Classifications

• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
  • C12P13/00—Preparation of nitrogen-containing organic compounds
  • C12P13/001—Amines; Imines
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C231/00—Preparation of carboxylic acid amides
  • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
  • C07C233/13—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
  • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
  • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
  • C12P41/006—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by reactions involving C-N bonds, e.g. nitriles, amides, hydantoins, carbamates, lactames, transamination reactions, or keto group formation from racemic mixtures
  • C12P41/007—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by reactions involving C-N bonds, e.g. nitriles, amides, hydantoins, carbamates, lactames, transamination reactions, or keto group formation from racemic mixtures by reactions involving acyl derivatives of racemic amines
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12Y—ENZYMES
  • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
  • C12Y304/21—Serine endopeptidases (3.4.21)
  • C12Y304/21062—Subtilisin (3.4.21.62)
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/07—Optical isomers

Definitions

• the present invention is directed to processes for the preparation of lisdexamfetamine and related derivatives, wherein the processes comprise coupling to racemic or enantiomerically enriched amphetamine and wherein the resulting product is advantageously enantiomerically or diastereomerically enriched in the desired stereoisomer BACKGROUND OF THE INVENTION
• Lisdexamfetamine dimesylate is approved and marketed in the United States for the treatment of attention-deficit hyperactivity disorder in pediatric patients.
• the active compound lisdexamfetamine contains D-amphetamine covalently linked to the essential amino acid L-lysine.
• Controlled release of D- amphetamine, a psychostimulant, occurs following administration of lisdexamfetamine to a patient.
• the controlled release has been reported to occur through hydrolysis of the amide bond linking D-amphetamine and L- lysine.
• Meudt The procedure involves reacting D-amphetamine with 2,6- bis(tert-butoxycarbonylamino)hexanoic acid in the presence of an
• alkylphosphonic anhydride to form a lysine amphetamine bearing tert- butylcarbamate protecting groups and cleaving the protecting groups in a one- pot reaction or in two or more separate steps.
• the lysine amphetamine bearing benzylcarbamate protecting groups is further purified by crystallizing from a mixture comprising (i) at least one of a C 1 -C 4 aliphatic alcohol, C 1 -C 4 aliphatic carboxylic acid, aliphatic tertiary amine, or water, and (ii) (C 1 -C 4 alkyl)-CO 2 (C 1 -C 4 alkyl), to provide the lysine-amphetamine compound in up to purity of at least 99.95% (w/w), when starting with a mixture of D-amphetamine and L-amphetamine having an enantiomeric ratio of less than 99:1 (D-amphetamine to L-amphetamine).
• the purified lysine is further purified by crystallizing from a mixture comprising (i) at least one of a C 1 -C 4 aliphatic alcohol, C 1 -C 4 aliphatic carboxylic acid, aliphatic
• amphetamine bearing benzylcarbamate protecting groups is converted to lisdexamfetamine dimesylate by catalytic hydrogenation to remove the benzyloxy protecting groups and subsequent addition of methanesulfonic acid to generate the final product.
• D- amphetamine is in turn prepared from racemic amphetamine by enantiomeric resolution of a diastereomeric salt using a chiral acid (e.g. tartaric acid) or by a multi-step synthesis from expensive raw materials 1R,2S-(-)-norephedrine or 1R,2S-(+)-norpseudoephedrine.
• a chiral acid e.g. tartaric acid
• a procedure for making D-amphetamine from either 1R,2S-(-)-norephedrine or 1R,2S-(+)-norpseudoephedrine is described in US 6,399,828 to Boswell and Lo (hereinafter Boswell).
• the procedure involves converting the 1R,2S-(-)-norephedrine or 1R,2S-(+)- norpseudoephedrine to the corresponding O-acetyl-phenylpropanolamine salt, followed by catalytic hydrogenation to D-amphetamine salt.
• a variation of this procedure is described in U.S. Patent application 2009/0292143 A1 to Buenger et al.
• the procedure involves converting the 1R,2S-(-)- norephedrine or 1R,2S-(+)-norpseudoephedrine to the corresponding 1-chloro- 1-phenyl-2-propanolamine salt, treating the 1-chloro-1-phenyl-2-propanolamine salt with activated carbon followed by catalytic hydrogenation to D- amphetamine salt.
• Buenger The procedure involves converting the 1R,2S-(-)- norephedrine or 1R,2S-(+)-norpseudoephedrine to the corresponding 1-chloro- 1-phenyl-2-propanolamine salt, treating the 1-chloro-1-phenyl-2-propanolamine salt with activated carbon followed by catalytic hydrogenation to D- amphetamine salt.
• WO 2010/058206 A1 to Fishbein and Mencel hereinafter Fishbein).
• the procedure involves converting catalytic hydrogenation of the oxazolidine of 1R,2S-(-)- norephedrine or 1R,2S-(+)-norpseudoephedrine to D-amphetamine.
• Jass A hybrid approach to lisdexamfetamine starting from 1R,2S-(-)- norephedrine is described in WO 2010/148305 A1 to Jass et al. (hereinafter Jass).1R,2S-(-)-norephedrine was first converted to the corresponding 1-chloro compound with thionyl chloride and the resulting chloro-D-amphetamine hydrochloride was coupled with a bis-protected lysine to give a bis-protected chloro-lisdexamfetamine intermediate. The bis-protected chloro- lisdexamfetamine was converted to the corresponding bis-protected lisdexamfetamine by catalytic hydrogenation, and then converted to
• the coupling of the amphetamine to the protected lysine amino acid derivative for each of these methods requires either an expensive leaving group such as the N-hydroxysuccinimide ester attached to the carboxyl group of the protected lysine amino acid to promote amide coupling conditions or other reagents used to activate a carboxylic acid group for reaction with an amine (e.g., D-amphetamine) include, for example, carbodiimides (such as dicyclohexylcarbodiimide; N,N'-diisopropylcarbodiimide; and I-ethy1-3-(3- dimethylaminopropyl) carbodiimide), phosphonium reagents (such as benzotriazol-I-yloxytris(dimethylamino)phosphonium hexafluorophosphate), uronium reagents (2-(1H-benzotriazole-I-yl)-I, I ,3,3-tetra
• a shorter, more cost-effective route would be provided by selective conversion of racemic amphetamine to lisdexamfetamine by taking advantage of the chirality of the protected lysine amino acid derivative.
• Miyazawa et al., J. Chem Soc. PerkinTrans 1, 2002, 390– 395 describe the ⁇ -chymotrypsin catalyzed conversion of a racemic amine and N-Z-(S)-phenylalanine esters to give primarily the S,S-diastereomer of the resulting amide.
• phenylethylamines structurally related to amphetamine.
• the resolution described by MUNOZ et al. is directed to compounds which (unlike lisdexamfetamine) contain only a single stereo-center.
• GONZALEZ-SABIN et al. in Tetrahedron Asymmetry, 2000, pp1315-1320, Vol.13 describe CAL-B- catalyzed resolution of ⁇ -substituted isopropylamines.
• GONZALEZ- SABIN describe the use of Candida antarctica lipase B for enantioselective acylation of racemic amines, wherein the major enantiomer product is the (R)- amide.
