Amorphous solid succinylated 3-(fatty acid amido)-2-hydroxy-1-(protected hydroxy)-propane salts and methods of making the same

Abstract

To provide methods for preparing an amorphous solid composition of a fatty acid metal salt.SOLUTION: Aspects of the disclosure include methods for preparing an amorphous solid composition of a fatty acid metal salt. In practicing the subject methods according to certain embodiments, a succinylated 3-(fatty acid amido)-2-hydroxy-1-(protected hydroxy)-propane organic salt is contacted with a metal base to produce a succinylated 3-(fatty acid amido)-2-hydroxy-1-(protected hydroxy)-propane metal salt; and the succinylated 3-(fatty acid amido)-2-hydroxy-1-(protected hydroxy)-propane metal salt is precipitated in a solvent to produce an amorphous solid succinylated 3-(fatty acid amido)-2-hydroxy-1-(protected hydroxy)-propane metal salt composition. An amorphous solid succinylated 3-(fatty acid amido)-2-hydroxy-1-(protected hydroxy)-propane lithium salt is also provided.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 926,778, filed October 28, 2019, the disclosure of which is incorporated herein by reference.

[0002] Introduction Imetelstat is a telomerase inhibitor that binds with high affinity to the template region of the RNA component of telomerase. Studies have shown that imetelstat inhibits telomerase activity and is effective against cell proliferation in many different cancer cell lines and human tumors. Imetelstat is being used in clinical trials in patients with hematological malignancies. Clinical trials in patients with myelofibrosis have shown that imetelstat can achieve complete clinical remission in certain patients.

[0003] The structure of imetelstat comprises an N3'→P5' thiophosphoramidate oligonucleotide. Its synthesis is achieved by solid-phase oligonucleotide synthesis, in which the first phosphoramidite nucleotide is attached to the support and subsequently sulfurized. Chain extension of the oligonucleotide building blocks is achieved by repeated reactions of the 3'-amino group of the solid-support-bound oligonucleotide with additional nucleotide phosphoramidite monomers. The imetelstat oligonucleotide is attached to the solid support via a palmitoyl-amide linker. Therefore, this fatty acid-amide linker is a building block in the synthesis of imetelstat. Summary of the Invention [Means for solving the problem]

[0004] Aspects of the disclosure include methods for preparing amorphous solid compositions of fatty acid metal salts. In embodiments, the subject methods include preparing a fatty acid metal salt from a fatty acid organic salt and precipitating the fatty acid metal salt from a solvent to produce an amorphous solid composition of fatty acid metal salt. In practicing the subject methods according to certain embodiments, a succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane organic salt is contacted with a metal base to produce a succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt, and the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt is precipitated in a solvent to produce an amorphous solid succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt composition. (Scheme I) [ka] In the formula, R is C 10 -C 20 Fatty acids (e.g., C 16 fatty acid), and PG is a protecting group.

[0005] In some embodiments, the metal is lithium. In some embodiments, the fatty acid is selected from palmitic acid, stearic acid, oleic acid, linoleic acid, myristoleic acid, and batyl fatty acid. In some embodiments, the protected hydroxy group includes a dimethoxy-triphenylmethyl protecting group. In certain embodiments, the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt is a compound of Formula I. [ka] The amorphous composition may be formed as a crude composition. In certain cases, the fatty acid metal salt may be crystalline (e.g., by high performance liquid chromatography (HPLC), proton nuclear magnetic resonance spectroscopy ( 11 H NMR), or a combination thereof) of 95% or greater by weight of the crude composition.

[0006] In some embodiments, precipitating the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt to form an amorphous solid composition comprises: 1) heating the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt in a non-polar solvent to form a heated succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt composition; and 2) cooling the heated succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt composition to form an amorphous solid of the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt. In certain cases, the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt is heated in the non-polar solvent to a temperature of about 45° C. to about 55° C., such as about 50° C. To precipitate the amorphous solid composition, the heated succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt composition may be cooled to a temperature of about −5° C. to about 5° C., such as about 0° C., to produce the amorphous solid composition. In certain cases, cooling the heated succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt composition comprises adding the heated succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt composition back to a cold non-polar solvent. The precipitated amorphous solid succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt composition can be isolated by filtration.

[0007] In certain embodiments, the method further comprises contacting 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane with succinic anhydride in the presence of an organic base to succinylate the 2-hydroxy group of 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane to prepare a succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane organic salt. In some cases, 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane is contacted with succinic anhydride in a polar solvent.

[0008] The disclosed embodiments also include an amorphous solid succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane lithium salt. In some embodiments, the fatty acid is selected from palmitic acid, stearic acid, oleic acid, linoleic acid, myristoleic acid, and batyl fatty acid. In some embodiments, the protected hydroxy group includes a dimethoxy-triphenylmethyl protecting group. In certain embodiments, the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt is a compound of Formula I: [ka]

[0009] In some embodiments, the present disclosure provides an amorphous solid succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane lithium salt of Formula I having a peak at about 19.5° 2θ in an X-ray powder diffraction pattern (XRPD) using Cu Kα radiation. In other embodiments, the present disclosure provides an amorphous solid succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane lithium salt of Formula I in which thermogravimetric analysis (TGA) exhibits a single weight loss step. In these embodiments, the single weight loss step may begin at about 225°C. The subject amorphous solid succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane lithium salt of Formula I may also be characterized by a TGA thermogram that exhibits a mass loss of less than 1% of the total mass of the sample upon heating between 30°C and 300°C. In another embodiment, the present disclosure provides an amorphous solid succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane lithium salt of Formula I, wherein the differential scanning calorimetry (DSC) curve exhibits an absorption peak at about 44.9°C. [Brief explanation of the drawings]

[0010] [Figure 1] 1 shows an X-ray powder diffraction pattern of an amorphous solid succinylated 3-(palmitoylamido)-2-hydroxy-1-(dimethoxytriphenylmethylhydroxy)-propane lithium salt, according to certain embodiments. [Figure 2] 1 shows a polarized light microscopy image of an amorphous solid succinylated 3-(palmitoylamido)-2-hydroxy-1-(dimethoxytriphenylmethylhydroxy)-propane lithium salt, according to certain embodiments. [Figure 3] 1 shows a thermogram from a thermogravimetric analysis (TGA) of an amorphous solid succinylated 3-(palmitoylamido)-2-hydroxy-1-(dimethoxytriphenylmethylhydroxy)-propane lithium salt, according to certain embodiments. [Figure 4]1 shows a plot from differential scanning calorimetry of an amorphous solid succinylated 3-(palmitoylamido)-2-hydroxy-1-(dimethoxytriphenylmethylhydroxy)-propane lithium salt, according to certain embodiments. DETAILED DESCRIPTION OF THE INVENTION

[0011] Select a definition for a chemical term The following terms have the following meanings unless otherwise indicated: Any term not defined has its art-recognized meaning.

[0012] As used herein, the terms "phosphate" and "phosphate group" are meant to include thiophosphate groups and oxophosphate groups.

[0013] As used herein, the term "phosphoramidite amino group" refers to an amino group, --NR, attached to the phosphorus atom of a phosphoramidite group. 4 R 5 and the term "phosphoramidite nitrogen" refers to the nitrogen atom of the phosphoramidite amino group.

[0014] "Alkyl" refers to monovalent saturated aliphatic hydrocarbyl groups having 1 to 10 carbon atoms, such as 1 to 6 carbon atoms (e.g., "alkyl of 1 to 6 carbon atoms"), or 1 to 5 carbon atoms (e.g., "alkyl of 1 to 5 carbon atoms"), or 1 to 4 (e.g., "alkyl of 1 to 4 carbon atoms"), or 1 to 3 carbon atoms (e.g., "alkyl of 1 to 3 carbon atoms"). This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), t-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-).

[0015] The term "substituted alkyl" refers to an alkyl group in which one or more carbon atoms of the alkyl chain are optionally substituted with -O-, -N-, -S-, -S(O) n -(n is 0-2), -NR- (R is hydrogen or alkyl), and substituted with a heteroatom such as alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-aryl, -SO2-heteroaryl, and -NR a R b (R a and R bmay be the same or different and are selected from the group consisting of hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, and heterocyclic. In some cases, "substituted alkyl" refers to an alkyl group, as defined herein, having 1 to 5 substituents selected from the group consisting of alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, thiol, thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, sulfonamido, and -NR a R b (R a and R b refers to an alkyl group, as defined herein, having 1 to 5 substituents selected from the group consisting of: (a) aryl, (b) heteroaryl, (c) cycloalkyl, (d) cycloalkenyl, (e) alkynyl, (f) aryl, (g) heteroaryl, (h) heterocyclic, (i) aryl, (j) heteroaryl, (j) heterocyclic, (j) aryl, (j) heterocyclic ...

[0016] "Alkylene" is either straight or branched chain, preferably has 1 to 6, more preferably 1 to 3 carbon atoms, and optionally includes -O-, -NR 10 -, -NR 10 C(O)-, -C(O)NR 10 -, etc. This term includes, by way of example, methylene (-CH-), ethylene (-CHCH-), n-propylene (-CHCHCH-), iso-propylene (-CHCH(CH)-), (-C(CH)CHCH-), (-C(CH)CHC(O)-), (-C(CH)CHC(O)NH-), (-CH(CH)CH-), and the like.

[0017] "Substituted alkylene" refers to an alkylene group having 1 to 3 hydrogens replaced with a substituent, as described for carbon in the definition of "substituted" below.

[0018] The term "alkane" refers to alkyl and alkylene groups as defined herein.

[0019] The terms “alkylaminoalkyl,” “alkylaminoalkenyl,” and “alkylaminoalkynyl” refer to R ’ is an alkyl group as defined herein, and R ” is an alkylene, alkenylene, or alkynylene group as defined herein; ’ NHR ” -refers to the group.

