巴西专利BR112012004677A2 niacin fatty acid conjugates and their uses

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专利摘要:
NIACIN FATTY ACID CONJUGATE AND ITS USES.The invention relates to niacin fatty acid conjugates; compositions comprising an effective amount of a niacin fatty acid conjugator; and methods of treating or preventing a metabolic disease comprising administering an effective amount of a niacin fatty acid conjugate.
公开号:BR112012004677A2
申请号:R112012004677-2
申请日:2010-08-31
公开日:2020-11-03
发明作者:Jill C. Milne；Michael R. Jirousek；Jean E. Bemis；Chi B. Vu
申请人:Catabasis Pharmaceuticals, Inc.；
IPC主号:

专利说明:

[0004] [0004] Omega-3 fatty acids have been shown to improve insulin sensitivity and glucose tolerance in normoglycemic men and in obese individuals.
[0005] [0005] The ability to provide the effects of niacin-5 and omega-3 fatty acids synergistically would provide a great benefit in the treatment of the aforementioned diseases. SUMMARY OF THE INVENTION
[0006] [0006] The invention is based, in part, on the discovery of niacin fatty acid conjugates and their demonstrated effects in embodying improved treatment that cannot be achieved by administering fatty acids or niacin, 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, high cholesterol, metabolic syndrome and cardiovascular disease.
[0007] [0007] Accordingly, in one aspect, a molecular conjugate is disclosed 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 for omega-3 fatty acids, the OO conjugate comprises at least one amide, and the conjugate is capable of hydrolysis to produce free niacin and free fatty acid.
[0008] [0008] In another aspect, compounds of Formula I are described:
[0009] [0009] In Formula I, any one or more of H can be replaced with a deuterium.
[0010] [0010] Pharmaceutical formulations comprising at least one niacin fatty acid derivative are also described.
[0011] [0011] Also described herein are methods of treating a disease amenable to treatment with a niacin fatty acid derivative in a patient in need thereof, by administering to the patient an effective amount of a niacin fatty acid derivative.
[0012] [0012] Also described herein are methods of treating metabolic disorders by administering to a patient in need thereof an effective amount of a fatty acid derivative of niacin.
[0013] [0013] The invention also includes pharmaceutical compositions comprising an effective amount of a niacin fatty acid derivative and a pharmaceutically acceptable carrier.
[0014] [0014] The details of the invention are set out in the accompanying description.
[0016] [0016] The niacin fatty acid derivatives were designed to bring together niacin analogues and omega-3 fatty acids into a single molecular conjugate.
[0017] [0017] The following definitions are used in connection with fatty acid derivatives of niacin:
[0018] [0018] The term "niacin fatty acid derivatives" includes any and all possible isomers, stereoisomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, and prodrugs of the niacin fatty acid derivatives described herein.
[0019] [0019] The articles "a" and "a" are used in this disclosure to refer to one or more than one (ie, at least one) of the grammatical object of the article.
[0020] [0020] The term "and/or" is used in this disclosure either
[0021] [0021] Unless otherwise specifically defined, the term "aryl" refers to cyclic groups, aromatic hydrocarbons that have 1 to 2 rings. 5 aromatics, including monocyclic or bicyclic groups, such as phenyl, biphenyl or naphthyl.
[0022] [0022] "C1 -C3 alkyl" refers to a saturated straight or branched chain hydrocarbon containing 1-3 carbon atoms.
[0023] [0023] "C1-C4 alkyl" refers to a saturated straight or branched chain hydrocarbon containing 1-4 carbon atoms.
[0024] [0024] "C1I-C5 alkyl" refers to a saturated straight or branched chain hydrocarbon containing 1-5 carbon atoms.
[0025] [0025] "C 1 -C 6 alkyl" refers to a saturated straight or branched chain hydrocarbon containing 1-6 carbon atoms.
[0026] [0026] The term "cycloalkyl" refers to a cyclic hydrocarbon containing 3-6 carbon atoms.
[0027] [0027] The term "heterocycle" as used herein refers to a cyclic hydrocarbon containing 3-6 atoms wherein at least one of the atoms is an O, N, or S. Examples of heterocycles include, but are not limited to, aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, tetrahydropyran, thiane, imidazolidine, oxazolidine, thiazolidine, dioxolane, dithiolane, piperazine, oxazine, dithiane, and dioxane.
[0028] [0028] The term "any of the side chains of naturally occurring amino acids" as used herein means a side chain of any of the following amino acids: Isoleucine, Alanine, Leucine, Asparagine, Lysine, Aspartate, Cysteine, Methionine , Phenylalanine, Glutamate, Threonine, Glutamine, Tryptophan, . 5 glycine, valine, proline, arginine, serine, histidine, tyrosine e.g.
[0029] [0029] The "fatty acids" as used herein means an omega-3 fatty acid and fatty acids that are metabolized in vivo to omega-3 fatty acids.
[0030] [0030] The term "niacin", as used herein, means the molecule known as niacin and any derivative thereof.
[0031] [0031] A "subject" is a mammal, e.g. a mouse, human, rat, guinea pig, dog, cat, etc.
[0033] [0033] Representative "pharmaceutically acceptable salts" include, for example, water-soluble and water-insoluble salts such as acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate, bisulfate, bicarbonate , bitartrate, borate, bromide, butyrate, calcium edetate, calcium camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fiunarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate maleate, magnesium, malate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsilate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2- oleate naphthoate, oxalate, palmitate, pamoate (1, l-methene-bis-2-hydroxy-3-naphthoate, einbonate), phosphate pantothenate /
[0034] [0034] The term "metabolic disease" as used herein refers to disorders, diseases and syndromes involving dyslipidemia, and the terms metabolic disorder, metabolic disease and metabolic syndrome are used interchangeably herein.
[0035] [0035] An "effective amount" when used in connection with a niacin fatty acid derivative is an amount effective to treat or prevent a metabolic disorder.
