balloon for 1 h. The catalyst was filtered off through . The filtrate was evaporated to give 49f (0.326 g) (yield, 56.8%) as an amorphous solid.
In some embodiments, the general ure for the sis of pyridium- type conjugates of methylphenidate is as follows: cogMe cogMe R1 CICO CH Cl #, I 50 HN N N/ O=f , OCHZCI 1 37 o=( m HCI o=rN OCPHz _ ocH2 /N+| CI /N+| CI— R1 \ 51 52 R1 = H, -COZEt, -CONH2, cogtBu, -CO-Gly-Ala-OtBu, l-OtBu, -CO-Asp(OtBu)-OtBu R2 = -CO-Gly-Ala, -CO-Val, p, -COZH The chloromethyl carbamate of methylphenidate 37 (1-1.5 mmol) and pyridine or pyridine tive 50 (1-7 mmol) in acetonitrile (6-10 mL) were heated for 3.5 h to 48 h at 70 °C. After the reaction was complete, the solvent was evaporated. The residue was purified to give the conjugate. The conjugate was either the final product or needed to be deprotected. All the protecting groups for these reactions were tert—butyl groups, which were removed with 4N HCl/dioxane, but other protecting groups may be used.
In other embodiments, the synthesis of MPH-COgCHg-pyridine chloride (51a), the structure of which is shown below, is as follows: COgMe ] The chloromethyl carbamate of methylphenidate 37 (0.326 g, 1 mmol) and pyridine (0.566 mL, 7 mmol) in acetonitrile (6 mL) were heated for 3.5 h at 70 °C. The solvent was evaporated and then coevaporated with e (2 x 5 mL). The resulting residue was dissolved in DCM (1 mL) and tert—butyl methyl ether (TBME) (15 mL) was added. The milky liquid was decanted. The e was dried in vacuum to give 51a (0.404 g) (yield, 99.8%) as an amorphous solid.
In other embodiments, the sis of MPH-COgCHg-nicotinoyl-OEt chloride (51 b), the structure of which is shown below, is as follows: COZMe o=( 51b The chloromethyl carbamate of methylphenidate 37 (0.326 g, 1 mmol) and ethyl nicotinate (0.453 g, 3 mmol) in acetonitrile (6 mL) were heated for 24 h at 70 °C.
The solvent was evaporated. The residue was dissolved in DCM (1.5 mL) and TBME (40 mL) was added. Solid formed and liquid was decanted. The above procedure was repeated twice. The resulting residue was dried in vacuum to give 51b (0.325 g) (yield, 68.1%) as an off-white solid.
In some embodiments, the sis of MPH-C02CH2-nicotinamide chloride (51c), the structure of which is shown below, is as follows: COZMe 0=l 51c CONH2 The chloromethyl carbamate of methylphenidate 37 (0.326 g, 1 mmol) and nicotinamide (0.122 g, 1 mmol) in itrile (6 mL) were heated for 26 h at 70 °C. The t was evaporated and to the resulting residue was added EtOAc (40 mL). Upon scratching with a spatula, solid formed gradually and was collected by filtration. The solid was further washed with EtOAc (3 x 3 mL) and dried in vacuum to yield 51c (0.298 9) (yield, 66.5%) as an off-white solid.
In some embodiments, the synthesis of MPH-C02CH2-nicotinoyl-O‘Bu chloride (51d), the structure of which is shown below, is as follows: COZMe 0:] 51d (1\‘ cogBu The chloromethyl carbamate of methylphenidate 37 (0.489 g, 1.5 mmol) and tert—butyl nicotinate (0.806 g, 4.5 mmol) in acetonitrile (10 mL) were heated for 7 h at 70 °C. The t was evaporated. To the e in DCM (1 mL) was added TBME (40 mL). The liquid was decanted and the residue was dissolved in DCM (1 mL) and then TBME (30 mL) was added. The resulting solid was collected, washed with TBME (3 x 4 mL) and dried in vacuum to yield 51d (0.325 9) (yield, 47.4%) an ite solid.
