WO2013036567A2

WO2013036567A2 - Methods, compositions, and compounds for the reduction of illegal methamphetamine production

Info

Publication number: WO2013036567A2
Application number: PCT/US2012/053850
Authority: WO
Inventors: Brent A. Johnson
Original assignee: Johnson Brent A
Priority date: 2011-09-07
Filing date: 2012-09-06
Publication date: 2013-03-14
Also published as: WO2013036567A3

Abstract

Disclosed herein are compounds and methods for using prodrugs of pseudoephedrine and ephedrine to inhibit illegal methamphetamine synthesis.

Description

METHODS, COMPOSITIONS, AND COMPOUNDS FOR THE REDUCTION OF ILLEGAL

METHAMPHETAMINE PRODUCTION

BACKGROUND

Methamphetamine abuse is a growing problem. A large part of this problem stems from the ease of synthesis of methamphetamine from the common legitimate medications ephedrine and pseudoephedrine. These compounds are converted to methamphetamine by a reduction reaction that is so simple to carry out that anyone can do it. It is estimated that 99% of clandestine drug laboratories in the US are involved in methamphetamine manufacture.

ephedrine

Ephedrine or pseudoephedrine is usually converted to methamphetamine by using either red phosphorous obtained from matches and iodine created in situ from HI (P/l method), or by the "Nazi method," which is a dissolving metal reduction that uses ammonia and lithium removed from batteries. The U.S. Drug Enforcement Agency (DEA) recognizes two classes of clandestine methamphetamine producers. The first class, called "super-labs," are those capable of making 10 pounds or more of methamphetamine in a 24-hour period. These labs are operated by criminal organizations. The second class, called small toxic labs (STL), are those that are operated independently. The STLs obtain their ephedrine or pseudoephedrine by purchasing an over the counter dosage form at a store or on the internet and extracting the drug. By contrast, the super-labs divert large amounts of the pseudoephedrine or ephedrine from legitimate uses. Although most labs are STLs, the super-labs actually produce a greater share of the methamphetamine being used in the US.

Clandestine methamphetamine production is more than just a drug problem, it is a safety and environmental problem. Methamphetamine labs often explode or catch fire. Furthermore, according to the DEA, one pound of clandestine methamphetamine production yields 5-6 pounds of hazardous waste. In 2003, the cost to the DEA for cleanup of methamphetamine labs was $16 million.

Both technical and legal solutions to this problem have been proposed or implemented with varying degrees of success. In 2005, Murray and colleagues (US 6,852,891) proposed a "method of inhibiting or preventing the use of anhydrous ammonia as a solvent in a dissolving metal reduction process comprises adding to anhydrous ammonia a chemical reagent which is capable of scavenging solvated electrons generated when alkali or alkaline earth metal is dissolved in the anhydrous ammonia, the chemical reagent being added to the anhydrous ammonia such that when alkali metal is dissolved in the anhydrous ammonia containing the chemical reagent and thereafter ephedrine, pseudoephedrine or combination thereof is introduced to the anhydrous ammonia to produce a reaction product, the methamphetamine yield in the reaction product is below 50%, preferably below 10%, and more preferably below 1 %. Preferred chemical reagents include Fe(lll)citrate, ferrocene, 2- chloro-6-(trichloromethyl)pyridine and 1 ,1 ,1 ,2-tetrafluoroethane." However, this method is ineffective in reducing methamphetamine synthesis via the P/l method.

Booth and colleagues (US 6,495,529) claimed that (-)-pseudoephedrine, the enantiomer of the commercial (+)-pseudoephedrine was "useful for relieving nasal and bronchial congestion" and had "fewer side effects" than the commercial product. Reduction of this compound would yield the enantiomer of methamphetamine, which does not have the effects that users of methamphetamines seek. However, this use was conceived in 1998, and no product has resulted to date.

Congress enacted the Combat Methamphetamine Epidemic Act in 2005, which required sales of ephedrine and pseudoephedrine over-the-counter products be stored behind the counter, restricted daily and monthly sales quantities, and required that sales be recorded. Most states have also enacted legislation to control over-the-counter sales of ephedrine and pseudoephedrine products.

Other compounds, such as phenylephrine, have replaced pseudoephedrine in some products. But pseudoephedrine is still in demand because for many people, phenylephrine is significantly less effective in relieving congestion and other symptoms.

Despite these efforts, the methamphetamine problem persists. Thus, there continues to be a need for additional methods of controlling this problem.

DESCRIPTION

Clandestine methamphetamine synthesis could be substantially curtailed by replacing the pseudoephedrine and ephedrine that is manufactured, transported, sold, stored, or administered to a mammal, including a human being, with prodrugs of the pseudoephedrine and ephedrine. Thus, pseudoephedrine or ephedrine would no longer be available for a criminal to steal or purchase for conversion to methamphetamine because it is replaced by the prodrug. The prodrug would be more difficult than pseudoephedrine and ephedrine to convert to methamphetamine, thus decreasing the availability of the drug and discouraging clandestine manufacture. Thus, it may have a substantial impact upon the STLs whose operators are unsophisticated in chemical methods, and reduce the hazard and environmental disaster associated with these labs. It may also provide a substantial barrier to the operators of super-labs. At the same time, because it is a prodrug instead of a different active altogether, it may still provide the relief characteristic of pseudoephedrine or ephedrine to mammals in need of that relief.

Manufacturing a prodrug of ephedrine or pseudoephedrine to replace ephedrine or

pseudoephedrine includes manufacturing the prodrug in any situation where pseudoephrine or ephedrine might be manufactured for a similar purpose. For example, in some embodiments, the prodrug would be manufactured for use in treating a mammal, including a human being, where pseudoephedrine or ephedrine might be used to treat that mammal.