[0036] [0036] The term "carrier" as used in this description encompasses carriers, excipients and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in loading or transporting a pharmaceutical agent from one organ, or body portion, to another organ, or body portion.
[0037] [0037] The term "treatment", as it pertains to a subject, refers to improving at least one symptom of the individual's illness.
[0038] [0038] "Disorder" is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or disease, unless otherwise noted.
[0039] [0039] The term "administer", "administration" or "administration" as used in this specification refers to either directly administering a compound or pharmaceutically acceptable salt of the compound or composition to a subject, or administering of a prodrug or analogue derivative of the compound or a pharmaceutically acceptable salt of the compound or composition for the subject, which can form an equivalent amount of active compound within the subject's body.
[0040] [0040] The term "prodrug", as used in this specification, means a compound that is convertible in vivo by metabolic means (e.g., by hydrolysis) to a fatty acid derivative of niacin.
[0041] [0041] The following abbreviations are used herein and have the definitions indicated: Boc and BOC are tert-butoxycarbonyl, Boc20 is di-tert-butyl, BSA is bovine serum albumin, CDI is [Iota]l, [Gamma]-carbonyldiimidazole , DCC is N, N-dicyclohexylcarbodiimide, DIEA is N, N-diisopropylethylamine, DMAP is 4-dimethylaminopyridine, DMEM is Modified from Dulbecco Eagle Medium, DMF is N, N-dimethylformamide, DOSS is dioctyl sodium sulfosuccinate, EDC and EDCI are 1-ethyl -3 - (3-dimethylaminopropyl)-carbodiimide, ELISA is enzyme-linked immunosorbent assay, EtOAc is ethyl acetate, FBS is fetal bovine serum, h is hour, HATU is 2 - (7- aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, HIV is human immunodeficiency virus, HPMC is hydroxypropyl methylcellulose, oxone is potassium peroxymonosulfate, Pd/C is palladium on carbon, TFA is trifluoroacetic acid, TGPs is propylene glycol tocopheryl succinate, and THF is tetrahydrofuran. COMPOUNDS
[0042] [0042] Accordingly, in one aspect, the present invention provides a molecular conjugate comprising a niacin and a covalently linked 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 conjugate comprises at least one amide and the conjugate is capable of hydrolysis to produce free niacin and free fatty acid.
[0043] [0043] In some embodiments, the fatty acid is selected from the group consisting of all-cz<'>s-7,10,13-hexadecatrienoic acid, α-linolenic acid, stearidonic acid, eicosatrienoic acid, eicosatetraenoic acid, eicosapentaenoic acid (EPA), docosapentaenoic acid, docosahexaenoic acid (DHA), tetracosapentaenoic acid and tetracosahexaenoic acid.
[0044] [0044] In another aspect, the present invention provides fatty acid derivatives of niacin according to Formula I: Formula I and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; wherein R1s R2, R3, R4, R5, Re, R7, R, Wi, W2, L, a, c, b, df, e, g, h, m, n, 0, Pp, 4, 2,
[0045] [0045] In some embodiments, R3 is Cl, F, or CN. . 5 [0046] In some embodiments, R3 is -CH3 or -CH2CH3.
[0047] [0047] In some embodiments, Wi is NH.
[0048] [0048] In some embodiments, W2 is NH.
[0049] [0049] In some embodiments, Wi is O.
[0050] [0050] In some embodiments, W2 is O.
[0051] [0051] In some embodiments, A and C are each independently H, or CH3.
[0052] [0052] In some embodiments, m is 0.
[0053] [0053] In other embodiments, m is 1.
[0054] [0054] In some embodiments, L is -S, or -SS-.
[0055] [0055] In some embodiments, L is -0 -,
[0056] [0056] In some embodiments, L is
[0057] [0057] In some embodiments, L is
[0058] [0058] In some embodiments, L is
[0059] [0059] In some embodiments, L is
[0060] [0060] In some embodiments, L is
[0061] [0061] In some embodiments, L is
[0062] [0062] In some embodiments, a b is 0Z, 2 is ethereal.
[0063] [0063] In some embodiments, a d is C(0) OR.
[0064] [0064] In some embodiments n, o, p, and Q are each.
[0065] [0065] In some embodiments, two of n, o, p, and Q are each.
[0066] [0066] In other embodiments, three of n, o, p, &e0Q are each.
[0067] [0067] In some embodiments, a Z is eRé l.
[0068] [0068] In some embodiments, a Z2 is eRei. - 5 [0069] In some embodiments, a 2 is and R is 7.
[0070] [0070] In other embodiments, a 2 is es6ési3.
[0071] [0071] In some embodiments, a Z is essential.
[0072] [0072] In some embodiments, a 2 is esecd.
[0073] [0073] In some embodiments, a Z is eVable.
[0074] [0074] In other embodiments, a Z is eVvél.
[0075] [0075] In some embodiments, a 2 is evé6bó.
[0076] [0076] In some embodiments, a 2 is esési.
[0077] [0077] In some embodiments, a 2 is es.
[0078] [0078] In other embodiments, a Z is and is echo.
[0079] [0079] In some embodiments, t is 1.
[0080] [0080] In some embodiments, r is 2, s is 6, Wi and W2 are each NH, m is 1, n, o, p, and Q are each, and L is O.
[0081] [0081] In some embodiments, r is 2, s is 6, Wi and W2 are each NH, m is 1, n, o, p, and Q are each, and L is-
[0082] [0082] In some embodiments, r is 2, s is 6, Wi and W2 are each NH, m is 1, N and O are each O, p and Q are each 1, and L is . 5 [0083] In some embodiments, r is 2, S is 6, Wi and W2 are each NH, m is 1, n, o, p, and Q are each 0, and L is
[0084] [0084] In some embodiments, r is 2, s is 6, Wi and W2 are each NH, m, n, and O are each 0, and p and Q are each 1.
[0085] [0085] In some embodiments, r is 2, S is 6, Wi and W2 are each NH, m is 1, N and O are each O, p and 0o are each 1, and L is
[0086] [0086] In some embodiments, r is 2, S is 6, Wi and W2 are each NH, m is 1, N and O are each 1, p and Q are each 0, eL is In some embodiments, r is 2, s is 6, m is 1, NE O are each 0, p and Q are each 1, In some embodiments, r is 2, sé 65, mé l, NE O are each l, p and Q are each 0,
[0089] [0089] In some embodiments, r is 2, Ss is 6, Wi and W2 are each NH, m is 1, n, 0, p, and Q are each, and L is
[0090] [0090] In some embodiments, r is 2, Ss is 6, Wi and W2 are each NH, m is l, n, o, p, and Q are each, and L is NR6.
[0091] [0091] In some embodiments, r is 2, s is 6, Wi and W2 are each NH, m, n, and O are each 0, and p and Q are each, and a c is -CH3 and the others c is -CH3.
[0092] [0092] In some embodiments, r is 2, s is 6, Wi and W2 are each NH, m is l1, N and O are each 1, p and Q are each (0, &eLéo = err
