News Column

Patent Issued for Fatty Acid Niacin Conjugates and Their Uses

July 14, 2014



By a News Reporter-Staff News Editor at Biotech Business Week -- Catabasis Pharmaceuticals, Inc. (Cambridge, MA) has been issued patent number 8765964, according to news reporting originating out of Alexandria, Virginia, by NewsRx editors (see also Pharmaceutical Companies).

The patent's inventors are Milne, Jill C. (Brookline, MA); Jirousek, Michael R. (Cambridge, MA); Bemis, Jean E. (Arlington, MA); Vu, Chi B. (Arlington, MA).

This patent was filed on December 30, 2013 and was published online on July 1, 2014.

From the background information supplied by the inventors, news correspondents obtained the following quote: "Oily cold water fish, such as salmon, trout, herring, and tuna are the source of dietary marine omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) being the key marine derived omega-3 fatty acids. Both niacin and marine omega-3 fatty acids (EPA and DHA) have been shown to reduce cardiovascular disease, coronary heart disease, atherosclerosis and reduce mortality in patients with dyslipidemia, hypercholesterolemia, or Type 2 diabetes, and metabolic disease. Niacin at high dose (1.5 to 4 grams per day) has been shown to improve very low-density lipoprotein ('VLDL') levels through lowering Apolipoprotein B ('ApoB') and raising high density lipoprotein ('HDL') through increasing Apolipoprotein A1 ('ApoA1') in the liver. Niacin can also inhibit diacylglycerol acyltransferase-2, a key enzyme for TG synthesis (Kamanna, V. S.; Kashyap, M. L. Am. J. Cardiol. 2008, 101 (8A), 20B-26B). Unfortunately, niacin has many actions outside of the liver that detract from its therapeutic utility. The most common side effect of niacin is flushing, which can limit the dose a patient can tolerate. Flushing is thought to occur through the GPR109 receptor in the vasculature. Non-flushing niacin derivatives have been disclosed in WO 2008/016968, and these derivatives are reported to potentially have the same beneficial effect on raising HDL as niacin while displaying a lesser degree of flushing.

"Omega-3 fatty acids (such as DHA and EPA) have been shown to improve insulin sensitivity and glucose tolerance in normoglycemic men and in obese individuals. Omega-3 fatty acids have also been shown to improve insulin resistance in obese and non-obese patients with an inflammatory phenotype. Lipid, glucose, and insulin metabolism have been show to be improved in overweight hypertensive subjects through treatment with omega-3 fatty acids. Omega-3 fatty acids (EPA/DHA) have also been shown to decrease triglycerides and to reduce the risk for sudden death caused by cardiac arrhythmias in addition to improve mortality in patients at risk of a cardiovascular event. Omega-3 fatty acids have also been taken as part of the dietary supplement portion of therapy used to treat dyslipidemia.

"Both DHA and EPA are characterized as long chain fatty acids (aliphatic portion between 12-22 carbons). Medium chain fatty acids are characterized as those having the aliphatic portion between 6-12 carbons. Lipoic acid is a medium chain fatty acid found naturally in the body. It plays many important roles such as free radical scavenger, chelator to heavy metals and signal transduction mediator in various inflammatory and metabolic pathways, including the NF-.kappa.B pathway (Shay, K. P. et al. Biochim. Biophys. Acta 2009, 1790, 1149-1160). Lipoic acid has been found to be useful in a number of chronic diseases that are associated with oxidative stress (for a review see Smith, A. R. et al Curr. Med. Chem. 2004, 11, p. 1135-46). Lipoic acid has now been evaluated in the clinic for the treatment of diabetes (Morcos, M. et al Diabetes Res. Clin. Pract. 2001, 52, p. 175-183) and diabetic neuropathy (Mijnhout, G. S. et al Neth. J. Med. 2010, 110, p. 158-162). Lipoic acid has also been found to be potentially useful in treating cardiovascular diseases (Ghibu, S. et al, J. Cardiovasc. Pharmacol. 2009, 54, p. 391-8), Alzheimer's disease (Maczurek, A. et al, Adv. Drug Deliv. Rev. 2008, 60, p. 1463-70) and multiple sclerosis (Yadav, V. Multiple Sclerosis 2005, 11, p. 159-65; Salinthone, S. et al, Endocr. Metab. Immune Disord. Drug Targets 2008, 8, p. 132-42). Lipoic acid can potentially be useful in treating or preventing hypertriglyceridemia and diabetic dyslipidemia. Recent data suggested that the triglyceride-lowering effect of lipoic acid is due in part to its ability to stimulate triglyceride clearance and down-regulate liver triglyceride secretion, most likely via inhibition of DGAT-2 (Moreau et al, Archives of Biochemistry and Biophysics 2009, 485, p. 63-'71).

