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(12) Patent Application Publication (10) Pub. No.: US 2011/0136742 A1 Mickle Et Al

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US 20110136742A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0136742 A1 Mickle et al. (43) Pub. Date: Jun. 9, 2011 (54) ANTIDEPRESSANT PRODRUGS A 6LX 3/5.375 (2006.01) A 6LX 3/553 (2006.01) (76) Inventors: Travis Mickle, Coralville, IA (US); A6II 3/42 (2006.01) Wendy Hirschelman Severs, A6II 3/44 (2006.01) Blacksburg, VA (US) A6II 3/42 (2006.01) A6II 3/405 (2006.01) (21) Appl. No.: 12/280,190 A63L/36 (2006.01) A63/4985 (2006.01) (22) PCT Fled: Feb. 22, 2007 A6II 3/4409 (2006.01) A6II 3/554 (2006.01) A6II 3/405 (2006.01) S371 (c)(1), A6IP 25/24 (2006.01) (2), (4) Date: Sep. 14, 2010 A6IP 25/22 (2006.01) Related U.S. Application Data A6IP 25/18 (2006.01) (52) U.S. Cl. ........ 514/17.6: 514/564: 514/321; 514/217; (60) Provisional application No. 60/776,216, filed on Feb. 514/237.8: 514/211.13: 514/378: 514/354; 24, 2006. 514/376; 514/.424; 514/239.2: 514/.466; 514/250; 514/423: 514/419 Publication Classification (57) ABSTRACT (51) Int. Cl. A6 IK 38/06 (2006.01) The invention provides antidepressant prodrugs comprising A6 IK 38/05 (2006.01) an antidepressant conjugated to one or more amino acids. The A 6LX 3L/95 (2006.01) invention also relates to pharmaceutical compositions com A6 IK 3L/4525 (2006.01) prising an antidepressant prodrug, and to methods of prepar A6 IK3I/55 (2006.01) ing and using the same. O O R O (i) R O (ii) R O Hook well-es N-os---- -- N-O s -k H O O N 'O (iii) O O N7 O NHHC ()s - HN N O o k y H. n (iv) R = Any amino acid side chain in a 1-3 amino acids R Anti-S NH) - HC O () NHS, DCC, dioxane (ii) addition of amino acid or did peptide, NMM, DMFI dioxane Ho (iii) protected amino acid or peptide succinate, NMM,EtOAc (iv) 4 NHC in dioxane Scheme 1. Synthesis of tranylcypromine amino acid and peptide conjugates Patent Application Publication Jun. 9, 2011 Sheet 1 of 2 US 2011/O136742 A1 O O R O (i) R O (ii) R O Hook w-r- N-O r -so-k - - N-(sok H O H (iii) O H' in O y H. n (iv) R = Any amino acid side chain a 1-3 armino acids (i) NHS, DCC, dioxane (ii) addition of amino acid or did peptide, NMM, DMF1 dioxane /H2O (iii) protected amino acid or peptide succinate, NM.M.EtOAc (iv) 4 NHC in dioxane Scheme f. Synthesis of tranylcypromine amino acid and peptide conjugates FIGURE 1 Patent Application Publication Jun. 9, 2011 Sheet 2 of 2 US 2011/0136742 A1 O O R O (i) R O (ii) O took Hrman CookO e-m-in-- - Cook A HC (iii) a-lokO Hn (iv) A = antidepressant fluoxetine or sertaline R = Any amino acid side chain n = 1-3 amino acids R A-NH NH) HC O n (i) NHS, DCC, dioxane (ii) addition of amino acid or didpeptide, NMM, DMF/ dioxane IHO (iii) protected amino acid or peptide succinate, NMM, EtOAC (iv) 4 NHCl in dioxane Fluoxetire Scheme 2. Synthesis of fluoxetine and sentraline amino acid and peptide conjugates FIGURE 2 US 2011/O 136742 A1 Jun. 9, 2011 ANTIDEPRESSANT PRODRUGS 0007 FIG.2 depicts a process for preparing fluoxetine and Sertraline prodrugs. CROSS-RELATED APPLICATIONS DETAILED DESCRIPTION OF THE INVENTION 0001. This application claims priority to U.S. Provisional Application 60/776,216 filed on Feb. 24, 2006 which is 0008. The present invention provides antidepressant pro hereby incorporated by reference in its entirety. drugs comprising an antidepressant covalently bound to one or more amino acids. FIELD OF THE INVENTION 0009. As used herein, an “antidepressant can be a mem ber of any class of antidepressants including, but not limited 0002 The invention relates to antidepressant prodrugs to, monoamine oxidase inhibitors (MAOIs); cyclic, e.g., tri comprising an antidepressant covalently bound to a chemical cyclic antidepressants (TCAS); selective serotonin reuptake moiety, particularly one or more amino acids. The invention inhibitors (SSRIs); reuptake inhibitors of serotonin, norepi also relates to pharmaceutical compositions comprising an nephrine, and/or dopamine; noradrenergic and specific sero antidepressant prodrug, and to methods of preparing and toninergic antidepressants; serotonin-2 receptor antagonists using the same. with or without serotonin reuptake inhibition; and reversible inhibitors of monoamine oxidase A (RIMAs). Exemplary BACKGROUND OF THE INVENTION antidepressants include, but are not limited to, tranylcyprom ine (Parnate(R), SarafemR), fluoxetine (ProzacR), sertraline 0003 Antidepressants are a class of psychotherapeutic (Zoloft(R), bupropion (WellbutrinR), and fluvoxamine (Lu drugs that are prescribed to treat a variety of psychiatric and vox(R) as well as paroxetine (Paxil.R.), desipramine (Nor medical disorders. According to the U.S. Substance Abuse pramin(R), nortriptyline (Aventyl(R), PamelorR), Venlafaxine and Mental Health Services Administration's (SAMHSA) (EffexorR), phenelzine (Nardil.R.), amisulpride (Solian(R), 2004 National Survey on Drug