• the present invention is directed to a process for the preparation of a diastereomerically enriched amphetamine derivative, a compound of formula (X)
• R 1 is selected from the group consisting of phenyl and benzyl; wherein the phenyl or benzyl is optionally substituted with one to three substituents independently selected from the group consisting of C 1-4 alkyl and C 1-4 alkoxy;
• R 2 is selected from the group consisting of C 1-5 alkyl
• R 3 is selected from the group consisting of hydrogen and C 1-4 alkyl;
• R 4 is an amino acid radical;
• R 1 is selected from the group consisting of phenyl and benzyl; wherein the phenyl or benzyl is optionally substituted with one to three substituents independently selected from the group consisting of C 1-4 alkyl and C 1-4 alkoxy;
• R 2 is selected from the group consisting of C 1-5 alkyl
• R 3 is selected from the group consisting of hydrogen and C 1-4 alkyl;
• R 4 is an amino acid radical;
• a compound of formula (V) is a first nitrogen protecting group, wherein PG 2 is a second nitrogen protecting group and wherein A 1 is selected from the group consisting of with a compound of formula (VI) (also known as amphetamine or 1-phenylpropan-2-amine); wherein the compound of formula (IV) is racemic or is present in an enantiomeric excess of one of its corresponding enantiomers (preferably the D- enantiomer); in the presence of an S-selective enzyme catalyst; wherein the S- selective enzyme catalyst is not a natural lipase; neat or in a solvent; to yield the corresponding compound of formula (VII); wherein the compound of formula (VII) is present in a diastereomeric excess (preferably in a
• diastereomeric a diastereomeric excess of at least about 60%, more preferably, in a diastereomeric excess of at least 75%, more preferably in a diastereomeric
• the present invention is further directed to a process for the preparation of pharmaceutically acceptable salts of lisdexamfetamine, preferably the dimesylate salt of lisdexamfetamine, as described in more detail herein.
• the present invention is further directed to a process for the preparation of a diastereomerically enriched a compound of formula (XX)
• R 1 is selected from the group consisting of phenyl and benzyl; wherein the phenyl or benzyl is optionally substituted with one to three substituents independently selected from the group consisting of C 1-4 alkyl and C 1-4 alkoxy;
• R 2 is selected from the group consisting of C 1-5 alkyl
• R 3 is selected from the group consisting of hydrogen and C 1-4 alkyl;
• R 4 is an amino acid radical;
• R 1 is selected from the group consisting of phenyl and benzyl; wherein the phenyl or benzyl is optionally substituted with one to three substituents independently selected from the group consisting of C 1-4 alkyl and C 1-4 alkoxy;
• R 2 is selected from the group consisting of C 1-5 alkyl
• R 3 is selected from the group consisting of hydrogen and C 1-4 alkyl
• R 4 is an amino acid radical
• the present invention is further directed to a product prepared according to any of the process(es) described herein.
• a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the product prepared according to any of the process(es) described herein.
• An illustration of the invention is a pharmaceutical composition made by mixing the product prepared according to any of the process(es) described herein and a pharmaceutically acceptable carrier.
• Illustrating the invention is a process for making a pharmaceutical composition comprising mixing the product prepared according to any of the process(es) described herein and a pharmaceutically acceptable carrier.
• the present invention is directed to a product prepared according to any of the process(es) described herein for use as a medicament.
• the present invention is directed to a product prepared according to any of the process(es) described herein for use in the treatment of attention deficit hyperactivity disorder (ADHD), major depressive disorder, cognitive impairment associated with schizophrenia, excessive daytime sleepiness or binge eating disorder.
• ADHD attention deficit hyperactivity disorder
• major depressive disorder cognitive impairment associated with schizophrenia
• excessive daytime sleepiness or binge eating disorder excessive daytime sleepiness or binge eating disorder.
• the present invention is directed to a composition
• a composition comprising a product prepared according to any of the process(es) described herein for the treatment of attention deficit hyperactivity disorder (ADHD), major depressive disorder, cognitive impairment associated with schizophrenia, excessive daytime sleepiness or binge eating disorder.
• ADHD attention deficit hyperactivity disorder
• major depressive disorder cognitive impairment associated with schizophrenia
• excessive daytime sleepiness or binge eating disorder a product prepared according to any of the process(es) described herein for the treatment of attention deficit hyperactivity disorder (ADHD), major depressive disorder, cognitive impairment associated with schizophrenia, excessive daytime sleepiness or binge eating disorder.
• ADHD attention deficit hyperactivity disorder
• cognitive impairment associated with schizophrenia excessive daytime sleepiness or binge eating disorder.
• Another example of the invention is the use of a product prepared according to any of the process(es) described herein in the preparation of a medicament for treating: (a) attention deficit hyperactivity disorder (ADHD), (b) major depressive disorder, (c) cognitive impairment associated with ADHD
• the present invention is directed to a product prepared according to any of the process(es) described herein for use in a methods for treating attention deficit hyperactivity disorder (ADHD), major depressive disorder, cognitive impairment associated with schizophrenia, excessive daytime sleepiness or binge eating disorder, in a subject in need thereof.
• ADHD attention deficit hyperactivity disorder
• major depressive disorder cognitive impairment associated with schizophrenia
• excessive daytime sleepiness or binge eating disorder in a subject in need thereof.
• the present invention is directed to processes for the preparation of diastereomerically enriched compounds of formula (X)
• the present invention is further directed to processes for the preparation of lisdexamfetamine, pharmaceutically acceptable salts thereof and derivatives thereof, as described in more detail herein.
• the present invention is directed to a process for the preparation of lisdexamfetamine or lisdexamfetamine dimesylate comprising S- selected enzyme catalyzed coupling of protected L-lysine with racemic amphetamine; wherein the product is diastereomerically enriched with lisdexamfetamine.
• the present invention is directed to a process for the preparation of lisdexamfetamine dimesylate, useful for the treatment of attention deficit hyperactivity disorder (ADHD) in children and adults.
• ADHD attention deficit hyperactivity disorder
• the process(es) of the present invention (for example the process(es) for the preparation of lisdexamfetamine and pharmaceutically acceptable salts thereof), use racemic amphetamine, yet nonetheless result in high diastereoselectivity in the final product.
• This provides a cost / and or handling advantage over previously disclosed processes, particularly for large scale / commercial manufacture.
• the process(es) of the present invention allow for the use of a relatively inexpensive carboxylic acid or alkyl ester coupling reaction (for example, a methyl ester coupling reaction), rather than the more expensive activated esters or coupling agents of previously disclosed processes.
• the present invention is directed to a process for the preparation of a compound of formula (X) wherein R 1 is selected from the group consisting of benzyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2- methoxyphenyl, 3-methoxyphenyl and 4-methoxyphenyl.
• R 1 is selected from the group consisting of benzyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2- methoxyphenyl, 3-methoxyphenyl and 4-methoxyphenyl.
• R 1 is selected from the group consisting of benzyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2- methoxyphenyl, 3-methoxyphenyl and 4-methoxyphenyl.
• R 1 is benzyl.
• the present invention is directed to a process for the preparation of a compound of formula (X) wherein R 2 is selected from the group consisting of C 1-5 alkyl. In another embodiment, the present invention is directed to a process for the preparation of a compound of formula (X) wherein R 2 is selected from the group consisting of methyl, ethyl, isopropyl and t-butyl. In another embodiment, the present invention is directed to a process for the preparation of a compound of formula (X) wherein R 2 is selected from the group consisting of methyl and ethyl. In another embodiment, the present invention is directed to a process for the preparation of a compound of formula (X) wherein R 2 is methyl.
