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WO1999036403A1 - Nouveaux inhibiteurs de recaptage de dopamine, leurs procedes de synthese et d'utilisation - Google Patents

Nouveaux inhibiteurs de recaptage de dopamine, leurs procedes de synthese et d'utilisation Download PDF

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Publication number
WO1999036403A1
WO1999036403A1 PCT/US1999/000711 US9900711W WO9936403A1 WO 1999036403 A1 WO1999036403 A1 WO 1999036403A1 US 9900711 W US9900711 W US 9900711W WO 9936403 A1 WO9936403 A1 WO 9936403A1
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group
alkanoyl
alkyl
compound
cycloaryl
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PCT/US1999/000711
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English (en)
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Jeffrey Winkler
Jeffrey A. Axten
Lori Krim
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The Trustees Of The University Of Pennsylvania
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Priority to AU21141/99A priority Critical patent/AU2114199A/en
Publication of WO1999036403A1 publication Critical patent/WO1999036403A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/04—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with only hydrogen atoms, halogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D225/00—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom
    • C07D225/02—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom not condensed with other rings

Definitions

  • the field of the invention is dopamine re-uptake inhibitors and methods of synthesizing and using such inhibitors.
  • 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.
  • a stereotyped drug abstinence syndrome e.g. intense central nervous system hyperactivity, perspiration, muscle twitching, and anorexia
  • 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.
  • both methylphenidate, which has the structure 1 inhibit the re-uptake of dopamine, and the two compounds have similar binding affinities for the dopamine transporter (DAT).
  • DAT dopamine transporter
  • K j is a measure of the binding affinity of a composition for an enzyme. K j 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 K j 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 K j for (-)- cocaine is 640 nanomolar and the value of K j for -threo-methylphenidate is 390 nanomolar.
  • an enzyme 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 K j values corresponding to the two activities.
  • the ratio ⁇ y dopamine uptake ⁇ s- cocaine binding i is preferably as high as possible.
  • K j COca ⁇ ne Dindm g represents the value of K j for a composition, with respect to inhibition of the cocaine binding activity of DAT
  • K j do P amine u P take represents the value of K j 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 ⁇ -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, ; 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 ⁇ -phenyl-2-piperidineacetate, ⁇ -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). 77zreo-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.
  • 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.
  • n is an integer selected from the group consisting of the integers from 0 to 7; wherein each R ⁇ is independently selected from the group consisting of cycloaryl, C j -Cg alkyl, C j -Cg alkoxy, hydroxyl, C 1 -C6 alkanoyl, halogen, amino, C j -
  • (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.
  • (fca) is a 1 -naphthalene, n is 0, m is 0, 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.
  • the invention also relates to a compound having the formula
  • the invention further relates to a compound having the formula
  • n is an integer selected from the group consisting of the integers from 0 to 7; wherein each R j is independently selected from the group consisting of cycloaryl, C j -Cg alkyl, C ⁇ C alkoxy, hydroxyl, C1-C6 alkanoyl, halogen, amino, C j - Cg alkylamino, nitro, sulfo, and sulfhydryl; wherein R ⁇ is selected from the group consisting C j -Cg 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, C ⁇ -Cg alkyl, C j -Cg alkoxy, hydroxyl, C1-C6 alkanoyl, halogen, carboxyl, C2"Cg alkanoxy, nitro, sulfo, and sulfhydr
  • the invention still further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound having the formula
  • n is an integer selected from the group consisting of the integers from 0 to 7; wherein each R j is independently selected from the group consisting of cycloaryl, C j -Cg alkyl, C j -Cg alkoxy, hydroxyl, C1-C6 alkanoyl, halogen, amino, C j - Cg 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 C j -Cg 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
  • the invention includes use of a compound for making a pharmaceutical composition, wherein the compound has the formula
  • n is an integer selected from the group consisting of the integers from 0 to 7; wherein each R j is independently selected from the group consisting of cycloaryl, C j -Cg alkyl, C j -Cg alkoxy, hydroxyl, C1-C6 alkanoyl, halogen, amino, C j - Cg 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 C j -Cg 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
  • 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
  • n is an integer selected from the group consisting of the integers from 0 to 7; wherein each R j is independently selected from the group consisting of cycloaryl, C j -Cg alkyl, C j -Cg alkoxy, hydroxyl, C1-C6 alkanoyl, halogen, amino, C j -
  • 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.
  • 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 o
  • n is an integer selected from the group consisting of the integers from 0 to 7; wherein each R j is independently selected from the group consisting of cycloaryl, C j -Cg alkyl, Ci -Cg alkoxy, hydroxyl, C1-C6 alkanoyl, halogen, amino, C j - Cg 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 C j -Cg alkyl and C1-C6 alkanoyl; wherein p is an integer selected from the group consisting of 3, 4.