Selling a prodrug of ephedrine or pseudoephedrine to replace ephedrine or pseudoephedrine includes selling the prodrug in any situation where pseudoephrine or ephedrine might also be sold for a similar purpose. For example, in some embodiments, the prodrug would be sold for use in treating a mammal, including a human being, where pseudoephedrine or ephedrine might be used to treat that mammal.

Transporting a prodrug of ephedrine or pseudoephedrine to replace ephedrine or

pseudoephedrine includes transporting the prodrug in any situation where pseudoephrine or ephedrine might also be transported for a similar purpose. For example, the prodrug would be transported to a location for use in treating a mammal, including a human being, where pseudoephedrine or ephedrine might be used to treat that mammal.

Storing a prodrug of ephedrine or pseudoephedrine to replace ephedrine or pseudoephedrine includes storing the prodrug in any situation where pseudoephrine or ephedrine might also be stored for a similar purpose. For example, the prodrug would be stored in a location for use in treating a mammal, including a human being, where pseudoephedrine or ephedrine might be used to treat that mammal.

Administering a prodrug of ephedrine or pseudoephedrine to replace ephedrine or

pseudoephedrine includes administering the prodrug in any situation where pseudoephrine or ephedrine might also be administered for a similar purpose. For example, the prodrug would be administered to a mammal, including a human being, where pseudoephedrine or ephedrine might be administered to treat that mammal. The more ephedrine or pseudoephedrine that is replaced by a prodrug, the more clandestine methamphetamine synthesis may be prevented. The ephedrine or pseudoephedrine replaced may be in a single composition or several different compositions, such as in a powder form; or in one or more units of at least one dosage form. Thus, some embodiments include a composition or several different compositions, or multiple units of a dosage form, comprising a prodrug of ephedrine or

pseudoephedrine. The composition, compositions, or dosage forms comprising the prodrug may be manufactured, sold, transported, or stored to replace ephedrine or pseudoephedrine. In these embodiments, the amount of the prodrug may be at least about 1 g, about 100 g, about 1 kg, or about 10 kg, up to about 1 ,000 kg, about 10,000 kg, about 100,000 kg, or about 1 ,000,000 kg of a prodrug of ephedrine or pseudoephedrine

Dosage forms may be provided for administration of the prodrug to a mammal, including a human being, such as a human being to treat a condition normally treated by ephedrine or pseudoephedrine.

The dosage forms may comprise any therapeutically effective amount of the prodrug. In some embodiments the dosage form comprises at least about 0.00003 moles, about 0.00006 moles, about

0.00009 moles, about 0.0002 moles, about 0.0004 moles, about 0.0007 moles, up to about 0.002 moles or about 0.007 moles.

The term "prodrug" has the ordinary meaning known to one of ordinary skill in the art. In some embodiments, a prodrug includes a compound which is converted to a therapeutically active compound after administration to a mammal such as a human being. For example, conversion may occur by hydrolysis of an ester group or some other biologically labile group. Prodrug preparation is well known in the art. For example, "Prodrugs and Drug Delivery Systems," which is a chapter in Richard B.

Silverman, Organic Chemistry of Drug Design and Drug Action, 2d Ed., Elsevier Academic Press:

Amsterdam, 2004, pp. 496-557, provides further detail on the subject.

In some embodiments, the prodrug may comprise a derivative of the benzylic hydroxide of ephedrine or pseudoephedrine. In some embodiments, the prodrug may be an ester of the benzylic hydroxide of ephedrine or pseudoephedrine. In some embodiments, the prodrug may be a stable compound having one of the formulas:

wherein X is a single bond, CO, C0₂₎ CON, S, P0₃, S0₂NH, CH₂0, CH2OCO, or C2H4OCO2,

R is H, or a moiety having from 0 to 30 carbon atoms, from 4 to 30 carbon atoms, or from 10 to 30 carbon atoms, and from 0 to 30 heteroatoms, 0 to 20 heteroatoms, 0 to 10 heteroatoms, or 0 to 5 heteroatoms selected from N, O, S, F, CI, I, Br, P, and combinations thereof, provided that at least 1 atom selected from C, N, O, or S is present.

Unless otherwise indicated, when a chemical structural feature such as phenyl is referred to as being "optionally substituted," it is meant that the feature may have no substituents (i.e. be unsubstituted) or may have one or more substituents. A feature that is "substituted" has one or more substituents. The term "substituent" has the ordinary meaning known to one of ordinary skill in the art. In some embodiments, the substituent is an ordinary organic moiety known in the art, which may have a molecular weight (e.g. the sum of the atomic masses of the atoms of the substituent) of: at least about 14 g/mol, less than about 500 g/mol, about 300 g/mol, about 200 g/mol, about 100 g/mol, and/or about 50 g/mol. In some embodiments, the substituent comprises: about 0-30, about 0-20, about 0-10, or about 0-5 carbon atoms; and about 0-30, about 0-20, about 0-10, or about 0-5 heteroatoms independently selected from: N, O, S, P, Si, F, CI, Br, I, and combinations thereof; provided that the substituent comprises at least one atom selected from: C, N, O, S, P, Si, F, CI, Br, and I. Examples of substituents include, but are not limited to, alkyl, alkenyl, alkynyl, carbazolyl, aryl, diarylamino, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxy, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O- carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, suifinyl, sulfonyl, haloalkyl, haloalkoxyl, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof.

In some embodiments, a stable compound includes a compound which is sufficiently stable to store under a normal atmosphere for at least 24 hours at room temperature.