In other embodiments, the synthesis of MPH-COgCHg-nicotinoyl-Gly-Ala chloride (52a), the structure of which is shown below, is as follows in steps A, B and C: COZMe 0=( 52a CONHCHZCONHCIDHCOZH A. Synthesis of tert—butyl 2-(2-(nicotinamido)acetamido)propanoate (50e), the structure of which is shown below: \ NU1 NHchogtBu 0 Me ] To H-Gly-Ala-O‘Bu (0.85 g, 4.2 mmol) in DCM (30 mL) was added Et3N (1.17 mL, 8.4 mmol). Nicotinoyl chloride hydrochloride (0.748 g, 4.2 mmol) was added in portions (4 times, over 20 min.) in an ice-bath. After adding, the e was stirred for 1 h below 5 °C. Water (30 mL) was added to quench the reaction, ed by DCM (50 mL). The DCM layer was further washed with 5% NaHCOs and brine (30 mL each) and dried over NagSO4. The solvent was evaporated and the residue was purified by silica gel column ography (6% MeOH/DCM) to give 50e (0.881 g) (yield, 68.3%) as an amorphous solid.
B. Synthesis of MPH-C02CH2-nicotinoyl-Gly-Ala-O‘Bu chloride (51e), the structure of which is shown below: COZMe O=f 51e OCH2 Kl/N+ Cl CONHCHZCONHSHCOZtBu The chloromethyl carbamate of methylphenidate 37 (0.489 g, 1.5 mmol) and tert—butyl 2-(2-(nicotinamido) acetamido)propanoate 50e (0.461 g, 1.5 mmol) in acetonitrile (10 mL) were heated for 24 h at 70 °C. The solvent was evaporated. The residue was dissolved in DCM (1.5 mL) and TBME (25 mL) was added. Solid formed and the liquid was decanted. The above procedure was repeated four times. The solid was collected, washed with TBME (3 x 2 mL) and dried in vacuum to give 51e (0.576 g) (yield, 60.7%) as an off-white solid.
] C. Synthesis of MPH-C02CH2-nicotinoyl-Gly-Ala chloride (52a): To 51e (0.367 g, 0.58 mmol)in DCM (1 mL) was added 4 M HCl/dioxane (5 mL). The mixture was stirred for 2 h. The solvent was evaporated. The residue was dissolved in DCM (2 mL) and TBME (25 mL) was added. The resulting solid was collected, washed with TBME (2 x 1 mL) and dried in vacuum to yield 52e (0.322 g) (yield, 96.1%) as a solid.
In other embodiments, the sis of MPH-COgCHg-nicotinoyl-Val chloride (52b), the structure of which is shown below, is as follows in steps A, B and C: COZMe O=l’ 52b CONHCIDHCOZH A. Synthesis of tert-butyl 3-methyl(nicotinamido)butanoate (50f), the structure of which is shown below: | NHCIDHCOZtBu N/ CH(CH3)2 501 was prepared by the same procedure as 50e and was ed by silica gel column chomatography (3% MeOH/DCM) to give 501 (0.882 g, 3 mmol scale) (yield, 98.4%) as a syrup.
B. Synthesis of MPH-C02CH2-nicotinoyl-Val-O‘Bu chloride (51f) ,the ure of which is shown below: COgMe CONHCIDHcogtBu CH(CH3)2 The chloromethyl carbamate of methylphenidate 37 (0.489 g, 1.5 mmol) and tert—butyl 3-methyl(nicotinamido)butanoate 501 (0.278 g, 1 mmol) in acetonitrile (10 mL) were heated for 40 h at 70 °C. The solvent was evaporated. To the residue in TBME (5 mL) was added hexanes (10 mL). The resulting solid was collected, washed WO 16668 2012/048641 with TBME/hexanes (1 :1, 6 x 3 mL) and dried in vacuum to give 51f (0.464 g) (yield, 76.8%).
C. Synthesis of MPH-Cochg-nicotinoyl-Val chloride (52b): To 51f (0.302 g, 0.5 mmol) in DCM (1 mL) was added 4N HCl/dioxane (5 mL).