  • 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, C j -Cg alkyl, C ⁇ -Cg alkoxy, hydroxyl, C1-C6 alkanoyl, halogen, carboxyl, C2"Cg alkanoxy, nitro, sulfo, and sulfhydryl, or wherein two of R 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 Q
  • the method comprises (i) reacting
  • n is an integer selected from the group consisting of the integers from 0 to 7; wherein each R j is independently selected from the group consisting of cycloaryl, C j -Cg alkyl, C j -Cg alkoxy, hydroxyl, C1-C6 alkanoyl, halogen, amino, C j -Cg 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 j -Cg alkyl and Cl- C6 alkanoyl; and (b) a cyclic ⁇ -methylene amine having the formula
  • each R3 is independently selected from the group consisting of hydrogen, C ⁇ -C alkyl, C j -Cg alkoxy, hydroxyl, C1-C6 alkanoyl, halogen, carboxyl, C2 ⁇ Cg 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 ⁇ -keto amide intermediate, (ii) reacting
  • 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.
  • the invention in another aspect, relates to a method of making threo- methylphenidate.
  • This method comprises combining phenyl glyoxylic acid piperidine amide, -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- ⁇ -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 t jreo-methylphenidate is formed.
  • the invention also includes a composition comprising threo- methylphenidate, synthesized by this method.
  • the invention relates to a method of synthesizing t/Veo-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 / 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, to
  • 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
  • n is an integer selected from the group consisting of the integers from 0 to 7; wherein each R j is independently selected from the group consisting of cycloaryl, C j -Cg alkyl, C j -Cg alkoxy, hydroxyl, C1-C6 alkanoyl, halogen, amino, C j - Cg 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 C ⁇ -Cg 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;
  • Figure 2 depicts thermal and photochemical decomposition of an aryl ⁇ -keto amide compound into isomers of a ⁇ -lactam compound.
  • the invention relates to compounds which inhibit presynaptic re-uptake of dopamine catalyzed by a cell surface protein designated the dopamine transporter (DAT).
  • DAT dopamine transporter
  • 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 o
  • n refers to an integer selected from the group consisting of the integers from 0 to 7, and refers to the number of R j attached to the "(fca)" group.
  • Each R j group is independently selected from the group consisting of cycloaryl, C j -Cg alkyl, C j -Cg alkoxy, hydroxyl, C1-C6 alkanoyl, halogen, amino, C j - Cg alkylamino, nitro, sulfo, and sulfhydryl.
  • Chem, 39:1201-1209 and include, for example, tert-butyl, methyl, chloro, fluoro, amino, nitro, hydroxy. and methoxy groups.
  • Other preferred R j groups include cycloaryl groups such as phenyl groups.
  • positions on the "(fca)" group which are not substituted by R j groups are instead be substituted by hydrogen or have no substituents, depending on the valence of the atom at that position.
  • (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.
  • m refers to an integer selected from the group consisting of 0 and 1.
  • m 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.
  • 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 C j -Cg alkyl and C1-C6 alkanoyl (i.e. -(CH2) j .gOH.
  • the alkyl and alkanoyl groups may be straight-chain or branched groups (e.g. tert-butyl).
  • R2 groups include methyl and ethyl groups.
  • 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.
  • 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.
  • the nitrogen-containing ring of the invention may be one of a variety of nitrogen-containing rings, including, for example, pyridine, pyrrolidine, and morpholine.
  • each X is carbon and p is 4, whereby the nitrogen-containing ring is pyridine.
  • 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.
  • 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, C -Cg alkyl, C j -Cg alkoxy, hydroxyl, C1-C6 alkanoyl, halogen, carboxyl, C2 ⁇ C alkanoxy, nitro, sulfo, and sulfhydryl.
  • Two of R groups, together, may be an oxo group or a double bond between two adjacent X atoms.
  • 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.
  • the dopamine re-uptake inhibitor compound has the formula
  • n, R j , (fca), R2, q, and R3 have the same meanings as described above.
  • the dopamine re-uptake inhibitor compound has the formula
  • n, R j , R2, q, and R have the same meanings as described above.
  • the dopamine re-uptake inhibitor compound of the invention has the formula O
  • n, R j , 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.
