BACKGROUND OF THE INVENTION Alterations in normal synaptic dopamine levels have been linked to a number of neurological disorders (Strange, 1992, In: Brain Biochemistrv and Brain Disorders, Oxford University Press, Oxford), such as hyperactivity and attention deficit disorder (ADD) in children. In addition, it is known that one of the pharmacological activities of cocaine is to inhibit presynaptic re-uptake of dopamine. Abuse of and addiction to stimulant drugs such as cocaine is a widespread societal problem. Among the reasons for the prevalence of stimulant drug abuse is a dearth of effective treatments for such abuse. Present treatments for cocaine abuse and addiction rely on abstinence of the abuser from continued cocaine use.

Cocaine induces psychic dependence, in that it induces a feeling of satisfaction in its users and a desire to repeat administration of the drug in order to produce pleasure or avoid discomfort. Cocaine uses infrequently exhibit symptoms of physical dependence. Therefore, abstinence from cocaine use does not usually produce a stereotyped drug abstinence syndrome (e. g. intense central nervous system hyperactivity, perspiration, muscle twitching, and anorexia), but may more commonly produce symptoms of lethargy or depression. Because abstinence from cocaine use does not necessarily induce a continuous craving to re-administer the drug, cocaine abusers experience periods during which reasoned thought can occur. However, the occurrence of incidents of stress, pain, or emotional turmoil, either related or non- related to cocaine abuse, can strengthen the urge to re-administer the drug, and relapse may occur, even in abusers who wish to discontinue cocaine use. If an efficacious

cocaine antagonist composition were available to such users, self-administration of the composition during a period of reasoned thought would preclude the abuser from attaining the sense of well being upon subsequent cocaine use, thereby helping the abuser to break his or her psychic dependence on the drug. Furthermore, sustained- release formulations of such cocaine antagonist compositions could be used to assist those whose psychic dependence upon cocaine is so great as to render a program of chronic self-administration impractical. Use of cocaine antagonist (s) as treatment for cocaine abusers and addicts has been suggested (Boja et al., 1992, Neuro. Report 3: 984-986; Slusher, et al., 1997, Drug and Alcohol Dependence 48: 43-50; Gatley et al., 1995, Eur. J. Pharmacol. 281: 141-149; Kitayama et al., 1992, Proc. Natl. Acad. Sci.

USA 89: 7782-7785).

Others have suggested that analogs of methylphenidate might be efficacious cocaine antagonists (e. g. Deutsch et al., 1996, J. Med. Chem. 39: 1201- 1209). However, prior investigators have been severely hampered by inability to synthesize a broad range of methylphenidate analogs, and instead have investigated only very narrow classes of such analogs, with disappointing results.

Physiologically, both methylphenidate, which has the structure 1, and cocaine, which has the structure 2, inhibit the re-uptake of dopamine, and the two compounds have similar binding affinities for the dopamine transporter (DAT). The inhibition constant, Ki, is a measure of the binding affinity of a composition for an enzyme. Ki is therefore also a measure of the suitability of the composition for

inhibiting the activity of the enzyme (i. e. the catalytic rate of an enzyme or the proportion of an enzyme bound to its normal substrate). Generally speaking, the lower the value of Ki is, the greater the ability of the composition to inhibit the activity of the enzyme is. With respect to inhibiting uptake of dopamine, the value of Ki for (-)- cocaine is 640 nanomolar and the value of Ki for d-threo-methylphenidate is 390 nanomolar.

When, as with DAT, an enzyme exhibits two activities (i. e. uptake of dopamine by DAT and binding of cocaine to DAT), a selected concentration of an inhibitor of the enzyme may inhibit one activity to a greater degree than it inhibits the other activity. The selectivity of the inhibitor for inhibiting an undesired activity (e. g. cocaine binding), relative to a desired activity (e. g. dopamine uptake) may conveniently be expressed as a ration of the Ki values corresponding to the two activities. For composition useful for attenuating the stimulatory effects of cocaine in a patient, the ratio K dopamine uptake<BR> <BR> i<BR> <BR> <BR> K cocaine binding i is preferably as high as possible. In this formula, Kicocaine binding represents the value of Ki for a composition, with respect to inhibition of the cocaine binding activity of DAT, and Kidopamine uptake represents the value of Ki for the composition, with respect to inhibition of the dopamine uptake activity of DAT.

It is not known whether methylphenidate and cocaine bind to DAT in the same manner. Froimowitz et al. proposed a pharmacophore common to methylphenidate and the cocaine analog CFT, which has the chemical structure 3.

CFT is a high affinity ligand for DAT. The p-amino ester moieties of methylphenidate and CFT are superimposed in Figure 1 (Froimowitz et al., 1995, Pharm. Res. 12: 1430- 1434). The proposed six atom pharmacophore sequence from the ammonium group through the methyl ester includes two asymmetric centers in methylphenidate and one of the four asymmetric centers in CFT.

Methylphenidate (Ritalin,TM; Ciba-Geigy Corporation, Summit, NJ) is the most commonly prescribed psychotropic medication for children in the United States. It is used primarily for the treatment of children diagnosed with ADD.

Methylphenidate is synonymous with methyl a-phenyl-2-piperidineacetate, a-phenyl- 2-piperidineacetate methyl ester, methyl phenidylacetate, and methylphenidan.

Methylphenidate is sold, in the form of the hydrochloride salt, as the product RitalinTM and its generic equivalents. A comprehensive description of the compound is found in Padmanabhan (1981, Analytical Profiles of Drug Substances, v. 10, Florey, Ed., Academic Press, New York).

Threo-methylphenidate is a mild central nervous system stimulant. The mode of action in humans is not fully understood, but presumably involves activation of the brain stem arousal system to effect stimulation of the patient. Dosing and administration information, contraindications, warnings, and precautions pertaining to administration of methylphenidate to humans is available in the art (e. g. Physician's Desk Reference @, Medical Economics Co., Inc., Montvale, NJ, 51st ed., 1997; PDRE GenericsTM, Medical Economics Co., Inc., Montvale, NJ, 2nd ed., 1996).

Methylphenidate is the treatment of choice for attention deficit disorder, and is also used in the treatment of narcolepsy, minimal cerebral dysfunction, and other conditions.

Numerous methods for synthesizing methylphenidate and for interconverting the diastereomers of methylphenidate have been described in the art (U. S. Patent No. 2,507,631 to Hartmann; U. S. Patent No. 2,835,519 to Rometsch; U. S.

Patent No. 2,957,880 to Rometsch; British Patent Nos. 788,226 and 878,167, each to Ciba Ltd.; Soviet Patent No. 466,229 to Yakhontov et al.; International Patent

Application Publication No. W09735836 of Fox et al.; International Patent Application Publication No. W09728124 of Langston et al.; Panizzon, 1944, Helv. Chim. Acta 27: 1748-1756; Naito et al., 1964, Chem. Pharm. Bull. 12: 588-590; Deutsch et al., 1996, J. Med. Chem. 39: 1201-1209 ; Earle et al., 1969, J. Chem. Soc. (C) 2093-2098).

These methods have various shortcomings, including low yield and the necessity to interconvert diastereomers of methylphenidate following synthesis. Furthermore, investigation of methylphenidate analogs has been hampered by the fact that these methods can be used to synthesize only a narrow range of analogs, such as methylphenidate analogs having ester modifications or phenyl ring substitutions.

The present invention overcomes the shortcomings of these synthetic methods, and provides methylphenidate and numerous methylphenidate analogs, including efficacious cocaine antagonists which inhibit binding of cocaine with DAT and analogs useful for treatment of various neurological disorders.

BRIEF SUMMARY OF THE INVENTION The invention relates to a compound having the formula wherein n is an integer selected from the group consisting of the integers from 0 to 7; wherein each R1 is independently selected from the group consisting of cycloaryl, Cl-C6 alkyl, Cl-C6 alkoxy, hydroxyl, C1-C6 alkanoyl, halogen, amino, Ci- C6 alkylamino, nitro, sulfo, and sulfhydryl; wherein (fca) is a fused cycloaryl group; wherein m is an integer selected from the group consisting of 0 and 1;

wherein R2 is selected from the group consisting Cl-C6 alkyl and C1-C6 alkanoyl; wherein p is an integer selected from the group consisting of 3,4,5, and 6; wherein each X is an atom independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur; wherein q is an integer selected from the group consisting of the integers from 0 to 16; and wherein each R3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, C1-C6 alkanoyl, halogen, carboxyl, C2-C6 alkanoxy, nitro, sulfo, and sulfhydryl, or wherein two of R3 are, together, an oxo group or a double bond between two adjacent X atoms.

In various embodiments of this compound, (fca) is a naphthalene group such as a 1-naphthalene group, n is 0, m is 0, p is 4, or each X is carbon. In a preferred embodiment of the compound, (fca) is a 1-naphthalene, n is 0, m is 0, p is 4, each X is carbon, q is 8, each R- is hydrogen, and Ri is selected from the group consisting of methyl and ethyl.

The invention also relates to a compound having the formula wherein n is an integer selected from the group consisting of the integers from 0 to 7;

wherein each Ri is independently selected from the group consisting of cycloaryl, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, C1-C6 alkanoyl, halogen, amino, Cl- C6 alkylamino, nitro, sulfo, and sulfhydryl; wherein (fca) is a fused cycloaryl group; wherein R2 is selected from the group consisting C1-C6 alkyl and C1-C6 alkanoyl; wherein q is an integer selected from the group consisting of the integers from 0 to 16; and wherein each R3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, C1-C6 alkanoyl, halogen, carboxyl, C2-C6 alkanoxy, nitro, sulfo, and sulfhydryl, or wherein two of R3 are, together, an oxo group or a double bond between two adjacent X atoms.

The invention further relates to a compound having the formula

wherein n is an integer selected from the group consisting of the integers from 0 to 7; wherein each Ri is independently selected from the group consisting of cycloaryl, Cl-C6 alkyl, Cl-C6 alkoxy, hydroxyl, C1-C6 alkanoyl, halogen, amino, Ci- C6 alkylamino, nitro, sulfo, and sulfhydryl;

wherein R2 is selected from the group consisting C alkyl and C1-C6 alkanoyl; wherein q is an integer selected from the group consisting of the integers from 0 to 16; and wherein each R3 is independently selected from the group consisting of hvdro en, C alkyl, alkoxy, hydroxyl, C1-C6 alkanoyl, halogen, carboxyl, C2-C6 alkanoxy, nitro, sulfo, and sulfhydryl, or wherein two of R3 are, together, an oxo group or a double bond between two adjacent X atoms.

The invention still further relates to a pharmaceutical composition comprising a compound having the formula wherein n is an integer selected from the group consisting of the integers from 0 to 7; wherein each Ri is independently selected from the group consisting of cycloaryl, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, C1-C6 alkanoyl, halogen, amino, Ci- C6 alkylamino, nitro, sulfo, and sulfhydryl; wherein (fca) is a fused cycloaryl group; wherein m is an integer selected from the group consisting of 0 and 1; wherein R2 is selected from the group consisting Ci-Cz, alkyi and C1-C6 alkanoyl; wherein p is an integer selected from the group consisting of 3,4,5, and 6; wherein each X is an atom independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur;

wherein q is an integer selected from the group consisting of the integers from 0 to 16; and wherein each R3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxvl, C1-C6 alkanoyl, halogen, carboxyl, C2-C6 alkanoxy, nitro, sulfo, and sulfhydryl, or wherein two of R3 are, together, an oxo group or a double bond between two adjacent X atoms.

The invention includes use of a compound for making a pharmaceutical composition, wherein the compound has the formula wherein n is an integer selected from the group consisting of the integers from 0 to 7; wherein each Ri is independently selected from the group consisting of cycloaryl, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, C1-C6 alkanoyl, halogen, amino, C1- C6 alkylamino, nitro, sulfo, and sulfhydryl; wherein (fca) is a fused cycloaryl group ; wherein m is an integer selected from the group consisting of 0 and 1; wherein R2 is selected from the group consisting C1-C6 alkyl and C1-C6 alkanoyl; wherein p is an integer selected from the group consisting of 3,4,5, and 6; wherein each X is an atom independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur; wherein q is an integer selected from the group consisting of the integers from 0 to 16; and

wherein each R3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, C1-C6 alkanoyl, halogen, carboxyl, alkanoxy, nitro, sulfo, and sulfhydryl, or wherein two of R3 are, together, an oxo group or a double bond between two adjacent X atoms.