[0020] The terms "alkaryl" or "aralkyl" refer to the groups -alkylene-aryl and -substituted alkylene-aryl, where alkylene, substituted alkylene, and aryl are defined herein.

[0021] "Alkoxy" refers to an -O-alkyl group, where alkyl is as defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy, and the like. The term "alkoxy" also refers to the groups alkenyl-O-, cycloalkyl-O-, cycloalkenyl-O-, and alkynyl-O-, where alkenyl, cycloalkyl, cycloalkenyl, and alkynyl are as defined herein.

[0022] The term "substituted alkoxy" refers to the groups substituted alkyl-O-, substituted alkenyl-O-, substituted cycloalkyl-O-, substituted cycloalkenyl-O-, and substituted alkynyl-O-, where substituted alkyl, substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyl, and substituted alkynyl are as defined herein.

[0023] The term "alkoxyamino" refers to the group --NH-alkoxy, where alkoxy is defined herein.

[0024] The term "haloalkoxy" refers to an alkyl-O- group in which one or more hydrogen atoms on the alkyl group has been replaced with a halo group and includes, by way of example, groups such as trifluoromethoxy.

[0025] The term "haloalkyl" refers to a substituted alkyl group as defined above in which one or more hydrogen atoms on the alkyl group have been replaced with a halo group. Examples of such groups include, but are not limited to, fluoroalkyl groups such as trifluoromethyl, difluoromethyl, trifluoroethyl, etc.

[0026] The term "alkylalkoxy" refers to the groups -alkylene-O-alkyl, alkylene-O-substituted alkyl, substituted alkylene-O-alkyl, and substituted alkylene-O-substituted alkyl, where alkyl, substituted alkyl, alkylene, and substituted alkylene are as defined herein.

[0027] The term "alkylthioalkoxy" refers to the groups -alkylene-S-alkyl, alkylene-S-substituted alkyl, substituted alkylene-S-alkyl, and substituted alkylene-S-substituted alkyl, where alkyl, substituted alkyl, alkylene, and substituted alkylene are as defined herein.

[0028] "Alkenyl" refers to straight or branched chain hydrocarbyl groups having 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms, and having at least one, and preferably one or two, sites of double bond unsaturation. Examples of this term include vinyl, allyl, and but-3-en-1-yl. Included within this term are cis and trans isomers or mixtures of these isomers.

[0029] The term "substituted alkenyl" refers to an alkenyl group, as defined herein, having from one to five substituents, or one to three substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, and -SO2-heteroaryl.

[0030] "Alkynyl" refers to a monovalent straight or branched chain hydrocarbyl group having two to six carbon atoms, preferably two to three carbon atoms, and having at least one, and preferably one or two, sites of triple bond unsaturation. Examples of such alkynyl groups include acetylenyl (-C≡CH) and propargyl (-CHC≡CH).

[0031] The term "substituted alkynyl" refers to an alkynyl group, as defined herein, having from one to five substituents, or one to three substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO-alkyl, -SO-substituted alkyl, SO-aryl, and -SO-heteroaryl.

[0032] "Alkynyloxy" refers to an -O-alkynyl group, where alkynyl is as defined herein. Alkynyloxy includes, by way of example, ethynyloxy, propynyloxy, and the like.

[0033] "Acyl" refers to the groups HC(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. For example, acyl includes the "acetyl" group CH3C(O)-

[0034] "Acylamino" is R 20 is hydrogen or alkyl, and alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein; —NR 20 C(O) alkyl, -NR 20 C(O) substituted alkyl, NR 20 C(O)cycloalkyl, -NR 20 C(O)-substituted cycloalkyl, -NR 20 C(O)cycloalkenyl, -NR 20 C(O)-substituted cycloalkenyl, -NR 20 C(O)alkenyl, -NR 20 C(O) substituted alkenyl, -NR 20 C(O)alkynyl, -NR 20 C(O) substituted alkynyl, -NR 20 C(O)aryl, -NR 20 C(O) substituted aryl, -NR 20C(O)heteroaryl, -NR 20 C(O)-substituted heteroaryl, -NR 20 C(O) heterocyclic, and -NR 20 Refers to a C(O)-substituted heterocyclic group.

[0035] The term "aminocarbonyl" or "aminoacyl" refers to R 21 and R 22 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; R 21 and R 22 optionally joined together with the nitrogen to which they are attached to form a heterocyclic or substituted heterocyclic group, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein, —C(O)NR 21 R 22 Refers to the base.

[0036] "Aminocarbonylamino" is R 21 , R 22 , and R 23 are independently selected from hydrogen, alkyl, aryl, or cycloalkyl, and two R groups are joined to form a heterocyclyl group; —NR 21 C(O)NR 22 R 23 Refers to the base.

[0037] The term "alkoxycarbonylamino" refers to the group -NRC(O)OR, where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclyl, where alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclyl are as defined herein.

[0038] The term "acyloxy" refers to the groups alkyl-C(O)O-, substituted alkyl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, aryl-C(O)O-, heteroaryl-C(O)O-, and heterocyclyl-C(O)O-, where alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclyl are as defined herein.

[0039] "Aminosulfonyl" is R 21 and R 22 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; R 21 and R 22 optionally, together with the nitrogen to which they are attached, form a heterocyclic or substituted heterocyclic group, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein; -SONR 21 R 22 Refers to the base.

[0040] "Sulfonylamino" is R 21 and R 22is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; R 21 and R 22 optionally joined together with the nitrogen to which they are attached to form a heterocyclic or substituted heterocyclic group, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein; —NR 21 SO2R 22 Refers to...

[0041] "Aryl" or "Ar" refers to a monovalent aromatic carbocyclic group of 6 to 18 carbon atoms having a single ring (such as is present in a phenyl group), or a ring system having multiple fused rings, which may or may not be aromatic, provided that the point of attachment is through an atom of an aromatic ring (examples of such aromatic ring systems include naphthyl, anthryl, and indanyl). Examples of this term include phenyl and naphthyl. Unless otherwise constrained by the definition of the aryl substituents, such aryl groups may be optionally substituted with one to five substituents, or one to three substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, -SO2-heteroaryl, and trihalomethyl. In such cases, the aryl group is substituted with from 1 to 5 substituents (eg, as described herein) and is referred to as a "substituted aryl."

[0042] "Aryloxy" refers to the group --O-aryl, where aryl is as defined herein, and includes optionally substituted aryl groups as defined herein, including, by way of example, phenoxy, naphthoxy, and the like.

[0043] "Amino" refers to the group -NH2.

[0044] The term "substituted amino" refers to the group -NRR, where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, and heterocyclyl, provided that at least one R is not hydrogen.

[0045] The term "azido" refers to the group -N3.

[0046] "Carboxyl," "carboxy," or "carboxylate" refers to -CO2H or salts thereof.

[0047] The term "carboxyl ester" or "carboxy esters," or "carboxyalkyl" or "carboxylalkyl" refers to any of the groups defined herein, including alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein, including -C(O)O-alkyl, -C(O) refers to the groups -O-substituted alkyl, -C(O)O-alkenyl, -C(O)O-substituted alkenyl, -C(O)O-alkynyl, -C(O)O-substituted alkynyl, -C(O)O-aryl, -C(O)O-substituted aryl, -C(O)O-cycloalkyl, -C(O)O-substituted cycloalkyl, -C(O)O-cycloalkenyl, -C(O)O-substituted cycloalkenyl, -C(O)O-heteroaryl, -C(O)O-substituted heteroaryl, -C(O)O-heterocyclic, and -C(O)O-substituted heterocyclic.

[0048] "(Carboxyl ester)oxy" or "carbonate" refers to -OC(O)O-alkyl, -OC(O)O-substituted alkyl, -OC(O)O-alkenyl ...substituted heteroaryl, -OC(O)O-substituted heteroaryl, -OC(O)O-substituted heterocyclic, -OC(O)O-substituted heterocyclic, -OC(O)O-substituted alkyl, -OC(O)O-substituted heterocyclic, -OC(O)O-substituted heterocyclic, -OC(O)O-substituted alkyl, -OC(O)O-substituted heterocyclic, -OC(O)O-substituted heterocyclic, -OC(O)O-substituted alkyl, -OC(O)O-substituted heterocyclic, -OC(O)O-substituted heterocyclic, -OC(O)O-substituted alkyl, -OC(O)O-substituted heterocyclic refers to the groups -OC(O)O-substituted alkenyl, -OC(O)O-alkynyl, -OC(O)O-substituted alkynyl, -OC(O)O-aryl, -OC(O)O-substituted aryl, -OC(O)O-cycloalkyl, -OC(O)O-substituted cycloalkyl, -OC(O)O-cycloalkenyl, -OC(O)O-substituted cycloalkenyl, -OC(O)O-heteroaryl, -OC(O)O-substituted heteroaryl, -OC(O)O-heterocyclic, and -OC(O)O-substituted heterocyclic.

[0049] "Cyano" or "nitrile" refers to the group --CN.

[0050] "Cycloalkyl" refers to cyclic alkyl groups of 3 to 10 carbon atoms having a single ring or multiple rings, including fused, bridged, and spirocyclic systems. Examples of suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like. Such cycloalkyl groups include, for example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl.

[0051] The term "substituted cycloalkyl" refers to a cycloalkyl group having from 1 to 5 substituents, or from 1 to 3 substituents, selected from alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, and -SO2-heteroaryl.

[0052] "Cycloalkenyl" refers to a non-aromatic cyclic alkyl group of 3 to 10 carbon atoms having a single ring or multiple rings and having at least one double bond, preferably 1 to 2 double bonds.

[0053] The term "substituted cycloalkenyl" refers to a cycloalkenyl group having from 1 to 5 substituents, or from 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, and -SO2-heteroaryl.