• the present invention is directed to a process for the preparation of a compound of formula (X) wherein R 3 is selected from the group consisting of hydrogen and C 1-3 alkyl. In an embodiment, the present invention is directed to a process for the preparation of a compound of formula (X) wherein R 3 is selected from the group consisting of hydrogen, methyl and ethyl. In another embodiment, the present invention is directed to a process for the preparation of a compound of formula (X) wherein R 3 is hydrogen or methyl.
• the present invention is directed to a process for the preparation of a compound of formula (X) wherein R 4 is selected from the group consisting of an amino acid radical and a nitrogen-protected amino acid radical.
• the present invention is directed to a process for the preparation of a compound of formula (X) wherein R 4 is PG A -NH-(CH 2 ) 4 - CH(NH-PG B ), wherein each of PG A and PG B are each an independently selected nitrogen protecting group.
• the present invention is directed to a process for the preparation of a compound of formula (X) wherein R 4 is PG A -NH-(CH 2 ) 4 -CH(NH-PG B ), and wherein each of PG A and PG B are the same and are a suitably selected nitrogen protection group, preferably a nitrogen protecting group selected from Boc, CBz, Alloc or Cinnoc, more preferably, PG A and PG B are the same and are Boc or CBz.
• the present invention is directed to a process for the preparation of a compound of formula (X) wherein R 5 is selected from the group consisting of hydrogen C 1-6 alkyl. In another embodiment, the present invention is directed to a process for the preparation of a compound of formula (X) wherein R 5 is selected from the group consisting of hydrogen and C 1-3 alkyl. In another embodiment, the present invention is directed to a process for the preparation of a compound of formula (X) wherein R 5 is selected from the group consisting of hydrogen, methyl and ethyl. In another embodiment, the present invention is directed to a process for the preparation of a compound of formula (X) wherein R 5 is selected from the group consisting of hydrogen and methyl.
• the present invention is directed to a process for the preparation of a compound of formula (X) wherein R 5 is hydrogen. In another embodiment, the present invention is directed to a process for the preparation of a compound of formula (X) wherein R 5 is methyl.
• R 5 is hydrogen.
• the term“alkyl” whether used alone or as part of a substituent group include straight and branched chains.
• alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t- butyl, pentyl and the like.
• “C X-Y alkyl” wherein X and Y are integers, shall mean a carbon chain composition of between X and Y carbon atoms.
• “C 1-4 alkyl” shall mean any straight or branched chain composition of between 1 and 4 carbon atoms (including methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl and t-butyl).
• “alkoxy” shall denote an oxygen ether radical of the above described straight or branched chain alkyl groups.
• C X-Y alkoxy wherein X and Y are integers, shall mean an oxygen ether radical of the above described straight or branched chain carbon chain composition of between X and Y carbon atoms.
• C 1-4 alkoxy shall mean any oxygen ether radical of the above described straight or branched chain composition of between 1 and 4 carbon atoms.
• amino acid shall mean a compound selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, phenylalanine, proline, serine, threonine, tyrosine, cysteine, methionine, lysine, arginine, histidine, tryptophan, aspartic acid, glutamic acid, asparagine and glutamine.
• the amino acid is selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, phenylalanine, proline, serine, cysteine, methionine, aspartic acid and glutamic acid.
• the amino acid is selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, phenylalanine and proline.
• the amino acid is selected from the group consisting of glycine, alanine, valine, leucine, isoleucine and phenylalanine.
• the amino acid is lysine.
• amino acid radical shall mean an amino acid selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, phenylalanine, proline, serine, threonine, tyrosine, cysteine, methionine, lysine, arginine, histidine, tryptophan, aspartic acid, glutamic acid, asparagine and glutamine, wherein the carboxy portion of the amino acid group is removed. More particularly, the amino acid radical is selected from the group consisting of the following structures:
• the amino acid radical is selected from the group consisting of amino acid radical of glycine, amino acid radical of alanine, amino acid radical of valine, amino acid radical of leucine, amino acid radical of isoleucine, amino acid radical of phenylalanine, amino acid radical of proline, amino acid radical of serine, amino acid radical of cysteine, amino acid radical of methionine, amino acid radical of aspartic acid and amino acid radical of glutamic acid.
• the amino acid radical is selected from the group consisting of amino acid radical of glycine, amino acid radical of alanine, amino acid radical of valine, amino acid radical of leucine, amino acid radical of isoleucine, amino acid radical of phenylalanine and amino acid radical of proline.
• the amino acid radical is selected from the group consisting of amino acid radical of glycine, amino acid radical of alanine, amino acid radical of valine, amino acid radical of leucine, amino acid radical of isoleucine and amino acid radical of
• the amino acid radical is the amino acid radical of lysine.
• the term“nitrogen-protected amino acid radical” shall mean any amino acid radical as defined herein, wherein at one or more of the nitrogen atoms present in the amino acid radical is substituted with a suitably selected nitrogen protecting groups. In an embodiment, one nitrogen atom present in the amino acid radical is substituted with a suitably selected nitrogen protecting groups. In another embodiment, each of the nitrogen atoms present in the amino acid radical is substituted with a suitably selected nitrogen protecting groups. In an embodiment, the nitrogen protecting group(s) on the nitrogen-protected amino acid radical are each independently selected from the group consisting of Boc, CBz, Alloc and Cinnoc; preferably, Boc or CBz.
• the nitrogen protecting groups are the same and are selected from the group consisting of Boc, CBz, Alloc and Cinnoc, preferably Boc or CBz.
• the nitrogen-protected amino acid radical is a nitrogen-protected amino acid radical of lysine, wherein the nitrogen-protected amino acid radical of lysine contains two nitrogen protecting groups, and wherein the two nitrogen protecting groups are the same and are selected from the group consisting of Boc, CBz, Alloc and Cinnoc (preferably, the two nitrogen protecting groups are the same and are selected from the group consisting of Boc and CBz).
• the amino acid radical contains additional reactive groups, such as an O atom (for example, as a terminal OH group) or a S atom (for example, as a terminal SH group), said reactive groups may be optionally protected with a suitably selected protecting groups, according to known methods.
• the protecting group is then removed, according to known methods, at a suitable subsequent step within the process.
• Conventional protecting groups, as well as methods of the attachment and removal of such groups are described in for example, T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, and similar standard texts.
• substituents e.g., alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, etc.
• that group may have one or more substituents, preferably from one to five substituents, more preferably from one to three substituents, most preferably from one to two substituents,
• substituents independently means that when more than one of such substituents is possible, such substituents may be the same or different from each other.
• notation“*” shall denote the presence of a
• the compounds according to this invention may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
• the enantiomer is present at an enantiomeric excess of greater than or equal to about 60%, more preferably, the enantiomer is present at an enantiomeric excess of greater than or equal to about 75%, more preferably, the enantiomer is present at an enantiomeric excess of greater than or equal to about 80%, more preferably, at an enantiomeric excess of greater than or equal to about 90%, more preferably still, at an enantiomeric excess of greater than or equal to about 95%, more preferably still, at an enantiomeric excess of greater than or equal to about 98%, most preferably, at an enantiomeric excess of greater than or equal to about 99%.
• the diastereomer is present at an diastereomeric excess of greater than or equal to about 60%, more preferably, the diastereomer is present at an diastereomeric excess of greater than or equal to about 75%, more preferably, the
• diastereomer is present at an diastereomeric excess of greater than or equal to about 80%, more preferably, at an diastereomeric excess of greater than or equal to about 90%, more preferably still, at an diastereomeric excess of greater than or equal to about 95%, more preferably still, at an diastereomeric excess of greater than or equal to about 98%, most preferably, at an
• crystalline forms for the compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention.