The pharmaceutical composition may, for example, be one which is intended to be used for treating a dopamine re-uptake disorder, such as cocaine abuse or addiction.

The invention also relates to a method of treating a patient afflicted with a dopamine re-uptake disorder, the method comprising administering to the patient a pharmaceutical composition which comprises a compound having the formula wherein n is an integer selected from the group consisting of the integers from 0 to 7; wherein each Ri is independently selected from the group consisting of cycloaryl, Cl-C6 alkyl, C1-C6 alkoxy, hydroxyl, C1-C6 alkanoyl, halogen, amino, Cl- C6 alkylamino, nitro, sulfo, and sulfhydryl; wherein (fca) is a fused cycloaryl group; wherein m is an integer selected from the group consisting of 0 and 1; wherein R2 is selected from the group consisting Cl-C6 alkyl and C1-C6 alkanoyl; wherein p is an integer selected from the group consisting of 3,4,5, and 6; wherein each X is an atom independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur;

wherein q is an integer selected from the group consisting of the integers from 0 to 16; and wherein each R3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, C1-C6 alkanoyl, halogen, carboxyl, alkanoxy, nitro, sulfo, and sulfhydryl, or wherein two of R are, together, an oxo group or a double bond between two adjacent X atoms.

For example, the dopamine re-uptake disorder for which the patient is treated may be cocaine abuse. Administration of the pharmaceutical composition to the patient preferably comprises administering a sustained release formulation of the compound to the patient. In one embodiment, the pharmaceutical composition is administered to the patient prior to the onset of the disorder.

The invention further relates to implantable sustained release device comprising a compound having the formula wherein n is an integer selected from the group consisting of the integers from 0 to 7; wherein each Ri is independently selected from the group consisting of cycloaryl, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, C1-C6 alkanoyl, halogen, amino, Ci- C6 alkylamino, nitro, sulfo, and sulfhydryl; wherein (fca) is a fused cycloaryl group; wherein m is an integer selected from the group consisting of 0 and 1; wherein R2 is selected from the group consisting C1-C6 alkyl and C1-C6 alkanoyl;

wherein p is an integer selected from the group consisting of 3,4,5, and 6 ; wherein each X is an atom independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur; wherein q is an integer selected from the group consisting of the integers from 0 to 16; wherein each R3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, alkoxy, hydroxyl, C1-C6 alkanoyl, halogen, carboxyl, alkanoxy, nitro, sulfo, and sulfhydryl, or wherein two of R3 are, together, an oxo group or a double bond between two adjacent X atoms; and wherein the device releases a cocaine antagonizing amount of the compound for a period of at least two week following implantation of the device into a human.

The invention also includes a method of making a compound having the formula

The method comprises (i) reacting (a) a fused cycloaryl a-keto ester having the formula

wherein n is an integer selected from the group consisting of the integers from 0 to 7;

wherein each Ri is independently selected from the group consisting of cycloaryl, Cl-C6 alkyl, C1-C6 alkoxy, hydroxyl, C1-C6 alkanoyl, halogen, amino, Cl-C6 alkylamino, nitro, sulfo, and sulfhydryl; wherein (fca) is a fused cycloaryl group; wherein m is an integer selected from the group consisting of 0 and 1; and wherein R4 is selected from the group consisting C 1-C6 alkyl and C I- C6 alkanoyl; and (b) a cyclic a-methylene amine having the formula wherein p is an integer selected from the group consisting of 3, 4, 5, and 6; wherein each X is an atom independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur; wherein q is an integer selected from the group consisting of the integers from 0 to 16; and wherein each R3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, C1-C6 alkanoyl, halogen, carboxyl, C2-C6 alkanoxy, nitro, sulfo, and sulfhydryl, or wherein two of R3 are, together, an oxo group or a double bond between two adjacent X atoms; to generate an fused cycloaryl a-keto amide intermediate, (ii) reacting (a) the fused cycloaryl a-keto amide intermediate and (b) an aryl sulfonylhydrazide in the presence of (c) an acidic solution comprising a catalyzing amount of sulfuric acid, to generate a fused cycloaryl sulfonylhydrazide amide intermediate;

(iii) reacting (a) the fused cycloaryl sulfonylhydrazide amide intermediate and (b) a deprotonating agent in the presence of (c) an organic solvent, to generate a (3-lactam intermediate; and (iv) reacting (a) the p-lactam intermediate and (b) an alcohol having the formula R2-OH in an acidic solution, wherein R2 is selected from the group consisting C1-C6 alkyl and C1-C6 alkanoyl, whereby the compound is formed.

The acidic solution is preferably selected from the group consisting of an acidified ethanol solution and an acidified solution of 1,2-dimethoxyethane. The organic solvent is preferably selected from the group consisting of toluene and 1,4- dioxane. The deprotonating solution preferably comprises a tert-butoxide salt and tert- butanol.

In another aspect, the invention relates to a method of making threo- methylphenidate. This method comprises combining phenyl glyoxylic acid piperidine amide, p-toluenesulfonylhydrazide, and an acidic solution, whereby a first intermediate product comprising phenyl glyoxylic acid piperidine amide tosylhydrazone is formed; thereafter combining the first intermediate product, an organic solvent, and a deprotonating solution, whereby a second intermediate product comprising trans-l-aza- 2-oxo-3-phenyl-bicyclo [4.2.0] octane is formed; and thereafter combining the second intermediate product and an acidified methanol solution, whereby threo-methylphenidate is formed.

The invention also includes a composition comprising threo- methylphenidate, synthesized by this method.

In still another aspect, the invention relates to a method of synthesizing threo-methylphenidate. This method comprises preparing a first reaction mixture by combining a first molar amount of phenyl glyoxylic acid piperidine amide, a second molar amount of p-toluenesulfonylhydrazide, and an acidic solution and subjecting the first reaction mixture to reflux for at least about four hours, wherein the second molar amount is at least equal to the first molar amount, and wherein the acidic solution comprises ethanol and at least a catalyzing amount of sulfuric acid, whereby a first intermediate product comprising phenyl glyoxylic acid piperidine amide tosylhydrazone is formed in the first reaction mixture; thereafter separating the first intermediate product from the first reaction mixture; thereafter preparing a second reaction mixture by combining the first intermediate product, toluene, and a deprotonating solution and subjecting the second reaction mixture to reflux for at least about ninety minutes, wherein the deprotonating solution comprises potassium tert-butoxide and tert-butanol, whereby a second intermediate product comprising trans-1-aza-2-oxo-3-phenyl-bicyclo [4.2.0] octane is formed in the second reaction mixture; thereafter mixing the second reaction mixture with a composition comprising water to form a separation mixture having an aqueous phase and an organic phase which comprises the second intermediate product; thereafter separating the organic phase from the aqueous phase; thereafter preparing a precipitation mixture by combining the organic phase with diethyl ether and light petroleum ether, whereby the second intermediate product precipitates in the precipitation mixture; thereafter separating the second intermediate product from the precipitation mixture; and thereafter preparing a third reaction mixture by combining the second intermediate product and a methanolating solution and subjecting the third reaction mixture to reflux for at least about thirty minutes, wherein the methanolating solution

comprises methanol and HCl at a concentration which is about equal to the concentration of HCl present in methanol saturated with HCl gas at zero degrees Celsius, whereby threo-methylphenidate is formed in the third reaction mixture.

In a preferred embodiment, the first reaction mixture is cooled prior to separating the first intermediate product from the first reaction mixture, and the precipitation mixture is cooled prior to separating the second intermediate product from the precipitation mixture.

The invention also relates to a compound having the formula wherein n is an integer selected from the group consisting of the integers from 0 to 7; wherein each R1 is independently selected from the group consisting of cycloaryl, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, C1-C6 alkanoyl, halogen, amino, C C6 alkylamino, nitro, sulfo, and sulfhydryl; wherein (cAr) is a cycloaryl group; wherein m is an integer selected from the group consisting of 0 and 1; wherein R2 is selected from the group consisting C1-C6 alkyl and C1-C6 alkanoyl; wherein p is an integer selected from the group consisting of 3,4,5, and 6; wherein each X is an atom independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur; wherein q is an integer selected from the group consisting of the integers from 0 to 16;

wherein each R3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, C1-C6 alkanoyl, halogen, carboxyl, C2-C6 alkanoxy, nitro, sulfo, and sulfhydryl, or wherein two of R3 are, together, an oxo group or a double bond between two adjacent X atoms; and wherein when p is 4, (cAr) is phenyl, and every X is carbon, not every R3 is hydrogen.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 depicts an outline of the synthetic method employed in Example 1 for synthesis of threo-methylphenidate.

Figure 2 depicts thermal and photochemical decomposition of an aryl a-keto amide compound into isomers of a p-lactam compound.

DETAILED DESCRIPTION The invention relates to compounds which inhibit presynaptic re-uptake of dopamine catalyzed by a cell surface protein designated the dopamine transporter (DAT). These dopamine re-uptake inhibitory compounds include methylphenidate and analogs of methylphenidate. Methods of synthesizing these inhibitors and methods of using pharmaceutical compositions comprising one or more of these inhibitors are also described. Such pharmaceutical compositions are useful for treating dopamine re- uptake disorders, including disorders associated with cocaine abuse and addiction.

The invention includes dopamine re-uptake inhibitor compounds having the formula

The designation"n"refers to an integer selected from the group consisting of the integers from 0 to 7, and refers to the number of R1 attached to the " (fca)" group. Each Ri group is independently selected from the group consisting of cycloaryl, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, C1-C6 alkanoyl, halogen, amino, C1- C6 alkylamino, nitro, sulfo, and sulfhydryl. Some of the preferred R1 groups are described in Deutsch et al., 1996, J. Med. Chem, 39: 1201-1209, and include, for example, tert-butyl, methyl, chloro, fluoro, amino, nitro, hydroxy. and methoxy groups.

Other preferred Rl groups include cycloaryl groups such as phenyl groups. Of course, positions on the" (fca)" group which are not substituted by Rl groups are instead be substituted by hydrogen or have no substituents, depending on the valence of the atom at that position.

The designation" (fca)" refers to a cycloaryl group, preferably a fused cycloaryl group. Cycloaryl groups include both cycloaryl groups in which all of the atoms which form the cycloaryl ring are carbon atoms and those (i. e."heterocycloaryl groups") in which one or more of the atoms which form the cycloaryl ring are atoms other than carbon, such as atoms selected from the group consisting of oxygen, nitrogen, and sulfur. Preferred cycloaryl groups include phenyl and naphthyl groups.

The designation"m"refers to an integer selected from the group consisting of 0 and 1. Thus, there is optionally a methylene group interposed between the cycloaryl group of the compound and the carbon atom to which the amide group is attached.

The designation"R2"refers to the substituent attached to the oxygen atom of the amide group of the compound of the invention. R2 is selected from the group consisting C1-C6 alkyl and C1-C6 alkanoyl (i. e.- (CH2) 1-60H. The alkyl and alkanoyl groups may be straight-chain or branched groups (e. g. tert-butyl). Preferred R2 groups include methyl and ethyl groups.

The designation"p"refers to an integer selected from the group consisting of 3,4,5, and 6, and relates to the number of atoms in the nitrogen-

containing ring of the compound of the invention. The number of atoms in the ring is equal to p + 2, and is preferably 6. Thus, p is preferably 4.

The designation"X"refers to atoms in the nitrogen-containing ring of the compound of the invention. Each X is an atom independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. Thus, the nitrogen-containing ring of the invention may be one of a variety of nitrogen-containing rings, including, for example, pyridine, pyrrolidine, and morpholine. Preferably, each X is carbon and p is 4, whereby the nitrogen-containing ring is pyridine.

The designation"q"refers to an integer selected from the group consisting of the integers from 0 to 16, and relates to the number of substituents of the nitrogen-containing ring of the compound of the invention at the"X"atoms thereof.

This number is preferably low, i. e. less than four, preferably less than one, and more preferably is zero.