[0054] "Cycloalkynyl" refers to a non-aromatic cycloalkyl group of 5 to 10 carbon atoms having a single ring or multiple rings and having at least one triple bond.

[0055] "Cycloalkoxy" refers to -O-cycloalkyl.

[0056] "Cycloalkenyloxy" refers to -O-cycloalkenyl.

[0057] "Halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.

[0058] "Hydroxy" or "hydroxyl" refers to the group --OH.

[0059] "Heteroaryl" refers to an aromatic group of 1 to 15 carbon atoms, such as 1 to 10 carbon atoms, within the ring, and 1 to 10 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Such heteroaryl groups can have a single ring (such as pyridinyl, imidazolyl, or furyl) or multiple fused rings in a ring system (e.g., in groups such as indolizinyl, quinolinyl, benzofuran, benzimidazolyl, or benzothienyl), provided that at least one ring within the ring system is aromatic and the point of attachment is through an aromatic ring atom. In certain embodiments, the nitrogen and / or sulfur ring atoms of a heteroaryl group are optionally oxidized to provide N-oxide (N→O), sulfinyl, or sulfonyl moieties. Examples of this term include pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl. Unless otherwise constrained by the definition of the heteroaryl substituent, such heteroaryl groups may be optionally substituted with one to five substituents, or one to three substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl and -SO2-heteroaryl, and trihalomethyl. In such cases, the heteroaryl group is substituted with from 1 to 5 substituents (eg, as described herein) and is referred to as a "substituted heteroaryl."

[0060] The term "heteroaralkyl" refers to the group -alkylene-heteroaryl, where alkylene and heteroaryl are defined herein. This term includes, by way of example, pyridylmethyl, pyridylethyl, indolylmethyl, and the like.

[0061] "Heteroaryloxy" refers to -O-heteroaryl.

[0062] "Heterocycle," "heterocyclic," "heterocycloalkyl," and "heterocyclyl" refer to saturated or unsaturated groups having a single ring or multiple fused rings, including fused-bridged and spiro ring systems, and having 3 to 20 ring atoms, including 1 to 10 heteroatoms. These ring atoms are selected from the group consisting of nitrogen, sulfur, or oxygen; in fused ring systems, one or more of the rings can be cycloalkyl, aryl, or heteroaryl, but the point of attachment is through the non-aromatic ring. In certain embodiments, the nitrogen and / or sulfur ring atoms of a heterocyclic group are optionally oxidized to provide an N-oxide, -S(O)-, or -SO2- moiety.

[0063] Examples of heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, and phenazine. , isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophenol, morpholinyl, thiomorpholinyl (also called thiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine, tetrahydrofuranyl, and the like.

[0064] Unless otherwise constrained by the definition of the heterocyclic substituent, such heterocyclic groups can be optionally substituted with 1 to 5, or 1 to 3, substituents selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, -SO2-heteroaryl, and fused heterocycle.

[0065] "Heterocyclyloxy" refers to the group --O-heterocyclyl.

[0066] The term "heterocyclylthio" refers to a heterocyclic -S- group.

[0067] The term "heterocyclene" refers to a diradical group formed from a heterocycle, as defined herein.

[0068] The term "hydroxyamino" refers to the group --NHOH.

[0069] "Nitro" refers to the -NO2 group.

[0070] "Oxo" refers to the atom (=O).

[0071] "Sulfonyl" refers to the groups SO-alkyl, SO-substituted alkyl, SO-alkenyl, SO-substituted alkenyl, SO-cycloalkyl, SO-substituted cycloalkyl, SO-cycloalkenyl, SO-substituted cycloalkenyl, SO-aryl, SO-substituted aryl, SO-heteroaryl, SO-substituted heteroaryl, SO-heterocyclic, and SO-substituted heterocyclic, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Examples of sulfonyl include methyl-SO-, phenyl-SO-, and 4-methylphenyl-SO-.

[0072] "Sulfonyloxy" refers to the groups -OSO2-alkyl, OSO2-substituted alkyl, OSO2-alkenyl, OSO2-substituted alkenyl, OSO2-cycloalkyl, OSO2-substituted cycloalkyl, OSO2-cycloalkenyl, OSO2-substituted cycloalkenyl, OSO2-aryl, OSO2-substituted aryl, OSO2-heteroaryl, OSO2-substituted heteroaryl, OSO2-heterocyclic, and OSO2-substituted heterocyclic, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cyclo ... heterocyclic, and OSO2-substituted heterocyclic, where alkyl, substituted aryl, alkenyl, substituted alkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0073] The term "aminocarbonyloxy" refers to the group -OC(O)NRR, where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic, where alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclic are as defined herein.

[0074] "Thiol" refers to the group --SH.

[0075] The term "thioxo" or "thioketo" refers to the atom (=S).

[0076] The term "alkylthio" or "thioalkoxy" refers to an -S-alkyl group, where alkyl is as defined herein. In certain embodiments, sulfur can be oxidized to -S(O)-. Sulfoxides can exist as one or more stereoisomers.

[0077] The term "substituted thioalkoxy" refers to the group --S-substituted alkyl.

[0078] The term "thioaryloxy" refers to an aryl-S- group, where the aryl group is as defined herein, including optionally substituted aryl groups, also as defined herein.

[0079] The term "thioheteroaryloxy" refers to the group heteroaryl-S-, where the heteroaryl group is as defined herein, including optionally substituted heteroaryl groups, also as defined herein.

[0080] The term "thioheterocyclooxy" refers to the group heterocyclyl-S-, where the heterocyclyl group is as defined herein, including optionally substituted heterocyclyl groups, which are also as defined herein.

[0081] Further to the disclosure herein, the term "substituted," when used to modify a specified group or radical, can also mean that one or more hydrogen atoms of the specified group or radical are replaced, each independently of one another, with the same or different substituents as defined below.

[0082] In addition to the groups disclosed for each individual term herein, one or more hydrogens on a saturated carbon atom of the specified group or radical (any two hydrogens on a single carbon may be substituted, e.g., ═O, ═NR) may be substituted. 70 , =N-OR 70 , ═N2 or ═S), unless otherwise specified, is R 60 is selected from the group consisting of optionally substituted alkyl, cycloalkyl, heteroalkyl, heterocycloalkylalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; and each R 70 are independently hydrogen or R 60 and each R 80 But independently, R 70 or alternatively, two R 80’together with the nitrogen to which they are attached form a 5-, 6-, or 7-membered heterocycloalkyl which may optionally contain 1 to 4 additional heteroatoms, the same or different, selected from the group consisting of O, N, and S, wherein the N may have —H or C1-C3 alkyl substituents; and each M + is a counterion with a net single positive charge, -R 60 , halo, =O, -OR 70 , -SR 70 , -NR 80 R 80 , trihalomethyl, -CN, -OCN, -SCN, -NO, -NO2, =N2, -N3, -SO2R 70 , -SO2O - M + , -SO2OR 70 , -OSO2R 70 , -OSO2O - M + , -OSO2OR 70 , -P(O)(O - )2(M + )2, -P(O)(OR 70 )O - M + , -P(O)(OR 70 )2, -C(O)R 70 , -C(S)R 70 , -C(NR 70 )R 70 , -C(O)O - M + , -C(O)OR 70 , -C(S)OR 70 , -C(O)NR 80 R 80 , -C(NR 70 )NR 80 R 80 , -OC(O)R 70 , -OC(S)R 70 , -OC(O)O - M + , -OC(O)OR 70 , -OC(S)OR 70 , -NR 70 C(O)R 70 , -NR 70 C(S)R 70 , -NR 70CO2 - M + , -NR 70 CO2R 70 , -NR 70 C(S)OR 70 , -NR 70 C(O)NR 80 R 80 , -NR 70 C(NR 70 )R 70 , and -NR 70 C(NR 70 )NR 80 R 80 Each M + are independently, e.g., K + , Na + , Li + Alkaline ions such as + N(R 60 )4, or ammonium ions such as [Ca 2+ ] 0.5 , [Mg 2+ ] 0.5 , or [Ba 2+ ] 0.5 (The "subscript 0.5" means that one of the counterions to such divalent alkaline earth ions may be an ionized form of an inventive compound and the other counterion may be an ionized form such as chloride, or a two-ionized compound disclosed herein may serve as a counterion to such divalent alkaline earth ion, or a doubly-ionized compound of the invention may serve as a counterion to such divalent alkaline earth ion.) A specific example is -NR 80 R 80 is meant to include -NH2, -NH-alkyl, N-pyrrolidinyl, N-piperazinyl, N-methyl-piperazin-1-yl, and N-morpholinyl.

[0083] Further to the disclosure herein, the substitution of hydrogen on an unsaturated carbon atom of a "substituted" alkene, alkyne, aryl, and heteroaryl group is represented by R unless otherwise specified. 60 , R 70 , R 80 , and M +is as previously defined, except that in the case of a substituted alkene or alkyne, the substituent is -O - M + , -OR 70 , -SR 70 , or -S - M + -R, provided that 60 , halo, -O - M + , -OR 70 , -SR 70 , -S - M + , -NR 80 R 80 , trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -N3, -SO2R 70 , -SO3 - M + , -SO3R 70 , -OSO2R 70 , -OSO3 - M + , -OSO3R 70 , -PO3 -2 (M + )2, -P(O)(OR 70 )O - M + , -P(O)(OR 70 )2, -C(O)R 70 , -C(S)R 70 , -C(NR 70 )R 70 , -CO2 - M + , -CO2R 70 , -C(S)OR 70 , -C(O)NR 80 R 80 , -C(NR 70 )NR 80 R 80 , -OC(O)R 70 , -OC(S)R 70 , -OCO2 - M + , -OCO2R 70 , -OC(S)OR 70 , -NR 70 C(O)R 70 , -NR 70 C(S)R 70, -NR 70 CO2 - M + , -NR 70 CO2R 70 , -NR 70 C(S)OR 70 , -NR 70 C(O)NR 80 R 80 , -NR 70 C(NR 70 )R 70 and -NR 70 C(NR 70 )NR 80 R 80 is.