• some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
• any element in particular when mentioned in relation to a compound of formula (I), shall comprise all isotopes and isotopic mixtures of said element, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form.
• a reference to hydrogen includes within its scope 1 H, 2 H (D), and 3 H (T).
• references to carbon and oxygen include within their scope respectively 12 C, 13 C and 14 C and 16 O and 18 O.
• the isotopes may be radioactive or non-radioactive.
• Radiolabelled compounds of formula (I) may comprise a radioactive isotope selected from the group of 3 H, 11 C, 18 F, 122 I, 123 I, 125 I, 131 I, 75 Br, 76 Br, 77 Br and 82 Br.
• the radioactive isotope is selected from the group of 3 H, 11 C and 18 F.
• the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment.
• a“phenylC 1 - C 6 alkylaminocarbonylC 1 -C 6 alkyl” substituent refers to a group of the formula
• HPLC High Performance Liquid Chromatography
• iPrOH Isopropyl Alcohol (or isopropanol)
• NQAD TM Nano Quantity Analyte Detector
• the S-selective and R-selective enzyme catalyst(s) which may be used in the process(es) of the present invention include, but are not limited to, a hydrolytic enzyme, also known as a hydrolases;. Hydrolases are generally divided into several sub classes, such as proteases (also often called peptidases), lipases, esterases, acylases, amidases, etc. The classification is largely based on the type of natural reaction that is catalysed by the enzymes.
• the S-selective enzyme catalyst is a hydrolase, wherein the hydrolase is not a natural (not chemically modified) lipase.
• the S-selective or R-selective enzyme catalyst is a hydrolase enzyme other than a natural (not chemically modified) lipase.
• the hydrolytic enzyme is selected from the group consisting of proteases, esterases, acylases and amidases.
• the hydrolytic enzyme is a protease.
• the S-selective or R- selective enzyme catalyst is a hydrolase (other than natural lipase) which can catalyse the formation of an amide bond. More particularly, the S-selective enzyme catalyst is a hydrolase (other than natural lipase) which can catalyse formation of an amide bond; wherein the amide bond is formed in the S-stereo- configuration. Similarly, the R-selective enzyme catalyst is a hydrolase which can catalyse formation of an amide bond; wherein the amide bond is formed in the R-stereo-configuration.
• the S-selective or R-selective enzyme catalyst is a suitably selected protease enzyme.
• the suitably selected protease is a protease enzyme derived from a Bacillus species, more preferably a protease enzyme derived from Bacillus lichenformis.
• the enzyme catalyst may be used in its native, soluble form or it may be chemically modified or stabilized, as would be recognized by those skilled in the art (for example, the enzyme may immobilized on a solid particle, crystallized, aggregated or cross- linked to form a solid).
• the enzyme catalyst is immobilized on solid particles (also known as solid support or substrate).
• the enzyme catalyst may be immobilized on solid particles in a non-covalent manner (in such a case the enzyme is located on the carrier (e.g. adsorbed onto the solid carrier) but not covalently attached), or in a covalently bonded manner.
• the enzyme may also be immobilized on itself, for example in Cross- linked Enzyme Crystals (CLEC’s) and Cross-linked Enzyme Aggregates (CLEA’s).
• CLEC Cross- linked Enzyme Crystals
• CLA Cross-linked Enzyme Aggregates
• the enzyme catalyst is immobilized.
• the enzyme catalyst is immobilized on solid particles.
• the enzyme catalyst is immobilized on solid particles in a covalent manner. In another embodiment of the present invention, the enzyme catalyst is immobilized on solid particles in a non-covalent manner. In another embodiment of the present invention, the enzyme catalyst s immobilized on itself in a crystallized, aggregated or cross-linked manner.
• the solid particles on which the enzyme catalyst may be immobilized include, but are not limited to (a) acrylic beads, and the like, (b) solid particles or beads made from a metacrylate resin, a polyacrylate resin, a polyacrylamide polymer, a vinyl polymer, an allyl polymer, and the like, (c) silica or aluminum oxide particles, and the like.
• the solid particles are acrylic beads.
• the S-selective or R-selective enzyme (preferably, hydrolase; more preferably protease) is encapsulated in a polyvinyl matrix.
• the amount or concentration of the enzyme catalyst per unit of substrate may vary.
• the loading (e.g. concentration) of enzyme catalyst decreases, the total amount of solid substrate which is needed to reach the desired enzyme catalyst load may increase or decrease; as does the amount of solid substrate which needs to be removed at the end of the reaction / process.
• the rate of reaction may be affected by the ability of the enzyme to dissociate and / or interact with the reagents.
• the enzyme catalyst may be obtained from natural sources, or may be produced by a genetically modified organism (for example, produced using host microorganisms such as E. coli, and the like).
• the enzyme catalyst may alternatively be genetically engineered (e.g. via altered amino acid sequence) in order to improve the catalytic properties for a certain substrate combination, solvent or other reaction conditions, as would be recognized by those skilled in the art.
• the enzyme catalyst is obtained from natural sources.
• the enzyme catalyst may also be a mixture, for example, a mixture of two or more, preferably two to three, more preferably two, independently selected enzymes; wherein each enzyme is individually immobilized or non- immobilized.
• the mixture may be a mixture of a suitably selected amidase and a suitably selected protease, each of which is independently immobilized or non-immobilized.
• S-selective enzyme catalysts wherein the S- selective enzyme catalyst is immobilized on dry acrylic beads, include, but are not limited to the following (available from for example, ALIGN CHEMICALS or CHIRALVISION).
• enzyme catalysts of the present invention are S-selective or R-selective.
• the S-selective enzyme catalyst promotes greater than about 60% selectivity for the S-enantiomer. In another embodiment of the present invention, the S-selective enzyme catalyst promotes greater than about 75% selectivity for the S-enantiomer. In another embodiment of the present invention, the S-selective enzyme catalyst promotes greater than about 80% selectivity for the S-enantiomer. In another embodiment of the present invention, the S-selective enzyme catalyst promotes greater than about 85% selectivity for the S-enantiomer. In another embodiment of the present invention, the S-selective enzyme catalyst promotes greater than about 90% selectivity for the S-enantiomer. In another embodiment of the present invention, the S-selective enzyme catalyst promotes greater than about 95% selectivity for the S-enantiomer.
• the R-selective enzyme catalyst promotes greater than about 60% selectivity for the R-enantiomer. In another embodiment of the present invention, the R-selective enzyme catalyst promotes greater than about 75% selectivity for the R-enantiomer. In another embodiment of the present invention, the R-selective enzyme catalyst promotes greater than about 80% selectivity for the R-enantiomer. In another embodiment of the present invention, the R-selective enzyme catalyst promotes greater than about 85% selectivity for the R-enantiomer. In another embodiment of the present invention, the R-selective enzyme catalyst promotes greater than about 90% selectivity for the R-enantiomer.
• the R-selective enzyme catalyst promotes greater than about 95% selectivity for the R-enantiomer.
• isolated form shall mean that the compound is present in a form which is separate from any solid mixture with another compound(s), solvent system or biological environment.
• the compounds prepared according to the process(es) of the present invention are present in an isolated form.
• the term“substantially pure form” shall mean that the mole percent of impurities in the isolated compound is less than about 5 mole percent, preferably less than about 2 mole percent, more preferably, less than about 1 mole percent, more preferably, less than about 0.5 mole percent, more preferably, less than about 0.2 mole percent, more preferably, less than about 0.1 mole percent.