The designation"R3"refers to the chemical identity of the substituents of the nitrogen-containing ring of the compound of the invention. Each R3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C 1-C6 alkoxy, hydroxyl, C1-C6 alkanoyl, halogen, carboxyl, C2-C6 alkanoxy, nitro, sulfo, and sulfhydryl. Two of R3 groups, together, may be an oxo group or a double bond between two adjacent X atoms. When two of the R3 groups together are a double bond, the nitrogen-containing ring may, for example, be a piperidine ring that is unsaturated at the 4-and 5-positions, wherein the ring is attached to the remainder of the compound at the 2-position of the piperidine ring.

Preferred inhibitor compounds include those wherein (fca) is a naphthalene group (e. g. wherein the naphthalene group is a 1-naphthalene group), those wherein n is 0, those wherein m is 0, those wherein p is 4, and those wherein p is 4 and each X is carbon, those wherein p is 4, each X is carbon, q is 8, each R3 is hydrogen, and R2 is selected from the group consisting of methyl and ethyl. Other preferred compounds are described in the Examples included herein (e. g. Compounds 7 to 13).

In one embodiment, the dopamine re-uptake inhibitor compound has the formula

wherein n, R1, (fca), R2, q, and R3 have the same meanings as described above.

In another preferred embodiment, the dopamine re-uptake inhibitor compound has the formula

wherein n, RI, R2, q, and R3 have the same meanings as described above.

In another embodiment, the dopamine re-uptake inhibitor compound of the invention has the formula

wherein n, RI m, R2, p, X, q, and R3 have the meanings as described above. The designation"cAr"refers to a cycloaryl group. The cycloaryl group is preferably phenyl or naphthyl. When p is 4, (cAr) is phenyl, and every X is carbon, not every R3 is hydrogen (i. e. the compound is not methylphenidate).

The invention also includes a method of making the dopamine re- uptake inhibitor compound of the invention. This method comprises (i) reacting (a) a cycloaryl a-keto ester having the formula wherein n is an integer selected from the group consisting of the integers from 0 to 7; wherein each Ri is independently selected from the group consisting of cycloaryl, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, C1-C6 alkanoyl, halogen, amino, C1-C6 alkylamino, nitro, sulfo, and sulfhydryl; wherein (fca) is a cycloaryl group such as fused cycloaryl group; wherein m is an integer selected from the group consisting of 0 and 1; and wherein R4 is selected from the group consisting C 1-C6 alkyl and C 1- C6 alkanoyl; and (b) a cyclic a-methylene amine having the formula

wherein p is an integer selected from the group consisting of 3,4,5, and 6; wherein each X is an atom independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur; wherein q is an integer selected from the group consisting of the integers from 0 to 16; and wherein each R3 is independently selected from the group consisting of hydrogen, C1-C6 alkyl. Cl-C6 alkoxy, hydroxyl, C 1-C6 alkanoyl, halogen, carboxyl, C2-C6 alkanoxy, nitro, sulfo, and sulfhydryl, or wherein two of R3 are, together, an oxo group or a double bond between two adjacent X atoms; to generate an cycloaryl a-keto amide intermediate (ii) reacting (a) the cycloaryl a-keto amide intermediate and (b) an aryl sulfonylhydrazide in the presence of (c) an acidic solution comprising a catalyzing amount of sulfuric acid, to generate a cycloaryl sulfonylhydrazide amide intermediate; (iii) reacting (a) the cycloaryl sulfonylhydrazide amide intermediate and (b) a deprotonating agent in the presence of (c) an organic solvent, to generate a i-lactam intermediate; and (iv) reacting (a) the (3-lactam intermediate and

(b) an alcohol having the formula R2-OH in an acidic solution, wherein R2 is selected from the group consisting Ci-Cz. alkyi and C1-C6 alkanoyl, whereby the compound is formed.

The acidic solution mentioned in item (ii) (c) is preferably selected from the group consisting of an acidified ethanol solution and an acidified solution of 1,2- dimethoxyethane.

The organic solvent mentioned in item (iii) (c) is preferably selected from the group consisting of toluene and 1,4-dioxane.

The deprotonating solution mentioned in item (iii) (c) preferably comprises a tert-butoxide salt (e. g. potassium tert-butoxide) and tert-butanol.

Where the reaction conditions for the synthetic steps of this method are not explicitly specified, they may vary and will be apparent to the skilled artisan.

Preferably the reaction conditions are similar to, or the same as (with the exception of the chemical identity of the reactants), the reaction conditions specified in the following synthetic method.

The present invention also relates to a method of synthesizing methylphenidate, as outlined in Figure 1. The invention provides a method of synthesizing the threo-diastereomer of methylphenidate, thereby eliminating the need to separate or interconvert diastereomers in order to produce the threo-diastereomer.

The need to separate or interconvert diastereomers is a significant drawback of prior art methods of synthesizing threo-methylphenidate.

The invention also includes a composition comprising threo- methylphenidate which is synthesized using the method of the invention.

Threo-methylphenidate is synthesized according to the method of the invention by preparing a first reaction mixture by combining phenyl glyoxylic acid piperidine amide (Compound II in Figure 1), p-toluenesulfonylhydrazide, and an acidic solution. Reaction of ethyl phenylglyoxylate (Compound I in Figure 1) with piperidine affords the a-ketoamide (Imai et al., 1987, Chem. Pharm. Bull. 35: 2646), which on condensation with tosylhydrazine yields the tosylhydrazone. Combination of these reagents leads to formation of phenyl glyoxylic acid piperidine amide tosylhydrazone (Compound III in Figure 1) in the first reaction mixture. Para-toluenesulfonyl- hydrazide has the following structure.

The phenyl glyoxylic acid piperidine amide tosylhydrazone formed in the first reaction mixture is then combined in a second reaction mixture with an organic solvent such as toluene and a deprotonating solution comprising a base which is a sufficiently strong base to deprotonate the hydrazone of Compound III. An example of such a deprotonating solution is a solution comprising potassium tert-butoxide in tert- butanol. Treatment of Compound III with potassium tert-butoxide in refluxing toluene yielded trans-1-aza-2-oxo-3-phenyl-bicyclo [4.2.0] octane (Compound IV in Figure 1), which was obtained in 60% yield on crystallization of the second reaction mixture.

This procedure represents a significant improvement over previously reported work. For example, in the first example of p-lactam formation from an (X- diazoamide, Corey et al. reported stereoselective formation of a p-lactam product in 50% yield by irradiation of Compound 6 (as illustrated in Figure 2), which was obtained by treatment of Compound 5a in Figure 2 with sodium hydride, although the stereochemistry of the p-lactam product was not established (Corey et al., 1965, J. Am.

Chem. Soc. 87: 2518-2519). The same authors also reported thermal decomposition of Compound 5a to yield the same product. Irradiation of Compound 5a leads to the formation of a 4: 1 mixture of Compound 6 and Compound 6a in Figure 2 in quantitative yield. By contrast, using the methods described herein a 3.5: 1 ratio of these compounds is obtained under thermal toluene reflux conditions.

The trans-1-aza-2-oxo-3-phenyl-bicyclo [4.2.0] octane formed in the second reaction mixture is then combined in a third reaction mixture with an acidified methanol solution, and threo-methylphenidate is formed in this third reaction mixture.

Methanolic hydrolysis of trans-l-aza-2-oxo-3-phenyl-bicyclo [4. 2.0] octane proceeds with little or no epimerization. Therefore, the diastereomer of methylphenidate formed in this reaction is entirely or substantially entirely the threo-diastereomer.

The synthetic method for generating methylphenidate described herein has proven to be highly efficient and amenable to modification of both the piperidine and the aryl moieties, unlike prior art methods, which were largely limited to modification of the aryl moiety. The role of the methylphenidate piperidine ring in binding to the DAT is evaluated by replacing piperidine in Scheme 1 with other secondary, preferably cyclic, amines. Similarly, replacement of ethyl phenylglyoxylate with other arylketoacid esters leads to the incorporation of other aryl groups into the methylphenidate framework.

Suitable a-ketoesters for analog production may be synthesized, for example, by addition of an aryllithium to diethyloxalate using known methods (Middleton et al., 1980, J. Org. Chem. 45: 2883). Using this procedure, the aryllithium compounds derived from 1-and 2-bromonaphthalene were used to generate Compounds 7 and 8, respectively, as described herein in Example 2. The homologated phenidate analog herein designated Compound 9 was prepared by stereoselective alkylation of 1-aza-bicyclo [4.2.0] octan-8-one, using a known method (Murahashi et al., 1988, Tetrahedron Lett. 5949-5952) involving use of benzyl bromide followed by reaction of the resulting substituted (3-lactam with acidic methanol.

Phenyl glyoxylic acid piperidine amide can be prepared by condensation of ethyl phenyl glyoxylate with piperidine as described (Achiwa et al., 1987, Chem.

Pharm. Bull. 35: 2646-2655), or by any other method. Para-toluenesulfonylhydrazide (also designatedp-toluenesulfonhydrazide) and tert-butanol are available from commercial sources (e. g. Sigma Chemical Co., St. Louis, MO). Potassium tert- butoxide is commercially available both in the form of a solid and in the form of a 1 molar solution in tert-butanol.

The yield of the first intermediate product is improved by subjecting the first reaction mixture to reflux after combining the phenyl glyoxylic acid piperidine

amide, the p-toluenesulfonylhydrazide, and the acidic solution. Any known method of subjecting the mixture to reflux may be used. By way of example, when the acidic solution of the first reaction mixture is an acidic ethanol solution, the first reaction mixture may be heated by contacting the vessel containing the first reaction mixture with, for example, a temperature-adjustable heating mantle to effect vaporization of ethanol in the vessel. Vaporized ethanol may be condensed using, for example, a jacketed condenser wherein when cold water passes through the jacket of the condenser, vaporized ethanol condenses on the interior surface of the condenser, and the condensed ethanol is returned by the influence of gravity to the vessel. When the first reaction mixture is subjected to reflux, reflux preferably continues for a period of about four hours, although any duration of reflux between about one hour and about four hours may be used.

The first reaction mixture is preferably made by combining a selected molar amount of the phenyl glyoxylic acid piperidine amide and at least about the same molar amount of the p-toluenesulfonylhydrazide. The concentration of the phenyl glyoxylic acid piperidine amide in the first reaction mixture may be, for example, about 2 molar. The concentration of the p-toluenesulfonylhydrazide in the first reaction mixture may also be, for example, about 2 molar. Concentrations of the phenyl glyoxylic acid piperidine amide and thep-toluenesulfonylhydrazide may be as high as the solubility limits of the compounds.

The acidic solution of the first reaction mixture may be any acidic solution in which phenyl glyoxylic acid piperidine amide andp- toluenesulfonylhydrazide are soluble and in which the first intermediate product precipitates. By way of example, the acidic solution may comprise ethanol and an acid such as sulfuric acid or 1,2-dimethoxyethane and an acid such as sulfuric acid or hydrochloric acid. Preferably, the acidic solution comprises an acidic ethanol solution comprising ethanol and at least a trace amount of sulfuric acid. By"a trace amount of sulfuric acid"is meant a sufficient concentration of acid to catalyze formation of the first intermediate product in the first reaction mixture. By way of example, the

concentration of acid which is useful in the first reaction mixture may be from about 1 millimolar to about 20 millimolar. Thus, for example, the concentration of sulfuric acid in the acidic ethanol solution may be from about 1 millimolar to about 20 millimolar.

The first intermediate product may be crystallized and recovered from the first reaction mixture prior to preparation of the second reaction mixture. Any crystallization procedure may be used. The first intermediate product may be crystallized by cooling the first reaction mixture to approximately normal ambient temperature (i. e. circa twenty degrees Celsius). The crystalline form of the first intermediate product may be separated from the first reaction mixture by filtration.

Following filtration, the crystalline form of the first intermediate product may be washed using a small amount of cold ethanol (e. g. about 5 milliliters of ethanol at about 25 degrees Celsius to wash about 12 grams of product), a small amount of diethyl ether (e. g. from about 10 to about 20 milliliters to wash about 12 grams of product), and the like. Following such a washing step, the first intermediate product may be air dried prior to preparing the second reaction mixture.