[0084] In addition to the groups disclosed for individual terms herein, the substituents of the hydrogen on the nitrogen atom of "substituted" heteroalkyl and cycloheteroalkyl groups are R 60 , R 70 , R 80 , and M + is as previously defined, -R 60 , -O - M + , -OR 70 , -SR 70 , -S - M + , -NR 80 R 80 , trihalomethyl, -CF3, -CN, -NO, -NO2, -S(O)2R 70 , -S(O)2O - M + , -S(O)2OR 70 , -OS(O)2R 70 , -OS(O)2O - M + , -OS(O)2OR 70 , -P(O)(O - )2(M + )2, -P(O)(OR 70 )O - M + , -P(O)(OR 70 )(OR 70 ), -C(O)R 70 , -C(S)R 70 , -C(NR 70 )R70 , -C(O)OR 70 , -C(S)OR 70 , -C(O)NR 80 R 80 , -C(NR 70 )NR 80 R 80 , -OC(O)R 70 , -OC(S)R 70 , -OC(O)OR 70 , -OC(S)OR 70 , -NR 70 C(O)R 70 , -NR 70 C(S)R 70 , -NR 70 C(O)OR 70 , -NR 70 C(S)OR 70 , -NR 70 C(O)NR 80 R 80 , -NR 70 C(NR 70 )R 70 and -NR 70 C(NR 70 )NR 80 R 80 is.

[0085] Further to the disclosure herein, in certain embodiments, a substituted group has 1, 2, 3, or 4 substituents, 1, 2, or 3 substituents, 1 or 2 substituents, or 1 substituent.

[0086] Unless otherwise indicated, the nomenclature of substituents not explicitly defined herein is arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment. For example, the substituent "arylalkyloxycarbonyl" refers to the group (aryl)-(alkyl)-OC(O)-.

[0087] With respect to any of the groups disclosed herein that contain one or more substituents, it is understood that such groups do not contain any substitutions or substitution patterns that are sterically infeasible and / or synthetically infeasible. In addition, the subject compounds include all stereochemical isomers arising from the substitution of these compounds.

[0088] "Stereoisomer" and "stereoisomers" refer to compounds that have the same atomic connectivity but different atomic arrangements in space. Stereoisomers include cis-trans isomers, E and Z isomers, enantiomers, and diastereomers.

[0089] It will be understood that the term "or a salt or solvate or stereoisomer thereof" is intended to include all permutations of salts, solvates, and stereoisomers, such as solvates of pharmaceutically acceptable salts of stereoisomers of the subject compounds. The term "or a salt thereof" is understood to be intended to include all permutations of salts. The term "or a pharmaceutically acceptable salt thereof" is understood to be intended to include all permutations of salts. The term "or a solvate thereof" is understood to be intended to include all permutations of solvates. The term "or a stereoisomer thereof" is understood to be intended to include all permutations of stereoisomers. The term "or a tautomer thereof" is understood to be intended to include all permutations of tautomers. Thus, for example, it will be intended to include solvates of pharmaceutically acceptable salts of tautomers of stereoisomers of the subject compounds.

[0090] As used herein, the term "isolated" is meant to describe a compound of interest that is in an environment that is different from the environment that the compound naturally occurs in. "Isolated" is meant to include compounds that are within a sample in which the compound of interest is substantially enriched and / or in which the compound of interest is partially or substantially purified.

[0091] Before further describing the present invention, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0092] Where a range of values ​​is provided, unless the context clearly dictates otherwise, it is understood that each intervening value between the upper and lower limits, and to one-tenth of the unit of any other value or lower limit of that intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the invention, subject to any specifically excluded limits in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also encompassed in the invention.

[0093] For clarity, it is understood that certain features of the invention described in the context of separate embodiments can also be provided in combination in a single embodiment. Conversely, for brevity, various features of the invention described in the context of a single embodiment can also be provided separately or in any suitable subcombination. All combinations of the embodiments related to the invention are specifically embraced by the present invention and are disclosed herein as if each and every combination were individually and explicitly disclosed, to the extent that such combinations include subject matter that is, for example, a stable compound (i.e., a compound that can be made, isolated, characterized, and tested for biological activity). In addition, all subcombinations of the various embodiments and their elements (e.g., elements of chemical groups listed in the embodiments describing such variables) are also specifically embraced by the present invention and are disclosed herein as if each and every such subcombination were individually and explicitly disclosed herein.

[0094] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs.Any methods and materials similar or equivalent to those described herein can also be used to practice or test the present invention, but the methods and materials of interest are described below.All publications mentioned herein are incorporated by reference to disclose and describe the methods and / or materials related to the cited publications.

[0095] It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. Accordingly, this statement is intended to serve as a predicate for the use of exclusive terminology such as "solely," "only," or the use of a "negative" limitation in connection with the recitation of claim elements.

[0096] It will be understood that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0097] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein should be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual dates of publication, which may need to be independently confirmed.

[0098] Unless otherwise noted, the methods and techniques of the present embodiments are generally carried out according to conventional methods well known in the art and as described in various general and more specific references cited and discussed throughout this specification. See, for example, Loudon, Organic Chemistry, Fourth Edition, New York: Oxford University Press, 2002, pp. 360-361, 1084-1085; Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience, 2001.

[0099] The nomenclature used herein to name the subject compounds is illustrated in the Examples herein. Where possible, this nomenclature has generally been derived using commercially available AutoNom software (MDL, San Leandro, Calif.).

[0100] Many general references are available that provide generally known chemical synthetic schemes and conditions useful for synthesizing the disclosed compounds (e.g., Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience, 2001, or Vogel, A. See Textbook of Practical Organic Chemistry, Including Qualitative Organic Analysis, Fourth Edition, New York: Longman, 1978).

[0101] The compounds described herein can be purified by any of the methods known in the art, including chromatographic methods such as high performance liquid chromatography (HPLC), preparative thin-layer chromatography, flash column chromatography and ion exchange chromatography.Any suitable stationary phase can be used, including normal phase and reverse phase, and ionic resin.For example, see Introduction to Modern Liquid Chromatography, 2nd Edition, ed.L.Snyder and J.J.Kirkland, John Wiley and Sons, 1979, and Thin Layer Chromatography, ed.E.Stahl, Springer-Verlag, New York, 1969.

[0102] During any of the processes for preparing the compounds of the present disclosure, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved by means of conventional protecting groups as described in such authoritative works as T.W. Greene and P.G.M. Buts, "Protective Groups in Organic Synthesis," Fourth edition, Wiley, New York 2006. The protecting groups may be removed at a convenient subsequent stage using methods known in the art.

[0103] The compounds described herein may contain one or more chiral centers and / or double bonds and therefore may exist as stereoisomers, such as double bond isomers (i.e., geometric isomers), enantiomers, or diastereomers. Accordingly, all possible enantiomers and stereoisomers of the compounds, including stereoisomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure), as well as mixtures of enantiomers and stereoisomers, are included in the description of the compounds herein. Mixtures of enantiomers and stereoisomers can be resolved into their component enantiomers or stereoisomers using separation or chiral synthesis techniques well known to those skilled in the art. Compounds may also exist in several tautomeric forms, including enol forms, keto forms, and mixtures thereof. Thus, the chemical structures depicted herein encompass all possible tautomeric forms of the exemplified compounds. The compounds described also include isotopically labeled compounds, in which one or more atoms have an atomic mass different from the atomic mass conventionally found in nature. Examples of isotopes that can be incorporated into compounds disclosed herein include, but are not limited to, 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 18 O. 17 O and the like. Compounds can exist in unsolvated forms as well as solvated forms, including hydrated forms. Generally, compounds can be hydrated or solvated. Certain compounds can exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the present disclosure.

[0104] As summarized above, the present disclosure provides a method for preparing an amorphous solid composition of a fatty acid metal salt. In carrying out the subject method according to certain embodiments, a succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane organic salt is contacted with a metal base to produce a succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt, and the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt is precipitated in a solvent to produce an amorphous solid composition of a fatty acid metal salt. The term "succinylation" is used herein in its conventional sense to refer to the addition of a succinyl group (-CO-CH-CH-COH) to the 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane (e.g., the C-2 position of the 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane). In embodiments, a succinyl group can be added to 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane by any convenient succinylation protocol, such as, for example, reaction with succinic anhydride in the presence of a base (e.g., an organic base such as triethylamine). By "fatty acid amide" is meant a structural moiety comprising an aliphatic group attached to an amide group (where R is C 16 C etc. 10 -C 20 where R' is the C3 carbon of 2-hydroxy-1-(protected hydroxy)propane, -R-CO-N-R'-). In embodiments (described in more detail below), the fatty acid is 16 Aliphatic chains such as alkyl chains C 10 -C 20 The fatty acid component may be saturated or may contain one or more unsaturations. In some cases, the fatty acid component is fully saturated. In other cases, the fatty acid component is monounsaturated. In still other cases, the fatty acid component is polyunsaturated, such as having two, three, four, or more saturations. In some embodiments, the fatty acid is selected from palmitic acid, stearic acid, oleic acid, linoleic acid, myristoleic acid, and batyl fatty acid.

[0105] Embodiments of the present disclosure describe amorphous solid compositions of fatty acid metal salts. The term "amorphous" is used herein in its conventional sense to refer to a solid material characterized by an undefined structural order and microscopic organization that lacks regular geometric arrangement in three dimensions. In some embodiments, the amorphous solid compositions of fatty acid metal salts are not crystalline (i.e., solid materials in which the molecules that form the solid are arranged in a highly ordered microscopic geometric organization that extends in three dimensions (e.g., form an ordered lattice-type structure)).