  • 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
  • n is an integer selected from the group consisting of the integers from 0 to 7; wherein each R j is independently selected from the group consisting of cycloaryl, C j -Cg alkyl, C j -Cg alkoxy, hydroxyl, C1-C6 alkanoyl, halogen, amino, C j -Cg 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 j -Cg alkyl and C 1 - C6 alkanoyl; and (b) a cyclic ⁇ -methylene amine having the formula
  • each R3 is independently selected from the group consisting of hydrogen, C j -Cg alkyl, C j -Cg alkoxy, hydroxyl, C1-C6 alkanoyl, halogen, carboxyl, C2 ⁇ Cg 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 ⁇ -keto amide intermediate (ii) reacting (a) the cycloaryl ⁇ -keto amide intermediate and
  • 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 (i ⁇ )(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.
  • a tert-butoxide salt e.g. potassium tert-butoxide
  • tert-butanol e.g. tert-butanol
  • reaction conditions for the synthetic steps of this method are not explicitly specified, they may vary and will be apparent to the skilled artisan.
  • 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 t/Veo-methylphenidate.
  • the invention also includes a composition comprising threo- methylphenidate which is synthesized using the method of the invention.
  • Tftreo-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 l), ?-toluenesulfonylhydrazide, and an acidic solution. Reaction of ethyl phenylglyoxylate (Compound I in Figure 1) with piperidine affords the ⁇ -ketoamide (Imai et al., 1987, Chem. Pharm. Bull. 35:2646), which on condensation with tosylhydrazine yields the tosylhydrazone.
  • R ⁇ r ⁇ -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.
  • a deprotonating solution is a solution comprising potassium tert-butoxide in tert- butanol.
  • tr ⁇ /75-l-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 t zreo-methylphenidate is formed in this third reaction mixture.
  • Methanolic hydrolysis of trara-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 t/Veo-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.
  • replacement of ethyl phenylglyoxylate with other arylketoacid esters leads to the incorporation of other aryl groups into the methylphenidate framework.
  • Suitable ⁇ -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
  • the homologated phenidate analog herein designated Compound 9 was prepared by stereoselective alkylation of l-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 ⁇ -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 designated >-toluenesulfonhydrazide
  • 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 ?-toluenesulfonylhydrazide, and the acidic solution.
  • Any known method of subjecting the mixture to reflux may be used.
  • 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.
  • 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 j- toluenesulfonylhydrazide.
  • concentration of the phenyl glyoxylic acid piperidine amide in the first reaction mixture may be, for example, about 2 molar.
  • 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.
  • the acidic solution may comprise ethanol and an acid such as sulfuric acid or 1 ,2 -dimethoxy ethane and an acid such as sulfuric acid or hydrochloric acid.
  • the acidic solution comprises an acidic ethanol solution comprising ethanol and at least a trace amount of sulfuric acid.
  • 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.
  • the concentration of acid which is useful in the first reaction mixture may be from about 1 millimolar to about 20 millimolar.
  • 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.
  • 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.
  • cold ethanol e.g. about 5 milliliters of ethanol at about 25 degrees Celsius to wash about 12 grams of product
  • diethyl ether e.g. from about 10 to about 20 milliliters to wash about 12 grams of product
  • 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.
  • 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.
  • concentration of the phenyl glyoxylic acid piperidine amide tosylhydrazone in the second reaction mixture may be, for example, from about 0J molar to about 0.5 molar.
  • concentration of the deprotonating agent in the second reaction mixture may also be, for example, from about 0J 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.
  • the second reaction mixture 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.
  • 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.
  • 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.
  • 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 HCl.
  • 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
  • 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 t/Veo-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.
  • 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.
  • 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.
  • 77zre ⁇ -methylphenidate may be separated from the third reaction mixture using any known method for removing methanol and acid from a composition.
  • 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 tbre ⁇ -methylphenidate may be separated from the solvents using any known method, such as filtration and may thereafter be air dried.
  • rbre ⁇ -methylphenidate made using the method of the invention may be combined with a pharaiaceutically-acceptable carrier to form a pharmaceutical composition suitable for administration to an animal such as a human.
  • pharmaceutically-acceptable carrier means a chemical composition with which t/jre ⁇ -methylphenidate may be combined and which, following the combination, can be used to administer t zre ⁇ -methylphenidate to a mammal such as a human.
  • compositions comprising t/zre ⁇ -methylphenidate may be administered systemically in oral solid formulations, ophthalmic, suppository, aerosol, topical or other similar formulations.
  • 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 tbre ⁇ -methylphenidate.
  • 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 tbreo-methylphenidate.
  • Large-scale production of tbre ⁇ -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.
  • 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.
  • laboratory methods may be used to produce milligram amounts of tbre ⁇ -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 tbre ⁇ -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).
  • the value of the inhibition constant K j 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 K j 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.