[0093] [0093] In some embodiments, r is 3, s is 5, and L is
[0094] [0094] In some embodiments, r is 3, s is 5, and L is
[0095] [0095] In some embodiments, r is 3, S is 5, and L is
[0096] [0096] In some embodiments, r is 3, s is 5, and L is . 5 [0097] In some embodiments, r is 3, s is 5, and L is
[0098] [0098] In some embodiments, r is 3, s is 5, and L is
[0099] [0099] In some embodiments, r is 3, s is 5, and n, o, p, and Q are each.
[0100] [0100] In some embodiments, r is 3, s is 5, and two den, o, p, e0Q are each.
[0101] [0101] In some embodiments, r is 3, s is 5, and Wi and W2 are each NH. [0102] In some embodiments, r is 3, sé5,mel,n,o,p, andpek are each, and L is 0.
[0103] [0103] In some embodiments, r is 3, s is 5, m and 1, n, o, p, e0Q are each, and L is -ss-.
[0104] [0104] In some embodiments, r is 3, s is 5, m and 1, N and O are each 0, p and Q are each 1, and L is
[0105] [0105] In some embodiments, r is 3, s is 5, m and 1, mn, 0o,p, &e0Q are each 0, and L is
[0106] [0106] In some embodiments, r is 3, s is 5, Mm, nN, and O are each 0, and p and Q are each 1.
[0107] [0107] In some embodiments, r is 3, s is 5, m and 1, Ne O are each l, p and Q are each 0, and L is
[0108] [0108] In some embodiments, r is 3, s is 5, m and 1, Ne O are each 0, p and Q are each 1, and L is
[0109] [0109] In some embodiments, r is 3, Ss is 557 m and 1, Neo0oO are each 0, p and Q are each 1, and L is In some embodiments, r is 3, s is 5, m and 1, Ne O are each l, p and Q are each O,
[0111] [0111] In some embodiments, r is 3, s is 5, m is 1, n, o, p, and Q are each, and L is NR6.
[0112] [0112] In some embodiments, r is 3, s is 5, mM, n, and O are each 0, and p and Q are each, and one c is -CH3 and the -5 other c is -CH3.
[0113] [0113] In some embodiments, r is 3, s is 5, m and l, N, and O are each l, p and Q are each 0, and L is
[0114] [0114] In Formula I, any one or more of H can be replaced with a deuterium.
[0115] [0115] In other illustrative embodiments, compounds of Formula I are as defined below:
[0116] [0116] N-(2 - (2 - (42.7%, 102, 1324, 162, 19Z)-docosa-4, 7, 10,13,16,19 r hexaenamidoethoxy) ethyl) nicotinamide (1-1) ;
[0117] [0117] N-(2 - ((2 - (4%, 72, 102%, 132%, 162, 19Z)-docosa-4, 7, 10,13,16,19 - hexaenamidoethyl)(methyl)amino) ethyl) nicotinamide (1-2);
[0118] [0118] N-(2 - (2 - (2 - (42, 72%, 102, 132, 162, 192)-docosa-4, 7, 10,13,16,19 - hexaenamidoethyl)disulfanyl)ethyl)nicotinamide (1-3);
[0119] [0119] N-(2 - (1 - (2 - (42, 7Z, 102, 132, 162, 192)-docosa-4, 7, 10,13,16,19 - hexaenamidoethyl)-2,5-dioxopyrrolidin -3-ylthio)ethyl)nicotinamide (1-4); [0120] Methyl 3 - (2 - (4%, 7Z, 1 OZ, 132, 16Z, 19Z)-docosa-4, 7, 10,13,16, 19 - hexaenamidoacetoxy) -2 - (nicotinamido) butanoate (1 -5);
[0121] [0121] 1,3-dihydroxypropan-2-yl 6 - (42, 72%, 1 OZ, 13%, 162, 19Z)-docosa-4, 7, 10,13,16,19 - hexaenamido-2-
[0122] [0122] N-(2 - (42.7%, 1 OZ, 132, 162, 19Z)-docosa-4, 7, 10,13,16,19 - hexaenamidoethyl) nicotinamide (1-7);
[0123] [0123] N-(2 - (52.8%, 112, 142, 17Z)-eicosa-5, -5 8,11,14, 117-pentaenamidoethyl) nicotinamide (1-8);
[0124] [0124] (28, 3R)-methyl 3-((S)-2-((42, 72.1 OZ, 132, 162, 19Z)-docosa-4, 7, 10,13,16,19 - hexaenamido ) propanoyloxy)-2-(nicotinamido)butanoate (1-9);
[0125] [0125] (28, 3R)-methyl 3 -((S)-2 -((52, 82, 112, 142, 17Z)-icosahedron-5, 8, 11,14,17 - pentaenamido)propanoyloxy)-2 - (nicotinamido)butanoate (1-10);
[0126] [0126] (S)-methyl 6 - ((4%Z, 72%, 1 OZ, 132, 162, 192)-docosa-4, 7, 10,13,16,19-hexaneamido) - 2 - (nicotinamido ) methyl hexanoate (1-11);
[0127] [0127] (S)-6-((42, 72, 1 OZ, 132, 162, 19Z)-docosa-4, 7, 10,13,16,19-hexaneamido)-2-(nicotinamido)hexanoic (1 -12);
[0128] (1- 13);
[0129] [0129] (S)-2-((52, 8Z, 11Z, 14Z, 17Z)-eicosa-5, 8, 11,14,17-pentaenamido)-6-(nicotinamido) hexanoic (1-14)
[0130] [0130] (S)-methyl 6-((52, 82, 11Z, 142, 17Z)-eicosa-5, 8, 11,14,17-pentaenamido)-2-(nicotinamido)hexanoate (1-15 ) ;
[0131] [0131] (S)-6-((52, 82, 112, 142, 17Z)-eicosa-5, 8, 11,14,17-pentaenamido)-2-(nicotinamido)hexanoic (1-16);
[0132] [0132] (S)-2-((42, 72, 102, 132, 162, 192)-docosa-4, 7, 10,13,16,19-hexaneamido)-6-(nicotinamido)hexanoic (1- 1);
[0133] [0133] (S)-5-((42, 72, 102, 132, 16Z, 192)-docosa--54, 7, 10,13,16,19-hexaneamido)-2-(nicotinamido) pentanoic ( 1-18);
[10134] [10134] (S) -2 - ((42, 72, 102, 132, 162, 19Z)-docosa-4, 7, 10,13,16,19-hexaneamido)-5 - (nicotinamido) pentanoic (1 - 19);
[0135] [0135] 4-(4%, 72, 102, 132, 162, 19Z)-docosa-4, 7, 10,13,16,19-hexaneamido-2-(nicotinamido)butanoic (1-20);
[0136] [0136] 2-(42, 72, 102, 132, 162, 19Z)-docosa-4, 7, 10,13,16,19-hexaneamido-4-(nicotinamido)butanoic (1-21); [0137] 3-(4%, 72%, 1 OZ, 132, 16Z, 19Z)-docosa-4, 7, 10,13,16,19-hexaneamido-2-(nicotinamido)propanoic (1-22);
[0138] [0138] 2-(42, 72, 102, 132, 162, 19Z)-docosa-4, 7, 10,13,16,19-hexaneamido-3-(nicotinamido)propanoic (1-23);
[0139] [0139] 2 - (2 - (42%, 72, 102, 132, 162, 19Z)-docosa-4, 7, 10,13,16,19-hexaenamidoethyl) 4 - (nicotinamido)butanoic (1-24) ;
[0140] [0140] (S) - 1,3-dihydroxypropan-2-yl 2 - ((42, 72, 102, 132, 162, 19Z)-docosa-4,7,10,13,16,19-hexaenamido) - 6 - (nicotinamido) hexanoate (1-25); | 25 [0141] (S)-1,3-dihydroxypropan-2-yl 5-((42, 72, 102, 132, 162, 192)-docosa-4,7,10,13,16,19-hexaenamido) -2 - (nicotinamido) pentanoate (1-26);
[0142] [0142] (S) - 1 , 3-dihydroxypropan-2-yl 2 - ((4%, 171Z, 102, 132, 162, 192) -docosa- o o o o o AO
[10143] [10143] 1,3-dihydroxypropan-2-yl 4-(42, T7Z, 102, 132, 162, 19Z)-docosa-4, 7, 10,13,16,19 - hexaenamido-2- - 5 — (nicotinamido) butanoate (1-28);
[0144] [0144] 1,3-dihydroxypropan-2-yl 2-(42, 72, 102, 132, 162, 19Z)-docosa-4, 7, 10,13,16,19 -hexaenamido-4-(nicotinamido)butanoate (1-29);
[0145] [0145] 1,3-dihydroxypropan-2-yl 3-(423, 72%, 102, 132, 162, 19Z)-docosa-4, 7, 10,13,16,19 -hexaenamido-2-(nicotinamido) propanoate (1-30);
[0146] [0146] 1,3-dihydroxypropan-2-yl 2-(427, 724.1 OZ, 13z2, 162, 19Z)-docosa-4, 7, 10,13,16,19 -hexaenamido-3-(nicotinamido) propanoate (1-31);
[0147] [0147] 1,3-dihydroxypropan-2-yl 2-(2-(437, 724.1 oz, 132, 162, 19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl) —4 - (nicotinamido)butanoate (1-32);
[0148] [0148] N-(4-(42, 72.1 OZ, 132, 162, 19Z)-docosa-4, 7, 10,13,16,19 -hexaenamidobutyl) nicotinamide (1-33);