Use and Health, an estimated moclobemide (Manerix (R), protriptyline (VivactilB), amox 8% of adults experienced at least one major depressive epi apine (AsendinR), maprotiline (Ludiomil.R.), isocarboxazid sode during the past year. While antidepressants can be used (Marplan R), dibenzepin (Noveril.R.), tianeptine (StablonR), mabanazine, nialamide, pirlindole, Safrazine, toloxatone, as effective therapy, they also present a risk of overdose, amineptine (Survector(R), medifoxamine (CledialR), oxitrip especially for Suicidal patients who may have both access and tan, rolipram, tofenacin, and viloxazine (Vivalan(R). Pre intent to consume high doses. Townsend, E. etal. “Substances ferred antidepressants include those that have primary or used in deliberate self-poisoning 1985-1997: trends and asso secondary amine functionality. Fluoxetine, Sertraline, and ciations with age, gender, repetition and Suicide intent Soc. tranylcypromine are preferred. Psychiatry Psychiatr. Epidemiol. 36: 228-34 (2001). Accord ing to the Drug Abuse Warning Network (DAWN), of the drugs mentioned in drug-related emergency department visits FC in 2002, antidepressants accounted for 5%. 0004 Older classes of antidepressants, including monoamine oxidase inhibitors (MAOIs) and especially tricy clic antidepressants, can cause adverse cardiovascular effects and are highly toxic in overdose, especially when combined CH with other drugs. Newer antidepressants, including selective N serotonin reuptake inhibitors (SSRIs), were developed in part to reduce the risk of toxicity in overdose. Sarko J. Antide pressants, Old and New: A Review of Their Adverse Effects Fluoxetine and Toxicity in Overdose.” Emerg. Med. Clin. North Am. 18(4): 637-54, 637, 639, 646 (2000); Glauser, J. “Tricyclic Antidepressant Poisoning Clev. C1.J. of Med. 67(10): 704 19, 709 (2000). While SSRIs have a reduced risk of cardio vascular side effects compared to tricyclics, SSRIs do have adverse side effects, most commonly nausea, vomiting, and diarrhea. Sarko at 638. 0005. In this invention, one or more amino acids is conju gated to an antidepressant. Among the advantages, the result ing prodrug may be resistant to overdose due to a natural gating mechanism at the site of hydrolysis that limits the release of free drug. The prodrug may also reduce side effects Such as diarrhea, upset stomach, vomiting, and weight loss. C BRIEF DESCRIPTION OF DRAWINGS C 0006 FIG. 1 depicts a process for preparing tranyl Sertraline cypromine prodrugs. US 2011/O 136742 A1 Jun. 9, 2011 0017. The prodrug can have one or more amino acid sub -continued stitutions. Preferably, the substitute amino acid is similar in structure, charge, and/or polarity to the replaced amino acid. For instance, isoleucine is similar to leucine, tyrosine is simi lar to phenylalanine, serine is similar to threonine, cysteine is similar to methionine, alanine is similar to valine, lysine is similar to arginine, asparagine is similar to glutamine, aspar tic acid is similar to glutamic acid, histidine is similar to Tranylcypromine proline, and glycine is similar to tryptophan. 0018. The peptide can comprise a homopolymer or a het 0010. The antidepressant can have any stereogenic con eropolymer of naturally-occurring or synthetic amino acids, figuration, including both dextro- and levo-isomers. Such as a homopolymer or heteropolymer of glutamic acid, 0011. The prodrug can be in a salt or ester form. Exem aspartic acid, serine, lysine, cysteine, threonine, asparagine, plary salts are known in the pharmaceutical art and include, arginine, tyrosine, or glutamine. for example, mesylate, hydrochloride, and Sulfate salts. 0019. In one embodiment, an amino acid has one or more 0012. The antidepressant is covalently bound (conju free C-terminal, N-terminal, and/or side chain group other gated) to a peptide comprising one or more amino acids. An than the point of attachment to the drug. The amino acid can amino acid can be bound to the drug via the N-terminus, the be in such a free state, or it can be an ester or salt thereof. C-terminus, or a side chain of the amino acid. The drug can be 0020 Exemplary peptides for the antidepressant prodrugs bound to the peptide via an amine, alcohol, or carboxylic acid of the present invention include Ala, Arg, ASn, Asp, Gly, Glu, group of the drug. The drug can be covalently bound to the His, Ile, Leu, Lys, Met, Pro, Phe, Ser, Trp, Thr, Tyr, Phe, peptide either directly, or indirectly through a linker. Covalent Gly, Glu, Pro, Lys, Asp, Gly, Boc-Phe, and Boc-Gly. attachment can be, e.g., an ester or carbonate bond. 0021 Exemplary methods of attaching one or more amino 0013 As used herein, "peptide' includes single amino acids to a drug are described in the Examples below. Addi acids, dipeptides, tripeptides, oligopeptides (2-70 amino tional methods related to peptide drug conjugates are acids), and polypeptides.
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