The mixture was stirred for 5 h. The solvent was evaporated. The residue was dissolved in DCM (1.5 mL) and TBME (25 mL) was added. The resulting solid was collected, washed with TBME (4 x 2 mL) and dried in vacuum to give 52b (0.329 g) (yield, 100%) as a solid.
In other embodiments, the synthesis of MPH-COgCHg-nicotinoyl-Gly-Asp chloride (52c), the structure of which is shown below, is as followsin steps A, B and C: cogMe o=l 52c OCH2 /N+| CI CONHchogt CH2C02H A. Synthesis of di-tert—butyl 2-(nicotinamido)succinate (509), the ure of which is shown below: \ NHCIDHCOZtBu N/ CHZCOZtBU 509 was prepared by the same procedure as 50e.
B. Synthesis of MPH-Cochg-nicotinoyl-Asp(O‘Bu)-O‘Bu chloride (519), the structure of which is shown below: COgMe O=( 51g ocH2 CONHCIDHCOZtBu CchogtBu The chloromethyl carbamate of methylphenidate 37 (0.489 g, 1.5 mmol) and t—Butyl 2-(nicotinamido)succinate 509 (0.35 g, 1 mmol) in acetonitrile (10 mL) were heated for 24 h at 70 °C. The solvent was evaporated. The residue was purified by silica gel column chomatography (7% MeOH/DCM, then 11% MeOH/DCM) to give 519 (0.452 g) (yield, 66.8%) as an amorphous solid.
C. Synthesis of MPH-COgCHg-nicotinoyl-Asp chloride (52c): 519 (0.45 g, 0.67 mmol) in 4N HCl/dioxane (5 mL) was stirred for 3 h. The t was evaporated. The residue was coevaporated with DCM (4 x 5 mL), then ved in DCM (4 mL) and TBME (25 mL) was added. The resulting solid was collected, washed with TBME (4 x 2 mL) and dried in vacuum to yield 52c (0.357 g) , 95.1%) as a solid.
In other embodiments, the sis of MPH-C02CH2-nicotinate chloride (52d), the structure of which is shown below, is as follows: COZMe o=( 52d 3-(tert-Butoxycarbonyl)((2-(2-methoxyoxophenylethyl)piperidine carbonyloxy)methyl)pyridium chloride 51d (0.202 g, 0.4 mmol) in 4N HCl/dioxane (5 mL) was stirred for 24 h. The solvent was evaporated. The residue was dissolved in DCM (1 mL) and TBME (20 mL) was added. The resulting solid was collected, washed with TBME (3 x 1 mL) and dried in vacuum to give 52d (0.172 g) (yield, 95.8%) as a solid.
In some embodiments, the synthesis of phosphate-(p—salicylate)-MPH (56), the structure of which is shown below, is as followsin steps A, B, C and D: MeO O N HOC2 + EDCl/HOBt w>—©’%n Et3N/THF Hg/Pd/C < >OH 2PN(CHMe2)2 tBuOOH EtAc/MeOH 1H -tetrazole/DCM MeO o O (P. MeO o o 9 OP(OBn)2 OP(OH)2 N Hg/Pd/C N MeOH 55 56 A. Synthesis of BnO-p—salicylate-MPH (53), the structure of which is shown below,: MeO o phenidate hydrochloride (2.698 g, 10 mmol), 4-benzyloxybenzoic acid (2.282 g, 10 mmol) and HOBt-H20 (1.532 g, 10 mmol) in THF (60 mL) were added to Et3N (3.07 mL, 22 mmol), followed by l(3-dimethylaminopropyl) carbodiimide) hydrochloride (EDCI) (2.109 g, 11 mmol). The mixture was stirred for 4 days. EtOAc (200 mL) was added and the e was washed with water (30 mL), 5% HOAc (50 mL) and brine (40 mL). The EtOAc layer was dried over Na2804. The solvent was evaporated and the residue was crystallized from EtOAc (12 mL). The solid was collected by filtration and washed with cold EtOAc (3 x 4 mL) to give 53 (3.48 g) , 78.5%) as a white solid.