[0149] [0149] N-(3 - (42, 72.1 OZ, 132, 162, 19Z)-docosa-4, 7, 10,13,16,19 - hexaenamidopropyl) nicotinamide (1-34);
[0150] [0150] N-(1-(4%, 72.1 OZ, 132, 162, 19Z)-docosa-4, 7, 10,13,16,19-hexaneamido-2-methyl-2-yl) nicotinamide ( 1 - 35);
[0151] [0151] N-(2-(423, 72.1 OZ, 132, 16Z, 19Z)-docosa-4, 7, 10,13,16,19-hexaneamido-2-methyl lpropy 1) nicotinamide (1-36 );
[0152] [0152] N-(2 - (2 - (42, 72%, 1 OZ, 132, 162, 192)-docosa-4, 7, 10,13,16,19 -hexaenamidoethylamino)ethyl) | 30 nicotinamide (1-37); = rat
[0153] [0153] N-(3 - (2 - (42, 7z2, 1 OZ, 132, 162, 192)-docosa-4, 7, 10,13,16,19 - hexaenamido ethyl Lamino) propyl) nicotinamide (1 - 38); [0154] N-(2 - (3 - (42, 72, 1 OZ, δ 132, 162, 19Z)-docosa-4, 7 10,13,16,19 - - 5 hexaenamidopropylamino)ethyl)nicotinamide (1- 39);
[0155] [0155] N-(2 -((3 -(42, 172, 1 oz, 132, 162, 192)-docosa-4, 7, 10,13,16,19 - hexaenamidopropyl)(ethyl)amino)ethyl) nicotinamide (1-40);
[0156] [0156] N-(2 - ((2 - (42, 72, 10Z, 132, 162, 192)-docosa-4, 7, 10,13,16,19 - hexaenamidoethyl)(isobutyl)amino)ethyl) nicotinamide (1-41);
[0157] [0157] N-(2 - (N-(2 - (42, 72, 10Z, 132, 162, 192)-docosa-4, 7, 10,13,16,19 - hexaenamidoethyl)acetamido)-ethyl) nicotinamide (1-42);
[0158] [0158] N-(2 - ((2 - (42, 72, 10Z, 132, 162, 192)-docosa-4, 7, 10,13,16,19 - hexaenamidoethyl)(2-morpholinoethyl)amino) ethyl) nicotinamide (1-43);
[0159] [0159] N-(2 - ((2 - (42.7%, 1 OZ, 132, 162, 192)-docosa-4, 7, 10,13,16,19 - hexaenamidoethyl) (3 - (piperazin- 1-yl)propyl)amino)ethyl)nicotinamide (1-44);
[0160] [0160] N-(3-(42, 7Z, 1 OZ, 132, 162, 19Z)-docosa-4, 7, 10,13,16,19-hexaneamido-2-oxopropyl) nicotinamide (1-45);
[0161] [0161] N-(3-(42, 72, 102, 132, 162, 19Z)-docosa-417,10,13,16,19-hexaneamido-2-morpholinopropyl)nicotinamide (1-46);
[0162] [0162] N-(3-(42, 72.1 OZ, 132, 162, 19Z)-docosa-4, 7, 10,13,16,19-hexaneamido-2-(piperazin-1-yl)propyl) nicotinamide (1-47);
[0163] [0163] N-(3 - (42, 72, 1 OZ, 132, 162, 19Z) -docosa-4, = eee
[0164] [0164] N-(5-(42, 74.10Z, 132, 162, 192)-docosa-4,17,10,13,16,19-hexaneamido-3-hydroxypentyl)nicotinamide. 5 (1-49);
[0165] [0165] N-(5-(43, 72.1 OZ, 132, 162, 192)-docosa-4, 7, 10,13,16, 19-hexaneamido-3-morpholinopentyl) nicotinamide (1-50);
[0166] [0166] N-(5-(42, 7Z, 1 OZ, 13Z, 162, 192)-docosa-4, 7, 10,13,16,19-hexaneamido-3-(piperazin-11-yl)pentyl) nicotinamide (1-51);
[0167] [0167] (S)-((R)-1-(nicotinamido)propan-2-yl) 2-((52, 8Z, 1 12, 142, 172)-eicosa-5,8,11,14, 17 and pentaenamido) ethyl propanoate (1-52);
[0168] [0168] (S)-((R)-1-(nicotinamido)propan-2-yl) 2-((527, 82%, 1 12, 142, 172)-eicosa-5,8,11,14, 17-pentaenamido)-3-methylbutanoate (1-53);
[0169] [0169] N-(2 - (2 - (2 - (42, 72, 102, 132, 162, 192)-docosa-4, 7, 10,13,16,19 - hexaenamidoethoxy)ethoxy)ethyl)nicotinamide (1-54);
[0170] [0170] N-(2 - (2 - (42, 72, 1 OZ, 132, 162, 192)-docosa-4, 7, 10,13,16,19 - hexaenamidoethylthio) ethyl) nicotinamide (1-55) ; [0171] (42, 72, 1 OZ, 132, 162, 192) - 1-(nicotinamido)propan-2-yl docosa-4, 7, 10,13,16,19 - hexaenoate (1-56);
[0172] [0172] (42%, 72.1 OZ, 1327, 162, 192)-4-methoxy-3-(nicotinamido)-4-oxobutan-2-yl docosa-4,7,10,13,16,19- hexaenoate (1-57);
[0173] [0173] N-(2-(42.7%, 102, 132, 162, 19Z)-docosa-4, 7, 10,13,16,19-hexaneamidoethyl)-6-methylnicotinamide (1- to OOOE ai 27 58);
[0174] [0174] N-(2-(52, 8Z, 1127, 142, 172)-eicosa-5, 8, 11,14,17-pentaenamidoethyl)-6-methylnicotinamide (1-59); i [0175] N-(2 - (42, 72, 102, 132, 16Z, 19Z)-docosa-4, - 5 7, 10,13,16,19-hexaenamidoethyl) —-6 - ethylnicotinamide (1- 60 );
[0176] [0176] 6-ethyl-N-(2-(52.8%, 11Z, 14%, 17Z)-eicosa-5, 8, 11,14,17-pentaenamidoethyl) nicotinamide (1-61);
[0177] [0177] G6-chloro-N-(2-(42, 72, 102, 132, 162, 192)-docosa-4, 7, 10,13,16,19 - hexaenamidoethyl) nicotinamide (1-62);
[0178] [0178] 6-chloro-N-(2-(52.8%, 11Z, 142, 17Z)-eicosa-5, 8, 11,14,17-pentaenamidoethyl) nicotinamide (1-63);
[0179] [0179] N-(2-(42, 72, 10zZ, 132, 162, 19Z)-docosa-4, 7, 10,13,16,19-hexaenamidoethyl)-6 -fluoronicotinamide (1-64);
[0180] [0180] G6-fluoro-N-(2-(52.8%, 112, 142, 172)-eicosa-5, 8, 11,14,17-pentaenamidoethyl) nicotinamide (1-65);
[0181] [0181] G6-cyano-N-(2-(42, 72, 102, 132, 162, 192)-docosa-4, 7, 10,13,16,19 - hexaenamidoethyl) nicotinamide (1-66);
[0182] [0182] 6-cyano-N-(2-(52, 82, 11Z, 142, 172)-eicosa-5, 8, 11,14,17-pentaenamidoethyl) nicotinamide (1-67);
[0183] [0183] (S) -6 - ((42, 72, 102, 132, 162, 192) -docosa- 4, 7, 10,13,16,19-hexaenamido) -2 - hexanoic acid - (methylnicotinamido 2) (1-68);
[0184] [0184] (S)-2-((4Z, 72, 102, 13Z, 162, 192)-docosa-4, 7, 10,13,16,19-hexaenamido)-6-hexanoic- (methylnicotinamido 2) ( 1-69); E A AC aaa EEE
[0185] [0185] (S) -6 - ((4%, 72, 10Z, 13z, 162, 192) -docosa- 4, 7, 10,13,16,19-hexaenamido) —-2 - (2 - ethylnicotinamido ) hexanoic acid (1-70);
[0186] [0186] (S)-2-((4%, 7Z, 1OZ, 132, 162, 192)-docosa-. 54, 7, 10,13,16,19-hexaneamido)-6-(2- ethylnicotinamido) nexanoic acid (1-71);
[0187] [0187] (S)-2-(2-chloronicotinamido)-6-((4Z, 72.1 oz, 132, 162, 19Z)-docosa-4,7,10,13,16,19-hexaneamido)hexanoic acid (1-72); [0188] (S)-6-(2-chloronicotinamido)-2-((42, 72zZ, 10Z, 132, 162, 192)-docosa-4,7,10,13, 16, 19-hexaenamido) hexanoic (1-73);
[0189] [0189] (S)-6-((42, 72, 1 OZ, 132, 162, 19Z)-docosa-4, 7, 10,13,16,19-hexaneamido)-2-(2-fluoronicotinamido)hexanoic acid (1-74);
[0190] [0190] (S)-2-((4Z, 72.1 Oz, 13Z, 162, 19Z)-docosa-4, 7, 10,13,16,19-hexaneamido)-6-(2-fluoronicotinamido)hexanoic acid (1-75);
[0191] [0191] (S)-2-(2-cyanonicotinamido)-6-((42, 72.1 oz, 132, 162, 19Z)-docosa-4,7,10,13,16,19-hexaenamido) hexanoic acid (1-76);
[0192] [0192] (S)-6-(2-cyanonicotinamido)-2-((42, 72.1 oz, 132, 16Z, 19Z)-docosa-4,7,10,13,16,19-hexaenamido) hexanoic (1-77);
[0193] [0193] N-(2-(2-(47, 72, 1 OZ, 132, 162, 192)-docosa-4, 7, 10,13,16,19 -hexaenamidoethoxy)ethyl)-6 methylnicotinamide-(1 -78);
[0194] [0194] N-(2 - ((2 - (42, 72, 10Z, 132, 162, 192)-docosa-4, 7, 10,13,16,19 - hexaenamidoethyl)(methyl)amino)ethyl) -6-methylnicotinamide (1-79);
[0195] [0195] N-(2 - (2 - (2 - (42, 72, 1 OZ, 132, 162, 192)- aa Ea a ao a aa o nas a EEN docosa-4, 7, 10,13,16 ,19 - hexaenamidoethyl) disulfanyl) ethyl) - 6-methylnicotinamide (1-80);
[0196] [0196] N-(2 - (2 - (42, 72, 1 OZ, 132, 162, 192)- docosa-4, 7, 10,13,16,19 - hexaenamidoethoxy) ethyl)-6 - 5 ethylnicotinamide -(1 -81);
