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(12) Patent Application Publication (10) Pub. No.: US 2014/0371314 A1 Bar-Tana (43) Pub

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(12) Patent Application Publication (10) Pub. No.: US 2014/0371314 A1 Bar-Tana (43) Pub US 20140371314A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0371314 A1 Bar-Tana (43) Pub. Date: Dec. 18, 2014 (54) DEUTERATED TETRAMETHYL DOC Publication Classification ACIDS, COMPOSITIONS COMPRISING THEMAND USES THEREOF (51) Int. Cl. (71) Applicant: SYNDROMEX LTD., Jerusalem (IL) C07C 55/02 (2006.01) (72) Inventor: Jacob Bar-Tana, Jerusalem (IL) (52) U.S. Cl. CPC ...................................... C07C 55/02 (2020.01) (21) Appl. No.: 14/363,912 USPC ........................................... 514/558:562/590 (22) PCT Fled: Dec. 6, 2012 (86) PCT NO.: PCT/L2012/050511 (57) ABSTRACT S371 (c)(1), (2), (4) Date: Jun. 9, 2014 This invention relates to deuterated tetramethyl dioic acids, Related U.S. Application Data compositions comprising them and uses thereof in the treat (60) Provisional application No. 61/568,441, filed on Dec. ment of Metabolic Syndrome and any diseases, disorders or 8, 2011. symptoms associated therewith. Patent Application Publication Dec. 18, 2014 Sheet 1 of 3 US 2014/0371314 A1 250000 -0 Compound 7"5mg/kg IV 2N 200000 -- Compound 7"50mh/kg PO S. -o- Compound 75mg/kg IV S - A - Compound 750mh/kg PO c 150000 O CD 100000 O O 50000 O Fig. 1A 16OOOO 14OOOO E 120000 -- Compound 1"5mg/kg IV 2 -- Compound 1"50mh/kg PO 100000 -O- Compound 1 5mg/kg IV O 80000 - A - Compound 150mh/kg PO E 9 60000 C 8 40000 Time (h) Fig. 1B Patent Application Publication Dec. 18, 2014 Sheet 2 of 3 US 2014/0371314 A1 AI6x/6uug„1punoduuoo—•— /\|6X/6uug/punoduuOO–e– 8 (u/6u) uOpenueouOO Patent Application Publication Dec. 18, 2014 Sheet 3 of 3 US 2014/0371314 A1 punoduuOO—•—Gºz),„Z punoduuOO–––GZ„A 9-61-I N ````SSS 08 G0 00|| (%) eSoonf pooq 6use - us US 2014/0371314 A1 Dec. 18, 2014 DEUTERATED TETRAMETHYL DOC 0007 each of R-Rs is independently selected from H. D. ACIDS, COMPOSITIONS COMPRISING CH and CD; wherein at least one of R-Rs is D or CD. THEMAND USES THEREOF 0008. In a compound of the invention, when a particular position is designated as having deuterium, it is understood FIELD OF THE INVENTION that the abundance of deuterium at that position is Substan 0001. This invention relates to deuterated tetramethyl tially greater than the natural abundance of deuterium, which dioic acids, compositions comprising them and uses thereof is 0.015%. A position designated as having deuterium typi in the treatment of Metabolic Syndrome and any diseases, cally has a minimum isotopic enrichment factor that is at least disorders or symptoms associated therewith. 3340 times greater than the natural abundance of deuterium (i.e., the term “D” or “deuterium” indicates at least 50.1% BACKGROUND OF THE INVENTION incorporation of deuterium). 0002 U.S. Pat. No. 4,634,795 discloses long-chain alpha, 0009. The term “isotopic enrichment factor as used omega-di-carboxylic acids and derivatives for the treatment herein means the ratio between the isotopic abundance and of obesity, hyperlipidemia and maturity-onset diabetes. the natural abundance of a specified isotope. US2002049345 discloses carboxylic acids and derivatives 0010. In other embodiments, a compound of the invention thereof, compositions comprising them for the treatment of has an isotopic enrichment factor for each designated deute obesity, hyperlipidemia and maturity onset diabetes. rium atom of at least 3500 (52.5% deuterium incorporation at US2009018.199 discloses methods for administering 3.3,14, each designated deuterium atom), at least 4000 (60% deute 14-tetramethyl hexadecane-1,16-dioic acid for lowering rium incorporation), at least 4500 (67.5% deuterium incor LDL, VLDL, total cholesterol, triglycerides, insulin resis poration), at least 5000 (75% deuterium), at least 5500 (82. tance and hypertension, and methods for elevating HDL in 5% deuterium incorporation), at least 6000 (90% deuterium subjects in need thereof. U.S. Pat. No. 4,908,385 provides a incorporation), at least 6333.3 (95% deuterium incorpora pharmaceutical composition containing at least one alpha tion), at least 6466.7 (97% deuterium incorporation), at least halogenated dicarboxylic acid. U.S. Pat. No. 4,711,896 6600 (99% deuterium incorporation), or at least 6633.3 (99. relates to alpha, omega-dicarboxylic acids and uses thereofas 5% deuterium incorporation). anti-diabetic agents and for lowering the level of plasma 0011. In compounds of the invention any atom not specifi lipids. US2002037876 relates to carboxylic acids and deriva cally designated as a particular isotope is meant to represent tives thereof for use in the treatment of metabolic syndrome the naturally abundant isotope of that atom. Unless otherwise X. stated, when a position is designated specifically as “H” or 0003) Isotopes are atoms which have nearly identical "hydrogen', the position is understood to have hydrogen at its properties but which have different masses due to changes in natural abundance isotopic composition. Also unless other the number of neutrons in their nuclei. Deuterium is an iso wise stated, when a position is designated specifically as “D’ tope of hydrogen with a nucleus comprising one neutron and or “deuterium, the position is understood to have deuterium one proton. Kinetic isotope effects are the observed changes at an abundance that is at least 3340 times greater (i.e., at least in the rate of reaction that occur when deuterium is substituted 50.1% incorporation of deuterium) than the natural abun for hydrogen. Deuterium isotope effects result from the dance of deuterium, which is 0.015%. greater energy required to break a covalent bond to deuterium 0012. The term “isotopologue' refers to a species that has Versus a covalent bond to hydrogen. One of the challenges of the same chemical structure and formula as a specific com incorporating deuterium into a pharmaceutical composition pound of this disclosure, with the exception of the positions of is the possibility of deuterium/hydrogen exchange within the isotopic Substitution and/or level of isotopic enrichment at physiological environment, eviscerating the effect of the one or more positions, e.g., HVS. D. compound. Further, when deuterium retards metabolism at 0013 The term “compound” as used herein includes a one site, “metabolic shunting can occur where the Suppres collection of molecules having an identical chemical struc sion of one metabolic pathway promotes metabolism at ture, except that there may be isotopic variation among the another site. constituent atoms of the molecules. Thus, it will be clear to those of skill in the art that a compound represented by a SUMMARY OF THE INVENTION particular chemical structure containing indicated deuterium 0004. The present invention provides a compound of gen atoms, will also contain lesser amounts of isotopologues hav eral formula (I), including any salts, esters, anhydrides or ing hydrogen atoms at one or more of the designated deute prodrugs thereof: rium positions in that structure. 0014. The relative amount of such isotopologues in a com pound of this disclosure will depend upon a number of factors (I) R R5 R7 R3 O including the isotopic purity of deuterated reagents used to V M make the compound and the efficiency of incorporation of C-C-C-L-C-C-C deuterium in the various synthesis steps used to prepare the / | | \, compound. HO R. R. R. R. OH 0015. In some embodiments, as set forth above, the rela tive amount of Such isotopologues in total will be less than 0005 wherein 49.9% of the compound. In other embodiments, the relative 0006 L is a straight or branched C-C alkylene; option amount of such isotopologues in total will be less than 47.5%, ally interrupted by at least one moiety selected from O, S, NH, less than 40%, less than 32.5%, less than 25%, less than Cs-Co cycloalkylene, Cs-Co cycloheteroalkylene, C-Cls 17.5%, less than 10%, less than 5%, less than 3%, less than arylene, C-Cls heteroarylene; 1%, or less than 0.5% of the compound. US 2014/0371314 A1 Dec. 18, 2014 0016. The term “stable compounds' as used herein, refers at least one of Rs-Rs is CDs. In yet other embodiments, at to compounds which possess stability sufficient to allow for least one of R-R is D and at least one of Rs-Rs is CDs. their manufacture and which maintain the integrity of the 0028. In some embodiments, a compound of the invention compound for a sufficient period of time to be useful for the is selected from: purposes detailed herein (e.g., formulation into therapeutic products, intermediates for use in production of therapeutic compounds, isolatable or storable intermediate compounds, Compound R = R2 = R3 = R4 Rs = R = R7 = Rs treating a disease or condition responsive to therapeutic II D CH agents). III H CD 0017. In some embodiments, any position in the com IV D CD pound of Formula (I) designated as having D has a minimum deuterium incorporation of at least 50.1% (e.g., at least 52.5%, at least 60%, at least 67.5%, at least 75%, at least 0029. In other embodiments, a compound of the invention 82.5%, at least 90%, at least 95%, at least 97%, at least 99%, is selected from: or at least 99.5%) at the designated position(s) of the com pound of Formula (I). Thus, in some embodiments, a compo sition comprising a compound of Formula (I) can include a Compound R = R2 R3 = R4 RS = Rs R7 = Rs distribution of isotopologues of the compound, provided at V D H CH CH VI D H CD CH least 50.1% of the isotopologues include a Dat the designated VII D H CH CD position(s). VIII D H CD CD 0018. In some embodiments, a compound of Formula (I) is IX D D CD CH “substantially free of other isotopologues of the compound, e.g., less than 49.9%, less than 25%, less than 10%, less than 5%, less than 2%, less than 1%, or less than 0.5% of other 0030.
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