• the compounds prepared according to the process(es) of the present invention are present in a substantially pure form.
• the term“substantially free of a corresponding salt form(s)” when used to described the compound of formula (I) shall mean that mole percent of the corresponding salt form(s) in the isolated base of formula (I) is less than about 5 mole percent, preferably less than about 2 mole percent, more preferably, less than about 1 mole percent more preferably, less than about 0.5 mole percent, more preferably less than about 0.2 mole percent, more preferably, less than about 0.1 mole percent.
• the compounds prepared according to the process(es) of the present invention are present in a form which is substantially free of corresponding salt form(s).
• the terms“treating”, “treatment” and the like shall include the management and care of a subject or patient (preferably mammal, more preferably human) for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present invention to prevent the onset of the symptoms or complications, alleviate the symptoms or complications, or eliminate the disease, condition, or disorder.
• prevention shall include (a) reduction in the frequency of one or more symptoms; (b) reduction in the severity of one or more symptoms; (c) the delay or avoidance of the development of additional symptoms; and / or (d) delay or avoidance of the development of the disorder or condition.
• a subject in need of thereof shall include any subject or patient (preferably a mammal, more preferably a human) who has experienced or exhibited at least one symptom of the disorder, disease or condition to be prevented.
• a subject in need thereof may additionally be a subject (preferably a mammal, more preferably a human) who has not exhibited any symptoms of the disorder, disease or condition to be prevented, but who has been deemed by a physician, clinician or other medical profession to be at risk of developing said disorder, disease or condition.
• the subject may be deemed at risk of developing a disorder, disease or condition (and therefore in need of prevention or preventive treatment) as a consequence of the subject's medical history, including, but not limited to, family history, pre-disposition, co-existing (comorbid) disorders or conditions, genetic testing, and the like.
• the term“subject” as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
• the subject has experienced and / or exhibited at least one symptom of the disease or disorder to be treated and / or prevented.
• terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
• composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
• term“about” is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to the experimental and/or measurement conditions for such given value.
• an amount or numeric value herein is expressed as“greater than about X%”, said expression is intended to mean a range of from about X% to about 100%, or any amount or range therein.
• reagent or reagent class/type e.g. base, solvent, etc.
• the individual reagents are independently selected for each reaction step and may be the same of different from each other.
• the organic or inorganic base selected for the first step may be the same or different than the organic or inorganic base of the second step.
• reaction step of the present invention may be carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems.
• first and second reaction or process steps may be run in the same solvent or mixture of solvents (i.e. solvent system); or alternatively may be run in different solvents or mixture of solvents following a suitable solvent exchange, which may be completed according to known methods.
• reaction or process step(s) as herein described (or claimed) are allowed to proceed for a sufficient period of time until the reaction is complete, as determined by any method known to one skilled in the art, for example, chromatography (e.g. HPLC).
• a“completed reaction or process step” shall mean that the reaction mixture contains a significantly diminished amount of the starting material(s) / reagent(s) and a significantly increased amount of the desired product(s), as compared to the amounts of each present at the beginning of the reaction.
• the amount of starting material remaining in the reaction mixture upon completion of the reaction or process step is less than about 50 mole %, more preferably less than about 35 mole %, more preferably less than about 25 mole %, more preferably less than about 20 mole %, more preferably, less than about 15 mole %, more preferably less than about 10 mole %, more preferably less than about 5 mole %, more preferably less than about 2 mole %, more preferably less than about 1 mole %.
• the amount of any desired reaction product, present in the reaction mixture, upon completion of the reaction or process step is greater than about 50 mole %, more preferably greater than about 75 mole %, more preferably greater than about 80 mole %, more preferably, greater than about 85 mole %, more preferably greater than about 90 mole %, more preferably greater than about 95 mole %, more preferably greater than about 98 mole %, more preferably greater than about 99 mole %.
• nitrogen protecting group shall mean a group which may be attached to a nitrogen atom to protect said nitrogen atom from participating in a reaction and which may be readily removed following the reaction.
• reaction step of the present invention may be carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems.
• the processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers
• these isomers may be separated by conventional techniques such as preparative chromatography.
• the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
• the compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-D-tartaric acid and/or (+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallization and regeneration of the free base.
• the compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
• chiral HPLC against a standard may be used to determine percent enantiomeric excess (%ee).
• the enantiomeric excess may be calculated as follows
• salts of the compounds of this invention refer to non-toxic“pharmaceutically acceptable salts.”
• Other salts may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts.
• Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
• suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts.
• alkali metal salts e.g., sodium or potassium salts
• alkaline earth metal salts e.g., calcium or magnesium salts
• suitable organic ligands e.g., quaternary ammonium salts.
• representative pharmaceutically acceptable salts include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride,
• acids which may be used in the preparation of pharmaceutically acceptable salts include, but are not limited to, the following: acids including acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)- (1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronic acid
• bases which may be used in the preparation of pharmaceutically acceptable salts include, but are not limited to, the following: bases including ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)- ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.
• the present invention is directed to a process for the preparation of diastereomerically enriched amphetamine derivatives, compounds of formula (X)
• R 1 is selected from the group consisting of phenyl and benzyl; wherein the phenyl or benzyl is optionally substituted with one to three substituents independently selected from the group consisting of C 1-4 alkyl and C 1-4 alkoxy;
• R 2 is selected from the group consisting of C 1-5 alkyl
• R 3 is selected from the group consisting of hydrogen and C 1-4 alkyl;
• R 4 is an amino acid radical;
• the compound of formula (XII) is preferably present in an amount in the range of from about 1 to about 10 molar equivalents (relative to the moles of the compound of formula (XI)), or any amount or range therein, more preferably, in an amount in the range of from about 2 to about 7 molar equivalents, more preferably, in an amount in the range of from about 4 to about 6 molar equivalents, more preferably, in an amount of about 5 molar equivalents;
• S-selective enzyme catalyst preferably a hydrolytic enzyme catalyst, more preferably a protease enzyme catalyst, more preferably a protease enzyme catalyst from a Bacillus species, more preferably a protease enzyme catalyst from Bacillus lichenformis, preferably an immobilized protease enzyme catalyst (from a bacillus species, preferably Bacillus lichenformis), for example, an immobilized protease enzyme catalyst selected from the group consisting of ALC-T2-250, SAV-T2-250, P6- T2-250, P8-T2-250, P40L-T2-150 and AUAL-T2-250 (commercially available from ChiralVision, Leiden, The Netherlands); preferably P6-T2-250, an immobilized protease enzyme catalyst of Bacillus licheniformis (commercially available as Protex 6L TM );
• the protease enzyme catalyst (preferably, and enzyme catalyst immobilized on a solid support) is preferably present in an amount in the range of from about 1 wt% to about 500 wt% (relative to the amount (or weight) of the compound of formula (XI)), or any amount or range therein, more preferably, in an amount in the range of from about 10 wt% to about 200 wt%, more preferably, in an amount in the range of from about 50 wt% to about 200 wt%; neat or in a suitably selected solvent or mixture of solvents (for example, in water, in an organic solvent or mixture of organic solvents or in an inorganic solvent or mixture of inorganic solvents, or in a mixture of water and suitably selected solvent), preferably in an organic solvent, more preferably in an organic solvent selected from the group consisting of tert-butyl-methylether (MTBE), tetrahydrofuran (THF), 2-methyl-tetrahydrofuran, 1,4-diox
• the compound of formula (XIa) shall mean the compound of formula (XI) wherein Q is R 4 .