  • a dopamine re-uptake disorder such as cocaine abuse
  • a non-dopamine compound e.g. cocaine
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • sustained-release formulations have been made for other pharmaceutical compositions
  • compositions of the invention may similarly be provided in the form of such extended- or sustained-release preparations.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • compositions 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.
  • 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.
  • a material such as glyceryl monostearate or glyceryl distearate may be used to coat tablets.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Douche preparations or solutions for vaginal irrigation may be made by combining the active ingredient with a pharmaceutically acceptable liquid carrier.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 lJ-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.
  • 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.
  • 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.
  • 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 0J 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.
  • a flavoring agent such as saccharin sodium
  • a volatile oil such as saccharin sodium
  • a buffering agent such as a a buffering agent
  • a surface active agent such as methylhydroxybenzoate.
  • the droplets provided by this route of administration preferably have an average diameter in the range from about 0J to about 200 nanometers.
  • 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 0J 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, 0J 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.
  • 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 OJ-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.
  • 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.
  • 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.
  • kits comprising a pharmaceutical composition of the invention and an instructional material.
  • 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.
  • 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.
  • 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.
  • DAT nerve cell dopamine transporter protein
  • 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 1 %, preferably by at least about 10%, more preferably by at least about 50%, and even more preferably by at least about 90%.
  • 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 ⁇ -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.
  • 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.
  • 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 potassium -toluensulfinate formed.
  • 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.
  • the second intermediate product which comprised tr ⁇ «s-l-aza-2-oxo-3-phenyl-bicyclo [4.2.0] octane, crystallized in the precipitation mixture.
  • 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.
  • HRMS means high resolution mass spectrum
  • a third reaction mixture was prepared comprising 10 milliliters of HCl- saturated methanol and 0.50 gram (0.00248 mole) tr ⁇ s-l-aza-2-oxo-3 -phenyl bicyclo [4.2.0] octane.
  • HCl-saturated methanol was prepared by saturating methanol with HCl 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 tbre ⁇ -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 tbre ⁇ -methylphenidate from tr w-l-aza-2-oxo-3 -phenyl bicyclo [4.2.0] octane.
  • the product, tbre ⁇ - methylphenidate exhibited the properties listed in Table 3.
  • Methyl phenidate analogs may, alternatively, be made by alkylating a 1 - aza-bicyclo ketone, as illustrated in the following benzylation of 1-aza- bicyclo[42.0]octan-8-one.
  • This compound was obtained in 80.0 % yield from its starting materials, and had characteristics listed in Table 4.
  • This compound was obtained in 84 % yield, with respect to its starting materials, and had the characteristics listed in Table 6.
  • This compound was obtained in 82 % yield from its starting materials, and had the characteristics listed in Table 7.
  • This compound was obtained in 81 % yield from its starting materials, and had the characteristics listed in Table 8.
  • ⁇ HRMS means high resolution mass spectroscopy.
  • This compound was obtained in 81 % yield from its starting materials, and had the characteristics listed in Table 9.
  • HRMS means high resolution mass spectroscopy.
  • This compound was obtained in 86 % yield from its starting materials, and had the characteristics listed in Table 10.
  • This compound was obtained in 90 % yield from its starting materials, and had the characteristics listed in Table 11.
  • This compound was obtained in 90 % yield from its starting materials, and had the characteristics listed in Table 12.
  • Example 3 Biological Evaluation of Novel Dopamine Re-uptake Inhibitors
  • DAT dopamine transporter
  • Methylphenidate analogs having a greater value for this ratio are more useful for treating cocaine abusers and addicts than methylphenidate analogs having lower values.
  • K 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

La présente invention concerne des inhibiteurs de recaptage de dopamine, leurs procédés de synthèse et d'utilisation. Lesdits inhibiteurs comprennent le méthylphénidate, le thréo-méthylphénydate et leurs analogues.