"The ability to provide the effects of non-flushing niacin and omega-3 fatty acid in a synergistic way would provide a great benefit in treating the aforementioned diseases."

Supplementing the background information on this patent, NewsRx reporters also obtained the inventors' summary information for this patent: "The invention is based in part on the discovery of fatty acid niacin conjugates and their demonstrated effects in achieving improved treatment that cannot be achieved by administering niacin or fatty acids alone or in combination. These novel conjugates are useful in the treatment or prevention of metabolic diseases including atherosclerosis, dyslipidemia, coronary heart disease, hypercholesterolemia, Type 2 diabetes, elevated cholesterol, metabolic syndrome and cardiovascular disease.

"Accordingly in one aspect, a molecular conjugate is described which comprises a niacin covalently linked to a fatty acid, wherein the fatty acid is selected from the group consisting of omega-3 fatty acids and fatty acids that are metabolized in vivo to omega-3 fatty acids, the conjugate comprises at least one amide, and the conjugate is capable of hydrolysis to produce free niacin and free fatty acid.

"In another aspect, a molecular conjugate is described which comprises a niacin covalently linked to a fatty acid, wherein the fatty acid is selected from the group consisting of omega-3 fatty acids and fatty acids that are metabolized in vivo to omega-3 fatty acids, wherein the niacin is not linked to the fatty acid through --OCH2O--, and the conjugate is capable of hydrolysis to produce free niacin and free fatty acid.

"In another aspect, compounds of the Formula I are described:

"##STR00001## and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers and stereoisomers thereof; wherein, R.sub.1, R.sub.2, and R.sub.3 are each independently selected from the group consisting of --H, -D, --Cl, --F, --CN, --NH.sub.2, --NH(C.sub.1-C.sub.3 alkyl), --N(C.sub.1-C.sub.3 alkyl).sub.2, --NH(C(O)C.sub.1-C.sub.3 alkyl), --N(C(O)C.sub.1-C.sub.3 alkyl).sub.2, --C(O)H, --C(O)C.sub.1-C.sub.3 alkyl, --C(O)OC.sub.1-C.sub.3 alkyl, --C(O)NH.sub.2, --C(O)NH(C.sub.1-C.sub.3 alkyl), --C(O)N(C.sub.1-C.sub.3 alkyl).sub.2, --C.sub.1-C.sub.3 alkyl, --O--C.sub.1-C.sub.3 alkyl, --S(O)C.sub.1-C.sub.3 alkyl and --S(O).sub.2C.sub.1-C.sub.3 alkyl; W.sub.1 and W.sub.2 are each independently null, O, S, NH, NR, or W.sub.1 and W.sub.2 can be taken together can form an imidazolidine or piperazine group, with the proviso that W.sub.1 and W.sub.2 can not be 0 simultaneously; each a, b, c, and d is independently --H, -D, --CH.sub.3, --OCH.sub.3, --OCH.sub.2CH.sub.3, --C(O)OR, or --O--Z, or benzyl, or two of a, b, c, and d can be taken together, along with the single carbon to which they are bound, to form a cycloalkyl or heterocycle; each n, o, p, and q is independently 0 or 1; each L is independently --O--, --S--, --S(O)--, --S(O).sub.2--, --S--S--,

"##STR00002## wherein the representation of L is not limited directionally left to right as depicted, rather either the left side or the right side of L can be bound to the W.sub.1 side of the compound of Formula I; each g is independently 2, 3 or 4; each h is independently 1, 2, 3 or 4; m is 0, 1, 2, or 3; each R.sub.6 is independently H or C.sub.1-C.sub.6 alkyl, or both R.sub.6 groups, when taken together with the nitrogen to which they are attached, form a heterocycle; each R.sub.7 is independently e, H, or straight or branched C.sub.1-C.sub.10 alkyl which can be optionally substituted with OH, NH.sub.2, CO.sub.2R, CONH.sub.2, phenyl, C.sub.6H.sub.4OH, imidazole or arginine; each e is independently H or any one of the side chains of the naturally occurring amino acids; each Z is independently --H, or