[0106] In embodiments, the organic salt of succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane can include, but is not limited to, triethylamine salt, triethanolamine salt, ammonium salt, arginine salt, benzathine salt, ethylenediamine salt, meglumine salt, procaine salt, N-methylglucamine salt, piperazine salt, tromethamine salt, N,N'-dibenzylethylene-diamine salt, chloroprocaine salt, diethanolamine salt, ethanolamine salt, diisopropylamine salt, diisopropylethylamine salt, among other organic cation salts. In certain embodiments, the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane organic salt is succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane triethylamine salt.

[0107] The succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane organic salt is contacted with a metal base in a solvent. Depending on the desired succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt, the metal base can include, but is not limited to, lithium tert-butoxide, lithium hydroxide, lithium ethoxide, lithium isopropoxide, lithium methoxide, potassium tert-butoxide, potassium hydroxide, potassium ethoxide, potassium isopropoxide, potassium methoxide, sodium tert-butoxide, sodium hydroxide, sodium ethoxide, sodium isopropoxide, sodium methoxide, magnesium tert-butoxide, magnesium hydroxide, magnesium ethoxide, magnesium isopropoxide, magnesium methoxide, calcium tert-butoxide, calcium hydroxide, ethoxide, calcium isopropoxide, and calcium methoxide. In embodiments, the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane organic salt is contacted in an amount sufficient to produce a succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt, such as succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane lithium salt, succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane sodium salt, succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane potassium salt, succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane magnesium salt, or succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane calcium salt.

[0108] The amount of metal base contacted with the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane organic salt can vary from 0.5 to 2 equivalents of metal base, including from 0.75 to 1.85 equivalents, such as from 1 to 1.8 equivalents, such as from 1.05 to 1.75 equivalents, such as from 1.10 to 1.70 equivalents, such as from 1.15 to 1.65 equivalents, such as from 1.2 to 1.6 equivalents, such as from 1.25 to 1.55 equivalents, and 1.3 to 1.5 equivalents, relative to the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane organic salt, including contacting the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane organic salt with 1.5 equivalents of metal salt.

[0109] In embodiments, the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane organic salt is contacted with a metal base in a solvent. The solvent for contacting the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane organic salt with the metal base can be any suitable solvent, polar or non-polar, in which the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane organic salt and the metal base are sufficiently soluble. In some embodiments, the solvent is non-polar, such as pentane, hexane, heptane, octane, or benzene. In other embodiments, the solvent is a polar solvent, such as dichloromethane, tetrahydrofuran, methyltetrahydrofuran, isopropyl acetate, dimethylformamide, acetonitrile, toluene, 2-methylbutan-2-ol (tAmOH), and N-methyl-2-pyrrolidone. In certain embodiments, the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane organic salt is contacted with a metal base in dichloromethane. In some embodiments, the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane organic salt is contacted with a metal base by contacting the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane organic salt with a solvent containing a metal base. In these embodiments, the solvent containing the metal base can be a non-polar solvent such as pentane, hexane, heptane, octane, or benzene. In certain embodiments, the solvent is hexane.

[0110] The succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane organic salt may be contacted with the metal base at a temperature in the range of -10°C to 10°C, including -9°C to 9°C, such as -8°C to 8°C, such as -7°C to 7°C, such as -6°C to 6°C, and -5°C to 5°C.

[0111] In some embodiments, the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane organic salt may be contacted with the metal base at a first temperature, and the reaction mixture is warmed to a second temperature. In one example, the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane organic salt is contacted with the metal base in a solvent at a first temperature and then warmed to a second temperature. In another example, the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane organic salt is contacted with the metal base in a solvent at a first temperature for a first period of time and then warmed to the second temperature for a second period of time. In these embodiments, the first temperature may range from -10°C to 0°C, including -9°C to -1°C, such as -8°C to -2°C, such as -7°C to -3°C, and -6°C to -4°C. The second temperature can also be in the range of 0°C to 20°C, such as 1°C to 19°C, such as 2°C to 18°C, such as 3°C to 17°C, such as 4°C to 16°C, such as 5°C to 15°C, and including 5°C to 10°C. The duration of the first period can vary depending on the concentration of the metal salt and the temperature and can range from 0.1 minutes to 30 minutes, such as 0.5 minutes to 25 minutes, such as 1 minute to 20 minutes, such as 5 minutes to 15 minutes, and including 5 minutes to 10 minutes. In some embodiments, the metal base is contacted with the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane organic salt and maintained in contact (e.g., stirring the reaction mixture) for the entire duration of the first period. In other embodiments, the metal base is added dropwise (or titrated) into the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane organic salt in a solvent over all or part of the first period. The duration of the second period may vary from 0.1 minutes to 30 minutes, such as 0.5 minutes to 25 minutes, such as 1 minute to 20 minutes, such as 5 minutes to 15 minutes, and including 5 minutes to 10 minutes.

[0112] In some embodiments, the method includes precipitating the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt from the reaction mixture to form an amorphous solid. To precipitate the amorphous solid succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt, the reaction mixture is contacted with the same or another nonpolar solvent to produce an amorphous solid succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt composition. Nonpolar solvents can include, but are not limited to, pentane, hexane, heptane, octane, and benzene, among other nonpolar solvents. In certain embodiments, the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt reaction mixture is contacted with heptane.

[0113] In some embodiments, the method includes first cooling the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt reaction mixture and then contacting the reaction mixture with a non-polar solvent (e.g., heptane). For example, the reaction mixture may be cooled to a temperature in the range of -10°C to 10°C, including -9°C to 9°C, such as -8°C to 8°C, such as -7°C to 7°C, such as -6°C to 6°C, and -5°C to 5°C.

[0114] In precipitating the amorphous solid succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt, methods according to certain embodiments include concentrating the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt in a non-polar solvent (e.g., heptane), such as by heating or rotary evaporation. The volume of solvent in the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane reaction mixture can be reduced by 5% or more, such as 10% or more, such as 15% or more, such as 20% or more, such as 25% or more, such as 30% or more, such as 35% or more, such as 40% or more, such as 45% or more, such as 50% or more, such as 55% or more, such as 60% or more, such as 65% or more, such as 70% or more, and including 75% or more. This may involve repeatedly adding a certain amount of non-polar solvent to the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt composition one or more times, such as two or more times, three or more times, and including five or more times, followed by further concentration.

[0115] To precipitate the amorphous succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt from a non-polar solvent, the composition in the non-polar solvent (e.g., heptane) can be first heated to produce a heated succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt composition, which can then be cooled to form the amorphous solid succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt. The succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt can be heated in the non-polar solvent to a temperature ranging from 20°C to 60°C, such as 25°C to 60°C, including 40°C to 55°C, and including 45°C to 55°C. The heated composition may be maintained at an elevated temperature for varying durations, including 1 minute or more, such as 2 minutes or more, such as 5 minutes or more, such as 10 minutes or more, such as 15 minutes or more, such as 30 minutes or more, and 60 minutes or more. In certain embodiments, the method includes heating the composition until the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt is solubilized in the solvent, such as by observing a clear solution by visual inspection.

[0116] The heated composition is cooled to precipitate the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt. The heated composition is cooled to a temperature of -20°C to 20°C, including -19°C to 19°C, -18°C to 18°C, -17°C to 17°C, -16°C to 16°C, -15°C to 15°C, -14°C to 14°C, -13°C to 13°C, -12°C to 12°C, -11°C to 11°C, -10°C to 10°C, and -5°C to 5°C. In certain embodiments, the heated succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt composition is cooled to 0°C. The cooled composition can be maintained at the reduced temperature (e.g., 0°C) for varying durations, including 1 minute or more, such as 2 minutes or more, such as 5 minutes or more, such as 10 minutes or more, such as 15 minutes or more, such as 30 minutes or more, and 60 minutes or more. In certain embodiments, the cooled succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt composition is maintained at the reduced temperature (e.g., 0°C) for 60 minutes.

[0117] The amorphous solid succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt composition can be isolated by filtration (e.g., vacuum filtration), or the solvent can be removed by heating or rotary evaporation. In certain embodiments, the amorphous solid succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt composition is isolated by drying under a nitrogen atmosphere or under vacuum at room temperature. In some embodiments, the amorphous solid succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt is isolated at a temperature between -20°C and 20°C, including between -19°C and 19°C, such as between -18°C and 18°C, such as between -17°C and 17°C, such as between -16°C and 16°C, such as between -15°C and 15°C, such as between -14°C and 14°C, such as between -13°C and 13°C, such as between -12°C and 12°C, such as between -11°C and 11°C, -10°C to 10°C, and -5°C to 5°C. In certain embodiments, the amorphous solid succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt is isolated at 0°C.

[0118] In some embodiments, the method includes precipitating an amorphous solid succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt by the reverse addition of a non-polar solvent to the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt reaction mixture. In this embodiment, a certain amount of the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt reaction mixture is contacted with a non-polar solvent. The non-polar solvent can include, but is not limited to, pentane, hexane, heptane, octane, and benzene, among other non-polar solvents. In certain cases, the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt reaction mixture is contacted with heptane.

[0119] The reaction mixture contacted with the non-polar solvent is concentrated, such as by heating or rotary evaporation. The volume of the reaction mixture can be reduced by 5% or more, including 10% or more, such as 15% or more, such as 20% or more, such as 25% or more, such as 30% or more, such as 35% or more, such as 40% or more, such as 45% or more, such as 50% or more, such as 55% or more, such as 60% or more, such as 65% or more, such as 70% or more, and 75% or more. This can be achieved by repeatedly adding a certain amount of non-polar solvent to the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt composition one or more times, including two or more times, three or more times, and five or more times, followed by further concentration.