PCT/US1999/000711 1998-01-13 1999-01-13 Nouveaux inhibiteurs de recaptage de dopamine, leurs procedes de synthese et d'utilisation WO1999036403A1 (fr)

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US8871772B2 (en) 2008-05-27 2014-10-28 Ampio Pharmaceuticals, Inc. Therapeutic methods and compounds
EP3296292A1 (fr) 2016-09-19 2018-03-21 Université de Liège Procede pour la preparation d'alkyl phenidates
US10584112B2 (en) 2016-12-11 2020-03-10 Kempharm, Inc. Methylphenidate-prodrugs, processes of making and using the same
US10906904B2 (en) 2015-07-02 2021-02-02 Horizon Orphan Llc ADO-resistant cysteamine analogs and uses thereof

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US6627625B1 (en) 1999-08-16 2003-09-30 Revaax Pharmaceuticals, Llc Treatment of behavioral disorders with β-lactam compounds
US6610681B1 (en) 1999-08-16 2003-08-26 Revaax Pharmaceuticals, Llc Neurotherapeutic clavulanate composition and method
WO2004080583A2 (fr) * 2003-03-07 2004-09-23 Isp Investments Inc. PROCEDE DE PREPARATION DE CHLORHYDRATE DE threo-METHYLPHENIDATE
WO2004080583A3 (fr) * 2003-03-07 2005-03-24 Isp Investments Inc PROCEDE DE PREPARATION DE CHLORHYDRATE DE threo-METHYLPHENIDATE
US7002016B2 (en) * 2003-03-07 2006-02-21 Isp Investments Inc. Process for the preparation of threo-methylphenidate hydrochloride
WO2006047330A2 (fr) * 2004-10-22 2006-05-04 Mark Froimowitz Analogues de methylphenidate et procedes d'utilisation associes
WO2006047330A3 (fr) * 2004-10-22 2006-09-21 Mark Froimowitz Analogues de methylphenidate et procedes d'utilisation associes
WO2006078887A2 (fr) 2005-01-20 2006-07-27 Institute For Molecular Medicine, Inc. Derives de methylphenidate et leurs utilisations
US8076485B2 (en) 2005-01-20 2011-12-13 Institute For Molecular Medicine, Inc. Methylphenidate derivatives and uses of them
US9463187B2 (en) 2005-01-20 2016-10-11 Ampio Pharmaceuticals, Inc. Methylphenidate derivatives and uses of them
US9522893B2 (en) 2008-05-27 2016-12-20 Ampio Pharmaceuticals, Inc. Therapeutic methods and compounds
US8871772B2 (en) 2008-05-27 2014-10-28 Ampio Pharmaceuticals, Inc. Therapeutic methods and compounds
US20120122927A1 (en) * 2008-06-06 2012-05-17 Ki-Ho Lee 3 or 4-substituted piperidine compounds
US8513285B2 (en) * 2008-06-06 2013-08-20 Sk Biopharmaceuticals Co., Ltd. 3 or 4-substituted piperidine compounds
AU2012286683C1 (en) * 2011-07-28 2016-04-21 Zevra Therapeutics, Inc. Methylphenidate-prodrugs, processes of making and using the same
JP2019112462A (ja) * 2011-07-28 2019-07-11 ケムファーム・インコーポレーテッド メチルフェニデート−プロドラッグ、その製造法及び使用法
RU2573835C2 (ru) * 2011-07-28 2016-01-27 Кемфарм Инк. Пролекарства метилфенидата, способы их получения и применения
US9079928B2 (en) 2011-07-28 2015-07-14 Kempharm, Inc. Methylphenidate-oxoacid conjugates, processes of making and using the same
US9453037B2 (en) 2011-07-28 2016-09-27 Kempharm, Inc Methylphenidate-prodrugs, processes of making and using the same
JP2014521656A (ja) * 2011-07-28 2014-08-28 ケムファーム・インコーポレーテッド メチルフェニデート−プロドラッグ、その製造法及び使用法
WO2013016668A3 (fr) * 2011-07-28 2013-03-21 Kempharm Inc. Promédicaments méthylphénidates, procédés de fabrication et d'utilisation de ceux-ci
JP2016222692A (ja) * 2011-07-28 2016-12-28 ケムファーム・インコーポレーテッド メチルフェニデート−プロドラッグ、その製造法及び使用法
AU2012286683B2 (en) * 2011-07-28 2015-12-17 Zevra Therapeutics, Inc. Methylphenidate-prodrugs, processes of making and using the same
US10231960B2 (en) 2011-07-28 2019-03-19 Kempharm Inc. Methylphenidate-prodrugs, processes of making and using the same
US10906904B2 (en) 2015-07-02 2021-02-02 Horizon Orphan Llc ADO-resistant cysteamine analogs and uses thereof
US11505550B2 (en) 2015-07-02 2022-11-22 Horizon Orphan Llc ADO-resistant cysteamine analogs and uses thereof
EP3296292A1 (fr) 2016-09-19 2018-03-21 Université de Liège Procede pour la preparation d'alkyl phenidates
WO2018050546A1 (fr) 2016-09-19 2018-03-22 Université de Liège Améliorations apportées ou se rapportant aux matériaux organiques
US10584113B2 (en) 2016-12-11 2020-03-10 Kempharm, Inc. Methylphenidate-prodrugs, processes of making and using the same
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