Wo 2009/148600 A2

(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 10 December 2009 (10.12.2009) WO 2009/148600 A2 (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C07C 311/41 (2006.01) A61K 31/661 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 31/63 (2006.01) C07F 9/141 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (21) International Application Number: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/US2009/003391 HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (22) International Filing Date: KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, 4 June 2009 (04.06.2009) ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, (25) Filing Language: English SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, TZ, (26) Publication Language: English UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 61/059,556 6 June 2008 (06.06.2008) US kind of regional protection available): ARIPO (BW, GH, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, (71) Applicant (for all designated States except US): CON¬ ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, CERT PHARMACEUTICALS, INC. [US/US]; 99 TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, Hayden Avenue, Suite 500, Lexington, MA 02421 (US). ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, TR), (72) Inventors; and OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, (75) Inventors/Applicants (for US only): LIU, Julie, F. [US/ MR, NE, SN, TD, TG). US]; 3 Withman Circle, Lexington, MA 02420 (US). HARBESON, Scott, L. [US/US]; 203 Pemberton Street, Published: Apt. 5, Cambridge, MA 02140 (US). — without international search report and to be republished (74) Agents: ABELLEIRA, Susan, M. et al; Hamilton, upon receipt of that report (Rule 48.2(g)) Brook, Smith & Reynolds, P.C., 530 Virginia Road, P.O. Box 9133, Concord, MA 01742-91 33 (US). (54) Title: DEUTERATED LYSINE-BASED COMPOUNDS (57) Abstract: This invention relates to novel lysine-based compounds, their derivatives, pharmaceutically acceptable salts, sol- vates, and hydrates thereof. This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering an HIV protease inhibitor. DEUTERATED LYSINE-BASED COMPOUNDS RELATED APPLICATION [1] This application claims the benefit of U.S. Provisional Application No. 61/059,556, filed on June 6, 2008. The entire teachings of the above application is incorporated herein by reference. BACKGROUND OF THE INVENTION [2] PPL-1 00, also known as PL-461 (the di-acid), PL-462 (the disodium salt), MK-8122 and as (IS, 5S)-(l-{5-[4-amino-benzenesulfonyl)-isobutylamino]-6- phosphonooxy-hexylcarbamoyl}-2,2-diphenyl-ethyl)-carbamic acid methyl ester sodium salt, prevents HIV viral replication through inhibition of HIV protease, the enzyme responsible for cleavage of HIV polyproteins. [3] PPL-100 is currently in clinical trials for the treatment of HIV infection. [4] PPL- 100 is a phosphorylated prodrug of the protease inhibitor PL- 100. In vivo, PPL-100 is metabolically converted to PL-100, the active entity effective against 63 protease inhibitor (PI)- resistant HIV strains. (Wu, JJ. ; et al., 6th Int Workshop Clin Pharmacol HIV Ther, (Quebec) April 28-30, 2005, Abst 4). In vivo rat studies with orally dosed PPL-100 have shown PL-100 to be the major metabolite in the portal vein and systemic circulation. Studies of PL-100 in human liver microsomes show that minor amounts of five different metabolites are formed. PL-100 appears to be both a substrate and an inhibitor of CYP3A4. (Wu, JJ. et al., 46th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), San Francisco, USA, September 27-30, 2006). [5] Results of clinical trials show that PPL-100 is safe and well tolerated up to a dose of 2400 mg per day. Mild (grade 1) adverse events include, but are not limited to, dizziness, proteinuria and elevated cholesterol. [6] Despite the beneficial activities of PPL-100, there is a continuing need for new compounds to treat the aforementioned diseases and conditions. SUMMARY OF THE INVENTION [7] This invention relates to novel lysine-based compounds, their derivatives, and pharmaceutically acceptable salts thereof. This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering an HIV protease inhibitor. DETAILED DESCRIPTION OF THE INVENTION [8] The terms "ameliorate" and "treat" are used interchangeably and include both therapeutic treatment and prophylactic treatment (reducing the likelihood of development). Both terms mean decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease (e.g., a disease or disorder delineated herein), lessen the severity of the disease or improve the symptoms associated with the disease. [9] "Disease" means any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ. [10] It will be recognized that some variation of natural isotopic abundance occurs in a synthesized compound depending upon the origin of chemical materials used in the synthesis. Thus, a preparation of PPL-100 will inherently contain small amounts of deuterated isotopologues. The concentration of naturally abundant stable hydrogen isotopes, notwithstanding this variation, is small and immaterial as compared to the degree of stable isotopic substitution of compounds of this invention. See, for instance, Wada E etal., Seikagaku 1994, 66:15; Gannes LZ et al., Comp Biochem Physiol MoI Integr Physiol 1998, 119:725. [11] Unless otherwise stated, when a position is designated specifically as "H" or "hydrogen", the position is understood to have hydrogen at its natural abundance isotopic composition. Also unless otherwise stated, when a position is designated specifically as "D" or "deuterium", the position is understood to have deuterium at an abundance that is at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 50.1% incorporation of deuterium). [12] The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance of D at a specified position in a compound of this invention and the naturally occurring abundance of that isotope. The natural abundance of deuterium is 0.015%. [13] In other embodiments, a compound of this invention has an isotopic enrichment factor for each deuterium present at a site designated as a potential site of deuteration on the compound of at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). It is understood that the isotopic enrichment factor of each deuterium present at a site designated as a site of deuteration is independent of other deuterated sites. For example, if there are two sites of deuteration on a compound one site could be deuterated at 52.5% while the other could be deuterated at 75%. The resulting compound would be considered to be a compound wherein the isotopic enrichment factor is at least 3500 (52.5%). [14] The term "isotopologue" refers to a species that differs from a specific compound of this invention only in the isotopic composition thereof. Isotopologues can differ in the level of isotopic enrichment at one or more positions and/or in the positions(s) of isotopic enrichment. [15] The term "compound," as used herein, refers to a collection of molecules having an identical chemical structure, except that there may be isotopic variation among the constituent atoms of the molecules. Thus, it will be clear to those of skill in the art that a compound represented by a particular chemical structure containing indicated deuterium atoms, will also contain lesser amounts of isotopologues having hydrogen atoms at one or more of the designated deuterium positions in that structure. The relative amount of such isotopologues in a compound of this invention will depend upon a number of factors including the isotopic purity of deuterated reagents used to make the compound and the efficiency of incorporation of deuterium in the various synthesis steps used to prepare the compound. However, as set forth above the relative amount of such isotopologues will be less than 49.9% of the compound. In other embodiments, the relative amount of such isotopologues - A - in toto will be less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the compound. [16] The invention also provides salts, of the compounds of the invention. [17] A salt of a compound of this invention is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group.

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