[0120] To precipitate the amorphous succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt from the non-polar solvent, the composition is heated to produce a heated succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt composition. The composition can be heated in the non-polar solvent to a temperature ranging from 20°C to 60°C, such as from 25°C to 60°C, including from 40°C to 55°C, and from 45°C to 55°C. The heated composition can be maintained at the elevated temperature for varying durations, such as from 1 minute or more, such as from 2 minutes or more, such as from 5 minutes or more, such as from 10 minutes or more, such as from 15 minutes or more, such as from 30 minutes or more, and including from 60 minutes or more. In certain embodiments, the method includes heating the composition until the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt is solubilized in the solvent, such as by visually observing a clear solution.

[0121] To cool the heated succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt composition, the heated composition is contacted with a cold non-polar solvent (e.g., heptane). In these embodiments, the heated succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt composition can be added to a non-polar solvent (e.g., heptane) at a temperature of -20°C to 20°C, including -19°C to 19°C, -18°C to 18°C, -17°C to 17°C, -16°C to 16°C, -15°C to 15°C, -14°C to 14°C, -13°C to 13°C, -12°C to 12°C, -11°C to 11°C, -10°C to 10°C, and -5°C to 5°C. In certain embodiments, the heated succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt composition is contacted with a non-polar solvent that is at a temperature of −10° C. The cooled composition can be maintained at a reduced temperature (e.g., 0° C.) for varying durations, including 0.1 hours or more, such as 0.5 hours or more, such as 1 hour or more, such as 1.5 hours or more, such as 2 hours or more, such as 2.5 hours or more, and 3 hours or more. In certain embodiments, the cooled succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt composition is maintained at a reduced temperature (e.g., 0° C.) for 3 hours.

[0122] In certain embodiments, the method includes subjecting the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt composition to one or more heating / cooling cycles. In these embodiments, each heating / cooling cycle includes heating the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt composition to a first temperature and maintaining the composition at the first temperature for a first period of time, followed by cooling the heated composition to a second temperature and maintaining the cooled composition at the second temperature for a second period of time. In these embodiments, the first temperature is in the range of 10°C to 30°C, including 15°C to 25°C, and up to a temperature of 20°C, and the first period of time is in the range of 30 minutes to 60 minutes, including 35 minutes to 55 minutes, and including 40 minutes to 50 minutes. The second temperature ranges from -10°C to 10°C, such as from -5°C to 5°C, and including 0°C, and the second time period ranges from 45 minutes to 90 minutes, such as from 55 minutes to 80 minutes, and including from 60 minutes to 75 minutes, such as from 50 minutes to 85 minutes. The heating / cooling cycle may be repeated one or more times, such as two or more times, and including three or more times.

[0123] The succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt composition precipitated in the non-polar solvent can be maintained at a reduced temperature for a period of time before isolation. In some cases, the precipitated succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt composition is maintained in the non-polar solvent at a temperature ranging from -10°C to 10°C, such as from -5°C to 5°C, and including 0°C. The precipitated succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt composition can be maintained at a reduced temperature for a varying period of time, such as 1 hour or more, such as 2 hours or more, such as 4 hours or more, such as 8 hours or more, such as 12 hours or more, and including 16 hours or more.

[0124] The amorphous solid succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt composition can be isolated by filtration (e.g., vacuum filtration), or the solvent can be removed by heating or rotary evaporation. In certain embodiments, the amorphous solid succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt composition is isolated by drying under a nitrogen atmosphere or under vacuum at room temperature. In some embodiments, the amorphous solid succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt is isolated at a temperature between -20°C and 20°C, including between -19°C and 19°C, such as between -18°C and 18°C, such as between -17°C and 17°C, such as between -16°C and 16°C, such as between -15°C and 15°C, such as between -14°C and 14°C, such as between -13°C and 13°C, such as between -12°C and 12°C, such as between -11°C and 11°C, -10°C to 10°C, and -5°C to 5°C. In certain embodiments, the amorphous solid succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt is isolated at 0°C. The isolated amorphous solid succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt may be dried to remove any residual solvent, such as under vacuum at ambient temperature.

[0125] In certain embodiments, the method further comprises preparing a succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane organic salt by contacting 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane with succinic anhydride in the presence of an organic base. The amount of succinic anhydride contacted with the 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane can vary from 0.75 equivalents to 1.95 equivalents, such as 1 equivalent to 1.9 equivalents, such as 1.1 equivalents to 1.85 equivalents, such as 1.15 equivalents to 1.80 equivalents, such as 1.25 equivalents to 1.75 equivalents, relative to the 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane, and from 0.5 equivalents to 2 equivalents of succinic anhydride, including contacting the 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane with 1.2 equivalents of succinic anhydride.

[0126] Depending on the type of organic salt desired, the organic base used can include, but is not limited to, triethylamine, triethanolamine, ammonia, arginine, benzathine, ethylenediamine, meglumine, procaine, N-methylglucamine, piperazine, tromethamine, N,N'-dibenzylethylene-diamine, chloroprocaine, diethanolamine, ethanolamine, diisopropylamine, diisopropylethylamine, among other organic bases. In these embodiments, 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane is contacted with succinic anhydride in a polar solvent such as dichloromethane, tetrahydrofuran, methyltetrahydrofuran, isopropyl acetate, dimethylformamide, acetonitrile, toluene, 2-methylbutan-2-ol (tAmOH), and N-methyl-2-pyrrolidone. The amount of organic base used can vary from 2.6 equivalents to 3.4 equivalents, such as 2.7 equivalents to 3.3 equivalents, such as 2.8 equivalents to 3.2 equivalents, such as 2.9 equivalents to 3.1 equivalents, relative to the 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane, and from 2.5 equivalents to 3.5 equivalents of organic base, including contacting the 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane with 3.0 equivalents of organic base (e.g., trimethylamine).

[0127] The 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane may be contacted with succinic anhydride in the presence of an organic base at a temperature ranging from 10°C to 30°C, such as from 12°C to 28°C, such as from 14°C to 26°C, including from 16°C to 24°C, and from 18°C ​​to 22°C.

[0128] The components used in each step of the subject methods for preparing the amorphous succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salts described herein can be purified or crude compositions, as desired. The term "purified" is used in its conventional sense to refer to a composition that has undergone at least some isolation or purification process, such as, for example, filtration of the reaction mixture or aqueous workup. In certain cases, purification includes liquid chromatography, recrystallization, distillation (e.g., azeotropic distillation), or other types of compound purification. In some embodiments, the reaction mixture is used as a crude mixture in a subsequent step in the methods described herein. The term "crude" is used herein in its conventional sense to refer to a composition that has not undergone purification or other workup of the reaction mixture. In certain cases, the crude composition reaction mixture can be purified by high-performance liquid chromatography (HPLC), proton nuclear magnetic resonance spectroscopy (NMR), or other methods. 1 The method may comprise preparing a succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane organic salt by contacting 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane with succinic anhydride in the presence of an organic base, and the method may comprise contacting the crude composition of succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane organic salt directly (i.e., without any purification or workup) with a metal base to produce the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt.

[0129] In embodiments, the fatty acid of the 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane compounds (i.e., organic salts, metal salts, etc.) described herein can vary, and in certain cases the fatty acid is selected from palmitic acid, stearic acid, oleic acid, linoleic acid, myristoleic acid, and batyl fatty acid.

[0130] The protected hydroxy group of the 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane compounds described herein may also vary in certain cases, and hydroxyl protecting groups include, but are not limited to, 1) alkyl ether type protecting groups such as alkyl ether, allyl ether, triphenylmethyl ether, dimethoxy-triphenylmethyl ether, benzyl ether, or p-methoxybenzyl ether protecting groups; 2) acetate, chloroacetate, dichloroacetate, trichloroacetate, tetra ... methyl methyl carbonate (Fmoc), 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (Teoc), benzyl carbonate (Cbz), t-butyl carbonate (Boc), or dimethylthiocarbmate (DMTC) 3) acetal-type protecting groups such as methoxymethyl ether (MOM), benzyloxymethyl ether (BOM), 2,2,2-trichloroethoxymethyl ether, 2-methoxymethyl ether (MEM), methylthiomethyl ether (MTM), p-methoxybenzyloxymethyl ether (PMBM), 2-(trimethylsilyl)ethoxymethyl ether (SEM), and tetrahydropyranyl ether (THP) protecting groups; and 2) silyl ether-type protecting groups such as trimethylsilyl (TMS), triethylsilyl (TES), isopropyldimethylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), t-butyldimethylsilyl (TBS), t-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS), tetraisopropyldisiloxanylidene (TIPDS), or di-t-butylsilylene (DTBS) protecting groups. In certain embodiments, the protected hydroxy group of the 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane compounds described herein is a dimethoxy-triphenylmethyl protecting group.

[0131] In certain embodiments, the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt is a compound of Formula I. [ka]

[0132] In some embodiments, the present disclosure also provides an amorphous solid succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane lithium salt of Formula I having a peak at about 19.5° 2θ in an X-ray powder diffraction pattern (XRPD, FIG. 1) using Cu Kα radiation. In other embodiments, the present disclosure provides an amorphous solid succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane lithium salt of Formula I in which a thermogravimetric analysis (TGA, FIG. 3) exhibits a single weight loss step. In these embodiments, the single weight loss step may begin at about 225° C. The subject amorphous solid succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane lithium salt of Formula I may also be characterized by a TGA thermogram that exhibits a mass loss of less than 1% of the total mass of the sample upon heating between 30° C. and 300° C. In another embodiment, the present disclosure provides an amorphous solid succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane lithium salt of Formula I, wherein the differential scanning calorimetry (DSC, FIG. 4) curve exhibits an absorption peak at about 44.9° C.