B. Synthesis of cylate-MPH (54), the structure of which is shown below,: MeO o 53 (3.48 g, 7.85 mmol) was hydrogenated under 10% Pd/C (wet, 700 mg) in MeOH (10 mL) and EtOAc (100 mL) with a hydrogen balloon for 15 h. The catalyst was filtered off through celite. The filtrate was evaporated to give 54 (2.94 g) as an amorphous solid.
C. Synthesis of (BnO)2-phosphate-(p—salicylate)-MPH (55), the structure of which is shown below,: MeO o 9 OP(OBn)2 ] To 54 (0.7 g, 1.98 mmol) in DCM (20 mL) was added dibenzyl diisopropylphosphoramidite (0.752 g, 2.178 mmol), ed by 1N-tetrazole solution in acetonitrile (0.45 M, 4.84 mL, 2.178 mmol). The mixture was stirred for 3 h.
Subsequently, 0.6 mL of 70% tert-BuOOH/water was added and stirred for 20 min. The solvent was evaporated. The residue in EtOAc (100 mL) was washed with water and brine (30 mL each) and dried over NagSO4. The solvent was ated and the residue was purified by silica gel column chomatography (EtOAc:hexanes, 1.2:1) to give 55 (0.99 g) (yield, 81.5%) as a syrup.
D. Synthesis of phosphate-(p—salicylate)-MPH (56), the structure of which is shown below,: MeO o 9 or>(on)2 55 (0.99 g, 1.61 mmol) was hydrogenated under 10% Pd/C (wet, 300 mg) in methanol (20 mL) with a hydrogen balloon for 3 h. The catalyst was filtered off through celite. The te was evaporated to give 56 (0.675 g) (yield, 96.5%) as an amorphous solid.
In some embodiments, the synthesis of Gly-(p—salicylate)-MPH (58) is as follows in steps A and B: MeO o O N EDCI/HOBt + BocNHCHCOZH —> 033 COT/S MeO 00,} C o N HC NHBoc NH2 A. sis of Boc-Gly-(p—salicylate)-MPH (57), the structure of which is shown below,: CHEW?NHBoc To 54 (0.353 g, 1 mmol), Boc-Gly-O-l-l (0.175 g, 1 mmol) and 20 (0.153 g, 1 mmol) in THF (10 mL) were added Et3N (0.15 mL, 1.1 mmol), followed by EDCI (0.211 g, 11 mmol). The mixture was stirred for 15 h. Then another 0.4 mmol of Boc—Gly-OH and EDCI were added and the mixture was again stirred for 3 h. EtOAc (100 mL) was added and the mixture was washed with water (2 x 30 mL) and brine (30 mL). The EtOAc layer was dried over Na2804. The solvent was evaporated and the residue was purified by silica gel column chomatography (2% MeOH/DCM) to give 57 (0.452 g) , 88.5%) as an amorphous solid.
B. Synthesis of Glyp(-salicylate))-lV|PH 5(8). lVlOe @« To 57 (0.45 g, 0.88 mmol ) in DCM (1 mL) was added 4 M HCI/dioxane (5 mL). The mixture was stirred for 1 h. The solvent was evaporated. The residue was coevaporated with DCM (3 x 5 mL) and then dissolved in DCM (2 mL). EtOAc (10 mL) and TBME (10 mL) were added. The resulting solid was collected, washed with EtOAc/TBME (1 :1, 3 x 2 mL) and dried in vacuum to give 58 (0.329 g) (yield, 83.5%) as an white solid.