Unless otherwise indicated, reference to a compound should be construed broadly to include pharmaceutically acceptable salts, tautomers, alternate solid forms, non-covalent complexes, and combinations thereof, of a chemical entity of the depicted structure or chemical name.

A pharmaceutically acceptable salt includes any salt of the parent compound that is suitable for administration to an animal or human. A pharmaceutically acceptable salt also refers to any salt which may form in vivo as a result of administration of an acid, another salt, or a prodrug which is converted into an acid or salt. A salt comprises one or more ionic forms of the compound, such as a conjugate acid or base, associated with one or more corresponding counter-ions. Salts can form from or incorporate one or more deprotonated acidic groups (e.g. carboxylic acids), one or more protonated basic groups (e.g. amines), or both (e.g. zwitterions).

Tautomers include isomers that are in rapid equilibrium with one another. For example, tautomers may be related by transfer of a proton, hydrogen atom, or hydride ion.

A structure is intended to include every possible stereoisomer, both pure or in any possible mixture.

Alternate solid forms include different solid forms than those that may result from practicing the procedures described herein. For example, alternate solid forms may be polymorphs, different kinds of amorphous solid forms, glasses, and the like.

Non-covalent complexes include complexes that may form between the compound and one or more additional chemical species that do not involve a covalent bonding interaction between the compound and the additional chemical species. They may or may not have a specific ratio between the compound and the additional chemical species. Examples might include solvates, hydrates, charge transfer complexes, and the like.

Generally these, compounds may be prepared by combining the corresponding acyl chloride or carboxylic acid anhydride with ephedrine or pseudoephedrine, possibly in the presence of a base. They also may be prepared from an ester such as the methyl or ethyl ester by transesterification. These kinds of reactions are well known in the art. For example, see Smith and March, March's Organic Chemistry: Reactions, Mechanisms, and Structure, 5^th Ed., New York: John Wiley & Sons, Inc., pp. 482-492, and 523-524.

A prodrug leaving group is the compound that would result if only the bond between pseudoephedrine and the remaining part of the molecule were hydrolyzed. Thus, in the structure above, the prodrug leaving group is RCO2H.

In some embodiments, R is hydrocarbyl having from 1 to 24 carbo i atoms.

Hydrocarbyl includes compounds having only carbon and hydrogen.

In some embodiments, R is alkyl having from 1 to 12 carbon atoms, such as methyl (CH3); ethyl (C2H5); propyl isomers (C3H7) such as propyl, isopropyl, etc.; cyclopropyl, (C3H6); butyl isomers (C4H9); cyclobutyl isomers (C4H8) such as cyclobutyl, methylcyclopropyl, etc.; pentyl isomers (C5H11); cyclopentyl isomers (C5H10); hexyl isomers (C6H13); cyclohexyl isomers (C6H12); heptyl isomers (C7H13); cycloheptyl isomers (C7H14); octyl isomers (C8H17); cyclooctyl isomers (CeHi6); nonyl isomers (C9H17); cyclononyl isomers (CgHis); decyl isomers (C10H21); cyclodecyl isomer (C10H20); undecyl isomers (C11H23); cycloundecyl isomers (C11H22); dodecyl isomers (C12H25); cyclododecyl isomers (C12H24); etc.

In some embodiments, -X-R may be one of the moieties shown below:



11

















20

21

With respect to any relevant structural feature depicted or otherwise identified herein, R^a may be H; C1-12 alkyl such as methyl (CH3); ethyl (C2H5); propyl isomers (C3H7) such as propyl, isopropyl, etc.; cyclopropyl, (C3H6); butyl isomers (C4H9); cyclobutyl isomers (C4H8) such as cyclobutyl, methylcyclopropyl, etc.; pentyl isomers (C5H11); cyclopentyl isomers (C5H10); hexyl isomers (G6H13); cyclohexyl isomers (C6H12); heptyl isomers (C7H13); cycloheptyl isomers (C7H14); octyl isomers (CsHi₇); cyclooctyl isomers (CeHie); nonyl isomers (C9H17); cyclononyl isomers (CgHia); decyl isomers (C10H21); cyclodecyl isomer (dohko); undecyl isomers (C11H23); cycloundecyl isomers (C11H22); dodecyl isomers (C12H25); cyclododecyl isomers (C12H24); or optionally substituted phenyl, such as unsubstituted phenyl, or phenyl substituted with 1, 2, or 3 substituents selected from: C1-3 alkyl (such as methyl, ethyl, propyl, isopropyl, cyclopropyl, etc.), OH, OCH₃, OC2H5, OC3H7, NH₂, NHCH_3l N(CH₃)₂, OCOCH3, C0₂H, CO2CH3, CO2C2H5, etc. In some embodiments, R^a may be H, CH₃, CH2CH3, C(CH₃)_2l C₄H₉, or unsubstituted phenyl.