[0133] Aspects of the disclosure Aspects of the subject matter described herein, including embodiments, may be useful alone or in combination with one or more other aspects or embodiments. Without limiting the scope of the disclosure, certain non-limiting aspects of the disclosure, numbered 1 through 32, are provided below. As will be apparent to one of ordinary skill in the art upon reading this disclosure, each individually numbered aspect may be used or combined with any of the preceding or subsequent individually numbered aspects. This is intended to support the support of all such combinations of aspects, and is not limited to the combinations of aspects explicitly provided below.

[0134] 1. A method for preparing an amorphous solid composition comprising a fatty acid metal salt, the method comprising: contacting the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane organic salt with a metal base to produce a succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt; and precipitating the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt to produce an amorphous solid succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt composition. 2. The method of embodiment 1, wherein the amorphous solid composition is a crude composition. 3. The crude composition is purified by high performance liquid chromatography (HPLC), proton nuclear magnetic resonance spectroscopy ( 1 1 H NMR), or a combination thereof, or a combination thereof. 4. The method of any one of aspects 1 to 3, wherein the crude reaction product is carried through all steps of the method. 5. A method, wherein the method comprises high performance liquid chromatography (HPLC), proton nuclear magnetic resonance spectroscopy ( 1 1 H NMR), or a combination thereof, is sufficient to obtain a fatty acid metal salt in an isolated yield of 90% or greater. 6. The method of any one of aspects 1-5, further comprising contacting the 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane with succinic anhydride in a polar solvent in the presence of an organic base. 7. The method of embodiment 6, wherein the polar solvent comprises dichloromethane. 8. Precipitating succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salts heating a succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt in a non-polar solvent to form a heated succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt composition; and cooling the heated succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt composition to form an amorphous solid of succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt. 9. The method of embodiment 8, wherein cooling the heated succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt composition comprises adding the heated succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt composition back to a cold non-polar solvent. 10. The method of any one of claims 8 to 9, wherein the method comprises heating the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt in a non-polar solvent to a temperature of 45-55°C. 11. The method of any one of aspects 8-10, wherein the method comprises cooling the heated succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt composition to a temperature of −10 to 0° C. 12. The method of any one of aspects 8-11, wherein the non-polar solvent comprises heptane. 13. The method of any one of aspects 8-12, wherein an amorphous solid of succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt is isolated. 14. The method of any one of aspects 1-13, wherein the amorphous solid of succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt is isolated by vacuum filtration. 15. The method of any one of aspects 1-14, wherein the fatty acid is selected from the group consisting of palmitic acid, stearic acid, oleic acid, linoleic acid, myristoleic acid, and batyl fatty acid. 16. The method of aspect 15, wherein the fatty acid is palmitic acid. 17. The method of any one of aspects 1-16, wherein the protected hydroxy group comprises a dimethoxy-triphenylmethyl protecting group. 18. 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane is a compound of formula II, [ka] Aspect 18. The method of any one of aspects 1-17, wherein DMT is dimethoxy-triphenylmethyl. 19. The method of any one of aspects 1-18, wherein the organic salt is a triethylamine salt. 20. The method of any one of aspects 1-18, wherein the metal base is selected from lithium hydroxide and lithium tert-butoxide. 21. A metal base in lithium tert-butoxide, as described in embodiment 20. 22. The method of any one of aspects 1-21, wherein the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt is a compound of formula I. [ka] 23. Amorphous solid succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane lithium salt. 24. The amorphous salt according to aspect 23, wherein the fatty acid is selected from the group consisting of palmitic acid, stearic acid, oleic acid, linoleic acid, myristoleic acid, and batyl fatty acid. 25. The amorphous salt according to aspect 24, wherein the fatty acid is palmitic acid. 26. The amorphous salt of any one of aspects 23-25, wherein the protected hydroxy groups comprise dimethoxy-triphenylmethyl protecting groups. 27. The amorphous salt of any one of aspects 23-26, wherein the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt is a compound of formula I. [ka] 28. The amorphous salt of embodiment 27, having an X-ray powder diffraction pattern (XRPD) comprising a peak at about 19.5 degrees 2θ. 29. The amorphous salt of aspect 27 or 28, wherein a thermogravimetric analysis (TGA) of the amorphous salt is characterized by a single weight loss step. 30. The amorphous salt according to aspect 29, wherein the weight loss step begins at about 225°C. 31. The amorphous salt of any one of aspects 27-30, wherein the amorphous salt has a TGA thermogram that exhibits a mass loss of less than 1% of the total mass of the sample upon heating between 30°C and 300°C. 32. The amorphous salt of any one of aspects 27-31, having an absorption peak at about 44.9°C by differential scanning calorimetry (DSC). [Example]

[0135] The following examples are presented to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention, nor are they intended to represent that the following experiments are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.), but some experimental error and deviation must be accounted for. Unless otherwise indicated, parts are parts by weight, molecular weights are weight average molecular weights, temperatures are in degrees Celsius, and pressures are at or near atmospheric. "Average" refers to the arithmetic mean. Standard abbreviations may be used, such as bp, base pairs; kb, kilobases; pl, picoliters; s or sec, seconds; min, minutes; h or hr, hours; aa, amino acids; kb, kilobases; bp, base pairs; nt, nucleotides; im, intramuscular; intraperitoneal; sc, subcutaneous, etc.

[0136] General synthetic procedure Many general references are available that provide generally known chemical synthetic schemes and conditions useful for synthesizing the disclosed compounds (e.g., Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience, 2001, or Vogel, A. See Textbook of Practical Organic Chemistry, Including Qualitative Organic Analysis, Fourth Edition, New York: Longman, 1978).

[0137] The compounds described herein can be purified by any purification protocol known in the art, including chromatography such as HPLC, preparative thin-layer chromatography, flash column chromatography, and ion exchange chromatography.Any suitable stationary phase can be used, including normal phase and reverse phase, and ionic resin.In certain embodiments, the disclosed compounds are purified through silica gel and / or alumina chromatography.See, for example, Introduction to Modern Liquid Chromatography, 2nd Edition, ed.L.S.Nyder and J.J.Kirkland, John Wiley and Sons, 1979, and Thin Layer Chromatography, ed.E.Stahl, Springer-Verlag, New York, 1969.

[0138] During any of the processes for preparation of the subject compounds, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This is described in detail in J.F.W. MacOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, TW Greene, and PGMWuts, “Protective Groups in Organic Synthesis”, Third edition, Wiley, New York 1999, “The Peptides”; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London. and New York 1981, “Methoden der organischen Chemie”, Houben-Weyl, 4 thThis can be achieved by means of conventional protecting groups as described in such reference works as H.-D. Jakubke and H. Jescheit, "Aminosauren, Peptide, Protein", Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and / or Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide and Derivate", Georg Thieme Verlag, Stuttgart 1974. The protecting groups can be removed at a convenient subsequent stage using methods known in the art.

[0139] The subject compounds can be synthesized via a variety of different synthetic routes using commercially available starting materials and / or starting materials prepared by conventional synthetic methods. Various examples of synthetic routes that can be used to synthesize the compounds disclosed herein are set forth in the following schemes.

[0140] Example 1 - Preparation of amorphous solid succinylated 3-(palmitoylamido)-2-hydroxy-1-(dimethoxytriphenylmethylhydroxy)-propane lithium salt from 3-(palmitoylamido)-2-hydroxy-1-(dimethoxytriphenylmethyl-protected hydroxy)-propane (Scheme II) [ka]

[0141] 3-(Palmitoylamido)-2-hydroxy-1-(dimethoxytriphenylmethyl-protected hydroxy)-propane (A) was contacted with succinic anhydride in dichloromethane in the presence of triethylamine. The solution was stirred at room temperature for 3 hours to form the succinylated 3-(palmitoylamido)-2-hydroxy-1-(dimethoxytriphenylmethylhydroxy)-propane triethylamine salt intermediate (B), without isolation. The succinylated 3-(palmitoylamido)-2-hydroxy-1-(dimethoxytriphenylmethylhydroxy)-propane triethylamine salt intermediate was diluted with ethyl acetate and cooled to 0-5°C. Subsequently, aqueous LiOH was added and stirred at 0-5°C for 5-10 minutes. The aqueous layer and the organic layer containing the lithium salt were separated, and the organic layer was washed with LiCl. The organic layer was again separated and concentrated by rotary evaporation. The concentrate was diluted with ethyl acetate and poured through a sintered glass funnel. The clear filtrate was concentrated by rotary evaporation and dried on a vacuum pump until a foamy solid was formed. Heptane was added to the foamy solid and heated to 50°C until clear. The clear solution was cooled to 45°C over 1 hour until cloudy. Further cooling to 20°C over 1 hour resulted in the formation of a gummy solid. The composition was further cooled to 5-10°C until it formed a hard solid. The slurry containing the hard solid was stirred overnight at 10°C. The hard solid was isolated by filtration and dried under vacuum with a nitrogen blanket at room temperature for 30 minutes. The solid was further dried under vacuum at ambient temperature for 16 hours.

[0142] Example 2 - Preparation of amorphous solid succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane lithium salt - normal addition mode The succinylated 3-(palmitoylamido)-2-hydroxy-1-(dimethoxytriphenylmethyl-protected hydroxy)-propane triethylamine salt was converted to the lithium salt via nonaqueous treatment with 1N LiOtBu in hexane. The crude succinylated 3-(palmitoylamido)-2-hydroxy-1-(dimethoxytriphenylmethyl-protected hydroxy)-propane organic salt composition was cooled to 0-5°C, followed by the addition of 1N LiOtBu in hexane (1.15 equiv.) and stirring at 0-5°C for 5-10 minutes. Heptane was added to the composition and concentrated to 10-15 mL by rotary evaporation. The heptane addition and rotary evaporation concentration were repeated twice. The lithium salt composition in heptane was heated to 50°C until clear. The heated composition was maintained at 50°C for 10-15 minutes under stirring and then cooled to 0°C over 1 hour until a gummy semisolid formed. The slurry was aged at 0° C. for 3 hours and then filtered under nitrogen gas at 0° C. The solid was further dried under nitrogen and partial vacuum at 0° C. for 30 minutes, then at 10° C. for 30 minutes. The solid succinylated 3-(palmitoylamido)-2-hydroxy-1-(dimethoxytriphenylmethyl-protected hydroxy)-propane lithium salt was dried under vacuum at room temperature for 16 hours.