The organic solvent of the second reaction mixture may be any solvent in which the first intermediate product is soluble or may be suspended and which has a boiling point which is sufficiently high to permit generation of a diazo compound and to permit conversion of the diazo compound into a carbenoid intermediate.

The organic solvent may, for example, be toluene or 1,4-dioxane.

The deprotonating solution may be any solution which comprises a deprotonating agent which is a sufficiently strong base to deprotonate the hydrazone of Compound III. The deprotonating solution may, by way of example, comprise a salt of tert-butoxide and tert-butanol, a solution of sodium methoxide, a solution of sodium hydroxide, or a solution of potassium hydroxide. Preferably, the deprotonating solution comprises 1.0 molar potassium tert-butoxide in tert-butanol.

The second reaction mixture is preferably made by combining a selected molar amount of the and at least about the same molar amount of the deprotonating

agent. The concentration of the phenyl glyoxylic acid piperidine amide tosylhydrazone in the second reaction mixture may be, for example, from about 0.1 molar to about 0.5 molar. The concentration of the deprotonating agent in the second reaction mixture may also be, for example, from about 0.1 molar to about 0.5 molar.

The yield of the second intermediate product is improved by subjecting the second reaction mixture to reflux after combining the first intermediate product, the deprotonating agent, and the organic solvent. Any known method of subjecting the mixture to reflux may be used. By way of example, when the organic solvent of the second reaction mixture is toluene, the second reaction mixture may be heated by contacting the vessel containing the second reaction mixture with, for example, a temperature-adjustable heating mantle to effect vaporization of toluene in the vessel.

Vaporized toluene may be condensed using, for example, a jacketed condenser wherein when cold water passes through the jacket of the condenser, vaporized toluene condenses on the interior surface of the condenser, and the condensed toluene is returned by the influence of gravity to the vessel. When the second reaction mixture is subjected to reflux, reflux preferably continues for a period of at least about ninety minutes, although any duration of reflux between about thirty minutes and about two hours may be used, the duration of reflux being variable, depending on how long must be maintained to permit the reaction to proceed to completion.

The second intermediate product may be crystallized and recovered from the second reaction mixture prior to preparation of the third reaction mixture.

Any crystallization procedure may be used. By way of example, the second intermediate product may be crystallized by cooling the second reaction mixture to approximately normal ambient temperature (i. e. about twenty degrees Celsius). The second reaction mixture may be'washed'by combining it with a composition comprising water to form an aqueous phase and an organic phase. The organic phase may be separated from the aqueous phase. This'washing'procedure may be repeated several times. The organic phase may be'dried'by sealing it in a container which contains a desiccant such as magnesium sulfate. The organic phase may then be

filtered, and the organic solvent may be evaporated. The'dried'second reaction mixture may be combined with organic solvents such as diethyl ether and light petroleum ether to form a precipitation mixture. The second intermediate product precipitates in the precipitation mixture.

Precipitation of the second intermediate product in the precipitation mixture may be accelerated using known methods, such as cooling the precipitation mixture, scratching the interior surface of a glass vessel containing the precipitation mixture using a glass rod, seeding the precipitation mixture, and the like. The crystalline second intermediate product may be separated from the precipitation mixture using any known method, such as filtration. Separation of the second intermediate product from the precipitation mixture may be improved by'washing'the crystalline second intermediate product using a solvent such as light petroleum ether and air drying the product. Furthermore, the yield of the crystalline second intermediate product from the precipitation mixture may be improved by evaporating liquid from the precipitation mixture and crystallizing the second intermediate product therefrom, as described herein.

The acidified methanol solution of the third reaction mixture preferably comprises HCI. When the acid of the acidified methanol solution is HCI, the concentration of HCl in the acidified methanol solution is preferably about equal to the concentration of HCl in a solution of methanol saturated with HCl gas at zero degrees Celsius.

In the third reaction mixture, it is preferable to combine a selected molar amount of the second intermediate product with a molar excess of methanol.

The yield of threo-methylphenidate is improved by subjecting the third reaction mixture to reflux after combining the second intermediate reaction product and the acidified methanol solution. Any known method of subjecting the mixture to reflux may be used. By way of example, the third reaction mixture may be heated by contacting the vessel containing the first reaction mixture with, for example, a temperature-adjustable heating mantle to effect vaporization of methanol in the vessel.

Vaporized methanol may be condensed using, for example, a jacketed condenser wherein when cold water passes through the jacket of the condenser, vaporized methanol condenses on the interior surface of the condenser, and the condensed methanol is returned by the influence of gravity to the vessel. When the third reaction mixture is subjected to reflux, reflux preferably continues for a period of at least about thirty minutes, although any duration of reflux between about thirty minutes and about two hours may be used, although the duration of reflux may vary, depending on how long the reaction must be maintained to permit the reaction to proceed to completion.

The third reaction mixture may also be prepared and permitted to react at about 25 degrees Celsius.

Threo-methylphenidate may be separated from the third reaction mixture using any known method for removing methanol and acid from a composition.

By way of example, methanol may be evaporated from the third reaction mixture. A solvent such as ethyl acetate may be mixed with the residue, and the mixture may be triturated. The triturated mixture may be diluted with a solvent such as diethyl ether.

Crystalline threo-methylphenidate may be separated from the solvents using any known method, such as filtration and may thereafter be air dried.

Threo-methylphenidate made using the method of the invention may be combined with a pharmaceutically-acceptable carrier to form a pharmaceutical composition suitable for administration to an animal such as a human. As used herein, the term"pharmaceutically-acceptable carrier"means a chemical composition with which threo-methylphenidate may be combined and which, following the combination, can be used to administer threo-methylphenidate to a mammal such as a human.

Pharmaceutical compositions comprising threo-methylphenidate may be administered systemically in oral solid formulations, ophthalmic, suppository, aerosol, topical or other similar formulations. In addition to threo-methylphenidate, such pharmaceutical compositions may contain pharmaceutically-acceptable carriers and other ingredients known to enhance and facilitate drug administration. Other possible

formulations, such as nanoparticles, liposomes, resealed erythrocytes, and immunologically based systems may also be used to administer threo-methylphenidate.

Because the method of the invention uses commercially available or easily synthesized starting materials, and further because the intermediate products formed during performance of the method can be recovered as crystalline products, the method is amenable to large-scale production of threo-methylphenidate. Large-scale production of threo-methylphenidate according to the method of the invention requires selection of reaction conditions, chemical process equipment, reactant quantities, reaction times, and the like, which are within the skill of the ordinary worker in the art. Thus, the method of the invention includes, but is not limited to, methods performed on a laboratory scale, methods performed on the scale of an industrial-type pilot plant, and methods performed on an industrial scale. By way of example, laboratory methods may be used to produce milligram amounts of threo-methylphenidate, as described in the Example herein, while pilot plant-scale or industrial-scale methods may be used to produce gram amounts, kilogram amounts, or more, of threo-methylphenidate.

One or more of the dopamine re-uptake inhibitor compounds of the invention may be incorporated into a pharmaceutical composition, as described elsewhere herein in greater detail. Such compositions are useful for treating a number of pathological conditions, including, for example, dopamine re-uptake disorders such as those associated with cocaine use, abuse, and addiction. The mechanism by which the inhibitor compounds of the invention are believed to exert their therapeutic effect involves inhibition, mediated by the compounds, of binding between DAT and compounds other than dopamine (e. g. cocaine). Although most, if not all of the dopamine re-uptake inhibitor compounds of the invention inhibit binding between DAT and dopamine, at least at very high concentrations, the value of the inhibition constant Ki of the compounds for inhibiting DAT-dopamine binding is much greater (i. e. at least about 2.5 times, preferably at least about 5 times, and more preferably at least about 10 times greater) than the value of the inhibition constant Ki of the

compounds for inhibiting binding of DAT and a non-dopamine compound (e. g. cocaine). It is this selectivity of the inhibitory activity of the compounds of the invention that enables their therapeutic use.

The therapeutic activity of the dopamine re-uptake inhibitor compounds of the invention may be explained, in a simplified manner, as follows. In a dopamine re-uptake disorder such as cocaine abuse, a non-dopamine compound (e. g. cocaine) binds with DAT, preventing normal re-uptake of dopamine by cells expressing DAT on their surface. Because DAT is normally expressed on the synaptic surfaces of nerves, most dopamine re-uptake disorders exhibit pathoneurological symptoms. The inhibitor compounds of the invention also bind with DAT. Binding of one of these inhibitor compounds with DAT prevents binding of the non-dopamine compound with DAT, and thereby prevents the attendant pathoneurological symptoms. Because the ability of the inhibitor compounds of the invention to inhibit DAT-non-dopamine compound binding is much greater than the ability of the inhibitor compounds to inhibit DAT- dopamine binding, the dopamine re-uptake disorder is alleviated.

An important class of dopamine re-uptake disorders which may be alleviated using the dopamine re-uptake inhibitor compounds of the invention are those associated with administration (usually non-prescribed self-administration) of cocaine to a patient. At least part of the habit-forming nature of cocaine abuse is attributable to the neurological effects of cocaine, which, in turn, are attributable to binding of cocaine with DAT. Such neurological effects are often experienced by the patient as feelings of euphoria, security, power, alertness, and the like. Psychological dependence upon cocaine may develop over time, experienced by the patient as a longing to achieve the previously noted neurological effects. Abstinence from cocaine use by a psychologically dependent patient can lead to depression and craving for the drug.

Subsequent use relieves such feelings, provides the previously noted effects, and thereby psychologically reinforces the patient's abusive or addictive behavior.

The dopamine re-uptake inhibitor compounds of the invention do not alleviate psychological or (rarely) physical symptoms of withdrawal associated with

abstinence from cocaine use. Instead, the inhibitor compounds of the invention prevent the pleasurable effects of cocaine and thereby prevent the psychological reinforcement experienced by the recovering cocaine abuser or addict during abstinence from cocaine use. Thus, a patient who wishes to discontinue cocaine use, but is occasionally, or even frequently, unable to maintain abstinence from cocaine use may use a pharmaceutical composition comprising one or more inhibitor compounds of the invention during a period when the patient's willpower or determination is high in order to deny himself or herself the psychological'reward'that would otherwise accompany relapsing cocaine use. The compositions of the invention therefore meet a great societal need for an effective means for assisting cocaine abusers and addicts who wish to discontinue their habits.

Because the compositions of the invention are intended to be voluntarily administered to a patient during a period when the patient's desire to be free of a cocaine habit is high in order that relapse at a later period will not be psychologically rewarded with the'high'that normally accompanies cocaine use, it is preferable that the pharmaceutical composition of the invention be available to the patient in a sustained- or extended-release form. In such a form, administration of the composition to the patient provides one or more dopamine re-uptake inhibitor compounds to the patient continuously over a period of hours, days, weeks, months, or even years. Such sustained-release formulations have been made for other pharmaceutical compositions (e. g. the Norplant implantable contraceptive device manufactured by Wyeth-Ayers, which effect continuous administration of levonorgestrel over a period of at least about 18 months). The pharmaceutical compositions of the invention may similarly be provided in the form of such extended-or sustained-release preparations. Where such preparations are provided in the form of capsules (i. e. as with Norplant@), the preparations are conveniently provided in the form of a kit which includes, for example, a scalpel or other subcutaneous access device, a disinfectant, a trocar, a local anesthetic, a bandage, a surgical drape, and the like.

The pharmaceutical composition of the invention may be administered to the patient while the patient is experiencing the dopamine re-uptake disorder or (particularly when the disorder is self-induced, such as with cocaine abuse), prior to the onset of the disorder.

The invention encompasses the preparation and use of medicaments and pharmaceutical compositions comprising one or more of the dopamine re-uptake inhibitors of the invention as an active ingredient. Such a pharmaceutical composition may consist of the active ingredient alone, in a form suitable for administration to a subject, or the pharmaceutical composition may comprise the active ingredient and one or more pharmaceutically acceptable carriers, one or more additional ingredients, or some combination of these. Administration of one of these pharmaceutical compositions to a subject is useful for treating a dopamine re-uptake disorder (e. g. cocaine abuse or addition) in the subject, as described elsewhere in the present disclosure. The active ingredient may be present in the pharmaceutical composition in the form of a physiologically acceptable ester or salt, such as in combination with a physiologically acceptable cation or anion, as is well known in the art.