[0197] [0197] N-(2 - ((2 - (42, 72, 10Z, 132, 162, 192)-docosa-4, 7, 10,13,16,19 - hexaenamidoethyl)(methyl)amino)ethyl) -6-ethylnicotinamide (1-82);
[0198] [0198] N-(2 - (2-(2-(47, 72, 10Z, 132, 162, 192)-docosa-4, 7, 10,13,16,19 - hexaenamidoethyl)disulfanyl)ethyl) - 6-ethylnicotinamide (1-83);
[0199] [0199] 6-Chloro-N-(2-(2-(4%, 72.1 OZ, 132, 162, 192)-docosa-4, 7, 10,13,16,19 - hexaenamidoethoxy)ethyl)nicotinamide (1-84);
[0200] [0200] 6-Chloro-N-(2 - ((2 - (42, 72.1 OZ, 132, 162, 19Z) -docosa-4, 7, 10,13,16,19 - hexaenamidoethyl) (methyl) amino) ethyl) nicotinamide (1-85);
[0201] [0201] 6-Chloro-N-(2 - (2 - (2 - (42, 72, 1 OZ, 132, 162, 19Z)-docosa-4, 7, 10,13,16,19 - hexaenamidoethyl) disulfanyl ) ethyl) nicotinamide (1-86);
[0202] [0202] G6-cyano-N-(2-(2-(42, 72.1 OZ, 132, 162, 19Z)-docosa-4, 7, 10,13,16,19 - hexaenamidoethoxy) ethyl) nicotinamide ( 1-87);
[0203] [0203] 6-cyano-N-(2 - ((2 - (42, 7zZ, 1 OZ, 132, 162, 19Z) -docosa-4, 7, 10,13,16,19 - hexaenamidoethyl) (methyl) amino) ethyl) nicotinamide (1-88);
[0204] [0204] 6-cyano-N-(2 - (2 - (2 - (42, 72, 1 OZ, 132, 162, 19Z)-docosa-4, 7, 10,13,16,19 - hexaenamidoethyl) disulfanyl ) ethyl) nicotinamide (1-89); Methods for using niacin fatty acid derivatives o E O o E Ear
[0205] [0205] The invention also includes methods for treating metabolic disorders, such as treating or preventing metabolic disorders, including dyslipidemia, atherosclerosis, coronary heart disease, hypercholesterolemia, Type 2 diabetes, high cholesterol, metabolic syndrome and disease. cardiovascular.
[0206] [0206] In one embodiment, the method comprises contacting a cell with a niacin fatty acid derivative in an amount sufficient to decrease the release of triglycerides or VLDL or LDL or cause an increase in reverse cholesterol transport or an increase in cholesterol. HDL concentrations.
[0207] [0207] also provided in the invention is a method for inhibiting, preventing, or treating a metabolic disease, or symptoms of a metabolic disease, in a subject.
[0209] [0209] The invention also includes pharmaceutical compositions useful for treating or preventing a metabolic disease, or for the disease of a metabolic inhibitor, or more than one of these activities.
[0210] [0210] The fatty acid derivatives of niacin may each be administered in amounts “that are sufficient to treat or prevent a metabolic disease or prevent the development of the same in individuals.
[0211] [0211] Administration of the niacin fatty acid derivatives can be carried out via any mode of administration for therapeutic agents.
[0212] [0212] Depending on the intended mode of administration, the compositions may be in solid, semi-solid or liquid dosage form, such as, for example, injectables, | pills, . 5 suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, *Syrups, powders, liquids, suspensions or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices.
[0213] [0213] Illustrative pharmaceutical compositions are gelatine tablets and capsules comprising — a niacin fatty acid derivative and a pharmaceutically acceptable carrier, such as: a) a diluent, e.g. purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oil, such as EPA or DHA, or their esters or triglycerides or their mixtures, omega-3 fatty acids or their derivatives , sucrose, lactose, dextrose, mannitol, sorbitol, sodium, cellulose, saccharin, glucose and/or glycine, b) a lubricant, for example silica, talc, stearic acid, its calcium or magnesium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and/or polyethylene glycol; for tablets too, c) a 2
[0214] [0214] liquids, particularly injectable, compositions "may, for example, be prepared by dissolving dispersion, etc. For example, the fatty acid derivative niacin is dissolved in or mixed with a solvent | pharmaceutically acceptable such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form an injectable solution or isotonic suspension.
[0215] [0215] The fatty acid derivatives of niacin can =
[0217] [0217] Fatty acid derivatives of niacin can also be delivered through the use of monoclonal antibodies as individual vehicles to which the niacin derivatives of fatty acids are coupled.
[0218] [0218] Parenteral administration is generally used subcutaneous injection, intramuscular or intravenous injections and infusions.
[0219] [0219] Compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present pharmaceutical compositions can contain from about 0.1% to about 80%, from about 5% to about 60 %, or from about 1% to about 20% of the niacin fatty acid derivative by weight or volume.
[0220] [0220] The dosage regimen using the fatty acid derivative niacin is selected according to a variety of factors including type, species, age, weight, sex, and medical condition of the patient; to the severity of the condition -
[0221] [0221] Effective dosage amounts of the present invention, when used for the indicated purposes, range from about 20 mg to about 5000 mg of the fatty acid derivative niacin per day.
[0222] [0222] Fatty acid derivatives of niacin can be administered in a single daily dose, or the total daily dosage can be administered in divided doses of two, as
[0223] [0223] Examples of useful synthetic routes for making niacin fatty acid derivatives of Formula I are set out in the Examples below and generalized in Schemes 1-9.
[0224] [0224] The amine protected mono-BOC of formula B can be obtained from commercial sources or prepared according to procedures described in Krapcho et al.
[0225] [0225] The acylated amine of formula F can be prepared using the procedures described in Andruszkiewicz et al.
[0226] [0226] Compound A can be amidated with the corresponding amine I (where i = O, 1, 2 or 3) using a coupling reagent such as DCC, CDI, EDC, or NTE
[0227] [0227] The M amine can be prepared according to the procedures described in Dahan et al. J. Org. Chem. Chem. 2007, 72, 2289-2296. Compound A can be coupled with the M amine using a coupling reagent such as DCC, CDI, EDC, OR optionally with a tertiary amine base and/or catalyst, e.g. DMAP, followed by deprotection of the BOC group with acids such as TFA or HCl in a solvent such as CH 2 Cl 2 or dioxane to produce the coupled compound N. Activation of compound N with a coupling agent such as HATU in the presence of an amine such as DIEA, followed by the addition of a fatty acid of formula D provides compounds of the formula O.