[0143] A dried, free-flowing solid having a purity of greater than 99.0 A% by HPLC was obtained in 91% isolated yield (uncorrected), which was purified by 1 H NMR (DMSO-d6) confirmed succinylated 3-(palmitoylamido)-2-hydroxy-1-(dimethoxytriphenylmethyl protected hydroxy)-propane lithium salt.

[0144] Example 3 - Preparation of amorphous solid succinylated 3-(palmitoylamido)-2-hydroxy-1-(dimethoxytriphenylmethylhydroxy)-propane lithium salt - Reverse addition mode To avoid a phase transition through an oily / sticky phase, a reverse addition of a hot T375-Li / heptane solution to cold heptane was designed and tested. The experiment was carried out in a 100 mL EasyMax container with vigorous mixing. A hot (50 °C) heptane solution of succinylated 3-(palmitoylamido)-2-hydroxy-1-(dimethoxytriphenylmethylhydroxy)-propane lithium salt described in Example 1 was slowly (portionwise) added to cold (-10 °C) heptane. Succinylated 3-(palmitoylamido)-2-hydroxy-1-(dimethoxytriphenylmethylhydroxy)-propane lithium salt solid immediately precipitated as a uniform, fine solid. The resulting slurry in heptane was aged at 0 °C for 3 hours. The cooled slurry was subjected to a heat / cool cycle in which it was heated to 0°C to 20°C over 40 minutes, held at 20°C for 10 minutes, and then cooled to 0°C over 1 hour and held at 0°C for 1 hour. The heat / cool cycle was repeated twice, and the slurry was then aged at 0°C for 16 hours. The slurry batch temperature was maintained between 0°C and 10°C, and no oily or sticky material was observed during or after the addition of the succinylated 3-(palmitoylamido)-2-hydroxy-1-(dimethoxytriphenylmethylhydroxy)-propane lithium salt solution.

[0145] Rapid filtration of the final succinylated 3-(palmitoylamido)-2-hydroxy-1-(dimethoxytriphenylmethylhydroxy)-propane lithium salt solid indicated an increase in particle size with heating-cooling cycles. Deliquoring was performed under vacuum at ambient temperature under nitrogen protection. The wet cake was dried overnight in a flask under vacuum at ambient temperature. The isolated succinylated 3-(palmitoylamido)-2-hydroxy-1-(dimethoxytriphenylmethylhydroxy)-propane lithium salt product (4.92 g) provided a 91% yield (uncorrected). Product loss in the mother liquor was 4.6% by HPLC analysis; note that there was no impurity scavenging with the mother liquor.

[0146] The isolated, dry solid of succinylated 3-(palmitoylamido)-2-hydroxy-1-(dimethoxytriphenylmethylhydroxy)-propane lithium salt from the reverse addition protocol was characterized by X-ray powder diffraction (XRPD, Figure 1), polarized light microscopy (PLM, Figure 2), thermogravimetric analysis (TGA, Figure 3), and differential scanning calorimetry (DSC, Figure 4). Elemental analysis revealed a lithium content of 1.36 wt% compared to a theoretical value of 0.94 wt%.

[0147] Example 4 - Physical Stability of Amorphous Solid Succinylated 3-(Palmitoylamido)-2-hydroxy-1-(dimethoxytriphenylmethylhydroxy)-propane Lithium Salt The physical stability of amorphous 3-(palmitoylamido)-2-hydroxy-1-(dimethoxytriphenylmethylhydroxy)-propane lithium salt was tested at room temperature under different relative humidities (RH). 300 mg of amorphous 3-(palmitoylamido)-2-hydroxy-1-(dimethoxytriphenylmethylhydroxy)-propane lithium salt was placed in an uncapped scintillation vial at 11%, 33%, and 75% RH for several days (Table 1). [Table 1]

[0148] As shown in Table 1, amorphous 3-(palmitoylamido)-2-hydroxy-1-(dimethoxytriphenylmethylhydroxy)-propane lithium salt remained solid for extended periods of time at room temperature and up to 33% relative humidity. The lithium salt is a stable solid that is easily isolated and stored, compared to 3-(palmitoylamido)-2-hydroxy-1-(dimethoxytriphenylmethylhydroxy)-propane organic salt, which formed a viscous, sticky liquid at room temperature. The lithium salt is also highly soluble in most organic solvents at near ambient temperatures. The high stability, ready storage, and high solubility of 3-(palmitoylamido)-2-hydroxy-1-(dimethoxytriphenylmethylhydroxy)-propane lithium salt make it a better starting material for use in the synthesis of compounds containing fatty acid amide linkers (e.g., imetelstat) compared to 3-(palmitoylamido)-2-hydroxy-1-(dimethoxytriphenylmethylhydroxy)-propane organic salt. In one embodiment, for example, the following items are provided: (Item 1) 1. A method for preparing an amorphous solid composition comprising a fatty acid metal salt, the method comprising: contacting the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane organic salt with a metal base to produce a succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt; and precipitating the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt to produce an amorphous solid succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt composition. (Item 2) 2. The method of claim 1, wherein the amorphous solid composition is a crude composition. (Item 3) The crude composition is purified by high performance liquid chromatography (HPLC), proton nuclear magnetic resonance spectroscopy ( 11 H NMR), or a combination thereof, the fatty acid metal salt has a purity of 90% or more. (Item 4) 4. The process according to any one of items 1 to 3, wherein the crude reaction product is carried through all steps of the process. (Item 5) The method may be performed by high performance liquid chromatography (HPLC), proton nuclear magnetic resonance spectroscopy ( 1 1 H NMR), or a combination thereof, is sufficient to obtain the fatty acid metal salt in an isolated yield of 90% or greater. (Item 6) 6. The method according to any one of items 1 to 5, further comprising contacting 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane with succinic anhydride in a polar solvent in the presence of an organic base. (Item 7) 7. The method of claim 6, wherein the polar solvent comprises dichloromethane. (Item 8) precipitating the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt, heating the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt in a non-polar solvent to form a heated succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt composition; and cooling the heated succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt composition to form an amorphous solid of the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt. (Item 9) 9. The method of claim 8, wherein cooling the heated succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt composition comprises adding the heated succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt composition back into a cold non-polar solvent. (Item 10) 10. The method of claim 8 or 9, wherein the method comprises heating the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt in the non-polar solvent to a temperature of 45 to 55°C. (Item 11) 11. The method according to any one of items 8 to 10, wherein the method comprises cooling the heated succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt composition to a temperature of −10 to 0° C. (Item 12) 12. The method according to any one of items 8 to 11, wherein the non-polar solvent comprises heptane. (Item 13) 13. The method according to any one of items 8 to 12, wherein the amorphous solid of the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt is isolated. (Item 14) 14. The method according to any one of items 1 to 13, wherein the amorphous solid of the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt is isolated by vacuum filtration. (Item 15) 15. The method according to any one of items 1 to 14, wherein the fatty acid is selected from the group consisting of palmitic acid, stearic acid, oleic acid, linoleic acid, myristoleic acid, and batyl fatty acid. (Item 16) Item 16. The method of item 15, wherein the fatty acid is palmitic acid. (Item 17) 17. The method of any one of items 1 to 16, wherein the protected hydroxy group comprises a dimethoxy-triphenylmethyl protecting group. (Item 18) the 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane is a compound of formula II, [ka] 18. The method according to any one of items 1 to 17, wherein DMT is dimethoxy-triphenylmethyl. (Item 19) 19. The method according to any one of items 1 to 18, wherein the organic salt is a triethylamine salt. (Item 20) 19. The method according to any one of items 1 to 18, wherein the metal base is selected from lithium hydroxide and lithium tert-butoxide. (Item 21) 21. The method according to item 20, wherein the metal base is in lithium tert-butoxide. (Item 22) 22. The method according to any one of items 1 to 21, wherein the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt is a compound of formula I: [ka] (Item 23) Amorphous solid succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane lithium salt. (Item 24) 24. The amorphous salt according to claim 23, wherein the fatty acid is selected from the group consisting of palmitic acid, stearic acid, oleic acid, linoleic acid, myristoleic acid, and batyl fatty acid. (Item 25) 25. The amorphous salt according to claim 24, wherein the fatty acid is palmitic acid. (Item 26) 26. The amorphous salt according to any one of items 23 to 25, wherein the protected hydroxy group comprises a dimethoxy-triphenylmethyl protecting group. (Item 27) 27. The amorphous salt according to any one of items 23 to 26, wherein the succinylated 3-(fatty acid amide)-2-hydroxy-1-(protected hydroxy)-propane metal salt is a compound of formula I: [ka] (Item 28) 28. The amorphous salt according to item 27, having an X-ray powder diffraction pattern (XRPD) containing a peak at about 19.5° 2θ. (Item 29) 29. The amorphous salt according to item 27 or 28, wherein thermogravimetric analysis (TGA) of the amorphous salt is characterized by a single weight loss step. (Item 30) 30. The amorphous salt according to claim 29, wherein the weight loss step begins at about 225°C. (Item 31) 31. The amorphous salt according to any one of items 27 to 30, wherein the amorphous salt has a TGA thermogram showing a mass loss of less than 1% of the total mass of the sample upon heating from 30°C to 300°C. (Item 32) 32. The amorphous salt according to any one of items 27 to 31, having an absorption peak at about 44.9°C by differential scanning calorimetry (DSC).

Claims

[Claim 1] An object, method or system as described in this specification and drawings.

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