As used herein, the term"pharmaceutically acceptable carrier"means a chemical composition with which the active ingredient may be combined and which, following the combination, can be used to administer the active ingredient to a subject.

As used herein, the term"physiologically acceptable"ester or salt means an ester or salt form of the active ingredient which is compatible with any other ingredients of the pharmaceutical composition and which is not deleterious to the subject to which the composition is to be administered.

The formulations of the pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of bringing the active ingredient into association with a carrier or one or more other accessory ingredients, and then, if necessary or desirable, shaping or packaging the product into a desired single-or multi-dose unit.

Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for ethical administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts.

Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and perform such modification with merely ordinary, if any, experimentation. Subjects to which administration of the pharmaceutical compositions of the invention is contemplated include, but are not limited to, humans and other primates, although the compositions should also be efficacious in other mammals.

Pharmaceutical compositions that are useful in the methods of the invention may be prepared, packaged, or sold in formulations suitable for oral, rectal, vaginal, parenteral, topical, pulmonary, intranasal, buccal, ophthalmic, or another route of administration. Other contemplated formulations include projected nanoparticles, liposomal preparations, resealed erythrocytes containing the active ingredient, and immunologically-based formulations.

A pharmaceutical composition of the invention may be prepared, packaged, or sold in bulk, as a single unit dose, or as a plurality of single unit doses.

As used herein, a"unit dose"is discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.

The relative amounts of the active ingredient, the pharmaceutically acceptable carrier, and any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and condition of the subject treated and further depending upon the route by which the composition is to be administered. By way of example, the composition may comprise between 0.1% and

100% (w/w) active ingredient. A unit dose of a pharmaceutical composition of the invention will generally comprise from about 1 nanogram to about 5 grams of the active ingredient, and preferably comprises from about 1 milligram to about 500 milligrams of the active ingredient.

In addition to the active ingredient, a pharmaceutical composition of the invention may further comprise one or more additional pharmaceutically active agents.

Controlled-or sustained-release formulations of a pharmaceutical composition of the invention may be made using conventional technology.

A formulation of a pharmaceutical composition of the invention suitable for oral administration may be prepared, packaged, or sold in the form of a discrete solid dose unit including, but not limited to, a tablet, a hard or soft capsule, a cachet, a troche, or a lozenge, each containing a predetermined amount of the active ingredient.

Other formulations suitable for oral administration include, but are not limited to, a powdered or granular formulation, an aqueous or oily suspension, an aqueous or oily solution, or an emulsion.

As used herein, an"oily"liquid is one which comprises a carbon- containing liquid molecule and which exhibits a less polar character than water.

A tablet comprising the active ingredient may, for example, be made by compressing or molding the active ingredient, optionally with one or more additional ingredients. Compressed tablets may be prepared by compressing, in a suitable device, the active ingredient in a free-flowing form such as a powder or granular preparation, optionally mixed with one or more of a binder, a lubricant, an excipient, a surface active agent, and a dispersing agent. Molded tablets may be made by molding, in a suitable device, a mixture of the active ingredient, a pharmaceutically acceptable carrier, and at least sufficient liquid to moisten the mixture. Pharmaceutically acceptable excipients used in the manufacture of tablets include, but are not limited to, inert diluents, granulating and disintegrating agents, binding agents, and lubricating agents. Known dispersing agents include, but are not limited to, potato starch and sodium starch glycolate. Known surface active agents include, but are not limited to,

sodium lauryl sulphate. Known diluents include, but are not limited to, calcium carbonate, sodium carbonate, lactose, microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate, and sodium phosphate. Known granulating and disintegrating agents include, but are not limited to, corn starch and alginic acid.

Known binding agents include, but are not limited to, gelatin, acacia, pre-gelatinized maize starch, polyvinylpyrrolidone, and hydroxypropyl methylcellulose. Known lubricating agents include, but are not limited to, magnesium stearate, stearic acid, silica, and talc.

Tablets may be non-coated or they may be coated using known methods to achieve delayed disintegration in the gastrointestinal tract of a subject, thereby providing sustained release and absorption of the active ingredient. By way of example, a material such as glyceryl monostearate or glyceryl distearate may be used to coat tablets. Further by way of example, tablets may be coated using methods described in U. S. Patents numbers 4,256,108; 4,160,452; and 4,265,874 to form osmotically-controlled release tablets. Tablets may further comprise a sweetening agent, a flavoring agent, a coloring agent, a preservative, or some combination of these in order to provide pharmaceutically elegant and palatable preparation.

Hard capsules comprising the active ingredient may be made using a physiologically degradable composition, such as gelatin. Such hard capsules comprise the active ingredient, and may further comprise additional ingredients including, for example, an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin.

Soft gelatin capsules comprising the active ingredient may be made using a physiologically degradable composition, such as gelatin. Such soft capsules comprise the active ingredient, which may be mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil.

Liquid formulations of a pharmaceutical composition of the invention which are suitable for oral administration may be prepared, packaged, and sold either in

liquid form or in the form of a dry product intended for reconstitution with water or another suitable vehicle prior to use.

Liquid suspensions may be prepared using conventional methods to achieve suspension of the active ingredient in an aqueous or oily vehicle. Aqueous vehicles include, for example, water and isotonic saline. Oily vehicles include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis, olive, sesame, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin. Liquid suspensions may further comprise one or more additional ingredients including, but not limited to, suspending agents, dispersing or wetting agents, emulsifying agents, demulcents, preservatives, buffers, salts, flavorings, coloring agents, and sweetening agents. Oily suspensions may further comprise a thickening agent. Known suspending agents include, but are not limited to, sorbitol syrup, hydrogenated edible fats, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, and cellulose derivatives such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose. Known dispersing or wetting agents include, but are not limited to, naturally-occurring phosphatides such as lecithin, condensation products of an alkylene oxide with a fatty acid, with a long chain aliphatic alcohol, with a partial ester derived from a fatty acid and a hexitol, or with a partial ester derived from a fatty acid and a hexitol anhydride (e. g. polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate, and polyoxyethylene sorbitan monooleate, respectively). Known emulsifying agents include, but are not limited to, lecithin and acacia. Known preservatives include, but are not limited to, methyl, ethyl, or n-propyl-para-hydroxybenzoates, ascorbic acid, and sorbic acid. Known sweetening agents include, for example, glycerol, propylene glycol, sorbitol, sucrose, and saccharin. Known thickening agents for oily suspensions include, for example, beeswax, hard paraffin, and cetyl alcohol.

Liquid solutions of the active ingredient in aqueous or oily solvents may be prepared in substantially the same manner as liquid suspensions, the primary difference being that the active ingredient is dissolved, rather than suspended in the

solvent. Liquid solutions of the pharmaceutical composition of the invention may comprise each of the components described with regard to liquid suspensions, it being understood that suspending agents will not necessarily aid dissolution of the active ingredient in the solvent. Aqueous solvents include, for example, water and isotonic saline. Oily solvents include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis, olive, sesame, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin.

Powdered and granular formulations of a pharmaceutical preparation of the invention may be prepared using known methods. Such formulations may be administered directly to a subject, used, for example, to form tablets, to fill capsules, or to prepare an aqueous or oily suspension or solution by addition of an aqueous or oily vehicle thereto. Each of these formulations may further comprise one or more of dispersing or wetting agent, a suspending agent, and a preservative. Additional excipients, such as fillers and sweetening, flavoring, or coloring agents, may also be included in these formulations.

A pharmaceutical composition of the invention may also be prepared, packaged, or sold in the form of oil-in-water emulsion or a water-in-oil emulsion. The oily phase may be a vegetable oil such as olive or arachis oil, a mineral oil such as liquid paraffin, or a combination of these. Such compositions may further comprise one or more emulsifying agents such as naturally occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soybean or lecithin phosphatide, esters or partial esters derived from combinations of fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of such partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. These emulsions may also contain additional ingredients including, for example, sweetening or flavoring agents.

A pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for rectal administration. Such a

composition may be in the form of, for example, a suppository, a retention enema preparation, and a solution for rectal or colonic irrigation.

Suppository formulations may be made by combining the active ingredient with a non-irritating pharmaceutically acceptable excipient which is solid at ordinary room temperature (i. e. about 20°C) and which is liquid at the rectal temperature of the subject (i. e. about 37°C in a healthy human). Suitable pharmaceutically acceptable excipients include, but are not limited to, cocoa butter, polyethylene glycols, and various glycerides. Suppository formulations may further comprise various additional ingredients including, but not limited to, antioxidants and preservatives.

Retention enema preparations or solutions for rectal or colonic irrigation may be made by combining the active ingredient with a pharmaceutically acceptable liquid carrier. As is well known in the art, enema preparations may be administered using, and may be packaged within, a delivery device adapted to the rectal anatomy of the subject. Enema preparations may further comprise various additional ingredients including, but not limited to, antioxidants and preservatives.

A pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for vaginal administration. Such a composition may be in the form of, for example, a suppository, an impregnated or coated vaginally-insertable material such as a tampon, a douche preparation, or a solution for vaginal irrigation.

Methods for impregnating or coating a material with a chemical composition are known in the art, and include, but are not limited to methods of depositing or binding a chemical composition onto a surface, methods of incorporating a chemical composition into the structure of a material during the synthesis of the material (i. e. such as with a physiologically degradable material), and methods of absorbing an aqueous or oily solution or suspension into an absorbent material, with or without subsequent drying.

Douche preparations or solutions for vaginal irrigation may be made by combining the active ingredient with a pharmaceutically acceptable liquid carrier. As is well known in the art, douche preparations may be administered using, and may be packaged within, a delivery device adapted to the vaginal anatomy of the subject.

Douche preparations may further comprise various additional ingredients including, but not limited to, antioxidants, antibiotics, antifungal agents, and preservatives.

As used herein,"parenteral administration"of a pharmaceutical composition includes any route of administration characterized by physical breaching of a tissue of a subject and administration of the pharmaceutical composition through the breach in the tissue. Parenteral administration thus includes, but is not limited to, administration of a pharmaceutical composition by injection of the composition, by application of the composition through a surgical incision, by application of the composition through a tissue-penetrating non-surgical wound, and the like. In particular, parenteral administration is contemplated to include, but is not limited to, subcutaneous, intraperitoneal, intravenous, intraarterial, intramuscular, or intrasternal injection and intravenous, intraarterial, or kidney dialytic infusion techniques.

Formulations of a pharmaceutical composition suitable for parenteral administration comprise the active ingredient combined with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline. Such formulations may be prepared, packaged, or sold in a form suitable for bolus administration or for continuous administration. Injectable formulations may be prepared, packaged, or sold in unit dosage form, such as in ampules or in multi-dose containers containing a preservative. Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable sustained-release or biodegradable formulations. Such formulations may further comprise one or more additional ingredients including, but not limited to, suspending, stabilizing, or dispersing agents. In one embodiment of a formulation for parenteral administration, the active ingredient is provided in dry (i. e. powder or granular) form

for reconstitution with a suitable vehicle (e. g. sterile pyrogen-free water) prior to parenteral administration of the reconstituted composition.

The pharmaceutical compositions may be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution. This suspension or solution may be formulated according to the known art, and may comprise, in addition to the active ingredient, additional ingredients such as the dispersing agents, wetting agents, or suspending agents described herein. Such sterile injectable formulations may be prepared using a non-toxic parenterally-acceptable diluent or solvent, such as water or 1,3-butane diol, for example. Other acceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and fixed oils such as synthetic mono-or di-glycerides. Other parentally- administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form, in a liposomal preparation, or as a component of a biodegradable polymer systems. Compositions for sustained release or implantation may comprise pharmaceutically acceptable polymeric or hydrophobic materials such as an emulsion, an ion exchange resin, a sparingly soluble polymer, or a sparingly soluble salt.

Formulations suitable for topical administration include, but are not limited to, liquid or semi-liquid preparations such as liniments, lotions, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes, and solutions or suspensions. Topically-administrable formulations may, for example, comprise from about 1 % to about 10% (w/w) active ingredient, although the concentration of the active ingredient may be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein.

A pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7

nanometers, and preferably from about 1 to about 6 nanometers. Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant may be directed to disperse the powder or using a self-propelling solvent/powder-dispensing container such as a device comprising the active ingredient dissolved or suspended in a low- boiling propellant in a sealed container. Preferably, such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. More preferably, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder compositions preferably include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.

Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the composition. The propellant may further comprise additional ingredients such as a liquid non-ionic or solid anionic surfactant or a solid diluent (preferably having a particle size of the same order as particles comprising the active ingredient).

Pharmaceutical compositions of the invention formulated for pulmonary delivery may also provide the active ingredient in the form of droplets of a solution or suspension. Such formulations may be prepared, packaged, or sold as aqueous or dilute alcoholic solutions or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration

preferably have an average diameter in the range from about 0.1 to about 200 nanometers.

The formulations described herein as being useful for pulmonary delivery are also useful for intranasal delivery of a pharmaceutical composition of the invention.

Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered in the manner in which snuff is taken i. e. by rapid inhalation through the nasal passage from a container of the powder held close to the nares.

Formulations suitable for nasal administration may, for example, comprise from about as little as 0.1 % (w/w) and as much as 100% (w/w) of the active ingredient, and may further comprise one or more of the additional ingredients described herein.

A pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for buccal administration. Such formulations may, for example, be in the form of tablets or lozenges made using conventional methods, and may, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations suitable for buccal administration may comprise a powder or an aerosolized or atomized solution or suspension comprising the active ingredient. Such powdered, aerosolized, or aerosolized formulations, when dispersed, preferably have an average particle or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.

A pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1-1.0% (w/w) solution or suspension of the active ingredient in an aqueous or oily

liquid carrier. Such drops may further comprise buffering agents, salts, or one or more other of the additional ingredients described herein. Other ophthalmalmically- administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form or in a liposomal preparation.

As used herein,"additional ingredients"include, but are not limited to, one or more of the following: excipients; surface active agents; dispersing agents; inert diluents; granulating and disintegrating agents; binding agents; lubricating agents; sweetening agents; flavoring agents; coloring agents; preservatives; physiologically degradable compositions such as gelatin; aqueous vehicles and solvents; oily vehicles and solvents; suspending agents; dispersing or wetting agents; emulsifying agents, demulcents; buffers; salts; thickening agents; fillers; emulsifying agents; antioxidants; antibiotics; antifungal agents; stabilizing agents; and pharmaceutically acceptable polymeric or hydrophobic materials. Other"additional ingredients"which may be included in the pharmaceutical compositions of the invention are known in the art and described, for example in Genaro, ed., 1985, Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, which is incorporated herein by reference.

A pharmaceutical composition of the invention may be administered to deliver a dose of between 1 ng/kg/day and 100 mg/kg/day, and preferably to deliver of between 50 ng/kg/day and 10 mg/kg/day, to a subject.

It is understood that the ordinarily skilled physician or veterinarian will readily determine and prescribe an effective amount of the compound to treat a dopamine re-uptake disorder in the subject. In so proceeding, the physician or veterinarian may, for example, prescribe a relatively low dose at first, subsequently increasing the dose until an appropriate response is obtained. It is further understood, however, that the specific dose level for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, gender, and diet of the subject, the time of administration, the route of administration, the rate of excretion, any drug combination, and the severity of the dopamine re-uptake disorder being treated.

Another aspect of the invention relates to a kit comprising a pharmaceutical composition of the invention and an instructional material. As used herein, an"instructional material"includes a publication. a recording, a diagram, or any other medium of expression which is used to communicate the usefulness of the pharmaceutical composition of the invention for treating a dopamine re-uptake disorder in a subject. The instructional material may also, for example, describe an appropriate dose of the pharmaceutical composition of the invention. The instructional material of the kit of the invention may, for example, be affixed to a container which contains a pharmaceutical composition of the invention or be shipped together with a container which contains the pharmaceutical composition. Alternatively, the instructional material may be shipped separately from the container with the intention that the instructional material and the pharmaceutical composition be used cooperatively by the recipient.

The invention also includes a kit comprising a pharmaceutical composition of the invention and a delivery device for delivering the composition to a subject. By way of example, the delivery device may be a squeezable spray bottle, a metered-dose spray bottle, an aerosol spray device, an atomizer, a dry powder delivery device, a self-propelling solvent/powder-dispensing device, a syringe, a needle, a tampon, or a dosage measuring container. The kit may further comprise an instructional material as described herein.

Definitions As used herein, the following terms have the meaning associated with them in this section.

A"dopamine re-uptake disorder"is a symptom or combination of symptoms experienced by a patient which are attributable to inhibition of dopamine re- uptake catalyzed by nerve cell dopamine transporter protein (DAT). Inhibition of dopamine re-uptake in one of these disorders may be mediated by a compound which is not normally present in the patient (e. g. cocaine) or by a compound which is normally

present in the patient at a different concentration. Inhibition of dopamine re-uptake mediated by cocaine is an example of a dopamine re-uptake disorder.

A"cocaine antagonizing amount"of a dopamine re-uptake inhibitor of the invention is an amount of the inhibitor which decreases the proportion of DAT bound with cocaine at equilibrium by at least about l %, preferably by at least about 10%, more preferably by at least about 50%, and even more preferably by at least about 90%.

An"aryl sulfonyl hydrazide"is a compound having the general formula A"fused cycloaryl group"is a chemical moiety comprising two or more cycloaryl moieties in which at least two of the cycloaryl moieties have at least two atoms in common. Examples of a fused cycloaryl groups include a naphthyl moiety (which comprises two fused phenyl moieties), a phenanthrene moiety, and an anthracene moiety.

A"catalyzing amount of sulfuric acid"is an amount of sulfuric acid which is sufficient to catalyze reaction of an aryl a-keto amide with an aryl sulfonyl hydrazide to yield an aryl sulfonylhydrazide amide. An example of a catalyzing amount of sulfuric acid is from about 1 millimolar to about 20 millimolar.

The invention is now described with reference to the following Examples. These Examples are provided for the purpose of illustration only and the invention should in no way be construed as being limited to these Examples, but rather should be construed to encompass any and all variations which become evident as a result of the teaching provided herein.

Example 1 Laboratorv Scale Synthesis of Threo-Methvlphenidate Phenyl glyoxylic acid piperidine amide was prepared by condensation of ethyl phenyl glyoxylate (Compound I in Figure 1) with piperidine as described (Achiwa et al., 1987, N. Chem. Pharm. Bull. 35: 2646-2655).

A first reaction mixture comprising 8.50 grams (0.039 mole) phenyl glyoxylic acid piperidine amide, 8.00 grams (0.043 mole) p-toluenesulfonylhydrazide, and 20 milliliters of an acidic solution, which comprised ethanol and a trace of sulfuric acid, was prepared and subjected to reflux for about four hours. The first reaction mixture was cooled to room temperature (i. e. about 20 degrees Celsius). After cooling, a white crystalline first intermediate product comprising phenyl glyoxylic acid piperidine amide tosylhydrazone, was present in the first reaction mixture. The first reaction mixture was filtered to separate the crystalline first intermediate product from the first reaction mixture. The crystalline first intermediate product was washed in situ on the filter with a small amount of cold ethanol (i. e. about 5 milliliters at about 25 degrees Celsius) and then with a small amount of diethyl ether (i. e. from about 10 milliliters to about 25 milliliters). Following these washing steps, the crystalline first intermediate product and was air dried on the filter. The yield of the first intermediate product was 12.0 grams, representing an 81 % reaction yield. The first intermediate product had the properties listed in Table 1.

Table 1. Properties of the first intermediate product (i. e. phenyl glyoxylic acid piperidine amide tosylhydrazone). melting point 191-193 degrees Celsius (decomposes) 1H NMR (500 MHz, CDC13) A : 8.48 (s, 1H); 7.80 (d, J 8.2 Hz, 2H); 7.55 (m, 2H); 7. 31-7.35 (m, 3H) ; 7.19 (d, J 8.2 Hz, 2H); 3.65 (app t, J 5.3 Hz, 2H); 3.14 (app t, 5.5 Hz, 2H); 2.28 (s, 3H); 1.60 (m, 4H); 1.40 (m, 2H) 13C NMR (125 MHz, CDC13) B: 161.9; 150.6; 144.0; 135.1; 132.1; 130.5; 129.5; 128.7; 127.9 ; 126.2; 42.1; 26.2; 25.5; 24.1; 21.4 IR (KBr) C: 1623.3; 1163.1 HRMSD calculated for C20H23N303S (M + NH4): 403.1804, found: 403.1809.

Notes: AChemical shift values, in parts per million BChemical shift values, in parts per milion C Infrared Peaks, in inverse centimeters D HRMS means high resolution mass spectrum A second reaction mixture was prepared comprising 9.25 grams (0.024 mole) phenyl glyoxylic acid piperidine amide tosylhydrazone, 200 milliliters of toluene, and 24.5 milliliters of a deprotonating solution comprising 1.0 molar potassium tert-butoxide in tert-butanol. After combining the components of the second reaction mixture, the second reaction mixture became a clear orange liquid upon heating. The second reaction mixture was then subjected to reflux for about ninety minutes, during which time the orange color attributable to the phenyl glyoxylic acid piperidine amide tosylhydrazone gradually disappeared and a precipitate comprising potassiump-toluensulfinate formed.

After cooling the second reaction mixture to room temperature, the second reaction mixture was mixed with 50 milliliters of water to form a mixture having an aqueous phase and an organic phase. The organic phase was separated from the aqueous phase, and the aqueous phase was discarded. The organic phase was mixed with 50 milliliters of water, and was again separated from the aqueous phase of

the mixture. The organic phase was dried by sealing the organic phase in a container which contained magnesium sulfate. Following drying, the organic phase was filtered and evaporated to yield 5.27 grams of a pale yellow oil. The pale yellow oil was dissolved in 10 milliliters of diethyl ether, and 15 milliliters of light petroleum ether was gradually added to the solution with swirling to yield a precipitation mixture.

Upon standing at room temperature, the second intermediate product, which comprised trans-1-aza-2-oxo-3-phenyl-bicyclo [4.2.0] octane, crystallized in the precipitation mixture. In some preparations, scratching of the container containing the precipitation mixture or seeding of the precipitation mixture was required. The precipitation mixture was cooled to about 5 degrees Celsius in a refrigerator, and the second intermediate product was collected by filtration, washed with a small amount (i. e. about 10 milliliters) of light petroleum ether, and air dried. The yield of the second intermediate product was 2.90 grams, representing a 60% yield with respect to the first intermediate product. Additional second intermediate product could be obtained by evaporating the precipitation mixture and crystallizing the second intermediate product as described herein. The second intermediate product had the properties listed in Table 2. The trans-stereochemistry of the second intermediate product was established by X-ray crystallographic analysis, using known methods.

Table 2. Properties of the second intermediate product (i. e. trans-1-aza-2-oxo-3- phenyl-bicyclo [4.2.0] octane). melting point 87 degrees Celsius H NMR (500 MHz, CDC13) A : 7.29-7.32 (m, 2H); 7.21-7.27 (m, 3H); 3.94 (d, J 1.5 Hz, 1H); 3.90 (app dd, J 13. 3,4.3 Hz, 1H); 3.34 (m, 1H); 2.77 (m, 1H); 2.15 (m, 1H); 1.89 (m, 1H); 1.66 (m, 1H); 1.34-1.46 (m, 3H) 13C NMR (125 MHz, CDCl3)B: 166.1; 135.5; 128.6; 128.4; 127.1; 63.3; 56.6; 38.8; 30.4; 24.3; 22.1 IR (KBr) C: 1745.7; 1399.1 HRMSD calculated for CHNO (M+H) : 202.1232, found: 202.1226.