With respect to any relevant structural feature depicted or otherwise identified herein, R^b may be H; C1-12 alkyl such as methyl (CH3); ethyl (C2H5); propyl isomers (C3H7) such as propyl, isopropyl, etc.; cyclopropyl, (C3H6); butyl isomers (C4H9); cyclobutyl isomers (C4H8) such as cyclobutyl, methylcyclopropyl, etc.; pentyl isomers (C5H11); cyclopentyl isomers (C5H10); hexyl isomers (C6H13); cyclohexyl isomers (C6H12); heptyl isomers (C7H13); cycloheptyl isomers (C7H14); octyl isomers (C8H17); cyclooctyl isomers (C₈Hi6); nonyl isomers (C9H17); cyclononyl isomers (C9H18); decyl isomers (C10H21); cyclodecyl isomer (C10H20); undecyl isomers (C11H23); cycloundecyl isomers (C11H22); dodecyl isomers (C12H25); cyclododecyl isomers (C12H24); or optionally substituted phenyl, such as unsubstituted phenyl, or phenyl substituted with 1 , 2, or 3 substituents selected from: C1-3 alkyl (such as methyl, ethyl, propyl, isopropyl, cyclopropyl, etc.), OH, OCH₃, OC2H5, OC3H7, NH₂, NHCH3, N(CH₃)₂, OCOCH3, C0₂H, CO2CH3, CO2C2H5, etc. In some embodiments, R^b may be H, CH₃, CH2CH3, C(CH₃)₂, C4H9, or unsubstituted phenyl. With respect to any relevant structural feature depicted or otherwise identified herein, R^c may be H; C1-12 alkyl such as methyl (CH3); ethyl (C2H5); propyl isomers (C3H7) such as propyl, isopropyl, etc.; cyclopropyl, (C3H6); butyl isomers (C₄Hg); cyclobutyl isomers (C₄H₈) such as cyclobutyl, methylcyclopropyl, etc.; pentyl isomers (C5H11); cyclopentyl isomers (C5H10); hexyl isomers (C6H13); cyclohexyl isomers (C6H12); heptyl isomers (C7H13); cycloheptyl isomers (C7H14); octyl isomers (C₈Hi7); cyclooctyl isomers (C₈Hi6); nonyl isomers (C9H17); cyclononyl isomers (CgHis); decyl isomers (C10H21); cyclodecyl isomer (CioH2o); undecyl isomers (C11H23); cycloundecyl isomers (C11H22); dodecyl isomers (C12H25); cyclododecyl isomers (C12H24); or optionally substituted phenyl, such as unsubstituted phenyl, or phenyl substituted with 1 , 2, or 3 substituents selected from: C1-3 alkyl (such as methyl, ethyl, propyl, isopropyl, cyclopropyl, etc.), OH, OCH₃, OC2H5, OC₃H₇, NH₂, NHCH3, N(CH₃)₂, OCOCHs, CO2H, CO2CH3, CO2C2H5, etc. In some embodiments, R^c may be H, CH₃, CH2CH3, C(CH₃)2, C4H9, or unsubstituted phenyl.

With respect to any relevant structural feature depicted or otherwise identified herein, R^d may be H; C1-12 alkyl such as methyl (CH3); ethyl (C2H5); propyl isomers (C3H7) such as propyl, isopropyl, etc.; cyclopropyl, (C3H6); butyl isomers (C4Hg); cyclobutyl isomers (C4H8) such as cyclobutyl, methylcyclopropyl, etc.; pentyl isomers (C5H11); cyclopentyl isomers (C5H10); hexyl isomers (C6H13); cyclohexyl isomers (C6H12); heptyl isomers (C7H13); cycloheptyl isomers (C7H14); octyl isomers (C₈Hi₇); cyclooctyl isomers (C₈Hi6); nonyl isomers (C9H17); cyclononyl isomers (CgHie); decyl isomers (C10H21); cyclodecyl isomer (Ci₀H2o); undecyl isomers (C11H23); cycloundecyl isomers (C11H22); dodecyl isomers (C12H25); cyclododecyl isomers (C12H24); or optionally substituted phenyl, such as unsubstituted phenyl, or phenyl substituted with 1 , 2, or 3 substituents selected from: C1-3 alkyl (such as methyl, ethyl, propyl, isopropyl, cyclopropyl, etc.), OH, OCH₃, OC₂H₅, OC₃H_7l NH₂, NHCH3, N(CH₃)₂, OCOCH3, C0₂H, COH, CO2CH3, CO2C2H5, NO2, etc. In some embodiments, R^d may be H, CH₃, CH2CH3, C(CH₃)2, C4H9, or unsubstituted phenyl.

With respect to any relevant structural feature depicted or otherwise identified herein, a may be 0, 1 , 3, 4, 5, or 6.

With respect to any relevant structural feature depicted or otherwise identified herein, A¹ may be a bond, CO, or C0₂.

With respect to any relevant structural feature depicted or otherwise identified herein, A² may be O, S, or R^a

With respect to any relevant structural feature depicted or otherwise identified herein, A³ may be a bond, CO, or C0₂. With respect to any relevant structural feature depicted or otherwise identmea nerein, may be a bond, CO, or C0₂.

In some embodiments, the prodrug leaving group, or RCO2H is a fatty acid. Fatty acids include linear carboxylic acids which have an even number of carbon atoms. Examples include, but are not limited to:

Saturated fatty acids, which have no C=C moieties and include, but are not limited to, myristic acid, palmitic acid, stearic acid, arachidic acid, and behenic acid.

• unsaturated fatty acids, including, but are not limited to, the following:

• monounsaturated fatty acids, which have one C=C group such as palmitoleic acid and oleic acid;

• diunsaturated fatty acids, which have two C=C groups, such as linoleic acid;

• triiunsaturated fatty acids, which have three C=C groups, such as a-linolenic acid and γ- linolenic acid;

• tetraunsaturated fatty acids, which have four C=C groups/such as arachidonic acid; and

• pentaunsaturated fatty acids, which have five C=C groups, such as eicosapentaenoic acid.

• Some fatty acids have 14 carbon atoms such as myristic acid.

• Some fatty acids have 16 carbon atoms such as palmitic and palmitoleic acid.

• Some fatty acids have 18 carbon atoms such as stearic acid, oleic acid, linoleic acid, a- linolenic a, and γ-linolenic acid.

• Some fatty acids have 20 carbon atoms such as eicosapentaenoic acid.