Pharmaceutical Kits In some embodiments, the present technology provides pharmaceutical kits comprising a prodrug or composition of the t technology that has increased water solubility than compared to the unconjugated methylphenidate. In some embodiments, a specific amount of individual doses in a package contain a pharmaceutically effective amount of the prodrugs or conjugate of the present technology. In some other embodiments, the kit comprises oral thin films or strips comprising prodrugs or conjugates of the present technology. The present technology es pharmaceutical kits for the treatment or prevention of ADHD, ADD or drug withdrawal symptoms in a patient. The patient may be a human or animal patient. le human patients e pediatric patients, geriatric (elderly) patients, and normative patients. The kit comprises a ic amount of the individual doses in a package containing a pharmaceutically effective amount of at least one conjugate of methylphenidate of the present logy. The kit can further include instructions for use of the kit. The specified amount of dual doses may contain from about 1 to about 100 individual s, alternatively from about 1 to about 60 individual dosages, alternatively from about 10 to about 30 individual dosages, including, about 1, about 2, about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 70, about 80, about 100, and include any additional increments f, for example, about 1, about 2, about 5, about 10 and multiplied factors thereof, (e.g., about x1, about x2, about x2.5, about x5, about x10, about x100, etc).
The presently described technology and its advantages will be better understood by reference to the ing examples. These examples are provided to describe specific embodiments of the t logy. By providing these specific examples, it is not intended limit the scope and spirit of the present technology. It will be understood by those skilled in the art that the full scope of the presently described technology encompasses the subject matter defined by the claims appending this specification, and any alterations, modifications, or equivalents of those claims.
EXAMPLES Example 1: Comparison of oral pharmacokinetic (PK) profiles of ates of methylphenidate and oxoacids.
Exemplary g conjugates of the present logy were synthesized as described above. The oral plasma concentrations of methylphenidate ed from nicotinate-CH20CO-MPH, phosphate-CH20CO-MPH, gallate-CH20CO-MPH, lactate- -MPH, MPH-C02CH2-nicotinoyl-Asp, MPH-C02CH2-nicotinoyl-Val, MPH- C02CH2-nicotinoyl-Gly-Ala, Valaminohexanoate-CH20CO-MPH, MPH-C02CH2- nicotinamide, 6-aminohexanoate-CH20CO-MPH, MPH-COgCHg-nicotinoyl-O‘Bu, MPH- COgCHg-nicotinate, MPH-COgCHg-nicotinoyl-OEt, MPH-COgCHg-pyridine, isonicotinate- CHgOCO-MPH and phosphate-(p—salicylate)-CH20CO-MPH were compared with unconjugated methylphenidate after oral administration in rats. Rats were dosed with oral solutions of the conjugated prodrugs in an amount equivalent to 2 mg/kg of methylphenidate free base and compared to an equimolar solution of unconjugated methylphenidate hydrochloride.
] The plasma concentrations of methylphenidate were measured by MS over time. Figures 13 - 30 demonstrate the different PK curves achieved by the different methylphenidate conjugates as compared with unconjugated forms and all of the specific pharmacokinetic parameter data is presented in Tables 2 - 4. The release of methylphenidate from the prodrugs varied depending on the linker and ds attached to methylphenidate. Changes in the amount of methylphenidate released from the prodrugs as measured by the area under the curve ranged from 0-185 %-AUC compared to unconjugated methylphenidate hloride.
The dosing vehicles for the PK experiments are as follows: Figure 13 - 10% Tween in water. s 14 and 15 — water. Figure 16 - conjugate in 50% PEG-400 in water; control: water. Figure 17 - 50% PEG-400 in water. Figure 18 - 10% Tween in water. Figures 19 - 27 — water. Figures 28 and 29 — phosphate buffered saline (PBS).
Figure 30 - 10% Tween in water.
Table 2. PK parameters for prodrugs of methylphenidate dosed via oral gavage in rats.