"##STR00003## with the proviso that there is at least one

"##STR00004## in the compound; each r is independently 2, 3, or 7; each s is independently 3, 5, or 6; each t is independently 0 or 1; each v is independently 1, 2, or 6; R.sub.4 and R.sub.5 are each independently --H, -D, --C.sub.1-C.sub.4 alkyl, -halogen, --OH, --C(O)C.sub.1-C.sub.4 alkyl, --O-aryl, --O-benzyl, --OC(O)C.sub.1-C.sub.4 alkyl, --C.sub.1-C.sub.3 alkene, --C.sub.1-C.sub.3 alkyne, --C(O)C.sub.1-C.sub.4 alkyl, --NH.sub.2, --NH(C.sub.1-C.sub.3 alkyl), --N(C.sub.1-C.sub.3 alkyl).sub.2, --NH(C(O)C.sub.1-C.sub.3 alkyl), --N(C(O)C.sub.1-C.sub.3 alkyl).sub.2, --SH, --S(C.sub.1-C.sub.3 alkyl), --S(O)C.sub.1-C.sub.3 alkyl, --S(O).sub.2C.sub.1-C.sub.3 alkyl; and each R is independently --H, --C(O)--C.sub.1-C.sub.3 alkyl, or straight or branched C.sub.1-C.sub.4 alkyl optionally substituted with OR, NR.sub.2, or halogen; provided that when m, n, o, p, and q are each 0, W.sub.1 and W.sub.2 are each null, and Z is

"##STR00005## then t must be 0; and when each of m, n, o, p, and q is 0, and W.sub.1 and W.sub.2 are each null, then Z must not be

"##STR00006##

"In another aspect, compounds of the Formula II are described:

"##STR00007## and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers and stereoisomers thereof; wherein, R.sub.1, R.sub.2, and R.sub.3 are each independently selected from the group consisting of --H, -D, --Cl, --F, --CN, --NH.sub.2, --NH(C.sub.1-C.sub.3 alkyl), --N(C.sub.1-C.sub.3 alkyl).sub.2, --NH(C(O)C.sub.1-C.sub.3 alkyl), --N(C(O)C.sub.1-C.sub.3 alkyl).sub.2, --C(O)H, --C(O)C.sub.1-C.sub.3 alkyl, --C(O)OC.sub.1-C.sub.3 alkyl, --C(O)NH.sub.2, --C(O)NH(C.sub.1-C.sub.3 alkyl), --C(O)N(C.sub.1-C.sub.3 alkyl).sub.2, --C.sub.1-C.sub.3 alkyl, --O--C.sub.1-C.sub.3 alkyl, --S(O)C.sub.1-C.sub.3 alkyl and --S(O).sub.2C.sub.1-C.sub.3 alkyl; W.sub.1 and W.sub.2 are each independently selected from null, O, S, NH, and NR; each a, b, c, and d is independently --H, -D, Halogen, --CH.sub.3, --OCH.sub.3, --OCF.sub.3, --OCH.sub.2CH.sub.3, --C(O)OR, or --O--Z, or benzyl, or two of a, b, c, and d can be taken together, along with the single carbon to which they are bound, to form a cycloalkyl or heterocycle; each n, o, p, and q is independently 0 or 1; each L is independently --O--, --S--, --S(O)--, --S(O).sub.2--, --S--S--,