[0228] [0228] Compound A can be amidated with the commercially available P amine “using an op reagent.
[0229] [0229] The T amine can be prepared from the “commercially available” diamine according to the procedures described in Dahan et al.
[0230] [0230] Compound A can be amidated with the commercially available amine X using a coupling reagent such as DCC, CDI, EDC, optionally with a tertiary amine base and/or catalyst, e.g. DMAP to give O compound Y. O BOC group in compound Y can be removed with acids such as TFA or HCl in a solvent such as CH2 Cl2 or dioxane.
[0231] [0231] Compound A can be amidated with commercially available cysteine methyl ester O using a coupling reagent such as DCC, CDI, EDC, OR optionally with a tertiary amine base and/or catalyst, e.g. DMAP, to give O AA compound. The commercially available maleimide derivative BB can be coupled with a fatty acid of formula D, using a coupling agent such as HATU or EDCI to give emma
[0232] [0232] The commercially available amino acid esters EE can be coupled with a fatty acid of formula D using a coupling agent such as EDCI or HATU, followed by alkaline hydrolysis of the methyl ester to obtain compounds of formula oO FF. Compounds of formula o FF can be coupled with commercially available BOC-amino GG acid derivatives using a . coupling agent such as EDCI or HATU. The BOC group can be removed by treatment with acids such as TFA or HCl to obtain compounds of formula HH, which can then be coupled with compound A to obtain compounds of formula II. EXAMPLES
[0233] [0233] The disclosure is further illustrated by the following examples, which are not to be interpreted — as limiting this disclosure in scope or spirit with the specific procedures described herein. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation on the scope of the disclosure is thus intended. It is to be further understood that recourse may be had in various other embodiments, modifications and equivalents thereof as may be suggested to those skilled in the art without departing from the spirit of the present OAS
[0236] [0236] The following non-limiting examples serve to illustrate compounds other OS embodiments derived from niacin fatty acids. It is to be understood that any embodiments listed in the Examples section are embodiments of the niacin fatty acid derivatives and, as such, are suitable for use in the above-described methods and compositions.
[0237] [0237] In a typical run, Nicotinic acid (2.0 g, 16.2 mmol) was taken up in CH 2 Cl 2 Z (20 mL) along with oxalyl chloride (1.4 mL, 16.2 mmol).
[0238] [0238] tert-butyl 2-(nicotinamido) ethylcarbamate (3.1 g, 11.7 mmol) was taken up in 25% TFA in CH 2 Cl 2 (10 mL). The resulting reaction mixture was allowed to stand at room temperature for 1 h. At this point, a considerable amount of precipitate formed and the clear filtrate was removed. The remaining solids were dried to give the TFA salt of N--(2-aminoethyl) nicotinamide (1.69).
[0239] [0239] N-(2-aminoethyl) nicotinamide TFA salt (5.0 mmol) was taken up in CH3CN (20 mL) along with (42, 72, 102, 132, 162, 19Z)-docosa-4 , 7, 10,13,16,19-hexaenoic acid (5.0 mmol), HATU (5.5 mmol) and DIEA (15 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours and diluted with EtOAcC. The organic layer was washed with saturated aqueous NaHCO3 , brine, dried over Na28 SO4 , filtered and concentrated under reduced pressure. Purification by silica gel chromatography (5% ne
[0240] [0240] N-(2-aminoethyl) nicotinamide TFA salt (1.6 g, 5.7 mmol) was taken up in CH 3 CN (15 mL) along with (52, 82%, 1 12, 142, 17Z )-eicosa-5, 8, 1 of 1,14,17-pentaenoic acid 01.7 g, 517 mmol), HATU (2.49, 6.3 mmol) and DIEA (3 mL, 17 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours and diluted with EtOAC. The organic layer was washed with saturated aqueous NaHCO 3 , brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. Purification by silica gel chromatography (5% MeoH-CH 2 Cl 2 ) gave N-(2-(52, 82, 11 2, 142, 172)-eicosa-5, 8, 11,14, 17 - pentaenamidoethyl) nicotinamide (1 .6 g, 62%). MS calcd for C2B8H39N302: 449.3, found: [M + HJ] <+> 450. Example 5 Preparation of v-(2-(2-(2-(47, 7z, 102, 132, 162, 19Z) - docosa-4, 7,10,13,16,19 - nexaenamidoethyl) disulfanyl) ethyl) nicotinamide (1) -3
[0241] [0241] Cystamine dihydrochloride (1.09, 4.44 mmol) was dissolved in MeOH (50 mL). Triethylamine (1.85 mL, 3 eq) was added to meet EEE
[0242] [0242] Separately, nicotinic acid (246 mg, 2.0 mmol) was taken up in CH3CN (10 mL) along with tert-butyl-2-(2-(2-aminoethyl)disulfanyl)ethylcarbamate (503 mg, 2. 0 mmol), EDCI (422 mg, 2.2 mmol).
[0243] [0243] tert-utyl 2 - (2 - (2 - (nicotinamido) ethyl) disulfanyl) ethylcarbamate (200 mg, 0.56 mmol) was taken neither
[0244] [0244] In a typical run, sodium hydroxide (400 mg, 10 mmol) was dissolved in MeOH (710 mL) and 2-(2-7 aminoethoxy) ethanamine dihydrochloride (1.0 g, 5.65 mmol) was added. The resulting reaction mixture was stirred at 1 ne
[0246] [0246] tert-utyl 2-(2-(nicotinamido)ethoxy)ethylcarbamate (140mg, 0.453mmol) was taken up in 25% TFA in CH2Cl2 (10mL). The reaction mixture was allowed to stand at room temperature for 2 hours and then concentrated to oemetemeneerarEETE SEARA
[0247] [0247] - (2-aminoethyl) - |. º7 methylethane-1 127 diamine (5.0 g, 42.7 mmol) was dissolved in cH2cCl2 (100 mL) and cooled to C. A solution of Boc20 (0.93 g, 4.27 mmol) in CH2Cl2 (10 mL ) was then added dropwise at 0[deg.]C over a period of 15 min. The resulting reaction mixture was stirred at 0[deg.]C for 30 min and then warmed to room temperature. AND ON
[0248] [0248] tert-butyl 2-((2-aminoethyl)(methyl)amino)ethylcarbamate (400mg, 1.84mmol) was taken up in CH3CN (10mL) along with Oo nicotinic acid (227mg, 1.84 mmol) and EDCI (353 mg, 2.02 mmol).
[0249] [0249] tert-butyl 2-(methyl(2-(nicotinamido)ethyl)amino)ethylcarbamate (90mg, 0.279mmol) was taken up in a 25% TFA in CH2Cl2 solution (5ml) and allowed to stand at room temperature for 3 h.
[0250] [0250] L-Alanine methyl ester hydrochloride (0.85 g, 6.1 mmol) was taken up in CH3CN (20 mL) along with (42, TZ, 102, 132, 162, 192)-docosa-4 ,7,10,13,16,19-hexaenoic acid (2.09, 6.1 mmol), EDCI (1.3 g, 6.72 mmol) and DIEA (1.3 mL). The resulting reaction mixture was stirred at room temperature for 2 h. It was then diluted with FtoAc and washed with dilute aqueous NaHCO3 and brine. The organic layer was dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain (5)-methyl acetaminophen.