Notes: AChemical shift values, in parts per million BChemical shift values, in parts per million CInfrared Peaks, in inverse centimeters D HRMS means high resolution mass spectrum A third reaction mixture was prepared comprising 10 milliliters of HCI- saturated methanol and 0.50 gram (0.00248 mole) trans-1-aza-2-oxo-3-phenyl bicyclo [4.2.0] octane. HCl-saturated methanol was prepared by saturating methanol with HCI gas while cooling the methanol in an ice water bath. The third reaction mixture was subjected to reflux for from about thirty to about ninety minutes, which permitted the reaction to proceed to completion. HCl-saturated methanol was evaporated, 5 milliliters of ethyl acetate was added to the residue, and the residue was triturated. The mixture of triturated residue and ethyl acetate was diluted by adding 10 milliliters of diethyl ether to the mixture. The residue, comprising threo-methylphenidate, was collected by filtration, washed with a small amount (i. e. from about 10 milliliters to about 20 milliliters) of diethyl ether, and air dried. The yield of the product was 600 milligrams, which represents a 90% yield of threo-methylphenidate from trans-1-aza-2-oxo-3-phenyl bicyclo [4.2.0] octane. The product, threo- methylphenidate exhibited the properties listed in Table 3.

Table 3. Properties of the product (i. e. threo-methylphenidate). melting point 206 degrees Celsius (decomposes) 1H NMR (500 MHz, D2O) : 7.33-7.40 (m, 3H) ; 7.24-7.27 (m, 2H) ; 3.92 (d, J 9.2 Hz, 1H) ; 3.76 (m, 1H); 3.65 (s, 3H); 3.38 (broad d, J 12.8 Hz, 1H) ; 3.00 (dt, J 12.9,3.1 Hz, 1H) ; 1.79 (m, 1H); 1.70 (m, 1H); 1.49-1.60 (m, 2H); 1.26-1.41 (m, 2H) 13C NMR (125 MHz, D20): 173.1; 133.2; 129.4; 128.8; 128.6; 57.7; 53.6; 53.2; 45.5; 26.2; 21.7; 21.2 IR (KBr): 2400-3000 (broad); 1738.8; 1429.9; 1171.8 HRMS calculated for C14HlgNO2 (M + H): 234.1494, found: 234.1489 Notes: AChemical shift values, in parts per million BChemical shift values, in parts per million C Infrared Peaks, in inverse centimeters D HRMS means high resolution mass spectroscopy.

Example 2 Preparation of Novel Dopamine Reuptake Inhibitors The synthetic procedures described in this Example were used to generate the methylphenidate analogs which were used, in experiments presented in Example 3 herein, as candidate compounds for inhibiting cocaine binding to DAT while only minimally inhibiting uptake of dopamine by DAT.

All of the procedures presented in this Example were performed in flame-dried glassware which had been purged with argon. The melting point of individual compounds was assessed using a Thomas Hoover capillary melting point apparatus and is uncorrected. Infrared spectra were recorded using a Perkin-Elmer 1600 series Fourier transform infrared spectrometer. 1 H and 13 C NMR spectra were recorded using a Bruker AM-500 spectrometer. High resolution mass spectra were assessed using a VG Micromass 7070H high resolution chemical ionization spectrometer equipped with a Kratos DS-50-S data handling system.

Arvl a-Keto Ester Formation A 2.5 molar solution of a selected, freshly titrated n-butyllithium in hexanes was added dropwise at room temperature to 1 equivalent of a 2 molar solution of the corresponding aryl halide dissolved in a 1: 1 mixture of anhydrous diethyl ether and anhydrous toluene. This solution was stirred for 15 minutes at room temperature and then stirred at 45-55°C for 30 minutes. In a separate flask, 4 equivalents of diethyloxalate in 3 molar anhydrous diethyl ether was cooled to-78 °C. To this cooled solution, the aryllithium was added dropwise using a cannula, and the mixture was stirred at-78 °C for 1 hour. To quench the reaction, 2 normal HC1 was added dropwise to the mixture at 0°C. Distilled water was then added to further dissolve the salts formed, and the resulting aqueous layer was extracted using ether. The ether extracts were washed with water, dried over MgS04, filtered, and evaporated. Excess diethyloxalate was removed from the crude aryl a-keto ester product via short path distillation at a pressure of 1 millimeter of mercury. The resulting material was purified by column chromatography to yield the purified aryl a-keto ester. a-Keto Amide Formation A neat mixture of a selected amine and the aryl a-keto ester (equimolar amounts of each) was stirred at 90-100 °C for 2-5 days. The resulting oil was triturated or, alternatively, purified by column chromatography to yield the a-keto amide. a-tosvlhydrazone Formation To a solution of the a-keto amide dissolved in dimethoxyethane was added 1.1 equivalent of p-toluenesulfonhydrazide at room temperature. This solution was cooled to 0 °C and anhydrous HC1 gas was bubbled through the solution for 30 seconds. The reaction mixture was gently refluxed for 3-12 hours, as determined by monitoring by thin layer chromatography. The solution was cooled, first to room temperature at which point a precipitate formed, and then further cooled to 0 °C.

Diethyl ether was added to induce further crystallization. The precipitate was collected by filtration, washed with cold ether, and subsequently allowed to air dry to yield the

pure tosylhydrazone. The tosylhydrazone was recrystallized in a 3: 1 mixture of ether: ethanol to yield needle-like crystals of the a-tosylhydrazone.

-lactam Formation To a solution of the a-tosylhydrazone in toluene was added 1.1 equivalent of a 1 molar solution of potassium tert-butoxide in tert-butanol. This solution was added dropwise at room temperature. The mixture was heated to reflux and monitored by both thin layer chromatography and the color of the reaction mixture.

The originally yellow solution turned bright orange as the diazo compound was formed. After 30 minutes at reflux, the solution re-assumed a yellow color and TLC indicated that no starting material was present. The reaction mixture was washed twice with water, and then washed with brine. The aqueous portions were combined and extracted with ethyl acetate. The organic extracts were combined, dried over MgSO4, filtered, and evaporated. The resulting oil (or semi-solid, in some experiments) was purified by flash column chromatography. If the product was solid, further purification by re-crystallization from ether was performed to yield a single diastereomer in the form of white crystals of the (3-lactam.

Amine salt Formation Anhydrous HC1 gas was gently bubbled through a solution of the ß- lactam in MeOH at 0 °C for approximately five minutes. The reaction mixture was stirred at for 1-5 hours room temperature, until thin layer chromatography indicated that all starting material had been consumed. The solvent was evaporated, and the remaining solid was triturated with ether. The off-white solid was collected by filtration, washed with ether, and recrystallized in a Methanol-ether mixture to yield white crystals of the amine salt.

Alkvlation of 1-Aza-Bicvelo [4.2.0] Octan-8-one Methyl phenidate analogs may, alternatively, be made by alkylating a 1- aza-bicyclo ketone, as illustrated in the following benzylation of 1-aza- bicyclo [4.2.0] octan-8-one.

A solution of the ßlactam 1-aza-bicyclo [4.2.0] octan-8-one in tetrahydrofuran (THF) was added dropwise to a freshly prepared solution of lithium diisopropanolamine (LDA; 1.5 equivalents) in THF which had been pre-cooled to-78 °C. The enolate was formed by allowing the reaction to proceed for 20 minutes at-78 °C, at which point 1.5 equivalents of benzyl bromide was added dropwise. The reaction mixture was warmed to 0 °C and stirred for an additional 30 minutes. The alkylation reaction was quenched by slow addition of water to the reaction mixture.

The organic and aqueous layers were separated, and the aqueous layer was washed using ethyl acetate. The organic portions were combined, washed with brine, dried over MgSO4, filtered, and evaporated to yield a single diastereomer of the alkylated lactam, which was subsequently purified by column chromatography.

The properties of several compounds are now described.

a-Tosvlhvdrazone Amide (Compound III in Figure 1) This compound was obtained in 80.0 % yield from its starting materials, and had characteristics listed in Table 4.

Table 4. Properties of Compound III in Figure 1. melting point 191 degrees Celsius (decomposes) 1H NMR (500 MHz, CDC13): d8.48 (s, 1 H), d 7.80 (d, 2 H, J = 8.32 Hz), d 7.55-7.57 (m, 2H), d7.31-7.36 (m, 3H), 7.19 (d, 2 H, J = 8. 14 Hz), d 3.65 (t, 2 H, J=5. 3Hz), d3.14 (t, 2H, J=5. 6Hz), d2.32 (s, 3 H), d 1. 59-1.62 (m, 4H), d 1.40-1.42 (m, 2 H) 13C NMR (125 MHz, CDC13): d 161.9,150.6,144.0,135.1,132.1,130.5, 1,21.5; IR (KBr pellet): 1251,1163,1081, 659,545 cm-1; Mass Spectrum m/z (relative intensity), HRMS calculated for C20H23N303S (M + NH4+) 403.1804, found 403.1809.

Notes: A Chemical shift values, in parts per million B Chemical shift values, in parts per million C Infrared Peaks, in inverse centimeters D HRMS means high resolution mass spectroscopy.

7-Phenvl-l-aza-bicvclo [4.2.0] octan-8-one (Compound IV in Figure 1) This compound was obtained in 60 % yield from its starting materials.

The ratio of the threo: erythro isomers was about 6: 1. This compound had the characteristics listed in Table 5.

Table 5. Properties of Compound IV in Figure 1. melting point 87 degrees Celsius 1H NMR (500 MHz, CDC13): d 7.29-7.32 (m, 2 H), d 7.21-7.27 (m, 3 H), d 3.94 (d, 1 H, J = 1.49 Hz), d 3.90 (dd, 1 H, J = 13.6,4.4 Hz), d 3.33-3. 36 (m, 1 H), d 2.75-2.81 (m, 1 H), d 2.13-2.17 (m, 1 H), d 1.88-1.91 (m, 1 H), d 1.65- 1.69 (m, 1 H), d 1.34-1.46 (m, 3 H); 13C NMR (125 MHz, CDCl3) : dl66.1,135.5,128.6,128.4,127.1,63.3,56.6, 38.8,30.4,24.3,22.1; IR (KBr pellet): 2943,1746,1450,1399,743 cm-1 ; Mass Spectrum m/z (relative intensity), HRMS calculated for C 1 3H 1 5NO (M + H+) 202.1232, found 202.1226.

Notes:Notes:AChemical shift values, in parts per million BChemical shift values, in parts per million C Infrared Peaks, in inverse centimeters D HRMS means high resolution mass spectroscopy.

1-Naphthvl Amine Salt (Compound 7) This compound was obtained in 84 % yield, with respect to its starting materials, and had the characteristics listed in Table 6.

Table 6. Properties of Compound 7. melting point 222 degrees Celsius (decomposes) 1H NMR (500 MHz, CD30D): d 8.10 (d, 1 H, J = 8.52 Hz), d 7.90 (dd, 1 H, J= (d, 1 H, J = 8. 00 Hz), d 7.58 (ddd, 1 H, J = 8.31,6.84, 1.36 Hz), d 7.51 (ddd, 1 H, J=8.03,6.85,1.00 Hz), d 7.41-7.47 (m, 2 H), d 4.75 (d, 1 H, J=9. 92Hz), d3.97-4.02 (m, 1 H), d 3.64 (s, 3 H), d 3.44-3.49 (m, 1 H), d3.11 (ddd, 1 H, J = 12. (d, 1 H, J= 14. 17Hz), d 1.64-1.73 (m, 2 H), d 1.35-1.45 (m, 2 H), d 1.25 (d, 1 H, J = 10.61 Hz); # 13C NMR (125 MHz, CD30D): d 174.1,135.8,132.9,131.7,130.3,128. 3, 127.4,127.3,126.6,123.9,59.7,53.5,50.3,46.7,27.5,23.4,22.9; IR (KBr pellet): 2942,1733,1579,1430,1318,1192cm~1 ; Mass Spectrum m/z (relative intensity), HRMS calculated for C 1 8H2 I N02 (M + H+) 284.1651, found 284.1649.

Notes: AChemical shift values, in parts per million BChemical shift values, in parts per million C Infrared Peaks, in inverse centimeters D HRMS means high resolution mass spectroscopy.

2-Naphthvl Amine Salt (Compound 8) This compound was obtained in 82 % yield from its starting materials, and had the characteristics listed in Table 7.