• the compound of formula (XIa) may therefore be represented by following structure:
• the compound of formula (XIb) shall mean the compound of formula (XI) wherein Q is R 4A .
• the compound of formula (XIb) may therefore be represented by following structure:
• Q is R 4 (an amino acid radical)
• the reaction of the compound of formula (XI) with the compound of formula (XII) yields the corresponding compound of formula (X).
• the compound of formula (XIII) may be de-protected by reacting with a suitably selected nucleophile such as 1,3-dimethylbarbituric acid, morpholine, and the like.
• the compound of formula (XII) is racemic amphetamine.
• the preferred ratio of racemic amphetamine (the compound of formula (XII)) to the compound of formula (XI) is in the range of from about 1/1 to about 10/1; or any ratio or range or ratios therein, preferably, the ratio is in the range of from about 2/1 to about 5/1, more preferably, the ratio is about 4/1.
• the compound of formula (XII) is amphetamine enriched with its corresponding D-enantiomer (D- amphetamine.
• the preferred ratio of the D-enantiomer enriched amphetamine / the compound of formula (XI) is in the range of from about 1/1 to about 10/1, or any ratio or range of ratios therein, preferably, the ratio is in the range of from about 2/1 to about 5/1, more preferably, the ratio is in the range of from about 3/1 about 4/1.
• the compound of formula (XII) is amphetamine enriched with its corresponding L-enantiomer (L- amphetamine).
• the preferred ratio of the D-enantiomer enriched amphetamine / the compound of formula (XI) is in the range of from about 1/1 to about 10/1, or any ratio or range of ratios therein, preferably, the ratio is in the range of from about 2/1 to about 5/1, more preferably, the ratio is in the range of from about 3/1 about 4/1.
• the maximum possible (theoretical) yield of desired product will be limited by the amount of the corresponding desired enantiomer present in the compound of formula (XII).
• the maximum possible (theoretical) yield of the desired compound of formula (X) is 50%.
• the compound of formula (XII) is enriched with its corresponding S-enantiomer, and the desired product is the corresponding S,S- diastereomer, then the maximum possible (theoretical) yield will greater than 50%, and is greater by the amount of S-enantiomer enrichment.
• the compound of formula (XII) is enriched with its corresponding R- enantiomer, but the desired product is the corresponding S,S-diastereomer, then the maximum possible (theoretical) yield will be less than 50%, and is less by the amount of R-enantiomer enrichment.
• the compound of formula (XIII) is isolated as a solid, preferably as a crystalline solid.
• the compound of formula (X) is isolated as a solid, preferably as a crystalline solid.
• the compound of formula (XIII) is isolated under selective crystallization conditions, wherein the compound of formula (XIII) is isolated as a crystalline solid in an enantiomeric or diastereomeric excess of the desired stereoisomer of at least about 60%, preferably at least about 75%, more preferably at least about 80%, more preferably at least about 90%, more preferably, at least about 95%, more preferably at least about 97%, more preferably at least about 98%, more preferably, at least about 99%.
• the compound of formula (X) is isolated under selective crystallization conditions, wherein the compound of formula (XIII) is isolated as a crystalline solid in an enantiomeric or diastereomeric excess of the desired stereoisomer of at least about 60%, preferably at least about 75%, more preferably at least about 80%, more preferably at least about 90%, more preferably, at least about 95%, more preferably at least about 97%, more preferably at least about 98%, more preferably, at least about 99%.
• the compound of formula (XIII) is isolated under selective crystallization conditions, wherein the compound of formula (XIII) is isolated as a crystalline solid in purity (as measured for example by HPLC) of at least about 60%, preferably at least about 75%, more preferably at least about 80%, more preferably at least about 90%, more preferably, at least about 95%, more preferably at least about 97%, more preferably at least about 98%, more preferably, at least about 99%.
• the compound of formula (X) is isolated under selective crystallization conditions, wherein the compound of formula (X) is isolated as a crystalline solid in purity (as measured for example by HPLC) of at least about 60%, preferably at least about 75%, more preferably at least about 80%, more preferably at least about 90%, more preferably, at least about 95%, more preferably at least about 97%, more preferably at least about 98%, more preferably, at least about 99%.
• the compound of formula (XIII) is recrystallized according to known methods.
• the compound of formula (X) is recrystallized according to known methods.
• the compound of formula (X) is further, optionally reacted with a suitably selected acid, to yield the corresponding acid addition salt, preferably the corresponding pharmaceutically acceptable acid addition salt.
• a suitably selected acid preferably the corresponding acid addition salt.
• the present invention is further directed to a process for the preparation of lisdexamfetamine, a compound of formula (I), as outlined in Scheme 2, below.
• PG 1 is a suitably selected first nitrogen protecting group
• PG 2 is a suitably selected second nitrogen protecting group
• PG 1 and PG 2 are independently selected from the group consisting of BOC, CBz, Alloc and Cinnoc
• PG 1 and PG 2 are selected to be the same nitrogen protecting group, more preferably PG 1 and PG 2 are the same and are selected from the group consisting of Boc, CBz, Alloc and Cinnoc, more preferably, PG 1 and PG 2 are the same and are selected from the group consisting of Boc and CBz
• a 1 is selected from the group consisting of C 1-5 alkyl, preferably C 1-4 alkyl, more preferably C 1-2 alky!; a known compound or compound prepared by known methods,
• the compound of formula (VI) is preferably present in an amount in the range of from about 1 to about 10 molar equivalents (relative to the moles of the compound of formula (V)), or any amount or range therein, more preferably, in an amount in the range of from about 2 to about 7 molar equivalents, more preferably, in an amount in the range of from about 4 to about 6 molar equivalents, more preferably, in an amount of about 5 molar equivalents;
• S-selective enzyme catalyst preferably a hydrolytic enzyme catalyst, more preferably a protease enzyme catalyst, more preferably a protease enzyme catalyst from a Bacillus species, more preferably a protease enzyme catalyst from Bacillus lichenformis, preferably an immobilized protease enzyme catalyst (from a bacillus species, preferably Bacillus lichenformis), for example, an immobilized protease enzyme catalyst selected from the group consisting of ALC-T2-250, SAV-T2-250, P6- T2-250, P8-T2-250, P40L-T2-150 and AUAL-T2-250 (commercially available from ChiralVision, Leiden, The Netherlands); preferably P6-T2-250, an immobilized protease enzyme catalyst of Bacillus licheniformis (commercially available as Protex 6L TM );
• the protease enzyme catalyst (preferably, and enzyme catalyst immobilized on a solid support) is preferably present in an amount in the range of from about 1 wt% to about 500 wt% (relative to the amount (or weight) of the compound of formula (XI)), or any amount or range therein, more preferably, in an amount in the range of from about 10 wt% to about 200 wt%, more preferably, in an amount in the range of from about 50 wt% to about 200 wt%; neat or in a suitably selected solvent or mixture of solvents (for example, in water, in an organic solvent or mixture of organic solvents or in an inorganic solvent or mixture of inorganic solvents, or in a mixture of water and suitably selected solvent), preferably in an organic solvent, more preferably in an organic solvent selected from the group consisting of tert-butyl-methylether (MTBE), tetrahydrofuran (THF), 2-methyl-tetrahydrofuran, 1,4-diox
• the compound of formula (VI) is racemic amphetamine.