It is believed that these compounds may not readily be converted to methamphetamine by either the P/HI method or by the "Nazi method." It is also believed that an attempt at saponification of these compounds followed by an attempt at reducing the resulting hydroxyl method will provide very low yields of methamphetamine with a large quantity of impurities, making isolation of a drug which provides a satisfactory result to the end user difficult.

In some embodiments, RCO2H is an amino acid, such as glycine, alanine, valine, leucine, isoleucine, methionine, proline, phenylalanine, tryptophan, serine, threonine, asparagine, glutamine, tyrosine, cysteine, lysine, arginine, histidine, aspartic acid, glutamic acid, or a salt, ester, amide, carbonate or carbamate of an amino acid.

To further complicate the reaction by the P/l method, a moiety which further interferes with the reaction may be added. One such moiety is a ketone. Since iodine is formed in situ in the presence of acid in this method of amphetamine synthesis, the a-carbon of a ketone may react to form an a- iodoketone. Thus, this side reaction may further interfere with preparation of methamphetamine. Another moiety which may interfere with both the P/l method and the Nazi method is hydroxyl (-OH). In particular benzylic hydroxyl may be especially problematic because of its similarity to the hydroxyl of ephedrine or pseudoephedrine to be reduced. Polyol moieties, such as those from sugars or other carbohydrates may also interfere with the reduction.

Another moiety which may interfere with the Nazi method is phenyl or aryl. Phenyl or aryi with an electronic withdrawing substituent may be particularly problematic for a clandestine manufacturer.

In some embodiments, R is has from 1 to 24 carbon atoms and from 1 to 24 oxygen atoms. In some embodiments, each oxygen atom is part of a hydroxyl, keto (C=0), acetal, hemiacetal, ketal, hemiketal, or an ester moiety.

An acetal moiety includes:

where R¹ and R² are independently hydrocarbyl.

A hemiacetal moiety includes:

wherein R¹ is hydrocarbyl.

ketal moiety includes:

where R¹ and R² are independently hydrocarbyl.

A hemiketal moiety includes

wherein R¹ is hydrocarbyl.

An ester moiety is -CO2-, where both the carbon and the saturated oxygen atom are directly attached to carbon atoms.

Useful examples of R include: [a] hydroxymethyl substituted phenyl, such as hydroxymethylphenyl,

di(hydroxymethyl)phenyl, tri(hydroxymethyl)phenyl, tetra(hydroxymethyl)phenyl, and penta(hydroxymethyl)phenyl;

[b] other benzylic alcohols such as 1-hydroxyethylphenyl, 1-hydroxypropylphenyl, and the like, and di-, tri-, tetra-, and penta-subsituted benzylic alcohols;

[c] phenyl with one or more keto and/or aldehyde moieties in the benzylic position;

[d] phenyl with a combination of different benzylic alcohol, keto, and/or aldehyde moieties;

[e] -(CHOH)_nCH₂OH, wherein n is from 0 to 23;

[f] -(CHOH)_n(C=0)H, wherein n is from 0 to 23;

[g] -(CHOH)n(C=0)(CHOH)_mCH₂OH, wherein n + m is from 0 to 22;

[h] phenyl, including:

[i] phenyl with one or more electron withdrawing substituents such as nitro, CN, halo, acyl, acyloxy, CF₃, CO2H, and the like;

[ii] phenyl with other substituents including:

• alkyl, such as methyl, ethyl, propyl isomers, butyl isomers, and the like;

alkoxy, such as methoxy, ethoxy, etc.;

hydroxyl;

amino, such as NH2, NH-alkyl, N(alkyl)2, etc.;

and the like.

In one embodiment the prodrug leaving group is a keto-acid or a polyketo-acid. In other words the prodrug leaving group is a carboxylic acid that has one or more ketone functional groups.

The prodrug may be modified to further interfere with methamphetamine synthesis by adding a moiety which is difficult to separate from ephedrine or pseudoephedrine during work-up of a saponification. Part of the work up procedure of methamphetamine synthesis relies on protonating the amine to make the compound water soluble, washing out impurities, and then recovering the methamphetamine by deprotonating the amine. Thus addition of an amine moiety could further complicate the separation process. In particular, the combination of an amine with one or more hydroxyl moieties could provide an impurity upon saponification that is difficult to separate and interferes with the reduction. For example, a prodrug which saponifies to form glucosamine would be useful.

Many prodrugs may be prepared by reacting an acid chloride (Cl-X-R) with pseudoephedrine or ephedrine, as shown in Scheme A. A base may be used for some reactions to help remove HCI generated during the reaction. In some embodiments, the hydrochloride salt of tne amine group may be reacted with the acid chloride.

Scheme A

Dicarboxylic acid ester prodrugs may be prepared by reacting a dicarboxylic acid anhydride with pseudoephedrine or ephedrine. Scheme B illustrates an example that may be generalized to many other dicarboxylic acids.

Scheme B

Some dicarboxylic acid diester prodrugs may be prepared by reaction with an acyl chloride ester. The acyl chloride ester may be prepared by reacting a dicarboxylic acid anhydride with an alcohol, followed by reaction with thionyl chloride or oxallyl chloride. Scheme C illustrates an example

thionyl chloride

or oxallyl chloride

Scheme C

Some carbamate protected amino acid based ester prodrugs may be prepared by reacting the amino acid with excess phosgene, possibly in the presence of a base, followed by an alcohol such as R^aOH. Reaction with water under mild conditions may free the carboxylic acids by hydrolysis, which may be converted to the acyl chloride using oxallyl chloride or another similar reagent. I his protected amino acid chloride may then be reacted with ephedrine or pseudoephedrine. Scheme D shoes an example that may be generalized to many compounds.