Table 7. Properties of Compound 8. melting point 215 degrees Celsius (decomposes); 1 1H NMR (500 MHz, CD30D): d 7.89-7.95 (m, 3 H), d 7.83 (s, 1 H), d 7.53- 7.57 (m, 2 H), d 7.41-7.43 (m, 1 H), d 4.09 (d, 1 H, J = 9. 79 Hz), d 3.98 (dt, 1 H, J=10.7,2.89 Hz), d 3.76 (s, 3 H), d 3.47-3.5 (m, 1 H), d 3.16 (dt, 1 H, J= 12.86,3.28 Hz), d 1.68-1.92 (m, 3 H), d 1.43-1.59 (m, 3 H); 13C NMR (125 MHz, CD30D): d 173.3,134.9,134.6,132.4,130.3,129.3, 128.9,128.8,127.9,127.8,126.4,59.2,55.4,53.5,46.7,27.9,23.4, 22.8; IR (KBr pellet): 2938,2710,1734,1558,1430,1193 cm-1; Mass Spectrum m/z (relative intensity), HRMS calculated for C I 8H2 I N02 (M + H+) 284.1651, found 284.1653.

Notes: A Chemical shift values, in parts per million B Chemical shift values, in parts per million C Infrared Peaks, in inverse centimeters D HRMS means high resolution mass spectroscopy.

Benzyl Amine Salt (Compound 9 ! This compound was obtained in 81 % yield from its starting materials, and had the characteristics listed in Table 8.

Table 8. Properties of Compound 9.

H NMR (500 MHz, CD30D): d 7.20-7.34 (m, 5 H), d 3.61 (s, 3 H), d 3.43- 3.46 (m, 2 H), d 2.97-3.10 (m, 4 H), d 2.12-2.16 (m, 1 H), d 1.91-1.97 (m, 2 H), d 1.51-1.77 (m, 3 H); 13C NMR (125 MHz, CD30D): d 174.0,138.7,129.9,129.7,128.1,59.4, ; IR (neat): 3390,2951,2850,2711,1732,1455,1434,1224,1172cl~1 ; Mass Spectrum m/z (relative intensity), HRMS calculated for C15H21NO2 (M + H+) 248.1651, found 248.1653.

Notes: AChemical shift values, in parts per million BChemical shift values, in parts per million C Infrared Peaks, in inverse centimeters D HRMS means high resolution mass spectroscopy.

Pvrrolidine Salt (Compound 10) This compound was obtained in 81 % yield from its starting materials, and had the characteristics listed in Table 9.

Table 9. Properties of Compound 10. melting point 183 degrees Celsius (decomposes) 1H NMR (500 MHz, CD30D): d 7.31-7.44 (m, 5 H), d 4.20 (dt, 1 H, J=10.39, (d, 1 H, J = 10. 87 Hz), d 3.74 (s, 3 H), d 3. 33-3.43 (m, 2 H), d 2.04-2.10 (m, 1 H), d 1.90-1.96 (m, 1 H), d 1.74-1.80 (m, 1 H), d 1.62-1.70 (m, 1 H); 13C NMR (125 MHz, CD30D): d 173.7,136.5,130.4,129.6,129.3,62.6, 54.8,53.2,47.2,30.2,24.7; IR (KBr pellet): 3448,2889,1733,1276,1167 cm-1 ; Mass Spectrum m/z (relative intensity), HRMS calculated for C13Hl7NO2 (M + H+) 220.1338, found 220.1339.

Notes: A Chemical shift values, in parts per million B Chemical shift values, in parts per million C Infrared Peaks, in inverse centimeters D HRMS means high resolution mass spectroscopy.

Hexamethvleneimine Salt (Compound 11) This compound was obtained in 86 % yield from its starting materials, and had the characteristics listed in Table 10.

Table 10. Properties of Compound 11. melting point 184 degrees Celsius (decomposes) 1H NMR (500 MHz, CD30D): d 6.87-7.01 (m, 5 H), d 3.56-3. 63 (m, 2 H), d 3.30 (s, 3 H), d d 2.87-2.97 (m, 2 H), d 1.45-1.57 (m, 2 H), d 1.29-1.39 (m, 2 H), d 1.05-1. 25 (m, 4 H); 13C NMR (125 MHz, CD30D): d 173.6,136.1,130.5,129.7,129.5,61.2, 55.3,53.3,47.1,29.2,27.4,26.5,25.9; IR (KBr pellet): 2933,1729,1585,1456,1435,1219,1168 cm-1 Mass Spectrum m/z (relative intensity), HRMS calculated for C15H21NO2 (M + H+) 248.1651, found 248.1655.

Notes: Chemical shift values, in parts per million B Chemical shift values, in parts per million C Infrared Peaks, in inverse centimeters D HRMS means high resolution mass spectroscopy.

Heptamethyleneimine Salt (Compound 12) This compound was obtained in 90 % yield from its starting materials, and had the characteristics listed in Table 11.

Table 11. Properties of Compound 12. melting point 167-169 degrees Celsius 1H NMR (500 MHz, CD30D): d 6.89-7.01 (m, 5 H), d 3.61 (ddd, 1 H, J=10.26,10.26,3.13 Hz), d 3.50 (d, 1 H, J=10.40 Hz), d 3.30 (s, 3 H), d 2.90- 3.10 (m, 2 H), d 1.05-1.66 (m, 10 H); NMR#13C (125 MHz, CD3OD): d 173.8, 136.1, 130.5, 129.7, 129.4, 59.7, 2,28.9,26.0,24.9,23.9; IR (KBr pellet): 1436,1258,1172 cm-1 ; Mass Spectrum m/z (relative intensity), HRMS calculated for C 16H23NO2 (M + H+) 262.1807, found 262.1795.

Notes: A Chemical shift values, in parts per million B Chemical shift values, in parts per million C Infrared Peaks, in inverse centimeters D HRMS means high resolution mass spectroscopy.

Morpholine Salt (Compound 13 ! This compound was obtained in 90 % yield from its starting materials, and had the characteristics listed in Table 12.

Table 11. Properties of Compound 12. melting point 80 degrees Celsius 1H NMR (500 MHz, D20): d 7.35-7.42 (m, 3 H), d (m, 2 H), d 4.02- 4.07 (m, 2 H), d 3.96 (ddd, 1 H, J = (ddd, 1 H, J = 13.2,10.5,2.68 Hz), d 3.66 (s, 3 H), d 3.60-3.64 (m, 1 H), d 3.45-3.51 (m, 1 H), d 3.39 (ddd, 1 H, J = 13.2,2.8,2.8 Hz), d 3.27 (ddd, 1 H, J = 14.14,10.51,3.76 Hz); 13CNMR (125MHz, D20): d 172.4,132.2,128.9,128.5,128.3,66.0,63.8, ; IR (KBr pellet): 2615,2462,1742,1582,1443,1280,1110 cm-i; Mass Spectrum m/z (relative intensity); HRMS calculated for C13Hl7NO3 (M + H+) 236.1286, found 236.1281.

Notes: A Chemical shift values, in parts per million BChemical shift values, in parts per million CInfrared Peaks, in inverse centimeters D HRMS means high resolution mass spectroscopy.

Example 3 Biological Evaluation of Novel Dopamine Re-uptake Inhibitors In the experiments presented in this Example, the ability of several methylphenidate analogs to inhibit binding of a radioactively-labeled cocaine analog to the dopamine transporter (DAT) protein in rat striatal homogenates was assessed.

These experiments demonstrate the usefulness of certain of these analogs as cocaine antagonists. Furthermore, the results of these experiments will be understood by the skilled artisan as indicative that methylphenidate analogs described herein may be used

in treatment of cocaine abusers and addicts, and to treat patients afflicted with other dopamine-related neurological disorders.

The materials and methods used in the experiments presented in this Example are now described.

Assays which assessed equilibrium binding of radio-labeled (i. e. 1251) IPT with DAT were performed in the presence and absence of methylphenidate analogs in order to determine the value of KiIPT binding as an approximation of the value of Kicocaine binding for each analog. IPT was used because the binding affinity and profile of IPT are comparable to that of the high affinity DAT ligand (and cocaine analog) designated CFT, and because IPT can be prepared with very high specific activity (e. g. 2000 Ci/mmol). IPT has the following chemical structure.

Assays which assessed equilibrium binding of radio-labeled (i. e. tritiated) dopamine with DAT were performed in the presence and absence of methylphenidate analogs in order to determine the value of Kidopamine uptake for each analog. Except as described herein, these bindings assays were performed as described (Kung et al., 1995, Synapse 20: 316-324).

These assays were performed using DAT obtained from rat striatal homogenates in the presence of a buffer solution containing 50 millimolar Tris-HCl (pH 7.4), 120 millimolar NaCI, and 0.1 % (w/v) bovine serum albumin. The data presented in the Table in this Example represent mean standard deviation values determined from three separate experiments. The value of the inhibition constant Dopamine uptake for (125I) IpT is 0 28 nanomolar. The value of the kinetic constant

Kd for binding of (125I)-IPT with DAT is 0.25 nanomolar. The value of the kinetic -, constant Km for binding of ('H)-dopamine with DAT is 1.2 millimolar.

The results obtained from the experiments presented in this Example are now described.

Values of KiIPT binding and Kidopamine uptake determined for each of the analogs described in this Example are listed in Table 13. The chemical formulae of the methylphenidate analogs used were as follows.

The structure of Compound 7 is

The structure of Compound 8 is The structure of Compound 9 is The structure of Compound 10 is

The structure of Compound 11 is The structure of Compound 12 is The structure of Compound 13 is X otCO2CH3 ...... T le le

Methylphenidate Analog KiIPT binding | Kidopamine uptake nanomolar nanomolar d-threo-methylphenidate 324 N/A dl-threo-methylphenidate 582 77 429 88 Compound 7194 Compound 8 79.5 ~ 7.1 85. 2 25 Compound 9 >5000 N/A Compound 101336108N/A Compound 111765113N/A Compound 12 3321 515 N/A Compoundl366891348N/A

Only the aromatic moiety of methylphenidate is altered in Compounds 7,8, and 9 (i. e. relative to methyl phenidate). The piperidine moiety of methylphenidate is altered in Compounds 10,11,12, and 13.

The data presented in this Example establish that increasing the size of the aryl moiety leads of methyl phenidate to enhanced binding to the DAT in the cases of the 1-naphthyl (i. e. Compound 7) and 2-naphthyl (i. e. Compound 8) analogs, relative to binding by methylphenidate. A seven-fold increase in DAT binding affinity has been achieved using the 2-naphthyl analog, Compound 8, relative to methylphenidate.

Changing the aryl moiety from phenyl to benzyl (i. e. Compound 9), in which a methylene group is interposed between the ester-bearing carbon and the phenyl ring,

significantly attenuates the binding affinity of the analog, relative to DAT binding by methylphenidate.

The data in this Example also establish that methylphenidate analog binding with DAT is sensitive to subtle changes in the piperidine ring of the analog.

Binding of each analog (i. e. Compounds 10,11,12, and 13) in which the piperidine ring was modified, relative to methylphenidate, was attenuated by a factor of 5 to 10.

Differentiation between inhibition of dopamine uptake and inhibition of cocaine binding, as expressed for example, in the ratio dopamine uptake<BR> i K cocaine binding In this Example, assessment of KiIPT binding was used to approximate of the value of Kicocaine binding Therefore, it was a goal of these experiments to identify methylphenidate analogs having the greatest value for the ratio dopamine uptake<BR> i<BR> <BR> <BR> lPT binding<BR> i Methylphenidate analogs having a greater value for this ratio are more useful for treating cocaine abusers and addicts than methylphenidate analogs having lower values.

Evaluation of the naphthyl analogs of methylphenidate (i. e. Compounds 7 and 8) reveals that although Compound 8 exhibited a higher binding affinity for the DAT than did Compound 7, the ratio dopamine aptake<BR> K ; KIPTibinding for Compound 7 was 10. The value of this ratio for both methylphenidate and the 2- naphthyl analog, Compound 8 is approximately 1. Therefore, Compound 7 is among the most selective compounds known for differentially inhibiting cocaine binding and dopamine re-uptake.

It is likely that even more selective cocaine antagonists may be identified by making additional methylphenidate analogs as described herein and by screening them as described in this Example. Such syntheses and screening require no more than routine experimentation by the skilled artisan.

The results presented in this Example demonstrate that differentiation between inhibition of cocaine binding and inhibition of dopamine re-uptake can be achieved using methylphenidate analogs.

The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety.

While this invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of this invention may be devised by others skilled in the art without departing from the true spirit and scope of the invention. The appended claims are intended to be construed to include all such embodiments and equivalent variations.