Methylphenidate AUC'O-4h Cmax Tmax 4h Cmax Tmax Cmax' Conjugate [ng/mLxh][ng/mL] [h] [ng/mLxh][ng/mL] [h] AUC-% % Tmax-% Nicotinate-CH20CO-MPH (P0) 64.3 83.8 0.300 93.0 110.1 0.250 69% 76% 120% Phosphate-CH20CO-MPH (PO)a 154.5 158.9 0.250 106.1 113.8 0.283 146% 140% 88% Phosphate-CH20CO-MPH (PO) 110.8 110.8 0.250 59.8 77.0 0.250 185% 144% 100% Gallate-CHZOCO-MPH (PO)b 85.6 77.3 0.600 106.1 113.8 0.283 81% 68% 212% Gallate-CH20CO-MPH(PO) 85.6 77.3 0.600 187.2 176.8 0.450 46% 44% 133% Lactate-CH20CO-MPH (PO) 132.3 122.5 0.300 182.3 162.8 0.250 73% 75% 120% MPH-C02CH2-nicotinoyl- Asp (PO) 125.6 97.3 0.300 116.3 111.1 0.250 108% 88% 120% MPH-COZCHg-nicotinoyl-Val (P0) 91.4 75.2 0.350 121.6 111.1 0.250 75% 68% 140% MPH-C02CH2-nicotinoyl- Gly-Ala (P0) 71.0 71.8 0.250 76.9 89.6 0.300 92% 80% 83% Valaminohexanoate- CH20CO-MPH (P0) 44.9 52.7 0.250 76.9 89.6 0.300 58% 59% 83% MPH-C02CH2-nicotinamide (P0) 63.4 78.6 0.300 49.5 86.8 0.250 128% 91% 120% ohexanoate- CH20CO-MPH (PO) 145.6 173.5 0.350 177.9 159.1 0.400 82% 109% 88% MPH-C02CH2-nicotinoyl- OtBu (P0) 71.4 54.9 0.400 78.1 73.9 0.300 91% 74% 133% ZCHg-nicotinate (P0) 75.5 52.6 0.450 78.1 73.9 0.300 97% 71% 150% MPH-C02CH2-nicotinoyl- OEt (P0) 62.7 36.9 0.450 49.5 86.8 0.250 127% 43% 180% MPH-COZCHg-pyridinePO) 72.0 87.1 0.250 49.5 86.8 0.250 145% 100% 100% WO 16668 Isonicotinate-CH20CO- MPH (P0) 51.9 69.8 0.250 42.1 79.9 0.250 123% 87% 100% Phosphate-(p-salicylate)- -MPH P0 35.3 57.1 0.250 42.1 79.9 0.250 84% 72% 100% aPK parameters for phosphate-CHZOCO-MPH calculated from combined data of three studies and for methylphenidate hydrochloride from combined data of six studies. bPK parameters for gallate-CHZOCO-MPH calculated from data of one study and for methylphenidate hydrochloride from combined data of six studies.
Table 3. PK parameters for prodrugs of phenidate dosed intranasally in rats.
Methylphenidate AUC'O-4h Cmax Tmax 4h Cmax Tmax Cmax' Conjugate [ng/mLxh][ng/mL] [h] [ng/mLxh][ng/mL] [h] AUC-% % Tmax-% MPH-C02CH2-nicotinamide (IN) 121.4 213.4 0.083 957.5 2137.0 0.083 13% 10% 100% 2CH2-nicotinoyl- OtBu (IN) 51.6 156.3 0.083 824.0 2373.5 0.083 6% 7% 100% MPH-COZCHg-nicotinate (IN) 38.8 122.0 0.083 1045.3 2210.4 0.116 4% 6% 71% MPH-C02CH2-pyridine(lN) 29.2 59.9 0.187 879.2 2128.4 0.083 3% 3% 226% Table 4. PK parameters for prodrugs of methylphenidate dosed intravenously in rats.
Methylphenidate AUC'O-4h c“'max Tmax AUCo.4h Cmax Tmax Cmax' Con'u ate [n /mLxh] [n /mL] [h] [n /mLxh] [n /mL] [h] AUC-% % Tmax'% MPH-COZCHZ-nicotinamide (IV) 62.5 67.3 0.633 320.2 295.8 0.517 20% 23% 1 23% MPH-C02CH2-pyridine (IV) 13.2 10.6 0.417 414.9 439.4 0.266 3% 2% 1 56% Example 2: Water solubility of methylphenidate conjugates of the present logy.