Scheme D

Some amide protected amino acid based ester prodrugs may be prepared in a manner similar to the carbamates. Excess acyl chloride is reacted with the amino acids and the acid anhydrides are hydrolyzed. The resulting protected amino acids may be converted to the amino acid acyl chloride using oxallyl chloride or another similar reagent. This protected amino acid chloride may then be reacted with ephedrine or pseudoephedrine. Scheme E shoes an example that may be generalized to many compounds.

Scheme E In any of schemes A-E, the amine of pseudoephedrine or ephedrine may be protected. For example, the compound below may be used in place of pseudoephedrine or ephedrine to obtain an N- protected prodrug.

One useful prodrug is depicted below. There are several ways it may be prepared. One method would to convert acetylsalicylic acid, i.e. aspirin, to the corresponding acyl chloride, and reacting with ephedrine or pseudoephedrine by methods known in the art, as shown in Scheme 1 below.

Scheme 1

Another useful prodrug is an ester of an aldonic acid, such as the compound depicted below.

Examples include, but are not limited to: glyceronic acid, erythronic acid, threonic acid, ribonic acid, arabinonic acid, xylonic acid, lyxonic acid, allonic acid, altronic acid, gluconic acid, mannonic acid, gulonic acid, idonic acid, galactonic acid, talonic acid, and the like.

These compounds may be prepared by a number of methods. For example, the hydroxyl groups of a sugar with a terminal aldehyde could be protected, the aldehyde could then be oxidized to a carboxylic acid, the acid converted to an anhydride or a acyl chloride, and the protecting groups removed, as shown in Scheme 2 below.

PG: protecting group

Scheme 2

The same basic idea could be extended to a number of different sugar related acids such as those derived from disaccharides and polysaccharides having a terminal aldehyde, or an acetal or hemiacetal moiety that may be converted to a carboxylic acid. Other sugar related acids that might be used include uronic acids, such as glucuronic acid, glacturonic acid, mannuronic acid; ascorbic acid; ribose, deoxyribose, fucose, and the like.

Sugar derivatives having other functionalities, such as amino sugars, might also be used in mine, is typical.

There are a number of ways these compounds could be prepared. Scheme 3 illustrates one method that might be used. The protected glucosamine is prepared as described in WO 03/022860. This compound is reacted with succinic anhydride to form the succinic acid ester shown. This is then converted to the acyl chloride and reacted with ephedrine or pseudoephedrine to give the protected product. The protected product is deprotected with ethylene diamine, followed by TFA or tosic acid as described in WO 03/022860.

Scheme 3

These sugar-derived prodrugs may be further modified by addition of a phenyl moiety. For example, benzoic acid could be added to one of the hydroxyl groups to form esters such as those shown below. The phenyl group may further interfere with methamphetamine synthesis, particularly by olving metal conditions.

In some embodiments, the prodrug leaving group comprises a phenyl ring comprising one or more substituents having a benzylic hydroxyl moiety and an amine moiety. The benzylic hydroxyl and the amine may be on the same substituent, or they may be on different substituents. In some embodiments, the benzylic hydroxyl moiety may be in the form of an ester which is formed by a linker, such as a dicarboxylic acid ester linker, which connects to the benzylic oxygen of pseudoephedrine or ephedrine. For example, some prodrugs may be compounds represented by one ot the fallowing formulas:

With respect to any relevant structural feature depicted or otherwise identified herein, R¹ may be hydrocarbyl, such as C1-12 hydrocarbyl, including -CH2-, -CH2CH2-, -CH=CH-, -C≡C-, -CH2CH2CH2- , -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, etc.; or optionally substituted aryl, such as substituted or unsubstituted phenyl. In some embodiments, the aryl or phenyl may have 0, 1 , 2, 3, or 4 substituents independently selected from: Ci-s alkyl, such as methyl, ethyl, propyl isomers, cyclopropyl, butyl isomers, cyclobutyl isomers (such as cyclobutyl, methylcyclopropyl, etc.), pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.; Ci-6 alkoxy, such as methoxy, ethoxy, propoxy isomers (e.g. isopropoxy, n-propoxyl, etc.), cyclopropoxy, butoxy isomers, cyclobutoxy isomers (such as cyclobutoxy, methylcyclobutoxy, etc.), pentoxy isomers, cyclopentoxy isomers, hexoxy isomers, cyclohexoxy isomers, etc.; Ci-s acyl such as formyl, acetyl, propionoyl butyryl, isobutyryl, cyclopropanecarbonyl, pentanoyl isomers (such as pentanoyl, methylbutanoyl, pivaloyl, etc.), cyclobutanecarbonyl isomers (such as methylcyclopropane carbonyl,

cyclobutanecarbonyl, etc.), hexanoyl isomers, cyclopentanecarbonyl isomers, etc.; C1-6 acyloxy such as formyloxy (e.g. -OC(O)H), acetyloxy, propionoyloxy butyryloxy, isobutyryloxy,