[0251] [0251] (5)-methyl 2-((4%, 72, 102, 132, 162, 192)-E docosa-4, 7, 10,13,16,19 -hexaenamido)propanoate (2.09, - 5 4.8 mmol) was taken up in THF (8 mL) along with aqueous SM NaOH (5 mL) and stirred vigorously at room temperature for 3 h.
[0253] [0253] the same synthetic sequence described above for the preparation of (25', 31i )-Methyl 3-((S8)-2-((42.7%, 102, 132, 162, 19Z)-docosa-4 , 7, 10,13,16,19-hexaenamido) o eeeneeveneememe EEE
[0254] [0254] H-Lysine-(BOC)-OMe hydrochloride (500 mg, 1.68 mmol) was taken up in CH3CN (10 nil) along with nicotinic acid (207 mg, 1.68 mmol), EDCI (354 mg, 1 .85 mmol) and DIFEA (0.90 mL).
[0255] Methyl [0255](is)-methyl 6-(fert-butoxycarbonyl)-2-(nicotinamido)hexanoate (260 mg, 0.71 mmol) was taken up in 4M HCl in dioxane (2 mL) and allowed to stand at room temperature. environment for 1 h.
The reaction mixture was diluted with EtOAc & concentrated under reduced pressure to provide methyl (5)-methyl 6-amino-2-hexanoate HCl salt (nicotinamido).
is 30 This material was taken up in CH3CN (5 mL) along with ne
NNEEEEEEEEEEEEEii——— 58 , with (42, 72, 102, 132, 162, 192)-docosa-4.7, 10.13, 16,19-hexaenoic acid (233 mg, 0.71 mmol), HATU (297 mg, 0.78 mmol) and DIEA (0.4 mL). The resulting reaction mixture was stirred at room temperature for 2 hours and diluted with EtOAC. The organic layer was washed with dilute aqueous NaHCO3 solution, brine, dried over Na2SO4, filtered Ee | concentrated under reduced pressure. Purification by silica gel chromatography (9:1 CH2Cl2/MeOH) provided (5)-methyl 6-((42, 72, 102, 132, 162, 192)-docosa-4, 7, 10,13, 16, 19 - hexaenamido) -2 - (nicotinamido) methyl hexanoate (280 mg, 72%). MS calculated for C35H49N304: 575.37, found: [M + H] <+> 576. Example 11 Preparation of (S)-6-((42, 72, 102, 132, 162, 192)-docosa-4, 7,10,13,16,19-hexaneamido)-2-(nicotinamido)hexanoic (1 - 12) | (S)-methyl 6-((42, 72, 102, 132, 162, 19Z)-docosa-4, 7, 10,13,16,19-hexaneamido)-2-(nicotinamido)methyl hexanoate (40 mg , 0.0695 mmol) was taken up in 2 mL of THF, along with 80 [mu][iota]º of a 5 M NaOH solution.
The resulting reaction mixture was stirred at room temperature for 2 h.
It was then acidified to pH 4 with HI 2 N and then extracted with EtOAC. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give 31 mg of (S)-6-((42, 72, 102, 132, 162, 19Z)-docosa-4, 7,10,13, 16, 19-hexaneamido)-2- hexanoic acid (nicotinamido) 30. the ESET
NEEEEEEEEEEEEi——/—= —"— 59 Calculated for C34H47N304 MS: 561.36, found: [M + HH) <+> 562. Example 12 í Preparation of (S)-methyl 2 - ((52, 82, LLZ , 142, 172)-.5 eicosa-5, 8, 11,14,17-pentaenamido)-6-(nicotinamido) hexanoate (1-13) H-Lysine-(BOC)-OMe Hydrochloride (500 mg, 1.68 mmol) was taken up in 25 mL of CH3CN, along with (52.82%, 112, 142, 17z)-eicosa-5, 8, 11.14, 17-pentaenoic acid (EPA, 509 mg , 1.68 mmol), HATU (702 mg, 1.85 mmol) and DIEA (880 [mu] [Epsilon], 5.04 mmol) The resulting reaction mixture was stirred at room temperature for 2 h.
It was then diluted with EtoAC (70 mL) and washed with brine (20 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure.
The resulting residue was purified by silica gel chromatography (CcH2Cl2, elution gradient 90% CcH2Cl2, 10% MeoOH) to give 870 mg of (S)-methyl 6-(tert-butoxycarbonyl)-2-((52, 82 , 112, 142, 17z)-eicosa-5,8,11,14,17-pentaenamido)hexanoate (95% yield). MS calculated for C32H52N20s: 544.39; found: [IM + HE] <+> 545. (S)-methyl 6 -(tert-butoxycarbonyl)-2 -((52, 82, 112, 142, 172)-eicosa-5, 8, 11, Methyl 14,17-pentaenamido)-hexanoate (870 mg, 1.60 mmol) was taken up in 4 mL of 4N HCl in dioxane and allowed to stand at room temperature for 10 min.
At 30° The reaction mixture was diluted with 10 mL of EtOAC and eee PCAAA
EEEEEEEEENEEE—— 60 , concentrated under reduced pressure to provide (S)-methyl 6-amino-2-((52, 82, 117, 142, 172)-eicosa-5, 8,11 ,14-hexanoate, 17-pentaenamido). This residue was taken up in 5 ml of CH3CN together. 5 with nicotinic acid (197 mg, 1.60 mmol), HATU (669 mg, 1.76 mmol) and DIEA (836 mL, 4.8 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours and diluted with EtOAC (20 mL). The organic layer was washed with brine (20 mL), dried (Na2SO4) and concentrated under reduced pressure.
The resulting residue was purified by chromatography (95% > CH 2 Cl 2 , 5% > MeOH) to give 300 mg of (S)-methyl 2-((5Z, 8Z, 112, 142, 172)-eicosa-5, 8, 11.,14,17-pentaenamido)-6-hexanoate (nicotinamido). MS calculated for C33H47N304: 549.36, found: [M + HH] <+> 550. Example 13 Preparation of (8) -2 - ((527.8%, LLZ, 142, 172)-eicosa-5.8 , 11, 14, 17-pentaenamido)-6-(nicotinamido) nexanoic (1-14)(S)-methyl 2-((52, 82, 112, 142, 172)-eicosa-5, 8, 11, Methyl 14,17-pentaenamido)-6-(nicotinamido)hexanoate (140 mg, 0.225 mmol) was taken up in 2 mL of THF, along with an aqueous solution of NaOH (35 mg in 2 mL of H 2 O). The resulting reaction mixture was stirred at room temperature for 2 h.
It was then acidified to pH 4 with 2N HCl and then extracted with EtOAc.
The organic layers eee
NEEENEEEEE——— 61 combined were dried (Na28S04) and concentrated under reduced pressure to give 31 mg of (S)-2-((52, 82, 112, 1472, 172)-eicosa-5, 8, 11, 14, 17 - pentaenamido) -6 - (nicotinamido) hexanoic. . 5 MS calculated for C34H47N304: 561.36, found: [M + H] <+> 562. MS calculated for C32H45N304: 535.34, found: [M + HJ] <+> 536. The present invention is not to be limited in scope by the specific embodiments disclosed in the examples which are intended as illustrations of some aspects of the invention and any embodiments that are functionally equivalent are within the scope of the present invention.
Indeed, various modifications of the invention other than those shown and described herein will become apparent to those skilled in the art and which are intended to fall within the scope of the appended claims.
EQUIVALENTS Those skilled in the art will recognize, OR be able to determine, using no more than routine experimentation, numerous equivalents to the specific embodiments specifically described herein.
Equivalents that are intended to be embraced within the scope of the claims that follow. The
and with