• the preferred ratio of racemic amphetamine (the compound of formula (VI)) to the compound of formula (V) is in the range of from about 1/1 to about 10/1; preferably, the ratio is in the range of from about 2/1 to about 5/1, more preferably, the ratio is about 4/1.
• the compound of formula (VI) is amphetamine enriched with its corresponding D-enantiomer (D- amphetamine).
• the preferred ratio of the D-enantiomer enriched amphetamine / the compound of formula (V) is in the range of from about 1/1 to about 10/1, or any ratio or range of ratios therein, preferably, the ratio is in the range of from about 2/1 to about 5/1, more preferably, the ratio is in the range of from about 3/1 about 4/1.
• the compound of formula (VI) is amphetamine enriched with its corresponding L-enantiomer (L- amphetamine).
• the preferred ratio of the L-enantiomer enriched amphetamine / the compound of formula (V) is in the range of from about 1/1 to about 10/1, or any ratio or range of ratios therein, preferably, the ratio is in the range of from about 2/1 to about 5/1, more preferably, the ratio is in the range of from about 3/1 about 4/1.
• dexamphetamine i.e. wherein the compound of formula (VI) is pure D- amphetamine or is present in an enantiomeric excess of its corresponding D- enantiomer of 100%
• the enzyme catalyst according to the process as outlined in Scheme 2 above, and further as illustrated in Example 8, which follows hereinafter.
• the enzyme catalyzed process(es) of the present invention are similarly advantageous over processes wherein lisdexamfetamine is prepared via peptide coupling. More particularly, the product mixture resulting from the enzyme catalyzed process(es) of the present invention are free of residual peptide coupling reagents and free of peptide coupling by-products, which by-products are often difficult to remove from the product lisdexamfetamine without loss of yield or additional purification steps.
• an object of the present invention is a process for the preparation of lisdexamfetamine or pharmaceutically acceptable salt thereof (preferably lisdexamfetamine dimesylate), wherein the product prepared according to the process has an improved impurity profile (as compared with the process(es) known in the art).
• the compound of formula (VII) is isolated as a solid, preferably as a crystalline solid.
• the compound of formula (VII) is isolated as an oil which is allowed to stand at room temperature, to yield a solid.
• the compound of formula (VII) is isolated under selective crystallization conditions, wherein the compound of formula (VII) is isolated as a crystalline solid in a diastereomeric excess of the desired (S,S)-diastereomer at least about 60%, preferably at least about 75%, more preferably at least about 80%, more preferably at least about 90%, more preferably, at least about 95%, more preferably at least about 97%, more preferably at least about 98%, more preferably, at least about 99%.
• the compound of formula (VII) is isolated under selective crystallization conditions, wherein the compound of formula (VII) is isolated as a crystalline solid in purity (as measured for example by HPLC) of at least about 60%, preferably at least about 75%, more preferably at least about 80%, more preferably at least about 90%, more preferably, at least about 95%, more preferably at least about 97%, more preferably at least about 98%, more preferably, at least about 99%.
• the compound of formula (VII) is recrystallized according to known methods, from a suitably selected organic solvent or mixture of organic solvents, such as diethyl ether, a mixture of dichloromethane and diethyl ether, and the like.
• the compound of formula (VII) is recrystallized from warm diethyl ether to yield the (S,S)-diastereomer as a white solid.
• the compound of formula (VII) is de-protected according to known methods, to yield the corresponding compound of formula (I).
• the compound of formula (VII) may be de-protected by reacting with a suitably selected acid such as HCl, and the like (i.e. acid hydrolysis) or may be de- protected by reacting under hydrogenation conditions.
• a suitably selected acid such as HCl, and the like (i.e. acid hydrolysis)
• the compound of formula (VII) is de-protected in the 1,4- dioxane and in the presence of methanesulfonic acid (wherein the
• methanesulfonic acid is present in an amount in the range of from about 2 to about 10 molar equivalents, preferably, in an amount in the range of from about 3 to about 7 molar equivalents, more preferably, in an amount in the range of from about 4 to about 6 molar equivalents, more preferably in an amount of about 5 molar equivalents); to yield the corresponding dimesylate salt of the compound of formula (I); wherein the dimesylate salt of the compound of formula (I) is preferably present in a diastereomeric excess (d.e.) greater than or equal to that of the d.e. of the compound of formula (VII), preferably, the d.e. of the compound of formula (I) is greater than the d.e.
• a diastereomeric excess d.e.
• the compound of formula (I) is further, optionally reacted with a suitably selected acid, to yield the corresponding acid addition salt.
• the compound of formula (I) is reacted with methanesulfonic acid; to yield the corresponding dimesylate salt of the compound of formula (I).
• the present invention is directed to a process for the preparation of a compound of formula (VII), a compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) (preferably a dimesylate salt of the compound of formula (I)), wherein the desired compound is prepared with an overall yield in the range of from about 10% to about 95%, or any amount or range therein, preferably in the range of from about 25% to about 75%, or any amount or range therein.
• the present invention is directed to a processes for the preparation of a compound of formula (VII), a compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) (preferably a dimesylate salt of the compound of formula (I)), wherein the desired compound is isolated as a solid in a diastereomeric excess of at least about 60%, preferably at least about 75%, more preferably at least about 80%, more preferably at least about 90%, more preferably, at least about 95%, more preferably at least about 97%, more preferably at least about 98%, more preferably, at least about 99%.
• the present invention is directed to a processes for the preparation of a compound of formula (VII), a compound of formula (I) or a pharmaceutically acceptable salt of the compound of formula (I) (preferably a dimesylate salt of the compound of formula (I)), wherein the desired compound is isolated as a solid in purity (as measured for example by HPLC) of at least about 60%, preferably at least about 75%, more preferably at least about 80%, more preferably at least about 90%, more preferably, at least about 95%, more preferably at least about 97%, more preferably at least about 98%, more preferably, at least about 99%.
• the present invention further comprises pharmaceutical compositions containing one or more compounds of formula (I) or compound of formula (X) with a pharmaceutically acceptable carrier.
• Pharmaceutical compositions containing one or more of the compounds of the invention described herein as the active ingredient can be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
• the carrier may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral).
• suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like;
• suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.
• Solid oral preparations may also be coated with substances such as sugars or be enteric-coated so as to modulate major site of absorption.
• the carrier will usually consist of sterile water and other ingredients may be added to increase solubility or preservation.
• injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives.
• one or more compounds of the present invention as the active ingredient is intimately admixed with a pharmaceutical carrier according to conventional
• suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like;
• suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.
• tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed.
• tablets may be sugar coated or enteric coated by standard techniques.
• the carrier will usually comprise sterile water, through other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included.
• injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
• the pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above.
• compositions herein will contain, per unit dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like, of from about 1 mg to about 100 mg or any amount or range therein, and may be given at a dosage of from about 0.1 mg/kg/day to about 1.5 mg/kg/day, or any amount or range therein, preferably from about 0.1 mg/kg/day to about 1 mg/kg/day, or any amount or range therein.
• the dosages may be varied depending upon the requirement of the patients, the severity of the condition being treated and the compound being employed. The use of either daily administration or post-periodic dosing may be employed.
• compositions are in unit dosage forms from such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
• the composition may be presented in a form suitable for once-weekly or once- monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection.
• a pharmaceutical carrier e.g.
• a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
• preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules.
• This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from about 0.01 mg to about 1,000 mg, or any amount or range therein, of the active ingredient of the present invention.