cyclopropanecarbonyloxy, pentanoyloxy isomers (such as pentanoyloxy, methylbutanoyloxy, pivaloyloxy, etc.), cyclobutanecarbonyloxy isomers (such as methylcyclopropanecarbony!oxy, cyclobutanecarbonyloxy, etc.), hexanoyloxy isomers, cyclopentanecarbonyloxy isomers, etc.; G2-6 alkyl carboxylate such as methyl carboxylate (e.g. CO2CH3), ethyl carboxylate, propyl carboxylate, isopropyl carboxylate, cyclopropyl carboxylate, butyl carboxylate isomers (such as butyl carboxylate, isobutyl carboxylate, etc.), cyclobutyl carboxylate isomers (such as cyclobutyl carboxylate, methylcyclopropyl carboxylate, etc.), pentyl carboxylate isomers, cyclopentyl carboxylate isomers, etc.; C1-6 -N-amides such as -NH-formyl, -NH-acetyl, -NH-propionoyl -NH-butyryl, -NH-isobutyryl, -NH- cyclopropanecarbonyl, -NH-pentanoyl isomers (such as -NH-pentanoyl, -NH-methylbutanoyl, -NH- pivaloyl, etc.), -NH-cyclobutanecarbonyl isomers (such as -NH-methylcyclopropane carbonyl, -NH- cyclobutanecarbonyl, etc.), -NH-hexanoyl isomers, -NH-cyclopentanecarbonyl isomers, -N(CH₃)- formyl, -N(CH₃)-acetyl, -N(CH₃)-propionoyl, -N(CH₃)-butyryl, -N(CH₃)-isobutyryl, -N(CH₃)- cyclopropanecarbonyl, _-N(CH₃)-pentanoyl isomers (such as -N(CH₃)-pentanoyl, -N(CH₃)- methylbutanoyl, -N(CH₃)-pivaloyl, etc.), -N(CH3)-cyclobutanecarbonyl isomers (such as -N(CH₃)- methylcyclopropane carbonyl, -N(CH₃)-cyclobutanecarbonyl, etc.), -N(CH2CH₃)-formyl, -N(CH2CH₃)- acetyl, -N(CH₂CH₃)-propionoyl, -N(CH₂CH₃)-butyryl, -N(CH₂CH₃)-isobutyryl, -N(CH₂CH₃)- cyclopropanecarbonyl, etc.; F; CI; Br; I; nitro; CN, and the like.

With respect to any relevant structural feature depicted or otherwise identified herein, R² may be H, or a moiety having from 0 to 20 carbon atoms, from 1 to 10 carbon atoms, or from 1 to 3 carbon atoms, and from 0 to 20 heteroatoms, 0 to 10 heteroatoms, 0 to 5 heteroatoms, or 0 to 3 heteroatoms selected from N, O, S, F, CI, I, Br, P, and combinations thereof, provided that at least 1 atom selected from C, N, 0, or S is present. In some embodiments, R² is an alkyi amine, e.g. -R³-NR⁴R⁵, wherein R³ is Ci-6 alkyi, and R⁴ and R⁵ are independently H or Ci-6 alkyi.

With respect to any relevant structural feature depicted or otherwise identified herein, Ph may be optionally substituted phenyl, including phenyl with 0, 1 , 2, 3, 4, or 5 substituents such as those substituents mentioned anywhere above with respect to a phenyl. In some embodiments, if R² is not an alkyi amine, then Ph has an alkyi amine substituent. These may be prepared by adapting methods described above or other methods well known in the art.

Some useful prodrugs may include:

The compounds depicted below are specifically contemplated for use herein. They may be prepared by methods known in the art, for example the following documents describe procedures which may be used to prepare one or more of these compounds: EP0313885; Auvinen, Acta

Pharmaceutica Fennica 87, 37-42 (1978); Marvola, Acta Pharmacol, et. toxicol. 1976, 38, 474-489; Marvola, Acta Pharmacol, et. toxicol. 1977, 40, 22-32; Trepanier, J. Med. Chem. 1973, 16, 342; Welsh, J. Am. Chem. Soc. 69, 128; Pfanz, Arch Pharm 1955, 288:65-72; Welsh, J. Org. Chem. 32, 119; and Fodor, J. Org. Chem. 14, 337.





40

42

43

In some embodiments, the prodrug may further be combined with excipients to interfere with the reduction, or a saponification or other ester hydrolysis, or both. For example, an buffer may be added to make hydrolysis of the ester more problematic.

Some embodiments provide a method of inhibiting clandestine methamphetamine synthesis comprising treating a cold, allergy, congestion, hypotension, narcolepsy, urinary incontinence or bedwetting by administering a therapeutically effective amount of a prodrug of ephedrine or pseudoephedrine to a patient in need thereof.

In some embodiments, a prodrug of ephedrine is used to treat a cold, allergy, congestion, hypotension, narcolepsy, urinary incontinence or bedwetting. In some embodiments, a prodrug of ephedrine is used to treat a cold, allergy, congestion, urinary incontinence or bedwetting.

For the purposes of this disclosure, "treat," "treating," or "treatment" includes the use of a compound, composition, therapeutically active agent, or drug in the diagnosis, cure, mitigation, treatment, or prevention of disease or other undesirable condition.

Although any prodrug is believed to be useful in the disclosed methods, compositions, and dosage forms disclosed herein, a prodrug is easily tested to optimize the difficulty in conversion of the prodrug to methamphetamine. This can be done by a variety of approaches. First, the prodrug could be tested by carrying out one of the many known clandestine methamphetamine preparation methods to determine the yield of methamphetamine, if any, made directly from the prodrug. Second, the prodrug could be tested by carrying out one of many known hydrolysis procedures on the prodrug to determine the yield of methamphetamine recovered, and/or the product of the hydrolysis procedure could be subjected to the clandestine methamphetamine preparation method to determine the yield of methamphetamine for the combined process

Thus, some embodiments provide a method of evaluating the difficulty of converting a prodrug of pseudoephedrine or ephedrine to methamphetamine comprising:

a. determining the yield of methamphetamine obtained by performing a reduction

procedure on the prodrug,

b. determining the yield of pseudoephedrine or ephedrine obtained by performing a recovery procedure on the prodrug, or

c. determining the yield of methamphetamine obtained by performing a recovery

procedure on the prodrug and a reduction procedure on the product of the recovery procedure.

This method may be practiced by determining the yield of the methamphetamine, pseudoephdrine or ephedrine without performing the reduction or recovery procedure. Thus, for example an individual who determines the yield of a reduction or a recovery procedure performed by another is practicing the method.