权利要求:
Claims (35)
[1]
1. A molecular conjugate characterized in that it comprises a niacin and a fatty acid selected from omega-3 fatty acids or fatty acids metabolized in vivo to omega-3 fatty acids and wherein the conjugate comprises at least one amide.
[2]
2. A compound, characterized in that it is of Formula 1: RR Oo fa A' Ron A Y — Ra N o p Formula I or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, enantiomer or stereoisomer thereof; wherein R1 , R2 and R3 are each independently selected from the group consisting of -H, -D, -Cl, -F, -CN, -NH>, -NH(C1-C; alkyl), -N(C1- C;alkyl)o, -NH(C(O)C1-C; alkyl), -N(C(O0)C-C3 alkyl)z, -C(O)H, -C(O)CC; alkyl, -C(O)OCY-C3 alkyl, -C(O)NH;, - 15º C(ONH(Cr-C;3 alkyl), -C(O)N(C1-C3 alkyl)2, -C1 -C3 alkyl, O-C1-C3 alkyl, S(O0)C1-C3 alkyl, and -S(0),C1-C;3 alkyl; Wi and W; are each independently null, O, S, NH, NR or Wi, and W7 can be taken together and can form either an imidazolidine or piperazine group, with the proviso that W, and W, cannot be O simultaneously; each a, b, c and d is independently -H, -D, -CH3, -OCH3, -OCH;CH; or -C(O)OR, -OZ or benzyl, or two of a, b, c and d can be taken together with the single carbon atom to which they are attached 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)>-, -SS-,
OH NRsPs R OR Sor R Rs but z X X From e ee ee ENA ONA ONE a
OH OH os Seo o oO oR O) o PP Do : dv. dv. OS Z d is. Ç & Revhs RNOR Renê N Os 2 . O, O, Ad Ro or R7 in each g is independently 2, 3 or 4; each h is independently 1, 2, 3 or 4; each R; is independently H or C1 -C; alkyl, or both Re groups, when taken together with the nitrogen to which they are attached, can form a heterocycle; each R; is independently e, H or Cy-C1,g linear or branched alkyl, which may optionally be substituted by OH, NH, COR, CONHL, phenyl, CGH,OH, imidazole or arginine; each e is independently H or any of the naturally occurring amino acid side chains; each Z is independently -H, or (o)'
ANS r tou the Ra, UV and Rs : : with the condition that there is at least one
À o (9) Roy Luiz * A — Ss ' À or ns 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; Ru and Rs are each hydrogen, deuterium, -C1-C, alkyl, -halogen, -OH, -C(O)C- Ca alkyl, -O-aryl, -O-benzyl, -OC(O)C1- C alkyl, -C7-C3-alkene, C1-C; alkyne, -C(O0)C1-Ca alkyl, -NH2, -NH(C-C;3 alkyl), -N-(C1-C; alkyl)α, -NH(C(O)C1-C;3 alkyl), -N(C(O)C1-C3 -alkyl)», -SH, -S(C1-C; alkyl), -S(O)C1-C;3 alkyl, -S(O)2 C1 -Ç; alkyl; and each R is independently -H or -C -C; alkyl; provided that when m, n, o, p and q are each 0, W, and W are each zero, and Z is (o) Ay r Ss then t must be 0; and when each of m, n, o, p and q is 0, and Wi and W1 are each zero, then Z must not be R; v Es — & s
[3]
3. Compound according to claim 2, characterized by the fact that Zé (o)' Adu r s
[4]
4. Compound according to claim 3, characterized in that t él.
[5]
5. Compound according to claim 4, characterized in that r is 2eséó.
[6]
6. Compound according to claim 4, characterized in that r is des.
[7]
7. Compound according to claim 4, characterized in that r is 7es and 3.
[8]
8. Compound according to claim 5, characterized in that L is —S-S-.
[9]
9, Compound according to claim 5, characterized in that Lé-O-.
[10]
10. — Compound, according to claim 5, characterized by the fact that Lé R7
They go .
[11]
11. — Compound, according to claim 5, characterized by the fact that Lé Rs
THE
[12]
12. — Compound, according to claim 5, characterized in that Lé oH OH oH Neon Sou Sor X Da OE do or OO
[13]
13. — Compound, according to claim 5, characterized by the fact that Lé PR o. OR o. OR & , DTD dy or
[14]
14. — Compound according to claim 5, characterized in that n, 0, p and q are each 1.
SM
[15]
15. — Compound according to claim 5, characterized in that two of n, o, p and q are each 1.
[16]
16. — Compound, according to claim 5, characterized in that Wi and W7 and each NH.
[17]
17. — Compound, according to claim 5, characterized by the fact that mé l,n,o,pegsãocadaum l and LéO.
[18]
18. — Compound, according to claim 5, characterized by the fact that mél,n,o,peqsãocadaum | they s-.
[19]
19. — Compound, according to claim 5, characterized by the fact that mél, neo are each 0, peqsão each l, and L is the H Non o: Cv :
[20]
20. — Compound, according to claim 5, characterized by the fact that mél,n,o,peqg are eachOeLé oH oo dv:
[21]
21. — Compound according to claim 5, characterized in that m, n and o are each O and p and q are each 1.
[22]
22. — Compound, according to claim 5, characterized in that mé l, neo are each 0 Oepeqg are each 1, and L is the PR dy
[23]
23. — Compound, according to claim 5, characterized by the fact that mé l,neoare each 1, pqsãocadaumOeLé os
[24]
24. — Compound, according to claim 5, characterized by the fact that mél,n,o,peqgsãocadaum l and Lé or =.
[25]
25. — Compound, according to claim 5, characterized by the fact that m 1l,n,o,p and q are each 1!e LéNRs.
[26]
26. — Compound according to claim 5, characterized in that m,neo are each 0, and p and q are each] 1 and a c is -CH; and the other c is -CH;3.
[27]
27. — Compound according to claim 5, characterized in that m l, neo are each 1, p q are each O and L is R; ex
[28]
28. — Compound according to claim 2, characterized in that the compound is selected from the group consisting of N-(2-(2-(42,72,10Z, 13Z, 167, 19Z)-docosa-4 ,7,10,13,16,19-hexaneamidoethoxy)ethyl)nicotinamide; N-(2-(2-(2-(42,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)disulfanyl)ethyl)nicotinamide; and N-(2-(2-(42,77,107,132Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethylamino)ethyl)nicotinamide.
[29]
29. — Compound according to claim 2, characterized in that the compound is selected from the group consisting of 1,3-dihydroxypropan-2-yl 6-(42,7Z,107Z,13Z,16Z,19Z)- docosa-4,7,10,13,16,19-hexaneamido-2-(nicotinamido)hexanoate; and 1,3-dihydroxypropan-2-yl 4-(42,77,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaneamido-2-(nicotinamido)butanoate.
[30]
30. — Compound according to claim 2, characterized in that the compound is selected from the group consisting of N-(2-(42,72Z,107,132Z,16Z,19Z)-docosa-4,7,10 ,13,16,19-hexaneamidoethyl)nicotinamide; N-(2-(52,82,11Z,14Z,]7Z)-eicosa-5,8,11,14,17-pentaenamidoethyl)nicotinamide; and N-(1-(472,77,107,132,16Z,19Z)-docosa-4,7,10,13,16,19-hexaneamido-2-methylpropan-2-yl)nicotinamide.
[31]
31. — Compound according to claim 2, characterized in that the compound is selected from the group consisting of (S)-6-((4Z2,72,10Z,13Z,16Z,19Z)-docosa-4 acid ,7,10,13,16,19-hexaneamido)-2-(nicotinamido)hexanoic acid; (S)-2-((47,72,107Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)-6-(nicotinamido)hexanoic acid; (S)-6-((5Z,8Z,112Z,14Z,17Z)-eicosa--5,8,11,14,17-pentaenamido)-2-(nicotinamido)hexanoic acid; (S)-2- acid
((5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenamido)-6-(nicotinamido)hexanoic acid; and 2-(2-(42,72,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaneamidoethyl)-4-(nicotinamido)butanoic acid.
[32]
32. — A compound according to claim 2, characterized in that the compound is selected from the group consisting of (S)-((R)-I-(nicotinamido)propan-2-yl) 2-((5Z) , 8Z, 11Z, 14Z, 17Z)-eicosa-5,8,11,14,17-pentaenamido)propanoate; and (S)-((R)-1-(nicotinamido)propan-2-yl) 2-((52,8Z,112Z,147Z,17Z)-eicosa-5,8,11,14,17-pentaenamido) -3- methylbutanoate.
[33]
33. — Pharmaceutical composition, characterized in that it comprises a compound as defined in claim 2 and a pharmaceutically acceptable carrier.
[34]
34. Use of a compound as defined in claim 2, for the preparation of a medicament for treating a metabolic disease.
[35]
35. - Use according to claim 34, characterized in that the 15th metabolic disease is selected from hypertriglyceridemia, hypercholesterolemia, fatty liver disease, atherosclerosis, coronary heart disease, Type 2 diabetes, diabetic nephropathy, diabetic neuropathy, retinopathy diabetes, metabolic syndrome or cardiovascular disease.
| s Í 120 t í t HS —— H í 110 SE ' ROC) PS AS '
N ASS ASS I so SS NS SS I | when the O... A... Steel À Í Vehicle Cmpd 1-7 Cmpd 1-7 cmpd 1-7 Niacin 5 MM : memo UM À OM À EB FIGURE 1 is 7 A o
NEEEEEEEEE— 2 IS FASN Expression f 21 s . Bad mm 8 5 Pd "NO < 04 EN DS 1
TT FS FSS E SS
12 SCD Expression z SCD Expression z FIGURE 2 2nd Ss . Only NUR RN or NS | ..... to "E 04 Ss " A ONE -. TE FPS FA PO E
SS SE TE PE ES VE * VE
It is 3 APOA1 Expression g 1a .e. EM, a. 3” NS to
H A ES LR 3 gi o o £ os AN tb X. O
PST FLORA ER So Ro) Y E FE *** pn <0.005,” p, 0.01, * <0.05 by 1-way ANOVA with Dunnett's Post test j
Ú misses the " - 11
ABSTRACT
NIACIN FATTY ACID CONJUGATES AND USES % The invention relates to niacin fatty acid conjugates; compositions comprising an effective amount of a niacin fatty acid conjugate; and methods for treating or preventing a metabolic disease comprising administering an effective amount of a niacin fatty acid conjugate.

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CA2772618A1|2011-03-10|

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法律状态:
2020-11-10| B15K| Others concerning applications: alteration of classification|Free format text: AS CLASSIFICACOES ANTERIORES ERAM: A01N 43/40 , A61K 31/44 Ipc: C07D 213/80 (2006.01), A61K 31/44 (2006.01), C07D |

2020-11-17| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

2020-11-24| B25G| Requested change of headquarter approved|Owner name: CATABASIS PHARMACEUTICALS, INC. (US) |

2020-12-29| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |

2021-04-27| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

2021-05-04| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

2021-08-17| B11B| Dismissal acc. art. 36, par 1 of ipl - no reply within 90 days to fullfil the necessary requirements|

2021-12-07| B350| Update of information on the portal [chapter 15.35 patent gazette]|

优先权:

申请号 | 申请日 | 专利标题

US23890309P| true| 2009-09-01|2009-09-01|

US61/238,903|2009-09-01|

US30852410P| true| 2010-02-26|2010-02-26|

US61/308,524|2010-02-26|

US31095210P| true| 2010-03-05|2010-03-05|

US61/310,952|2010-03-05|

PCT/US2010/047262|WO2011028689A1|2009-09-01|2010-08-31|Fatty acid niacin conjugates and their uses|

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