• the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
• the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
• the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
• enteric layers or coatings such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
• liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include, aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
• Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
• the method of treating disorders described in the present invention may also be carried out using a pharmaceutical composition comprising any of the compounds as defined herein and a pharmaceutically acceptable carrier.
• the pharmaceutical composition may contain between about 0.01 mg and about 1000 mg of the compound, or any amount or range therein; preferably from about 1.0 mg to about 500 mg of the compound, or any amount or range therein, and may be constituted into any form suitable for the mode of administration selected.
• Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.
• compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), granules, and powders, and liquid forms, such as solutions, syrups, elixirs, emulsions, and suspensions.
• forms useful for parenteral administration include sterile solutions, emulsions and suspensions.
• compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
• compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in that art.
• the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
• the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
• suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta- lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
• Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
• liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl- cellulose and the like.
• suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl- cellulose and the like.
• sterile suspensions and solutions are desired.
• Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
• a pharmaceutical carrier which carrier may take a wide variety of forms depending of the form of preparation desired for administration (e.g. oral or parenteral).
• Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers may be found in The Handbook of Pharmaceutical Excipients, published by the American
• compositions have been described in numerous publications such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3, edited by Lieberman et al; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al; published by Marcel Dekker, Inc.
• Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever treatment of, for example, attention deficit hyperactivity disorder is required.
• the daily dosage of the products may be varied over a wide range from about 1 mg per day to about 100 mg per day.
• the compositions are preferably provided in the form of tablets containing, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 30.0, 50.0 and 70.0 and 100, milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
• An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.1 mg/kg to about 1.5 mg/kg of body weight per day, or any amount or range therein.
• the range is from about 0.1 to about 1 mg/kg of body weight per day, or any amount or range therein.
• the compounds may be administered on a regimen of 1 to 4 times per day.
• Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.
• a Metrohm Titrino 702 SM dosing unit was set up in "Set Endpoint Titration" mode in order to keep the pH of the reaction mixture constant at pH 7.30 by automatically dosing 1 M NaOH. Note: the reaction mixture apparently formed a buffered system at pH 7.05.
• the resultant mixture was stirred at 100 rpm at 40°C for 68 h, after which time HPLC and LCMS indicated virtually complete consumption of the starting material.
• the reaction mixture was decanted with the aid of MeCN (3x 50 mL) and the decanted liquids were passed through a paper filter. The volatiles of the filtrate were removed in vacuo resulting in a yellowish oil to which water (200 mL) and 1 M KHSO 4 (50 mL) were added (resulting in pH 2).
• Lisdexamfetamine melted at around 103°C.
• the isolated product was crystallized from methanol in three runs to yield bis-CBz-protected Lisdexamfetamine (14.6 g, 61% yield).
• Dextroamphetamine tartrate salt (1.6 g, 5 equiv.) was treated with a NaOH solution and extracted with diethyl ether. The organic layer was dried and concentrated to yield the free-base of dextroamphetamine as a colorless oil. The free base was added to a solution of CBz-L-Lys(CBz)-OMe (0.5 g) and immobilized protease of Bacillus licheniformis (250 mg, ChiralVision product code IMMP6-T2-250) in acetonitrile (10 mL). The reaction mixture was stirred at 40°C for 40 hours. The reaction mixture was diluted with DCM (20 mL) and filtrated using a phase separator to remove the enzyme.
• CBz-L-Lys(CBz)-OMe 0.5 g
• immobilized protease of Bacillus licheniformis 250 mg, ChiralVision product code IMMP6-T2-250
• reaction mixture was stirred at room temperature and monitored by HPLC. After 1 hour, the initially clear yellow solution had turned into a thick yellow mixture and HPLC showed complete conversion.
• Methanesulfonic acid (0.30 mL, 0.41 equiv.) was added to a solution of (S,S)-lisdexamfetamine freebase (3.0 g, prepared as described above) in n- butanol (48 mL) at 40°C. After 30 minutes at 40°C, another portion of methanesulfonic acid (1.19 ml, 1.61 equiv.) was added over 30 minutes. The resulting suspension was stirred at 40°C for 30 minutes after which time isopropyl acetate (30 mL) was added over 10 minutes.
• reaction mixture was then filtered under nitrogen atmosphere and immediately added drop-wise (over 90 min) to a solution of L-lysine methyl ester dihydrochloride (9 g, 1 equiv.) and K 2 CO 3 (32 g, 6 equiv.) in water (200 mL) at 0°C. After the mixture was stirred for 10 minutes, the cooling medium was removed and stirring was continued for 18 hours during which time the reaction mixture was allowed to come to room temperature. The THF layer was separated and the water layer was extracted with diethyl ether (2x 100 mL).
• Cinnoc-L- Lys(Cinnoc)-OMe was washed with 1N HCl (2x 100 mL), brine (100 mL), dried and evaporated to yield Cinnoc-L- Lys(Cinnoc)-OMe as a residue.
• the resulting material was purified by flash chromatography (silica, 20-40% ethyl acetate in heptane) to yield Cinnoc-L- Lys(Cinnoc)-OMe as a white solid (5.0 g, 26% yield)
• Cinnoc-L-Lys(Cinnoc)-OMe prepared as in Example 13, above, 4.9 g
• rac-amphetamine 7.0 g, 5 equiv.
• acetonitrile 80 mL
• immobilized protease of Bacillus licheniformis 2.5 g, ChiralVision, product code IMMP6-T2-250
• the enzyme was first washed with dry acetonitrile (4x 30 mL), prior to the addition to Cinnoc-L-Lys(Cinnoc)-OMe).
• the reaction mixture was stirred at 40°C and monitored by HPLC.
• HPLC analysis showed ca.87% of the desired product and 8% starting material.
• a chiral HPLC analysis of the reaction mixture showed ca.92% d.e. for the product.
• the formed precipitate was collected by filtration, taken up in DCM (400 mL) and the remaining solid (enzyme) was removed by filtration. The volatiles were evaporated to yield bis- Cinnoc-lisdexamfetamine as a residue (5.8 g, 96% yield, not corrected for purity).
• HPLC 74% purity and 97% d.e. (determined using Method B as described in Example 19)
• Screw cap vials (8 mL) equipped with magnetic stirring bars were charged each with Boc-L-Lys(Boc)-OMe (prepared as in Example 2 above, 100 mg), the indicated quantity of racemic amphetamine, internal standard
• Screw cap vials (8 mL) were charged each with Boc-L-Lys(Boc)-OMe (prepared for Example as in Exampel 2 above, 100 mg), rac-amphetamine (3 equiv), internal standard (veratrole) and the indicated solvent (1.5 mL). To each of the resulting solutions was added the indicated immobilized protease (100 mg, ChiralVision). The vials were inserted into preheated reaction blocks at 40 °C and their contents were shaken at 400 rpm and analyzed after 65 h.
• Sample preparation An appropriate amount of the analyte (sample) was dissolved in a 1:1 mixture of MTBE and MeCN
• Method B Sample preparation: An appropriate amount of the analyte (sample) was dissolved in EtOH.
• Sample preparation An appropriate amount of the analyte (sample) was dissolved in iPrOH.
• Sample preparation An appropriate amount of the analyte (sample) was dissolved in iPrOH.
• Sample preparation An appropriate amount of the analyte (sample) was dissolved in EtOH.
• Sample preparation An appropriate amount of the analyte (sample) was dissolved in iPrOH.
• Solid, Oral Dosage Form– Prophetic Example As a specific embodiment of an oral composition, 100 mg of the compound prepared as in Example 5 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule. While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents.

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