"##STR00008## ##STR00009## ##STR00010## wherein the representation of L is not limited directionally left to right as depicted, rather either the left side or the right side of L can be bound to the W.sub.1 side of the compound of Formula I; each g is independently 2, 3 or 4; each h is independently 1, 2, 3 or 4; each m is independently 0, 1, 2, or 3; if m is more than 1, then L can be the same or different; each m1 is independently 0, 1, 2, or 3; k is 0, 1, 2, or 3; each R.sub.6 is independently H or C.sub.1-C.sub.6 alkyl, or both R.sub.6 groups, when taken together with the nitrogen to which they are attached, form a heterocycle; each R.sub.7 is independently e, H, or straight or branched C.sub.1-C.sub.10 alkyl which can be optionally substituted with OH, NH.sub.2, CO.sub.2R, CONH.sub.2, phenyl, C.sub.6H.sub.4OH, imidazole or arginine; each e is independently H or any one of the side chains of the naturally occurring amino acids; each R.sub.9 is independently --H, -D, C.sub.1-C.sub.4 alkyl, halogen, cyano, oxo, thiooxo, --OH, C(O)C.sub.1-C.sub.4 alkyl, O-aryl, O-benzyl, OC(O)C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.3 alkene, C.sub.1-C.sub.3 alkyne, C(O)C.sub.1-C.sub.4 alkyl, NH.sub.2, NH(C.sub.1-C.sub.3 alkyl), N(C.sub.1-C.sub.3 alkyl).sub.2, NH(C(O)C.sub.1-C.sub.3 alkyl), N(C(O)C.sub.1-C.sub.3alkyl).sub.2, SH, S(C.sub.1-C.sub.3 alkyl), S(O)C.sub.1-C.sub.3 alkyl, S(O).sub.2C.sub.1-C.sub.3 alkyl; each Z is independently --H, or

"##STR00011## with the proviso that there is at least one

"##STR00012## in the compound; each r is independently 2, 3, or 7; each s is independently 3, 5, or 6; each t is independently 0 or 1; each v is independently 1, 2, or 6; R.sub.4 and R.sub.5 are each independently --H, -D, --C.sub.1-C.sub.4 alkyl, -halogen, --OH, --C(O)C.sub.1-C.sub.4 alkyl, --O-aryl, --O-benzyl, --OC(O)C.sub.1-C.sub.4 alkyl, --C.sub.1-C.sub.3 alkene, --C.sub.1-C.sub.3 alkyne, --C(O)C.sub.1-C.sub.4 alkyl, --NH.sub.2, --NH(C.sub.1-C.sub.3 alkyl), --N(C.sub.1-C.sub.3 alkyl).sub.2, --NH(C(O)C.sub.1-C.sub.3 alkyl), --N(C(O)C.sub.1-C.sub.3 alkyl).sub.2, --SH, --S(C.sub.1-C.sub.3 alkyl), --S(O)C.sub.1-C.sub.3 alkyl, --S(O).sub.2C.sub.1-C.sub.3 alkyl; and each R is independently --H, --C(O)--C.sub.1-C.sub.3 alkyl, or straight or branched C.sub.1-C.sub.4 alkyl optionally substituted with OR, NR.sub.2, or halogen; provided that when m, n, o, p, and q are each 0, W.sub.1 and W.sub.2 are each null, and Z is

"##STR00013## then t must be 0; and when each of m, n, o, p, and q is 0, and W.sub.1 and W.sub.2 are each null, then Z must not be

"##STR00014##

"In Formula I and II, any one or more of H may be substituted with a deuterium. It is also understood in Formula I and II that a methyl substituent can be substituted with a C.sub.1-C.sub.6 alkyl.

"Also described are pharmaceutical formulations comprising at least one fatty acid niacin derivative.

"Also described herein are methods of treating a disease susceptible to treatment with a fatty acid niacin derivative in a patient in need thereof by administering to the patient an effective amount of a fatty acid niacin derivative.

"Also described herein are methods of treating metabolic diseases by administering to a patient in need thereof an effective amount of a fatty acid niacin derivative.

"The invention also includes pharmaceutical compositions that comprise an effective amount of a fatty acid niacin derivative and a pharmaceutically acceptable carrier. The compositions are useful for treating or preventing a metabolic disease. The invention includes a fatty acid niacin derivative provided as a pharmaceutically acceptable prodrug, hydrate, salt, enantiomer, stereoisomer, or mixtures thereof.

"The details of the invention are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, illustrative methods and materials are now described. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications cited in this specification are incorporated herein by reference in their entireties."

For the URL and additional information on this patent, see: Milne, Jill C.; Jirousek, Michael R.; Bemis, Jean E.; Vu, Chi B.. Fatty Acid Niacin Conjugates and Their Uses. U.S. Patent Number 8765964, filed December 30, 2013, and published online on July 1, 2014. Patent URL: http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=8765964.PN.&OS=PN/8765964RS=PN/8765964

Keywords for this news article include: Catabasis Pharmaceuticals Inc., Pharmaceutical Companies, Lipids, Proinsulin, Legal Issues, Apolipoproteins, Peptide Hormones, Biopharmaceutical Company.

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