A reduction procedure is any method known to be useful to convert pseudoephedrine or ephedrine to methamphetamine. Examples include various forms of the Nazi method or the P/l reduction method. A recovery procedure is any method known to be useful to convert a prodrug to a parent drug outside of the body. For example, acid or base catalyzed ester hydrolysis are recovery procedures.

The product of the recovery procedure is the material that results from the recovery procedure which may or may not contain ephedrine or pseudoephedrine.

Determining the yield of methamphetamine means to determine how much amphetamine resulted from a process as compared to how much of a precursor material was used or how much amphetamine was expected to result from a process.

In some embodiments, the reduction procedure is a dissolving metal reduction. In other embodiments, the reduction procedure involves phosphorous and iodine. In some embodiments, the recovery procedure is base-catalyzed hydrolysis of an ester. In other embodiments, the recovery procedure is acid-catalyzed hydrolysis of an ester.

Example 1 A chemical manufacturer in Mexico prepares a prodrug of ephedrine for shipment to the United

States for medicinal use. While a 10,000 kg shipment is being made, criminals hijack the truck and smuggle it into the United States. A super-lab purchases the prodrug from the criminals, and attempts to convert the prodrug to methamphetamine. The resulting product produces no high, and the operators of the super-lab are unable to sell the product.

Example 2

A large pharmaceutical manufacturer stores 100,000 kg of a prodrug of pseudoephedrine in a large warehouse for use in preparing dosage forms. Criminals break in and steal 1 ,000 kg of the prodrug and sell it to a super-lab in Arizona. The super-lab is unable to produce any useful product.

Example 3

A pharmaceutical company introduces a commercial prodrug of pseudoephedrine to the market. Because the prodrug is now available, the Federal government bans all over-the-counter sales of pseudoephedrine, and severely restricts prescription sales of pseudoephedrine. The prodrug is used effectively by consumers to treat their cold symptoms. An operator of an STL purchases 100 g of the prodrug intending to make methamphetamine for personal use and small-scale sales. She runs a small batch using the Nazi method and tests part of on herself. After half an hour, she realizes that she is not experiencing any high and exclaims "this stuff is no good." Frustrated, she tosses the product into the garbage and attempts to run a small batch using the P/l method. She again samples the product and experiences no high. Unable to obtain any decent methamphetamine, she checks herself into rehab and discontinues use of methamphetamine.

Claims

CLAIMS What is claimed is:

1. A commercial dosage form comprising a therapeutically effective amount of a prodrug of ephedrine or pseudoephedrine.

2. The dosage form of claim 1 which comprises a prodrug of pseudoephedrine.

3. The dosage form of claim 1 which comprises a prodrug of ephedrine.

4. The dosage form of claim 1 which comprises from about 0.00003 moles to about 0.02 moles of said prodrug.

5. The dosage form of claim 1 which comprises from about 0.00009 moles to about 0.002 moles of said prodrug.

6. A method of inhibiting methamphetamine synthesis comprising manufacturing, selling, transporting, or storing a prodrug of ephedrine or pseudoephedrine to replace ephedrine or pseudoephedrine.

7. The method of claim 6, wherein the quantity of ephedrine or pseudoephedrine replaced is greater than about 1 g.

8. The method of claim 7, wherein the quantity of ephedrine or pseudoephedrine replaced is from about 1 g to about 100,000,000 kg.

9. The method of claim 8 wherein the quantity of ephedrine or pseudoephedrine replaced is from about 10 g to about 100,000 kg.

10. A composition comprising a prodrug of ephedrine or pseudoephedrine in a quantity of from about 1 g to about 10,000 kg.

11. The composition of claim 10 wherein the prodrug is a stable compound having the formula

wherein R is H, or a moiety consisting of:

a. from 0 to 30 carbon atoms,

b. from 0 to 91 hydrogen atoms, and c. from 0 to 30 atoms selected from: N, 0, S, F, CI, I, Br, P, and combinations thereof.

12. A method of inhibiting methamphetamine synthesis comprising treating a cold, allergy, congestion, hypotension, narcolepsy, urinary incontinence or bedwetting by administering a therapeutically effective amount of a prodrug of ephedrine or pseudoephednne to a patient in need thereof.

13. A method of inhibiting methamphetamine synthesis comprising manufacturing, selling, transporting, or storing a prodrug of ephedrine or pseudoephednne at a quantity of from about 1 g to about 100,000,000 kg.

14. The method of claim 12, comprising manufacturing/ selling, transporting, or storing a prodrug of ephedrine or pseudoephednne at a quantity of from about 10 g to about 100,000,000 kg.

15. A plurality of units of at least one dosage form comprising a quantity of from about 1 g to about 10,000 kg of a prodrug of ephedrine or pseudoephednne.

16. A method of evaluating the difficulty of converting a prodrug of pseudoephednne or ephedrine to methamphetamine comprising:

a. determining the yield of methamphetamine obtained by performing a reduction

procedure on the prodrug,

b. determining the yield of pseudoephednne or ephedrine obtained by performing a

recovery procedure on the prodrug, or

c. determining the yield of methamphetamine obtained by performing a recovery procedure on the prodrug and a reduction procedure on the product of the recovery procedure.

17. The method of claim 16 wherein the reduction procedure is a dissolving metal reduction.

18. The method of claim 16 wherein the reduction procedure involves phosphorous and iodine.

19. The method of claim 16 wherein the recovery procedure is base-catalyzed hydrolysis of an ester.

20. The method of claim 16 wherein the recovery procedure is acid-catalyzed hydrolysis of an ester.