The water solubility of phosphate-CH20CO-methylphenidate and unconjugated methylphenidate was determined at ambient temperature and the results are found in Table 5.
Table 5. Water solubility of methylphenidate conjugates of oxoacids nd Solubility in Water phosphate-CH20CO-methylphenidate 432 mg/mL methylphenidate hydrochloride 169 mg/mL The results for unconjugated methylphenidate hydrochloride are consistent with the solubility data found in the literature (191 mg/mL at 32 °C). The water solubility of the phosphate-CH20CO-methylphenidate conjugate is about 2.5 times higher than the unconjugated form.
In the t specification, use of the singular includes the plural except where specifically indicated.
The presently described technology is now described in such full, clear, concise and exact terms as to enable any person skilled in the art to which it pertains, to practice the same. It is to be understood that the foregoing describes preferred embodiments of the technology and that modifications may be made therein without departing from the spirit or scope of the ion as set forth in the appended claims.

Claims (10)

1. A prodrug composition sing at least one conjugate of methylphenidate wherein the conjugate is of the ing structure: wherein G2 is selected from the group consisting of standard amino acids, nonstandard amino acids and synthetic amino acids; and wherein the amino acid is attached to the rest of the molecule by an amide linkage.
2. The prodrug composition of claim 1, n the amino acid is threonine.
3. The prodrug composition of claim 1, wherein the amino acid is serine.
4. The prodrug composition of claim 1, wherein the prodrug of methylphenidate has one of the following structures: O O O O O O N O CH N+ 2 N O CH N+ NH O NH O O O OH OH OH OH
5. The prodrug composition of claim 1, wherein the conjugate is a pharmaceutically acceptable anionic, amphoteric, zwitterionic or cationic salt form or salt mixtures thereof.
6. The prodrug composition of claim 5, wherein the anionic salt form is selected from the group consisting of acetate, l-aspartate, besylate, bicarbonate, carbonate, d-camsylate, ylate, citrate, edisylate, formate, fumarate, ate, hydrobromide/bromide, hloride/chloride, d-lactate, l-lactate, d,l-lactate, d,lmalate , l-malate, te, pamoate, ate, succinate, sulfate, bisulfate, dtartrate , l-tartrate, d,l-tartrate, meso-tartrate, benzoate, gluceptate, d-glucuronate, hybenzate, isethionate, malonate, methylsufate, 2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate, thiocyanate, acefyllinate, aceturate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphocarbonate, decanoate, hexanoate, e, cypionate, dichloroacetate, te, ethyl sulfate, furate, fusidate, galactarate (mucate), galacturonate, gallate, gentisate, glutamate, glutamate, ate, glycerophosphate, heptanoate (enanthate), hydroxybenzoate, ate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, methanesufonate, myristate, napadisilate, oleate, oxalate, ate, e, te, propionate, pyrophosphate, salicylate, salicylsulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate, tribrophenate, valerate, valproate, adipate, 4- acetamidobenzoate, camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, and undecylenate.
7. The prodrug composition of claim 5, wherein the cationic salt form is selected from the group ting of sodium, potassium, calcium, magnesium, zinc, aluminium, lithium, cholinate, um, ammonium and tromethamine.
8. The prodrug composition of any one of claims 1 to 7, wherein the composition is in the form comprising a tablet, a capsule, a caplet, a troche, a e, an oral powder, a solution, a thin strip, an oral thin film (OTF), an oral strip, a rectal film, a transdermal patch, a syrup, a suspension, an inhalation compound or a suppository.
9. The prodrug composition of claim 1, wherein the conjugate is of the following structure: wherein G2 is selected from the group consisting of standard amino acids, nonstandard amino acids and synthetic amino acids; and n the amino acid is attached to the rest of the molecule by an amide
10. The prodrug composition according to claim 1, substantially as herein described with reference to any one of the anying examples and/or figures.
NZ618113A 2011-07-28 2012-07-27 Methylphenidate-prodrugs, processes of making and using the same NZ618113B2 (en)

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